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Pain management during childbirth Mother in labor appears to be in pain Specialtyobstetrician [edit on Wikidata] Pain management during childbirth is the treatment or prevention of pain that a woman may experience during labor and delivery. The amount of pain a woman feels during labor depends partly on the size and position of her baby, the size of her pelvis, her emotions, the strength of the contractions, and her outlook.[1] Tension increases pain during labor.[2] Virtually all women worry about how they will cope with the pain of labor and delivery. Childbirth is different for each woman and predicting the amount of pain experienced during birth and delivery can not be certain.[1] Some women do fine with "natural methods" of pain relief alone. Many women blend "natural methods" with medications and medical interventions that relieve pain. Building a positive outlook on childbirth and managing fear may also help some women cope with the pain. Labor pain is not like pain due to illness or injury. Instead, it is caused by contractions of the uterus that are pushing the baby down and out of the birth canal. In other words, labor pain has a purpose.[1] ## Contents * 1 Preparation * 2 Non-pharmacological * 3 Water and childbirth * 4 Medical and pharmaceutical methods of pain control * 4.1 Opioids * 4.2 Epidural and spinal blocks * 4.3 Pudendal block * 4.4 Inhaled analgesia * 5 Pain management after childbirth * 6 See also * 7 References ## Preparation[edit] Preparation for childbirth can affect the amount of pain experienced during childbirth. It is possible to take a childbirth class, consult with those managing the pregnancy, and writing down questions can assist in getting the information that a woman needs to help manage pain. Simple interaction with friends and family can alleviate concerns.[1] ## Non-pharmacological[edit] Moche – female figure in birthing position Many methods help women to relax and make pain more manageable. A review of the effectiveness of non-medical approaches to pain relief found that water immersion, relaxation methods, and acupuncture relieved pain.[3] These and other non-pharmacologic pain management options are further discussed below. * Breathing and relaxation techniques[1][3] * Relaxation methods may be helpful in reducing the risk of assisted vaginal births.[3] * Warm showers or baths[1] * Massage[1][2] * Many types of massage can be used during various stages of labor. Literature suggests light touch or stroke massage techniques may aid in the release of oxytocin, which may help stimulate contractions and facilitate cervical dilatation. Various types of massage may also help soothe and distract from the pain of labor.[4] * Warm or cold compresses, such as heat on lower back or cold washcloth on forehead[1] * Applying warm compresses, especially to the lower back area, while the cervix is dilating may help reduce pain during the first stage of labor and may even help to decrease the length of labor itself, however, the evidence supporting this is limited.[4] * Changing positions while in labor (stand, crouch, sit, walk, etc.)[1] * Use of a labor ball[1] * Using a labor ball during childbirth first began in the 1980s. It is best used during the first stage of labor. Evidence suggests using a birthing ball can facilitate pain relief by supporting the perineum and providing gentle stimulation to the area during cervical dilatation. It may also aid in fetal descent through various positioning exercises and with gravity. [5] * Listening to music[1] * Although little evidence supports music as an effective method in decreasing pain, it may provide a distraction or assist in creating a more positive birth experience which may ultimately decrease the chance of negative postpartum outcomes.[4] * Acupuncture[3] * The use of acupuncture may be associated with fewer assisted vaginal births and caesarean sections.[3] * Continuous supportive care of a loved one, hospital staff member, or doula[1] * The presence of a doula or support attendant may decrease the need for pharmacological pain control and increase the likelihood of spontaneous vaginal births as opposed to cesarean section.[6] A positive support person may also assist in creating an environment leading to a more positive birth experience.[7] * Other methods include hypnosis, biofeedback, sterile water injection, aromatherapy, and TENS, however there are limited studies that demonstrate the effectiveness of in reducing pain during labor and delivery by using these methods.[3] ## Water and childbirth[edit] Main article: Water birth According to the American Office of Women's Health, laboring in a tub of warm water, also called hydrotherapy, helps women feel physically supported, and keeps them warm and relaxed. It may also be easier for laboring women to move and find comfortable positions in the water.[1] Water immersion during the first stage of labor may help decrease the need for analgesia and possibly shorten the duration of labor, however, there is limited data to suggest that water immersion during the second and third stages of labor significantly reduce the use of pharmacologic interventions.[8][9] In waterbirthing, a woman remains in the water for delivery. The American Academy of Pediatrics has expressed concerns about delivering in water because of a lack of studies showing its safety and because of the rare but reported chance of complications.[1] ## Medical and pharmaceutical methods of pain control[edit] Physicians, nurse practitioners, physician assistants, nurses and midwives will typically ask the woman in labor if there is a need of pain relief. Many pain relief options work well when given by a trained and experienced clinician. Clinicians also can use different methods for pain relief at different stages of labor. Still, not all options are available at every hospital and birthing center. Depending on the health history of the mother, the presence of allergies or other concerns, some choices will work better than others.[1] ### Opioids[edit] There are many methods of pain relief during labor. Opioids are a type of analgesia that is commonly used during childbirth to assist in pain relief.[10] They can be injected directly into the muscle in the form of a shot or put into an IV. These medications may cause unwanted side effects like drowsiness, itching, nausea, or vomiting to the laboring mother.[10] Although they are short acting in the laboring mother, it takes longer for an infant to clear these medications. All opioids can cross the placenta and may poorly affect the baby by causing problems with heart rate, breathing, or brain function. For this reason, opioids are not given close to delivery.[10] They can be beneficial in early labor, however, since they can help dull pain, but do not impair the mother’s ability to move or push. Their use also does not seem to be linked to a higher chance of cesarean sections.[10] There are many things to consider when deciding to use opioids during a delivery and these options, as well as the risks and benefits, should be discussed early in the first stage of labor with a trained medical professional. Asking questions about the procedures and medications which may affect the baby are valid questions.[11] ### Epidural and spinal blocks[edit] Further information: Epidural administration Further information: Spinal anaesthesia An anesthetic medication is injected into the spine. An epidural is a procedure that involves placing a tube (catheter) into the lower back, into a small space below the spinal cord. Small doses of medicine can be given through the tube as needed throughout labor. With a spinal block, a small dose of medicine is given as a shot into the spinal fluid in the lower back. Spinal blocks usually are given only once during labor. Epidural and spinal blocks allow most women to be awake and alert with very little pain during labor and childbirth. With an epidural, pain relief starts 10 to 20 minutes after the medicine has been given. The degree of numbness felt can be adjusted. With spinal block, good pain relief starts right away, but it only lasts one to two hours.[1] Although movement is possible, walking may not be if the medication affects motor function. An epidural can lower blood pressure, which can slow the baby's heartbeat. Fluids given through IV are given to lower this risk. Fluids can cause shivering. But women in labor often shiver with or without an epidural. If the covering of the spinal cord is punctured by the catheter, a bad headache may develop. Treatment can help the headache. An epidural can cause a backache that can occur for a few days after labor. An epidural can prolong the first and second stages of labor. If given late in labor or if too much medicine is used, it might be hard to push when the time comes. An epidural increases risk of assisted vaginal delivery.[1] ### Pudendal block[edit] Further information: Pudendal anesthesia In this procedure a doctor injects numbing medicine into the vagina and the nearby pudendal nerve. This nerve carries sensation to the lower part of the vagina and vulva. This method of pain control is only used late in labor, usually right before the baby's head comes out. With a pudendal block, there is some pain relief but the laboring woman remains awake, alert, and able to push the baby out. The baby is not affected by this medicine and it has very few disadvantages.[1][12] ### Inhaled analgesia[edit] Further information: Inhalational anaesthetic Another form of pharmacologic pain relief available for laboring mothers is inhaled nitrous oxide. This is typically a 50/50 mixture of nitrous oxide with air that is an inhaled analgesic and anesthetic. Nitrous oxide has been used for pain management in childbirth since the late 1800s. The use of inhaled analgesia is commonly used in the UK, Finland, Australia, Singapore and New Zealand, and is gaining in popularity in the United States.[13] Although this method of pain control does not provide as much pain relief as an epidural, there are many benefits to this type of analgesia. Nitrous oxide is inexpensive and can be used safely at any stage of labor. It is useful for women wanting mild pain relief while maintaining mobility and have less monitoring than would be required with an epidural.[13] It is also useful in early labor to assist with pain relief and used in conjunction with other non-pharmacologic pain methods such as birthing balls, position changes, and even possibly water birth. The gas is self-administered so the laboring mom has full control of how much gas she wishes to inhale at any given time.[13] Nitrous oxide has the added benefit of limited side effects. Some mothers may experience some dizziness, nausea, vomiting, or drowsiness, however, since dosing is determined by the patient, once these symptoms begin she can limit her use. The gas takes effect quickly, but also lasts a short period of time so she must hold the mask to her face in order to benefit from the effects of analgesia.[13] There is very little effect to the baby since it is quickly eliminated by the baby as soon as it begins breathing.[13] Evidence does not suggest any clinically significant risk factors in the use of nitrous oxide gas as opposed to other methods of pain management both non-pharmacologic and pharmacologic in terms of Apgar or cord blood gas. There is also limited evidence to determine whether there are any increased occupational risks to the healthcare provider associated with the use of nitrous oxide.[13] ## Pain management after childbirth[edit] Perineal pain after childbirth has immediate and long-term negative effects for women and their babies. These effects can interfere with breastfeeding and the care of the infant.[14] The pain from injection sites and possible episiotomy is managed by the frequent assessment of the report of pain from the mother. Pain can come from possible lacerations, incisions, uterine contractions and sore nipples. Appropriate medications are usually administered.[15] Routine episiotomies have not been found to reduce the level of pain after the birth.[16] ## See also[edit] * Epidural * Lumbar puncture * Combined spinal and epidural anaesthesia * Intrathecal administration ## References[edit] 1. ^ a b c d e f g h i j k l m n o p q r "Pregnancy Labor and Birth". Office on Women’s Health, U.S. Department of Health and Human Services. 1 February 2017. Retrieved 15 July 2017. This article incorporates text from this source, which is in the public domain. 2. ^ a b Smith, Caroline A; Levett, Kate M; Collins, Carmel T; Jones, Leanne; Smith, Caroline A (2012). "Massage, reflexology and other manual methods for pain management in labour". Cochrane Database of Systematic Reviews (2): CD009290. doi:10.1002/14651858.CD009290.pub2. PMID 22336862. 3. ^ a b c d e f Jones L, Othman M, Dowswell T, Alfirevic Z, Gates S, Newburn M, Jordan S, Lavender T, Neilson JP (2012). "Pain management for women in labour: an overview of systematic reviews". Reviews. 3 (3): CD009234. doi:10.1002/14651858.CD009234.pub2. PMC 7132546. PMID 22419342. S2CID 7358365. 4. ^ a b c Smith, Caroline A; Levett, Kate M; Collins, Carmel T; Armour, Mike; Dahlen, Hannah G; Suganuma, Machiko (2018-03-28). "Relaxation techniques for pain management in labour". Cochrane Database of Systematic Reviews. 3: CD009514. doi:10.1002/14651858.cd009514.pub2. ISSN 1465-1858. PMC 6494625. PMID 29589650. 5. ^ Makvandi, Somayeh; Latifnejad Roudsari, Robab; Sadeghi, Ramin; Karimi, Leila (2015-09-30). "Effect of birth ball on labor pain relief: A systematic review and meta-analysis". Journal of Obstetrics and Gynaecology Research. 41 (11): 1679–1686. doi:10.1111/jog.12802. ISSN 1341-8076. PMID 26419499. S2CID 476947. 6. ^ Hodnett, Ellen D.; Gates, Simon; Hofmeyr, G. Justus; Sakala, Carol (2012-10-17). Hodnett, Ellen D (ed.). "Continuous support for women during childbirth". The Cochrane Database of Systematic Reviews. 10: CD003766. doi:10.1002/14651858.CD003766.pub4. ISSN 1469-493X. PMC 4175537. PMID 23076901. 7. ^ Taheri, Mahshid; Takian, Amirhossien; Taghizadeh, Ziba; Jafari, Nahid; Sarafraz, Nasrin (2018-05-02). "Creating a positive perception of childbirth experience: systematic review and meta-analysis of prenatal and intrapartum interventions". Reproductive Health. 15 (1): 73. doi:10.1186/s12978-018-0511-x. ISSN 1742-4755. PMC 5932889. PMID 29720201. 8. ^ Cluett, Elizabeth R; Burns, Ethel; Cuthbert, Anna (2018-05-16). "Immersion in water during labour and birth". Cochrane Database of Systematic Reviews. 5: CD000111. doi:10.1002/14651858.cd000111.pub4. ISSN 1465-1858. PMC 6494420. PMID 29768662. 9. ^ "Immersion in Water During Labor and Delivery - ACOG". www.acog.org. Retrieved 2019-01-25. 10. ^ a b c d "ACOG Practice Bulletin No. 177: Obstetric Analgesia and Anesthesia". Obstetrics & Gynecology. 100 (1): 177–191. April 2017. doi:10.1097/00006250-200207000-00032. ISSN 0029-7844. 11. ^ "Pregnancy Labor and Birth". Office on Women’s Health, U.S. Department of Health and Human Services. 1 February 2017. Retrieved 15 July 2017. This article incorporates text from this source, which is in the public domain.[verification needed] 12. ^ Maclean, Allan; Reid, Wendy (2011). "40". In Shaw, Robert (ed.). Gynaecology. Edinburgh New York: Churchill Livingstone/Elsevier. pp. 599–612. ISBN 978-0-7020-3120-5. 13. ^ a b c d e f Likis, Frances E.; Andrews, Jeffrey C.; Collins, Michelle R.; Lewis, Rashonda M.; Seroogy, Jeffrey J.; Starr, Sarah A.; Walden, Rachel R.; Mcpheeters, Melissa L. (2014-01-01). "Nitrous Oxide for the Management of Labor Pain: A Systematic Review". Anesthesia & Analgesia. 118 (1): 153–167. doi:10.1213/ANE.0b013e3182a7f73c. ISSN 0003-2999. PMID 24356165. S2CID 6307442. 14. ^ Shepherd, Emily; Grivell, Rosalie M. (24 July 2020). "Aspirin (single dose) for perineal pain in the early postpartum period". The Cochrane Database of Systematic Reviews. 7: CD012129. doi:10.1002/14651858.CD012129.pub3. ISSN 1469-493X. PMC 7388929. PMID 32702783. 15. ^ Henry, p. 122. sfn error: no target: CITEREFHenry (help) 16. ^ Jiang, H; Qian, X; Carroli, G; Garner, P (8 February 2017). "Selective versus routine use of episiotomy for vaginal birth". The Cochrane Database of Systematic Reviews. 2: CD000081. doi:10.1002/14651858.CD000081.pub3. PMC 5449575. PMID 28176333. * v * t * e Pain By region/system Head and neck * Headache * Neck * Odynophagia (swallowing) * Toothache Respiratory system * Sore throat * Pleurodynia Musculoskeletal * Arthralgia (joint) * Bone pain * Myalgia (muscle) * Acute * Delayed-onset Neurologic * Neuralgia * Pain asymbolia * Pain disorder * Paroxysmal extreme pain disorder * Allodynia * Chronic pain * Hyperalgesia * Hypoalgesia * Hyperpathia * Phantom pain * Referred pain * Congenital insensitivity to pain * congenital insensitivity to pain with anhidrosis * congenital insensitivity to pain with partial anhidrosis Other * Pelvic pain * Proctalgia * Back * Low back pain Measurement and testing * Pain scale * Cold pressor test * Dolorimeter * Grimace scale (animals) * Hot plate test * Tail flick test * Visual analogue scale Pathophysiology * Nociception * Anterolateral system * Posteromarginal nucleus * Substance P Management * Analgesia * Anesthesia * Cordotomy * Pain eradication Related concepts * Pain 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Contraction induction * Oxytocin# * Carbetocin * Demoxytocin * #WHO-EM * ‡Withdrawn from market * Clinical trials: * †Phase III * §Never to phase III * v * t * e Analgesics (N02A, N02B) Opioids Opiates/opium * Codeine# (+paracetamol, +aspirin) * Morphine# (+naltrexone) * Opium * Laudanum * Paregoric Semisynthetic * Acetyldihydrocodeine * Benzylmorphine * Buprenorphine (+naloxone) * Butorphanol * Desomorphine * Diamorphine (heroin) * Dihydrocodeine (+paracetamol) * Dihydromorphine * Ethylmorphine * Hydrocodone (+paracetamol, +ibuprofen, +aspirin) * Hydromorphinol * Hydromorphone * Levorphanol * Metopon * Nalbuphine * Nicocodeine * Nicodicodine * Nicomorphine * Oxycodone (+paracetamol, +aspirin, +ibuprofen, +naloxone, +naltrexone) * Oxymorphone * Thebacon Synthetic * Alfentanil * Alphaprodine * Anileridine * Bezitramide * Carfentanil * Dextromoramide * Dextropropoxyphene * Dezocine * Dimenoxadol * Dipipanone * Ethoheptazine * Fentanyl# (+fluanisone) * Ketobemidone * Lofentanil * 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#WHO-EM * ‡Withdrawn from market * Clinical trials: * †Phase III * §Never to phase III *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Pain management during childbirth

c0474368

wikipedia

https://en.wikipedia.org/wiki/Pain_management_during_childbirth

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In the apparently unique family reported by Lynch et al. (1960), 5 males in 3 generations showed both secondary hypogonadism (associated with low titers of pituitary gonadotropic hormones) and congenital ichthyosis. The authors suggested that close linkage may be responsible for the occurrence of hypogonadism with ichthyosis, a well-known X-linked trait. However, ichthyosis and hypogonadism is listed as a separate mutation since linkage can only be postulated. If indeed the 2 traits are due to 2 linked genes, one can say with 95% confidence that the recombination value is not greater than 20%. The disorder was transmitted by 6 females in whom there was opportunity for crossover. The affected males do not reproduce. (In earlier editions of these catalogs, ichthyosis with male hypogonadism was listed as a distinct X-linked recessive, single gene disorder. With the identification of close linkage of Kallmann syndrome (308700) and X-linked ichthyosis (308100), and the description of deletions leading to the coexistence of these 2 disorders, it becomes a distinct possibility that the affected males in the family reported by Lynch et al. (1960) suffered from a 'contiguous gene syndrome.') In a well-studied Mexican-American kindred with many affected persons, Perrin et al. (1976) reported that anosmia is an additional feature (see 308700) and that linkage with Xg is clearly excluded. Linkage with new markers should be examined in this family: is this family distinct from the families with deletion causing Kallmann syndrome and ichthyosis? Dodinval et al. (1981) described 2 affected brothers. RUD syndrome is a neurocutaneous disorder characterized by epilepsy, mental retardation, infantilism, congenital ichthyosis, and retinitis pigmentosa. Rud (1927) described a 22-year-old Danish male with ichthyosis, hypogenitalism, epilepsy, polyneuritis, and hyperchromic macrocytic anemia. Two years later, Rud (1929) reported a second case in a 29-year-old female with partial gigantism and diabetes mellitus in addition to ichthyosis and hypogenitalism. Munke et al. (1983) found reports of 28 patients with Rud syndrome. The male:female ratio was 2:1, consistent with some of the cases being instances of an X-linked recessive disorder. Wisniewski et al. (1985) pointed to 2 reports of apparent X-linked inheritance. Their own observations concerned 2 brothers and their mother, who was thought to show heterozygous manifestation. The sons, aged 11 and 10 years, had severe visual impairment from bilateral maculopathy and the other features of RUDS. The mother had decreased visual acuity, increased pigment granularity of both maculae with decreased foveal reflexes, and exaggerated keratosis pilaris of both thighs. (The possibility that this family suffered from a 'contiguous gene syndrome' should be investigated with the search for cytogenetic or molecular genetic evidence of deletion in Xp.) Traupe (1989) provided a useful critical review of 'Rud syndrome.' Einar Rud, a Danish physician, recorded in his 1927 paper that the patient had 15 brothers and sisters and that he was the only one affected. He explicitly stated that the patient was mentally alert ('kvik,' in Danish). The polyneuropathy in the first patient reported by Rud had begun at age 18. The second patient had 'partial gigantism,' whereas his first patient had short stature. The woman was not mentally retarded and did not show any neurologic involvement. Rud (1929) stated that the mother, a brother, and a sister had ichthyosis vulgaris but did not suffer from any of the other symptoms. Traupe (1989) suggested that the designation 'Rud syndrome' be abandoned; from a review of reports he concluded that both the neurologic involvement and the ichthyosis remain ill defined. GU \- Secondary hypogonadism Neuro \- Seizures \- Mental retardation \- Polyneuritis Nose \- Anosmia Skin \- Congenital ichthyosis Inheritance \- X-linked ( ? contiguous gene syndrome) Eyes \- Retinitis pigmentosa Lab \- Low pituitary gonadotropic hormones Heme \- Hyperchromic macrocytic anemia ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ICHTHYOSIS AND MALE HYPOGONADISM

c0270709

omim

https://www.omim.org/entry/308200

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Small cell lung cancer (SCLC) is a highly aggressive malignant neoplasm, accounting for 10-15% of lung cancer cases, characterized by rapid growth, and early metastasis. SCLC usually manifests as a large hilar mass with bulky mediastinal lymphadenopathy presenting clinically with chest pain, persistent cough, dyspnea, wheezing, hoarseness, hemoptysis, loss of appetite, weight loss, and neurological and endocrine paraneoplastic syndromes. SCLC is primarily reported in elderly people with a history of long-term tobacco exposure. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Small cell lung cancer

c0149925

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=70573

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Lev's disease Other namesLenegre–Lev syndrome SpecialtyCardiology Lev's disease is an acquired complete heart block due to idiopathic fibrosis and calcification of the electrical conduction system of the heart. Lev's disease is most commonly seen in the elderly, and is often described as senile degeneration of the conduction system. One form has been associated with SCN5A.[1] ## Contents * 1 Presentation * 1.1 Associated conditions * 2 History * 3 See also * 4 References * 5 External links ## Presentation[edit] ### Associated conditions[edit] Stokes–Adams attacks can be precipitated by this condition. These involve a temporary loss of consciousness resulting from marked slowing of the heart when the atrial impulse is no longer conducted to the ventricles. This should not be confused with the catastrophic loss of heartbeat seen with ventricular fibrillation or asystole. ## History[edit] It was described independently by Maurice Lev and Jean Lenègre in 1964,[2][3] but the condition is generally called after Lev. ## See also[edit] * Heart block ## References[edit] 1. ^ Schott JJ, Alshinawi C, Kyndt F, et al. (1999). "Cardiac conduction defects associate with mutations in SCN5A". Nat. Genet. 23 (1): 20–1. doi:10.1038/12618. PMID 10471492. 2. ^ Lev M (1964). "Anatomic basis for atrioventricular block". Am J Med. 37: 742–8. doi:10.1016/0002-9343(64)90022-1. PMID 14237429. 3. ^ Lenegre J (1964). "Etiology and pathology of bilateral bundle branch block in relation to complete heart block". Prog Cardiovasc Dis. 6: 409–444. doi:10.1016/s0033-0620(64)80001-3. PMID 14153648. ## External links[edit] Classification D * ICD-9-CM: 426.0 * OMIM: 113900 * MeSH: C566873 * DiseasesDB: 33970 This article about a medical condition affecting the circulatory system is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Lev's disease

c1879286

wikipedia

https://en.wikipedia.org/wiki/Lev%27s_disease

{"mesh": ["C566873"], "umls": ["C1879286"], "icd-9": ["426.0"], "wikidata": ["Q3961680"]}

Unintended side effects of vaccines which may be beneficial or bad Women and children in line for a vaccination in Guinea-Bissau. It is estimated that millions of child deaths could be prevented every year if the non-specific effects of vaccines were taken into consideration in immunization programs.[1] Non-specific effects of vaccines (also called "heterologous effects" or "off-target effects") are effects which go beyond the specific protective effects against the targeted diseases. Non-specific effects can be strongly beneficial by increasing protection against non-targeted infections.[1] This has been shown with two live attenuated vaccines, BCG vaccine and measles vaccine, through multiple randomized controlled trials.[1] Theoretically, non-specific effects of vaccines may be detrimental, increasing overall mortality despite providing protection against the target diseases. Although observational studies suggest that diphtheria-tetanus-pertussis vaccine (DTP) may be detrimental, these studies are at high risk of bias and have failed to replicate when conducted by independent groups.[2] Ongoing research suggests that non-specific effects of vaccines may depend on the vaccine, the vaccination schedule, and the sex of the infant.[3] For example, one hypothesis suggests that all live attenuated vaccines reduce mortality more than explained by prevention of target infections, while all inactivated vaccines may increase overall mortality despite providing protection against the target disease. These effects may be long-lasting, at least up to the time point where a new type of vaccine is given. The non-specific effects can be very pronounced, with significant effects on overall mortality and morbidity. In a situation with herd immunity to the target disease, the non-specific effects can be more important for overall health than the specific vaccine effects.[3] The non-specific effects should not be confused with the side effects of vaccines (such as local reactions at the site of vaccination or general reactions such as fever, head ache or rash, which usually resolve within days to weeks – or in rare cases anaphylaxis). Rather, non-specific effects represent a form of general immunomodulation, with important consequences for the immune system's ability to handle subsequent challenges. It is estimated that millions of child deaths in low income countries could be prevented every year if the non-specific effects of vaccines were taken into consideration in immunization programs.[1] ## Contents * 1 History * 2 Live attenuated versus inactivated vaccines * 2.1 BCG vaccine * 2.2 Oral Poliovirus Vaccine * 2.3 Measles vaccine * 2.4 Diphtheria-tetanus-pertussis vaccine * 2.5 Smallpox vaccine * 3 Sex differences * 4 Interactions between health interventions * 5 Influence of pre-existing specific immunity * 6 High-income countries * 7 Immunological mechanisms * 7.1 Heterologous T-cell immunity * 7.2 Trained innate immunity * 8 Controversy * 9 Implications for world health * 10 The Arc of the Swallow * 11 References * 12 External links ## History[edit] The Bandim Health Project Office built in 2008. The hypothesis that vaccines have non-specific effects was formulated in the early 1990s by Peter Aaby at the Bandim Health Project in West Africa.[4] The first indication of the importance of the non-specific effects of vaccines came in a series of randomized controlled trials (RCTs) in the late 1980s. It was tested whether a high-titer (high-dose) measles vaccine (HTMV) given at 4–6 months of age was as effective against measles infection as the standard measles vaccine (MV) given at 9 months of age. Early administration of the HTMV prevented measles infection just as effectively as did the standard MV given at 9 months of age. However, early administration of the HTMV was associated with twofold higher overall mortality among females (there was no difference in mortality for males).[5][6][7] In other words, the girls given HTMV died more often despite having the same protection against measles as the infants given standard MV. The discovery forced WHO to withdraw the HTMV in 1992.[8] It was later discovered that it was not the HTMV, but rather a subsequent inactivated vaccine (DTP or IPV for different children), that caused the increase in female mortality.[9] Although the mechanism was different than initially thought, this finding represents unexpected effects of a change in the vaccine program not attributable to the disease-specific protection provided by the vaccines. This first observation that vaccines could protect against the target disease but at the same time affect mortality after infection with other pathogens, in a sex-differential manner, led to several further studies showing that other vaccines might also have such nonspecific effects. ## Live attenuated versus inactivated vaccines[edit] Numerous observational studies and randomised trials (RCTs) have found that the impact on mortality of live and inactivated vaccines differ markedly. All live vaccines studied so far (BCG, measles vaccine, oral polio vaccine (OPV) and smallpox vaccine) have been shown to reduce mortality more than can be explained by prevention of the targeted infection(s). In contrast, inactivated vaccines (diphtheria-tetanus-pertussis (DTP), hepatitis B, inactivated polio vaccine) may have deleterious effects in spite of providing target disease protection.[10] ### BCG vaccine[edit] The live attenuated BCG vaccine developed against tuberculosis has been shown to have strong beneficial effects on the ability to combat non-tuberculosis infections.[3][11] Scar after BCG vaccination Several studies have suggested that BCG vaccination may reduce atopy, particularly when given early in life. Furthermore, in multiple observational studies BCG vaccination has been shown to provide beneficial effects on overall mortality.[12] These observations encouraged randomised controlled trials to examine BCG vaccination's beneficial non-specific effects on overall health.[13][14][15][16] Since BCG vaccination is recommended to be given at birth in countries that have a high incidence of tuberculosis it would have been unethical to randomize children into 'BCG' vs. 'no BCG' groups. However, many low-income countries delay BCG vaccination for low-birth-weight (LBW) infants; this offered the opportunity to directly test the effect of BCG on overall mortality. In the first two randomised controlled trials receipt of BCG+OPV at birth vs. OPV only ('delayed BCG') was associated with strong reductions in neonatal mortality; these effects were seen as early as 3 days after vaccination. BCG protected against sepsis as well as respiratory infections.[17][18] Among BCG vaccinated children, those who develop a BCG scar or a positive skin test (TST) are less likely to develop sepsis and exhibit an overall reduction in child mortality of around 50%.[15][19][20] In a recent WHO-commissioned review based on five clinical trials and nine observational studies, it was concluded that "the results indicated a beneficial effect of BCG on overall mortality in the first 6–12 months of life.[17] Relevant follow-up in some of the trials was short, and all of the observational studies were regarded as being at risk of bias, so the confidence in the findings was rated as very low according to the GRADE criteria and "There was a suggestion that BCG vaccination may be more beneficial the earlier it is given". Furthermore, "estimated effects are in the region of a halving of mortality risk" and "any effect of BCG vaccine on all-cause mortality is not likely to be attributable to any great extent to fewer deaths from tuberculosis (i.e. to a specific effect of BCG vaccine against tuberculosis)".[2] Based on the evidence, the WHO's Strategic Group of Experts on Immunization concluded that "the non-specific effects on all-cause mortality warrant further research".[21] ### Oral Poliovirus Vaccine[edit] Oral Poliovirus Vaccine (OPV) was developed in the 1950s by Dr. Albert Sabin and is made from live attenuated polioviruses of three serotypes.[22] The first evidence of non-specific effects of OPV was protection by vaccination with OPV of serotype 2 against disease caused by serotype 1 poliovirus without any evidence of cross-neutralization.[23] Vaccination with trivalent OPV helped to stop outbreak of paralytic disease caused by Enterovirus 71 in Bulgaria.[24] In large prospective clinical trials OPV was shown to protect against seasonal influenza and other acute respiratory diseases.[25][26] Immunization with OPV was also shown to lead to a faster healing of genital herpes lesions.[27] Immunization with OPV was found to reduce all-cause childhood mortality [28][29] even in the absence of wild poliovirus circulation, hospital admission rate,[30] incidence of bacterial diarrhea,[31] and otitis media.[32] Vaccination with OPV results in Interferon induction that is believed to be the main mediator of the non-specific protective effects of OPV.[33] ### Measles vaccine[edit] Standard titer measles vaccine is recommended at 9 months of age in low-income countries where measles infection is endemic and often fatal. Many observational studies have shown that measles-vaccinated children have substantially lower mortality than can be explained by the prevention of measles-related deaths.[34] Many of these observational studies were natural experiments, such as studies comparing the mortality before and after the introduction of measles vaccine and other studies where logistical factors rather than maternal choice determined whether a child was vaccinated or not. These findings were later supported in randomized trials from 2003 to 2009 in Guinea-Bissau. An intervention group of children given standard titer measles vaccine at 4.5 and 9 month of age had a 30% reduction in all-cause mortality compared to the children in the control group, which were only vaccinated against measles at 9 month of age.[10] In a recent WHO-commissioned review based on four randomized trials and 18 observational studies, it was concluded that "There was consistent evidence of a beneficial effect of measles vaccine, although all observational studies were assessed as being at risk of bias and the GRADE rating was of low confidence. There was an apparent difference between the effect in girls and boys, with girls benefitting more from measles vaccination", and furthermore "estimated effects are in the region of a halving of mortality risk" and "if these effects are real then they are not fully explained by deaths that were established as due to measles".[2] Based on the evidence, the WHO's Strategic Advisory Group of Experts on Immunization concluded that "the non-specific effects on all-cause mortality warrant further research".[21][1] ### Diphtheria-tetanus-pertussis vaccine[edit] DTP vaccine against diphtheria, tetanus and pertussis does not seem to have the same beneficial effects as BCG, measles vaccine, OPV and smallpox vaccine, and in fact opposite effects are observed.[35] The negative effects are seen as long as DTP vaccine is the most recent vaccine. BCG or measles vaccine given after DTP reverses the negative effects of DTP.[35] The negative effects are seen mostly in females.[35] The negative effects are found in several observational studies. However, six WHO-commissioned studies concluded that there were strong beneficial effects of DTP on overall mortality.[36][37][38][39][40][41] However, controversy ensued as these studies had important methodological shortcomings.[42][43] For example, the WHO-commissioned studies had counted "no information about vaccination" as "unvaccinated", and they had retrospectively updated vaccine information from surviving children, while no similar update could be made for dead children, creating a so-called "survival bias" which will always produce highly beneficial effect estimates for the most recent vaccine.[44] In a recent WHO-commissioned review of DTP based on ten observational studies, it was concluded that, "the findings were inconsistent, with a majority of the studies indicating a detrimental effect of DTP, and two studies indicating a beneficial effect. All of the studies were regarded as being at risk of bias, so the confidence in the findings was rated as very low according to the GRADE criteria." Furthermore, "three observational studies provided a suggestion that simultaneous administration of BCG and DTP may be preferable to the recommended schedule of BCG before DTP; and there was suggestion that mortality risk may be higher when DTP is given with, or after, measles vaccine compared with when it is given before measles vaccine (from five, and three, observational studies, respectively). These results are consistent with hypotheses that DTP vaccine may have detrimental effects on mortality, although a majority of the evidence was generated by a group centred in Guinea-Bissau who have often written in defence of such a hypothesis."[2] A large cohort study of over one million Danish children came even to the conclusion that the group of children with fewer DTP vaccinations (without MMR) experienced increased mortality.[45] ### Smallpox vaccine[edit] When smallpox vaccine was introduced in the early 19th century, there were anecdotal descriptions of non-specific beneficial effects. In the second half of the 20th century the potential for beneficial non-specific effects of smallpox vaccine was reviewed, and new evidence on "para-immune effects" was added.[46] More recent studies have focused on the phasing out of smallpox vaccine in the 1970s and compared vaccinated and unvaccinated cohorts. Smallpox vaccine leaves a very characteristic scar. In low-income countries, having a smallpox vaccine scar has been associated with reductions of more than 40% in overall mortality among adults;[47][48] in high-income countries smallpox vaccination has been associated with a tendency for reduced risk of asthma,[49] and significantly reduced risk of malignant melanoma [50] and infectious disease hospitalizations.[51] There are no studies that contradict these observations. However no randomized trials testing the effect of smallpox vaccine on overall mortality and morbidity have been conducted. ## Sex differences[edit] Non-specific effects are frequently different in males and females. There are accumulating data illustrating that males and females may respond differently to vaccination, both in terms of the quality and quantity of the immune response.[5][6][7][35][52] If true, then we must consider whether vaccination schedules should differ for males and females, or as has been suggested "should we treat the sexes differently in order to treat them equally?"[52] ## Interactions between health interventions[edit] The non-specific effects of vaccines can be boosted or diminished when other immunomodulating health interventions such as other vaccines, or vitamins, are provided.[53] ## Influence of pre-existing specific immunity[edit] The beneficial NSEs of live vaccines are stronger with earlier vaccination, possibly due to maternal antibodies.[54] Boosting with live vaccines also seems to enhance the beneficial effects. ## High-income countries[edit] The non-specific effects were primarily observed in low-income countries with high infectious disease burdens, but they may not be limited to these areas. Recent Danish register-based studies have shown that the live attenuated measles-mumps-rubella vaccine (MMR) protects against hospital admissions with infectious diseases and specifically getting ill by respiratory syncytial virus.[55][56][57] ## Immunological mechanisms[edit] The findings from the epidemiological studies on the non-specific effects of vaccines pose a challenge to the current understanding of vaccines, and how they affect the immune system, and also question whether boys and girls have identical immune systems and should receive the same treatment. The mechanisms for these effects are unclear. It is not known how vaccination induces rapid beneficial or harmful changes in the general susceptibility to infectious diseases, but the following mechanisms are likely to be involved. ### Heterologous T-cell immunity[edit] It is well known from animal studies that infections, apart from inducing pathogen-specific T-cells, also induce cross-reactive T-cells through epitope sharing, so-called heterologous immunity.[58][59] Heterologous T-cell immunity can lead to improved clearance of a subsequent cross-reactive challenge, but it may also lead to increased morbidity.[60] This mechanism may explain why DTP could have negative effects. It would, however, not explain effects occurring shortly after vaccination, as for instance the rapidly occurring beneficial effects of BCG vaccine,[17] as the heterologous effect would only be expected to be present after some weeks, as the adaptive immune response need time to develop. Also, it is difficult to explain why the effect would vanish once a child receives a new vaccine. ### Trained innate immunity[edit] The concept that not only plants and insects, but also humans have innate immune memory may provide new clues to why vaccines have non-specific effects. Studies into BCG have recently revealed that BCG induces epigenetic changes in the monocytes in adults, leading to increased pro-inflammatory cytokine production upon challenges with unrelated mitogens and pathogens (trained innate immunity).[61] In SCID mice that have no adaptive immune system, BCG reduced mortality from an otherwise lethal candida infection. The effects of BCG presented when tested after 2 weeks, but would be expected to occur rapidly after vaccination, and hence might be able to explain the very rapid protection against neonatal septicaemia seen after BCG vaccine.[62] Trained innate immunity may also explain the generally increased resistance against broad disease categories, such as fevers and lower respiratory tract infections; such effects would be difficult to explain merely by shared epitopes, unless such epitopes were almost universally common on pathogens. Lastly, it is plausible that the effects are reversible by a different vaccine. Hence, trained innate immunity may provide a biological mechanism for the observed non-specific effects of vaccines.[61] ## Controversy[edit] In 2000 Aaby and colleagues presented data from Guinea-Bissau which suggested that DTP vaccination could, under some circumstances (e.g. absence of pertussis) be associated with increases in overall mortality, at least until children received measles vaccine. In response, WHO sponsored the analysis of a variety of data sets in other populations to test the hypothesis. None of these studies replicated the observation of increased mortality associated with DTP vaccination.[36][37][38][39][40][41] WHO subsequently concluded, that the evidence was sufficient to reject the hypothesis for an increased nonspecific mortality following DTP vaccination.[63] However, Aaby and colleagues subsequently pointed out that the studies which failed to show any mortality increase associated with DTP vaccination used methods of analysis that can introduce a bias against finding such an effect.[44] In these studies, data on childhood vaccinations were typically collected in periodic surveys, and the information on vaccinations, which occurred between successive home visits, was updated at the time of the second visit. The person-time at risk in unvaccinated and vaccinated states was then divided up according to the date of vaccination during the time interval between visits. This method opens up a potential bias, insofar as the updating of person time at risk from unvaccinated to vaccinated is only possible for children who survive to the second follow-up. Those who die between visits typically do not have vaccinations between the first visit and death recorded, and thus they will tend to be allocated as deaths in unvaccinated children – thus incorrectly inflating the mortality rate among unvaccinated children.[44] This bias has been described before, but in different contexts, as the distinction between 'landmark' and 'retrospective updating' analysis of cohort data.[64] The retrospective updating method can lead to a considerable bias in vaccine studies, biasing observed mortality rate ratios towards zero (a large effect), whereas the landmark method leads to a non-specific misclassification and biases the mortality rate ratio towards unity(no effect). An additional problem with the literature on the nonspecific effects of vaccines has been the variety and unexpected nature of the hypotheses which have appeared (in particular relating to sex-specific effects), which has meant that it has not always been clear whether some apparent 'effects' were the result of post hoc analyses or whether they were reflections of a priori hypotheses. This was discussed at length at a review of the work of Aaby and his colleagues in Copenhagen in 2005.[43] The review was convened by the Danish National Research Foundation and the Novo Nordisk Foundation who have sponsored much of the work of Aaby and his colleagues. An outcome of the review was the explicit formulation of a series of testable hypotheses, agreed by the Aaby group.[43] It was hoped that independent investigators would design and conduct studies powered to confirm or refute these hypotheses. Also, the two foundations sponsored a workshop on the analysis of vaccine effects, which was held in London in 2008.[43] The workshop resulted in three papers.[64][65][66] The proceedings were forwarded to WHO which subsequently concluded that it would "keep a watch on the evidence of nonspecific effects of vaccination".[67] In 2013, WHO established a working group tasked with reviewing the evidence for the non-specific effects of BCG, measles and DTP vaccines. Two independent reviews were conducted, an immunological review[68] and an epidemiological review.[2] The results were presented at the April 2014 meeting of WHO's Strategic Gourp of Experts on Immunizations (SAGE). WHO/SAGE concluded that further research into the potential NSEs of vaccines was warranted.[21] ## Implications for world health[edit] The neutrality of this article is disputed. Relevant discussion may be found on the talk page. Please do not remove this message until conditions to do so are met. (August 2017) (Learn how and when to remove this template message) Dr. Frank Shann from Australia recently assessed the consequences of changing the current EPI schedule to an alternative schedule taking non-specific effects into account, and concluded: "If all neonates in high-mortality regions were given BCG at birth, and the revised immunization schedule ... were adopted, with extra doses of measles vaccine at 14 weeks and 19 months (at a cost of only US $0.60/dose delivered), ~1 million (30%) of the 3.2 million neonatal deaths each year might be prevented in developing countries, and 1.5 million (30%) of the 4.8 million deaths between 1 month and 5 years of age might be prevented". Furthermore: "This very large reduction in mortality in children <5 years of age would be achieved at a low cost using only vaccines that are already in the routine EPI schedule".[1] ## The Arc of the Swallow[edit] In 2008, Danish crime novel author Sissel-Jo Gazan (author of the Danish crime novel Dinosaur Feather) became interested in the work of the Bandim Health Project and based her science crime novel The Arc of the Swallow (Svalens Graf) on the research into non-specific effects of vaccines. The novel was published in Danish in 2013; it was on the best-seller list for months and won the Readers' Prize 2014 in Denmark. It was published in English in the UK on November 6, 2014 and in the US on April 7, 2015. ## References[edit] 1. ^ a b c d e Shann F (February 2013). "Nonspecific effects of vaccines and the reduction of mortality in children". Clinical Therapeutics. 35 (2): 109–14. doi:10.1016/j.clinthera.2013.01.007. PMID 23375475. 2. ^ a b c d e WHO/SAGE. "Epidemiology review Report to SAGE" (PDF). Retrieved 7 May 2015. 3. ^ a b c Benn CS, Netea MG, Selin LK, Aaby P (13 May 2013). "A small jab - a big effect: nonspecific immunomodulation by vaccines". Trends in Immunology. 34 (9): 431–9. doi:10.1016/j.it.2013.04.004. PMID 23680130. 4. ^ Aaby, P; Andersen, M; Sodemann, M; Jakobsen, M; Gomes, J; Fernandes, M (20 November 1993). "Reduced childhood mortality after standard measles vaccination at 4-8 months compared with 9-11 months of age". BMJ. 307 (6915): 1308–11. doi:10.1136/bmj.307.6915.1308. PMC 1679462. PMID 8257884. 5. ^ a b Holt, EA; Moulton, LH; Siberry, GK; Halsey, NA (November 1993). "Differential mortality by measles vaccine titer and sex". The Journal of Infectious Diseases. 168 (5): 1087–96. doi:10.1093/infdis/168.5.1087. PMID 8228340. 6. ^ a b Aaby, P; Samb, B; Simondon, F; Knudsen, K; Seck, AM; Bennett, J (1994). "Sex-specific differences in mortality after high-titre measles immunization in rural Senegal". Bull World Health Organ. 72 (5): 761–70. PMC 2486568. PMID 7955026. 7. ^ a b Aaby, P; Knudsen, K; Whittle, H; Lisse, IM; Thaarup, J; Poulsen, A (June 1993). "Long-term survival after Edmonston-Zagreb measles vaccination in Guinea-Bissau: increased female mortality rate". Journal of Pediatrics. 122 (6): 904–8. doi:10.1016/s0022-3476(09)90015-4. PMID 8501567. 8. ^ "Expanded programme on immunization (EPI). Safety of high titre measles vaccines". Wkly Epidemiol Rec. 67 (48): 357–61. 1992. PMID 1449986. 9. ^ Aaby, Peter; Jensen, Henrik; Samb, Badara; Cisse, Badara; Sodemann, Morten; Jakobsen, Marianne; Poulsen, Anja; Rodrigues, Amabelia; Lisse, Ida Marie; Simondon, Francois; Whittle, Hilton (28 June 2003). "Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies". The Lancet. 361 (9376): 2183–2188. doi:10.1016/S0140-6736(03)13771-3. PMID 12842371. S2CID 19968745. 10. ^ a b Aaby, P; Martins, CL; Garly, ML; Bale, C; Andersen, A; Rodrigues, A (2010). "Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial". BMJ. 341 (6495): c6495. doi:10.1136/bmj.c6495. PMC 2994348. PMID 21118875. 11. ^ Aaby, P; Kollmann, TR; Benn, CS (October 2014). "Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges". Nature Immunology. 15 (10): 895–9. doi:10.1038/ni.2961. PMID 25232810. S2CID 2856426. 12. ^ Steenhuis, TJ; van Aalderen, WM; Bloksma, N (2008). "Bacille-Calmette-Guerin vaccination and the development of allergic disease in children: a randomized, prospective, single-blind study". Clin Exp Allergy. 38 (1): 79–85. doi:10.1111/j.1365-2222.2007.02859.x. PMID 17956585. S2CID 24476148. 13. ^ Roth, AE; Nielsen, J (2 January 2007). "A non-beneficial effect of BCG on non-tuberculous childhood mortality?". Vaccine. 25 (1): 12–3. doi:10.1016/j.vaccine.2005.09.005. PMID 16198453. 14. ^ Roth, A; Jensen, H; Garly, ML; Djana, Q; Martins, CL; Sodemann, M; Rodrigues, A; Aaby, P (June 2004). "Low birth weight infants and Calmette-Guérin bacillus vaccination at birth: community study from Guinea-Bissau". The Pediatric Infectious Disease Journal. 23 (6): 544–50. doi:10.1097/01.inf.0000129693.81082.a0. PMID 15194836. S2CID 11989145. 15. ^ a b Roth, A; Gustafson, P; Nhaga, A; Djana, Q; Poulsen, A; Garly, ML; Jensen, H; Sodemann, M; Rodriques, A; Aaby, P (June 2005). "BCG vaccination scar associated with better childhood survival in Guinea-Bissau". International Journal of Epidemiology. 34 (3): 540–7. doi:10.1093/ije/dyh392. PMID 15659474. 16. ^ Roth, A; Garly, ML; Jensen, H; Nielsen, J; Aaby, P (2006). "Bacillus Calmette-Guerin vaccination and infant mortality". Expert Rev Vaccines. 5 (2): 277–93. doi:10.1586/14760584.5.2.277. PMID 16608427. 17. ^ a b c Biering-Sorensen, S; Aaby, P; Napirna, BM; Roth, A; Ravn, H; Rodrigues, A (Mar 2012). "Small randomized trial among low-birth-weight children receiving bacillus Calmette-Guerin vaccination at first health center contact". Pediatr Infect Dis J. 31 (3): 306–8. doi:10.1097/inf.0b013e3182458289. PMID 22189537. S2CID 1240058. 18. ^ Aaby, P; Roth, A; Ravn, H; Napirna, BM; Rodrigues, A; Lisse, IM (15 July 2011). "Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?". J Infect Dis. 204 (2): 245–52. doi:10.1093/infdis/jir240. PMID 21673035. 19. ^ Roth, A; Sodemann, M; Jensen, H; Poulsen, A; Gustafson, P; Weise, C; Gomes, J; Djana, Q; Jakobsen, M; Garly, ML; Rodrigues, A; Aaby, P (September 2006). "Tuberculin reaction, BCG scar, and lower female mortality". Epidemiology. 17 (5): 562–8. doi:10.1097/01.ede.0000231546.14749.ab. PMID 16878042. S2CID 40917911. 20. ^ Garly, ML; Martins, CL; Balé, C; Baldé, MA; Hedegaard, KL; Gustafson, P; Lisse, IM; Whittle, HC; Aaby, P (20 June 2003). "BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG?". Vaccine. 21 (21–22): 2782–90. doi:10.1016/s0264-410x(03)00181-6. PMID 12798618. 21. ^ a b c WHO (2014). "Meeting of the Strategic advisory group of experts on immunization, april 2014 – conclusions and recommendations". Wkly Epidemiol Rec. 89 (21): 221–36. PMID 24864348. 22. ^ Sabin, AB. Characteristics and genetic potentialities of experimentally produced and naturally occurring variants of poliomyelitis virus. Ann NY Acad Sci 1955; 61: 924-38. 23. ^ Hale, JH, Doraisingham, M, Kanagaratnam, K, Leong, KW, Monteiro, ES. Large-scale use of Sabin type 2 attenuated poliovirus vaccine in Singapore during a type 1 poliomyelitis epidemic. 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The Effect of Oral Polio Vaccine at Birth on Infant Mortality: A Randomized Trial. Clin Infect Dis 2015; 61(10): 1504-11. 29. ^ Andersen, A, Fisker, AB, Rodrigues, A, et al. National Immunization Campaigns with Oral Polio Vaccine Reduce All-Cause Mortality: A Natural Experiment within Seven Randomized Trials. Front Public Health 2018; 6: 13. 30. ^ Sorup, S, Stensballe, LG, Krause, TG, Aaby, P, Benn, CS, Ravn, H. Oral Polio Vaccination and Hospital Admissions With Non-Polio Infections in Denmark: Nationwide Retrospective Cohort Study. Open forum infectious diseases 2016; 3(1): ofv204. 31. ^ Upfill-Brown, A, Taniuchi, M, Platts-Mills, JA, et al. Nonspecific Effects of Oral Polio Vaccine on Diarrheal Burden and Etiology Among Bangladeshi Infants. Clin Infect Dis 2017; 65(3): 414-9. 32. ^ Seppala, E, Viskari, H, Hoppu, S, et al. Viral interference induced by live attenuated virus vaccine (OPV) can prevent otitis media. Vaccine 2011; 29(47): 8615-8. 33. ^ Voroshilova, MK. 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PMID 25725054. 58. ^ Welsh, RM; Che, JW; Brehm, MA; Selin, LK (May 2010). "Heterologous immunity between viruses". Immunological Reviews. 235 (1): 244–66. doi:10.1111/j.0105-2896.2010.00897.x. PMC 2917921. PMID 20536568. 59. ^ Welsh, RM; Selin, LK (June 2002). "No one is naive: the significance of heterologous T-cell immunity". Nat Rev Immunol. 2 (6): 417–26. doi:10.1038/nri820. PMID 12093008. S2CID 37492938. 60. ^ Selin, LK; Wlodarczyk, MF; Kraft, AR; Nie, S; Kenney, LL; Puzone, R (June 2011). "Heterologous immunity: immunopathology, autoimmunity and protection during viral infections". Autoimmunity. 44 (4): 328–47. doi:10.3109/08916934.2011.523277. PMC 3633594. PMID 21250837. 61. ^ a b Kleinnijenhuis, J; Quintin, J; Preijers, F; Joosten, LAB; Ifrim, DC; Saeed, S (23 Oct 2012). "Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes". Proc Natl Acad Sci U S A. 109 (43): 17537–42. doi:10.1073/pnas.1202870109. PMC 3491454. PMID 22988082. 62. ^ Aaby, P; Benn, CS (23 Oct 2012). "Saving lives by training innate immunity with bacille Calmette-Guerin vaccine". Proc Natl Acad Sci U S A. 109 (43): 17317–8. doi:10.1073/pnas.1215761109. PMC 3491466. PMID 23071307. 63. ^ WHO (22 November 2002). "Global Advisory Committee on Vaccine Safety, 20–21 June" (PDF). Weekly Epidemiological Record. 77 (47): 389–404. Retrieved 7 May 2015. 64. ^ a b Farrington, CP; Firth, MJ; Moulton, LH; Ravn, H; Andersen, PK; Evans, S (2009). "Epidemiological studies of the non-specific effects of vaccines: II - methodological issues in the design and analysis of cohort studies". Trop Med Int Health. 14 (9): 977–85. doi:10.1111/j.1365-3156.2009.02302.x. PMID 19531116. S2CID 13903114. 65. ^ Shann, F; Nohynek, H; Scott, JA; Hesseling, A; Flanagan, KL (2010). "Randomized Trials to Study the Nonspecific Effects of Vaccines in Children in Low-Income Countries". Pediatric Infectious Disease Journal. 29 (5): 457–61. doi:10.1097/inf.0b013e3181c91361. PMID 20431383. S2CID 13918714. 66. ^ Fine, PEM; Williams, TN; Aaby, P; Källander, K; Moulton, LH; Flanagan, KL (2009). "Epidemiological studies of the 'non-specific effects' of vaccines: I - data collection in observational studies". Trop Med Int Health. 14 (9): 969–76. doi:10.1111/j.1365-3156.2009.02301.x. PMID 19531117. S2CID 205390916. 67. ^ WHO (18 July 2008). "Meeting of Global Advisory Committee on Vaccine Safety". Wkly Epidemiol Rec. 83 (32): 285–92. PMID 18689006. 68. ^ WHO. "Systematic Review of the Non-specific Immunological Effects of Selected Routine" (PDF). WHO. The Oxford University. Retrieved 7 May 2015. ## External links[edit] * Bandim Health Project on non-specific effects *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

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## Summary ### Clinical characteristics. Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss. ### Diagnosis/testing. The diagnosis of KS is established in a proband of any age with a history of infantile hypotonia, developmental delay, and/or intellectual disability AND one or both of the following: * Typical dysmorphic features (long palpebral fissures with eversion of the lateral third of the lower eyelid, and ≥2 of the following: arched and broad eyebrows with the lateral third displaying notching or sparseness; short columella with depressed nasal tip; large, prominent, or cupped ears; persistent fingertip pads) * A heterozygous pathogenic variant in KMT2D or a heterozygous or hemizygous pathogenic variant in KDM6A ### Management. Treatment of manifestations: Thickened feedings and positioning after meals to treat gastroesophageal reflux; gastrostomy tube placement if feeding difficulties are severe. If cognitive difficulties are evident, psychoeducational testing and special education services to address the individual child's needs. Evaluation by a developmental pediatrician or psychiatrist if behavior suggests autism spectrum disorders. Standard antiepileptic treatment for seizures. Prevention of secondary complications: Prophylactic antibiotic treatment prior to and during any procedure (e.g., dental work) may be indicated for those with specific heart defects. Surveillance: Monitor height, weight, and head circumference at each well-child visit and, at a minimum, yearly. Developmental milestones should be followed with each well-child visit. Monitor vision and hearing on a yearly basis. ### Genetic counseling. KMT2D-related KS is inherited in an autosomal dominant manner; KDM6A-related KS is inherited in an X-linked manner. * Autosomal dominant inheritance. The proportion of KS caused by a de novo KMT2D pathogenic variant is unknown but is likely high based on clinical experience. In the rare case that a parent of the proband is affected, the risk to the sibs is 50%. * X-linked inheritance. If the mother of the proband has a KDM6A pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may have features of KS. Once the causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for KS are possible. ## Diagnosis Consensus clinical diagnostic criteria for Kabuki syndrome (KS) have been published [Adam et al 2019]. ### Suggestive Findings KS should be suspected in individuals with any combination of the five cardinal manifestations as defined by Niikawa et al [1988], specific structural anomalies, and/or functional differences. Cardinal manifestations 1. Typical facial features: * Long palpebral fissures with eversion of the lateral third of the lower eyelid * Highly arched and broad eyebrows with the lateral third displaying sparseness or notching * Short columella with depressed nasal tip * Large, prominent, and/or cupped ears 2. Skeletal anomalies: * Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis * Brachydactyly V * Brachymesophalangy * Clinodactyly of fifth digits 3. Dermatoglyphic abnormalities: persistence of fetal fingertip pads Note: While absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can be observed, this type of analysis is not routinely done in clinical practice in most centers. 4. Mild-to-moderate intellectual disability 5. Postnatal growth deficiency Structural anomalies in KS can include the following: * Ophthalmologic anomalies including ptosis and strabismus * Ear pits (a potentially helpful diagnostic clue when seen with other typical findings) * Cleft lip and/or palate * Dental anomalies including widely spaced teeth and hypodontia * Congenital heart defects * Gastrointestinal anomalies including anal atresia * Genitourinary anomalies including cryptorchidism in males Functional differences can include the following: * Hearing loss * Feeding problems * Endocrinologic abnormalities including isolated premature thelarche in females * Increased susceptibility to infections and autoimmune disorders * Seizures ### Establishing the Diagnosis The diagnosis of KS is established in a proband of any age with a history of infantile hypotonia, developmental delay, and/or intellectual disability AND one or both of the following [Adam et al 2019]: * Typical dysmorphic features (see *) at some point of life * A heterozygous pathogenic variant in KMT2D or a heterozygous or hemizygous pathogenic variant in KDM6A (Table 1) * Typical dysmorphic features include long palpebral fissures (a palpebral fissure measurement ≥2 SD above the mean for age) with eversion of the lateral third of the lower eyelid AND two or more of the following: * Arched and broad eyebrows with the lateral third displaying notching or sparseness * Short columella with depressed nasal tip * Large, prominent, or cupped ears * Persistent fingertip pads Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Kabuki syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Kabuki syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Kabuki syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. Single-gene testing. Sequence analysis of KMT2D and KDM6A detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. * Perform sequence analysis of KMT2D first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. * Sequence analysis and gene-targeted deletion/duplication analysis of KDM6A can be considered next if no pathogenic variant is found. Note: Affected individuals with classic features who have a mosaic heterozygous pathogenic variant in KMT2D have been reported; therefore, Lepri et al [2017] suggested that targeted next-generation sequencing may be a more appropriate method of mutation detection compared to traditional Sanger sequencing. A multigene panel that includes KMT2D, KDM6A, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the diagnosis of Kabuki syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible. If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Kabuki Syndrome (KS) View in own window Gene 1, 2Proportion of KS Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method Sequence analysis 4Gene-targeted deletion/duplication analysis 5 KDM6A~3%-5% 6~80% 6~20% 7 KMT2D~75% 6>99% 85 reported 9 Unknown 10, 11NA 1\. Genes are listed in alphabetic order. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. See Molecular Genetics for information on allelic variants detected in this gene. 4\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. Bögershausen et al [2016], Cocciadiferro et al [2018], Yap et al [2019] 7\. Van Laarhoven et al [2015], Bögershausen et al [2016], Cocciadiferro et al [2018], Yap et al [2019] 8\. Hannibal et al [2011], Li et al [2011], Micale et al [2011], Paulussen et al [2011], Banka et al [2012], Makrythanasis et al [2013], Bögershausen et al [2016] 9\. Banka et al [2012], Riess et al [2012], Cocciadiferro et al [2018] 10\. For approximately 30% of individuals with a clinical diagnosis of Kabuki syndrome, the genetic cause remains unknown. Therefore, locus heterogeneity for one or more as-yet-unidentified genes remains a possibility [Bögershausen & Wollnik 2013]. 11\. Further candidate genes for KS or conditions with features that overlap with KS include RAP1A, RAP1B, and KDM6C [Bögershausen et al 2016]. ## Clinical Characteristics ### Clinical Description This section summarizes findings in more than 400 individuals with a molecularly confirmed diagnosis of Kabuki syndrome (KS). #### Growth Individuals with KS typically exhibit normal growth parameters at birth. * Infants with KS frequently exhibit failure to thrive for a variety of reasons (see Gastrointestinal). * In adolescence and adulthood, more than half of individuals with KS develop obesity [Cheon & Ko 2015], which can exacerbate other health problems, such as recurrent patellar dislocation (see Musculoskeletal). * Without treatment (see Endocrine, Short stature), postnatal growth deficiency is evident by age 12 months. Lack of a typical growth spurt during puberty exacerbates short stature [Schott et al 2016a]. Microcephaly may or may not accompany short stature. #### Ophthalmologic Ocular findings occur in more than one third of individuals with Kabuki syndrome and include blue sclerae, strabismus, ptosis, coloboma, Marcus Gunn phenomenon (also referred to as jaw winking), and corneal abnormalities such as Peters anomaly. * Rarely, more severe eye anomalies may occur, such as optic nerve hypoplasia, colobomatous microphthalmia, and anophthalmia [Chen et al 2014, McVeigh et al 2015]. * Functional visual problems may include difficulties with motor coordination, visuoperception, and visuomotor integration [Caciolo et al 2018]. Failure to detect and treat these issues can exacerbate learning problems [Lehman et al 2017]. * As a result of the everted lower eyelid, children with KS can demonstrate excessive tearing, which is not usually a significant problem. However, nocturnal lagophthalmos, which occurs in many children with KS, can predispose to corneal abrasion and scarring. #### Ears and Hearing Most individuals with KS have prominent and cup-shaped ears. Ear pits are also relatively common. From a medical standpoint, chronic otitis media is a major cause of morbidity, including conductive hearing loss. It is not clear, however, whether this finding is related to an underlying susceptibility to infection or to the craniofacial abnormalities, such as palatal insufficiency. Up to 50% of individuals with KS have hearing loss. Although chronic otitis media is the most common cause, sensorineural hearing loss can rarely occur and some individuals have progressive hearing loss. Inner-ear malformations including Mondini dysplasia, vestibular enlargement, aplastic cochlea and semicircular canals, and aqueductal enlargement have been reported. At least one individual with a clinical diagnosis of Kabuki syndrome who had profound progressive sensorineural hearing loss received a cochlear implant with a reported improvement in quality of life [Vesseur et al 2016]. #### Craniofacial Cleft lip and/or palate affects approximately one third of individuals with KS. Submucous cleft palate may be underascertained [Paik & Lim 2016]. Almost three quarters of affected individuals have a high-arched palate. As with all children with palatal abnormalities, feeding difficulties, frequent otitis media, and speech difficulties are more common in this subset of affected individuals. A number of individuals have lower lip pits [Porntaveetus et al 2018]. The typical facial features (elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; and large, prominent, or cupped ears) are considered part of the diagnostic criteria of KS and are therefore present in almost all individuals who have a clinical diagnosis of KS. A majority of individuals with a molecularly confirmed diagnosis of KS are also found to have these characteristic facial features [Adam et al 2019]. #### Dental A number of different dental anomalies in individuals with KS have been noted [Porntaveetus et al 2018]. Hypodontia is most common, with absent lateral upper incisors, absent lower incisors, ectopic upper six-year molars, and missing second premolars also being described. Abnormally shaped teeth (e.g., flathead-screwdriver-shaped appearance of the upper incisors), small teeth, widely spaced teeth, and malocclusion may also be seen. #### Cardiovascular Approximately 70% of individuals with KS have a congenital heart defect [Digilio et al 2017]. Many heart defects have been described in association with KS, but left-sided obstructive lesions, especially coarctation of the aorta, are the most common. Other defects may include (alone or in combination): septal defects, bicuspid aortic valve, mitral valve anomalies, conotruncal heart defects, and hypoplastic left heart syndrome. Hypertrophic cardiomyopathy and aortic root dilation have been occasionally reported. #### Respiratory Eventration of the diaphragm has been rarely reported [Zarate et al 2012]. Laryngeal abnormalities may pose problems with anesthesia (see Management, Treatment of Manifestations). #### Gastrointestinal Feeding difficulties are quite common (~70%) and may be related to hypotonia, poor oromotor coordination, and swallowing difficulties [Cheon & Ko 2015] that may require nasogastric or gastrostomy tube placement. Many individuals with KS have gastroesophageal reflux. Abnormalities involving the gastrointestinal system are not common in KS; however, the following may be seen rarely: * Anorectal anomalies including imperforate anus, anovestibular fistula, and anteriorly placed anus [Siminas et al 2015] * Congenital diaphragmatic hernia and eventration of the diaphragm * Cholestasis from a variety of causes * Chronic diarrhea from malabsorption and/or celiac disease #### Genitourinary Renal and urinary tract anomalies are seen in more than 25% of affected individuals [Courcet et al 2013]. Common renal findings include anomalies of kidney position and ascent (single fused kidneys, crossed fused renal ectopia) and renal dysplasia; hydronephrosis is the most common urinary tract finding. Other anomalies may include ureteropelvic junction obstruction and duplication of the collecting system. Hypospadias and cryptorchidism can occur in males [Bögershausen & Wollnik 2013]. #### Musculoskeletal Joint hypermobility is seen in 50%-75% of individuals with KS. Joint dislocations, especially involving the hips, patellae, and shoulders, are not uncommon. As in most conditions with joint laxity, this finding improves with age. * Variable degrees of scoliosis and kyphosis are seen and may be associated with vertebral anomalies (hemivertebrae, butterfly vertebrae, sagittal clefts). * Persistent fetal fingertip pads are considered one of the five cardinal manifestations of KS and are therefore found in a large proportion of affected individuals [Adam et al 2019]. * Absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can also be observed, although analysis for these features is not frequently done in current clinical practice. * Other hand findings (brachydactyly V, brachymesophalangy, and clinodactyly of the 5th digits) can also be seen, but these features rarely lead to clinical issues and are used more as a clue to the diagnosis (see Suggestive Findings). #### Endocrine Premature thelarche in girls is the most common endocrine abnormality described (16%-41%) [Banka et al 2012]. This finding does not represent premature puberty and is likely to resolve with time. Short stature, even absent growth hormone deficiency, has responded to growth hormone therapy without exacerbating disproportion: * In a study by Schott et al [2016a], average adult height without growth hormone therapy was between -2.99 SD (standard deviations) and -1.08 SD in males and between -5.57 and -1.47 SD in females. * After one year of growth hormone treatment, the average height standard deviation score improved from -2.40 to -1.69 [Schott et al 2016b]. * Those who initiated growth hormone therapy at an earlier age received the most benefit in terms of catch-up growth. * After one year of growth hormone therapy, body proportions were not significantly affected. Hyperinsulinism is likely underascertained in affected individuals and may be a presenting sign in neonates. * Failure to recognize and treat hyperinsulinism in a timely fashion can lead to irreversible neurologic damage and exacerbate developmental issues. * It is estimated that about 1% of neonates with hyperinsulinism have a diagnosis of Kabuki syndrome [Yap et al 2019]. Other. The following findings have been described in a small subset of individuals with KS in the literature: * Adrenal insufficiency * Combined pituitary hormone deficiency * Diabetes insipidus * Frank growth hormone deficiency * Hypothyroidism * Primary ovarian dysfunction * True precocious puberty #### Immunologic Immune dysfunction including both humoral immune deficiency and autoimmune disease has been described [Lindsley et al 2016]. Clinical findings in affected individuals may mimic those seen in individuals with common variable immune deficiency. * Frequent and recurrent infections, such as frequent sinopulmonary infections and recurrent otitis media, are found in a majority of affected individuals [Lin et al 2015]. * Hypogammaglobulinemia and IgA deficiency are common. * Diminished B-cell populations have also been reported [Lindsley et al 2016]. * Autoimmune conditions such as vitiligo, immune thrombocytopenia (ITP), hemolytic anemia, and even diabetes mellitus have also been described in affected individuals, most commonly in childhood or adolescence [Brackmann et al 2013, Giordano et al 2014, Lindsley et al 2016]. #### Neurologic Most children with KS are hypotonic and joint laxity may be a contributing factor. * Hypotonia may contribute to significant feeding problems in infancy (see Growth). As with other conditions in which hypotonia is a feature, this finding tends to improve with age. * Seizures are seen more frequently in KS (10%-39%) than in the general population and represent a spectrum of findings including infantile spasms [Liu et al 2015]. Good seizure control is generally achieved with standard anti-seizure medications. #### Neuroimaging Although most people with Kabuki syndrome undergo brain imaging at some point for indications such as seizures and/or developmental delay, major structural brain anomalies are rare. Reported findings have included the following [Banka et al 2015, Liu et al 2015, Teranishi et al 2018]: * Cerebellar and brain stem atrophy * Dandy-walker malformation * Delayed myelination * Mild ventriculomegaly Note: Prior to the identification of the genetic causes of KS, symptomatic Chiari I malformation was reported in multiple affected individuals [Ciprero et al 2005]. This specific finding has not been highlighted in recent publications on individuals with a confirmed molecular diagnosis. However, this does not preclude symptomatic Chiari I malformation as a clinical feature in individuals with molecularly confirmed KS. #### Development Intellectual disability, usually in the mild to moderate range, has been reported in a majority of individuals; however, reports of rare individuals with pathogenic variants in either KMT2D or KDM6A who have IQ levels above 70 have been published [Lederer et al 2012, Cheon et al 2014, Lederer et al 2014, Morgan et al 2015, Butcher et al 2017, Lehman et al 2017, Sakata et al 2017, Caciolo et al 2018]. Most individuals with KS are able to speak and to ambulate. * Average IQ scores in individuals with KMT2D pathogenic variants range from the high 50s to high 60s [Lehman et al 2017, Caciolo et al 2018]. Rare case reports of affected individuals who are basically nonverbal have been published [Lindgren et al 2013, Miyake et al 2013]. * Neuropsychiatric testing has identified deficits in both comprehension and production of verbal language, but this may be related, in part, to hearing, neurologic, orofacial, and cognitive deficits [Morgan et al 2015]. * No specific language profile has been identified. However, all language subdomains including syntax, morphology, pragmatics, and semantics may be affected. * Dysarthria (reduced rate and stress, distorted pitch, harsh vocal quality, hypernasality, and imprecise consonants) has also been described. * On formal neuropsychiatric testing, individuals with KS tend to score better in the areas of vocabulary comprehension and working memory and score lower in the areas of nonverbal reasoning and processing speed [Lehman et al 2017]. * In terms of adaptive skills, individuals with KS have more difficulties with daily living than with communication. * An educational environment that stresses audio-verbal learning over visual learning may beneficial (see Ophthalmologic). #### Behavior Individuals with KS tend to be described as pleasant and outgoing. * Attention-deficit disorder and/or hyperactivity are present in a subset of affected individuals. Other behavioral problems including anxiety disorder, self-harm, and sleep disturbance have been rarely reported [Banka et al 2015, Caciolo et al 2018]. * Autism continues to be a rare but described finding in affected individuals [Paděrová et al 2016, Sertçelik et al 2016]. Whether this is truly part of the spectrum of KS or is a coincidental secondary diagnosis due to the frequency of autism spectrum disorders in the general population remains to be seen. #### Benign Tumors Pilomatricomas, benign tumors of the hair shaft that commonly occur on the head and neck, have been described rarely in those with Kabuki syndrome [Bernier et al 2017]. In most cases, removal by a dermatologist is sufficient. #### Malignancies Although pathogenic somatic variants in KMT2D and KDM6A have been seen in a variety of sporadic tumors [Huether et al 2014], malignancies (primarily as case reports) have only been described in a few individuals with KS. There is no clear evidence of a significant predisposition to the development of cancer in individuals with KS [Roma et al 2015, Karagianni et al 2016]. Therefore, no tumor screening protocol for individuals with KS has been developed. ### Phenotype Correlations by Gene KMT2D * Those with a KMT2D pathogenic variant are more likely to have the distinctive Kabuki facial phenotype, which may reflect the fact that a portion of those without a KMT2D pathogenic variant may indeed have been misdiagnosed. * In general, those with a KMT2D pathogenic variant are also more likely to have renal anomalies, feeding problems, premature thelarche in females, joint dislocations, and palatal anomalies than are those without a KMT2D pathogenic variant [Bögershausen & Wollnik 2013, Courcet et al 2013]. KDM6A. The following are more common in individuals with a pathogenic variant in KDM6A [Banka et al 2015, Yap et al 2019]: * Hypoglycemia due to hyperinsulinism * Hypertrichosis * Long halluces * Large central incisors Affected males are more likely to have moderate-to-severe developmental delay / cognitive impairment than are females, who may have mild-to-moderate intellectual disability. In general, females with a pathogenic variant in KDM6A tend to have milder features than affected males, despite the fact that KDM6A escapes X-chromosome inactivation [Banka et al 2015]. ### Genotype-Phenotype Correlations KMT2D * Heterozygous pathogenic missense variants in the terminal regions of KMT2D may increase the risk for autoimmune disease [Lindsley et al 2016]. * Those with whole-gene deletion of KMT2D or pathogenic truncating variants that occur in the first half of the gene may have more severe intellectual disability [Lehman et al 2017]. KDM6A * Based on small numbers, pathogenic variants at the 3' end of the gene are more common than those at the 5' end [Bögershausen et al 2016]. * Splice site variants, as compared to nonsense, missense, and small in/dels, are the most common type of singe-nucleotide variant [Bögershausen et al 2016]. ### Penetrance Penetrance for pathogenic variants in KMT2D appears to be complete; not enough information is available to make any conclusions regarding penetrance for those with pathogenic variants in KDM6A. Variable expressivity may lead to underascertainment of mildly affected individuals. ### Prevalence KS has been reported in almost all ethnic groups. The prevalence in Japan is estimated at 1:32,000 [Niikawa et al 1988]. The prevalence outside Japan presumably approximates that seen in the Japanese population. White et al [2004] calculated a minimum birth incidence of 1:86,000 in Australia and New Zealand. ## Differential Diagnosis ### Table 2. Disorders to Consider in the Differential Diagnosis of Kabuki Syndrome (KS) View in own window DisorderGene(s)MOIClinical Features Overlapping w/KSDistinguishing from KS CHARGE syndromeCHD7AD * Cleft palate * Congenital heart defects * Ocular coloboma * Growth restriction In CHARGE syndrome: * Square face * Short, wide ear w/little or no earlobe * Prominent columella * Broad nasal root In KS: fingertip pads 22q11.2 deletion syndromeSee footnote 1AD * Cleft palate * Congenital heart defects * Urinary tract anomalies In 22q11 deletion syndrome: * Short & narrow palpebral fissures w/hooded eyelids * Bulbous nasal tip * Small, C-shaped ears w/overfolded superior &/or lateral helices IRF6-related disorders 2IRF6AD * Cleft lip & palate * Lip pits * IRF6-related disorders are not assoc w/atypical growth & development, cardiac malformations, or typical Kabuki syndrome facies. * Pterygia is not expected in KS. Branchiootorenal (BOR) syndromeEYA1 SIX5 SIX1AD * Ear pits * Cupped ears * Hearing loss * Renal anomalies In BOR syndrome: * Otherwise normal craniofacies, growth, & development * Common renal anomalies incl renal hypoplasia &/or agenesis; (vs in KS: common renal anomalies incl hydronephrosis & malposition). * Branchial cleft cysts may be present (not reported in KS). Hypermobile Ehlers-Danlos syndrome (EDS)UnknownAD * Significant joint hypermobility (incl congenital hip dislocation & patellar dislocations) * Blue sclerae Hypermobile EDS & Larsen syndrome are not assoc w/major malformations involving other organ systems or the typical minor anomalies seen in KS. Larsen syndrome (see FLNB-Related Disorders)FLNBAD X-chromosome anomalies / variety of other chromosome anomaliesNASee footnote 3 * Similar facial features * Congenital heart defects * Growth retardation Chromosome anomalies can easily be distinguished from KS by chromosome analysis or CMA. Hardikar syndrome (OMIM 612726)Unknown * Prolonged hyperbilirubinemia * Cleft lip & palate Individuals w/KS do not typically develop pigmentary retinopathy or sclerosing cholangitis, as seen in Hardikar syndrome. AD = autosomal dominant; CHARGE = coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies; CMA = chromosomal microarray; MOI = mode of inheritance 1\. Deletion of genes within the DiGeorge chromosome region is the only genetic abnormality known to be associated with 22q11.2 deletion syndrome. 2\. IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome at the mild end to popliteal pterygium syndrome at the more severe end. 3\. Dependent on anomaly ## Management Comprehensive management guidelines for Kabuki syndrome (KS) were developed in 2010 but have not been updated; these guidelines are available online (pdf). ### Evaluations Following Initial Diagnosis To establish the extent of disease and the needs of an individual diagnosed with KS, the following evaluations are recommended if they have not already been completed: ### Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Kabuki Syndrome View in own window System/ConcernEvaluationComment GrowthMeasurement of height, weight, & head circumferenceFTT is a common sequela of feeding difficulties. OphthalmologicOphthalmology evaluationFor assessment of strabismus, refractive error, ptosis, & corneal abnormalities HearingBaseline audiology evaluationTo assess for conductive &/or sensorineural hearing loss MouthDirected evaluation of the palate for palatal anomaliesConsider referral to a craniofacial specialist if palatal anomalies are suspected. Consider dental evaluation for those age >3 yrs. CardiacEchocardiogram w/visualization of the aortic archTo assess for congenital heart defects incl coarctation of the aorta Consider EKG.If arrhythmia is suspected RespiratoryConsider chest radiographs to assess for diaphragmatic eventuation.In those w/respiratory issues, chronic cough, or recurrent pneumonia Gastrointestinal/ FeedingAssess nutritional status, feeding, GERD. * Consider assessment by feeding team &/or VFSS for those w/suspected dysphagia. * Infants may have FTT; adolescents & adults may have obesity. GenitourinaryBaseline renal ultrasoundTo evaluate for renal anomalies & hydronephrosis Physical examination for hypospadias &/or cryptorchidism in males MusculoskeletalConsider radiographs of the spine in those w/scoliosis.To assess for vertebral anomalies EndocrinologicAssess for hyperinsulinism. 1In neonates & infants w/persistent hypoglycemia Assess for hypothyroidism & growth hormone deficiency. 2In those w/abnormal growth velocity ImmunologicT cell count, T cell subsets, & serum immunoglobulin levels at time of diagnosis or at age 1 yr (whichever is later)Refer to immunologist if: * Levels are abnormal; or * Patient has history of recurrent infections. NeurologicEEGIn those w/suspected seizures Head MRITo evaluate for: * Structural brain malformation in those w/seizures * Chiari I malformation in those w/suggestive symptoms 3 Psychiatric/ BehavioralNeuropsychiatric evaluationScreen individuals age >12 mos for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. Miscellaneous/ OtherDevelopmental assessmentEvaluate motor, speech/language, general cognitive, & vocational skills. Consultation w/clinical geneticist &/or genetic counselor ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; FTT = failure to thrive; GERD = gastroesophageal reflux disease; VFSS = videofluoroscopic swallowing study 1\. This may include collection of a "critical sample," such as obtaining plasma levels of insulin, free fatty acids, beta-hydroxybutyrate, and glycemic response to glucagon during a period of low plasma glucose [Yap et al 2019]. 2\. Thyroid function tests may include free T4 and TSH levels. Assessment for growth hormone deficiency can be challenging and is best directed by an endocrinologist. Tests may include measurement of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3, in addition to consideration of a growth hormone stimulation test using either arginine or clonidine [Schott et al 2016b]. 3\. Symptoms may include headaches, ocular disturbances, otoneurologic disturbances, lower cranial nerve signs, cerebellar ataxia, spasticity, or seizures. ### Treatment of Manifestations ### Table 4. Treatment of Manifestations in Individuals with Kabuki Syndrome View in own window Manifestation/ConcernTreatmentConsiderations/Other Strabismus, refractive error, ptosis, lagophthalmosStandard treatment per ophthalmologist Hearing lossConsider: * Pressure equalizing tubes for those w/conductive hearing loss; * Hearing aids for those w/sensorineural hearing loss. 1 Refer to an ENT specialist & audiologist; see Hereditary Hearing Loss and Deafness Overview. Cleft lip &/or palateStandard treatment * Management through a specialized craniofacial clinic is ideal. * The palate may be shorter, which can lead to velopharyngeal insufficiency after typical cleft repair. Dental anomaliesOrthodontic referral if hypodontia or significant malocclusion is noted Congenital heart defects &/or arrhythmiaStandard treatment per cardiologistIt is unclear whether risk for aortic aneurysm is ↑; however, if catheterization or angioplasty is being considered, a potential ↑ risk of aortic aneurysm should be communicated to treating team. Feeding difficulties/GERDStandard treatment, which may incl thickening feeds & appropriate positioning after meals in infants & toddlersPharmacologic treatment for GERD may be considered. Consider gastrostomy tube.In those w/severe feeding difficulties &/or poorly coordinated suck & swallow Chronic diarrheaRefer to gastroenterologist.Consider evaluation for malabsorption &/or celiac disease. Hypospadias/ CryptorchidismStandard treatment per urologist Hyperinsulinism & hypothyroidismStandard treatment per endocrinologist Short statureConsider growth hormone therapy.Refer to endocrinologist. Recurrent infectionsIntravenous immunoglobulin therapy may be considered in those w/documented immunoglobulin deficiency.Refer to immunologist. Seizure disorderStandard antiepileptic treatment per neurologist Short statureGrowth hormone treatment may be considered. 2Refer to endocrinologist. Premature thelarcheNo treatment is warranted if there are no other signs of premature puberty. Need for anesthesiaCare in positioning during intubation due to joint laxity, which can affect the cervical spineEducate regarding potential structural airway anomalies that could make intubation difficult. 1\. Cochlear implants can also be considered, as per ENT and audiologist recommendations. 2\. Schott et al [2016a] See Therapies Under Investigation for discussion of histone deacetylase inhibitors and ketogenic diet as hypothesized treatments for individuals with KS. Currently neither of these therapies is recommended as a primary treatment for individuals with KS, outside of a clinical trial. #### Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states. Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed. Neurodevelopmental therapies should target language and motor abilities to improve daily living skills and behaviors [Caciolo et al 2018]. Ages 5-21 years * In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. * Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: * Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. * Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. #### Motor Dysfunction Gross motor dysfunction * Physical therapy is recommended to maximize mobility. * Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing. Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding due to poor oral motor control. #### Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat ADHD, when necessary. ### Surveillance ### Table 5. Recommended Surveillance for Individuals with Kabuki Syndrome View in own window System/ConcernEvaluationFrequency GrowthMeasurement of at least height & weight 1At each appointment OphthalmologicOphthalmology or optometry to assess visionAt least annually HearingHearing assessmentAt least annually MusculoskeletalClinical evaluation for scoliosisAt each appointment until skeletal maturity EndocrinologicThyroid function testsEvery 2-3 yrs ImmunologicAssessment of complete blood countEvery 2-3 yrs Miscellaneous/ OtherMonitor developmental progress & educational needs.At each visit during childhood & adolescence 1\. Adolescents and adults may develop obesity. ### Agents/Circumstances to Avoid In those with joint laxity, activities that increase the risk of joint damage (e.g., bouncing on a trampoline) should be avoided. ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Therapies Under Investigation Based on the function of KMT2D and KDM6A as regulators of chromatin expression (see Molecular Genetics), it has been hypothesized that histone deacetylase inhibitors (HDACi) could have a beneficial effect on individuals with Kabuki syndrome. Bjornsson et al [2014] created a mouse model of KS and found that treatment with HDACi normalized the structural and functional differences seen in certain brain areas in these affected mice, leading to improved neurogenesis and memory. This has yet to be tested in humans with KS, but clinical trials based on these mouse studies are in the planning phase. Since ketosis acts as an endogenous HDACi, others have hypothesized that placing individuals with KS on a ketogenic diet could improve their cognitive issues [Benjamin et al 2017]. This is NOT currently a recommended treatment for KS, although some families and physicians have trialed this diet independently. Since the ketogenic diet as a treatment for KS has not been studied as part of a clinical trial, no results of these types of experimental treatments are available in the peer-reviewed literature. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Kabuki Syndrome

c0796004

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK62111/

{"mesh": ["C537705"], "synonyms": ["Kabuki Make-Up Syndrome", "Niikawa-Kuroki Syndrome"]}

Neuroglycopenia is a shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia. Glycopenia affects the function of neurons, and alters brain function and behavior. Prolonged or recurrent neuroglycopenia can result in loss of consciousness, damage to the brain, and eventual death.[1][2][3] ## Contents * 1 Signs and symptoms * 2 Metabolic responses * 3 Neuroglycopenia without hypoglycemia * 4 References ## Signs and symptoms[edit] * Abnormal mentation, impaired judgment * Nonspecific dysphoria, anxiety, moodiness, depression, crying, fear of dying, suicidal thoughts * Negativism, irritability, belligerence, combativeness, rage * Personality change, emotional lability * Fatigue, weakness, apathy, lethargy, daydreaming * Confusion, amnesia, dizziness, delirium * Staring, "glassy" look, blurred vision, double vision * Automatic behavior * Difficulty speaking, slurred speech * Ataxia, incoordination, sometimes mistaken for "drunkenness" * Focal or general motor deficit, paralysis, hemiparesis * Paresthesia, headache * Stupor, coma, abnormal breathing * Generalized or focal seizures * Plasma glucose 20 mg/dL (1.1 mmol/L) or lower [4][5][6] Not all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by the severity of the hypoglycemia. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects or a hard-to-define malaise.[medical citation needed] The symptoms of a single person do tend to be similar from episode to episode. In the large majority of cases, hypoglycemia severe enough to cause seizures or unconsciousness can be reversed without obvious harm to the brain. Cases of death or permanent neurological damage occurring with a single episode have usually involved prolonged, untreated unconsciousness, interference with breathing, severe concurrent disease, or some other type of vulnerability. Nevertheless, brain damage or death has occasionally resulted from severe hypoglycemia. ## Metabolic responses[edit] This section does not cite any sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2015) (Learn how and when to remove this template message) Most neurons have the ability to use other fuels besides glucose (e.g. lactic acid, ketones). Knowledge of the "switchover" process is incomplete.[further explanation needed] The most severe neuroglycopenic symptoms occur with hypoglycemia caused by excess insulin because insulin reduces the availability of other fuels by suppressing ketogenesis and gluconeogenesis. A few types of specialized neurons, especially in the hypothalamus, act as glucose sensors, responding to changing levels of glucose by increasing or decreasing their firing rates. They can elicit a variety of hormonal, autonomic, and behavioral responses to neuroglycopenia. The hormonal and autonomic responses include release of counterregulatory hormones. There is some evidence that the autonomic nervous system can alter liver glucose metabolism independently of the counterregulatory hormones. Adjustment of efficiency of transfer of glucose from blood across the blood–brain barrier into the central nervous system represents a third form of compensation which occurs more gradually. Levels of glucose within the central nervous system are normally lower than the blood, regulated by an incompletely understood transfer process. Chronic hypoglycemia or hyperglycemia seems to result in an increase or decrease in efficiency of transfer to maintain CNS levels of glucose within an optimal range. In both young and old individuals, the brain may habituate to low glucose levels with a reduction of noticeable symptoms, sometimes despite neuroglycopenic impairment. In insulin-dependent diabetic patients this phenomenon is termed hypoglycemia unawareness and is a significant clinical problem when improved glycemic control is attempted. Another aspect of this phenomenon occurs in type I glycogenosis, when chronic hypoglycemia before diagnosis may be better tolerated than acute hypoglycemia after treatment is underway. ## Neuroglycopenia without hypoglycemia[edit] A rare metabolic disease of the blood-brain glucose transport system has been described in which severe neuroglycopenic effects occurred despite normal blood glucose levels. Low levels of glucose were discovered in the cerebrospinal fluid (CSF), a condition referred to as hypoglycorrhachia [or hypoglycorrhacia]. Hypoglycorrhachia is associated with Glucose transporter type 1 GLUT1 deficiency syndrome (GLUT1DS).[7] Perhaps a much more common example of the same phenomenon occurs in the people with poorly controlled type 1 diabetes who develop symptoms of hypoglycemia at levels of blood glucose which are normal for most people. ## References[edit] 1. ^ Ray, Kausik K; Seshasai, Sreenivasa Rao Kondapally; Wijesuriya, Shanelle; Sivakumaran, Rupa; Nethercott, Sarah; Preiss, David; Erqou, Sebhat; Sattar, Naveed (2009). "Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials". The Lancet. 373 (9677): 1765–72. doi:10.1016/S0140-6736(09)60697-8. PMID 19465231. 2. ^ "Applied physiology of glucose control", K Beardsall et al. 2006[page needed] 3. ^ http://www.medscape.com/viewarticle/728284_2[full citation needed](registration required) 4. ^ http://www.healthdictionary.info/Neuroglycopenic.htm[full citation needed] 5. ^ Hypoglycemia~clinical at eMedicine 6. ^ http://www.mayoclinic.org/diseases-conditions/hypoglycemia/basics/symptoms/con-20021103[full citation needed] 7. ^ Klepper, Jörg (2008). "Glucose transporter deficiency syndrome (GLUT1DS) and the ketogenic diet". Epilepsia. 49 (Suppl 8): 46–9. doi:10.1111/j.1528-1167.2008.01833.x. PMID 19049586. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Neuroglycopenia

c0342311

wikipedia

https://en.wikipedia.org/wiki/Neuroglycopenia

{"umls": ["C0342311"], "wikidata": ["Q10336460"]}

A number sign (#) is used with this entry because homocystinuria-megaloblastic anemia, cblG complementation type, is caused by homozygous or compound heterozygous mutation in the MTR gene (156570) on chromosome 1q43. Description Homocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase. Clinical features are somewhat variable, but include delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE (236270) and CblG (Watkins and Rosenblatt, 1988). Most patients present in early infancy, but some patients with CblG have shown later onset (Outteryck et al., 2012). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (summary by Leclerc et al., 1996). CblE is caused by mutation in the MTRR gene (602568). Watkins and Rosenblatt (1989) commented on the clinical and biochemical heterogeneity in patients with cblE and cblG. Clinical Features Thomas et al. (1985) and Rosenblatt et al. (1987) reported a boy with methylcobalamin deficiency who presented at age 6 weeks with lethargy, staring spells and vomiting after varicella infection. He was hypotonic and unresponsive to stimuli and required intubation and ventilation. Findings included homocystinuria, hypomethioninemia, megaloblastic anemia, and normal serum folate and B12 levels. No methylmalonic aciduria was detected. Skin fibroblasts could not grow when methionine was replaced by homocysteine in the medium. Clinical response to vitamin B12 (hydroxocobalamin) was dramatic, with disappearance of homocystine and rise in blood methionine. Although the patient was originally thought to have CblE, methionine synthetase activity was decreased in patient fibroblasts when the assay was performed under both optimal and suboptimal reducing conditions, consistent with CblG. Gulati et al. (1996) analyzed cell lines derived from 2 cblG patients: 1 patient had onset in the first 4 months of life of severe neurologic dysfunction and homocystinuria, but no megaloblastic anemia, whereas the other patient had mental retardation, macrocytic anemia, and homocystinuria. Leclerc et al. (1996) studied cell lines from 2 Caucasian boys with methylcobalamin deficiency. One presented at age 3 months with failure to thrive, severe eczema, megaloblastic anemia, methylmalonic aciduria, homocystinuria, and methylmalonic aciduria; the other presented at age 4 years with developmental delay, tremors, gait instability, megaloblastic anemia, and homocystinuria. Kvittingen et al. (1997) reported a child with methionine synthase deficiency who presented with neonatal homocystinuria, hypomethioninemia, and severe neurologic symptoms, including developmental delay and seizures. Over an 8-year period both off and on treatment, the patient did not develop megaloblastic anemia. The activity of methionine synthase in fibroblasts was severely deficient, and formation of methylcobalamin from labeled cyanocobalamin was very low. Complementation studies indicated a cblG defect. In addition, the patient was homozygous for the 677C-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (607093.0003). Kvittingen et al. (1997) hypothesized that the MTHFR polymorphism protected the patient against anemia, and speculated that homozygosity for the MTHFR 677C-T mutation may cause the dissociation between hematologic and neurologic disease seen in some patients with vitamin B12 deficiency. Wilson et al. (1998) reported a brother and sister what they termed the 'cblG variant form' of methionine synthase deficiency, defined as no detectable methionine synthase activity and lack of binding of the cobalamin cofactor to the enzyme. The boy developed generalized seizures at 3 days of age, became progressively hypotonic, and developed respiratory failure at 10 weeks of age. An initial diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency (236250) was made on the basis of elevated plasma and urine homocysteine but low plasma methionine without macrocytic anemia. With treatment based on that diagnosis, he was well enough to be weaned from the respirator by 14 weeks of age. At 2 years of age, he had severe psychomotor retardation and microcephaly. A definitive diagnosis of methionine synthase deficiency was made by means of complementation analysis of cultured fibroblasts, which placed him in the cblG complementation group. He was subsequently treated with vitamin B12, betaine, and aspirin, and, at age 8 years, methionine was added. He required femoral osteotomies and bilateral adductor- and heel-cord release for neuromuscular hip dislocations and contractures. At age 10 years, he had short stature, microcephaly, rotary nystagmus, thin fingers, and spasticity. He smiled but was not able to sit or speak. The younger sister was found to have elevated plasma homocysteine and low methionine at 6 days of age. She also was presumed to have MTHFR deficiency and was started on therapy for that, but medications were discontinued by her mother after a few days because the child appeared to be doing well. At 3 months of age, she had seizures and respiratory distress, and medication was restarted. By 18 months of age, she was microcephalic and severely developmentally delayed. The diagnosis of cblG was established at 2 years of age, and she was treated in the same manner as her brother. At 9 years, she had short stature, microcephaly, rotary nystagmus, and pes planus. She was able to walk, responded to simple commands, and could speak a few words. Wilson et al. (1998) reported another boy with the so-called cblG variant. He presented with short stature, failure to thrive, progressive weakness, hypotonia, ocular nystagmus, jaundice, feeding difficulties, and diarrhea at 7 to 10 weeks of age (Wildin and Scott, 1992). He had severe megaloblastic anemia and neutropenia, homocysteinemia, hypomethioninemia, and formiminoglutamic aciduria without methylmalonic aciduria, which led to the diagnosis of a defect in methionine synthesis. Treatment resulted in improved metabolite levels, improvement of tone, and reduction of nystagmus, but poor growth, developmental delay, feeding difficulties requiring a gastrostomy, persistent anemia, and immunologic deficits were present at age 4 years. All 3 of these patients were found to have biallelic null mutations in the MTR gene (156570.0004-156570.0007), resulting in absence of the protein. Labrune et al. (1999) described a girl, born of first-cousin parents, who presented at the age of 18 months with megaloblastic anemia. One month later, she developed pulmonary hypertension and renal failure, leading after renal biopsy to the diagnosis of hemolytic uremic syndrome. Investigations showed reduced methionine synthase activity under standard reducing conditions, compatible with cblG complementation group. At age 13 years, this girl required hemodialysis after acute rejection of a renal transplant. ### Clinical Variability Carmel et al. (1988) described the cblG mutation in a 21-year-old white woman who had been misdiagnosed as having multiple sclerosis. Her manifestations closely resembled subacute combined degeneration. Mild macrocytic anemia was present. Throughout childhood she had been awkward and had poor coordination. Urinary homocystine excretion was elevated, plasma methionine was decreased, and urinary cystathionine excretion was normal. No methylmalonic acid was detected in the urine. This constellation of findings suggested either the cblE or cblG mutation. Complementation analysis showed complementation with fibroblasts from 2 patients with the cblE mutation, but not with cells from 2 patients with the cblG mutation, indicating that the patient's defect corresponded to the latter mutation. Methionine synthase activity in fibroblast extracts was subnormal. Outteryck et al. (2012) reported a young woman who presented at age 23 years with pain in the lower limbs. She had macrocytosis without anemia. Over the following 6 years, she developed progressive paraparesis and cognitive dysfunction. Brain and spinal cord MRI showed moderate cerebral atrophy with periventricular leukoencephalopathy and mild thinning of the cervical spinal cord; she also had optic neuropathy. Biochemical studies showed hyperhomocysteinemia, homocystinuria, hypomethioninemia, and absence of methylmalonic aciduria. Studies of cultured fibroblasts showed a defect in homocysteine remethylation, and complementation studies confirmed a cblG defect. Treatment with hydroxycobalamin and oral betaine resulted in rapid biochemical and slower clinical improvement. Outteryck et al. (2012) noted the unusual presentation of the disorder in this patient. Biochemical Features Patients with cblG have reduced methionine synthase activity even under standard assay conditions. Hall et al. (1989) presented evidence suggesting a defect in S-adenosyl methionine binding in cblG cells. Clinical Management Rosenblatt and Cooper (1990) commented that, whereas therapy with OH-Cbl has been effective in many cblE patients, a few of the cblG patients have been more difficult to treat and have required additional treatment with folates and betaine. Inheritance The transmission pattern of methionine synthase deficiency in the family reported by Wilson et al. (1998) was consistent with autosomal recessive inheritance. Molecular Genetics Gulati et al. (1996) analyzed the molecular basis for methionine synthase deficiency in cell lines derived from 2 cblG patients. The 79/76 cell line had low levels of methionine synthase activity and a diminished level of methionine synthase mRNA. In the WG1892 cell line, they detected compound heterozygous mutations in the MTR gene (156570.0001 and 156570.0002). Leclerc et al. (1996) cloned the gene for methionine synthase and demonstrated mutations in this gene in 2 cblG cell lines which had deficient methionine synthase enzyme activity (see 156570.0003). In 2 sibs with severe cblG, Wilson et al. (1998) identified compound heterozygosity for 2 null mutations in the MTR gene (156570.0004 and 156570.0005). Another patient with a severe form of the disorder was compound heterozygous for 2 null mutations in the MTR gene (156570.0006 and 156570.0007). In a panel of 21 patients with methylcobalamin deficiency G (cblG) disorder, Watkins et al. (2002) identified 13 novel mutations. These included 5 deletions and 2 nonsense mutations that resulted in synthesis of truncated proteins that lacked portions critical for enzyme function. In addition, a previously described missense mutation, P1173L (156570.0001), was detected in 16 patients in an expanded panel of 24 patients with cblG. Analysis of haplotypes constructed using sequence polymorphisms identified within the MTR gene demonstrated that this mutation, a C-to-T transition in a CpG island, has occurred on at least 2 separate genetic backgrounds. History A possible case of deficiency of methionine synthase was reported by Arakawa et al. (1967), but the evidence was at best equivocal (Mudd, 1977). The patient was a 6-month-old girl with mental retardation, megaloblastic anemia, and high folate activity in the serum and red cells. Assays of liver showed the specific activity of N-5-methyltetrahydrofolate-homocysteine methyltransferase, measured in the presence of cyanocobalamin, to be 32 to 45% of that in control liver. The patient was not homocystinuric. INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Eyes \- Nystagmus (in some patients) \- Blindness (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Hypotonia \- Abnormal gait \- Seizures \- Cerebral atrophy HEMATOLOGY \- Megaloblastic anemia LABORATORY ABNORMALITIES \- Homocystinuria \- Hyperhomocystinemia \- Hypomethioninemia MISCELLANEOUS \- Onset in infancy \- Later onset has been reported \- Symptoms are responsive to cobalamin treatment MOLECULAR BASIS \- Caused by mutation in the methionine synthase gene (MTR, 156570.0001}) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA, cblG COMPLEMENTATION TYPE

c1855128

omim

https://www.omim.org/entry/250940

{"mesh": ["C565394"], "omim": ["250940"], "orphanet": ["2170", "622"], "synonyms": ["Alternative titles", "HOMOCYSTINURIA-MEGALOBLASTIC ANEMIA DUE TO DEFECT IN COBALAMIN METABOLISM, cblG COMPLEMENTATION TYPE", "METHYLCOBALAMIN DEFICIENCY, cblG TYPE", "METHIONINE SYNTHASE DEFICIENCY"], "genereviews": ["NBK1328"]}

Disease of arteries, arterioles and capillaries This article is about the vascular phenomenon. For other uses, see Embolism (disambiguation). Not to be confused with ebullism or aneurysm. Embolism Micrograph of embolic material in the artery of a kidney. The kidney was surgically removed because of cancer. H&E stain. SpecialtyVascular surgery An embolism is the lodging of an embolus, a blockage-causing piece of material, inside a blood vessel.[1] The embolus may be a blood clot (thrombus), a fat globule (fat embolism), a bubble of air or other gas (gas embolism), amniotic fluid (amniotic fluid embolism), or foreign material. An embolism can cause partial or total blockage of blood flow in the affected vessel.[2] Such a blockage (a vascular occlusion) may affect a part of the body distant from the origin of the embolus. An embolism in which the embolus is a piece of thrombus is called a thromboembolism. An embolism is usually a pathological event, i.e., accompanying illness or injury. Sometimes it is created intentionally for a therapeutic reason, such as to stop bleeding or to kill a cancerous tumor by stopping its blood supply. Such therapy is called embolization. ## Contents * 1 Classification * 1.1 Arterial * 1.2 Venous * 1.3 Paradoxical (venous to arterial) * 1.4 Direction * 2 Etymology * 3 See also * 4 References * 5 External links ## Classification[edit] There are different types of embolism, some of which are listed below. Embolism can be classified based on where it enters the circulation, either in arteries or in veins. Arterial embolism are those that follow and, if not dissolved on the way, lodge in a more distal part of the systemic circulation. Sometimes, multiple classifications apply; for instance a pulmonary embolism is classified as an arterial embolism as well,[3] in the sense that the clot follows the pulmonary artery carrying deoxygenated blood away from the heart. However, pulmonary embolism is generally classified as a form of venous embolism, because the embolus forms in veins, e.g. deep vein thrombosis. ### Arterial[edit] Main article: Arterial embolism Arterial embolism can cause occlusion in any part of the body. It is a major cause of infarction (tissue death from blockage of the blood supply). An embolus lodging in the brain from either the heart or a carotid artery will most likely be the cause of a stroke due to ischemia. An arterial embolus might originate in the heart (from a thrombus in the left atrium, following atrial fibrillation or be a septic embolus resulting from endocarditis). Emboli of cardiac origin are frequently encountered in clinical practice. Thrombus formation within the atrium occurs mainly in patients with mitral valve disease, and especially in those with mitral valve stenosis (narrowing), with atrial fibrillation (AF). In the absence of AF, pure mitral regurgitation has a low incidence of thromboembolism. The risk of emboli forming in AF depends on other risk factors such as age, hypertension, diabetes, recent heart failure, or previous stroke. Thrombus formation can also take place within the ventricles, and it occurs in approximately 30% of anterior-wall myocardial infarctions, compared with only 5% of inferior ones. Some other risk factors are poor ejection fraction (<35%), size of infarct, and the presence of AF. In the first three months after infarction, left-ventricle aneurysms have a 10% risk of emboli forming. Patients with prosthetic valves also carry a significant increase in risk of thromboembolism. Risk varies, based on the valve type (bioprosthetic or mechanical); the position (mitral or aortic); and the presence of other factors such as AF, left-ventricular dysfunction, and previous emboli. Emboli often have more serious consequences when they occur in the so-called "end circulation": areas of the body that have no redundant blood supply, such as the brain and heart. ### Venous[edit] 3D Medical Animation still shot showing Pulmonary Embolism Further information: Pulmonary embolism Further information: Thrombosis prophylaxis Assuming a normal circulation, an embolus formed in a systemic vein will always impact in the lungs, after passing through the right side of the heart. This will form a pulmonary embolism that will result in a blockage of the main artery of the lung and can be a complication of deep-vein thrombosis. The most common sites of origin of pulmonary emboli are the femoral veins. The deep veins of the calf are the most common sites of actual thrombi. ### Paradoxical (venous to arterial)[edit] In paradoxical embolism, also known as crossed embolism, an embolus from the veins crosses to the arterial blood system. This is generally found only with heart problems such as septal defects (holes in the cardiac septum) between the atria or ventricles. The most common such abnormality is patent foramen ovale, occurring in about 25% of the adult population, but here the defect functions as a valve which is normally closed, because pressure is slightly higher in the left side of the heart. Sometimes, for example if a patient coughs just when an embolus is passing, it might cross to the arterial system. ### Direction[edit] The direction of the embolus can be one of two types: * Anterograde * Retrograde In anterograde embolism, the movement of emboli is in the direction of blood flow. In retrograde embolism, the emboli move in opposition to the blood flow direction; this is usually significant only in blood vessels with low pressure (veins) or with emboli of high weight. ## Etymology[edit] The word embolism comes from the Greek ἐμβολισμός, meaning "interpressure". ## See also[edit] * Embolectomy ## References[edit] 1. ^ Dorland's (2012). Dowland's Illustrated Medical Dictionary (32nd ed.). Elsevier. p. 606. ISBN 978-1-4160-6257-8. 2. ^ Britannica Concise Encyclopedia 2007 3. ^ MedlinePlus > Arterial embolism Sean O. Stitham, MD and David C. Dugdale III, MD. Also reviewed by David Zieve, MD. Reviewed last on: 5/8/2008. Alternative link: [1] ## External links[edit] Classification D * ICD-10: I74, I82, O88, T79.0-T79.1 * ICD-9-CM: 444.9 * MeSH: D004617 * DiseasesDB: 18165 * SNOMED CT: 414086009 * MR of Fat Embolism Brain Injury from Fat Embolism * v * t * e Cardiovascular disease (vessels) Arteries, arterioles and capillaries Inflammation * Arteritis * Aortitis * Buerger's disease Peripheral artery disease Arteriosclerosis * Atherosclerosis * Foam cell * Fatty streak * Atheroma * Intermittent claudication * Critical limb ischemia * Monckeberg's arteriosclerosis * Arteriolosclerosis * Hyaline * Hyperplastic * Cholesterol * LDL * Oxycholesterol * Trans fat Stenosis * Carotid artery stenosis * Renal artery stenosis Other * Aortoiliac occlusive disease * Degos disease * Erythromelalgia * Fibromuscular dysplasia * Raynaud's phenomenon Aneurysm / dissection / pseudoaneurysm * torso: Aortic aneurysm * Abdominal aortic aneurysm * Thoracic aortic aneurysm * Aneurysm of sinus of Valsalva * Aortic dissection * Aortic rupture * Coronary artery aneurysm * head / neck * Intracranial aneurysm * Intracranial berry aneurysm * Carotid artery dissection * Vertebral artery dissection * Familial aortic dissection Vascular malformation * Arteriovenous fistula * Arteriovenous malformation * Telangiectasia * Hereditary hemorrhagic telangiectasia Vascular nevus * Cherry hemangioma * Halo nevus * Spider angioma Veins Inflammation * Phlebitis Venous thrombosis / Thrombophlebitis * primarily lower limb * Deep vein thrombosis * abdomen * Hepatic veno-occlusive disease * Budd–Chiari syndrome * May–Thurner syndrome * Portal vein thrombosis * Renal vein thrombosis * upper limb / torso * Mondor's disease * Paget–Schroetter disease * head * Cerebral venous sinus thrombosis * Post-thrombotic syndrome Varicose veins * Gastric varices * Portacaval anastomosis * Caput medusae * Esophageal varices * Hemorrhoid * Varicocele Other * Chronic venous insufficiency * Chronic cerebrospinal venous insufficiency * Superior vena cava syndrome * Inferior vena cava syndrome * Venous ulcer Arteries or veins * Angiopathy * Macroangiopathy * Microangiopathy * Embolism * Pulmonary embolism * Cholesterol embolism * Paradoxical embolism * Thrombosis * Vasculitis Blood pressure Hypertension * Hypertensive heart disease * Hypertensive emergency * Hypertensive nephropathy * Essential hypertension * Secondary hypertension * Renovascular hypertension * Benign hypertension * Pulmonary hypertension * Systolic hypertension * White coat hypertension Hypotension * Orthostatic hypotension * v * t * e Pathology of pregnancy, childbirth and the puerperium Pregnancy Pregnancy with abortive outcome * Abortion * Ectopic pregnancy * Abdominal * Cervical * Interstitial * Ovarian * Heterotopic * Embryo loss * Fetal resorption * Molar pregnancy * Miscarriage * Stillbirth Oedema, proteinuria and hypertensive disorders * Gestational hypertension * Pre-eclampsia * HELLP syndrome * Eclampsia Other, predominantly related to pregnancy Digestive system * Acute fatty liver of pregnancy * Gestational diabetes * Hepatitis E * Hyperemesis gravidarum * Intrahepatic cholestasis of pregnancy Integumentary system / dermatoses of pregnancy * Gestational pemphigoid * Impetigo herpetiformis * Intrahepatic cholestasis of pregnancy * Linea nigra * Prurigo gestationis * Pruritic folliculitis of pregnancy * Pruritic urticarial papules and plaques of pregnancy (PUPPP) * Striae gravidarum Nervous system * Chorea gravidarum Blood * Gestational thrombocytopenia * Pregnancy-induced hypercoagulability Maternal care related to the fetus and amniotic cavity * amniotic fluid * Oligohydramnios * Polyhydramnios * Braxton Hicks contractions * chorion / amnion * Amniotic band syndrome * Chorioamnionitis * Chorionic hematoma * Monoamniotic twins * Premature rupture of membranes * Obstetrical bleeding * Antepartum * placenta * Circumvallate placenta * Monochorionic twins * Placenta accreta * Placenta praevia * Placental abruption * Twin-to-twin transfusion syndrome Labor * Amniotic fluid embolism * Cephalopelvic disproportion * Dystocia * Shoulder dystocia * Fetal distress * Locked twins * Nuchal cord * Obstetrical bleeding * Postpartum * Pain management during childbirth * placenta * Placenta accreta * Preterm birth * Postmature birth * Umbilical cord prolapse * Uterine inversion * Uterine rupture * Vasa praevia Puerperal * Breastfeeding difficulties * Low milk supply * Cracked nipples * Breast engorgement * Childbirth-related posttraumatic stress disorder * Diastasis symphysis pubis * Postpartum bleeding * Peripartum cardiomyopathy * Postpartum depression * Postpartum psychosis * Postpartum thyroiditis * Puerperal fever * Puerperal mastitis Other * Concomitant conditions * Diabetes mellitus * Systemic lupus erythematosus * Thyroid disorders * Maternal death * Sexual activity during pregnancy * Category * v * t * e Trauma Principles * Polytrauma * Major trauma * Traumatology * Triage * Resuscitation * Trauma triad of death Assessment Clinical prediction rules * Revised Trauma Score * Injury Severity Score * Abbreviated Injury Scale * NACA score Investigations * Diagnostic peritoneal lavage * Focused assessment with sonography for trauma Management Principles * Advanced trauma life support * Trauma surgery * Trauma center * Trauma team * Damage control surgery * Early appropriate care Procedures * Resuscitative thoracotomy Pathophysiology Injury * MSK * Bone fracture * Joint dislocation * Degloving * Soft tissue injury * Resp * Flail chest * Pneumothorax * Hemothorax * Diaphragmatic rupture * Pulmonary contusion * Cardio * Internal bleeding * Thoracic aorta injury * Cardiac tamponade * GI * Blunt kidney trauma * Ruptured spleen * Neuro * Penetrating head injury * Traumatic brain injury * Intracranial hemorrhage Mechanism * Blast injury * Blunt trauma * Burn * Penetrating trauma * Crush injury * Stab wound * Ballistic trauma * Electrocution Region * Abdominal trauma * Chest trauma * Facial trauma * Head injury * Spinal cord injury Demographic * Geriatric trauma * Pediatric trauma Complications * Posttraumatic stress disorder * Wound healing * Acute lung injury * Crush syndrome * Rhabdomyolysis * Compartment syndrome * Contracture * Volkmann's contracture * Embolism * air * fat * Chronic traumatic encephalopathy * Subcutaneous emphysema *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Embolism

c0013922

wikipedia

https://en.wikipedia.org/wiki/Embolism

{"mesh": ["D004617"], "icd-9": ["444.9"], "icd-10": ["T79.0", "O88", "I82", "I74", "T79.1"], "wikidata": ["Q275466"]}

Gitelman syndrome Other namesPrimary renal tubular hypokalemic hypomagnesemia with hypocalciuria A model of transport mechanisms in the distal convoluted tubule. Sodium chloride (NaCl) enters the cell via the apical thiazide-sensitive NCC and leaves the cell through the basolateral Cl− channel (ClC-Kb), and the Na+/K+-ATPase. Indicated also are the recently identified magnesium channel TRPM6 in the apical membrane, and a putative Na/Mg exchanger in the basolateral membrane. These transport mechanisms play a role in familial hypokalemia-hypomagnesemia or Gitelman syndrome. SpecialtyEndocrinology Anatomy of a Nephron; functional unit of the kidney[1] Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH.[2] The disorder is caused by genetic mutations resulting in improper function of the thiazide-sensitive sodium-chloride symporter (also known as NCC, NCCT, or TSC) located in the distal convoluted tubule of the kidney.[2] The distal convoluted tubule of the kidney serves a minimal role in salt absorption and a greater role in managing the excretion of electrolytes like magnesium and calcium to produce more concentrated urine.[3] Genetic mutations along the sodium chloride symporter, lead to inadequate transport of multiple electrolytes along this channel such as sodium, chloride, calcium, magnesium, and potassium. The net effect is an electrolyte imbalance consistent with thiazide diuretic therapy Gitelman syndrome was formerly considered a subset of Bartter syndrome until the distinct genetic and molecular bases of these disorders were identified. Bartter syndrome is also an autosomal recessive hypokalemic metabolic alkalosis, but it derives from a mutation to the NKCC2 found in the thick ascending limb of the loop of Henle.[4] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 History * 7 References * 8 External links ## Signs and symptoms[edit] Affected individuals may not have symptoms in some cases.[2] Symptomatic individuals present with symptoms identical to those of patients who are on thiazide diuretics, given that the affected transporter is the exact target of thiazides,[5] (unlike in Bartter syndrome, in which patients present as though on loop diuretics). Clinical signs of Gitelman syndrome include a high blood pH in combination with low levels of chloride, potassium, and magnesium in the blood and decreased calcium excretion in the urine.[2] In contrast to people with Gordon's syndrome, those affected by Gitelman syndrome generally have low or normal blood pressure. Individuals affected by Gitelman syndrome often complain of severe muscle cramps or weakness, numbness, thirst, waking up at night to urinate, salt cravings, abnormal sensations, chondrocalcinosis, or weakness expressed as extreme fatigue or irritability.[2] Though cravings for salt are most common and severe, cravings for sour foods (e.g. vinegar, lemons, and sour figs) have been noted in some persons affected.[6] More severe symptoms such as seizures, tetany, and paralysis have been reported.[2] Abnormal heart rhythms and a prolonged QT interval can be detected on electrocardiogram[2] and cases of sudden cardiac death have been reported due to low potassium levels. Quality of life is decreased in Gitelman syndrome[7] Phenotypic variations observed among patients probably result from differences in their genetic background and may depend on which particular amino acid in the NCCT protein has been mutated. In a study by Riviera-Munoz et al. identified a subset of individuals with Gitelman syndrome with a severe phenotypic expression. The clinical manifestations observed in this group were neuromuscular manifestations, growth retardation, and ventricular arrhythmias. The patients were mostly male and were found to have at least one allele of a splice defect on the SLC12A3 gene.[8] ## Cause[edit] Gitelman syndrome has an autosomal recessive pattern of inheritance. The sodium chloride symporter is a protein made up of 1021 amino acids and 12 transmembrane domains.[9] Mutations that occur on the SLC12A3 gene range from missense, nonsense, frame-shift and splice-site mutations which occur throughout the gene.[9] Most cases of Gitelman syndrome are linked to inactivating mutations in the SLC12A3 gene, resulting in a loss of function of the thiazide-sensitive sodium-chloride co-transporter (NCCT).[2] This genetic mutation in SLC12A3 is present in 80% of adults with Gitelman syndrome.[2] More than 180 mutations of this transporter protein have been described.[2] This cell membrane protein participates in the control of ion homeostasis at the distal convoluted tubule portion of the nephron. Loss of this transporter also has the indirect effect of increasing calcium reabsorption in a transcellular fashion. This has been suggested to be the result of a putative basolateral Na+/Ca2+ exchanger and apical calcium channel.[citation needed] When the sodium-chloride cotransporter (NCCT) is inactivated, continued action of the basolateral Na+/K+-ATPase creates a favourable sodium gradient across the basolateral membrane. This increases the reabsorption of divalent cations by secondary active transport. It is currently unknown why calcium reabsorption is increased while magnesium absorption is decreased, often leading to a low level of magnesium in the blood .[citation needed] A secondary effect of the inactivated sodium-chloride cotransporter is the subsequent activation of the renin-angiotensin aldosterone system (RAAS). RAAS activation is a byproduct of the failure of the distal convoluted tubule in reuptaking electrolytes specifically sodium and chloride leading to cellular dehydration. RAAS attempts to compensate for this dehydration resulting in low serum blood potassium.[10] A small percentage of Gitleman syndrome cases can be attributed to mutations in the CLCNKB gene. This gene is related to the function of the renal chloride channel CLC-Kb located at the basolateral membrane of cells in the thick ascending limb of the Henle's loop. Genetic variations or mutations in the CLCNKB was initially linked to classic Bartter Syndrome. When mutations are not found within the SLC12A3 gene, screening can be done to rule out involvement of CLCNKB gene.[9] Gitelman syndrome is inherited in an autosomal-recessive manner: one defective allele has to be inherited from each parent. ## Diagnosis[edit] Diagnosis of Gitelman syndrome can be confirmed after eliminating of other common pathological sources of hypokalemia and metabolic alkalosis.[10] A complete metabolic panel (CMP) or basic metabolic panel (BMP) can be used to evaluate serum electrolyte levels. Renin and aldosterone can be tested in the blood. Electrolyte measurement and aldosterone levels can be done via urine.[10] The pathognomonic clinical markers include low serum levels of potassium, sodium, chloride, and magnesium in the blood as a result of urinary excretion.[11] Urinary fractional excretion potassium is high or inappropriately normal in the context of hypokalaemia, and high levels or urinary sodium and chloride are observed. Other clinical indicators include elevated serum renin and aldosterone in the blood stream, and metabolic alkalosis. The symptomatic features of this syndrome are highly variable ranging from asymptomatic to mild manifestations (weakness, cramps) to severe symptoms (tetany, paralysis, rhabdomyolysis).[10] Symptom severity is multi-factorial, with phenotypic expression varying amongst individuals within the same family. Genetic testing is another measure of identifying the underlying mutations which cause the pathologic symptoms of the disease. This mode of testing is available at select laboratories.[10] Work-up to exclude the differential diagnosis of the electrolyte abnormalities is key.[12] * In Gitelman syndrome hypocalcuria is present, and a urine calcium:creatinine ratio may help distinguish it from Bartter syndrome as the two disorders can be clinically indistinguishable. Additionally in Bartter syndrome maximal urine concentrating ability is lost. * Laxative abuse can mimic the serum electrolyte abnormalities, but fractional excretion of potassium will be low * Diuretic abuse could be suspected if urinary chloride excretion varies by time of day, but may require a diuretic assay to detect * Surreptitious vomiting can cause metabolic alkalosis and hypokalaemia, but urinary chloride levels will be low * Medication history; Proton-pump inhibitors can cause an isolated hypomagnesaemia phenotype, and aminoglycosides such as gentamicin can cause a transient metabolic alkalosis with hypokalaemia and hypomagnesaemia that resolves 2–6 weeks after drug termination. * Primary aldosteronism will cause metabolic alkalosis and hypokalaemia, but hypertension will be present and serum renin will be low * EAST syndrome, though neurological features will predominate * Renal cysts and diabetes syndrome can cause hypomagnesaemia and hypocalcuria, but is distinguished by early onset chronic kidney disease and an autosomal dominant inheritance pattern of renal cysts and/or diabetes ## Treatment[edit] Most asymptomatic individuals with Gitelman syndrome can be monitored without medical treatment.[2] Dietary modification of a high salt diet incorporated with,[10] potassium and magnesium supplementation to normalize blood levels is the mainstay of treatment.[2] Large doses of potassium and magnesium are often necessary to adequately replace the electrolytes lost in the urine.[2] Diarrhea is a common side effect of oral magnesium which can make replacement by mouth difficult but dividing the dose to 3-4 times a day is better tolerated.[2] Severe deficits of potassium and magnesium require intravenous replacement. If low blood potassium levels are not sufficiently replaced with replacement by mouth, aldosterone antagonists (such as spironolactone or eplerenone) or epithelial sodium channel blockers such as amiloride can be used to decrease urinary wasting of potassium.[2] In patients with early onset of the disease such as infants and children, indomethacin is the drug of choice utilized to treat growth disturbances.[10] Indomethacin in a study by Blanchard et. al 2015 was shown to increase serum potassium levels, and decrease renin concentration. Adverse effects of indomethacin include a decrease in the glomerular filtration rate, and gastrointestinal disturbances.[13] Cardiac evaluation is promoted in the prevention of dysrhythmias and monitoring of QT interval activity.[10] Medications that extend or prolong the QT interval (macrolides, antihistamines, beta-2 agonists) should be avoided in these patients to prevent cardiac death.[3] ## Epidemiology[edit] Gitelman syndrome is estimated to have a prevalence of 1 in 40,000 homozygous people .[2] The ratio of men to women affected is 1:1. This disease is encountered typically past the 1st decade of life, during adolescence or adulthood but can occur in the neonatal period. Heterozygous carriers of the SLC12A3 gene mutations are 1% of the population.[10] Parents with Gitelman syndrome have a low probability of passing the disorder to their offspring roughly 1 in 400 unless they are both carriers of the disease.[9] ## History[edit] The condition is named for Hillel J. Gitelman (1932– January 12, 2015), an American nephrologist working at University of North Carolina School of Medicine. He first described the condition in 1966, after observing a pair of sisters with the disorder. Gitelman and his colleagues later identified and isolated the gene responsible (SLC12A3) by molecular cloning.[14][15][16][17][18] ## References[edit] 1. ^ Fischer, Artwork by Holly (2013-01-31), English: This is an image of a kidney nephron and its structure., retrieved 2020-04-01 2. ^ a b c d e f g h i j k l m n o p Nakhoul, F; Nakhoul, N; Dorman, E; Berger, L; Skorecki, K; Magen, D (February 2012). "Gitelman's syndrome: a pathophysiological and clinical update". Endocrine (Review). 41 (1): 53–7. doi:10.1007/s12020-011-9556-0. PMID 22169961. S2CID 5820317. 3. ^ a b Seyberth, Hannsjörg W.; Schlingmann, Karl P. (October 2011). "Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects". Pediatric Nephrology. 26 (10): 1789–1802. doi:10.1007/s00467-011-1871-4. ISSN 0931-041X. PMC 3163795. PMID 21503667. 4. ^ Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP (June 1996). "Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2". Nat. Genet. 13 (2): 183–8. doi:10.1038/ng0696-183. PMID 8640224. S2CID 42296304. 5. ^ O'Shaughnessy KM, Karet FE (2004). "Salt handling and hypertension". J. Clin. Invest. 113 (8): 1075–81. doi:10.1172/JCI21560. PMC 385413. PMID 15085183. 6. ^ Pieter Du Toit van der Merwe, Megan A. Rensburg, William L. Haylett, Soraya Bardien, and M. Razeen Davids (2017). "Gitelman syndrome in a South African family presenting with hypokalaemia and unusual food cravings". BMC Nephrol. 18 (38): 38. doi:10.1186/s12882-017-0455-3. PMC 5270235. PMID 28125972.CS1 maint: multiple names: authors list (link) 7. ^ Cruz, Dinna N.; Shaer, Andrea J.; Bia, Margaret J.; Lifton, Richard P.; Simon, David B. (February 2001). "Gitelman's syndrome revisited: An evaluation of symptoms and health-related quality of life". Kidney International. 59 (2): 710–717. doi:10.1046/j.1523-1755.2001.059002710.x. ISSN 0085-2538. PMID 11168953. 8. ^ Riveira-Munoz, Eva; Chang, Qing; Godefroid, Nathalie; Hoenderop, Joost G.; Bindels, René J.; Dahan, Karin; Devuyst, Olivier; Belgian Network for Study of Gitelman Syndrome (April 2007). "Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome". Journal of the American Society of Nephrology: JASN. 18 (4): 1271–1283. doi:10.1681/ASN.2006101095. ISSN 1046-6673. PMID 17329572. 9. ^ a b c d Knoers, Nine VAM Levtchenko, Elena N (2008-07-30). "Gitelman syndrome". Orphanet Journal of Rare Diseases. BioMed Central Ltd. 3: 22. doi:10.1186/1750-1172-3-22. OCLC 804470918. PMC 2518128. PMID 18667063.CS1 maint: multiple names: authors list (link) 10. ^ a b c d e f g h i "Gitelman Syndrome". NORD (National Organization for Rare Disorders). Retrieved 2020-03-29. 11. ^ Viganò, Cristina; Amoruso, Chiara; Barretta, Francesco; Minnici, Giuseppe; Albisetti, Walter; Syrèn, Marie-Louise; Bianchetti, Mario G.; Bettinelli, Alberto (2013-01-01). "Renal phosphate handling in Gitelman syndrome—the results of a case–control study" (PDF). Pediatric Nephrology. 28 (1): 65–70. doi:10.1007/s00467-012-2297-3. ISSN 1432-198X. PMID 22990302. S2CID 13727845. 12. ^ Urwin, Stephanie; Willows, Jamie; Sayer, John A. (2020). "The challenges of diagnosis and management of Gitelman syndrome". Clinical Endocrinology. 92 (1): 3–10. doi:10.1111/cen.14104. ISSN 1365-2265. PMID 31578736. 13. ^ Blanchard, Anne; Vargas-Poussou, Rosa; Vallet, Marion; Caumont-Prim, Aurore; Allard, Julien; Desport, Estelle; Dubourg, Laurence; Monge, Matthieu; Bergerot, Damien; Baron, Stéphanie; Essig, Marie (February 2015). "Indomethacin, Amiloride, or Eplerenone for Treating Hypokalemia in Gitelman Syndrome". Journal of the American Society of Nephrology : JASN. 26 (2): 468–475. doi:10.1681/ASN.2014030293. ISSN 1046-6673. PMC 4310664. PMID 25012174. 14. ^ synd/2329 at Who Named It? 15. ^ Gitelman HJ, Graham JB, Welt LG (1966). "A new familial disorder characterized by hypokalemia and hypomagnesemia". Trans. Assoc. Am. Physicians. 79: 221–35. PMID 5929460. 16. ^ Unwin RJ, Capasso G (2006). "Bartter's and Gitelman's syndromes: their relationship to the actions of loop and thiazide diuretics" (PDF). Current Opinion in Pharmacology. 6 (2): 208–213. doi:10.1016/j.coph.2006.01.002. PMID 16490401. Archived from the original (PDF) on 2013-10-23. 17. ^ "Dr. Hillel Jonathan Gitelman". The News & Observer. Retrieved 5 March 2018. 18. ^ "Hillel J. Gitelman '54". Princeton Alumni Weekly. May 13, 2015. Retrieved 5 March 2018. ## External links[edit] Classification D * ICD-10: N25.8 \+ E87.6 \+ E83.4 * OMIM: 263800 * MeSH: D053579 * DiseasesDB: 31860 * SNOMED CT: 707756004 External resources * eMedicine: article/238670 * Orphanet: 358 * "Gitelman syndrome". MedlinePlus. U.S. National Library of Medicine. * v * t * e Kidney disease Glomerular disease * See Template:Glomerular disease Tubules * Renal tubular acidosis * proximal * distal * Acute tubular necrosis * Genetic * Fanconi syndrome * Bartter syndrome * Gitelman syndrome * Liddle's syndrome Interstitium * Interstitial nephritis * Pyelonephritis * Balkan endemic nephropathy Vascular * Renal artery stenosis * Renal ischemia * Hypertensive nephropathy * Renovascular hypertension * Renal cortical necrosis General syndromes * Nephritis * Nephrosis * Renal failure * Acute renal failure * Chronic kidney disease * Uremia Other * Analgesic nephropathy * Renal osteodystrophy * Nephroptosis * Abderhalden–Kaufmann–Lignac syndrome * Diabetes insipidus * Nephrogenic * Renal papilla * Renal papillary necrosis * Major calyx/pelvis * Hydronephrosis * Pyonephrosis * Reflux nephropathy * v * t * e Genetic disorder, membrane: Solute carrier disorders 1-10 * SLC1A3 * Episodic ataxia 6 * SLC2A1 * De Vivo disease * SLC2A5 * Fructose malabsorption * SLC2A10 * Arterial tortuosity syndrome * SLC3A1 * Cystinuria * SLC4A1 * Hereditary spherocytosis 4/Hereditary elliptocytosis 4 * SLC4A11 * Congenital endothelial dystrophy type 2 * Fuchs' dystrophy 4 * SLC5A1 * Glucose-galactose malabsorption * SLC5A2 * Renal glycosuria * SLC5A5 * Thyroid dyshormonogenesis type 1 * SLC6A19 * Hartnup disease * SLC7A7 * Lysinuric protein intolerance * SLC7A9 * Cystinuria 11-20 * SLC11A1 * Crohn's disease * SLC12A3 * Gitelman syndrome * SLC16A1 * HHF7 * SLC16A2 * Allan–Herndon–Dudley syndrome * SLC17A5 * Salla disease * SLC17A8 * DFNA25 21-40 * SLC26A2 * Multiple epiphyseal dysplasia 4 * Achondrogenesis type 1B * Recessive multiple epiphyseal dysplasia * Atelosteogenesis, type II * Diastrophic dysplasia * SLC26A4 * Pendred syndrome * SLC35C1 * CDOG 2C * SLC39A4 * Acrodermatitis enteropathica * SLC40A1 * African iron overload see also solute carrier family *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Gitelman syndrome

c0268450

wikipedia

https://en.wikipedia.org/wiki/Gitelman_syndrome

{"gard": ["8547"], "mesh": ["D053579"], "umls": ["C0268450"], "icd-10": ["N25.8", "E83.4", "E87.6"], "orphanet": ["358"], "wikidata": ["Q1053120"]}

## Clinical Features Atkin et al. (1985) reported a 3-generation family with 11 moderately to severely retarded males and 3 mildly retarded females. Phenotypic manifestations included short stature, macrocephaly, 'coarse' facial features with prominent forehead and supraorbital ridges, hypertelorism, broad nasal tip with anteverted nostrils, and thick lips. All postpubertal males had macroorchidism, and moderate obesity was noted in 6 males and all 3 women. All but one of the affected family members had a diastema between the maxillary central incisors. Although noting similarities, the authors distinguished the syndrome from Coffin-Lowry syndrome (CLS; 303600) and fragile X syndrome (FXS; 300624). Clark and Baraitser (1987) and Baraitser et al. (1995) described patients with mental retardation who shared many features with the patients described by Atkin et al. (1985); see 300602. The distinguishing features were short stature and hypertelorism in the patients reported by Atkin et al. (1985). INHERITANCE \- X-linked dominant GROWTH Height \- Short stature Weight \- Obesity HEAD & NECK Head \- Macrocephaly Face \- Coarse facial features \- Prominent forehead \- Heavy supraorbital ridges Eyes \- Hypertelorism \- Downslanting palpebral fissures Nose \- Broad nasal tip \- Anteverted nostrils Mouth \- Thick lips \- Prominent lower lip \- Prominent median palatal raphe \- Exaggerated median tongue furrow Teeth \- Central incisor gap \- Microdontia (maxillary lateral incisors) GENITOURINARY Internal Genitalia (Male) \- Macroorchidism SKELETAL \- Joint laxity Spine \- Scoliosis \- Hyperkyphosis Limbs \- Genu valga \- Genu recurvata Hands \- Tapered fingers \- Short, broad hands NEUROLOGIC Central Nervous System \- Mental retardation, moderate to severe \- Seizures \- Mental retardation, mild (carrier females) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ATKIN-FLAITZ SYNDROME

c0796206

omim

https://www.omim.org/entry/300431

{"mesh": ["C538195"], "omim": ["300431"], "orphanet": ["1193"], "synonyms": ["Alternative titles", "ATKIN SYNDROME"]}

Fitz-Hugh-Curtis syndrome (FHCS) is a condition in which a woman has swelling of the tissue covering the liver as a result of having pelvic inflammatory disease (PID). Symptoms most often include pain in the upper right abdomen just below the ribs, fever, nausea, or vomiting. The symptoms of pelvic inflammatory disease - pain in the lower abdomen and vaginal discharge \- are often present as well. FHCS is usually caused by an infection of chlamydia or gonorrhea that leads to PID; it is not known why PID progresses to FHCS in some women. Fitz-Hugh-Curtis syndrome is treated with antibiotics. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Fitz-Hugh-Curtis syndrome

c0341816

gard

https://rarediseases.info.nih.gov/diseases/6452/fitz-hugh-curtis-syndrome

{"mesh": ["C537936"], "synonyms": ["Gonococcal perihepatitis", "Perihepatitis syndrome"]}

This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Immunodeficiency–centromeric instability–facial anomalies syndrome" – news · newspapers · books · scholar · JSTOR (August 2008) (Learn how and when to remove this template message) ICF syndrome Other namesImmunodeficiency-centromeric instability-facial anomalies syndrome ICF syndrome (or Immunodeficiency, Centromere instability and Facial anomalies syndrome)[1] is a very rare autosomal recessive[2] immune disorder. ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 See also * 6 References * 7 External links ## Presentation[edit] It is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. ICF syndrome patients exhibit facial anomalies which include hypertelorism, low-set ears, epicanthal folds and macroglossia. ## Genetics[edit] Mutations in four genes can cause this syndrome:[3] Cell division cycle associated protein 7 (CDCA7), DNA-methyltransferase 3b (DNMT3B), Lymphoid specific helicase (HELLS) and Zinc finger- and BTB domain containing protein 24 (ZBTB24). The CDCA7 gene is located on chromosome 2 (2q31.1). The DNMT3B gene is located on chromosome 20 (20q11.2)).[4][5] The HELLS gene is located on chromosome 10 (10q23.33) The ZBTB24 gene is located on chromosome 6 (6q21) This disease is inherited in an autosomal recessive manner.[2] ## Diagnosis[edit] This section is empty. You can help by adding to it. (July 2017) ## Treatment[edit] For ICF patients the most diffused therapy consists of repeated intravenous infusions of immunoglobulins for the patients entire lifespan. In 2007, Gennery et al. cured the humoral and cellular immunological defect in three ICF1 patients by hematopoietic stem cell transplantation (HSCT). The only side effect was related to the development of autoimmune phenomena in two of them.[6] This is the only documented case of restoring the immune conditions and growth improvement in these patients.[7] ## See also[edit] * Bare lymphocyte syndrome * List of cutaneous conditions ## References[edit] 1. ^ Online Mendelian Inheritance in Man (OMIM): 242860 2. ^ a b Brown, Dc; Grace, E; Sumner, At; Edmunds, At; Ellis, Pm (October 1995). "ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome". Human Genetics. 96 (4): 411–6. doi:10.1007/BF00191798. PMID 7557962. 3. ^ Ren R, Hardikar S, Horton JR, Lu Y, Zeng Y, Singh AK, Lin K, Coletta LD, Shen J, Lin Kong CS, Hashimoto H, Zhang X, Chen T, Cheng X (2019) Structural basis of specific DNA binding by the transcription factor ZBTB24. Nucleic Acids Res 4. ^ Jiang, Yl; Rigolet, M; Bourc'His, D; Nigon, F; Bokesoy, I; Fryns, Jp; Hultén, M; Jonveaux, P; Maraschio, P; Mégarbané, A; Moncla, A; Viegas-Péquignot, E (January 2005). "DNMT3B mutations and DNA methylation defect define two types of ICF syndrome". Human Mutation. 25 (1): 56–63. doi:10.1002/humu.20113. PMID 15580563. 5. ^ Online Mendelian Inheritance in Man (OMIM): 602900 6. ^ Gennery, A. R.; Slatter, M. A.; Bredius, R. G.; Hagleitner, M. M.; Weemaes, C.; Cant, A. J.; Lankester, A. C. (2007). "Hematopoietic Stem Cell Transplantation Corrects the Immunologic Abnormalities Associated with Immunodeficiency Centromeric Instability Facial Dysmorphism Syndrome". Pediatrics. 120 (5): e1341–e1344. doi:10.1542/peds.2007-0640. PMID 17908720. 7. ^ https://www.ptglab.com/news/blog/icf-syndrome-a-gene-silencing-chromatin-disorder/ IFC Syndrome: A gene silencing chromatin disorder ## External links[edit] Classification D * ICD-10: D84.8 * OMIM: 242860 * MeSH: C537362 * DiseasesDB: 32366 External resources * Orphanet: 2268 * Orphanet Journal of Rare Diseases link to ICF syndrome [1] * v * t * e Lymphoid and complement disorders causing immunodeficiency Primary Antibody/humoral (B) Hypogammaglobulinemia * X-linked agammaglobulinemia * Transient hypogammaglobulinemia of infancy Dysgammaglobulinemia * IgA deficiency * IgG deficiency * IgM deficiency * Hyper IgM syndrome (1 * 2 * 3 * 4 * 5) * Wiskott–Aldrich syndrome * Hyper-IgE syndrome Other * Common variable immunodeficiency * ICF syndrome T cell deficiency (T) * thymic hypoplasia: hypoparathyroid (Di George's syndrome) * euparathyroid (Nezelof syndrome * Ataxia–telangiectasia) peripheral: Purine nucleoside phosphorylase deficiency * Hyper IgM syndrome (1) Severe combined (B+T) * x-linked: X-SCID autosomal: Adenosine deaminase deficiency * Omenn syndrome * ZAP70 deficiency * Bare lymphocyte syndrome Acquired * HIV/AIDS Leukopenia: Lymphocytopenia * Idiopathic CD4+ lymphocytopenia Complement deficiency * C1-inhibitor (Angioedema/Hereditary angioedema) * Complement 2 deficiency/Complement 4 deficiency * MBL deficiency * Properdin deficiency * Complement 3 deficiency * Terminal complement pathway deficiency * Paroxysmal nocturnal hemoglobinuria * Complement receptor deficiency This immunology article is a stub. You can help Wikipedia by expanding it. * v * t * e This genetic disorder article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Immunodeficiency–centromeric instability–facial anomalies syndrome

c0398788

wikipedia

https://en.wikipedia.org/wiki/Immunodeficiency%E2%80%93centromeric_instability%E2%80%93facial_anomalies_syndrome

{"mesh": ["C537362"], "umls": ["C0398788"], "orphanet": ["2268"], "wikidata": ["Q1869923"]}

A rare multiple congenital anomalies syndrome usually characterized by microcephaly, ocular anomalies such as microphthalmia, and apple-peel intestinal atresia. Facial dysmorphism is reported in some cases and may include narrow or sloped forehead, hypertelorism, microphthalmia, dysplastic, edematous deep-set eyes, short palpebral fissures, large or low set ears, broad nasal root, anteverted or broad nasal tip, long philtrum, micrognathia, thin upper vermillion, large mouth and skin tag on the cheek. Motor delay and intellectual disability have been reported. Heart, brain, craniofacial abnormalities, renal hypoplasia and other anomalies (e.g. lower limb edema, thrombocytopenia) are variably present. Rarely, cases without intestinal atresia, microcephaly or developmental delay can be found. Severe lethal cases have also been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Stromme syndrome

c1855705

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=506307

{"mesh": ["C565460"], "omim": ["243605"], "icd-10": ["Q13.8"], "synonyms": ["Apple-peel intestinal atresia-ocular anomalies-microcephaly syndrome", "Jejunal atresia-microcephaly-ocular anomalies syndrome"]}

A number sign (#) is used with this entry because of evidence that short stature, microcephaly, and endocrine dysfunction (SSMED) is caused by homozygous or compound heterozygous mutation in the XRCC4 gene (194363) on chromosome 5q14. Description In patients with SSMED, short stature and microcephaly are apparent at birth, and there is progressive postnatal growth failure. Endocrine dysfunction, including hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus, is present in affected adults. Progressive ataxia has been reported in some patients, with onset ranging from the second to fifth decade of life. In addition, a few patients have developed tumors, suggesting that there may be a predisposition to tumorigenesis. In contrast to syndromes involving defects in other components of the nonhomologous end-joining (NHEJ) complex (see, e.g., 606593), no clinically overt immunodeficiency has been observed in SSMED, although laboratory analysis has revealed lymphopenia or borderline leukopenia in some patients (Murray et al., 2015; Bee et al., 2015; de Bruin et al., 2015; Guo et al., 2015). Clinical Features Neilan et al. (2008) reported a 14-year-old girl (patient 3) with short stature, microcephaly, and developmental delay, who at age 12 years developed motor difficulties, including gait disturbances, falls, tremors, choking and gagging on food, difficulty tying shoelaces, and problems navigating stairs. Prenatal ultrasound had shown dilated cerebral ventricles, and she required tube feedings in the first week of life. Examination revealed deep-set eyes, mild pigmentary retinopathy, beaked nose, sensorineural hearing loss, and bilateral hand weakness. Tendon stretch reflexes were increased at the patellae and absent at the ankles, with extensor plantar responses. She had fluctuating rigidity in the upper extremities, with mild coarse postural tremor bilaterally and a shuffling gait with bradykinesia, and also exhibited dysmetria and dysdiadochokinesia. Nerve conduction studies demonstrated mild sensory polyneuropathy, and neuroimaging revealed small caudate nuclei, prominent cerebral ventricles, and thin corpus callosum. Neilan et al. (2008) diagnosed the patient with Cockayne syndrome (216400). Guo et al. (2015) restudied this patient when she was 23 years of age. Her features, which included short stature, microcephaly, developmental delay, deep-set eyes, and progressive neuronal degeneration including ataxia, resembled those of patients with Cockayne syndrome; however, she had no history of photosensitivity and a relatively slow progression of symptoms. In addition, cellular tests for abnormal responses to UV light performed on a fibroblast culture from patient cells were negative. At 19 years of age, she was diagnosed with a low-grade thalamic glioma, which was not removed. Other features included hyperopia, diabetes mellitus, hypothyroidism, moderate hearing loss, and slurred speech. She had no significant infectious history, no signs of abnormal immune response, and no abnormalities in blood cell counts or immunoglobulin levels. Shaheen et al. (2014) reported a 4-year-old Saudi Arabian girl with severe short stature and microcephaly (height, -7.1 SD; head circumference, -8.3 SD), triangular 'bird-like' face, and short philtrum, who also exhibited speech delay but had normal motor development. From a cohort of 208 patients with a diagnosis of microcephalic primordial dwarfism, Murray et al. (2015) identified 6 patients from 5 families who had biallelic mutations in the XRCC4 gene (see MOLECULAR GENETICS). All 6 patients had significant reductions in both head and body size at birth, with median occipitofrontal head circumference (OFC) of -3.59 SD, length -4.94 SD, and weight -3.14 SD. Postnatally, patients developed extreme microcephaly (median OFC, -8.15 SD) along with significant short stature (median height, -4.6 SD). In addition, affected individuals exhibited facial similarities, including fine sparse hair, small chin, and broad nasal tip. Developmental delay was present in only some of the patients, and no recurrent developmental malformations were apparent, although 2 patients had multiple malformations, including 1 with small bilateral kidneys, ectopic kidney, and 'chronic lung disease,' and another with unilateral renal agenesis and cryptorchidism. No malignancies were reported, and there was no clinical suspicion of immunodeficiency. Detailed immunologic and hematologic investigation showed no evidence of immunodeficiency or bone marrow failure in most patients; however, 1 Saudi Arabian boy had an isolated lymphopenia involving all T-cell and B-cell subsets, although he exhibited normal responses to vaccines. Bee et al. (2015) reported 50-year-old Italian monozygotic twin brothers, born to first-cousin parents, who had a progressive neurologic syndrome and dilated cardiomyopathy. Both brothers had short stature with short limbs, hypotelorism, cryptorchidism, and pes cavus. Gait difficulties developed in the fourth to fifth decades of life. Examination at age 50 revealed cognitive impairment in both, as well as nystagmus, slowing of eye pursuits, dysarthria, dysmetria, diffuse pyramidal signs, ataxia, and wide-based camptocormic gait with slight steppage. One brother was diagnosed with dilated cardiomyopathy at age 27 years, with hypertrophy of the interventricular septum and an ejection fraction of 25%; he received an implantable cardioverter/defibrillator at age 44. Cardiac assessment of his twin at age 50 showed a left ventricular diastolic defect with an ejection fraction of 52%. This brother also exhibited multinodular thyroid hypertrophy. Laboratory evaluation showed mildly elevated blood glucose in both brothers; in addition, both had elevated gonadotropins and low testosterone, which was attributed to hypergonadotropic hypogonadism due to bilateral cryptorchidism. Neurophysiologic studies revealed an axonal sensory neuropathy in both twins, and brain MRI showed mild atrophy of the cerebellar vermis in both. Muscle biopsy showed only type 2 fiber hypotrophy. Neuropsychologic assessment revealed severe attention deficit with constructive apraxia and deficient visuospatial memory. De Bruin et al. (2015) studied a brother and sister from rural Chile who exhibited severe short stature, microcephaly, gonadal failure, and early-onset metabolic syndrome. Both sibs were small for gestational age and displayed progressive postnatal growth failure. The 40-year-old brother had bilateral cryptorchidism and underwent with right orchiopexy at age 7 years; his left testicle was atrophic. In addition, he underwent hemithyroidectomy for multinodular goiter at age 10; multiple thyroid nodules were also detected in his sister at age 31, but no tissue was analyzed. Both sibs failed to undergo puberty, and laboratory analysis was consistent with severe hypergonadotropic hypogonadism. At age 16, both sibs also exhibited insulin resistance despite normal oral glucose tolerance tests, and both were later diagnosed with diabetes and dyslipidemia. The brother underwent cataract surgery at age 37. Physical examination at age 40 showed severe short stature and microcephaly (height, -6.8 SD; OFC, -3.3 SD) as well as acanthosis nigricans, clinodactyly, small testes, and a high-pitched voice. Although he never showed clinical signs of immunodeficiency, he had mild lymphopenia with a decrease in natural killer and B cells, as well as CD4+ T cells. His sister had persistent anemia of unknown origin throughout childhood but no other signs of hematologic or immunologic disease. At 30 years of age, she underwent removal of a jejunal wall tumor which was determined to be a gastrointestinal stromal tumor; 1 year later, she was found to have diffuse intraabdominal metastases, which progressed despite treatment, and she died at 36 years of age. Rosin et al. (2015) studied 3 Turkish brothers, born of first-cousin parents, who exhibited short stature, pronounced microcephaly, and mild psychomotor delay. Dysmorphic facial features included long face with sloping forehead and prominent chin, long and beaked nose, midface hypoplasia, mild hypotelorism, and synophrys. MRI in the oldest brother, aged 14 years, showed a simplified gyral pattern. The 2 older brothers had mild thrombocytopenia, but no other hematologic abnormalities. The 10.5-year-old brother also had undescended testes and the 6-month-old had inguinal hernia. Rosin et al. (2015) also studied a 14-year-old Swiss girl with short stature, microcephaly, and mild developmental delay. Dysmorphic features included long face with high forehead and prominent chin, deep-set eyes, mild strabismus, high nasal bridge, prominent and long philtrum, prominent columella, malpositioning of teeth, long neck, excessive white lines on palms, and mild truncal obesity. None of the patients had recurrent infections or other signs of immunologic problems. Molecular Genetics By autozygome analysis in 16 patients diagnosed with primordial dwarfism, Shaheen et al. (2014) identified a 4-year-old Saudi Arabian girl who was homozygous for a missense mutation in the XRCC4 gene (W43R; 194363.0001). XRCC4 knockdown in control fibroblasts resulted in significant impairment of DNA damage repair following ionizing radiation but not UV exposure. Murray et al. (2015) analyzed exome sequencing data from a cohort of 208 patients diagnosed with microcephalic primordial dwarfism and identified homozygosity for the XRCC4 W43R mutation in a Saudi Arabian boy with short stature, microcephaly, and lymphopenia. Resequencing of the XRCC4 gene in that cohort identified compound heterozygosity for truncating mutations in 5 more patients from 4 families (194363.0002-194363.0006). All mutations segregated with disease in the respective families. In 50-year-old Italian twin brothers, born of first-cousin parents, with short stature, cognitive impairment, hypergonadotropic hypogonadism, axonal sensory neuropathy, and dilated cardiomyopathy, Bee et al. (2015) excluded mutation in the TIM14 (608977) and FXN (606829) genes by direct sequencing. By whole-exome sequencing, they identified homozygosity for the previously reported R225X mutation in the XRCC4 gene (194363.0005). The brothers' unaffected father and sister were heterozygous for R225X; DNA was unavailable from their mother. In a brother and sister from rural Chile with short stature, microcephaly, hypergonadotropic hypogonadism, and early-onset metabolic syndrome, de Bruin et al. (2015) sequenced candidate genes and excluded mutation in the IGF1 (147440) signaling pathway or in 3M syndrome (see 273750)-associated genes. Homozygosity analysis suggested that their parents were fourth-degree relatives, and exome sequencing identified a homozygous missense mutation in the XRCC4 gene (D82E; 194363.0007) that segregated with disease in the family. In 3 Turkish brothers with short stature, microcephaly, and mild developmental delay, Rosin et al. (2015) identified homozygosity for a missense mutation in XRCC4 (R161Q; 194363.0008) that was found to cause splicing defects. In a similarly affected Swiss girl, they identified compound heterozygosity for 2 previously reported XRCC4 mutations, a 1-bp deletion (c.25delC; 194363.0002) and a nonsense mutation (R275X; 194363.0003). In a woman with short stature, microcephaly, hypothyroidism, diabetes mellitus, and progressive ataxia, Guo et al. (2015) excluded mutation in Cockayne syndrome (see 216400)-associated genes and performed whole-exome sequencing, which revealed compound heterozygosity for the R225X mutation (194363.0005) and a 1-bp deletion (760delG; 194363.0009) in the XRCC4 gene. In contrast to individuals with LIG4 defects (see 606593), this patient had no history of chronic infections and showed a normal immune response; consistent with these clinical findings, functional analysis in patient cells demonstrated a severe defect in DSB repair but enhanced accuracy in an in vitro assay for V(D)J recombination. Guo et al. (2015) concluded that this represents a separation-of-impact phenotype, in which marked deficiency in radiation-induced DSB repair can be uncoupled from defective V(D)J recombination. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Intrauterine growth failure \- Truncal obesity, mild (in some patients) HEAD & NECK Head \- Microcephaly Face \- Triangular face \- Long face \- Sloping forehead \- High forehead \- Small chin Ears \- Hearing loss, sensorineural (rare) Eyes \- Hypotelorism \- Deep-set eyes \- Nystagmus \- Slowing of eye pursuits \- Cataracts (rare) Nose \- Long nose \- Beaked nose \- High nasal bridge \- Broad nasal tip Teeth \- Malpositioned teeth CARDIOVASCULAR Heart \- Cardiomyopathy, dilated (rare) CHEST Breasts \- Absent thelarche GENITOURINARY External Genitalia (Male) \- Inguinal hernia \- Micropenis Internal Genitalia (Male) \- Cryptorchidism Kidneys \- Small kidneys \- Ectopic kidney \- Unilateral renal agenesis SKELETAL Skull \- Microcephaly Limbs \- Short limbs Hands \- Clinodactyly (rare) Feet \- Pes cavus (rare) SKIN, NAILS, & HAIR Skin \- Acanthosis nigricans Hair \- Fine, sparse hair MUSCLE, SOFT TISSUES \- Hypotrophic type 2 muscle fibers NEUROLOGIC Central Nervous System \- Developmental delay \- Speech delay \- Cognitive impairment \- Severe attention deficit \- Constructive apraxia \- Visuospatial memory deficit \- Dysarthria \- Dysmetria \- Dysdiadochokinesia \- Ataxia, progressive \- Pyramidal signs, diffuse \- Wide-based gait \- Atrophy of cerebellar vermis, mild \- Dilated cerebral ventricles \- Small caudate nuclei \- Simplified gyral pattern Peripheral Nervous System \- Sensory neuropathy VOICE \- High-pitched voice METABOLIC FEATURES \- Mildly elevated glucose \- Dyslipidemia ENDOCRINE FEATURES \- Multinodular thyroid hypertrophy \- Hypothyroidism \- Insulin resistance \- Diabetes mellitus HEMATOLOGY \- Lymphopenia, mild \- Anemia, persistent IMMUNOLOGY \- No clinical signs of immunodeficiency NEOPLASIA \- Gastrointestinal stromal tumor of jejunum (rare) \- Thalamic glioma, low grade (rare) MISCELLANEOUS \- Endocrine and neurologic defects may become apparent later in life MOLECULAR BASIS \- Caused by mutation in the X-ray repair complementing defective repair in Chinese hamster cells-4 gene (XRCC4, 194363.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SHORT STATURE, MICROCEPHALY, AND ENDOCRINE DYSFUNCTION

c4225288

omim

https://www.omim.org/entry/616541

{"omim": ["616541"], "orphanet": ["436182"], "synonyms": []}

Mitral valve prolapse Other namesFloppy mitral valve syndrome, systolic click murmur syndrome, billowing mitral leaflet, Barlow's syndrome[1] In mitral valve prolapse, the leaflets of the mitral valve prolapse back into the left atrium. SpecialtyCardiology Mitral valve prolapse (MVP) is a valvular heart disease characterized by the displacement of an abnormally thickened mitral valve leaflet into the left atrium during systole.[2] It is the primary form of myxomatous degeneration of the valve. There are various types of MVP, broadly classified as classic and nonclassic. In severe cases of classic MVP, complications include mitral regurgitation, infective endocarditis, congestive heart failure, and, in rare circumstances, cardiac arrest. The diagnosis of MVP depends upon echocardiography, which uses ultrasound to visualize the mitral valve. MVP is estimated to affect 2–3% of the population.[2] The condition was first described by John Brereton Barlow in 1966.[1] It was subsequently termed mitral valve prolapse by J. Michael Criley.[3] ## Contents * 1 Signs and symptoms * 1.1 Murmur * 1.2 Mitral valve prolapse syndrome * 1.3 Mitral regurgitation * 2 Risk factors * 3 Genetics * 4 Diagnosis * 4.1 Classic versus nonclassic * 4.2 Symmetric versus asymmetric * 4.3 Flail versus non-flail * 5 Treatment * 5.1 Prevention of infective endocarditis * 6 Prognosis * 7 Epidemiology * 8 History * 9 References * 10 Further reading * 11 External links ## Signs and symptoms[edit] ### Murmur[edit] Upon auscultation of an individual with mitral valve prolapse, a mid-systolic click, followed by a late systolic murmur heard best at the apex, is common. The length of the murmur signifies the time period over which blood is leaking back into the left atrium, known as regurgitation. A murmur that lasts throughout the whole of systole is known as a holo-systolic murmur. A murmur that is mid to late systolic, although typically associated with less regurgitation, can still be associated with significant hemodynamic consequences.[4] In contrast to most other heart murmurs, the murmur of mitral valve prolapse is accentuated by standing and valsalva maneuver (earlier systolic click and longer murmur) and diminished with squatting (later systolic click and shorter murmur). The only other heart murmur that follows this pattern is the murmur of hypertrophic cardiomyopathy. A MVP murmur can be distinguished from a hypertrophic cardiomyopathy murmur by the presence of a mid-systolic click which is virtually diagnostic of MVP. The handgrip maneuver diminishes the murmur of an MVP and the murmur of hypertrophic cardiomyopathy. The handgrip maneuver also diminishes the duration of the murmur and delays the timing of the mid-systolic click.[5] Both valsalva maneuver and standing decrease venous return to the heart thereby decreasing left ventricular diastolic filling (preload) and causing more laxity on the chordae tendineae. This allows the mitral valve to prolapse earlier in systole, leading to an earlier systolic click (i.e. closer to S1), and a longer murmur. ### Mitral valve prolapse syndrome[edit] Historically, the term mitral valve prolapse syndrome has been applied to MVP associated with palpitations, atypical precordial pain, dyspnea on exertion, low body mass index, and electrocardiogram abnormalities (ventricular tachycardia), syncope, low blood pressure, headaches, lightheadedness, and other signs suggestive of autonomic nervous system dysfunction (dysautonomia).[2] ### Mitral regurgitation[edit] Mitral valve prolapse can result in mitral regurgitation, shown here, in which blood abnormally flows from the left ventricle back into the left atrium. Main article: Mitral regurgitation Mitral valve prolapse is frequently associated with mild mitral regurgitation,[6] where blood aberrantly flows from the left ventricle into the left atrium during systole. In the United States, MVP is the most common cause of severe, non-ischemic mitral regurgitation.[2] This is occasionally due to rupture of the chordae tendineae that support the mitral valve.[5] ## Risk factors[edit] MVP may occur with greater frequency in individuals with Ehlers-Danlos syndrome, Marfan syndrome[7] or polycystic kidney disease.[8] Other risk factors include Graves disease[citation needed] and chest wall deformities such as pectus excavatum.[9] For unknown reasons, MVP patients tend to have a low body mass index (BMI) and are typically leaner than individuals without MVP.[10][11] Rheumatic fever is common worldwide and responsible for many cases of damaged heart valves. Chronic rheumatic heart disease is characterized by repeated inflammation with fibrinous resolution. The cardinal anatomic changes of the valve include leaflet thickening, commissural fusion, and shortening and thickening of the tendinous cords.[12] The recurrence of rheumatic fever is relatively common in the absence of maintenance of low dose antibiotics, especially during the first three to five years after the first episode. Heart complications may be long-term and severe, particularly if valves are involved. Rheumatic fever, since the advent of routine penicillin administration for Strep throat, has become less common in developed countries. In the older generation and in much of the less-developed world, valvular disease (including mitral valve prolapse, reinfection in the form of valvular endocarditis, and valve rupture) from undertreated rheumatic fever continues to be a problem.[13] In an Indian hospital between 2004 and 2005, 4 of 24 endocarditis patients failed to demonstrate classic vegetations. All had rheumatic heart disease (RHD) and presented with prolonged fever. All had severe eccentric mitral regurgitation (MR). (One had severe aortic regurgitation (AR) also.) One had flail posterior mitral leaflet (PML).[14] Micrograph demonstrating thickening of the spongiosa layer (blue) in myxomatous degeneration of the aortic valve. Movat's stain. The mitral valve, so named because of its resemblance to a bishop's mitre, is the heart valve that prevents the backflow of blood from the left ventricle into the left atrium of the heart. It is composed of two leaflets, one anterior and one posterior, that close when the left ventricle contracts. Each leaflet is composed of three layers of tissue: the atrialis, fibrosa, and spongiosa. Patients with classic mitral valve prolapse have excess connective tissue that thickens the spongiosa and separates collagen bundles in the fibrosa. This is due to an excess of dermatan sulfate, a glycosaminoglycan. This weakens the leaflets and adjacent tissue, resulting in increased leaflet area and elongation of the chordae tendineae. Elongation of the chordae tendineae often causes rupture, commonly to the chordae attached to the posterior leaflet. Advanced lesions—also commonly involving the posterior leaflet—lead to leaflet folding, inversion, and displacement toward the left atrium.[10] ## Genetics[edit] An association with primary cilia defects has been reported.[15] The mutations were found in the Zinc finger protein DZIP1 (DZIP1) gene. ## Diagnosis[edit] Transesophageal echocardiogram of mitral valve prolapse. Diagnosis of mitral valve prolapse is based on modern echocardiographic techniques which can pinpoint abnormal leaflet thickening and other related pathology. Echocardiography is the most useful method of diagnosing a prolapsed mitral valve. Two- and three-dimensional echocardiography are particularly valuable as they allow visualization of the mitral leaflets relative to the mitral annulus. This allows measurement of the leaflet thickness and their displacement relative to the annulus. Thickening of the mitral leaflets >5 mm and leaflet displacement >2 mm indicates classic mitral valve prolapse.[10] Prolapsed mitral valves are classified into several subtypes, based on leaflet thickness, type of connection to the mitral annulus, and concavity. Subtypes can be described as classic, nonclassic, symmetric, asymmetric, flail, or non-flail.[10] All measurements below refer to adult patients; applying them to children may be misleading. ### Classic versus nonclassic[edit] Prolapse occurs when the mitral valve leaflets are displaced more than 2 mm above the mitral annulus high points. The condition can be further divided into classic and nonclassic subtypes based on the thickness of the mitral valve leaflets: up to 5 mm is considered nonclassic, while anything beyond 5 mm is considered classic MVP.[10] ### Symmetric versus asymmetric[edit] Classical prolapse may be subdivided into symmetric and asymmetric, referring to the point at which leaflet tips join the mitral annulus. In symmetric coaptation, leaflet tips meet at a common point on the annulus. Asymmetric coaptation is marked by one leaflet displaced toward the atrium with respect to the other. Patients with asymmetric prolapse are susceptible to severe deterioration of the mitral valve, with the possible rupture of the chordae tendineae and the development of a flail leaflet.[10] ### Flail versus non-flail[edit] Asymmetric prolapse is further subdivided into flail and non-flail. Flail prolapse occurs when a leaflet tip turns outward, becoming concave toward the left atrium, causing the deterioration of the mitral valve. The severity of flail leaflet varies, ranging from tip eversion to chordal rupture. Dissociation of leaflet and chordae tendineae provides for unrestricted motion of the leaflet (hence "flail leaflet"). Thus patients with flail leaflets have a higher prevalence of mitral regurgitation than those with the non-flail subtype.[10] ## Treatment[edit] Individuals with mitral valve prolapse, particularly those without symptoms, often require no treatment.[16] Those with mitral valve prolapse and symptoms of dysautonomia (palpitations, chest pain) may benefit from beta-blockers (e.g., propranolol). People with prior stroke or atrial fibrillation may require blood thinners, such as aspirin or warfarin. In rare instances when mitral valve prolapse is associated with severe mitral regurgitation, surgical repair or replacement of the mitral valve may be necessary. Mitral valve repair is generally considered preferable to replacement. Current ACC/AHA guidelines promote repair of mitral valve in people before symptoms of heart failure develop. Symptomatic people, those with evidence of diminished left ventricular function, or those with left ventricular dilatation need urgent attention. ### Prevention of infective endocarditis[edit] Individuals with MVP are at higher risk of bacterial infection of the heart, called infective endocarditis. This risk is approximately three- to eightfold the risk of infective endocarditis in the general population.[2] Until 2007, the American Heart Association recommended prescribing antibiotics before invasive procedures, including those in dental surgery. Thereafter, they concluded that "prophylaxis for dental procedures should be recommended only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis."[17] Many organisms responsible for endocarditis are slow-growing and may not be easily identified on routine blood cultures (these fastidious organisms require special culture media to grow). These include the HACEK organisms, which are part of the normal oropharyngeal flora and are responsible for perhaps 5 to 10% of infective endocarditis affecting native valves. It is important when considering endocarditis to keep these organisms in mind. ## Prognosis[edit] Generally, MVP is benign. However, MVP patients with a murmur, not just an isolated click, have an increased mortality rate of 15-20%.[18] The major predictors of mortality are the severity of mitral regurgitation and the ejection fraction.[19] ## Epidemiology[edit] Prior to the strict criteria for the diagnosis of mitral valve prolapse, as described above, the incidence of mitral valve prolapse in the general population varied greatly.[10] Some studies estimated the incidence of mitral valve prolapse at 5 to 15 percent or even higher.[20] One 1985 study suggested MVP in up to 35% of healthy teenagers.[21] Recent elucidation of mitral valve anatomy and the development of three-dimensional echocardiography have resulted in improved diagnostic criteria, and the true prevalence of MVP based on these criteria is estimated at 2-3%.[2] As a part of the Framingham Heart Study, for example, the prevalence of mitral valve prolapse in Framingham, MA was estimated at 2.4%. There was a near-even split between classic and nonclassic MVP, with no significant age or sex discrimination.[11] MVP is observed in 7% of autopsies in the United States.[18] ## History[edit] The term mitral valve prolapse was coined by J. Michael Criley in 1966 and gained acceptance over the other descriptor of "billowing" of the mitral valve, as described by John Brereton Barlow.[22] ## References[edit] 1. ^ a b Barlow JB, Bosman CK (February 1966). "Aneurysmal protrusion of the posterior leaflet of the mitral valve. An auscultatory-electrocardiographic syndrome". Am. Heart J. 71 (2): 166–78. doi:10.1016/0002-8703(66)90179-7. PMID 4159172. 2. ^ a b c d e f Hayek E, Gring CN, Griffin BP (2005). "Mitral valve prolapse". Lancet. 365 (9458): 507–18. doi:10.1016/S0140-6736(05)17869-6. PMID 15705461. 3. ^ Criley JM, Lewis KB, Humphries JO, Ross RS (July 1966). "Prolapse of the mitral valve: clinical and cine-angiocardiographic findings". Br Heart J. 28 (4): 488–96. doi:10.1136/hrt.28.4.488. PMC 459076. PMID 5942469. 4. ^ Ahmed, Mustafa I.; Sanagala, Thriveni; Denney, Thomas; Inusah, Seidu; McGiffin, David; Knowlan, Donald; O’Rourke, Robert A.; Dell’Italia, Louis J. (August 2009). "Mitral Valve Prolapse With a Late-Systolic Regurgitant Murmur May Be Associated With Significant Hemodynamic Consequences". The American Journal of the Medical Sciences. 338 (2): 113–115. doi:10.1097/MAJ.0b013e31819d5ec6. PMID 19561453. 5. ^ a b Tanser, Paul H. (reviewed Mar 2007). "Mitral Valve Prolapse", The Merck Manuals Online Medical Library, Retrieved 2011-01-08. 6. ^ Kolibash AJ (1988). "Progression of mitral regurgitation in patients with mitral valve prolapse". Herz. 13 (5): 309–17. PMID 3053383. 7. ^ "Related Disorders: Mitral Valve Prolapse". Archived from the original on 2007-02-25. Retrieved 2007-07-11. 8. ^ Lumiaho, A; Ikäheimo, R; Miettinen, R; Niemitukia, L; Laitinen, T; Rantala, A; Lampainen, E; Laakso, M; Hartikainen, J (2001). "Mitral valve prolapse and mitral regurgitation are common in patients with polycystic kidney disease type 1". American Journal of Kidney Diseases. 38 (6): 1208–16. doi:10.1053/ajkd.2001.29216. PMID 11728952. 9. ^ "Pectus Excavatum: Epidemiology". Medscape. Retrieved 14 April 2016. 10. ^ a b c d e f g h Playford, David; Weyman, Arthur (2001). "Mitral valve prolapse: time for a fresh look". Reviews in Cardiovascular Medicine. 2 (2): 73–81. PMID 12439384. Archived from the original on 2014-09-03. Retrieved 2009-03-24. 11. ^ a b Freed LA, Levy D, Levine RA, Larson MG, Evans JC, Fuller DL, Lehman B, Benjamin EJ (1999). "Prevalence and clinical outcome of mitral-valve prolapse". N Engl J Med. 341 (1): 1–7. doi:10.1056/NEJM199907013410101. PMID 10387935. 12. ^ Cotran, Ramzi S.; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L.; Abbas, Abul K. (2005). Robbins and Cotran pathologic basis of disease. St. Louis, Mo: Elsevier Saunders. ISBN 978-0-7216-0187-8. Archived from the original on 10 September 2005. 13. ^ NLM/NIH: Medline Plus Medical Encyclopedia: Rheumatic fever 14. ^ S Venkatesan; et al. (Sep–Oct 2007). "Can we diagnose Infective endocarditis without vegetation?". Indian Heart Journal. 59 (5). 15. ^ Toomer KA, Yu M, Fulmer D, Guo L, Moore KS, Moore R, Drayton KD, Glover J, Peterson N, Ramos-Ortiz S, Drohan A, Catching BJ, Stairley R, Wessels A, Lipschutz JH, Delling FN, Jeunemaitre X, Dina C, Collins RL1, Brand H10, Talkowski ME10, Del Monte F11, Mukherjee R, Awgulewitsch A, Body S, Hardiman G, Hazard ES, da Silveira WA, Wang B, Leyne M, Durst R, Markwald RR, Le Scouarnec S, Hagege A, Le Tourneau T, Kohl P, Rog-Zielinska EA, Ellinor PT, Levine RA, Milan DJ, Schott JJ, Bouatia-Naji N, Slaugenhaupt SA, Norris RA (2019) Primary cilia defects causing mitral valve prolapse. Sci Transl Med 11(493) 16. ^ "Mitral valve prolapse". Mayo Clinic. 17. ^ Wilson W, Taubert KA, Gewitz M, et al. (2007). "Prevention of infective endocarditis: guidelines from the American Heart Association" (PDF). Journal of the American Dental Association. 138 (6): 739–45, 747–60. doi:10.14219/jada.archive.2007.0262. PMID 17545263. 18. ^ a b Mitral Valve Prolapse at eMedicine 19. ^ Rodgers, Ellie (May 11, 2004). "Mitral Valve Regurgitation". Healthwise, on Yahoo. Retrieved 2007-07-11.[permanent dead link] 20. ^ Levy D, Savage D (1987). "Prevalence and clinical features of mitral valve prolapse". Am Heart J. 113 (5): 1281–90. doi:10.1016/0002-8703(87)90956-2. PMID 3554946. 21. ^ Warth DC, King ME, Cohen JM, Tesoriero VL, Marcus E, Weyman AE (May 1985). "Prevalence of mitral valve prolapse in normal children". Journal of the American College of Cardiology. 5 (5): 1173–7. doi:10.1016/S0735-1097(85)80021-8. PMID 3989128. 22. ^ Barlow JB, Bosman CK (1966). "Aneurysmal protrusion of the posterior leaflet of the mitral valve. An auscultatory-electrocardiographic syndrome". Am Heart J. 71 (2): 166–78. doi:10.1016/0002-8703(66)90179-7. PMID 4159172. ## Further reading[edit] * Confronting Mitral Valve Prolapse Syndrome by Lyn Frederickson, 1992, ISBN 0-44639-407-6 * Taking Control: Living With the Mitral Valve Prolapse Syndrome by Kristine A. Scordo, 2006, ISBN 1-42431-576-X * Mitral Valve Prolapse: A Comprehensive Patient's Guide to a Happier and Healthier Life by Ariel Soffer, M.D., 2007, ISBN 0-61515-205-8 ## External links[edit] Scholia has a topic profile for Mitral valve prolapse. * Mitral valve prolapse at Curlie Classification D * ICD-10: I34.1 * ICD-9-CM: 394.0, 424.0 * OMIM: 157700 * MeSH: D008945 * DiseasesDB: 8303 External resources * MedlinePlus: 000180 * eMedicine: emerg/316 * Patient UK: Mitral valve prolapse * v * t * e Cardiovascular disease (heart) Ischaemic Coronary disease * Coronary artery disease (CAD) * Coronary artery aneurysm * Spontaneous coronary artery dissection (SCAD) * Coronary thrombosis * Coronary vasospasm * Myocardial bridge Active ischemia * Angina pectoris * Prinzmetal's angina * Stable angina * Acute coronary syndrome * Myocardial infarction * Unstable angina Sequelae * hours * Hibernating myocardium * Myocardial stunning * days * Myocardial rupture * weeks * Aneurysm of heart / Ventricular aneurysm * Dressler syndrome Layers Pericardium * Pericarditis * Acute * Chronic / Constrictive * Pericardial effusion * Cardiac tamponade * Hemopericardium Myocardium * Myocarditis * Chagas disease * Cardiomyopathy * Dilated * Alcoholic * Hypertrophic * Tachycardia-induced * Restrictive * Loeffler endocarditis * Cardiac amyloidosis * Endocardial fibroelastosis * Arrhythmogenic right ventricular dysplasia Endocardium / valves Endocarditis * infective endocarditis * Subacute bacterial endocarditis * non-infective endocarditis * Libman–Sacks endocarditis * Nonbacterial thrombotic endocarditis Valves * mitral * regurgitation * prolapse * stenosis * aortic * stenosis * insufficiency * tricuspid * stenosis * insufficiency * pulmonary * stenosis * insufficiency Conduction / arrhythmia Bradycardia * Sinus bradycardia * Sick sinus syndrome * Heart block: Sinoatrial * AV * 1° * 2° * 3° * Intraventricular * Bundle branch block * Right * Left * Left anterior fascicle * Left posterior fascicle * Bifascicular * Trifascicular * Adams–Stokes syndrome Tachycardia (paroxysmal and sinus) Supraventricular * Atrial * Multifocal * Junctional * AV nodal reentrant * Junctional ectopic Ventricular * Accelerated idioventricular rhythm * Catecholaminergic polymorphic * Torsades de pointes Premature contraction * Atrial * Junctional * Ventricular Pre-excitation syndrome * Lown–Ganong–Levine * Wolff–Parkinson–White Flutter / fibrillation * Atrial flutter * Ventricular flutter * Atrial fibrillation * Familial * Ventricular fibrillation Pacemaker * Ectopic pacemaker / Ectopic beat * Multifocal atrial tachycardia * Pacemaker syndrome * Parasystole * Wandering atrial pacemaker Long QT syndrome * Andersen–Tawil * Jervell and Lange-Nielsen * Romano–Ward Cardiac arrest * Sudden cardiac death * Asystole * Pulseless electrical activity * Sinoatrial arrest Other / ungrouped * hexaxial reference system * Right axis deviation * Left axis deviation * QT * Short QT syndrome * T * T wave alternans * ST * Osborn wave * ST elevation * ST depression * Strain pattern Cardiomegaly * Ventricular hypertrophy * Left * Right / Cor pulmonale * Atrial enlargement * Left * Right * Athletic heart syndrome Other * Cardiac fibrosis * Heart failure * Diastolic heart failure * Cardiac asthma * Rheumatic fever *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Mitral valve prolapse

c0026267

wikipedia

https://en.wikipedia.org/wiki/Mitral_valve_prolapse

{"mesh": ["D008945"], "umls": ["C0026267"], "icd-9": ["394.0", "424.0"], "wikidata": ["Q735652"]}

## Summary ### Clinical characteristics. Sitosterolemia is characterized by: * Hypercholesterolemia (especially in children) which (1) shows an unexpected significant lowering of plasma cholesterol level in response to low-fat diet modification or to bile acid sequestrant therapy; or (2) does not respond to statin therapy; * Tendon xanthomas or tuberous (i.e., planar) xanthomas that can occur in childhood and in unusual locations (heels, knees, elbows, and buttocks); * Premature atherosclerosis, which can lead to angina, aortic valve involvement, myocardial infarction, and sudden death; * Hemolytic anemia, abnormally shaped erythrocytes (stomatocytes), and large platelets (macrothrombocytopenia). On occasion, the abnormal hematologic findings may be the initial presentation or the only clinical feature of this disorder. Arthritis, arthralgias, and splenomegaly may sometimes be seen and one study has concluded that "idiopathic" liver disease could be undiagnosed sitosterolemia. The clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis and the fact that the phenotype in infants is likely to be highly dependent on diet. ### Diagnosis/testing. In an individual with sitosterolemia, increased plasma concentrations of plant sterols (especially sitosterol, campesterol, and stigmasterol) are observed – if the diet includes plant-derived food, which contain plant sterols – once the plant sterols have accumulated in the body. The diagnosis of sitosterolemia is established in a proband with greatly increased plant sterol concentrations in plasma and/or by identification of biallelic pathogenic variants in ABCG5 and/or ABCG8. ### Management. Treatment of manifestations: Treatment should begin at the time of diagnosis, though there is little experience treating children younger than age two years. Treatment can decrease plasma concentrations of cholesterol and sitosterol by 10% to 50%. Often existing xanthomas regress. Treatment recommendations include a diet low in shellfish sterols and plant sterols (vegetable oils, margarine, nuts, seeds, avocados, and chocolate) and use of the sterol absorption inhibitor, ezetimibe. In those with an incomplete response to ezetimibe, use of a bile acid sequestrant such as cholestryramine may be considered. Partial ileal bypass surgery may be considered as a last resort for those with poor response to maximal therapies. If arthritis, arthralgias, anemia, thrombocytopenia, and/or splenomegaly require treatment, the first step is management of the sitosterolemia, followed by routine symptomatic management. Surveillance: Begin monitoring at the time of diagnosis on an annual basis: plasma concentrations of plant sterols (primarily beta-sitosterol and campesterol) and cholesterol; the size, number, and distribution of xanthomas; and CBC and platelet count, and liver transaminases (for elevation). In persons with long-standing untreated sitosterolemia, noninvasive imaging is used to exclude coronary and carotid plaque as well as valvular atherosclerotic manifestations. Agents/circumstances to avoid: Margarines and other products containing stanols (e.g., campestanol and sitostanol) that are recommended for use by persons with hypercholesterolemia are contraindicated as they can exacerbate plant stanol accumulation. Evaluation of relatives at risk: Early diagnosis of at-risk relatives either through measurement of plasma concentrations of plant sterols or through molecular genetic testing (if the family-specific pathogenic variants are known) allows early institution of treatment and surveillance to optimize outcome. Pregnancy management: There are no adequate and well-controlled studies of ezetimibe in pregnant women; ezetimibe can be used during pregnancy only if the potential benefits justifiy the risk to the fetus. Since no studies have been published on the fetal effects of ezetimibe, it should be used with caution during pregnancy. ### Genetic counseling. Sitosterolemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol. Once the sitosterolemia-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible. ## Diagnosis Formal diagnostic criteria for sitosterolemia have not been established. ### Suggestive Findings Sitosterolemia should be suspected in individuals with the following: * Hypercholesterolemia (especially in children) that shows unexpected significant response (i.e., lowering of plasma cholesterol level) to low-fat diet modification (e.g., low saturated fat/low cholesterol/low plant-derived foods) or to bile acid sequestrant (e.g. cholestyramine) therapy [Cobb et al 1996, Park et al 2014] * Hypercholesterolemia that does not respond to statin therapy [Nguyen et al 1990, Cobb et al 1996] * Tendon xanthomas or tuberous xanthomas, which may occur in childhood and in unusual locations (heels, knees, elbows, and buttocks) [Niu et al 2010] * Premature atherosclerosis, which may lead to angina, myocardial infarction, and sudden death [Kidambi & Patel 2008] * Hemolytic anemia usually associated with abnormally shaped erythrocytes (stomatocytes) and/or thrombocytopenia usually associated with large platelets (macrothrombocytopenia) Note: The hematologic abnormalities can be the initial presentation [Rees et al 2005, Su et al 2006] or the only clinical feature of the disorder [Wang et al 2011]. Note: The complete clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis. Furthermore, the phenotype in infants is likely to be highly dependent on diet. ### Establishing the Diagnosis The diagnosis of sitosterolemia is established in a proband with greatly increased plant sterol concentrations in plasma and/or by identification of biallelic pathogenic variants one or both of the genes listed in Table 1. Measurement of plasma plant sterol concentrations. Individuals with sitosterolemia have greatly increased plant sterol concentrations (especially sitosterol, campesterol, and stigmasterol) in plasma. Shellfish sterols can also be elevated. * Typical plant sterol concentrations in healthy individuals are 100 times lower than cholesterol (0.21 ± 0.7 mg/dL); thus, their contribution to the total sterol concentration is negligible. These plant sterols and shellfish sterols are not detected by standard laboratory methods of cholesterol measurement and require specialized analysis typically utilizing gas chromatography (GC), gas chromatography / mass spectrometry (GC/MS), high-pressure liquid chromatography (HPLC) or separation with tandem mass spectrometry (LC-MS/MS). * In untreated individuals with sitosterolemia the sitosterol concentration can be 30- to 100-fold increased (i.e., as high as 10 to 65 mg/dL) [Kidambi & Patel 2008]. Plasma concentrations of sitosterol above 1 mg/dL are considered to be diagnostic of sitosterolemia (except in infants, in whom further testing may be necessary; see following Note). Note: (1) In individuals with sitosterolemia the plant sterol transporters sterolin-1 (encoded by ABCG5) and sterolin-2 (encoded by ABCG8) are abnormal at birth; however, the increase in the plasma concentration of sitosterol and other plant sterols does not occur until plant-derived foods (which contain plant sterols) are consumed and the plant sterols accumulate in the body. Thus, even using GC, GC/MS, HPLC, or LC-MS/MS to measure plasma sitosterol concentrations, the diagnosis of sitosterolemia cannot be excluded until the child is consuming foods that contain plant oils. Formula-fed infants with sitosterolemia may have high plasma concentrations of cholesterol and plant sterols. (2) Total parenteral nutrition with intralipid often contains plant sterols; caution is advised in interpreting diagnostic testing for sitosterolemia in this situation. (3) Breast-fed infants with sitosterolemia likely will not have increased concentrations of plant sterols until after weaning [Rios et al 2010]. Of note, one breastfed infant age three months with sitosterolemia had increased plasma concentrations of sitosterol [Niu et al 2010]. False positive results have been observed: * Normal infants ingesting commercial infant formula (which contains plant sterols) may have a transient increase in plasma plant sterols, probably due to immature transporters [Mellies et al 1976, Steiner 2011]. * Patients with cholestasis or liver disease receiving parenteral nutrition (which often contains plant sterols in intralipids) may be unable to effectively clear the plant sterols [Bindl et al 2000, Llop et al 2008, Kurvinen et al 2011]. Infants without obvious cholestasis or liver disease receiving parenteral nutrition who do not have sitosterolemia may also exhibit elevation of plasma plant sterols. * Heterozygotes (carriers of one ABCG5 or ABCG8 pathogenic variant) may occasionally have mildly elevated concentration of sitosterol [Lee et al 2001], which can be exacerbated with plant sterols [Myrie et al 2012]. (Note, however, that plasma concentrations of sitosterol are usually normal in carriers [Kwiterovich et al 2003]). False negative results can be observed in: * Individuals using ezetimibe or ezetimibe combinations, or bile acid-binding resin; AND/OR * Individuals on a diet low in plant-derived foods. Note: (1) In general plasma cholesterol concentration is not diagnostic because it can be normal in individuals with sitosterolemia, and elevations of plasma cholesterol concentration can be seen in numerous common disorders. (2) In sitosterolemia, plasma concentrations of cholesterol in children can be high, even in the range seen in homozygous familial hypercholesterolemia [Togo et al 2009, Niu et al 2010, Rios et al 2010, Renner et al 2016]. Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of sitosterolemia has not been considered are more likely to be diagnosed using genomic testing (see Option 2). #### Option 1 When the phenotypic and laboratory findings suggest the diagnosis of sitosterolemia, the molecular genetic testing approach is use of a multigene panel. A panel that includes ABCG5 or ABCG8 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. #### Option 2 When the diagnosis of sitosterolemia is not considered because an individual has atypical phenotypic features or laboratory results, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that may not be detected by sequence analysis. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. ### Table 1. Molecular Genetic Testing Used in Sitosterolemia View in own window Gene 1, 2Proportion of Sitosterolemia Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Detectable by Method Sequence analysis 4Gene-targeted deletion/duplication analysis 5 ABCG542%>95% 6None reported 7, 8 ABCG858%>95% 6None reported 7, 8 1\. Genes are listed in alphabetic order. 2\. See Table A. Genes and Databases for chromosome locus and protein. 3\. See Molecular Genetics for information on allelic variants detected in these genes. 4\. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here. 5\. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 6\. From 40 publications [Berge et al 2000, Hubacek et al 2001, Lu et al 2001, Heimerl et al 2002, Sehayek et al 2004, Wang et al 2004, Wilund et al 2004, Rees et al 2005, Solcà et al 2005, Su et al 2006, Kratz et al 2007, Mannucci et al 2007, Togo et al 2009, Niu et al 2010, Rios et al 2010, Tsubakio-Yamamoto et al 2010, Keller et al 2011, Wang et al 2011, Chong et al 2012, Horenstein et al 2013, Colima Fausto et al 2016, Rodriguez et al 2016, Tada et al 2016, Bardawil et al 2017, Bastida et al 2017, Buonuomo et al 2017, Jamwal et al 2017, Ono et al 2017, Yagasaki et al 2017, Brinton et al 2018, Fang et al 2018, Kawamura et al 2018, Martin et al 2018, Tada et al 2018, Huang et al 2019, Su et al 2019, Tada et al 2019, Veit et al 2019, Wang et al 2019, Sun et al 2020] 7\. No data on detection rate of gene-targeted deletion/duplication analysis are available. 8\. Although no deletions or duplications of ABCG5 or ABCG8 have been reported to cause sitosterolemia, the identification of only one ABCG5 or ABCG8 pathogenic variant in affected individuals could theoretically be explained by deletion of the other allele [Lu et al 2001]. ## Clinical Characteristics ### Clinical Description To date, approximately 110 individuals with biallelic pathogenic variants in ABCG5 and/or ABCG8 have been reported [Berge et al 2000, Hubacek et al 2001, Lu et al 2001, Heimerl et al 2002, Sehayek et al 2004, Wang et al 2004, Wilund et al 2004, Rees et al 2005, Solcà et al 2005, Su et al 2006, Kratz et al 2007, Mannucci et al 2007, Togo et al 2009, Niu et al 2010, Rios et al 2010, Tsubakio-Yamamoto et al 2010, Keller et al 2011, Wang et al 2011, Chong et al 2012, Horenstein et al 2013, Colima Fausto et al 2016, Rodriguez et al 2016, Tada et al 2016, Bardawil et al 2017, Bastida et al 2017, Buonuomo et al 2017, Jamwal et al 2017, Ono et al 2017, Yagasaki et al 2017, Brinton et al 2018, Fang et al 2018, Kawamura et al 2018, Martin et al 2018, Tada et al 2018, Huang et al 2019, Su et al 2019, Tada et al 2019, Veit et al 2019, Wang et al 2019, Sun et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports. Presentation. The clinical presentation of sitosterolemia varies from xanthomas and atherosclerosis and its complications to a milder phenotype with few to no specific symptoms and signs [Kidambi & Patel 2008]. Hypercholesterolemia. Individuals with sitosterolemia show an unexpected significant lowering of plasma cholesterol level in response to low-fat or low plant-derived food diet modification or to bile acid sequestrant therapy, and do not respond to statin therapy. There is evidence of an age-related change in sterol homeostasis in sitosterolemia, where plasma concentrations of cholesterol in children with sitosterolemia can be in the hypercholesterolemia range and decrease to normal cholesterol levels by adulthood [Mymin et al 2018]. Tendon or tuberous xanthomas. Although the tuberous xanthomas are more typically seen in adults, they may appear at any age, even in children. Children may have xanthomas in unusual locations such as the buttocks, heels, elbows, and knees. Xanthomas have been reported in children as young as ages one to two years [Shulman et al 1976, Hubacek et al 2001, Niu et al 2010], four years [Togo et al 2009], and six years [Salen et al 2006, Mannucci et al 2007]. A child age ten years with tendon xanthomas was reported [Solcà et al 2005]. Premature atherosclerosis. Ten individuals with sitosterolemia with early-onset (age 5-33 years) atherosclerosis with or without sudden death have been reported [Miettinen 1980, Kwiterovich et al 1981, Salen et al 1985, Watts & Mitchell 1992, Kolovou et al 1996, Heimerl et al 2002, Katayama et al 2003, Mymin et al 2003, Salen et al 2006, Tsubakio-Yamamoto et al 2010]. * Assessment for premature atherosclerosis should include noninvasive imaging to exclude coronary and carotid plaque as well as atherosclerotic manifestations (e.g. heart murmurs and vascular bruits). * Because of the limited number of reports, the incidence of coronary artery disease is not known. Hematologic abnormality. Hemolytic anemia and/or thrombocytopenia can be the initial presentation [Rees et al 2005, Su et al 2006] or the only clinical feature of the disorder [Wang et al 2011, Zheng et al 2019]. The hemolytic anemia may be associated with low hemoglobin levels of 76 to 109 g/L and the thrombocytopenia has been reported with platelet counts as low as 12 to 82 x 109/L [Wang et al 2014, Zheng et al 2019]. Other findings * On occasion arthritis, arthralgias, and splenomegaly are also seen. * Miettinen et al [2006] described an individual with chronic non-A non-B hepatitis and cirrhosis in whom the diagnosis of sitosterolemia was serendipitously made by plasma analysis of sitosterol, and further confirmed by the finding of the biallelic ABCG8 pathogenic variants. Following liver transplantation, the sitosterolemia unexpectedly resolved and plant sterol levels fell to the same levels seen in unaffected individuals. Although it is unknown if the liver problem was initially due to the sitosterolemia, the findings suggest that "idiopathic" liver disease could indeed be undiagnosed sitosterolemia. The authors concluded that an unaffected liver can overcome the intestinal transport defect in clearing the plant sterols from the circulation. Intrafamilial variability has been reported in two consanguineous families: * In one family, phenotypic variablilty was seen in three affected sibs and one affected first cousin with the same genotype [Wang et al 2004]. One child had abdominal pain, anemia, xanthomas, and early cardiac death; the others had high plasma concentrations of cholesterol and plant sterols but no other symptoms. * In another family the mother and brother of the proband were homozygous for the same nucleotide change in ABCG5. All had increased concentrations of plasma sitosterol; however, only the proband (age 6 years) had xanthomas. The mother and brother, who had no evidence of xanthomas, had much lower cholesterol concentrations [Mannucci et al 2007]. ### Genotype-Phenotype Correlations No genotype-phenotype correlations for ABCG5 and ABCG8 have been identified. ### Nomenclature The disorder was named β-sitosterolemia by the investigators who first described it [Bhattacharyya & Connor 1974]. ### Prevalence To date, about 110 individuals with molecularly confirmed sitosterolemia have been reported worldwide [Tada et al 2018]. Because the usual clinical test for plasma concentration of cholesterol does not measure plant sterols, sitosterolemia is likely to be underdiagnosed. In a population-based study, the data suggest a much higher prevalence than that indicated by the small number of known cases [Wilund et al 2004]; these researchers identified one individual with sitosterolemia out of 2542 persons in whom plasma concentration of plant sterols was analyzed, data that support a prevalence of 1/384 to 1/48,076 (95% confidence interval). Sitosterolemia has been described in persons of Hutterite, Amish, Japanese, and Chinese ancestry as well as in other populations [Lu et al 2001]. Populations that show a high prevalence include: * The Old Order Amish. Carrier frequency up to 4% * North American Hutterites. Carrier frequency 8% [Chong et al 2012] * The inhabitants of Kosrae (Micronesia). Adult carrier frequency 13% [Sehayek et al 2004] A founder effect is evident in certain populations [Lu et al 2001]: * Northern Europeans / individuals of northern European heritage more frequently have pathogenic variants in ABCG8. * Chinese, Japanese, and Indian individuals tend to have pathogenic variants in ABCG5. ## Differential Diagnosis ### Hereditary Disorders in the Differential Diagnosis of Sitosterolemia ### Table 2. Genes of Interest in the Differential Diagnosis of Sitosterolemia View in own window Gene(s)DisorderMOIFeatures of Differential Disorder Overlapping w/sitosterolemiaDistinguishing from sitosterolemia ABCA1Tangier disease (analphalipoprotein-emia)ARStomatocytosis * Extreme ↓ circulating HDL-C levels (<1-2 mg/dL) * Extreme hypercholesterolemia APOB LDLR PCSK9Familial hypercholesterolemia 1 (also called heterozygous FH)ADXanthomas in children * Extreme hypercholesterolemia: LDL-C levels >190 mg/dL in untreated adults * LDL-C levels >130 mg/dL in untreated children/adolescents * Not assoc w/macro-thrombocytopenia Homozygous FH 2ADXanthomas in children * Both parents of affected child have hypercholesterolemia. * LDL-C levels are generally >500 mg/dL in untreated adults (levels can be lower in children). * Not assoc w/macro-thrombocytopenia CYP27A1Cerebrotendinous xanthomatosisARXanthomas in children * ↑ concentrations of plasma cholestanol, childhood-onset protracted diarrhea, & cataracts * Typically, neurologic involvment in affected adults LCATLecithin-cholesterol aceyl transferase (LCAT) deficiency (OMIM 245900)ARStomatocytosis * Extreme ↓ circulating HDL-C levels (<10 mg/dL) * ↑ VLDL-C & triglycerides AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; FH = familial hypercholesterolemia; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; VLDL-C = very low-density lipoprotein cholesterol 1\. FH results from a heterozygous pathogenic variant in APOB, LDLR, or PCSK9. 2\. Homozygous FH results from biallelic (homozygous or compound heterozygous) pathogenic variants in APOB, LDLR, or PCSK9. ### Other Disorders in the Differential Diagnosis of Sitosterolemia The combination of hemolysis and thrombocytopenia can occur in the following conditions (in which large platelets are not observed): * Liver disease * Thrombotic thrombocytopenic purpura * Systemic lupus erythematosus (SLE) Stomatocytosis can be associated with Rhnull condition. ## Management ### Evaluations Following Initial Diagnosis ### Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Sitosterolemia View in own window System/ConcernEvaluationComment Plant sterol levelsMeasure plasma concentrations of plant sterols (primarily beta-sitosterol & campesterol) & cholesterol. XanthomasDetermine size, number, & distribution of xanthomas (tendon & tuberous). HeartCardiology consultation to evaluate for atherosclerosis & cardiac valve abnormalitiesConsider use of coronary artery calcium score (from cardiac CT) or coronary arteriography as needed. Hematologic abnormalities * CBC w/smear to look for platelet abnormalities &/or thrombocytopenia * Eval for possible hemolysis/ hemolytic anemia LiverBaseline liver function (albumin, ALT, AST, ALP, bilirubin) SpleenEvaluate for splenomegaly.If present, consultation w/hematologist & gastroenterologist JointsEvaluate for arthralgias &/or arthritis. Genetic counselingBy genetics professionals 1To inform individuals & families re nature, MOI, & implications of sitosterolemia in order to facilitate medical & personal decision making CBC = complete blood count; MOI = mode of inheritance 1\. Medical geneticist, certified genetic counselor, certified advanced genetic nurse ### Treatment of Manifestations Treatment should begin at the time of diagnosis, though there is little experience treating children younger than age two years. Treatment can decrease the plasma concentrations of cholesterol and sitosterol by 10% to 50%. Existing xanthomas often regress. Arthritis, arthralgias, anemia, thromobocytopenia, and/or splenomegaly require treatment, the first step being management of the sitosterolemia, followed by routine management of the finding (by the appropriate consultants) as needed. Note: Sitosterolemia does not respond to standard statin treatment. ### Table 4. Treatment of Manifestations in Individuals with Sitosterolemia View in own window ManifestationTreatmentConsiderations/Other Elevated plant sterol levels * Diet low in shellfish sterols & plant sterols (i.e., avoidance of vegetable oils, margarine, nuts, seeds, avocados, chocolate, & shellfish) * Treatment w/sterol absorption inhibitor ezetimibe (10 mg/day in adults) * Bile acid sequestrants such as cholestryramine (8-15 g/day) may be considered in those w/incomplete response to ezetimibe. Partial ileal bypass surgery (i.e., shortening of the ileum) has been used to ↑ intestinal bile acid loss.Partial or complete ileal bypass surgery in persons w/sitosterolemia has resulted in ≥50% ↓ of plasma & cellular sterol & stanol levels but should be used only as a last resort now that ezetimibe is available. ### Surveillance ### Table 5. Recommended Annual Surveillance for Individuals with Sitosterolemia View in own window System/ConcernEvaluation Plant sterol levels * Plasma concentrations of plant sterols (primarily beta-sitosterol & campesterol) & cholesterol * Evaluate size, number, & distribution of xanthomas. Hematologic abnormalitiesCBC & platelet count Liver functionLiver transaminases Atherosclerosis & coronary artery disease (esp in those w/longstanding untreated sitosterolemia)Noninvasive imaging to exclude coronary & carotid plaque as well as valvular atherosclerotic manifestations CBC = complete blood count ### Agents/Circumstances to Avoid Margarines and other products containing stanols (e.g., campestanol and sitostanol), which are recommended for use by persons with hypercholesterolemia, are contraindicated in those with sitosterolemia as they can exacerbate plant stanol accumulation [Connor et al 2005]. Note: Foods with high plant sterol content including shellfish, vegetable oils, margarine, nuts, avocados, and chocolate should be taken in moderation due to increased intestinal absorption of plant sterols in those with sitosterolemia [Bhattacharyya & Connor 1974]. ### Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early institution of treatment and surveillance. Evaluations include the following: * Molecular genetic testing if the ABCG5 or ABCG8 pathogenic variants have been identified in an affected family member * Measurement of plasma concentrations of plant sterols if the family-specific pathogenic variants are not known See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management Guidelines for the management of women with sitosterolemia during pregnancy have not been established. There are no adequate and well-controlled studies of ezetimibe in pregnant women; ezetimibe can be used during pregnancy only if the potential benefits justify the risk to the fetus (Ezetimibe drug monograph). See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Sitosterolemia

c0342907

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK131810/

{"mesh": ["C537345"], "synonyms": ["Beta-Sitosterolemia", "Phytosterolæmia", "Phytosterolemia", "Sitosterolæmia"]}

A number sign (#) is used with this entry because 5 haplotypes arising from 3 coding SNPs in the TAS2R38 gene (607751) are associated with distinct phenotypes of phenylthiocarbamide (PTC) taste sensitivity. Description The sense of bitter taste is mediated by a group of bitter taste receptor proteins that reside on the surface of taste cells within the taste buds of the tongue. These proteins are 7-transmembrane domain, G protein-coupled receptors that are encoded by the TAS2R gene family (see TAS2R10; 604791), which contains at least 25 functional genes (Kim et al., 2005). Humans worldwide display a bimodality in sensitivity to the bitter taste of PTC, with approximately 75% of individuals perceiving it as intensely bitter, whereas the rest perceive it as tasteless. This difference has been the basis of study of taste perception in humans for over 70 years. Kim and Drayna (2004) provided an historical review of the subject. Propylthiouracil (PROP) and PTC are members of a class of compounds known as thioureas. The compounds carry the chemical group N-C=S, which is responsible for their characteristic bitter taste (Bartoshuk et al., 1994; Drewnowski and Rock, 1995). Clinical Features Variation in the ability to taste PTC was discovered by Fox (1931). Supplementation of the standard test using quinine in the intermediate cases was suggested by Kalmus (1958). There has been a suggestion that PTC tasting in man is related to a component of saliva: Cohen and Ogdon (1949) claimed that PTC tasters can taste PTC only if it is dissolved in their own saliva. If the tongue is dried and then presented with PTC dissolved in someone else's saliva, it is tasteless. Jones and McLachlan (1991) described a technique for fitting mixture distributions to data on PTC sensitivity. It has long been proposed that there is a relationship between athyreotic hypothyroidism (218700; formerly called athyreotic cretinism) and PTC nontasting (e.g., Shepard, 1961). Both PTC and PROP are structurally similar to the naturally occurring antithyroid substance l-goitrin; all members of this class of chemicals have antithyroidal activity and are not tasted by PTC nontasters (Shepard, 1961). Nearly all individuals with athyreotic hypothyroidism are nontasters. Tepper (1998) reviewed the literature for the ability to taste PTC and PROP and the implications for food preference and dietary habits. Tepper (1998) discussed the classic explanation for the persistence of the PROP polymorphism, i.e., a selective advantage for avoidance of harmful compounds in the environment that are often bitter tasting (Drewnowski and Rock, 1995). This taste aversion may have special relevance for the avoidance of certain bitter-tasting vegetables. PROP and PTC are chemically related to the isothiocyanates and goitrin, bitter-tasting compounds that are present in cruciferous vegetables such as cabbage, broccoli, brussels sprouts, turnips, and kale. When eaten in large quantities, these compounds interfere with iodine metabolism, producing thyroid enlargement and goiterlike symptoms. Tepper (1998) noted that the incidence of thyroid deficiency disease is relatively rare among PTC tasters. In modern society, however, avoidance of bitter-tasting foods may have health disadvantages, since epidemiologic studies indicate that diets low in fruits and vegetables and high in fat may be associated with increased risk of heart disease and cancer. Kinnamon (2000) reviewed the role of taste receptors in taste transduction. Inheritance Reddy and Rao (1989) examined the genetics of PTC taste thresholds by studying 100 nuclear families. They concluded that variability in thresholds is controlled by a major locus with incomplete dominance, as well as by a multifactorial component. Olson et al. (1989) studied 120 families and concluded that the data fitted best a 2-locus model in which one locus controls PTC tasting and the other locus controls a more general taste ability. Mapping Chautard-Freire-Maia (1974) found evidence for linkage of PTC to blood group Kell (KEL; 110900). Crandall and Spence (1974) tested linkage of PTC with 18 autosomal loci. None was found, although linkage of Gm (147100) and PTC was suggested by analysis of recombination in the male parent. A number of small scores, when combined, hinted that KEL and PTC may be linked to Colton, Km, and Kidd (Jk), which were thought to be on chromosome 7 (Keats et al., 1978). Conneally et al. (1976) found close linkage of PTC and KEL, with a lod score of 10.78 at theta = 0.045. Spence et al. (1984) analyzed 2 new sets of data on the PTC-KEL linkage. The new data gave a theta of 0.28 (sexes combined); male theta was estimated as 0.29 and female as 0.23. The estimate of theta for all published data was 0.14 (lod = 8.94), with statistically significant evidence of heterogeneity among the published studies. Reed et al. (1999) identified a locus on chromosome 5p15 as giving the strongest evidence for linkage to PROP tasting, with the peak score near D5S2505. In addition to chromosome 5, there was a suggestion of linkage on chromosome 7, about 35 to 40 cM centromeric to the KEL locus, with a maximum t-score of 2.34 (P = 0.008) near D7S1789 and D7S796. The results of the study by Reed et al. (1999) suggested that the region on chromosome 7 may also influence the taster phenotype. Prodi et al. (2002) reported linkage to 7q35 in a Sardinian genetic isolate. Kim et al. (2003) identified a small region on chromosome 7q that showed strong linkage disequilibrium between SNP markers and PTC taste sensitivity in unrelated subjects. This region was narrowed to a 2.6-Mb interval using the Utah CEPH families and further narrowed to a 150-kb interval of linkage disequilibrium extending from about 139,835,000 to 139,981,000 basepairs on the chromosome 7 sequence. Drayna et al. (2003) undertook a genetic analysis of the ability to taste PTC. They obtained a quantitative measure of PTC tasting ability in 267 members of 26 large 3-generation Utah CEPH families that had been used for genetic mapping. Significant bimodality was found for the distribution of age and gender adjusted scores (P less than 0.001). They performed a genome screen by using 1,324 markers with an average spacing of 4 cM. Analyses were first carried out with a recessive genetic model that had traditionally been assumed for the trait, and a threshold score of 8.0 delineating tasters from nontasters. In this qualitative analysis, the maximum genomewide lod score was 4.74 at 246 cM on chromosome 7; 17 families showed segregation of the dichotomous PTC phenotype. No other lod scores were significant; the next highest score was on chromosome 10 (lod = 1.64 at 85 cM), followed by chromosome 3 (lod = 1.29 at 267 cM). Treating PTC taste ability as a quantitative variable, they found a maximum quantitative genomewide lod score of 8.85 at 246 cM on chromosome 7. Drayna (2003) stated that position 246 cM resides in the region 7q35-q36, and is probably at or near the boundary of these 2 cytogenetic bands. Drayna et al. (2003) found evidence for other possible quantitative loci on chromosomes 1 (lod = 2.31 at 344 cM) and 16 (lod = 2.01 at 14 cM). A subsequent 2-locus whole genome scan conditional on the chromosome 7 quantitative trait locus identified the chromosome 16 locus (2-locus lod = 3.33 at 14 cM). Drayna et al. (2003) replicated the original linkage findings with KEL on 7q. Molecular Genetics Kim et al. (2003) cloned the TAS2R38 gene (607751) and identified 3 coding SNPs giving rise to 5 haplotypes worldwide that completely explained the bimodal distribution of PTC taste sensitivity. Distinct phenotypes were associated with specific haplotypes, which demonstrated that the TAS2R38 gene has a direct influence on PTC taste sensitivity, and that sequence variants at different sites interact with each other within the encoded gene product. Fisher et al. (1939) hypothesized that the pervasive phenotypic variation in PTC perception is due to balancing natural selection, which may have favored heterozygotes. Wooding et al. (2004) examined patterns of DNA sequence variation to test the PTC gene for evidence of long-term selected pressures. They analyzed the entire coding region of PTC (1,002 bp) in a sample of 330 chromosomes from different populations (62 African, 138 Asian, 110 European, and 20 North American) by use of statistical tests for natural selection that take into account the potentially confounding effects of human population growth. Two haplotypes of intermediate frequency corresponding to 'taster' and 'nontaster' phenotypes were found. These haplotypes had similar frequencies across Africa, Asia, and Europe. Genetic differentiation between the continental population samples was low in comparison with estimates based on other genes. In addition, a significant deviation from neutrality was found because of an excess of variants of intermediate frequency when human population growth was taken into account. These results supported the hypothesis of Fisher et al. (1939) and suggested that balancing natural selection has acted to maintain 'taster' and 'nontaster' alleles at the PTC locus. Kim et al. (2005) sequenced 24 human TAS2R genes in 55 unrelated individuals of African, Asian, European, and North American Native ancestry, and found a high degree of nucleotide variation. A total of 144 SNPs were identified with an average of 4.2 variant amino acids per gene. In aggregate, the 24 genes analyzed specified 151 different protein-coding haplotypes. Data analysis showed that the observed excess of nonsynonymous nucleotide substitutions was much higher than expected given observations in other genes. Kim et al. (2005) hypothesized that natural selection may have been relaxed on these genes and that local adaptation in human bitter taste receptor genes is common, driven by the fitness advantages of avoiding toxins found in plants. The findings were consistent with the view that different alleles of the TAS2R genes encode receptors that recognize different ligands. Population Genetics Kim and Drayna (2004) stated that the frequency of PTC nontasters in Caucasians is approximately 28%. Henkin and Gillis (1977) observed that 2 of 8 people served a pie made from berries of the tree Antidesma bunius, a popular fruit in southeast Asia and Florida, found their dessert bitter and inedible, whereas the remainder found it edible and sweet. They studied 170 predominantly Caucasian American male and female volunteers aged 7 to 89 years and found that 15% found antidesma berries bitter and 68% found PTC bitter. The results were independent of age, sex, race, national origin, color blindness, and ichthyosis. The antidesma nonresponders deemed it slightly sour, sweet, salty, or tasteless. None of those who found antidesma bitter tasted PTC, and no PTC responders found antidesma bitter. Analysis of 3 families in which the father, but not the mother, was an antidesma responder identified only 1 son who shared the antidesma response. The substance responsible for the antidesma taste response was unknown, but it was found to be water soluble and heat stable. History Nebert (1997) suggested that the first example of pharmacogenetics was the phenylthiourea nontaster trait first described by Snyder (1932). Nebert (1997) used the occasion of the sixty-fifth anniversary of that discovery to review other discoveries in chronologic sequence: G6PD deficiency (300908) in 1956; N-acetylation polymorphism (243400) in 1959; genetic variation in ethanol metabolism by alcohol dehydrogenase and aldehyde dehydrogenase in 1964; debrisoquine/sparteine oxidation polymorphism, found in 1977 and subsequently shown to be due to polymorphism of the CYP2D6 gene (124030); and thiopurine methyltransferase polymorphism (TPMT; 187680), first found in 1980. Animal Model Azen et al. (1986) found close linkage between genes for proline-rich proteins of saliva (PRPs; see 168730, etc.) and taste for some bitter substances in mice. This suggested that PTC and genes for salivary proline-rich proteins, which are clustered on chromosome 12, might be linked in man; however, O'Hanlon et al. (1988) demonstrated that they are not linked. Endocrine \- Relationship between PTC nontasting to cretinism Misc \- Variation in ability to taste PTC Inheritance \- Autosomal dominant \- possibly two loci involved ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

THIOUREA TASTING

c1868400

omim

https://www.omim.org/entry/171200

{"omim": ["171200"]}

Acquired progressive lymphangioma Other namesBenign lymphangioendothelioma SpecialtyOncology Acquired progressive lymphangioma is a group of lymphangiomas that occur anywhere in young individuals, grow slowly, and present as bruise-like lesions or erythematous macules.[1]:597 ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. ## External links[edit] Classification D * ICD-10: D18.1 * ICD-O: M9170/1 * v * t * e Tumours of blood vessels Blood vessel * Hemangiosarcoma * Blue rubber bleb nevus syndrome * Hemangioendothelioma * Composite * Endovascular papillary * Epithelioid * Kaposiform * Infantile * Retiform) * Spindle cell * Proliferating angioendotheliomatosis * Hemangiopericytoma * Venous lake * Kaposi's sarcoma * African cutaneous * African lymphadenopathic * AIDS-associated * Classic * Immunosuppression-associated * Hemangioblastoma * Hemangioma * Capillary * Cavernous * Glomeruloid * Microvenular * Targeted hemosiderotic * Angioma * Cherry * Seriginosum * Spider * Tufted * Universal angiomatosis * Angiokeratoma * of Mibelli * Angiolipoma * Pyogenic granuloma Lymphatic * Lymphangioma/lymphangiosarcoma * Lymphangioma circumscriptum * Acquired progressive lymphangioma * PEComa * Lymphangioleiomyomatosis * Cystic hygroma * Multifocal lymphangioendotheliomatosis * Lymphangiomatosis Either * Angioma/angiosarcoma * Angiofibroma This Dermal and subcutaneous growths article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Acquired progressive lymphangioma

c0024217

wikipedia

https://en.wikipedia.org/wiki/Acquired_progressive_lymphangioma

{"mesh": ["D008202"], "umls": ["C0024217"], "icd-10": ["D18.1"], "wikidata": ["Q4674778"]}

Brittle diabetes is a term that is sometimes used to describe hard-to-control diabetes (also called labile diabetes). It is characterized by wide variations or “swings” in blood glucose (sugar) in which blood glucose levels can quickly move from too high (hyperglycemia) to too low (hypoglycemia). These episodes are hard to predict and can disrupt quality of life. They can require frequent or lengthy hospitalizations and can be fatal. People with type 1 diabetes are at greatest risk. While many people with type 1 diabetes experience hypoglycemia, only a small proportion of people with type 1 diabetes experience the frequent blood glucose swings described as “brittle.” People with long-standing type 2 diabetes may also have difficulty controlling blood glucose, but few have these frequent swings. People of any age with diabetes can be affected with these frequent ups and downs in blood glucose levels. Some research suggests that women may be affected more often than men. Frequent episodes of hypoglycemia can lead to hypoglycemic unawareness and make the condition worse. Keeping diabetes under good control for at least several weeks can restore hypoglycemic awareness. New technologies such as continuous glucose monitors and insulin pumps may help improve control. In diabetes, many factors can trigger frequent changes in blood glucose levels. For example, people who don’t test blood glucose or take diabetes medications as prescribed often experience significant fluctuations in blood glucose levels. Other causes of unstable blood glucose levels include emotional stress, eating disorders, drug or alcohol use, malabsorption, gastroparesis, and celiac disease. The development of new treatments for diabetes has made it easier for most people to control their blood glucose levels. Artificial pancreas technology is currently being tested in clinical trials and aims to help people with type 1 diabetes more easily manage blood glucose levels. In 2016, the U.S. Food and Drug Administration approved a hybrid model of an artificial pancreas, an automated system that requires users to adjust insulin intake at mealtimes. NIH-funded research on islet cell transplantation has also shown promising results in restoring blood glucose control. This research specifically includes people who have experienced episodes of severe hypoglycemia. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Brittle diabetes

c0342302

gard

https://rarediseases.info.nih.gov/diseases/11900/brittle-diabetes

{"mesh": ["D003922"], "synonyms": ["Labile diabetes", "Brittle diabetes mellitus", "Brittle type 1 diabetes"]}

A rare, multiple congenital anomalies syndrome with cardiac involvement as a major feature characterized by QT prolongation, congenital heart defects, syndactyly, facial dysmorphism and neurodevelopmental features. There three clinical phenotypes recognized, the classical types that present with a prolonged QT interval and either with (TS1) or without (TS2) cutaneous syndactyly of fingers and toes. The atypical form (ATS) causes multi-system health concerns but not necessarily with prolonged QT. ## Epidemiology To date more than 60 cases have been reported worldwide. ## Clinical description Timothy syndrome (TS) often manifests during the neonatal period. However, in many cases it is diagnosed later, between the ages of 2-4 years old. In TS1, cardiac concerns may become apparent under anesthesia during finger separation surgery. Typical cardiac manifestations in all TS types include a rate corrected QT interval >480 ms, functional 2:1 atrio-ventricular (AV) block associated with bradycardia, tachyarrhythmias and congenital heart defects (patent ductus arteriosus, patent foramen ovale, atrial or venticular septal defects, tetralogy of Fallot, hypertrophic cardiomyopathy). Facial dysmorphia often includes round face, depressed nasal bridge, low set ears, thin vermilion of the upper lip, and hypoplasic premaxillary. Widely placed teeth with poor enamel is common. Hair is generally sparse. Cutaneous syndactyly is typical of TS1, and often noted in ATS individuals. In TS2, congenital hip abnormalities and/or hypotonia are often noted. Pulmonary health concerns include frequent pneumonia. Gastro-intestinal issues include severe constipation, and in some ATS children, complications of chronic constipation may require surgical removal. Immunodeficiencies are common. Endocrinological concerns includes unusual fluctuations in blood sugar levels resulting in life threatening hypoglycemia, primarily associated with infections, and sleep issues; some children may require growth hormones. Neuronal-developmental concerns can be profound, autism or autistic spectrum disorders are noted, delayed speech and other physical, mental and social developmental milestones are generally delayed. ## Etiology TS is due to mutations in the CACNA1C gene (12p13.33). The clinical phenotypes correlate with genotype. TS1 is specifically due to a G406R (c.1216 G>A) change in exon 8A. TS2 has the exact same G406R (c. 1216 G>A) change but in the alternatively spliced exon 8. ATS can be recognized by any CACNA1C change (excluding the G406R change) that causes multi-system health concerns. ## Diagnostic methods TS diagnosis is based on observed clinical features and molecular genetic testing confirmation. ## Differential diagnosis Non-syndromic autosomal Long QT syndrome, Jervell and Lange-Nielsen syndrome, Andersen-Tawil syndrome, Acquired Long QT syndrome, syndactyly and heart-hand related syndromes, autism associated syndromes. ## Antenatal diagnosis Echocardiography can often identify fetal distress secondary to cardiac finding of 2:1 AV Block or bradycardia. When the pathogenic CACNA1C variant has been identified in a family member, prenatal genetic testing is possible for at risk pregnancies. ## Genetic counseling Most cases arise de novo; however, in some cases, TS has been identified as an inherited autosomal dominant trait resulting from parental germline mosaicism. ## Management and treatment The main objective is to prevent ventricular fibrillation (VF) and possible sudden death. Interventions should be considered as early as possible and include the combination of left cardiac sympathetic denervation (LCSD) with an implantable cardioverter-defibrillator (ICD). A pacemaker can be placed during the first days of life to control 2:1 AV block and resultant bradycardia. Beta-blockers and/or other antiarrhythmia drugs can be administered to maintain QT interval and prevent ventricular tachyarrhythmias. Drugs that prolong QT interval should be avoided, and all medical procedures requiring anesthesia should be performed with caution. Additional congenital heart defects, respiratory infections, hypoglycemia, and skeletal/smooth muscle anomalies should be managed according to standard protocols. Drugs and dietary practices that could lead to hypoglycemia should be avoided for patients treated with beta-blockers. ## Prognosis Without prompt and appropriate treatment for cardiac concerns, the disease is usually fatal in infancy and early childhood due to arrhythmias precipitated by infections, severe illnesses, hypoglycemia or from complications associated with anesthesia. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Timothy syndrome

c1832916

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=65283

{"gard": ["9294"], "mesh": ["C536962"], "omim": ["601005", "618447"], "umls": ["C1832916"], "icd-10": ["I45.8"], "synonyms": ["LQT8", "Long QT syndrome type 8", "Long QT syndrome-syndactyly syndrome"]}

A number sign (#) is used with this entry because of evidence that this form of congenital cerebellar ataxia with mental retardation (CAMRQ4) is caused by homozygous mutation in the ATP8A2 gene (605870) on chromosome 13q12. One such family has been reported. Description Cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ) is a genetically heterogeneous disorder characterized by congenital cerebellar ataxia and mental retardation (summary by Gulsuner et al., 2011). For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050). Clinical Features Onat et al. (2013) reported a consanguineous Turkish family in which 4 individuals had a severe neurologic disorder characterized by mental retardation, dysarthria, and truncal ataxia with or without quadrupedal gait. Brain MRI showed mild atrophy of the cerebral cortex, corpus callosum, and inferior cerebellum. The family had previously been reported as 'family C' by Ozcelik et al. (2008). ### Etiology of Quadrupedal Locomotion Ozcelik et al. (2008) maintained that quadrupedal locomotion in the affected individuals results from abnormal function of brain structures that are critical for gait. Humphrey et al. (2008) concluded that the tendency toward quadrupedal locomotion in affected individuals is an adaptive and effective compensation for problems with balance caused by congenital cerebellar hypoplasia. Thus, the unusual gait could be attributed to the local cultural environment. Herz et al. (2008) also concluded that quadrupedal locomotion is more likely an adaptation to severe truncal ataxia, resulting from a combination of uneven, rough surfaces in rural areas, imitation of affected sibs, and lack of supportive therapy. Ozcelik et al. (2008) responded and defended their position. Inheritance The transmission pattern of CAMRQ4 in the family reported by Onat et al. (2013) was consistent with autosomal recessive inheritance. Molecular Genetics In 3 affected members of a consanguineous Turkish family with cerebellar ataxia, mental retardation, and dysequilibrium syndrome (CAMRQ4), Onat et al. (2013) identified a homozygous mutation in the ATP8A2 gene (I376M; 605870.0001). The mutation, which was found by homozygosity mapping and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in several large control databases, in 1,210 control chromosomes, or in 750 patients with unknown neurologic disorders. The mutation occurred at a highly conserved residue and was predicted to alter the secondary structure of the protein, but no functional studies were performed. INHERITANCE \- Autosomal recessive NEUROLOGIC Central Nervous System \- Mental retardation \- Truncal ataxia \- Dysarthria \- Inability to walk \- Quadrupedal locomotion (in some patients) \- Cerebral atrophy \- Cerebellar atrophy \- Atrophy of the corpus callosum MISCELLANEOUS \- Onset at birth \- One family has been reported (last curated June 2013) MOLECULAR BASIS \- Caused by mutation in the ATPase, class I, type 8A, member 2 gene (ATP8A2, 605870.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

CEREBELLAR ATAXIA, MENTAL RETARDATION, AND DYSEQUILIBRIUM SYNDROME 4

c0394006

omim

https://www.omim.org/entry/615268

{"doid": ["0050997"], "omim": ["615268"], "orphanet": ["1766"], "synonyms": ["Alternative titles", "CEREBELLAR ATAXIA AND MENTAL RETARDATION WITH OR WITHOUT QUADRUPEDAL LOCOMOTION 4"]}

Plexiform fibrohistiocytic tumor is a rare tumor that arises primarily on the upper extremities of children and young adults.[1]:612 ## See also[edit] * Sarcoma ## References[edit] 1. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0. This Dermal and subcutaneous growths article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Plexiform fibrohistiocytic tumor

c1266126

wikipedia

https://en.wikipedia.org/wiki/Plexiform_fibrohistiocytic_tumor

{"umls": ["C1266126"], "wikidata": ["Q16885443"]}

Syndactyly type 3 (SD3) is a limb abnormality present at birth that is characterized by complete fusion of the 4th and 5th fingers on both hands. In most cases only the soft tissue is fused, but in some cases the bones of the fingers (distal phalanges) are fused. There is evidence that SD3 is caused by mutations in the GJA1 gene, which has also been implicated in a condition called oculodentodigital dysplasia. SD3 is the characteristic digital abnormality in this condition. SD3 is inherited in an autosomal dominant manner. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Syndactyly type 3

c1861366

gard

https://rarediseases.info.nih.gov/diseases/5088/syndactyly-type-3

{"mesh": ["C538154"], "omim": ["186100"], "umls": ["C1861366"], "orphanet": ["93404"], "synonyms": ["SDTY3", "Syndactyly of the ring and little finger", "Syndactyly of fingers four and five", "Ring and little finger syndactyly"]}

See also: Triploid syndrome This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (February 2017) Diploid triploid mosaic Other namesDiploidy Triploidy, 2n/3n Mixoploidy, Triploidy Mosaicism, Diploid Triploid Mosaicism, DTM, Mosaic Triploid Two children with DTM SpecialtyMedical genetics Diploid-triploid mosaicism (DTM) is a chromosome disorder. Individuals with diploid-triploid syndrome have some cells with three copies of each chromosome for a total of 69 chromosomes (called triploid cells) and some cells with the usual 2 copies of each chromosome for a total of 46 chromosomes (called diploid cells).[1] Having two or more different cell types is called mosaicism. Diploid-triploid mosaicism can be associated with truncal obesity, body/facial asymmetry, weak muscle tone (hypotonia), delays in growth, mild differences in facial features, fusion or webbing between some of the fingers and/or toes (syndactyly) and irregularities in the skin pigmentation. Intellectual disabilities may be present but are highly variable from person to person ranging from mild to more severe. The chromosome disorder is usually not present in the blood; a skin biopsy, or analyzing cells in the urine is needed to detect the triploid cells.[1] A regular human carries 23 pairs of chromosomes in his or her cells. Cells containing two pairs of chromosomes are known as diploid cells. Those with diploid triploid mosaicism have some cells which are triploid, meaning that they have three copies of chromosomes, or a total of 69 chromosomes. Triploidy is distinct from trisomy, in which only one chromosome exists in three pairs. A well-known example of trisomy is trisomy 21 or Down syndrome.[2] ## References[edit] 1. ^ a b "Diploid-triploid mosaicism". Genetic and Rare Diseases Information Center (GARD). 22 March 2010. Retrieved 31 March 2014. 2. ^ "Diploidly Triploidly" (PDF). Unique, Rare Chromosome Disorder Support Group. www.rarechromo.org. 2005. Archived from the original (PDF) on 2016-03-04. Retrieved 31 March 2014. ## External links[edit] Classification D * MeSH: C548012 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Diploid triploid mosaic

c2932665

wikipedia

https://en.wikipedia.org/wiki/Diploid_triploid_mosaic

{"gard": ["10715"], "mesh": ["C548012"], "wikidata": ["Q17138746"]}

This page will be copied to Wiktionary using the transwiki process. The information in this article appears to be suited for inclusion in a dictionary, and this article's topic meets Wiktionary's criteria for inclusion, has not been transwikied, and is not already represented. It will be copied into Wiktionary's transwiki space from which it can be formatted appropriately. If this page does not meet the criteria, please remove this notice. Otherwise, the notice will be automatically removed after transwiki completes. If this template is placed on a glossary article, it should be removed immediately after the transwiki is completed, and not replaced with {{TWCleanup}}, as there is no consensus for the deletion of glossary articles. A thrombohemorrhagic event is a process that involves either a blood clot or bleeding, such as a heart attack or stroke. ## References[edit] * Thrombohemorrhagic event entry in the public domain NCI Cancer Dictionary This article about a medical condition affecting the circulatory system is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Thrombohemorrhagic event

c1336741

wikipedia

https://en.wikipedia.org/wiki/Thrombohemorrhagic_event

{"umls": ["C1336741"], "wikidata": ["Q7798339"]}

the condition of having more than two paired sets of chromosomes Not to be confused with "polypoid", resembling a polyp. This image shows haploid (single), diploid (double), triploid (triple), and tetraploid (quadruple) sets of chromosomes. Triploid and tetraploid chromosomes are examples of polyploidy. Polyploidy is a condition in which the cells of an organism have more than two paired (homologous) sets of chromosomes. Most species whose cells have nuclei (eukaryotes) are diploid, meaning they have two sets of chromosomes—one set inherited from each parent. However, some organisms are polyploid, and polyploidy is especially common in plants. Most eukaryotes have diploid somatic cells, but produce haploid gametes (eggs and sperm) by meiosis. A monoploid has only one set of chromosomes, and the term is usually only applied to cells or organisms that are normally haploid. Males of bees and other Hymenoptera, for example, are monoploid. Unlike animals, plants and multicellular algae have life cycles with two alternating multicellular generations. The gametophyte generation is haploid, and produces gametes by mitosis, the sporophyte generation is diploid and produces spores by meiosis. Polyploidy may occur due to abnormal cell division, either during mitosis, or commonly during metaphase I in meiosis. In addition, it can be induced in plants and cell cultures by some chemicals: the best known is colchicine, which can result in chromosome doubling, though its use may have other less obvious consequences as well. Oryzalin will also double the existing chromosome content. Polyploidy occurs in highly differentiated human tissues in the liver, heart muscle, bone marrow and the placenta.[1] It occurs in the somatic cells of some animals, such as goldfish,[2] salmon, and salamanders, but is especially common among ferns and flowering plants (see Hibiscus rosa-sinensis), including both wild and cultivated species. Wheat, for example, after millennia of hybridization and modification by humans, has strains that are diploid (two sets of chromosomes), tetraploid (four sets of chromosomes) with the common name of durum or macaroni wheat, and hexaploid (six sets of chromosomes) with the common name of bread wheat. Many agriculturally important plants of the genus Brassica are also tetraploids. Polyploidization can be a mechanism of sympatric speciation because polyploids are usually unable to interbreed with their diploid ancestors. An example is the plant Erythranthe peregrina. Sequencing confirmed that this species originated from E. × robertsii, a sterile triploid hybrid between E. guttata and E. lutea, both of which have been introduced and naturalised in the United Kingdom. New populations of E. peregrina arose on the Scottish mainland and the Orkney Islands via genome duplication from local populations of E. × robertsii.[3] Because of a rare genetic mutation, E. peregrina is not sterile.[4] ## Contents * 1 Terminology * 1.1 Types * 1.2 Classification * 1.2.1 Autopolyploidy * 1.2.2 Allopolyploidy * 1.2.3 Aneuploid * 1.2.4 Endopolyploidy * 1.2.5 Monoploid * 1.3 Temporal terms * 1.3.1 Neopolyploidy * 1.3.2 Mesopolyploidy * 1.3.3 Paleopolyploidy * 1.4 Other similar terms * 1.4.1 Karyotype * 1.4.2 Homoeologous chromosomes * 2 Examples * 2.1 Animals * 2.1.1 Humans * 2.1.2 Fishes * 2.2 Plants * 2.2.1 Crops * 2.2.1.1 Examples * 2.3 Fungi * 2.4 Chromalveolata * 2.5 Bacteria * 2.6 Archaea * 3 See also * 4 References * 5 Further reading * 6 External links ## Terminology[edit] ### Types[edit] Organ-specific patterns of endopolyploidy (from 2x to 64x) in the giant ant Dinoponera australis Polyploid types are labeled according to the number of chromosome sets in the nucleus. The letter x is used to represent the number of chromosomes in a single set: * haploid (one set; 1x) * diploid (two sets; 2x) * triploid (three sets; 3x), for example sterile saffron crocus, or seedless watermelons, also common in the phylum Tardigrada[5] * tetraploid (four sets; 4x), for example Salmonidae fish,[6] the cotton Gossypium hirsutum[7] * pentaploid (five sets; 5x), for example Kenai Birch (Betula papyrifera var. kenaica) * hexaploid (six sets; 6x), for example wheat, kiwifruit[8] * heptaploid or septaploid (seven sets; 7x) * octaploid or octoploid, (eight sets; 8x), for example Acipenser (genus of sturgeon fish), dahlias * decaploid (ten sets; 10x), for example certain strawberries * dodecaploid (twelve sets; 12x), for example the plants Celosia argentea and Spartina anglica [9] or the amphibian Xenopus ruwenzoriensis. ### Classification[edit] #### Autopolyploidy[edit] Autopolyploids are polyploids with multiple chromosome sets derived from a single taxon. Two examples of natural autopolyploids are the piggyback plant, Tolmiea menzisii[10] and the white sturgeon, Acipenser transmontanum.[11] Most instances of autopolyploidy result from the fusion of unreduced (2n) gametes, which results in either triploid (n \+ 2n = 3n) or tetraploid (2n \+ 2n = 4n) offspring.[12] Triploid offspring are typically sterile (as in the phenomenon of 'triploid block'), but in some cases they may produce high proportions of unreduced gametes and thus aid the formation of tetraploids. This pathway to tetraploidy is referred to as the “triploid bridge”.[12] Triploids may also persist through asexual reproduction. In fact, stable autotriploidy in plants is often associated with apomictic mating systems.[13] In agricultural systems, autotriploidy can result in seedlessness, as in watermelons and bananas.[14] Triploidy is also utilized in salmon and trout farming to induce sterility.[15][16] Rarely, autopolyploids arise from spontaneous, somatic genome doubling, which has been observed in apple (Malus domesticus) bud sports.[17] This is also the most common pathway of artificially induced polyploidy, where methods such as protoplast fusion or treatment with colchicine, oryzalin or mitotic inhibitors are used to disrupt normal mitotic division, which results in the production of polyploid cells. This process can be useful in plant breeding, especially when attempting to introgress germplasm across ploidal levels.[18] Autopolyploids possess at least three homologous chromosome sets, which can lead to high rates of multivalent pairing during meiosis (particularly in recently formed autopolyploids, also known as neopolyploids) and an associated decrease in fertility due to the production of aneuploid gametes.[19] Natural or artificial selection for fertility can quickly stabilize meiosis in autopolyploids by restoring bivalent pairing during meiosis, but the high degree of homology among duplicated chromosomes causes autopolyploids to display polysomic inheritance.[20] This trait is often used as a diagnostic criterion to distinguish autopolyploids from allopolyploids, which commonly display disomic inheritance after they progress past the neopolyploid stage.[21] While most polyploid species are unambiguously characterized as either autopolyploid or allopolyploid, these categories represent the ends of a spectrum between of divergence between parental subgenomes. Polyploids that fall between these two extremes, which are often referred to as segmental allopolyploids, may display intermediate levels of polysomic inheritance that vary by locus.[22][23] About half of all polyploids are thought to be the result of autopolyploidy,[24][25] although many factors make this proportion hard to estimate.[26] #### Allopolyploidy[edit] Allopolyploids or amphipolyploids or heteropolyploids are polyploids with chromosomes derived from two or more diverged taxa. As in autopolyploidy, this primarily occurs through the fusion of unreduced (2n) gametes, which can take place before or after hybridization. In the former case, unreduced gametes from each diploid taxa – or reduced gametes from two autotetraploid taxa – combine to form allopolyploid offspring. In the latter case, one or more diploid F1 hybrids produce unreduced gametes that fuse to form allopolyploid progeny.[27] Hybridization followed by genome duplication may be a more common path to allopolyploidy because F1 hybrids between taxa often have relatively high rates of unreduced gamete formation – divergence between the genomes of the two taxa result in abnormal pairing between homoeologous chromosomes or nondisjunction during meiosis.[27] In this case, allopolyploidy can actually restore normal, bivalent meiotic pairing by providing each homoeologous chromosome with its own homologue. If divergence between homoeologous chromosomes is even across the two subgenomes, this can theoretically result in rapid restoration of bivalent pairing and disomic inheritance following allopolyploidization. However multivalent pairing is common in many recently formed allopolyploids, so it is likely that the majority of meiotic stabilization occurs gradually through selection.[19][21] Because pairing between homoeologous chromosomes is rare in established allopolyploids, they may benefit from fixed heterozygosity of homoeologous alleles.[28] In certain cases, such heterozygosity can have beneficial heterotic effects, either in terms of fitness in natural contexts or desirable traits in agricultural contexts. This could partially explain the prevalence of allopolyploidy among crop species. Both bread wheat and Triticale are examples of an allopolyploids with six chromosome sets. Cotton, peanut, or quinoa are allotetraploids with multiple origins. In Brassicaceous crops, the Triangle of U describes the relationships between the three common diploid Brassicas (B. oleracea, B. rapa, and B. nigra) and three allotetraploids (B. napus, B. juncea, and B. carinata) derived from hybridization among the diploid species. A similar relationship exists between three diploid species of Tragopogon (T. dubius, T. pratensis, and T. porrifolius) and two allotetraploid species (T. mirus and T. miscellus).[29] Complex patterns of allopolyploid evolution have also been observed in animals, as in the frog genus Xenopus.[30] #### Aneuploid[edit] Organisms in which a particular chromosome, or chromosome segment, is under- or over-represented are said to be aneuploid (from the Greek words meaning "not", "good", and "fold"). Aneuploidy refers to a numerical change in part of the chromosome set, whereas polyploidy refers to a numerical change in the whole set of chromosomes.[31] #### Endopolyploidy[edit] Polyploidy occurs in some tissues of animals that are otherwise diploid, such as human muscle tissues.[32] This is known as endopolyploidy. Species whose cells do not have nuclei, that is, prokaryotes, may be polyploid, as seen in the large bacterium Epulopiscium fishelsoni.[33] Hence ploidy is defined with respect to a cell. #### Monoploid[edit] A monoploid has only one set of chromosomes and the term is usually only applied to cells or organisms that are normally diploid. The more general term for such organisms is haploid. ### Temporal terms[edit] #### Neopolyploidy[edit] A polyploid that is newly formed. #### Mesopolyploidy[edit] That has become polyploid in more recent history; it is not as new as a neopolyploid and not as old as a paleopolyploid. It is a middle aged polyploid. Often this refers to whole genome duplication followed by intermediate levels of diploidization. #### Paleopolyploidy[edit] This phylogenetic tree shows the relationship between the best-documented instances of paleopolyploidy in eukaryotes. Main article: Paleopolyploidy Ancient genome duplications probably occurred in the evolutionary history of all life. Duplication events that occurred long ago in the history of various evolutionary lineages can be difficult to detect because of subsequent diploidization (such that a polyploid starts to behave cytogenetically as a diploid over time) as mutations and gene translations gradually make one copy of each chromosome unlike the other copy. Over time, it is also common for duplicated copies of genes to accumulate mutations and become inactive pseudogenes.[34] In many cases, these events can be inferred only through comparing sequenced genomes. Examples of unexpected but recently confirmed ancient genome duplications include baker's yeast (Saccharomyces cerevisiae), mustard weed/thale cress (Arabidopsis thaliana), rice (Oryza sativa), and an early evolutionary ancestor of the vertebrates (which includes the human lineage) and another near the origin of the teleost fishes.[35] Angiosperms (flowering plants) have paleopolyploidy in their ancestry. All eukaryotes probably have experienced a polyploidy event at some point in their evolutionary history. ### Other similar terms[edit] #### Karyotype[edit] Main article: Karyotype A karyotype is the characteristic chromosome complement of a eukaryote species.[36][37] The preparation and study of karyotypes is part of cytology and, more specifically, cytogenetics. Although the replication and transcription of DNA is highly standardized in eukaryotes, the same cannot be said for their karyotypes, which are highly variable between species in chromosome number and in detailed organization despite being constructed out of the same macromolecules. In some cases, there is even significant variation within species. This variation provides the basis for a range of studies in what might be called evolutionary cytology. #### Homoeologous chromosomes[edit] Main article: Homoeology Homoeologous chromosomes are those brought together following inter-species hybridization and allopolyploidization, and whose relationship was completely homologous in an ancestral species. For example, durum wheat is the result of the inter-species hybridization of two diploid grass species Triticum urartu and Aegilops speltoides. Both diploid ancestors had two sets of 7 chromosomes, which were similar in terms of size and genes contained on them. Durum wheat contains a hybrid genome with two sets of chromosomes derived from Triticum urartu and two sets of chromosomes derived from Aegilops speltoides. Each chromosome pair derived from the Triticum urartu parent is homoeologous to the opposite chromosome pair derived from the Aegilops speltoides parent, though each chromosome pair unto itself is homologous. ## Examples[edit] ### Animals[edit] Examples in animals are more common in non-vertebrates[38] such as flatworms, leeches, and brine shrimp. Within vertebrates, examples of stable polyploidy include the salmonids and many cyprinids (i.e. carp).[39] Some fish have as many as 400 chromosomes.[39] Polyploidy also occurs commonly in amphibians; for example the biomedically-important genus Xenopus contains many different species with as many as 12 sets of chromosomes (dodecaploid).[40] Polyploid lizards are also quite common, but are sterile and must reproduce by parthenogenesis.[citation needed] Polyploid mole salamanders (mostly triploids) are all female and reproduce by kleptogenesis,[41] "stealing" spermatophores from diploid males of related species to trigger egg development but not incorporating the males' DNA into the offspring. While mammalian liver cells are polyploid, rare instances of polyploid mammals are known, but most often result in prenatal death. An octodontid rodent of Argentina's harsh desert regions, known as the plains viscacha rat (Tympanoctomys barrerae) has been reported as an exception to this 'rule'.[42] However, careful analysis using chromosome paints shows that there are only two copies of each chromosome in T. barrerae, not the four expected if it were truly a tetraploid.[43] This rodent is not a rat, but kin to guinea pigs and chinchillas. Its "new" diploid (2n) number is 102 and so its cells are roughly twice normal size. Its closest living relation is Octomys mimax, the Andean Viscacha-Rat of the same family, whose 2n = 56. It was therefore surmised that an Octomys-like ancestor produced tetraploid (i.e., 2n = 4x = 112) offspring that were, by virtue of their doubled chromosomes, reproductively isolated from their parents. Polyploidy was induced in fish by Har Swarup (1956) using a cold-shock treatment of the eggs close to the time of fertilization, which produced triploid embryos that successfully matured.[44][45] Cold or heat shock has also been shown to result in unreduced amphibian gametes, though this occurs more commonly in eggs than in sperm.[46] John Gurdon (1958) transplanted intact nuclei from somatic cells to produce diploid eggs in the frog, Xenopus (an extension of the work of Briggs and King in 1952) that were able to develop to the tadpole stage.[47] The British scientist J. B. S. Haldane hailed the work for its potential medical applications and, in describing the results, became one of the first to use the word "clone" in reference to animals. Later work by Shinya Yamanaka showed how mature cells can be reprogrammed to become pluripotent, extending the possibilities to non-stem cells. Gurdon and Yamanaka were jointly awarded the Nobel Prize in 2012 for this work.[47] #### Humans[edit] Further information: Triploid syndrome True polyploidy rarely occurs in humans, although polyploid cells occur in highly differentiated tissue, such as liver parenchyma, heart muscle, placenta and in bone marrow.[1][48] Aneuploidy is more common. Polyploidy occurs in humans in the form of triploidy, with 69 chromosomes (sometimes called 69, XXX), and tetraploidy with 92 chromosomes (sometimes called 92, XXXX). Triploidy, usually due to polyspermy, occurs in about 2–3% of all human pregnancies and ~15% of miscarriages.[citation needed] The vast majority of triploid conceptions end as a miscarriage; those that do survive to term typically die shortly after birth. In some cases, survival past birth may be extended if there is mixoploidy with both a diploid and a triploid cell population present. There has been one report of a child surviving to the age of seven months with complete triploidy syndrome. He failed to exhibit normal mental or physical neonatal development, and died from a Pneumocystis carinii infection, which indicates a weak immune system.[49] Triploidy may be the result of either digyny (the extra haploid set is from the mother) or diandry (the extra haploid set is from the father). Diandry is mostly caused by reduplication of the paternal haploid set from a single sperm, but may also be the consequence of dispermic (two sperm) fertilization of the egg.[50] Digyny is most commonly caused by either failure of one meiotic division during oogenesis leading to a diploid oocyte or failure to extrude one polar body from the oocyte. Diandry appears to predominate among early miscarriages, while digyny predominates among triploid zygotes that survive into the fetal period.[citation needed] However, among early miscarriages, digyny is also more common in those cases less than ​8 1⁄2 weeks gestational age or those in which an embryo is present. There are also two distinct phenotypes in triploid placentas and fetuses that are dependent on the origin of the extra haploid set. In digyny, there is typically an asymmetric poorly grown fetus, with marked adrenal hypoplasia and a very small placenta.[citation needed] In diandry, a partial hydatidiform mole develops.[50] These parent-of-origin effects reflect the effects of genomic imprinting.[citation needed] Complete tetraploidy is more rarely diagnosed than triploidy, but is observed in 1–2% of early miscarriages. However, some tetraploid cells are commonly found in chromosome analysis at prenatal diagnosis and these are generally considered 'harmless'. It is not clear whether these tetraploid cells simply tend to arise during in vitro cell culture or whether they are also present in placental cells in vivo. There are, at any rate, very few clinical reports of fetuses/infants diagnosed with tetraploidy mosaicism. Mixoploidy is quite commonly observed in human preimplantation embryos and includes haploid/diploid as well as diploid/tetraploid mixed cell populations. It is unknown whether these embryos fail to implant and are therefore rarely detected in ongoing pregnancies or if there is simply a selective process favoring the diploid cells. #### Fishes[edit] A polyploidy event occurred within the stem lineage of the teleost fishes.[35] ### Plants[edit] Speciation via polyploidy: A diploid cell undergoes failed meiosis, producing diploid gametes, which self-fertilize to produce a tetraploid zygote. Polyploidy is frequent in plants, some estimates suggesting that 30–80% of living plant species are polyploid, and many lineages show evidence of ancient polyploidy (paleopolyploidy) in their genomes.[51][52][53][54] Huge explosions in angiosperm species diversity appear to have coincided with the timing of ancient genome duplications shared by many species.[55] It has been established that 15% of angiosperm and 31% of fern speciation events are accompanied by ploidy increase.[56] Polyploid plants can arise spontaneously in nature by several mechanisms, including meiotic or mitotic failures, and fusion of unreduced (2n) gametes.[57] Both autopolyploids (e.g. potato[58]) and allopolyploids (such as canola, wheat and cotton) can be found among both wild and domesticated plant species. Most polyploids display novel variation or morphologies relative to their parental species, that may contribute to the processes of speciation and eco-niche exploitation.[52][57] The mechanisms leading to novel variation in newly formed allopolyploids may include gene dosage effects (resulting from more numerous copies of genome content), the reunion of divergent gene regulatory hierarchies, chromosomal rearrangements, and epigenetic remodeling, all of which affect gene content and/or expression levels.[59][60][61][62] Many of these rapid changes may contribute to reproductive isolation and speciation. However seed generated from interploidy crosses, such as between polyploids and their parent species, usually suffer from aberrant endosperm development which impairs their viability,[63][64] thus contributing to polyploid speciation. Some plants are triploid. As meiosis is disturbed, these plants are sterile, with all plants having the same genetic constitution: Among them, the exclusively vegetatively propagated saffron crocus (Crocus sativus). Also, the extremely rare Tasmanian shrub Lomatia tasmanica is a triploid sterile species. There are few naturally occurring polyploid conifers. One example is the Coast Redwood Sequoia sempervirens, which is a hexaploid (6x) with 66 chromosomes (2n = 6x = 66), although the origin is unclear.[65] Aquatic plants, especially the Monocotyledons, include a large number of polyploids.[66] #### Crops[edit] The induction of polyploidy is a common technique to overcome the sterility of a hybrid species during plant breeding. For example, triticale is the hybrid of wheat (Triticum turgidum) and rye (Secale cereale). It combines sought-after characteristics of the parents, but the initial hybrids are sterile. After polyploidization, the hybrid becomes fertile and can thus be further propagated to become triticale. In some situations, polyploid crops are preferred because they are sterile. For example, many seedless fruit varieties are seedless as a result of polyploidy. Such crops are propagated using asexual techniques, such as grafting. Polyploidy in crop plants is most commonly induced by treating seeds with the chemical colchicine. ##### Examples[edit] * Triploid crops: some apple varieties (such as Belle de Boskoop, Jonagold, Mutsu, Ribston Pippin), banana, citrus, ginger, watermelon,[67] saffron crocus, white pulp of coconut * Tetraploid crops: very few apple varieties, durum or macaroni wheat, cotton, potato, canola/rapeseed, leek, tobacco, peanut, kinnow, Pelargonium * Hexaploid crops: chrysanthemum, bread wheat, triticale, oat, kiwifruit[8] * Octaploid crops: strawberry, dahlia, pansies, sugar cane, oca (Oxalis tuberosa)[68] * Dodecaploid crops: some sugar cane hybrids[69] Some crops are found in a variety of ploidies: tulips and lilies are commonly found as both diploid and triploid; daylilies (Hemerocallis cultivars) are available as either diploid or tetraploid; apples and kinnow mandarins can be diploid, triploid, or tetraploid. ### Fungi[edit] Schematic phylogeny of the fungi. Red circles indicate polyploidy, blue squares indicate hybridization. From Albertin and Marullo, 2012[70] Besides plants and animals, the evolutionary history of various fungal species is dotted by past and recent whole-genome duplication events (see Albertin and Marullo 2012[70] for review). Several examples of polyploids are known: * autopolyploid: the aquatic fungi of genus Allomyces,[71] some Saccharomyces cerevisiae strains used in bakery,[72] etc. * allopolyploid: the widespread Cyathus stercoreus,[73] the allotetraploid lager yeast Saccharomyces pastorianus,[74] the allotriploid wine spoilage yeast Dekkera bruxellensis,[75] etc. * paleopolyploid: the human pathogen Rhizopus oryzae,[76] the genus Saccharomyces,[77] etc. In addition, polyploidy is frequently associated with hybridization and reticulate evolution that appear to be highly prevalent in several fungal taxa. Indeed, homoploid speciation (hybrid speciation without a change in chromosome number) has been evidenced for some fungal species (such as the basidiomycota Microbotryum violaceum[78]). Schematic phylogeny of the Chromalveolata. Red circles indicate polyploidy, blue squares indicate hybridization. From Albertin and Marullo, 2012[70] As for plants and animals, fungal hybrids and polyploids display structural and functional modifications compared to their progenitors and diploid counterparts. In particular, the structural and functional outcomes of polyploid Saccharomyces genomes strikingly reflect the evolutionary fate of plant polyploid ones. Large chromosomal rearrangements[79] leading to chimeric chromosomes[80] have been described, as well as more punctual genetic modifications such as gene loss.[81] The homoealleles of the allotetraploid yeast S. pastorianus show unequal contribution to the transcriptome.[82] Phenotypic diversification is also observed following polyploidization and/or hybridization in fungi,[83] producing the fuel for natural selection and subsequent adaptation and speciation. ### Chromalveolata[edit] Other eukaryotic taxa have experienced one or more polyploidization events during their evolutionary history (see Albertin and Marullo, 2012[70] for review). The oomycetes, which are non-true fungi members, contain several examples of paleopolyploid and polyploid species, such as within the genus Phytophthora.[84] Some species of brown algae (Fucales, Laminariales[85] and diatoms[86]) contain apparent polyploid genomes. In the Alveolata group, the remarkable species Paramecium tetraurelia underwent three successive rounds of whole-genome duplication[87] and established itself as a major model for paleopolyploid studies. ### Bacteria[edit] Each Deinococcus radiodurans bacterium contains 4-8 copies of its chromosome.[88] Exposure of D. radiodurans to X-ray irradiation or desiccation can shatter its genomes into hundred of short random fragments. Nevertheless, D. radiodurans is highly resistant to such exposures. The mechanism by which the genome is accurately restored involves RecA-mediated homologous recombination and a process referred to as extended synthesis-dependent strand annealing (SDSA).[89] Azotobacter vinelandii can contain up to 80 chromosome copies per cell.[90] However this is only observed in fast growing cultures, whereas cultures grown in synthetic minimal media are not polyploid.[91] ### Archaea[edit] The archaeon Halobacterium salinarium is polyploid[92] and, like Deinococcus radiodurans, is highly resistant to X-ray irradiation and desiccation, conditions that induce DNA double-strand breaks.[93] Although chromosomes are shattered into many fragments, complete chromosomes can be regenerated by making use of overlapping fragments. 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Principles of Genetics (4th ed.). Hoboken, New Jersey: John Wiley & Sons. ISBN 978-0-471-69939-2. * The Arabidopsis Genome Initiative (2000). "Analysis of the genome sequence of the flowering plant Arabidopsis thaliana". Nature. 408 (6814): 796–815. Bibcode:2000Natur.408..796T. doi:10.1038/35048692. PMID 11130711. * Eakin, G. S.; Behringer, R. R. (2003). "Tetraploid development in the mouse". Developmental Dynamics. 228 (4): 751–766. doi:10.1002/dvdy.10363. PMID 14648853. * Gaeta, R. T.; Pires, J. C.; Iniguez-Luy, F.; Leon, E.; Osborn, T. C. (2007). "Genomic Changes in Resynthesized Brassica napus and Their Effect on Gene Expression and Phenotype". The Plant Cell Online. 19 (11): 3403–3417. doi:10.1105/tpc.107.054346. PMC 2174891. PMID 18024568. * Gregory, T. R.; Mable, B. K. (2005). "Polyploidy in animals". In Gregory, T. R. (ed.). The Evolution of the Genome. San Diego, California: Elsevier. pp. 427–517. * Jaillon, O.; Aury, J.-M.; Brunet, F.; Petit, J.-L.; Stange-Thomann, N.; Mauceli, E.; Bouneau, L.; Fischer, C.; Ozouf-Costaz, C.; Bernot, A.; Nicaud, S.; Jaffe, D.; Fisher, S.; Lutfalla, G.; Dossat, C.; Segurens, B.; Dasilva, C.; Salanoubat, M.; Levy, M.; Boudet, N.; Castellano, S.; Anthouard, V.; Jubin, C.; Castelli, V.; Katinka, M.; Vacherie, B.; Biémont, C.; Skalli, Z.; Cattolico, L.; Poulain, J.; et al. (2004). "Genome duplication in the teleost fish Tetraodon nigroviridis reveals the early vertebrate proto-karyotype". Nature. 431 (7011): 946–957. Bibcode:2004Natur.431..946J. doi:10.1038/nature03025. PMID 15496914. * Paterson, A. H.; Bowers, J. E.; Van De Peer, Y.; Vandepoele, K. (2005). "Ancient duplication of cereal genomes". New Phytologist. 165 (3): 658–661. doi:10.1111/j.1469-8137.2005.01347.x. PMID 15720677. * Raes, J.; Vandepoele, K.; Simillion, C.; Saeys, Y.; Van De Peer, Y. (2003). "Investigating ancient duplication events in the Arabidopsis genome". Journal of Structural and Functional Genomics. 3 (1–4): 117–129. doi:10.1023/A:1022666020026. PMID 12836691. S2CID 9666357. * Simillion, C.; Vandepoele, K.; Van Montagu, M. C.; Zabeau, M.; Van De Peer, Y. (2002). "The hidden duplication past of Arabidopsis thaliana". Proceedings of the National Academy of Sciences. 99 (21): 13627–13632. Bibcode:2002PNAS...9913627S. doi:10.1073/pnas.212522399. JSTOR 3073458. PMC 129725. PMID 12374856. * Soltis, D. E.; Soltis, P. S.; Schemske, D. W.; Hancock, J. F.; Thompson, J. N.; Husband, B. C.; Judd, W. S. (2007). "Autopolyploidy in Angiosperms: Have We Grossly Underestimated the Number of Species?". Taxon. 56 (1): 13–30. JSTOR 25065732. * Soltis, D. E.; Buggs, R. J. A.; Doyle, J. J.; Soltis, P. S. (2010). "What we still don't know about polyploidy". Taxon. 59 (5): 1387–1403. doi:10.1002/tax.595006. JSTOR 20774036. * Taylor, J. S.; Braasch, I.; Frickey, T.; Meyer, A.; Van De Peer, Y. (2003). "Genome Duplication, a Trait Shared by 22,000 Species of Ray-Finned Fish". Genome Research. 13 (3): 382–390. doi:10.1101/gr.640303. PMC 430266. PMID 12618368. * Tate, J. A.; Soltis, D. E.; Soltis, P. S. (2005). "Polyploidy in plants". In Gregory, T. R. (ed.). The Evolution of the Genome. San Diego, California: Elsevier. pp. 371–426. * Van De Peer, Y.; Taylor, J. S.; Meyer, A. (2003). "Are all fishes ancient polyploids?". Journal of Structural and Functional Genomics. 3 (1–4): 65–73. doi:10.1023/A:1022652814749. PMID 12836686. S2CID 14092900. * Van De Peer, Y. (2004). "Tetraodon genome confirms Takifugu findings: Most fish are ancient polyploids". Genome Biology. 5 (12): 250. doi:10.1186/gb-2004-5-12-250. PMC 545788. PMID 15575976. * Van de Peer, Y.; Meyer, A. (2005). "Large-scale gene and ancient genome duplications". In Gregory, T. R. (ed.). The Evolution of the Genome. San Diego, California: Elsevier. pp. 329–368. * Wolfe, K. H.; Shields, D. C. (1997). "Molecular evidence for an ancient duplication of the entire yeast genome". Nature. 387 (6634): 708–713. Bibcode:1997Natur.387..708W. doi:10.1038/42711. PMID 9192896. S2CID 4307263. * Wolfe, K. H. (2001). "Yesterday's polyploids and the mystery of diploidization". Nature Reviews Genetics. 2 (5): 333–341. doi:10.1038/35072009. PMID 11331899. S2CID 20796914. ## External links[edit] * Polyploidy on Kimball's Biology Pages * The polyploidy portal a community-editable project with information, research, education, and a bibliography about polyploidy. * v * t * e Cytogenetics: chromosomes Basic concepts * Karyotype * Ploidy * Genetic material/Genome * Chromatin * Euchromatin * Heterochromatin * Chromosome * Chromatid * Nucleosome * Nuclear organization Types * Autosome/Sex chromosome (or allosome or heterosome) * Macrochromosome/Microchromosome * Circular chromosome/Linear chromosome * Extra chromosome (or accessory chromosome) * Supernumerary chromosome * A chromosome/B chromosome * Lampbrush chromosome * Polytene chromosome * Dinoflagellate chromosomes * Homologous chromosome * Isochromosome * Satellite chromosome * Centromere position * Metacentric * Submetacentric * Telocentric * Acrocentric * Holocentric * Centromere number * Acentric * Monocentric * Dicentric * Polycentric Processes and evolution * Mitosis * Meiosis * Structural alterations * Chromosomal inversion * Chromosomal translocation * Numerical alterations * Aneuploidy * Euploidy * Polyploidy * Paleopolyploidy * Polyploidization Structures * Telomere: Telomere-binding protein (TINF2) * Protamine Histone * H1 * H2A * H2B * H3 * H4 Centromere * A * B * C1 * C2 * E * F * H * I * J * K * M * N * O * P * Q * T See also * Extrachromosomal DNA * Plasmid * List of organisms by chromosome count * List of sequenced genomes * International System for Human Cytogenetic Nomenclature * v * t * e Speciation * Introduction * History * Laboratory experiments * Glossary Basic concepts * Species (Species problem · Species complex) * Reproductive isolation * Anagenesis * Cladogenesis * Cospeciation * Evidence of evolution * Evolutionary biology portal Geographic modes * Allopatric (Peripatric · Quantum · Centrifugal · Founder effect) * Parapatric (Clines · Ring species) * Sympatric Isolating factors * Adaptation * Natural selection * Sexual selection * Ecological speciation (Parallel speciation · Allochrony) * Nonecological speciation * Assortative mating * Haldane's rule Hybrid concepts * Hybrid speciation (Polyploidy · Klepton · Recombination) * Reinforcement (evidence) * Secondary contact * Character displacement Speciation in taxa * Birds * Fish * Insects * Plants * Fossils (Paleopolyploidy · Punctuated equilibrium · Macroevolution · Chronospecies) *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Polyploidy

c0032578

wikipedia

https://en.wikipedia.org/wiki/Polyploidy

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A number sign (#) is used with this entry because holoprosencephaly-11 (HPE11) is caused by heterozygous mutation in the CDON gene (608707) on chromosome 11q24. For a general phenotypic description and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100). Clinical Features Bae et al. (2011) reported 4 unrelated patients with HPE11. One patient had agenesis of the corpus callosum, hypotelorism, growth hormone deficiency, global developmental delay, and thick eyebrows with synophrys. Another had agenesis of the corpus callosum, alobar HPE, hypotelorism, cleft lip/palate, and absent columella; absent pituitary and polysplenia were noted in this patient at autopsy. Clinical details of the other 2 patients were limited, but 1 had alobar findings. Molecular Genetics In 4 unrelated individuals with holoprosencephaly spectrum disorders, Bae et al. (2011) identified 4 different putatively pathogenic heterozygous mutations in the CDON gene (608707.0001-608707.0004). One of the patients had a confirmed de novo mutation. The patients were identified from a cohort of 282 patients screened. Cellular expression and immunoprecipitation studies of the equivalent mutations in rat cDNA indicated that the mutations did not interfere with CDON-SHH (600725) binding, but decreased the ability of CDON to support SHH-dependent signaling by interfering with CDON's ability to interact with certain SHH coreceptors. The findings indicated that CDON must associate with both SHH ligand and other SHH receptor components at the cell surface for proper signaling to occur, and that disruption of these interactions can lead to HPE. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Absent columella Eyes \- Proptosis \- Hypotelorism \- Thick eyebrows \- Synophrys Mouth \- Cleft lip \- Cleft palate ABDOMEN Spleen \- Polysplenia NEUROLOGIC Central Nervous System \- Holoprosencephaly \- Global developmental delay \- Agenesis of the corpus callosum \- Absent pituitary MISCELLANEOUS \- Four unrelated patients have been reported (as of September 2011) \- De novo mutation \- Variable severity MOLECULAR BASIS \- Caused by mutation in the cell adhesion molecule-related/downregulated by oncogenes gene (CDON, 608707.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

HOLOPROSENCEPHALY 11

c0079541

omim

https://www.omim.org/entry/614226

{"doid": ["0110877"], "mesh": ["D016142"], "omim": ["614226"], "orphanet": ["2162"]}

A number sign (#) is used with this entry because of evidence that erythrokeratodermia variabilis et progressiva-6 (EKVP6) is caused by heterozygous mutation in the TRPM4 gene (606936) on chromosome 19q13. Description EKVP6 is characterized by erythematous hyperkeratotic plaques that develop within the first year of life, beginning on distal extremities and progressing to involve the face, wrists, and ankles, with sparing of volar surfaces. Intrafamilial variation in severity has been observed, and most affected individuals experience slowly progressive spontaneous remission after puberty (Wang et al., 2019). For a general phenotypic description and discussion of genetic heterogeneity of EKVP, see EKVP1 (133200). Clinical Features Wang et al. (2019) studied 2 unrelated 4-generation Chinese families segregating an autosomal dominant form of progressive symmetric erythrokeratodermia, and 1 sporadic patient of Han Chinese ethnicity. All affected individuals developed erythematous hyperkeratotic plaques on the dorsal aspect of their distal extremities within the first year of life. During childhood, the lesions progressed to involve the wrists, ankles, and the periorificial areas, most prominently on the face; volar aspects of extremities were mostly spared. Severely affected individuals experienced mild pruritus, and there was wide variation in disease severity among affected individuals from both families, ranging from generalized erythrokeratodermia to lesions restricted to the dorsum of hands and feet. Teeth, hair, and nails were normal, and skin lesions showed no seasonal variation. Most patients noted slowly progressive spontaneous remission after puberty. Histopathology of lesional skin showed psoriasiform hyperplasia of the epidermis with focal parakeratosis and mild perivascular lymphocytic infiltration in the superficial dermis. None of the affected individuals reported symptoms of cardiac arrhythmias or history of cardiac disorders, and no arrhythmias were detected on repeated electrocardiograms in 3 affected individuals. Molecular Genetics In 2 unrelated 4-generation Chinese families segregating autosomal dominant progressive symmetric erythrokeratodermia, Wang et al. (2019) identified heterozygosity for a missense mutation in the TRPM4 gene (I1040T; 606936.0007). In a Han Chinese girl similarly affected with erythrokeratodermia, they identified heterozygosity for a de novo missense mutation in TRPM4 (I1033M; 606936.0008). The proband from 1 of the families (family 1) was screened for mutation in known EKVP-associated genes and no causative mutations were found. INHERITANCE \- Autosomal dominant SKIN, NAILS, & HAIR Skin \- Erythematous hyperkeratotic plaques on dorsal surface of extremities \- Erythematous hyperkeratotic plaques on periorificial areas \- Pruritis, mild (in severely affected patients) Skin Histology \- Psoriasiform hyperplasia of epidermis \- Focal parakeratosis \- Perivascular lymphocytic infiltration, mild, in superficial dermis MISCELLANEOUS \- Onset in first year of life \- Initial lesions on distal extremities \- Intra- and interfamilial variation in disease severity \- Slowly progressive spontaneous remission after puberty MOLECULAR BASIS \- Caused by mutation in the transient receptor potential cation channel, subfamily M, member-4 gene (TRPM4, 606936.0007 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 6

None

omim

https://www.omim.org/entry/618531

{"omim": ["618531"]}

This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article may be confusing or unclear to readers. Please help us clarify the article. There might be a discussion about this on the talk page. (April 2009) (Learn how and when to remove this template message) This article is written like a personal reflection, personal essay, or argumentative essay that states a Wikipedia editor's personal feelings or presents an original argument about a topic. Please help improve it by rewriting it in an encyclopedic style. (April 2009) (Learn how and when to remove this template message) (Learn how and when to remove this template message) Orofacial Myofunctional Disorders (OMD) (sometimes called “oral myofunctional disorder", and “tongue thrust”) are muscle disorders of the face, mouth, lips, or jaw due to chronic mouth breathing.[1] Recent studies on the incidence and prevalence of tongue thrust behaviors are not available. However, according to previous research, 38% of various populations have OMD. The incidence is as high as 81% in children exhibiting speech/articulation problems (Kellum, 1992). ## Contents * 1 Indications * 2 Causes * 3 Consequences of tongue thrust * 4 Open mouth posture * 5 Treatment * 5.1 Goals/benefits of therapy * 6 See also * 7 References * 8 Further reading ## Indications[edit] OMD refers to the abnormal resting posture of the orofacial musculature, atypical chewing, and swallowing patterns, dental malocclusions, blocked nasal airways, and speech problems.[2] OMD are patterns involving oral and/or orofacial musculature that interferes with normal growth, development, or function of structures, or calls attention to itself. OMD are found in both children and adults. OMD that are commonly seen in children include tongue thrust that is also known as swallowing with an anterior tongue posture. OMD also refers to factors such as nonnutritive sucking behaviors, such as thumb sucking, clenching, bruxing, etc. that led to abnormal development of dentition and oral cavity. OMD in adult and geriatric populations are due to various neurological impairments, oral hygiene, altered functioning of muscles due to aging, systemic diseases, etc. Tongue thrusting is a type of orofacial myofunctional disorder, which is defined as habitual resting or thrusting the tongue forward and/or sideways against or between the teeth while swallowing, chewing, resting, or speaking. Abnormal swallowing patterns push the upper teeth forward and away from the upper alveolar processes and cause open bites. In children, tongue thrusting is common due to immature oral behavior, narrow dental arch, prolonged upper respiratory tract infections, spaces between the teeth (diastema), muscle weakness, malocclusion, abnormal sucking habits, and open mouth posture due to structural abnormalities of genetic origin. Large tonsils and adenoids also contribute to tongue thrust swallowing. From the dental perspective, teeth move in relation to the balance of the soft tissue; the normal relationship of teeth lies in occlusion; and any deviation from the normal occlusion can lead to dental distress.[3] Tongue posture plays an important role in swallowing and dentofacial growth. In case of tongue thrust swallowing, the tip of the tongue can come against or between the dentition; the midpoint may be collapsed or extended unilaterally or bilaterally; or the posterior part of the hard palate. In these conditions, there are chances of abnormal dentofacial growth and other concerns regarding the development of the craniofacial complex. There are pertinent symptomatic questions that can be considered for the diagnosis of tongue thrust swallow. Some of these questions are geared toward tongue protrusion and an opening of lips when the client is in repose; habitual mouth breathing; digit sucking; existence of high and narrow palatal arch; ankyloglossia (tongue-tie); malocclusions, (Class II, III); weak chewing muscles (masseter); weak lip muscles (orbicularis oris); overdeveloped chin muscles (mentalis); muscular imbalance; abnormal dentition. Tongue thrusting and speech problems may co-occur. Due to unconventional postures of the tongue and other articulators, interdental and frontal lisping are very common. The alveolar sounds /s/ and /z/ are produced more anteriorly thus leading to interdental fricative like sounds, /th/.[4] ## Causes[edit] 1. Upper airway constrictions (e.g., deviated nasal septum) or obstructions (e.g., enlarged tonsils) or infections (e.g., rhinitis) 2. General hypotonia or low body tone 3. Low-lying resting posture of the tongue 4. Imbalance in dental growth 5. Inadequate development of facial and cranial bones 6. Inappropriate development of muscles in the head and neck areas While identifying the causes of tongue thrust, it is important to remember that the resting posture of the tongue, jaw, and lips are crucial to the normal development of the mouth and its structures. If the tongue rests against the upper front teeth, the teeth may protrude forward, and adverse tongue pressure can restrict the development of the oral cavity. The tongue lies low in the mouth or oral cavity and is typically forwarded between upper and lower teeth. If tongue thrust behavior is not corrected, it may affect the normal dental development. The teeth may be pushed around in different directions during the growth of permanent teeth. ## Consequences of tongue thrust[edit] 1. Lisping (e.g., saying “thun” for sun) 2. Imprecise articulation of speech sounds 3. Open-mouth posture 4. Open bite 5. Abnormal eruption of teeth and dental arch 6. Abnormal tone of facial muscles 7. Prolonged meal times due to ineffective chewing and swallowing 8. Spillage of food/fluid from the anterior mouth 9. Negative cosmetic effects 10. Lower self-esteem 11. Problems with the fitting of dentures in future ## Open mouth posture[edit] The adaptation from nasal to mouth breathing takes place when changes such as chronic middle ear infections, sinusitis, allergic rhinitis, upper airway infections, and sleep disturbances (e.g., snoring) take place. In addition, mouth breathing is often associated with a decrease in oxygen intake into the lungs. Mouth breathing can particularly affect the growing face, as the abnormal pull of these muscle groups on facial bones slowly deforms these bones, causing misalignment. The earlier in life these changes take place, the greater the alterations in facial growth, and ultimately an open mouth posture is created where the upper lip is raised and the lower jaw is maintained in an open posture. The tongue, which is normally tucked under the roof of the mouth, drops to the floor of the mouth and protrudes to allow a greater volume of air intake. Consequently, an open mouth posture can lead to malocclusions and problems in swallowing. Other causes of open-mouth posture are the weakness of lip muscles, overall lack of tone in the body or hypotonia, and prolonged/chronic allergies of the respiratory tract. ## Treatment[edit] See also: Oral myology An orofacial myofunctional therapist reeducates the movement of muscles including teaching the client how to breathe properly, restore correct swallowing patterns, and establish adequate labial-lingual postures.[3][5][6] An interdisciplinary nature of treatment is always desirable to reach functional goals in terms of swallowing, speech, and other aesthetic factors. A team approach has been shown to be effective in correcting orofacial myofunctional disorders. The teams include an orthodontist, dental hygienist, certified orofacial myologist, general dentist, otorhinolaryngologist, and a speech-language pathologist. ### Goals/benefits of therapy[edit] 1. Eliminate mouth breathing and open-mouth posture 2. Improve nasal breathing patterns 3. Reinforce and establish a resting posture of the tongue away from the teeth, against the hard palate 4. Establish appropriate oral, lingual, and facial muscle patterns that promote correct gestures for chewing and eating 5. Retrain oral, lingual, and facial muscles to facilitate correct resting posture of tongue, lips, and jaw 6. Establish mature swallowing patterns 7. Prevent relapses after orthodontic treatment 8. Improve the relationship between dental arches; reduce open bite and overjet 9. Maintain overall facial muscle tone needed for chewing, swallowing, and speech 10. Create an oral environment that creates favorable conditions for the development of dentition 11. Eliminate dry mouth condition or xerostomia 12. Improve oral hygiene 13. Eliminate digit-sucking behaviors to facilitate normal growth of the palatal arch ## See also[edit] * James Nestor * Mouth breathing * Napoleon Dynamite * Obligate nasal breathing ## References[edit] 1. ^ "Orofacial Myofunctional Disorders". Cincinnati Children's Hospital Medical Center. Retrieved 2020-06-21. 2. ^ Hanson ML (March 1988). "Orofacial myofunctional therapy: historical and philosophical considerations". Int J Orofacial Myology. 14 (1): 3–10. PMID 3075197. 3. ^ a b Garliner, Daniel (1974). Myofunctional therapy in dental practice : abnormal swallowing habits : diagnosis, treatment (2 ed.). Coral Gables (Florida): Institute for Myofunctional Therapy. OCLC 708481369. 4. ^ Bigenzahn W, Fischman L, Mayrhofer-Krammel U (1992). "Myofunctional therapy in patients with orofacial dysfunctions affecting speech". Folia Phoniatrica et Logopaedica. 44 (5): 238–44. doi:10.1159/000266155. PMID 1490647. 5. ^ Benkert KK (1997). "The effectiveness of orofacial myofunctional therapy in improving dental occlusion". Int J Orofacial Myology. 23: 35–46. PMID 9487828. 6. ^ Hemmings K, Griffiths B, Hobkirk J, Scully C (August 2000). "ABC of oral health. Improving occlusion and orofacial aesthetics: tooth repair and replacement". BMJ. 321 (7258): 438–41. doi:10.1136/bmj.321.7258.438. PMC 1127801. PMID 10938058. ## Further reading[edit] * Nestor, James (2020). Breath: The New Science of a Lost Art. Riverhead Books. ISBN 978-0735213616. * v * t * e Orthodontics Diagnosis * Bolton analysis * Cephalometric analysis * Cephalometry * Dentition analysis * Failure of eruption of teeth * Little's Irregularity Index * Malocclusion * Scissor bite * Standard anatomical position * Tooth ankylosis * Tongue thrust Conditions * Overbite * Open bite * Crossbite * Prognathism * Retrognathism * Maxillary hypoplasia * Condylar hyperplasia * Overeruption * Mouth breathing Appliances * ACCO appliance * Archwire * Activator appliance * Braces * Damon system * Elastics * Frankel appliance * Invisalign * Lingual arch * Lip bumper * List of orthodontic functional appliances * List of palatal expanders * Lingual braces * Headgear * Orthodontic technology * Orthodontic spacer * Palatal lift prosthesis * Palatal expander * Quad helix * Retainer * SureSmile * Self-ligating braces * Splint activator * Twin Block Appliance Procedures * Anchorage (orthodontics) * Cantilever mechanics * Fiberotomy * Interproximal reduction * Intrusion (orthodontics) * Molar distalization * SARPE * Serial extraction Materials * Beta-titanium * Nickel titanium * Stainless steel * TiMolium * Elgiloy * Ceramic * Composite Notable contributors * Edward Angle * Spencer Atkinson * Clifford Ballard * Raymond Begg * Hans Peter Bimler * Samir Bishara * Arne Björk * Charles B. Bolton * Holly Broadbent Sr. * Allan G. Brodie * Charles J. Burstone * Peter Buschang * Calvin Case * Harold Chapman (Orthodontist) * David Di Biase * Jean Delaire * Terry Dischinger * William B. Downs * John Nutting Farrar * Rolf Frankel * Sheldon Friel * Thomas M. Graber * Charles A. Hawley * Reed Holdaway * John Hooper (Orthodontist) * Joseph Jarabak * Harold Kesling * Albert Ketcham * Juri Kurol * Craven Kurz * Benno Lischer * James A. McNamara * Birte Melsen * Robert Moyers * Hayes Nance * Ravindra Nanda * George Northcroft * Dean Harold Noyes * Frederick Bogue Noyes * Albin Oppenheim * Herbert A. Pullen * Earl W. Renfroe * Robert M. Ricketts * Alfred Paul Rogers * Ronald Roth * Everett Shapiro * Frederick Lester Stanton * Earl Emanuel Shepard * Cecil C. Steiner * David L. Turpin * Charles H. Tweed * Katherine Vig * Edmund H. Wuerpel * Won-Sik Yang Organizations * American Association of Orthodontists * American Board of Orthodontics * British Orthodontic Society * Canadian Association of Orthodontists * Indian Orthodontic Society * Italian Academy of Orthodontic Technology * Society for Orthodontic Dental Technology (Germany) Journals * American Journal of Orthodontics and Dentofacial Orthopedics * The Angle Orthodontist * Journal of Orthodontics Institution * Angle School of Orthodontia *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Orofacial myofunctional disorders

None

wikipedia

https://en.wikipedia.org/wiki/Orofacial_myofunctional_disorders

{"wikidata": ["Q1956669"]}

Complement component 2 deficiency is a disorder that causes the immune system to malfunction, resulting in a form of immunodeficiency. Immunodeficiencies are conditions in which the immune system is not able to protect the body effectively from foreign invaders such as bacteria and viruses. People with complement component 2 deficiency have a significantly increased risk of recurrent bacterial infections, specifically of the lungs (pneumonia), the membrane covering the brain and spinal cord (meningitis), and the blood (sepsis), which may be life-threatening. These infections most commonly occur in infancy and childhood and become less frequent in adolescence and adulthood. Complement component 2 deficiency is also associated with an increased risk of developing autoimmune disorders such as systemic lupus erythematosus (SLE) or vasculitis. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. Between 10 and 20 percent of individuals with complement component 2 deficiency develop SLE. Females with complement component 2 deficiency are more likely to have SLE than affected males, but this is also true of SLE in the general population. The severity of complement component 2 deficiency varies widely. While some affected individuals experience recurrent infections and other immune system difficulties, others do not have any health problems related to the disorder. ## Frequency In Western countries, complement component 2 deficiency is estimated to affect 1 in 20,000 individuals; its prevalence in other areas of the world is unknown. ## Causes Complement component 2 deficiency is caused by mutations in the C2 gene. This gene provides instructions for making the complement component 2 protein, which helps regulate a part of the body's immune response known as the complement system. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. The complement component 2 protein is involved in the pathway that turns on (activates) the complement system when foreign invaders, such as bacteria, are detected. The most common C2 gene mutation, which is found in more than 90 percent of people with complement component 2 deficiency, prevents the production of complement component 2 protein. A lack of this protein impairs activation of the complement pathway. As a result, the complement system's ability to fight infections is diminished. It is unclear how complement component 2 deficiency leads to an increase in autoimmune disorders. Researchers speculate that the dysfunctional complement system is unable to distinguish what it should attack, and it sometimes attacks normal tissues, leading to autoimmunity. Alternatively, the dysfunctional complement system may perform partial attacks on invading molecules, which leaves behind foreign fragments that are difficult to distinguish from the body's tissues, so the complement system sometimes attacks the body's own cells. It is likely that other factors, both genetic and environmental, play a role in the variability of the signs and symptoms of complement component 2 deficiency. ### Learn more about the gene associated with Complement component 2 deficiency * C2 ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Complement component 2 deficiency

c3150275

medlineplus

https://medlineplus.gov/genetics/condition/complement-component-2-deficiency/

{"gard": ["1452"], "omim": ["217000"], "synonyms": []}

A rare congenital limb malformation characterized by complete or partial duplication of one of the three middle digits in a hand or foot. It most commonly affects the fourth digit. The malformation may be unilateral or bilateral and can occur as an isolated defect or in association with other anomalies. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Central polydactyly

c0431903

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=295004

{"umls": ["C0431903"], "icd-10": ["Q69.0"], "synonyms": ["Mesoaxial polydactyly"]}

17q23.1q23.2 microdeletion syndrome is a condition caused by a small deletion of genetic material from chromosome 17. The deletion occurs at a location encompassing bands 23.1 to 23.2 on the long (q) arm of the chromosome. People with 17q23.1q23.2 microdeletion syndrome may have developmental delay, microcephaly, short stature, heart defects and limb abnormalities. Most cases are approximately 2.2 Mb in size and include the transcription factor genes TBX2 and TBX4 which have been implicated in a number of developmental pathways, including those of the heart and limbs. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

17q23.1q23.2 microdeletion syndrome

c3150607

gard

https://rarediseases.info.nih.gov/diseases/10936/17q231q232-microdeletion-syndrome

{"omim": ["613355"], "orphanet": ["261279"], "synonyms": ["Monosomy 17q23.1-q23.2", "Del(17)(q23.1q23.2)", "Chromosome 17q23.1-q23.2 deletion syndrome", "17q23.1-q23.2 microdeletion syndrome", "Monosomy 17q23.1q23.2"]}

Heterotaxia (coming from the Greek 'heteros' meaning different and 'taxis' meaning arrangement) is the right/left transposition of thoracic and/or abdominal organs. It encompasses a wide variety of disorders since there are multiple possibilities of right/left reversals, which may be complete (situs inversus totalis or situs inversus i.e. all the organs normally found on the right are on the left and vice versa) or partial (incomplete situs inversus i.e. a limited number of organs are inversed - or situs inversus ambiguous i.e. a normally lateral organ is centrally located). ## Epidemiology The incidence of all lateralization defects is approximately 1/15 000. ## Clinical description The severity of malformations is highly variable among members of a family. Complete situs inversus is not, in itself, a problem. On the contrary, partial situs inversus can be associated with any type of cardiac malformation, as well as renal, biliary, midline anomalies, etc. Asplenia and polysplenia are frequent. Asplenia refers to a lateralization defect with a small or absent spleen. It is thought to be due to the presence of a double right side (consequently, the left side is identical to the right). This is also referred to as right isomerism. Polysplenia describes a lateralization defect with multiple small spleens. It is thought to be due to the presence of a double left side (the right side is identical to the left). This is referred to as left isomerism. In 1955, Björn Ivemark described a series of autopsies of hearts from patients with asplenia. Thus, Ivemark syndrome corresponds to heterotaxia with asplenia. In some cases, the heart malformation is isolated, without any other anomaly; it is often a transposition of great vessels or a double outlet right ventricle, both resulting from a defective rotation of the heart outflow. In pair organs (which are not quite symmetrical) such as the lungs, kidneys or suprarenal glands, the symmetry is inversed or absent. In X-linked heterotaxia, abnormalities in the development of the midline are present. They can manifest as arhinencephalia, myelomeningocele, urological anomalies, hypertelorism, cleft palate and mostly, anomaly of the sacral spine and the anus. Heterotaxia with recurrent respiratory infections are named ciliary dyskninesia (see this term). ## Etiology In patients with heterotaxia, mutations have been identified in several genes (LEFTY A, ACVR2B, NODAL, CFC1, INVERSINE). All patients were heterozygous (neither compound heterozygous nor homozygous). Autosomal recessive transmission has only been reported in genetically modified mice. This suggests the existence of digenism in humans. Finally, the gene involved in X-linked transmission has been identified: it encodes ZIC3 (Zinc-finger protein of cerebellum) and is located at Xq26.2. ## Diagnostic methods Diagnosis relies on medical imaging or on the identification of mutations in the ZIC3 gene, in the case of X-linked forms. ## Antenatal diagnosis Prenatal scan can show lateralization abnormality and is systematically performed in case of a positive family history. ## Genetic counseling The origin of lateralization defects can be genetic and three types of pattern of transmission have been proposed: autosomal recessive (the most frequent), autosomal dominant (rare) and X-linked (very rare with few families reported). ## Management and treatment Heart malformations and associated lesions require a specific management, but the lateralization defect itself does not require any particular treatment. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Heterotaxia

c3178805

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=450

{"gard": ["10875"], "mesh": ["D059446"], "omim": ["270100", "306955", "601086", "605376", "606325", "613751", "614779", "616749", "617205"], "umls": ["C3178805"], "icd-10": ["Q89.3"], "synonyms": ["Heterotaxy syndrome", "Lateralization defect", "Visceral heterotaxy"]}

A chronic inflammation of the arachnoid layer of the meninges, of which adhesive arachnoiditis is the most severe form, characterized by debilitating, intractable neurogenic back and limb pain and a range of other neurological problems. ## Epidemiology The prevalence is unknown. About 25,000 cases of arachnoiditis occur each year, mostly in North and South America, Asia and Europe, where spinal operations are more prevalent. ## Clinical description Patients present with chronic, persistent deafferentiation pain in the lower back, limbs and trunk that is increased by activity, hyporeflexia, loss of temperature sensation, numbness, and often widespread allodynia, dysesthesia and hyperpathia. Patients may also experience proprioception alterations (including loss of balance, tinnitus and reduced hearing and vision), motor weakness, muscle cramps, fasciculation, anhidrosis, and bladder, bowel and sexual dysfunction. Arachnoiditis may, in a minority of cases, involve the brain as well as the spinal cord, possibly causing communicating hydrocephalus. ## Etiology Arachnoiditis can be mechanically (localized) or chemically (diffuse) induced, and is often associated with spinal operations (60% of cases), neuroaxial (spinal and epidural) anesthesia (22%), spinal taps (7%), myelography (3%), pain relief procedures and secondary infections. It can also be caused by bacterial and viral spinal infections (7%) and repeated subarachnoid injections of anticancer drugs or antimetabolites. Syringomyelia, cauda equina syndrome, pseudomeningoceles, intrathecal cysts or tethering of the spinal cord and nerve roots (NR) may complicate lumbosacral arachnoiditis. Arachnoiditis occurs as a progression of inflammatory changes. In the early (inflammatory) phase NR are edematous (enhanced), while in the late proliferation stage (adhesive arachnoiditis) NR are clumped and asymmetric. The flow of cerebrospinal fluid from the distal dural sac to the brain is impeded, intrathecal pressure increases and this causes back pain and postural headache. In some cases the scar tissue calcifies (arachnoiditis ossificans). ## Diagnostic methods Diagnosis is based on patient history, clinical presentation and a causative event, and can be confirmed by MRI with contrast. When MRI is not possible, myelogram followed by CT scan is indicated. The adhesions generally occur on the dorsal segments, are arranged peripherally, and have been described as looking `like the bark of a tree' when viewed by myelography. ## Differential diagnosis Differential diagnoses include intra-spinal hematoma or dislodged disc fragment if the condition presents immediately after surgery, and Failed Back Surgery Syndrome (FBSS). Some patients are diagnosed with fibromyalgia (see this term), but these symptoms are likely to occur as a secondary feature due to the altered spinal dynamics. ## Management and treatment In the early phase, treatment includes large doses of IV methylprednisolone for five days, preferably within three months of the causative injury, followed by a protocol directed to control neuropathic pain using a multimodal approach that includes an anti-inflammatory, an anticonvulsant and an antidepressant. Large doses of opiates, that can cause hyperalgesia, hypersensitivity and tachyphylaxis, and lead to dependence, should be discouraged. If necessary, to treat exacerbation ``flare-ups'', IV infusions of NMDA receptors antagonists (including lidocaine, MgSO4, ketamine) can be given. ## Prognosis Once the proliferative stage has begun, arachnoiditis will be permanent and is complicated by the aging process of the spine. Operations, injections or any other invasions of the spine may exacerbate the disease significantly. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Arachnoiditis

c0003708

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=137817

{"gard": ["5839"], "mesh": ["D001100"], "omim": ["182950"], "umls": ["C0003708", "C0270617"], "icd-10": ["G03.9"], "synonyms": ["Adhesive arachnoiditis", "Chronic arachnoiditis"]}

Cardiac anomalies-heterotaxy syndrome is characterised by non-compaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect. Laterality sequence anomalies are also present. So far, the syndrome has been described in nine members from three generations of the same family. Transmission is autosomal dominant and linkage to chromosome 6p24.3-21.2 was reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Cardiac anomalies-heterotaxy syndrome

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=137628

{"icd-10": ["Q28.8"]}

A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-3 (CORD3) is caused by homozygous or compound heterozygous mutation in the ABCA4 (601691) on chromosome 1p22. For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970. Clinical Features Klevering et al. (2002) analyzed phenotype information from the charts of 12 patients with autosomal recessive CORD caused by mutations in the ABCA4 gene and found that although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Klevering et al. (2002) concluded that given the wide clinical spectrum of CORD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassification is difficult and may not be very useful. Fishman et al. (2003) examined 30 patients with autosomal recessive CORD, 16 of whom harbored plausible disease-causing variations in the ABCA4 gene. Among the mutation-positive patients, 2 distinctly different fundus phenotypes were observed: 12 showed diffuse pigmentary degenerative changes (type 1), whereas 4 showed either no pigmentary changes or only a mild degree of peripheral pigment degeneration (type 2). All 16 patients showed either a central scotoma (6 patients) or both a central scotoma and some degree of peripheral field loss (10 patients). Both cone and rod a- and b-wave electroretinogram (ERG) amplitudes were reduced in all patients, which is diagnostic for CORD. Cideciyan et al. (2004) studied surrogate measures of retinoid cycle kinetics, lipofuscin accumulation, and rod and cone photoreceptor and RPE loss in STGD1 and CORD3 patients with ABCA4 mutations and a wide spectrum of disease severity. There were different extents of photoreceptor/RPE loss and lipofuscin accumulation in different regions of the retina. Slowing of retinoid cycle kinetics was not present in all patients; when present, it was not homogeneous across the retina; and the extent of slowing correlated well with the degree of degeneration. The orderly relationship between these phenotypic features permitted the development of a model of disease sequence in retinal degeneration due to ABCA4 mutation, which predicted lipofuscin accumulation as a key early component of disease expression with abnormal slowing of the rod and cone retinoid cycle occurring at later stages of the disease sequence. Mapping Cremers et al. (1998) performed ophthalmologic examination and haplotype analysis in a consanguineous family with individuals showing either retinitis pigmentosa (RP) (601718) or cone-rod dystrophy (CORD). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at chromosome 1p21-p13 (lod score, 4.22), a genomic segment that harbors the ABCA4 gene, known to be involved in Stargardt disease and age-related macular degeneration. Molecular Genetics Cremers et al. (1998) analyzed the ABCA4 gene in a consanguineous family with RP and CORD and identified homozygosity for a 5-prime splice site mutation in intron 30 (601691.0009) in the 4 RP patients; the 5 patients with CORD were compound heterozygotes for the mutation in intron 30 and a 5-prime splice site mutation in intron 40 (601691.0010). Four unaffected members of this family were heterozygous for the mutation in intron 40. Both splice site mutations were found in heterozygosity in 2 unrelated patients with Stargardt disease (STGD1; 248200) in whom the second mutation was either a missense mutation or unknown, but not in 100 control individuals. Cremers et al. (1998) suggested that the intron 30 splice site mutation represents a true null allele, whereas the intron 40 mutation probably renders the exon 40 5-prime splice site partially functional. To evaluate the importance of the ABCA4 gene as a cause of autosomal recessive CORD, Maugeri et al. (2000) studied 5 patients with autosomal recessive CORD and 15 patients with isolated CORD, all from Germany and the Netherlands. They found 19 ABCA4 mutations in 13 (65%) of 20 patients. In 6 patients, mutations were identified in both ABCA4 alleles; in 7 patients, mutations were detected in 1 allele. The complex ABCA4 allele L541P/A1038V (601691.0023) was found exclusively in German patients with CORD; 1 patient carried this complex allele in homozygous state, and 5 others were compound heterozygotes. Ducroq et al. (2002) evaluated the prevalence of ABCA4 mutations in a cohort of 55 patients with autosomal recessive or sporadic cone-rod dystrophy. They screened the 50 exons of the ABCA4 gene as well as the flanking intronic sequences using DHPLC and identified 16 different mutant alleles in 13 (23.6%) of 55 patients. Among these 13 patients, 2 were homozygotes (from 2 consanguineous families; see, e.g., 601691.0024), 4 were compound heterozygotes, and 7 were simple heterozygotes. There was no significant difference in the frequency of ABCA4 mutations between autosomal recessive and sporadic cases of CORD (6 of 29 versus 7 of 26 cases, respectively). Ducroq et al. (2002) estimated that this screen detected approximately 80% of mutations present in these families, with unidentified mutations potentially located in promoter or intron sequences or in undiscovered exons, and stated that the corrected mutation frequency would then be 29.5% of all CORD cases. For a sporadic case of cone-rod dystrophy with no ABCA4 mutation, they estimated that the risk of the disease being inherited as an autosomal recessive condition can be estimated to be 15.6% using the Bayesian calculation. Fishman et al. (2003) examined 16 patients with autosomal recessive CORD and ABCA4 mutation and observed 2 distinctly different fundus phenotypes: 12 showed diffuse pigmentary degenerative changes (type 1), whereas 4 showed either no pigmentary changes or only a mild degree of peripheral pigment degeneration (type 2). Of the 12 patients classified as type 1, 4 harbored an A1038V change (601691.0016): in 2 this was the only sequence variation identified; in 1 case, it was observed in compound heterozygosity with a nonsense mutation; and in 1 case it was found as a complex allele with an L541P mutation (see 601691.0023). In the additional 8 patients classified as type 1, 2 showed 2 different heterozygous missense mutations, 3 had a single heterozygous missense mutation, and 3 had a heterozygous splice site mutation within intron 40 (601691.0010). In the 4 patients with considerably less funduscopically apparent pigmentary change (type 2), a heterozygous missense mutation was observed: in 2 instances L1201R (601691.0025), and in another 2 L2027F (601691.0004). Ducroq et al. (2006) analyzed a large multiplex Christian Arab family with presumed autosomal recessive CORD and 6 consanguineous loops and found segregation of 3 distinct haplotypes at the CORD3 locus. Sequencing of the ABCA4 gene revealed 3 different mutations segregating with the disease in this family: 4 patients were homozygous for a splice-site mutation; 4 were compound heterozygous for the splice-site mutation and 1 of 2 missense mutations, respectively; and 1 patient was compound heterozygous for the 2 missense mutations. Review of clinical data from the 9 affected individuals confirmed the diagnosis of CORD in 8 of them, but the patient who was compound heterozygous for 2 missense mutations was found to exhibit typical signs of Stargardt disease without extension to the peripheral retina, with severely reduced photopic responses but normal scotopic amplitudes on ERG. Ducroq et al. (2006) emphasized the pitfalls of homozygosity mapping in highly inbred families when the heterozygote carrier frequency is high in the general population. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

CONE-ROD DYSTROPHY 3

c1858806

omim

https://www.omim.org/entry/604116

{"doid": ["0111013"], "mesh": ["C565827"], "omim": ["604116", "120970"], "orphanet": ["1872"], "synonyms": []}

A form of hereditary cerebral hemorrhage with amyloidosis characterized by an age of onset of 50 years of age, dementia and lobar intracerebral hemorrhage. This subtype is due to a mutation in the APP gene (21q21.2), encoding the beta-amyloid precursor protein. This mutation causes an increased accumulation of amyloid-beta protein in the walls of the arteries and capillaries of the meninges, cerebellar cortex and cerebral cortex, leading to the weakening and eventual rupture of these vessels. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ABeta amyloidosis, Italian type

c2931672

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=324713

{"mesh": ["C537944"], "omim": ["605714"], "icd-10": ["E85.4+", "I68.0*"], "synonyms": ["ABetaE22K amyloidosis", "HCHWA, Italian type", "Hereditary cerebral hemorrhage with amyloidosis, Italian type"]}

Dykes et al. (1979) described 2 brothers, aged 62 and 66 years, who had this combination. Another brother, who died at age 58, had ichthyosis and a progressive neurologic disorder. Dysarthria and ataxia began after age 50. The ichthyosis was of distinctive type. Normal steroid sulfatase excluded the X-linked form (308100). X-linked inheritance of the syndrome is, of course, possible. The hepatosplenomegaly suggested a storage disease, but its nature was not evident. Inheritance \- Autosomal recessive \- X-linked not ruled out Neuro \- Dysarthria \- Ataxia Lab \- Normal steroid sulfatase GI \- Hepatosplenomegaly Skin \- Ichthyosis ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ICHTHYOSIS, HEPATOSPLENOMEGALY, AND CEREBELLAR DEGENERATION

c1275088

omim

https://www.omim.org/entry/242520

{"mesh": ["C535727"], "omim": ["242520"], "orphanet": ["2274"]}

This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Carbamoyl phosphate synthetase I deficiency" – news · newspapers · books · scholar · JSTOR (December 2007) (Learn how and when to remove this template message) Carbamoyl phosphate synthetase I deficiency Other namesCPS I deficiency SpecialtyMedical genetics Carbamoyl phosphate synthetase I deficiency (CPS I deficiency)[1] is an autosomal recessive metabolic disorder that causes ammonia to accumulate in the blood due to a lack of the enzyme carbamoyl phosphate synthetase I. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia. ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 References * 7 External links ## Signs and symptoms[edit] Carbamoyl phosphate synthetase I deficiency often becomes evident in the first few days of life. An infant with this condition may be lacking in energy (lethargic) or unwilling to eat, and have a poorly controlled breathing rate or body temperature. Some babies with this disorder may experience seizures or unusual body movements, or go into a coma. Complications of carbamoyl phosphate synthetase I deficiency may include developmental delay and mental retardation. In some affected individuals, signs and symptoms of carbamoyl phosphate synthetase I deficiency may be less severe, and may not appear until later in life. ## Genetics[edit] Carbamoyl phosphate synthetase I deficiency has an autosomal recessive pattern of inheritance. CPS I deficiency is inherited in an autosomal recessive manner.[1] This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. ## Pathophysiology[edit] Mutations in the CPS1 gene cause carbamoyl phosphate synthetase I deficiency. Carbamoyl phosphate synthetase I deficiency belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys. In carbamoyl phosphate synthetase I deficiency, the enzyme that regulates the urea cycle is damaged or missing. The urea cycle cannot proceed normally, and nitrogen accumulates in the bloodstream in the form of ammonia. Ammonia is especially damaging to the nervous system, and excess ammonia causes neurological problems and other signs and symptoms of carbamoyl phosphate synthetase I deficiency. ## Diagnosis[edit] This section is empty. You can help by adding to it. (December 2016) ## Treatment[edit] Depending on clinical status and the blood ammonia level, the logical first step is to reduce protein intake and to attempt to maintain energy intake. Initiate intravenous infusion of 10% glucose (or higher, if administered through a central line) and lipids. Intravenous sodium benzoate and sodium phenylacetate may be helpful. Arginine is usually administered with benzoate and phenylacetate. This is best administered in the setting of a major medical center where facilities for hemodialysis in infants is available. Glycerol phenylbutyrate is a pre-prodrug that undergoes metabolism to form phenylacetate. Results of a phase 3 study comparing ammonia control in adults showed glycerol phenylbutyrate was noninferior to sodium phenylbutyrate. In a separate study involving young children ages 2 months through 5 years, glycerol phenylbutyrate resulted in a more evenly distributed urinary output of PAGN over 24 hours and accounted for fewer symptoms from accumulation of phenylacetate. In patients with an extremely high blood ammonia level, rapid treatment with hemodialysis is indicated. Metabolic disease specialists should provide long-term care with very close and frequent follow-up. ## References[edit] 1. ^ a b Online Mendelian Inheritance in Man (OMIM): 237300 ## External links[edit] Classification D * ICD-10: E72.29 * ICD-9-CM: 270.6 * OMIM: 237300 * MeSH: D020165 External resources * eMedicine: ped/314 * GeneReviews/NCBI/NIH/UW entry on Urea Cycle Disorders Overview * Carbamoyl phosphate synthetase I deficiency at NLM Genetics Home Reference * v * t * e Inborn error of amino acid metabolism K→acetyl-CoA Lysine/straight chain * Glutaric acidemia type 1 * type 2 * Hyperlysinemia * Pipecolic acidemia * Saccharopinuria Leucine * 3-hydroxy-3-methylglutaryl-CoA lyase deficiency * 3-Methylcrotonyl-CoA carboxylase deficiency * 3-Methylglutaconic aciduria 1 * Isovaleric acidemia * Maple syrup urine disease Tryptophan * Hypertryptophanemia G G→pyruvate→citrate Glycine * D-Glyceric acidemia * Glutathione synthetase deficiency * Sarcosinemia * Glycine→Creatine: GAMT deficiency * Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine * Carnosinemia * Histidinemia * Urocanic aciduria Proline * Hyperprolinemia * Prolidase deficiency Glutamate/glutamine * SSADHD G→propionyl-CoA→ succinyl-CoA Valine * Hypervalinemia * Isobutyryl-CoA dehydrogenase deficiency * Maple syrup urine disease Isoleucine * 2-Methylbutyryl-CoA dehydrogenase deficiency * Beta-ketothiolase deficiency * Maple syrup urine disease Methionine * Cystathioninuria * Homocystinuria * Hypermethioninemia General BC/OA * Methylmalonic acidemia * Methylmalonyl-CoA mutase deficiency * Propionic acidemia G→fumarate Phenylalanine/tyrosine Phenylketonuria * 6-Pyruvoyltetrahydropterin synthase deficiency * Tetrahydrobiopterin deficiency Tyrosinemia * Alkaptonuria/Ochronosis * Tyrosinemia type I * Tyrosinemia type II * Tyrosinemia type III/Hawkinsinuria Tyrosine→Melanin * Albinism: Ocular albinism (1) * Oculocutaneous albinism (Hermansky–Pudlak syndrome) * Waardenburg syndrome Tyrosine→Norepinephrine * Dopamine beta hydroxylase deficiency * reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine * aspartate) * Argininemia * Argininosuccinic aciduria * Carbamoyl phosphate synthetase I deficiency * Citrullinemia * N-Acetylglutamate synthase deficiency * Ornithine transcarbamylase deficiency/translocase deficiency Transport/ IE of RTT * Solute carrier family: Cystinuria * Hartnup disease * Iminoglycinuria * Lysinuric protein intolerance * Fanconi syndrome: Oculocerebrorenal syndrome * Cystinosis Other * 2-Hydroxyglutaric aciduria * Aminoacylase 1 deficiency * Ethylmalonic encephalopathy * Fumarase deficiency * Trimethylaminuria *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Carbamoyl phosphate synthetase I deficiency

c0751753

wikipedia

https://en.wikipedia.org/wiki/Carbamoyl_phosphate_synthetase_I_deficiency

{"gard": ["7269"], "mesh": ["D020165"], "umls": ["C0751753"], "icd-9": ["270.6"], "orphanet": ["147"], "wikidata": ["Q5037834"]}

Killian–Jamieson diverticulum Killian–Jamieson diverticulum. Arrowhead points at the closed upper esophageal sphincter, arrow points at the diverticulum partly filled with contrast medium. SpecialtyGastroenterology A Killian–Jamieson diverticulum is an outpouching of the esophagus just below the upper esophageal sphincter.[1] The physicians that first discovered the diverticulum were Gustav Killian and James Jamieson. Diverticula are seldom larger than 1.5 cm, and are less frequent than the similar Zenker's diverticula. As opposed to a Zenker's, which is typically a posterior and inferior outpouching from the esophagus, a Killian–Jamieson diverticulum is typically an anterolateral outpouching at the level of the C5-C6 vertebral bodies, due to a congenital weakness in the cervical esophagus just below the cricopharyngeal muscle. It is usually smaller in size than a Zenker's diverticulum, and typically asymptomatic.[2] Although congenital, it is more commonly seen in elderly patients.[3] ## References[edit] 1. ^ Tang, Shou-jiang; Tang, Linda; Chen, Edward; Myers, Larry L. (2008). "Flexible endoscopic Killian-Jamieson diverticulotomy and literature review (with video)". Gastrointestinal Endoscopy. 68 (4): 790–793. doi:10.1016/j.gie.2008.01.005. ISSN 0016-5107. PMID 18402951. 2. ^ O'Rourke, A. K.; Weinberger, P. M.; Postma, G. N. (2012). "Killian-Jamieson diverticulum". Ear, Nose, & Throat Journal. 91 (5): 196. doi:10.1177/014556131209100507. PMID 22614553. 3. ^ Siow, S. L.; Mahendran, H. A.; Hardin, M (2015). "Transcervical diverticulectomy for Killian-Jamieson diverticulum". Asian Journal of Surgery. 40 (4): 324–328. doi:10.1016/j.asjsur.2015.01.007. PMID 25779884. ## External links[edit] Classification D * ICD-10: Q39.6 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Killian–Jamieson diverticulum

None

wikipedia

https://en.wikipedia.org/wiki/Killian%E2%80%93Jamieson_diverticulum

{"wikidata": ["Q1695992"]}

Non-hypoproteinemic hypertrophic gastropathy is a rare gastroesophageal disease characterized by diffusely enlarged gastric folds, excessive mucus secretion, normal serum protein and gastric TGF-alpha levels. Patients typically present anemia, abdominal pain not related to eating or bowel habits and absence of peripheral edema. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Non-hypoproteinemic hypertrophic gastropathy

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=329883

{"icd-10": ["K29.6"], "synonyms": ["Hypertrophic gastropathy without hypoproteinemia"]}

a pattern characterized by disorderly eating foods in every life activity Binge eating SpecialtyPsychiatry SymptomsEating addiction Binge eating is a pattern of disordered eating which consists of episodes of uncontrollable eating. It is a common symptom of eating disorders such as binge eating disorder and bulimia nervosa. During such binges, a person rapidly consumes an excessive quantity of food. A diagnosis of binge eating is associated with feelings of loss of control.[1] ## Contents * 1 Diagnosis (DSM-5) * 2 Warning signs * 3 Causes * 4 Health risks * 5 Effects * 6 Treatments * 7 History * 7.1 1959: Binge Eating Disorder First Documentation * 7.2 1987: The APA's DSM * 7.3 2008: The BEDA Form * 7.4 2013: Full Recognition into the DSM * 7.5 January 2015: Drug Therapy is Introduced * 8 See also * 9 References * 10 External links ## Diagnosis (DSM-5)[edit] The Diagnostic and Statistical Manual of Mental Disorders, or rather the DSM, is a manual that is produced by the American Psychiatric Association (APA). In the DSM-5, which was released in 2013 by the APA, they included a disorder diagnosis criteria for Binge Eating Disorder (BED). It is as follows:[2] * Recurrent and persistent episodes of binge eating * Binge eating episodes are associated with three (or more) of the following: * Eating much more rapidly than normal * Eating until feeling uncomfortably full * Eating large amounts of food when not physically hungry * Eating alone because of being embarrassed by how much one is eating * Feeling disgusted with oneself, depressed, or very guilty after overeating * Marked distress regarding binge eating * Absence of regular compensatory behaviors (such as purging) ## Warning signs[edit] Typical warning signs of binge eating disorder include the disappearance of large amount of foods in relatively short periods of time. A person who may be experiencing binge eating disorder may appear to be uncomfortable when eating around others or in public.[3] A person may develop new and extreme eating patterns that they have never done before. These might include diets that cut out certain food groups completely such as a no dairy or no carb diet. They might also steal or hoard food in unusual places.[3] A person may be experiencing fluctuations in their weight. In addition they may have feelings of disgust, depression, or guilt about over eating.[3] Another possible warning sign of binge eating is that a person may be obsessed with their body image or weight.[4] ## Causes[edit] There are no direct causes of binge eating; however, long term dieting, psychological issues, and an obsession with body image have been linked to binge eating. There are multiple factors that increase a person's risk of developing binge eating disorder. Family history can play a role if that person had a family member who was affected by binge eating. Said person may not have a supportive or friendly home environment and they have a hard time expressing their problems with BED. Having a history of going on extreme diets may cause an urge to binge eat. Psychological issues such as feeling negatively about oneself or the way they look may trigger a binge.[5] ## Health risks[edit] There are several physical, emotional, and social health risks when one is suffering from BED. Among the health risks is the chance of extreme weight gain. Two-thirds of those with the BED become overweight or obese. With obesity comes a myriad of health complications: sleep apnea, cancer, heart disease, high blood pressure, type 2 diabetes, arthritis.[6] ## Effects[edit] Typically the eating is done rapidly and a person will feel emotionally numb and unable to stop eating.[7] Most people who have eating binges try to hide this behavior from others, and often feel ashamed about being overweight or depressed about their overeating. Although people who do not have any eating disorder may occasionally experience episodes of overeating, frequent binge eating is often a symptom of an eating disorder. BED is characterized by uncontrollable, excessive eating, followed by feelings of shame and guilt. Unlike those with bulimia, those with BED symptoms typically do not purge their food, fast, or excessively exercise to compensate for binges. Additionally, these individuals tend to diet more often, enroll in weight-control programs and have a history of family obesity.[8] However, many who have bulimia also have binge-eating disorder. Along with the social and physical health that is effected when suffering from BED, there are psychiatric disorders that are often linked to BED. Some of them being, but are not limited to: depression, bipolar disorder, anxiety disorder, substance abuse/use disorder.[9] ## Treatments[edit] There are many ways to treat binge eating disorder mainly through different types of therapy. There is Behavioral Weight Loss therapy (BWL) that is meant to help a person make gradual lifestyle changes to their diet and eating habits. Cognitive Behavioral Therapy (CBT) targets the chaotic eating habits of a person with BED and encourages a regular meal plan. Interpersonal Psychotherapy (IPT) addresses the social deficits of BED and promotes lifestyle changes. Dialectical Behavioral Therapy (DBT) is used to teach healthy ways of dealing with emotional arousals or urges.[10] ## History[edit] ### 1959: Binge Eating Disorder First Documentation[edit] Binge Eating Disorder was first documented by psychiatrist Albert Stunkard in his paper “Eating Patterns and Obesity” in 1959. In his paper, Stunkard reports seeing people eating large amounts of food at infrequent rates. He also reported that some of these cases unhealthy eating habits were seen during a time period he called “night eating”. After this report, the terminology of “Binge Eating” caught on for diagnosing the episodes of infrequent eating of large amounts of food, whether or not the episode is connected with night eating.[11] ### 1987: The APA's DSM[edit] The American Psychiatric Association (APA) mentioned and listed Binge Eating under the listed criteria and features of Bulimia in the Diagnostic and Statistical Manual of Mental Disorders (DSM) - 3 in 1987. By including Binge Eating in the DSM-3, even if not on its own as a separate eating disorder, brought awareness to the disorder and gave it mental disorder legitimacy. This allowed for people to receive the appropriate treatment for binge eating and for their disorder to be legitimized.[11] ### 2008: The BEDA Form[edit] In 2008 the nonprofit called the Binge Eating Disorder Associated (BEDA) forms in order to help, support, and be an advocate for the Binge Eating Disorder (BED) community. To inform the public and spread the awareness of BED, BEDA holds events throughout the year, holds an annual conference, while also hosting a Weight Stigma Awareness Week which supports BED research.[11] ### 2013: Full Recognition into the DSM[edit] In 2013, when the APA released the newly revised edition of DSM-5, BED is declared as its own (eating) disorder. This official announcement helped legitimize BED. With this proclamation, significant change occurred causing for people who suffer from BED to receive the appropriate treatment they need under their insurance plan.[11] ### January 2015: Drug Therapy is Introduced[edit] In January 2015, the Food and Drug Administration (FDA) approved the drug lisdexamfetamine dimesylate, also known as Vyvanse, for the treatment of BED, allowing for the several who are affected to receive drug related help, on top of outside help. The FDA reported that there were only a few side-effects.[11] ## See also[edit] Wikiquote has quotations related to: Binge eating * Binge drinking * Binge eating disorder * Cognitive behavioral treatment of eating disorders * Counterregulatory eating * Overeating * Polyphagia * Prader-Willi Syndrome ## References[edit] 1. ^ Mitchell, James E.; Michael J. Devlin; Martina de Zwaan; Carol B. Peterson; Scott J. Crow (2007). Binge-Eating Disorder: Clinical Foundations and Treatment. Guilford Press. p. 4. ISBN 978-1606237571. Retrieved 15 September 2016. 2. ^ Marx, Russell (2014). "New in the DSM-5: Binge Eating Disorder". Retrieved 2020-02-19. 3. ^ a b c "Binge Eating Disorder". nationaleatingdisorder.org. 26 February 2017. Retrieved 2020-02-19. 4. ^ Spurrell, EB (March 2002). "Age of onset for binge eating: are there different pathways to binge eating?". International Journal of Obesity and Related Metabolic Disorders. 26 (1997): 55–65. doi:10.1038/sj.ijo.0801949. PMID 11896484. 5. ^ Hodges, EL (March 2002). "Family characteristics of binge-eating disorder patients". International Journal of Eating Disorders. 26 (3): 299–307. doi:10.1002/(sici)1098-108x(199803)23:2<145::aid-eat4>3.0.co;2-k. PMID 9503239. 6. ^ "Serious Health Problems Caused By Binge Eating". WebMD. Retrieved 2020-03-09. 7. ^ D. Zweig, Rene; Robert L. Leahy (2012). Treatment Plans and Interventions for Bulimia and Binge-Eating Disorder. Guilford Press. p. 28. ISBN 9781462504947. Retrieved 4 October 2016. 8. ^ Nolen-Hoeksema, Susan (2013). (Ab)normal Psychology. McGraw Hill. p. 345–346. ISBN 978-0078035388. 9. ^ "Binge Eating Disorder". Springer Reference. SpringerReference. Springer-Verlag. 2011. doi:10.1007/springerreference_44139. 10. ^ Iacovino, Juliette (2012). "Psychological Treatments for Binge Eating Disorder". Current Psychiatry Reports. 14 (4): 432–446. doi:10.1007/s11920-012-0277-8. PMC 3433807. PMID 22707016. 11. ^ a b c d e Marcin, Ashley (September 30, 2015). "Binge Eating Disorder History: A Timeline". healthline.com. Retrieved 2020-02-19. ## External links[edit] Classification D External resources * MedlinePlus: 003265 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Binge eating

c0596170

wikipedia

https://en.wikipedia.org/wiki/Binge_eating

{"mesh": ["D056912"], "umls": ["C0596170"], "wikidata": ["Q2303219"]}

A rare, congenital, bone development disorder characterized by a spectrum of terminal limb malformations including hypoplasia/absence of central rays of the hands and feet (that can occur in one to all four digits), variable degrees of median clefts of the hands and/or feet, aplasia and syndactyly, with a wide range of severity ranging from malformed central finger/toe to a lobster claw-like appearance of the hands and feet. It can occur as an isolated malformation or it can be a feature in various syndromes. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Isolated split hand-split foot malformation

c0265554

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2440

{"gard": ["6319"], "mesh": ["C574275"], "omim": ["183600", "225300", "246560", "313350", "605289", "606708"], "umls": ["C0265554"], "icd-10": ["Q71.6", "Q72.7"], "synonyms": ["Ectrodactyly", "SHFM", "Split hand foot malformation"]}

## Description Classic congenital or infantile nystagmus presents as conjugate, horizontal oscillations of the eyes, in primary or eccentric gaze, often with a preferred head turn or tilt. Other associated features may include mildly decreased visual acuity, strabismus, astigmatism, and occasionally head nodding. Eye movement recordings reveal that infantile nystagmus is predominantly a horizontal jerk waveform, with a diagnostic accelerating velocity slow phase. However, pendular and triangular waveforms may also be present. The nystagmus may rarely be vertical. As these patients often have normal visual acuity, it is presumed that the nystagmus represents a primary defect in the parts of the brain responsible for ocular motor control; thus the disorder has sometimes been termed 'congenital motor nystagmus' (Tarpey et al., 2006; Shiels et al., 2007). For a discussion of genetic heterogeneity of congenital nystagmus, see NYS1 (310700). Clinical Features Allen (1942) described a family in which many affected members had congenital nystagmus, presumably inherited in an autosomal dominant pattern. Congenital nystagmus has also been observed as a probably dominant trait among the Old Order Amish of Holmes Co., Ohio (McKusick, 1986). Dell'Osso et al. (1993) studied a family containing 4 sibs with congenital nystagmus to test the hypothesis that instability of the neural integrator responsible for gaze holding is its cause. They concluded that there is no gaze-holding abnormality. The parents and 5 other sibs had no visual problems or clinically apparent motility disorders. However, the father and 2 of the other sibs had saccadic instabilities. Kerrison et al. (1998) reported a large African American family in which 21 of 54 living family members had congenital nystagmus inherited in an autosomal dominant pattern. Clinical examinations were performed on 14 individuals. Among 7 affected persons whose parents were able to report whether the nystagmus was present congenitally, onset at birth was noted in 2 and between 3 and 6 months in 5. Best-corrected binocular Snellen visual acuity ranged from 20/30 to 20/100, with a mode of 20/50. Strabismus was present in 14 examined patients (36%). Eye movement recordings, performed on 5 persons, included asymmetric pendular (3), asymmetric pendular combined with dual waveform jerk (1), and unidirectional jerk nystagmus (1). Mapping By genomewide analysis of a large African American kindred with autosomal dominant congenital nystagmus, Kerrison et al. (1996) found linkage to an 18-cM region on chromosome 6p12 between markers D6S271 and D6S455. The maximum 2-point lod score was 10.15 at D6S459. History In another autosomal dominant pedigree, Hammerstein and Gebauer (1989) found congenital nystagmus in association with hypoplasia of the macula and a balanced translocation, t(5;16)(q31.3;p13.5). However, because nystagmus is a known association of hypoplasia of the macula, which by definition is not present in primary congenital nystagmus, the complication found by Hammerstein and Gebauer (1989) is probably irrelevant to the location of the gene for autosomal dominant congenital nystagmus. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Nystagmus, horizontal \- Strabismus \- Asymmetric pendular movements \- Dual waveform jerk movements \- Jerk nystagmus \- Mildly reduced visual acuity MISCELLANEOUS \- Onset in infancy \- Genetic heterogeneity ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

NYSTAGMUS 2, CONGENITAL, AUTOSOMAL DOMINANT

c1834079

omim

https://www.omim.org/entry/164100

{"mesh": ["C537854"], "omim": ["164100"], "synonyms": ["Alternative titles", "NYSTAGMUS, CONGENITAL MOTOR, 2"]}

Adenosine monophosphate deaminase 1 (AMPD1) deficiency is an inherited condition that can affect the muscles used for movement (skeletal muscles). Many people with AMPD1 deficiency do not have symptoms. People who do have symptoms typically have muscle pain (myalgia), cramping, and weakness after exercise, and often get tired faster than others. Some affected people appear to have more severe symptoms. AMPD1 deficiency is caused by changes (mutations) in the AMPD1 gene and is inherited in an autosomal recessive manner. Other types of AMPD deficiency include the acquired type (due to a muscle or joint condition), and the coincidental inherited type (due to both mutations in the AMPD1 gene and a separate muscle or joint disorder). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Adenosine monophosphate deaminase 1 deficiency

c0268123

gard

https://rarediseases.info.nih.gov/diseases/547/adenosine-monophosphate-deaminase-1-deficiency

{"omim": ["615511"], "umls": ["C0268123"], "orphanet": ["45"], "synonyms": ["AMP deaminase 1 deficiency", "Myoadenylate deaminase deficiency", "AMPD1 deficiency", "Myopathy due to myoadenylate deaminase deficiency", "MMDD", "Adenosine monophosphate deaminase deficiency", "AMP deaminase deficiency"]}

A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-59 (RP59) is caused by homozygous mutation in the DHDDS gene (608172) on chromosome 1p36. Congenital disorder of glycosylation type Ibb (CDG1BB) can be caused by compound heterozygous mutation in the DHDDs gene. One such patient has been reported. For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000; for congenital disorder of glycosylation, see 212065. Clinical Features Zuchner et al. (2011) studied an Ashkenazi Jewish family in which 3 of 4 sibs were diagnosed with retinitis pigmentosa (RP) in their teenage years. Early symptoms consisted of impaired night and peripheral vision. Clinical examination of the affected individuals revealed pigmentary retinal degeneration, and the diagnosis of RP was confirmed by rod and cone responses on electroretinograms (ERGs). The remainder of the physical examination was unremarkable, and laboratory studies, including x-ray bone body survey and bone density scan, were all normal, although 2 of the affected sibs had a history of lytic bone disease diagnosed 15 years previously. Lam et al. (2014) provided follow-up of the Ashkenazi Jewish family originally reported by Zuchner et al. (2011). Funduscopy showed diffuse pigmentary retinal degeneration with vascular attenuation consistent with RP. Impaired night vision and peripheral field defects developed in the second decade of life; ERG responses were nondetectable in 2 of the sibs and indicated cone-rod dysfunction in the third. By the fourth decade of life, vision had progressively deteriorated to legal blindness with constriction of visual fields to less than 10 degrees. Zelinger et al. (2011) examined 18 Ashkenazi Jewish patients with RP59 and observed a spectrum of findings, with visual acuities ranging from light perception to 20/20 vision. Funduscopic findings at various disease stages included waxy appearance of the optic nerve head, attenuation of retinal blood vessels, and bone spicule-like pigmentation. Optical coherence tomography (OCT) imaging in early disease showed preserved central retinal photoreceptors but a decline in photoreceptor layer thickness with distance from the fovea, and occasionally the presence of cystoid macular edema. Kinetic visual fields revealed reduced peripheral function in the youngest patients studied and only small central islands of vision remaining later in life. ERG responses were nondetectable in most patients. Wen et al. (2013) found that patients with RP59 had increased levels of shortened plasma and urinary dolichols compared to controls, and they suggested that this assay could serve as a biomarker. Sabry et al. (2016) noted that patients with RP59 do not present with serum glycoprotein hypoglycosylation, but show abnormal serum and urine dolichols, as demonstrated by Wen et al. (2013). ### Congenital Disorder of Glycosylation Type Ibb Sabry et al. (2016) reported a boy, born of unrelated parents, with a fatal multisytem disorder. The infant had intrauterine growth retardation, axial hypotonia, peripheral hypertonia, enlarged liver, micropenis, and cryptorchidism. He had transient elevation of liver enzymes, renal failure, and seizures. He made no eye contact and had poor feeding with failure to thrive. Ophthalmologic examination at age 2 months showed pale papillae and there was no response on ERG; he also had sensorineural deafness. The infant died at age 8 months during an episode of status epilepticus. Laboratory studies showed hypoglycosylation of plasma proteins; patient fibroblasts showed increased levels of truncated dolichol-linked oligosaccharides, and microsomes derived from the patient showed low levels of dolichol-phosphate. The biochemical findings were consistent with congenital disorder of glycosylation type I. Inheritance The transmission pattern of RP59 in the family reported by Zelinger et al. (2011) was consistent with autosomal recessive inheritance. Mapping Zelinger et al. (2011) performed homozygosity mapping in Ashkenazi Jewish patients with autosomal recessive RP and identified a 1.7-Mb shared homozygous region on chromosome 1p36.11. Molecular Genetics In an Ashkenazi Jewish family in which 3 of 4 sibs had RP, Zuchner et al. (2011) screened all known RP genes but found no mutations. Whole-exome sequencing identified a single variant in the DHDDS gene (K42E; 608172.0001) that was present in homozygosity in the affected sibs but not present in their unaffected sib and for which the unaffected parents were heterozygous. Zuchner et al. (2011) stated that variant was likely to have arisen from an ancestral founder, as it was detected in heterozygosity in 8 of 717 Ashkenazi Jewish controls but was not found in 6,977 confirmed non-Ashkenazi white controls; the variant was also found once in 5,893 additional white controls for whom genomewide genotype data were not available. In 15 (12%) of 123 Ashkenazi Jewish (AJ) probands with RP, Zelinger et al. (2011) identified homozygosity for the K42E founder mutation. The K42E mutation was found in heterozygosity in 1 of 322 ethnically matched controls, indicating a carrier frequency of 0.3% in the AJ population; it was not detected in an additional set of 109 AJ patients with RP, in 20 AJ patients with other inherited retinal diseases, or in 70 patients with retinal degeneration of other ethnic origins. Sabry et al. (2016) demonstrated that the K42E variant was unable to complement the growth defect in yeast lacking the ortholog RER2, consistent with a loss of function. Yeast transfected with the mutation also showed hypoglycosylation of carboxypeptidase Y. These defects could be restored with wildtype DHDDS. ### Congenital Disorder of Glycosylation Type Ibb By sequencing genes required for dolichol biosynthesis in a boy with congenital disorder of glycosylation type Ibb, Sabry et al. (2016) identified compound heterozygosity for nonsense (608172.0004) and splice site (608172.0005) mutations in the DHDDS gene, which segregated with the disorder in the family. Patient cells showed 20 to 25% residual normal DHDDS mRNA, likely from the leaky splice site mutation, and 35% residual DHDDS activity compared to controls. The patient also carried the homozygous F304S polymorphism in the ALG6 gene (604566), which is considered to be a disease modifier that exacerbates the disease in patients with mutations in other genes of the glycosylation pathway. Sabry et al. (2016) noted that the phenotype was much more severe than that reported in the patients with RP59. Animal Model By morpholino-knockdown of Dhdds in zebrafish, Zuchner et al. (2011) observed virtually identical photoreceptor defects as those observed with N-linked glycosylation-interfering mutations in the light-sensing protein rhodopsin (RHO; 180380), which result in RP4 (613731) in humans. INHERITANCE \- Autosomal recessive GROWTH Other \- Intrauterine growth retardation (patient A) \- Failure to thrive (patient A) HEAD & NECK Ears \- Sensorineural deafness (patient A) Eyes \- Visual acuity ranges from 20/20 to light perception only \- Impaired night vision \- Reduced peripheral vision (early) \- Central islands of vision only (late) \- Waxy-appearing optic nerve head \- Attenuated retinal blood vessels \- Bone spicule-like pigmentation \- Cystoid macular edema (in some patients) \- Electroretinography responses nondetectable (in most patients) ABDOMEN Liver \- Enlarged liver (patient A) \- Elevated liver enzymes (patient A) Gastrointestinal \- Poor feeding (patient A) GENITOURINARY External Genitalia (Male) \- Micropenis (patient A) \- Cryptorchidism (patient A) Kidneys \- Renal failure (patient A) MUSCLE, SOFT TISSUES \- Axial hypotonia (patient A) NEUROLOGIC Central Nervous System \- Spasticity (patient A) \- Seizures (patient A) LABORATORY ABNORMALITIES \- Hypoglycosylation of plasma proteins (patient A) \- Increased levels of shortened plasma and urinary dolichols MISCELLANEOUS \- One infant (Patient A) with fatal CDG type I has been reported (last curated January 2018) MOLECULAR BASIS \- Caused by mutation in the dehydrodolichyl diphosphate synthase gene (DHDDS, 608172.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

RETINITIS PIGMENTOSA 59

c0035334

omim

https://www.omim.org/entry/613861

{"doid": ["0110352"], "mesh": ["D012174"], "omim": ["613861"], "orphanet": ["791"], "genereviews": ["NBK1417"]}

In a family with a form of dominant epidermolysis bullosa present from birth or early life and affecting predominantly the hands and feet, Savolainen et al. (1981) found deficiency of procollagen glucosyltransferase (EC 2.4.1.66), the enzyme that catalyzes glucosylation of galactosylhydroxylysyl residues in the biosynthesis of collagen. The deficiency was found in serum, skin and cultured skin fibroblasts, and the urine showed a marked deficiency of galactosylhydroxylysyl-glucosyltransferase. The blisters occurred on any part of the skin that was subjected to trauma, were serous, and healed without scarring. Affected persons in 2 families with recessive epidermolysis bullosa dystrophica and in 1 family with a generalized form of dominant epidermolysis bullosa simplex did not show this enzyme deficiency. This may be an addition to the very small group of dominant disorders with an enzyme deficiency. Winberg and Gedde-Dahl (1986) were of the view that loose linkage was the best explanation of the finding of galactosylhydroxylysyl glucosyltransferase in the Finnish family since 1 or 2 of the patients with epidermolysis bullosa simplex in this family were enzymologically normal and 2 non-EBS patients had the enzyme deficiency. They calculated a maximum lod score of 1.10 at a map distance of 18% recombination. Chance cosegregation of 2 rare traits is another possibility. Inheritance \- Autosomal dominant Lab \- Galactosylhydroxylysyl glucosyltransferase deficiency Skin \- Early onset, non-scarring epidermolysis bullosa ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

EPIDERMOLYSIS BULLOSA WITH DEFICIENCY OF GALACTOSYLHYDROXYLYSYL GLUCOSYLTRANSFERASE

c1851570

omim

https://www.omim.org/entry/131880

{"mesh": ["C565049"], "omim": ["131880"]}

Dependorf (1912) described bilateral fusion of the deciduous incisors in sisters, aged 4 and 5.5 years, and also a rarer condition, bilateral fusion of a deciduous mandibular canine with the second incisor. See 147250. Inheritance \- Autosomal recessive Teeth \- Fused deciduous incisors \- Fused mandibular canine with second incisor ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

TEETH, FUSED

c0016873

omim

https://www.omim.org/entry/273000

{"mesh": ["D005671"], "omim": ["273000"], "icd-10": ["K00.2"]}

A number sign (#) is used with this entry because Fanconi anemia complementation group D1 can be caused by homozygous or compound heterozygous mutation in the BRCA2 gene (600185) on chromosome 13q13. Description Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011). For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650. Biochemical Features Timmers et al. (2001) presented evidence that FA complementation group D is heterogeneous, consisting of 2 distinct loci, FANCD1 and FANCD2 (227646). They identified mutations in the FANCD2 gene in cell lines (PD20, VU008, and PD733) from 3 unrelated families with FANCD. Retroviral transduction of the cloned FANCD2 cDNA into FANCD2 cells resulted in functional complementation of mitomycin C sensitivity. The authors found, however, that the gene mutated in the FANCD cell lines HSC62 and VU423 was distinct from FANCD2 and does not map to chromosome 3; they designated this locus FANCD1. Clinical Features Based on patient outcome data as reported to the International Fanconi Anemia Registry, the cumulative incidence of bone marrow failure by age 40 years is 90%, with median time to onset of 7 years. In contrast, the cumulative incidence of hematologic malignancy, defined as the onset of acute leukemia or myelodysplastic syndrome (MDS), by age 40 years is 33%, with no significant difference between the FA complementation groups A (607139), C (227645), and G (614082) (Kutler et al., 2003). Wagner et al. (2004) reported the genetic, hematologic, and clinical findings in 7 children from 5 kindreds with mutation in the BRCA2 gene segregating with Fanconi anemia. They described the presence of unique characteristics in these families and suggested the use of different monitoring and treatment practices for this specific patient cohort. They identified 6 children in these kindreds with the cooccurrence of BRCA2 mutations, Fanconi anemia, and early-onset acute leukemia. Leukemia occurred at a median of 2.2 years of age in the BRCA2 patients, in contrast to a median onset of 13.4 years in all other Fanconi anemia patients in the International Registry. Breast cancer was noted in 4 of the 5 kindreds. Of the 6 children with leukemia, 4 were treated with bone marrow transplantation and 2 were alive at 3 and 9 months after treatment. Wagner et al. (2004) suggested that BRCA2 testing should be considered in all patients with Fanconi anemia in whom the complementation group cannot be defined or in whom leukemia is diagnosed at or before 5 years of age. Alter et al. (2007) described a female infant with FANCD1 in whom hydrocephalus, fused kidneys, and growth retardation had been identified in utero. At birth, she had intrauterine growth retardation, corneal opacities (diagnosed as Peters anomaly; see 604229), an anteriorly placed anus, small kidneys, and long thumbs with increased laxity; this constellation led to a later diagnosis of VACTERL-H (276950). Other physical findings included microcephaly, facial dysmorphia, microphthalmia, esotropia, growth failure, cafe-au-lait spots, and malposition of the kidneys. The surgical procedures during the first year included a ventricoperitoneal shunt, anoplasty, and repair of a tethered spinal cord due to a lipoma of the filum terminale. The karyotype was 46,XX, with 'structural chromosome changes that may reflect chromosome instability.' The chromosome breakage test for Fanconi anemia done at the age of 20 months showed chromosome breakage with both diepoxybutane and mitomycin C. At age 3.1 years, she was diagnosed with medulloblastoma. In an analysis of the clinical and molecular features associated with BRCA2 mutations in FANCD1 patients using data from 27 patients (26 previously reported), Alter et al. (2007) noted 5 of 27 (19%) with VATER association (192350), suggesting that there may be a higher proportion of VATER association among patients with FANCD1 than among those with Fanconi anemia overall. They noted that a VATER phenotype had been reported in Fanconi anemia of complementation groups A, C, E (600901), F (603467), and G. Leukemia was reported in 13 patients, and solid tumours in 15; 6 patients had 2 or more malignancies. The small group of patients with biallelic mutations in BRCA2 was distinctive in the severity of the phenotype with early onset and high rates of leukemia and specific solid tumours. The authors postulated that these may comprise an extreme variant of Fanconi anaemia. Weinberg-Shukron et al. (2018) reported 2 sisters with Fanconi anemia, aged 20 and 15 years, from a nonconsanguineous family of Ethiopian ancestry, who presented with short stature, primary amenorrhea, and absence of spontaneous pubertal development. Both sisters had a normal female karyotype and hypergonadotrophic hypogonadism, and had no detectable uterus or ovaries on initial imaging studies, findings consistent with complete XX ovarian dysgenesis. Thyroid, adrenal, and ovarian antibodies and serum antimullerian hormone were undetectable. Cortisol levels and findings from adrenal imaging were normal. After 18 months of receiving oral estradiol, in doses that were increased gradually, followed by ongoing treatment with a combined estrogen-progesterone oral contraceptive, both sisters had grown to mean familial height and had secondary sexual characteristics, adult-sized uteri, and regular menstrual periods. Physical examination revealed microcephaly and a few small cafe-au-lait spots in both sisters. The sisters had normal intelligence. The older sister was in a long-term (more than 14 years) remission from acute myelocytic leukemia which had been diagnosed when she was 5 years of age. An older brother of the sisters had died from acute promyelocytic leukemia at 13 years of age. Three other siblings (2 female and 1 male) were healthy and had normal puberty. Lymphocytes from the 2 affected sisters showed many chromosomal breaks after exposure to mitomycin C. BRCA2 mRNA was lower in the affected sisters than in their unaffected relatives and unrelated controls. Molecular Genetics Howlett et al. (2002) found biallelic inactivation of BRCA2 in Fanconi anemia D1 cell lines (600185.0018-600185.0023). Their results linked Fanconi anemia genes with BRCA1 (113705) and BRCA2 in a common pathway. Germline mutations of genes in this pathway may result in cancer risks similar to those observed in families with BRCA1 and BRCA2 mutations. Hirsch et al. (2004) described the clinical, cytogenetic, and molecular findings in 2 Fanconi anemia complementation group D1 kindreds initially identified through a young child with a solid tumor (medulloblastoma and Wilms tumor). Each kindred subsequently had a second affected child; 1 developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies demonstrated an unusually high spontaneous chromosome aberration, contrasted with other FA subtypes. Molecular analysis revealed biallelic mutations in the BRCA2 gene (600185.0027-600185.0030). The patients did not exhibit bone marrow failure. Hirsch et al. (2004) suggested that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role of BRCA2 in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood. In 2 brothers who developed Wilms tumor (see 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: an 886delGT (600185.0027) and S1882X (600185.0031). One boy developed a glioblastoma (see 613029); the other had recurrent medulloblastoma (see 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48. The FANCD1 patient identified by Alter et al. (2007) with VACTERL-H association carried compound heterozygous mutations in the BRCA2 gene, the 6174delT mutation (600185.0009) and Q3066X (600185.0032). In 2 sisters with Fanconi anemia who presented primarily with XX ovarian dysgenesis, Weinberg-Shukron et al. (2018) detected compound heterozygosity for a nonsense mutation (V2527X) and a frameshift mutation (c.9693delA) in the BRCA2 gene. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Intrauterine growth retardation \- Failure to thrive HEAD & NECK Head \- Microcephaly Face \- Dysmorphic facial features, nonspecific (in some patients) CARDIOVASCULAR Heart \- Cardiac defects (in some patients) ABDOMEN Gastrointestinal \- Imperforate anus GENITOURINARY Internal Genitalia (Female) \- Primary ovarian dysgenesis SKELETAL Hands \- Hypoplastic thumbs \- Abnormal thumbs SKIN, NAILS, & HAIR Skin \- Cafe au lait spots HEMATOLOGY \- Bone marrow failure NEOPLASIA \- Increased susceptibility to leukemia \- Increased susceptibility to solid cancers LABORATORY ABNORMALITIES \- Multiple chromosomal breaks \- Chromosomal breakage induced by diepoxybutane (DEB), and mitomycin C MISCELLANEOUS \- Onset in infancy or early childhood \- Extreme sensitivity to chemotherapy MOLECULAR BASIS \- Caused by mutation in the BRCA2 gene (BRCA2, 600185.0009 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

FANCONI ANEMIA, COMPLEMENTATION GROUP D1

c1838457

omim

https://www.omim.org/entry/605724

{"doid": ["0111089"], "mesh": ["C563980"], "omim": ["605724"], "orphanet": ["319462"], "synonyms": ["Alternative titles", "FAD1"], "genereviews": ["NBK1294", "NBK1401", "NBK5192"]}

Congenital eyelid retraction is a very rare kinetic eyelid anomaly that can affect the upper or lower eyelid, presents at birth, that in some cases can result in corneal exposure, and that may be associated with accessory levator muscle slips. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Congenital eyelid retraction

c4274470

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99176

{"icd-10": ["Q10.3"]}

A number sign (#) is used with this entry because of evidence that arrhythmogenic right ventricular dysplasia-10 (ARVD10) is caused by heterozygous mutation in the desmoglein-2 gene (DSG2; 125671) on chromosome 18q12. For a phenotypic description and a discussion of genetic heterogeneity of ARVD, see ARVD1 (107970). Molecular Genetics Pilichou et al. (2006) analyzed the DSG2 gene in 54 probands of Italian descent with arrhythmogenic right ventricular cardiomyopathy who were negative for mutations in the TGFB3 (190230), DSP (125647), and PKP2 (602861) genes, and identified 5 missense mutations, 2 insertion-deletions, 1 nonsense mutation, and 1 splice site mutation. The mutations were found in heterozygosity in 7 probands (see, e.g., 125671.0006) and in compound heterozygosity in 1 proband (125671.0007-125671.0008). None of the patients had effort-induced polymorphic ventricular arrhythmias or gross skin/hair abnormalities. Endomyocardial biopsies performed in 5 mutation-positive patients revealed a mean area of residual myocardium of approximately 47%, fibrous tissue of 24%, and fatty tissue of 20%. Electron microscopy in 3 of the biopsied patients revealed a decreased desmosome number, intercalated disc paleness, and intercellular gap widening. Awad et al. (2006) identified 33 cases of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) in which no mutation in the PKP2 or DSP genes had been found. Amplification and sequencing of the exonic and adjacent intronic sequence of the entire DSG2 gene identified mutations in 4 individuals. Three of the 4 probands had a heterozygous missense mutation in DSG2. The fourth proband had a missense mutation on 1 DSG2 allele and a nonsense mutation on the other (see 125671.0001). His unaffected mother and sister shared the nonsense mutation. Awad et al. (2006) suggested that this could indicate incomplete penetrance, or that this mutation is insufficient to result in ARVD/C in isolation. Syrris et al. (2007) sequenced the DSG2 gene in 86 Caucasian ARVC patients known to be negative for mutations in the DSP, PKP2, and JUP (173325) genes and detected 8 mutations in 9 probands (see, e.g., V55M, 125671.0009); the mutations were not found in 400 control chromosomes. Clinical evaluation of 24 family members with DSG2 mutations demonstrated penetrance of 58 to 75%, depending on the criteria used. Morphologic abnormalities of the right ventricle were evident in 66% of mutation carriers, left ventricular involvement in 25%, and classic right precordial T-wave inversion in only 26%. Sustained ventricular arrhythmia was present in 8%, and a family history of sudden death or aborted sudden death in 66%. Syrris et al. (2007) concluded that mutations in DSG2 show a high degree of penetrance with variable severity of expression; regarding the low prevalence of classic ECG changes, the authors suggested that current diagnostic criteria be expanded to account for left ventricular disease, childhood disease expression, and incomplete penetrance. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Cardiomyopathy, right ventricular \- Fibrofatty replacement of right ventricular myocardium \- Ventricular arrhythmia (PVC, nonsustained VT, sustained VT) \- Palpitations \- Sudden cardiac death MISCELLANEOUS \- Genetic heterogeneity \- Mean age at diagnosis is 38 years(range 11-63 years) MOLECULAR BASIS \- Caused by mutation in the desmoglein 2 gene (DSG2, 125671.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10

c1862511

omim

https://www.omim.org/entry/610193

{"doid": ["0110081"], "mesh": ["C566254"], "omim": ["107970", "610193"], "orphanet": ["217656", "293888", "293910", "293899"], "synonyms": ["Familial isolated arrhythmogenic ventricular cardiomyopathy, biventricular form", "Familial isolated arrhythmogenic ventricular cardiomyopathy, left dominant form", "Familial isolated arrhythmogenic ventricular dysplasia, classic form", "Familial isolated ARVD", "Familial isolated ARVC", "Familial isolated arrhythmogenic ventricular cardiomyopathy, classic form", "Alternative titles", "Familial isolated arrhythmogenic ventricular dysplasia", "Familial isolated arrhythmogenic ventricular cardiomyopathy", "Familial isolated arrhythmogenic right ventricular cardiomyopathy", "ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY 10", "Familial isolated arrhythmogenic ventricular cardiomyopathy, right dominant form"], "genereviews": ["NBK1131"]}

In a 12-year-old girl with obstructive lung disease, the offspring of first-cousin parents, Afzelius et al. (1985) found that the clinical characteristics of the immotile cilia syndrome (see 244400), including chronic rhinitis, sinusitis, bronchitis, severely decreased mucociliary clearance of the lungs, and nasal polyps, were associated with nasal cilia about twice normal in length but normal in cross-sectional dimension. HEENT \- Chronic rhinitis \- Sinusitis \- Nasal polyps Pulmonary \- Obstructive lung disease \- Immotile cilia \- Bronchitis \- Decreased mucociliary clearance Lab \- Nasal cilia abnormally long but with normal diameter Inheritance \- Autosomal recessive ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

CILIARY DYSKINESIA WITH EXCESSIVELY LONG CILIA

c0340036

omim

https://www.omim.org/entry/242680

{"mesh": ["C536287"], "omim": ["242680", "244400"], "orphanet": ["244"], "synonyms": ["IMMOTILE CILIA SYNDROME DUE TO EXCESSIVELY LONG CILIA", "Alternative titles", "PCD"]}

Prolapse of the tear gland of the third eyelid in animals Close-up of a cherry eye Cherry eye is a disorder of the nictitating membrane (NM), also called the third eyelid, present in the eyes of dogs and cats.[1] Cherry eye is most often seen in young dogs under the age of two.[2] Common misnomers include adenitis, hyperplasia, adenoma of the gland of the third eyelid; however, cherry eye is not caused by hyperplasia, neoplasia, or primary inflammation.[3] In many species, the third eyelid plays an essential role in vision by supplying oxygen and nutrients to the eye via tear production.[4] Normally, the gland can turn inside-out without detachment.[3] Cherry eye results from a defect in the retinaculum which is responsible for anchoring the gland to the periorbita. This defect causes the gland to prolapse and protrude from the eye as a red fleshy mass.[3] Problems arise as sensitive tissue dries out and is subjected to external trauma[3] Exposure of the tissue often results in secondary inflammation, swelling, or infection.[3] If left untreated, this condition can lead to dry eye syndrome and other complications.[4] ## Contents * 1 Description * 2 Treatment * 2.1 Non-surgical * 2.2 Surgical * 2.2.1 Anchoring method * 2.2.2 Envelope/pocket method * 3 Prognosis * 3.1 Without treatment * 3.2 Post treatment * 4 See also * 5 References * 6 External links ## Description[edit] Cherry eye is most common in young dogs, especially breeds such as Cavalier King Charles Spaniel, English Bulldog, Lhasa Apso, Shih Tzu, West Highland White Terrier, Pug, Bloodhound, American Cocker Spaniel, and Boston Terrier.[1] Cherry eye is rare in felines, but can occur. This defect is most common in the Burmese breed of felines.[5] A similar condition exists in dwarf lop-eared rabbits, which occurs in the harderian gland. Similar surgical treatment is necessary.[3] Cherry eye is not considered a genetic problem, as no proof of inheritance has been determined.[6] The NM contains many glands which merge and appear as a single gland.[7] Typically, glands secrete tears for lubrication of the cornea.[7] Lack of anchoring allows the gland to flip up, causing the gland to prolapse. Symptoms include a visible fleshy mass, abnormal tear production, and a discharge or drainage from the eye. Cherry eye is typically diagnosed by examination of the conjunctiva and nictitating membrane.[2] The most obvious symptom of cherry eye is a round fleshy mass in the medial canthus of the eye, similar in appearance to the fruit it is named for.[7] This mass may be unilateral or ‘’bilateral’’. Both eyes may develop cherry eye at different times in the animal's life.[1] Other symptoms of cherry eye include drainage from the eye and abnormal tear production. Initially, cherry eye results in overproduction of tears, but eventually changes to unsubstantial tear production.[1] ## Treatment[edit] ### Non-surgical[edit] Cherry eye, if caught early, can be resolved with a downward diagonal-toward-snout closed-eye massage of the affected eye or occasionally self-corrects alone or with antibiotics and steroids.[3] Sometimes the prolapse will correct itself with no interference, or with slight physical manual massage manipulation as often as necessary coupled with medication.[3] ### Surgical[edit] Surgery is the most common means of repairing a cherry eye. Surgery involves gland replacement, not excision, by anchoring the membrane to the orbital rim or using a pocket technique.[3] In severely infected cases, preoperative antibiotics may be necessary by means of antibiotic eye ointment.[3] Removal of the gland was once an acceptable treatment, and made the eye appear completely normal.[5] Despite cosmetic appeal, removal of the gland reduces tear production by 30 percent. Tear production is essential in maintaining and protecting the eye from the external environment.[5] Reduced tear production is especially problematic in breeds of animals predisposed to Keratoconjunctivitis sicca (KCS), also known as dry eye syndrome. With surgeries performed in this manner, KCS often results later in life.[3] Close-up of prolapsed gland in small breed dog KCS is not common in dogs, affecting one per cent of the dog population.[8] KCS is a chronic degenerative conjunctivitis that can lead to impaired vision and blindness.[2] KCS has a wide array of causes including drug toxicity, cherry eye, previous surgery, trauma, and irradiation.[2] KCS can be treated, but treatment often spans the entirety of the animal's life.[2] In contrast to this, several replacement surgical procedures exist to remedy cherry eye.[2] Replacement of the gland results in lower instances of dry eye later in life.[9] Surgery types are broken into two groups: anchoring procedures and pocket/envelope procedures.[1] At least 8 surgical techniques currently exist.[1] In anchoring procedures, the prolapsed gland must be sutured to the periorbital fascia, the sclera, or the base of the third eyelid.[5] In contrast, pocket procedures involve suturing healthy tissue around the prolapsed to enclose and secure it.[5] Each of these techniques may be performed with an anterior or superior approach, depending on which direction of suturing will cause the least complications to the eye.[5] #### Anchoring method[edit] Originally, the anchoring method involved suturing the gland to the globe. This method was superseded over time due to the risky and difficult nature of the surgery, along with a high rate of recurrence.[3] Anchoring approaches from posterior may disrupt normal fluid excretion.[9] Subsequently, an anterior approach was introduced.[9] Disadvantages of anchoring techniques include restricted mobility of third eyelid, which is essential in the functions of fluid distribution and self-cleaning.[9] New procedures are currently being explored to allow tacking of the NM without restricting movement of the third eyelid.[9] Few studies compare results of surgeries, therefore choosing a procedure is a matter of preference.[9] #### Envelope/pocket method[edit] The envelope method, often called the pocket technique, requires suturing of tissue around the prolapse, encasing it in a layer of conjunctiva.[5] Pocket techniques are easiest for doctors to learn.[1] Pocket methods also have anterior and posterior versions. Posterior suturing techniques are the most commonly used because they cause the least complications, with no alterations in tear production.[9] Surgery should only be attempted by experienced surgeons.[3] Inappropriate surgical techniques can result in many complications including cysts on the eye.[9] ## Prognosis[edit] ### Without treatment[edit] Previously, treatment was thought optional until the role of NM was fully understood.[1] The NM gland is responsible for 40–50% of tear production.[10] If exposed for extended periods of time, the gland is at risk for trauma, secondary infection, and reduced tear production.[10] Many complications can arise if left untreated: early closed-eye massage manipulation is recommended to prevent inflammation .[3] ### Post treatment[edit] Postoperative treatment includes antibiotic eye ointment three times daily for two weeks.[5] It is possible to have a relapse of the gland after surgery and require multiple surgeries.[3] With treatment, it is possible for animals to live a normal life. ## See also[edit] * Conjunctivitis, commonly referred to as pink eye ## References[edit] 1. ^ a b c d e f g h Gelatt, K. N. (2000). Essentials of Veterinary Ophthalmology. Baltimore: Lippincott Williams & Wilkins. 2. ^ a b c d e f Gelatt, K. N. (2001). Color Atlas of Veterinary Ophthalmology. Baltimore: Lippincott Williams & Wilkins. 3. ^ a b c d e f g h i j k l m n o Slatter, D. (2001). Fundamentals of Veterinary Ophthalmology: Third Edition. Philadelphia: W.B. Saunders Company. 4. ^ a b Robledo, E. P., Serrano, R. D., Sanches, N. Q., & Ramirez, A. M. (n.d.). "Effect of Pet Vision in a Canine with Keratoconjunctivitis Sicca (Dry Eye) Archived 2012-12-18 at the Wayback Machine". Retrieved 1 December 2012. 5. ^ a b c d e f g h Griffin, C., & Glaze, M. B. (2008). "Eyes and Ears". St John U.S.V.I. November 3–6. International Veterinary Seminars. 6. ^ Christmas, R. E. (1992).But Some breeds are considered to be more susceptible to its development than others, including the Bulldog, Boston Terrier, Bull Terrier, Lhasa Apso, Cocker Spaniel, St. Bernard, Shar-pei, Shih Tzu and Poodle "Common Ocular Problems of Shih Tzu Dogs". Canadian Veterinary Journal, Volume 33, 392. 7. ^ a b c Sarma, B. (2010). "Cherry Eye in Dogs. Intas Polivet, 11, pp. 80–81. 8. ^ Blount, W. (n.d.). "Dry Eye: More formally known as Keratoconjuntivis Sicca or KCS". Retrieved 1 December 2012. 9. ^ a b c d e f g h Plummer, C., Kallberg, M., Gelatt, K., Gelatt, J., & Barrie, K. P. (2008). "Intranictitans tacking for replacement of prolapsed gland of the third eyelid in dogs". Veterinary Ophthalmology, pp. 228–233. 10. ^ a b "Prolapsed gland of the third eyelid". American College of Veterinary Ophthalmologists. Archived from the original on 2017-08-04. Retrieved 2017-08-03. ## External links[edit] * Cherry Eye from The Pet Health Library *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Cherry eye

c0521742

wikipedia

https://en.wikipedia.org/wiki/Cherry_eye

{"wikidata": ["Q928925"]}

Sorsby's fundus dystrophy Other namesSorsby pseudoinflammatory fundus dystrophy Sorsby's fundus dystrophy is inherited in an autosomal dominant manner. Sorsby's fundus dystrophy (SFD) is a very rare genetic disorder characterized by the loss of central vision.[1][2][3] It was first described by Sorsby and Mason in 1949.[4] ## Contents * 1 Signs and symptoms * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Signs and symptoms[edit] Patients typically begin lose their central vision in their 40s.[1] ## Genetics[edit] The inheritance pattern is autosomal dominant. It is related to a mutation in the TIMP3 gene.[1][5] ## Diagnosis[edit] This section is empty. You can help by adding to it. (January 2018) ## Treatment[edit] This section is empty. You can help by adding to it. (January 2018) ## References[edit] 1. ^ a b c "SORSBY FUNDUS DYSTROPHY; SFD". omim.org. Retrieved 2017-01-21. 2. ^ "Sorsby's fundus dystrophy". www.orpha.net. Retrieved 2017-01-21. 3. ^ Weisinger, H. S.; Pesudovs, K. (2001-07-01). "Sorsby's fundus dystrophy". Optometry (St. Louis, Mo.). 72 (7): 435–440. PMID 11486938. 4. ^ Sorsby, A.; Mason, M. E. J. (1949-02-01). "A fundus dystrophy with unusual features". The British Journal of Ophthalmology. 33 (2): 67–97. doi:10.1136/bjo.33.2.67. PMC 510908. PMID 18111349. 5. ^ Wijesuriya, S. D.; Evans, K.; Jay, M. R.; Davison, C.; Weber, B. H.; Bird, A. C.; Bhattacharya, S. S.; Gregory, C. Y. (1996-02-01). "Sorsby's fundus dystrophy in the British Isles: demonstration of a striking founder effect by microsatellite-generated haplotypes". Genome Research. 6 (2): 92–101. doi:10.1101/gr.6.2.92. PMID 8919688. ## External links[edit] Classification D * ICD-10: H35.5 * OMIM: 136900 * MeSH: C564992 External resources * Orphanet: 59181 * Sorsby's fundus dystrophy at OMIM * Sorsby's fundus dystrophy at Orpha.net *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Sorsby's fundus dystrophy

c1850938

wikipedia

https://en.wikipedia.org/wiki/Sorsby%27s_fundus_dystrophy

{"gard": ["10511"], "mesh": ["C564992"], "omim": ["136900"], "umls": ["C0339515"], "orphanet": ["59181"], "synonyms": [], "wikidata": ["Q30314095"]}

Pseudoachondroplasia is an inherited disorder of bone growth. It was once thought to be related to another disorder of bone growth called achondroplasia, but without that disorder's characteristic facial features. More research has demonstrated that pseudoachondroplasia is a separate disorder. All people with pseudoachondroplasia have short stature. The average height of adult males with this condition is 120 centimeters (3 feet, 11 inches), and the average height of adult females is 116 centimeters (3 feet, 9 inches). Individuals with pseudoachondroplasia are not unusually short at birth; by the age of two, their growth rate falls below the standard growth curve. Other characteristic features of pseudoachondroplasia include short arms and legs; a waddling walk; joint pain in childhood that progresses to a joint disease known as osteoarthritis; an unusually large range of joint movement (hyperextensibility) in the hands, knees, and ankles; and a limited range of motion at the elbows and hips. Some people with pseudoachondroplasia have legs that turn outward or inward (valgus or varus deformity). Sometimes, one leg turns outward and the other inward, which is called windswept deformity. Some affected individuals have a spine that curves to the side (scoliosis) or an abnormally curved lower back (lordosis). People with pseudoachondroplasia have normal facial features, head size, and intelligence. ## Frequency The exact prevalence of pseudoachondroplasia is unknown; it is estimated to occur in 1 in 30,000 individuals. ## Causes Mutations in the COMP gene cause pseudoachondroplasia. This gene provides instructions for making a protein that is essential for the normal development of cartilage and for its conversion to bone. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears. The COMP protein is normally found in the spaces between cartilage-forming cells called chondrocytes, where it interacts with other proteins. COMP gene mutations result in the production of an abnormal COMP protein that cannot be transported out of the cell. The abnormal protein builds up inside the chondrocyte and ultimately leads to early cell death. Early death of the chondrocytes prevents normal bone growth and causes the short stature and bone abnormalities seen in pseudoachondroplasia. ### Learn more about the gene associated with Pseudoachondroplasia * COMP ## Inheritance Pattern Pseudoachondroplasia is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Most cases result from new mutations in the gene and occur in people with no history of the disorder in their family. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Pseudoachondroplasia

c0410538

medlineplus

https://medlineplus.gov/genetics/condition/pseudoachondroplasia/

{"gard": ["4540"], "mesh": ["C535819"], "omim": ["177170"], "synonyms": []}

## Clinical Features Abou Jamra et al. (2011) reported a consanguineous Syrian family (MR013) in which 3 individuals had nonsyndromic mental retardation. Symptoms included mild motor delay, moderate intellectual disability, proper speech and social interaction, and no discrete facial gestalt. Arthrogryposis of small joints was noted, and 2 had deformities of the feet. Mapping By homozygosity mapping of a consanguineous Syrian family with mental retardation, Abou Jamra et al. (2011) found linkage to a 1.2-Mb region on chromosome 18p between SNPs rs4606805 and rs1787846 (lod score of 3.03). INHERITANCE \- Autosomal recessive SKELETAL \- Arthrogryposis of several small joints Feet \- Foot deformity (in some patients) NEUROLOGIC Central Nervous System \- Intellectual disability, moderate \- Motor delay, mild \- No speech delay Behavioral Psychiatric Manifestations \- Amicable disposition \- Cheerful disposition MISCELLANEOUS \- Based on a report of 1 consanguineous Syrian family (last curated November 2011) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MENTAL RETARDATION, AUTOSOMAL RECESSIVE 19

c3280541

omim

https://www.omim.org/entry/614343

{"doid": ["0060308"], "omim": ["614343"], "orphanet": ["88616"], "synonyms": ["AR-NSID", "NS-ARID"]}

Gelatinous drop-like corneal dystrophy Other namesSubepithelial amyloidosis of the cornea A completely opaque cornea with multiple drop-like nodular opacities. Some blood vessels are present in the opaque cornea Apple green dichroism of subepithelial deposition of amyloid viewed under polarized light. Congo red stain. Gelatinous drop-like corneal dystrophy, also known as amyloid corneal dystrophy, is a rare form of corneal dystrophy. The disease was described by Nakaizumi as early as 1914.[1] ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Treatment * 5 References * 6 External links ## Presentation[edit] The main pathological features in this dystrophy are mulberry-shaped gelatinous masses beneath the corneal epithelium. Patients suffer from photophobia, foreign body sensation in the cornea. The loss of vision is severe. The amyloid nodules have been found to contain lactoferrin, but the gene encoding lactoferrin is unaffected. This form of corneal amyloidosis appears to be more frequent in Japan.[2] ## Genetics[edit] A number of mutations causing this disease have been described in the M1S1 (TACSTD2) gene encoding Tumor-associated calcium signal transducer 2, but not all patients have these mutations, suggesting involvement of other genes.[3] ## Diagnosis[edit] This section is empty. You can help by adding to it. (September 2017) ## Treatment[edit] Recurrence within a few years occurs in all patients following corneal transplantation. Soft contact lenses are effective in decreasing recurrences. ## References[edit] 1. ^ Nakaizumi, K. : A rare case of corneal dystrophy. Acta. Soc. Ophthal. Jpn. 18: 949-950, 1914 2. ^ Online Mendelian Inheritance in Man (OMIM): 204870 3. ^ Klintworth GK (2009). "Corneal dystrophies". Orphanet J Rare Dis. 4 (1): 7. doi:10.1186/1750-1172-4-7. PMC 2695576. PMID 19236704. ## External links[edit] Classification D * ICD-10: H18.5 * OMIM: 204870 * MeSH: C535480 External resources * Orphanet: 98957 Media related to Gelatinous droplike corneal dystrophy at Wikimedia Commons * v * t * e Types of corneal dystrophy Epithelial and subepithelial * Epithelial basement membrane dystrophy * Gelatinous drop-like corneal dystrophy * Lisch epithelial corneal dystrophy * Meesmann corneal dystrophy * Subepithelial mucinous corneal dystrophy Bowman's membrane * Reis–Bucklers corneal dystrophy * Thiel-Behnke dystrophy Stroma * Congenital stromal corneal dystrophy * Fleck corneal dystrophy * Granular corneal dystrophy * Lattice corneal dystrophy * Macular corneal dystrophy * Posterior amorphous corneal dystrophy * Schnyder crystalline corneal dystrophy Descemet's membrane and endothelial * Congenital hereditary endothelial dystrophy * Fuchs' dystrophy * Posterior polymorphous corneal dystrophy * X-linked endothelial corneal dystrophy This article about an ophthalmic disease is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Gelatinous drop-like corneal dystrophy

c0339273

wikipedia

https://en.wikipedia.org/wiki/Gelatinous_drop-like_corneal_dystrophy

{"gard": ["9647"], "mesh": ["C535480"], "umls": ["C0339273"], "orphanet": ["98957"], "wikidata": ["Q4178686"]}

Cardiac tumours are benign or malignant neoplasms arising primarily in the inner lining, muscle layer, or the surrounding pericardium of the heart. They can be primary or metastatic. ## Epidemiology Primary cardiac tumours are rare in paediatric practice with a prevalence of 1.7/1000 to 28/1000 in autopsy series. In contrast, the incidence of cardiac tumours during foetal life has been reported to be approximately 1.4/1000. The incidence of cardiac metastases associated with all types of malignant tumours is estimated to be approximatively 1% (and is 10-20 times higher than primary malignancies of the heart). ## Clinical description The vast majority of primary cardiac tumours in children are benign, whilst approximately 10% are malignant. In contrast, the majority of secondary tumours are malignant. In adults, however, the frequency and type of cardiac tumours in adults differ from those in children with 75% being benign and 25% being malignant. Myxomas are the most common primary tumours in adults constituting 40% of benign tumours. Sarcomas make up 75% of malignant cardiac masses. Rhabdomyoma is the most common cardiac tumour during foetal life and childhood. It accounts for more than 60% of all primary cardiac tumours. The manifestations of a cardiac tumour in foetal life include arrhythmia, congestive heart failure, hydrops, and not infrequently stillbirth. In postnatal life cardiac tumours may lead to cyanosis, murmur, respiratory distress, myocardial dysfunction, valvular insufficiency, arrhythmias, and sudden death. ## Diagnostic methods Echocardiography, Computing Tomography (CT) and Magnetic Resonance Imaging (MRI) of the heart are the main non-invasive diagnostic tools. Cardiac catheterisation is seldom necessary. Tumour biopsy with histological assessment remains the gold standard for confirmation of the diagnosis. ## Management and treatment Surgical resection of primary cardiac tumours should be considered to relieve symptoms and mechanical obstruction to blood flow. Patients with primary cardiac malignancies may benefit from palliative surgery but this approach should not be recommended for patients with metastatic cardiac tumours. Surgery, chemotherapy and radiotherapy may prolong survival. ## Prognosis The outcome of surgical resection in symptomatic, non-myxomatous benign cardiac tumours is favourable. The prognosis for malignant primary cardiac tumours is generally extremely poor. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Primary pediatric heart tumor

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=875

{"icd-10": ["C38.0", "D15.1"], "synonyms": ["Cardiac tumor of child", "Heart tumor of child"]}

This article includes a list of references, related reading or external links, but its sources remain unclear because it lacks inline citations. Please help to improve this article by introducing more precise citations. (June 2014) (Learn how and when to remove this template message) Coxa vara Different femoral abnormalities. SpecialtyMedical genetics Coxa vara is a deformity of the hip, whereby the angle between the head and the shaft of the femur is reduced to less than 120 degrees. This results in the leg being shortened and the development of a limp. It may be congenital and is commonly caused by injury, such as a fracture. It can also occur when the bone tissue in the neck of the femur is softer than normal, causing it to bend under the weight of the body. This may either be congenital or the result of a bone disorder. The most common cause of coxa vara is either congenital or developmental. Other common causes include metabolic bone diseases (e.g. Paget's disease of bone), post-Perthes deformity, osteomyelitis, and post traumatic (due to improper healing of a fracture between the greater and lesser trochanter). Shepherd's Crook deformity is a severe form of coxa vara where the proximal femur is severely deformed with a reduction in the neck shaft angle beyond 90 degrees. It is most commonly a sequela of osteogenesis imperfecta, Pagets disease, osteomyelitis, tumour and tumour-like conditions (e.g. fibrous dysplasia). Coxa vara can happen in cleidocranial dysostosis. ## Contents * 1 Anatomy * 2 Types * 2.1 Developmental * 2.2 Congenital * 3 See also * 4 References * 5 External links ## Anatomy[edit] In early skeletal development, a common physis serves the greater trochanter and the capital femoral epiphysis. This physis divides as growth continues in a balance that favors the capital epiphysis and creates a normal neck shaft angle (angle between the femoral shaft and the neck). The corresponding angle at maturity is 135 ± 7 degrees. Another angle used for the measurement of coxa vara is the cervicofemoral angle which is approximately 35 degrees at infancy and increases to 45 degrees after maturity. ## Types[edit] ### Developmental[edit] * primary defect in endochondral ossification of the medial part of the femoral neck (Most common cause) * Excessive interuterine pressure on the developing fetal hip * vascular insult * Faulty maturation of the cartilage and metaphyseal bone of the femoral neck Clinical feature: presents after the child has started walking but before six years of age. Usually associated with a painless hip due to mild abductor weakness and mild limb length discrepancy. If there is a bilateral involvement the child might have a waddling gait or trendelenburg gait with an increased lumbar lordosis. The greater trochanter is usually prominent on palpation and is more proximal. Restricted abduction and internal rotation. X-ray: decreased neck shaft angle, increased cervicofemoral angle, vertical physis, shortened femoral neck decrease in femoral anteversion. HE angle (Hilgenriener epiphyseal angle- angle subtended between a horizontal line connecting the triradiate cartilage and the epiphysis); normal angle is <30 degrees. Treatment: HE angle of 45–60 degrees: observation and periodic follow up. Indication for surgery: HE angle more than 60 degrees, progressive deformity, neckshaft angle <90 degrees, development of Trendelenburg gait Surgery: subtrochanteric valgus osteotomy with adequate internal rotation of distal fragment to correct anteversion; common complication is recurrence. If HE angle is reduced to 38 degrees, less evidence of recurrence; post operative spica cast is used for a period of 6–8 weeks. Coxa vara is also seen in Niemann–Pick disease. ### Congenital[edit] Presence at birth is extremely rare and associated with other congenital anomalies such as proximal femoral focal deficiency, fibular hemimelia or anomalies in other part of the body such as cleidocranial dyastosis. The femoral deformity is present in the subtrochantric area where the bone is bent. The cortices are thickened and may be associated with overlying skin dimples. External rotation of the femur with valgus deformity of knee may be noted. This condition does not resolve and requires surgical management. Surgical management includes valgus osteotomy to improve hip biomechanics and length and rotational osteotomy to correct retroversion and lengthening. ## See also[edit] * Coxa valga * Genu valgus ## References[edit] * S.Swischuk, S.John: Differential Diagnosis in Pediatric Radiology, Williams & Wilkins 1995, ISBN 0-683-08046-6 * D Resnick: Diagnosis of Bone and Joint Disorders Vol V, Saunders 1995, ISBN 0-7216-5071-6 ## External links[edit] Classification D * ICD-10: M21.1, Q65.8 * ICD-9-CM: 736.32, 755.62 * MeSH: D060905 * DiseasesDB: 34852 * v * t * e Acquired musculoskeletal deformities Upper limb shoulder * Winged scapula * Adhesive capsulitis * Rotator cuff tear * Subacromial bursitis elbow * Cubitus valgus * Cubitus varus hand deformity * Wrist drop * Boutonniere deformity * Swan neck deformity * Mallet finger Lower limb hip * Protrusio acetabuli * Coxa valga * Coxa vara leg * Unequal leg length patella * Luxating patella * Chondromalacia patellae * Patella baja * Patella alta foot deformity * Bunion/hallux valgus * Hallux varus * Hallux rigidus * Hammer toe * Foot drop * Flat feet * Club foot knee * Genu recurvatum Head * Cauliflower ear General terms * Valgus deformity/Varus deformity * Joint stiffness * Ligamentous laxity * v * t * e Congenital malformations and deformations of musculoskeletal system / musculoskeletal abnormality Appendicular limb / dysmelia Arms clavicle / shoulder * Cleidocranial dysostosis * Sprengel's deformity * Wallis–Zieff–Goldblatt syndrome hand deformity * Madelung's deformity * Clinodactyly * Oligodactyly * Polydactyly Leg hip * Hip dislocation / Hip dysplasia * Upington disease * Coxa valga * Coxa vara knee * Genu valgum * Genu varum * Genu recurvatum * Discoid meniscus * Congenital patellar dislocation * Congenital knee dislocation foot deformity * varus * Club foot * Pigeon toe * valgus * Flat feet * Pes cavus * Rocker bottom foot * Hammer toe Either / both fingers and toes * Polydactyly / Syndactyly * Webbed toes * Arachnodactyly * Cenani–Lenz syndactylism * Ectrodactyly * Brachydactyly * Stub thumb reduction deficits / limb * Acheiropodia * Ectromelia * Phocomelia * Amelia * Hemimelia multiple joints * Arthrogryposis * Larsen syndrome * RAPADILINO syndrome Axial Skull and face Craniosynostosis * Scaphocephaly * Oxycephaly * Trigonocephaly Craniofacial dysostosis * Crouzon syndrome * Hypertelorism * Hallermann–Streiff syndrome * Treacher Collins syndrome other * Macrocephaly * Platybasia * Craniodiaphyseal dysplasia * Dolichocephaly * Greig cephalopolysyndactyly syndrome * Plagiocephaly * Saddle nose Vertebral column * Spinal curvature * Scoliosis * Klippel–Feil syndrome * Spondylolisthesis * Spina bifida occulta * Sacralization Thoracic skeleton ribs: * Cervical * Bifid sternum: * Pectus excavatum * Pectus carinatum *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Coxa vara

c0239138

wikipedia

https://en.wikipedia.org/wiki/Coxa_vara

{"gard": ["8750"], "mesh": ["D060905"], "umls": ["C0239138"], "icd-9": ["755.62", "736.32"], "icd-10": ["Q65.8", "M21.1"], "wikidata": ["Q1138267"]}

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-43 (EIEE43) is caused by heterozygous mutation in the GABRB3 gene (137192) on chromosome 15q11. For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350). Clinical Features The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) reported 4 unrelated patients with infantile epileptic encephalopathy. The patients had onset of multiple seizure types within the first year of life, including absence, myoclonic, and generalized tonic-clonic seizures. Three patients with available clinical information showed global developmental delay; 2 of these had behavioral abnormalities. The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) concluded that their results implicated the GABRB3 gene in epileptic encephalopathy. The Epi4K Consortium (2016) reported follow-up of the patients reported by the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013), who ranged from 11 to 20 years of age. One had mildly delayed development and the 3 others had mild to severe intellectual disability. The Epi4K Consortium (2016) reported 7 additional patients with EIEE43. Six had onset of multiple seizures types within the first year of life. Only 2 of these patients had normal development prior to onset of seizures. All had mild to profound intellectual disability. The seventh patient, a 19-year-old girl with severe intellectual disability, had delayed development apparent at age 6 months, but did not develop seizures until age 12 years. One case had a family history of genetic epilepsy and febrile seizures plus (GEFS+). Combined with the 4 previously reported patients (11 patients total) 5 had severe to profound intellectual disability, 3 had mild to moderate disability, and the degree of cognitive impairment was unclear in the remaining 3. Predominant seizure types were myoclonic, tonic, absence, and generalized tonic-clonic seizures. EEG showed multiple variable abnormalities, including generalized spike-wave discharges, background slowing, and hypsarrhythmia. Molecular Genetics In 4 unrelated patients with EIEE43, the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified different de novo heterozygous mutations in the GABRB3 gene. The patients were part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. A statistical likelihood analysis indicated that the probability of this finding occurring by chance was p = 4.1 x 10(-10). Functional studies of the mutations were not performed. The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) concluded that their results implicated the GABRB3 gene in epileptic encephalopathy. In 7 previously unreported patients with EIEE43, the Epi4K Consortium (2016) identified heterozygous mutations in the GABRB3 gene (see, e.g., 137192.0005-137192.0008). The mutations were found by targeted sequencing of 27 candidate genes in 531 patients with a similar disorder. Functional studies of the variants and studies of patient cells were not performed. Five of the mutations were confirmed de novo, 1 could not be confirmed de novo, and 1 segregated with a GEFS+ phenotype in a family (proband EG0258). GABRB3 mutations accounted for 1.3% of the cohort. INHERITANCE \- Autosomal dominant MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Epileptic encephalopathy \- Seizures \- Multiple seizures types \- Delayed psychomotor development \- Intellectual disability \- Ataxia \- Dyspraxia \- Dyskinesia \- Brain imaging shows hypomyelination (in some patients) Behavioral Psychiatric Manifestations \- Abnormal behavior \- Hyperactivity MISCELLANEOUS \- Onset in first year of life (in most patients) \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the gamma-aminobutyric acid receptor, beta-3 gene (GABRB3, 137192.0005 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 43

c0238111

omim

https://www.omim.org/entry/617113

{"doid": ["0080447"], "mesh": ["D065768"], "omim": ["617113"], "orphanet": ["2382"]}

These occur at the corners of the mouth. They are frequently of pencil-lead size, from 1 to 4 mm deep and may be filled with cellular debris. Preauricular pits may be associated. Everett and Wescott (1961) found 2 cases among 1,000 school children of Portland, Oregon. Witkop (1965) and these authors found evidence of dominant inheritance but could not distinguish between autosomal and X-linked dominance. Baker (1966) found lip pits in 12% of Caucasoids and 20% of blacks. Congenital preauricular sinuses occurred more frequently in persons with pits than in those without pits. Inheritance \- Autosomal dominant Mouth \- Commissural lip pits Ears \- Preauricular pits ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

COMMISSURAL LIP PITS

c0399605

omim

https://www.omim.org/entry/120500

{"omim": ["120500"]}

A number sign (#) is used with this entry because of evidence that familial advanced sleep phase syndrome-3 (FASPS3) is caused by heterozygous mutation in the PER3 gene (603427) on chromosome 1p36. One such family has been reported. Description Advanced sleep phase syndrome is characterized by early sleep time (sleep onset) and early morning awakening (sleep offset) (summary by Zhang et al., 2016). For a discussion of genetic heterogeneity of advanced sleep phase syndrome, see FASPS1 (604348). Clinical Features Zhang et al. (2016) reported a family in which 3 individuals had advanced sleep phase syndrome, with much earlier sleep onset and offset times compared to unaffected family members and conventional sleepers. In addition, all 3 individuals showed clinical features of seasonal affective disorder (see 608516). Inheritance The transmission pattern of FASPS3 in the family reported by Zhang et al. (2016) was consistent with autosomal dominant inheritance. Molecular Genetics In 3 affected members of a family with FASPS3 and features of seasonal affective disorder, Zhang et al. (2016) identified heterozygosity for 2 missense mutations in the PER3 gene on the same allele (P415A and H417R; 603427.0001). The mutations, which were found by screening of candidate circadian genes, segregated with the disorder in the family. In vitro luciferase reporter assays showed that the variant allele reduced PER3 repressor activity compared to wildtype. The mutant protein was also expressed at levels lower than control values, due to decreased protein stability, and failed to stabilize the PER1 (602260) and PER2 (603426) proteins, which play critical roles in circadian timing. Expression of the variant allele in transgenic mice resulted in a longer circadian period under constant light and phase shifts of the sleep-wake cycle in a shorter light period, as observed in winter, as well as increased depression-like behavior. Circadian rhythm changes were also observed in Drosophila that expressed the variant allele. The findings suggested that PER3 plays a role in sleep and mood regulation, especially in response to seasonal changes in day length. Animal Model Zhang et al. (2016) found that Per3-null mice showed depressive-like behavior which was exacerbated when the photoperiod was shortened, reminiscent of seasonal affective disorder in humans. INHERITANCE \- Autosomal dominant NEUROLOGIC Behavioral Psychiatric Manifestations \- Early sleep onset \- Early sleep offset \- Short circadian rhythm cycle \- Depression \- Seasonal affective disorder MISCELLANEOUS \- One family has been reported (last curated March 2016) MOLECULAR BASIS \- Caused by mutation in the period circadian regulator 3 gene (PER3, 603427.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ADVANCED SLEEP PHASE SYNDROME, FAMILIAL, 3

c1858496

omim

https://www.omim.org/entry/616882

{"doid": ["0110013"], "mesh": ["C565789"], "omim": ["616882"], "orphanet": ["164736"]}

## Description Asperger syndrome is considered to be a form of childhood autism (see, e.g., 209850). The DSM-IV (American Psychiatric Association, 1994) specifies several diagnostic criteria for Asperger syndrome, which has many of the same features as autism. In general, patients with Asperger syndrome and autism exhibit qualitative impairment in social interaction, as manifest by impairment in the use of nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures, failure to develop appropriate peer relationships, and lack of social sharing or reciprocity. Patients also exhibit restricted, repetitive and stereotyped patterns of behavior, interests, and activities, including abnormal preoccupation with certain activities and inflexible adherence to routines or rituals. Asperger syndrome is primarily distinguished from autism by the higher cognitive abilities and a more normal and timely development of language and communicative phrases. Gillberg et al. (2001) described the development of the Asperger syndrome (and high-functioning autism) Diagnostic Interview (ASDI), which they claimed has a strong validity in the diagnosis of the disorder. ### Genetic Heterogeneity of Susceptibility to Asperger Syndrome ASPG1 maps to chromosome 3q. Other autosomal loci include ASPG2 (608631) on chromosome 17p, ASPG3 (608781) on 1q21-q22, and ASPG4 (609954) on 3p24-p21. Two X-linked forms, ASPGX1 (300494) and ASPGX2 (300497), are associated with mutation in the NLGN3 gene (300336) and the NLGN4 gene (300427), respectively. Clinical Features Asperger (1944) described a syndrome, which he termed 'autistic psychopathy,' in which persons of apparently normal intelligence exhibited an impairment in social interaction and behavioral abnormalities without delays in language development. Mapping Auranen et al. (2002) found that in their collection of 38 Finnish families in which a proband had autism, approximately one-third of the probands had a first-degree relative with Asperger syndrome or developmental dysphagia. The authors defined this group as having 'autism spectrum disorders.' In 18 families with both autism and Asperger syndrome, the most significant evidence for linkage was found on chromosome 3q25-q27, with a maximum 2-point lod score of 4.31 at theta = 0.0 with D3S3037. Population Genetics Bertrand et al. (2001) performed a prevalence study of autism spectrum disorders in Brick Township, New Jersey. There were 6.7 cases per 1,000 children, aged 3 to 10 years, in 1998. The prevalence for children whose condition met full diagnostic criteria for autistic disorder was 4.0 cases per 1,000 children, and the prevalence for pervasive developmental disorder (PDD)-not otherwise specified (NOS) and Asperger syndrome was 2.7 cases per 1,000 children. INHERITANCE \- Isolated cases \- Multifactorial NEUROLOGIC Central Nervous System \- Normal, timely language development Behavioral Psychiatric Manifestations \- Impaired social interactions \- Impaired use of nonverbal behaviors, such as eye-to-eye gaze, facial expression, body posture, and gestures \- Impaired ability to form peer relationships \- Lack of spontaneous play \- Restrictive behavior, interests, and activities \- Stereotyped, repetitive behavior \- Inflexible adherence to routines or rituals \- Relatively higher cognitive abilities than classic autism ( 608636 ) MISCELLANEOUS \- Onset in early childhood \- Genetic heterogeneity (see, e.g., 608631 , 300494 , 300497 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ASPERGER SYNDROME, SUSCEPTIBILITY TO, 1

c1837646

omim

https://www.omim.org/entry/608638

{"omim": ["608638"]}

fungal disease of elm trees spread by beetles Dutch Elm Disease Branch death, or flagging, at multiple locations in the crown of a diseased elm Common namesDED Causal agentsOphiostoma ulmi Ophiostoma himal-ulmi Ophiostoma novo-ulmi Hostselm trees Vectorselm bark beetle EPPO CodeCERAUL DistributionEurope, North America and New Zealand Dutch elm disease (DED) is caused by a member of the sac fungi (Ascomycota) affecting elm trees, and is spread by elm bark beetles. Although believed to be originally native to Asia, the disease was accidentally introduced into America and Europe, where it has devastated native populations of elms that did not have resistance to the disease. It has also reached New Zealand. The name "Dutch elm disease" refers to its identification in 1921 and later in the Netherlands by Dutch phytopathologists Bea Schwarz and Christine Buisman, who both worked with Professor Johanna Westerdijk.[1][2] The disease affects species in the genera Ulmus and Zelkova; therefore it is not specific to the Dutch elm hybrid.[3][4][5] ## Contents * 1 Overview * 1.1 Field resistance * 1.2 Mechanism * 1.3 Symptoms * 2 Disease range * 2.1 Europe * 2.2 North America * 2.3 New Zealand * 3 Preventive treatment * 3.1 Mechanical * 3.2 Chemical * 3.3 Biological * 4 Resistant trees * 4.1 Testing for disease resistance * 4.2 Hybrid cultivars * 4.3 Species and species cultivars * 4.3.1 North America * 4.3.2 Europe * 4.3.2.1 United Kingdom * 4.3.2.2 Spain * 5 Possible earlier occurrences * 5.1 The 'Elm Decline' * 5.2 Historic period * 6 See also * 7 References * 8 Further reading * 9 External links ## Overview[edit] The causative agents of DED are ascomycete microfungi.[6] Three species are now recognized: * Ophiostoma ulmi, which afflicted Europe from 1910, reaching North America on imported timber in 1928.[7] * Ophiostoma himal-ulmi,[8] a species endemic to the western Himalaya. * Ophiostoma novo-ulmi, an extremely virulent species from Japan which was first described in Europe and North America in the 1940s and has devastated elms in both continents since the late 1960s.[9][10] Beetle feeding galleries on wych elm trunk An infected English elm at West Point, NY, July 2010 DED is spread in North America by three species of bark beetles (Family: Curculionidae, Subfamily: Scolytinae): * The native elm bark beetle, Hylurgopinus rufipes. * The smaller European elm bark beetle, Scolytus multistriatus. * The banded elm bark beetle, Scolytus schevyrewi. In Europe, while S. multistriatus still acts as a vector for infection, it is much less effective than the large elm bark beetle, S. scolytus. H. rufipes can be a vector for the disease, but is inefficient compared to the other vectors. S. schevyrewi was found in 2003 in Colorado and Utah. Other reported DED vectors include Scolytus sulcifrons, S. pygmaeus, S. laevis, Pteleobius vittatus and Р. kraatzi.[11] Other elm bark beetle species are also likely vectors. ### Field resistance[edit] 'Field resistance' is an umbrella term covering the various factors by which some elms avoid infection in the first place, rather than survive it. A clear example would be the European White Elm Ulmus laevis which, while having little or no genetic resistance to DED, synthesizes a triterpene, Alnulin, rendering the bark distasteful to the vector beetles, obliging them to look further afield for more suitable elms. Another would be the inability of the beetles to see elms which did not break the silhouette. 'Weeping' elms are often spared infection owing to the beetles' aversion to hanging upside-down while feeding. ### Mechanism[edit] In an attempt to block the fungus from spreading farther, the tree reacts by plugging its own xylem tissue with gum and tyloses, bladder-like extensions of the xylem cell wall. As the xylem (one of the two types of vascular tissue produced by the vascular cambium, the other being the phloem) delivers water and nutrients to the rest of the plant, these plugs prevent them from travelling up the trunk of the tree, starving the tree of water and nutrients, therefore, eventually killing it. ### Symptoms[edit] The first sign of infection is usually an upper branch of the tree with leaves starting to wither and yellow in summer, months before the normal autumnal leaf shedding. This progressively spreads to the rest of the tree, with further dieback of branches. Eventually, the roots die, starved of nutrients from the leaves. Often, not all the roots die: the roots of some species, notably the English elm, Ulmus minor 'Atinia' (formerly Ulmus procera), can repeatedly put up suckers, which flourish for approximately 15 years, after which they, too, succumb.[9] ## Disease range[edit] ### Europe[edit] Dutch elm disease was first noticed in continental Europe in 1910, and spread slowly and eventually extended to all other countries except Greece and Finland.[12] In Britain, the disease was first identified in 1927 by T R Peace on English elm in Hertfordshire.[13] This first strain was a relatively mild one, which killed only a small proportion of elms, more often just killing a few branches, and had largely died out by 1940 owing to its susceptibility to viruses. The disease was isolated in The Netherlands in 1921 by Bea Schwarz, a pioneering Dutch phytopathologist, and this discovery would lend the disease its name.[14] Salisbury Cathedral from Lower Marsh Close, 1820, Andrew W. Mellon Collection, National Gallery of Art, Washington, D.C. Circa 1967, a new, far more virulent, strain arrived in Britain, apparently via east coast ports on shipments of rock elm U. thomasii logs from Canada destined for the small-boat industry, confirmed in 1973 when another consignment was examined at Southampton Docks.[13] This strain proved both highly contagious and lethal to European elms; more than 25 million trees died in the United Kingdom alone, while France lost 97% of its elms.[15] The disease spread rapidly northwards, reaching Scotland within 10 years.[13] By 1990, very few mature elms were left in Britain or much of continental Europe. One of the most distinctive English countryside trees (See John Constable's painting Salisbury Cathedral from the South-West), the English elm U. procera Salisb., is particularly susceptible as it is the elm most favoured by the Scolytus beetles. Thirty years after the outbreak of the epidemic, nearly all these trees, which often grew to more than 45 m high, are gone. The species still survives in hedgerows, as the roots are not killed and send up root sprouts ("suckers"). These suckers rarely reach more than 5 m tall before succumbing to a new attack of the fungus. However, established hedges kept low by clipping have remained apparently healthy throughout the nearly 40 years since the onset of the disease in the United Kingdom. Sign on A27, Brighton The largest concentrations of mature elms in Europe are now in Amsterdam and The Hague. In 2005, Amsterdam was declared the "Elm City of Europe": the city’s streets and canals are lined with at least 75,000 elms, including several generations of research-elms (see below: Resistant trees).[16][17] Some 30,000 of the 100,000 mature trees in The Hague are elms, planted because of their tolerance of salty sea-winds. Since the 1990s, a programme of antifungal injections of the most prominent 10,000 elms, and of sanitation felling, has reduced annual elm losses in The Hague from 7% to less than 1% (see below: Preventive treatment). The losses are made up by the planting of disease-resistant cultivars.[18] The largest concentration of mature elm trees remaining in England is in Brighton and Hove, East Sussex, where of the 30,000 elms in 1983[19] 15,000 still stand (2005 figures), several of which are estimated to be over 400 years old. Their survival is owing to the isolation of the area, between the English Channel and the South Downs, and the assiduous efforts of local authorities to identify and remove infected sections of trees immediately when they show symptoms of the disease.[20] Empowered by the Dutch Elm Disease (Local Authorities) (Amendment) Order 1988,[21] local authorities may order the destruction of any infected trees or timber, although in practice they usually do it themselves, successfully reducing the numbers of elm bark beetle Scolytus spp., the vector of elm disease.[22] Sanitary felling has also, to date, preserved most of the 250,000 elms on the Isle of Man,[23] where average temperature and wind speed inhibit the activity of the beetles, which need a temperature of at least 20 degrees to fly and a wind speed of less than five metres per second.[24][25] Felling a diseased elm, Edinburgh, November 2011 The largest concentration of mature elms in Scotland is in Edinburgh, where over 5000 remained in 2009 from some 35,000 in 1976.[26] The city council gives the overall number of elms as 15,000 (2016).[27] Edinburgh's Leith Links and Meadows have some of the highest concentrations of mature elms among U.K. parks (2014). A policy of sanitary felling has kept losses in the city to an average of 1000 a year.[28] Elm was the most common tree in Paris from the 17th century; before the 1970s there were some 30,000 ormes parisiens. Today, only 1000 mature elms survive in the city, including examples in the large avenues (Avenue d'Italie, Avenue de Choisy, Boulevard Lefebvre, Boulevard de Grenelle, Boulevard Garibaldi) and two very old specimens, one in the garden of the Tuileries in front of the l'Orangerie and another in the Place Saint-Gervais in front of l'hôtel de ville de Paris. Losses are now being made up with disease-resistant cultivars, especially the Dutch-French research elm 'Nanguen' (Lutèce), named for the ancient Roman name for the city: Lutetia.[29] ### North America[edit] Arborist removing infected elm in Saint Paul, Minnesota DED was first reported in the United States in 1928, with the beetles believed to have arrived in a shipment of logs from The Netherlands destined for use as veneer in the Ohio furniture industry. Quarantine and sanitation procedures held most cases within 150 miles of metropolitan New York City until 1941 when war demands began to curtail them.[30] The disease spread from New England westward and southward, almost completely destroying the famous elms in the "Elm City" of New Haven, Connecticut, reaching the Detroit area in 1950,[31] the Chicago area by 1960, and Minneapolis by 1970. Of the estimated 77 million elms in North America in 1930, over 75% had been lost by 1989.[32] Rows of American elm trees south of the Lincoln Memorial Reflecting Pool on the National Mall in Washington, D.C. (November 11, 2006) The disease first appeared on the planted rows of American elm trees (Ulmus amercana) on the National Mall in Washington, D.C., during the 1950s and reached a peak in the 1970s. The United States National Park Service (NPS) used a number of methods to control the epidemic, including sanitation, pruning, injecting trees with fungicide and replanting with DED-resistant American elm cultivars (see Ulmus americana cultivars). The NPS combated the disease's local insect vector, the smaller European elm bark beetle (Scolytus multistriatus), by trapping and by spraying with insecticides. As a result, the population of American elms planted on the Mall and its surrounding areas has remained intact for more than 80 years.[33] DED reached eastern Canada during World War II, and spread to Ontario in 1967, Manitoba in 1975 and Saskatchewan in 1981. In Toronto, 80% of the elm trees have been lost to Dutch elm disease; many more fell victim in Ottawa, Montreal and other cities during the 1970s and 1980s. Quebec City still has about 21,000 elms, thanks to a prevention program initiated in 1981.[34] Alberta and British Columbia are the only provinces that are currently free of Dutch elm disease, although, in an isolated case, an elm tree in Wainwright, Alberta, was found diseased in June 1998 and was immediately destroyed.[35] The presence of DED was monitored in this area during subsequent years but was not seen again. Today, Alberta has the largest number of elms unaffected by Dutch elm disease in the world.[36] The provinces of Alberta, Manitoba, and Saskatchewan all prohibit the pruning of elm trees during the middle of the year (taking effect in April, and lasting through the end of September, July, and August respectively), which they deem to be the most active time of year for bark beetles.[37][38][39] It is also illegal to use, store, sell, or transport elm firewood.[40][41][42] The largest surviving urban forest of elm trees in North America is believed to be in the city of Winnipeg, where close to 200,000 elms remain – at least double that of Amsterdam, the "Elm City of Europe". The city spends $3 million annually to aggressively combat the disease using Dursban Turf and the Dutch Trig vaccine.[43][44] ### New Zealand[edit] Dutch elm disease has reached New Zealand. It was found in Napier where it was eradicated and was also found in the Auckland Region in 1989. The Ministry of Agriculture funded a national management programme but it was cancelled to allow more funds to be available for pests of a higher priority.[45] A major outbreak occurred in New Zealand in July 2013, particularly at the site of Kingseat Hospital, south of Auckland.[46] Auckland has 20,000 elms.[47] ## Preventive treatment[edit] ### Mechanical[edit] Diseased elm ringbarked to slow down transmission before felling. The first attempts to control Dutch elm disease consisted of pruning trees to remove and burn diseased timber. While this method was effective in New York State and adjacent areas, its cost made it uneconomical except in large cities where elms were considered valuable attractions. ### Chemical[edit] In the US, when Dutch elm disease spread away from the Atlantic coast, control focused on controlling the bark beetle by using insecticides such as DDT and dieldrin, which were sprayed heavily across all parts of elm trees, usually twice a year in the spring and again at a lower concentration in the summer. In its early years, it was generally thought by observers that pesticides did slow the spread of the disease across the United States[48] but as early as 1947, concern was raised that many bird species were killed in large numbers by ingesting poisoned invertebrates.[48][49] In areas sprayed during the 1950s, local people observed birds such as the American woodcock, American robin, white-breasted nuthatch, brown creeper and various Poecile species dying. Biologist Rachel Carson consequently argued for improved sanitation and against spraying elms, which she saw as having been more effective in areas with earlier and greater experience countering Dutch elm disease.[50] Although modern critics of Carson have argued that the bird deaths were caused by other factors such as mercury poisoning in the soil,[51] spraying against elm bark beetles declined very rapidly after 1962, a trend aided by fungicides without dangerous side-effects being discovered for the first time after many years of research.[52] Lignasan BLP (carbendazim phosphate), introduced in the 1970s, was the first fungicide used to control Dutch elm disease. This had to be injected into the base of the tree using specialized equipment, and was never especially effective. It is still sold under the name "Elm Fungicide". Arbotect (thiabendazole hypophosphite) became available some years later, and it has been proven effective. Arbotect must be injected every two to three years to provide ongoing control; the disease generally cannot be eradicated once a tree is infected. Arbotect is not effective on root graft infections from adjacent elm trees. It is more than 99.5% effective for three years from beetle infections, which is the primary mode of tree infection. Alamo (propiconazole) has become available more recently, though several university studies show it to be effective only for the current season in which it is injected. Alamo is primarily recommended for treatment of oak wilt. Multistriatin is a pheromone produced by female elm bark beetles, which can be produced synthetically. It has potential in being used to trap male beetles, which carry the fungus. ### Biological[edit] Because of the ban on the use of chemicals on street and park trees in the Netherlands, the University of Amsterdam developed a biological vaccine by the late 1980s. Dutch Trig is nontoxic, consisting of a suspension in distilled water of spores of a strain of the fungus Verticillium albo-atrum that has lost much of its pathogenic capabilities, injected in the elm in spring. The strain is believed to have enough pathogenicity left to induce an immune response in the elm, protecting it against DED during one growing season. This is called induced resistance.[53] Trials with the American elm have been very successful; in a six-year experiment with the American elm in Denver, CO, annual Dutch elm disease losses declined significantly after the first year from 7 percent to between 0.4 and 0.6 percent;[44] a greater and more rapid reduction in disease incidence than the accompanying tree sanitation and plant health care programs.[54] Preventive treatment is usually only justified when a tree has unusual symbolic value or occupies a particularly important place in the landscape. ## Resistant trees[edit] Research to select resistant cultivars and varieties began in the Netherlands in 1928, followed by the United States in 1937 (see Ulmus americana cultivars). Initial efforts in the Netherlands involved crossing varieties of U. minor and U. glabra, but later included the Himalayan or Kashmir elm U. wallichiana as a source of antifungal genes. Early efforts in the USA involved the hybridization of the Siberian elm U. pumila with American red elm U. rubra to produce resistant trees. Resulting cultivars lacked the traditional shape and landscape value of the American elm; few were planted. In 2005, the National Elm Trial (USA) began a 10-year evaluation of 19 cultivars in plantings across the United States. The trees in the trial are exclusively American developments; no European cultivars have been included. Recent research in Sweden has established that early-flushing clones are less susceptible to DED owing to an asynchrony between DED susceptibility and infection.[55] ### Testing for disease resistance[edit] Elms are tested for resistance by inoculation with the fungal pathogen in late May when the tree's growth is at its annual peak. Clones raised for testing are grown to an age of 3 or 4 years. In Europe, the inoculum is introduced into the cambium by a knife wound. However this method, developed in the Netherlands, was considered too severe in America, where the principal disease vector is the bark beetle Scolytus multistriatus, a far less effective vector than the larger beetle endemic to Europe, Scolytus scolytus, which is unknown in America. In the method devised by the USDA, the inoculum is introduced to the cambium via a 2 mm-diameter hole drilled through the bark in the lower third of the tree. This method was further refined by the University of Wisconsin team, which drilled holes in the branches to simulate natural infection by the bark beetles feeding in the twig crotches, but results from this method were found to exaggerate the genetic resistance of the host. Consequently, tests were conducted on specimens in a controlled environment, either in greenhouses or customized plant chambers, facilitating more accurate evaluation of both internal and external symptoms of disease. Another variable is the composition of the inoculum; while an inoculum strength of 106 spores / ml is standard in both continents, its composition reflects the different Ophiostoma species, subspecies and hybrids endemic to the two continents. In Italy for example, two subspecies, americana and novo-ulmi, are present together with their hybrid, whereas in North America, ssp. novo-ulmi is unknown.[56] The differences in method and inocula possibly explain why the American cultivar 'Princeton', displaying high resistance in the USA, has often succumbed to Dutch elm disease in Europe.[57] ### Hybrid cultivars[edit] Inoculation of virulent strains of Ophiostoma in elm cambium, Dorschkamp Institute for Forestry and Landscape planning, Wageningen 1984 (photograph: Mihailo Grbić) Many attempts to breed disease resistant cultivar hybrids have usually involved a genetic contribution from Asian elm species which have demonstrable resistance to this fungal disease. Much of the early work was undertaken in the Netherlands. The Dutch research programme began in 1928, and ended after 64 years in 1992, during which time well over 1000 cultivars were raised and evaluated. Still in use are cultivars such as 'Groeneveld', 'Lobel', 'Dodoens', 'Clusius' and 'Plantijn' although the resistance levels in these trees aren't high enough for good protection. The programme had three major successes: 'Columella', 'Nanguen' `LUTÈCE`, and 'Wanoux' `VADA`,[58] all found to have an extremely high resistance to the disease when inoculated with unnaturally large doses of the fungus. Only 'Columella' was released during the lifetime of the Dutch programme, in 1987; patents for the `LUTÈCE` and `VADA` clones were purchased by the French Institut National de la Recherche Agronomique (INRA), which subjected the trees to 20 years of field trials in the Bois de Vincennes, Paris, before releasing them to commerce in 2002 and 2006, respectively. Asian species featured in the American DED research programs were the Siberian elm U. pumila, Japanese elm U. davidiana var. japonica, and the Chinese elm U. parvifolia, which gave rise to several dozen hybrid cultivars resistant not just to DED, but also to the extreme cold of Asian winters. Among the most widely planted of these, both in North America and in Europe, are 'Sapporo Autumn Gold', 'New Horizon' and 'Rebona'. Some hybrid cultivars, such as 'Regal' and 'Pioneer' are the product of both Dutch and American research. Hybridization experiments using the slippery or red elm U. rubra resulted in the release of 'Coolshade' and 'Rosehill' in the 1940s and 50s; the species last featured in hybridization as the female parent of 'Repura' and 'Revera', both patented in 1993, although neither has yet appeared in commerce. In Italy, research is continuing at the Istituto per la Protezione delle Piante, Florence, to produce a range of disease-resistant trees adapted to the warmer Mediterranean climate, using a variety of Asiatic species crossed with the early Dutch hybrid 'Plantyn' as a safeguard against any future mutation of the disease.[59] Two trees with very high levels of resistance, 'San Zanobi' and 'Plinio',[60] were released in 2003. 'Arno' and 'Fiorente' were patented in 2006 and entered commerce in 2012. All four have the Siberian elm U. pumila as a parent, the source of disease-resistance and drought-tolerance genes. 'Morfeo' was released in 2011; it arose from a crossing of the Dutch hybrid clone '405' (female parent) and the Chenmou Elm, the latter a small tree from the provinces of Anhui and Jiangsu in eastern China, The '405' clone is a crossing of an English U. × hollandica and a French U. minor. In The Netherlands a new program has been initiated. From the old proving grounds of the Dorschkamp Research Institute, 10 fourth-generation hybrids survive in a DED-ridden area. These have been tested and some have a very high level of resistance. At Noordplant Nursery new hybrids have been tested since 2013. ### Species and species cultivars[edit] #### North America[edit] Results of artificial inoculation of Ophiostoma strains in elm cambium, Arlington Experimental Station, Wisconsin 1987 (photograph: Mihailo Grbić) Ten resistant American elm cultivars are now in commerce in North America, but only two ('Princeton' and 'Valley Forge') are currently available in Europe. No cultivar is "immune" to DED; even highly resistant cultivars can become infected, particularly if already stressed by drought or other environmental conditions where the disease prevalence is high. With the exception of 'Princeton', no trees have yet been grown to maturity. Trees cannot be said to be mature until they have reached an age of 60 years. Notable cultivars include: * 'Princeton', is a cultivar selected in 1922 by Princeton Nurseries for its landscape merit. By coincidence, this cultivar was found to be highly resistant in inoculation studies carried out by the USDA in the early 1990s. As trees planted in the 1920s still survive, the properties of the mature plant are well known. However, 'Princeton' has not proven resistant in Europe, where the main vector of the disease is the larger elm bark beetle, Scolytus scolytus, capable of introducing far more fungal spores into the tree; many of the 50 trees planted by HRH Charles, Prince of Wales, in 2006 at Highgrove had died from Dutch elm disease by 2011.[57] * 'American Liberty', is, in fact, a set of six cultivars of moderate to high resistance produced through selection over several generations starting in the 1970s. Although 'American Liberty' is marketed as a single variety, nurseries selling the "Liberty Elm" actually distribute the six cultivars at random and thus, unfortunately, the resistance of any particular tree cannot be known. One of the cultivars, 'Independence', is covered by patent (U. S. Plant patent 6227). The oldest 'American Liberty' elm was planted in about 1980. * 'Valley Forge', released in 1995, has demonstrated the highest resistance of all the clones to Dutch elm disease in controlled USDA tests. * 'Lewis and Clark' = Prairie Expedition TM, released in 2004 to commemorate the bicentenary of the Lewis & Clark expedition, was cloned from a tree found growing in North Dakota which had survived unscathed when all around had succumbed to disease. In 2007, the Elm Recovery Project of the University of Guelph Arboretum in Ontario, Canada, reported that cuttings from healthy surviving old elms surveyed across Ontario had been grown to produce a bank of resistant trees, isolated for selective breeding of highly resistant cultivars.[61] The University of Minnesota USA is testing various elms, including a huge now-patented century-old survivor known as "The St. Croix Elm", which is located in a Minneapolis-St. Paul, MN suburb (Afton) in the St. Croix River valley—a designated National Scenic Riverway. The slippery or red elm U. rubra is marginally less susceptible to Dutch elm disease than the other American species, but this quality seems to have been largely ignored in American research. No cultivars were ever selected, although the tree was used in hybridization experiments (see above). In 1993, Mariam B. Sticklen and James L. Sherald reported the results of NPS-funded experiments conducted at Michigan State University in East Lansing that were designed to apply genetic engineering techniques to the development of DED-resistant strains of American elm trees.[62] In 2007, AE Newhouse and F Schrodt of the State University of New York College of Environmental Science and Forestry in Syracuse reported that young transgenic American elm trees had shown reduced DED symptoms and normal mycorrhizal colonization.[63] By 2013, researchers in both New York State and North Carolina were conducting field trials of genetically engineered DED-resistant American elms. #### Europe[edit] Among European species, there is the unique example of the European white elm U. laevis, which has little innate resistance to DED, but is eschewed by the vector bark beetles and only rarely becomes infected. Recent research has indicated it is the presence of certain organic compounds, such as triterpenes and sterols, which serves to make the tree bark unattractive to the beetle species that spread the disease.[64] In Europe the testing of clones of surviving field elms for innate resistance has been carried out since the 1990s by national research institutes, with findings centrally assessed and published.[65] The first results of this ongoing project suggest that in some countries a very small number of native field elm genotypes have comparatively high levels of tolerance to DED. In Spain, for example, of around 5,000 native elms evaluated to 2013, some 25 genotypes (0.5% of those tested) fall into this category; and it is now hoped that the controlled crossing of the best seven of these (genetically and aesthetically) will produce Ulmus minor hybrids with effective 'field resistance' and market appeal.[66] Similar results are beginning to emerge in trials on surviving field elms in Greece.[67] ##### United Kingdom[edit] Much of the work in the United Kingdom is by the Forestry Commission's research arm, which has had Dutch elm disease on its agenda since the 1920s. In 1994 a Research Information Note (no 252) was published, written by John Gibbs, Clive Brasier and Joan Webber who are still active in the field; and in 2010 a Pathology Advisory Note, as well as throughout the period a stream of more academic papers: notable results have been the observation that the progress of the disease through Scotland has been quite slow, and that genetic engineering has been tried to improve the resistance of the English elm. In England the Conservation Foundation has begun propagating, distributing and planting clones of surviving indigenous elms, including field elms (but not the highly susceptible English elm), as part of a scheme to return elms to city and countryside.[68][69] The Foundation is currently running two elm programmes: the 'Great British Elm Experiment' and 'Ulmus londinium', an elm programme for London – these use saplings cultivated through micropropagation from mature parent elms found growing in the British countryside: parent trees are monitored for disease, while saplings are offered free to schools and community groups, who are asked to monitor their trees' progress on the Foundation's online elm map; elms are available at a small price to others who do not qualify for a free tree; in London, places with 'elm' in their name are offered a sapling – in an attempt to find out why some elms have survived while others succumbed to Dutch elm disease. The spread of DED to Scotland has focused attention on a small number of Wych elms U. glabra surviving in areas of high infectivity, prompting the Royal Botanic Garden Edinburgh to begin a programme of cloning of the trees and inoculation of their saplings with the fungus, with a view to determining innate resistance (2010).[70] In 2001–2004, English elm U. procera was genetically engineered to resist disease, in experiments at Abertay University, Dundee, Scotland, by transferring antifungal genes into the elm genome using minute DNA-coated ball bearings.[71][72] However, owing to the hostility to GM developments, there are no plans to release the trees into the countryside. ##### Spain[edit] In Spain, the Escuela Técnica Superior de Ingenieros de Montes, Universidad Politecnica de Madrid , charged with discovering disease-resistant elms for use in forestry, has raised and patented seven cultivars of the field elm Ulmus minor, although two have subsequently been found to have Siberian elm U. pumila DNA, the species introduced to Spain in the 16th century. Although none have been released to commerce (2020), the clone 'Ademuz', pure U. minor, has been imported into the UK since 2014, and widely planted there. ## Possible earlier occurrences[edit] ### The 'Elm Decline'[edit] From analysis of fossil pollen in peat samples, it is apparent that elms, an abundant tree in prehistoric times, all but disappeared from northwestern Europe during the mid-Holocene period around 4000 BC, and to a lesser extent around 1000 BC. This roughly synchronous and widespread event has come to be known as the 'Elm Decline'. When first detected in the mid-20th century, the decline was attributed to the impact of forest-clearance by Neolithic farmers, and of elm-coppicing for animal fodder, though the numbers of settlers could not have been large. The devastation caused recently by DED has provided an alternative explanation. Examination of subfossil elm wood showing signs of the changes associated with the disease has suggested that a form of DED may have been responsible. Fossil finds from this period of elm bark beetles support this theory. A consensus today is that the Elm Decline was probably driven by both factors.[73][74] ### Historic period[edit] A less devastating form of the disease, caused by a different fungus, had possibly been present in north-west Europe for some time. Dr Oliver Rackham of Cambridge University presented evidence of an outbreak of elm disease in north-west Europe, c. 1819–1867. "Indications from annual rings [a reference to the dark staining in an annual ring in infected elms] confirm that Dutch elm disease was certainly present in 1867," he wrote, quoting contemporary accounts of diseased and dying elms, including this passage in Richard Jefferies' 1883 book, Nature near London: > There is something wrong with elm trees. In the early part of this summer, not long after the leaves were fairly out upon them, here and there a branch appeared as if it had been touched with red-hot iron and burnt up, all the leaves withered and browned on the boughs. First one tree was thus affected, then another, then a third, till, looking round the fields, it seemed as if every fourth or fifth tree had thus been burnt. [...] Upon mentioning this I found that it had been noticed in elm avenues and groups a hundred miles distant, so that it is not a local circumstance. Earlier still, Rackham noted, "The name Scolytus destructor was given to the great bark beetle on evidence, dating from c. 1780, that it was destroying elms around Oxford."[75] In Belgium, elm die-back and death was observed in 1836 and 1896 in Brussels, and in 1885–1886 in Ghent. In the later outbreaks the die-back was attributed to the elm bark beetle.[76] It has been suggested that "for thousands of years elms have flourished in natural balance with the scolytidae, combating occasional infections of Dutch elm disease."[77] Sir Thomas Browne, writing in 1658, noted in The Garden of Cyrus an elm disease that was spreading through English hedgerows, and described symptoms reminiscent of DED.[78] ## See also[edit] * Forest pathology * Forest disturbance by invasive insects and diseases in the United States ## References[edit] 1. ^ Schwarz, M.B. (1922). "Das Zweigsterben der Ulmen, Trauerweiden und Pfirsichbaume". Mededelingen Phytopathologisch Laboratorium, Willie Commelin Scholten. 5: 1–73. 2. ^ Buisman, C. (1928). "De oorzaak van de iepenziekte". Tijdschr Ned Heidemaatsch. 40: 338–345. 3. ^ "Dutch elm disease in Britain". UK Forestry Commission. 4. ^ Dutch Elm Disease. Plant Sciences. Macmillan Science Library. 5. ^ Smalley, EB (1963). "Seasonal fluctuations in susceptibility of young elm seedlings to Dutch elm disease". Phytopathology. 53 (7): 846–853. 6. ^ Ascomycetes: Phylum Ascomycota, Biology of Plants, Seventh Edition, W. H. Freeman and Company, 2005. 7. ^ Clinton, G. P., McCormick, Florence A., Dutch elm disease, Graphium ulmi; New Haven, 1936 8. ^ M.D., C.M.; Mehrotra, M.D. (1995). "Ophiostoma himal-ulmi sp. nov., a new species of Dutch elm disease fungus endemic to the Himalayas". Mycological Research. 99 (2): 205–215. doi:10.1016/S0953-7562(09)80887-3. ISSN 0953-7562. 9. ^ a b Spooner, Brian; Roberts, Peter (2010) [2005]. Fungi. Collins New Naturalist Library. 96. HarperCollins. p. 235. ISBN 978-0-00-740605-0. 10. ^ Johnson, O. (2011). Champion Trees of Britain and Ireland. Royal Botanic Gardens, Kew. ISBN 978-1842464526 11. ^ Ижевский, С.С.; Никитский, Н.Б.; Волков, О.Г.; Долгин, М.М (2005). Иллюстрированный справочник. жуков-ксилофагов – вредителей леса и лесоматериалов Российской Федерации (PDF). Тула: Российская Академия Наук, Уральское отделение, Коми научный центр, Институт биологии. (Izhevsky, SS; et al. (2005). "An illustrated guide to the xylophagous beetles injuring forests and timber in the Russian Federation". Russian Academy of Sciences, Ural Branch, Komi Science Center, Institute of Biology. Tula). p. 165. 12. ^ Clouston, B., Stansfield, K., eds., After the Elm (London, 1979) 13. ^ a b c Harris, E. (2017). The European White Elm, Ulmus laevis Pall. Quarterly Journal of Forestry, Vol. 111, No. 4, October 2017. p.263. Royal Forestry Society. 14. ^ Holmes, Francis W.; Heybroek, H.M. (1990). Dutch elm disease: the early papers : selected works of seven Dutch women phytopathologists. APS Press. ISBN 978-0-89054-110-4. 15. ^ "Lutèce®, a resistant variety brings elms back to Paris". All The News. Nantes, France: Institut national de la recherche agronomique (INRA). 15 April 2005. Archived from the original on 25 November 2006. 16. ^ "Amsterdam, City of Trees". DutchAmsterdam. 18 May 2011. 17. ^ Amsterdamse Bomem Archived 2011-07-24 at the Wayback Machine 18. ^ "The City and its elm population". The Hague in the Netherlands. DutchTrig®. Archived from the original on 29 October 2013. 19. ^ Research on Dutch Elm Disease in Europe, ed. D. A. Burdekin (London, 1983) 20. ^ Brighton and Hove Council page on the city's elm collection Archived 2011-06-14 at the Wayback Machine (viewed 2 June 2010) 21. ^ "Dutch Elm Disease (DED)". Environment and Planning: Land and premises: Conservation: Trees & landscapes. Lewes District Council. 2009. Archived from the original on 5 July 2009. 22. ^ Gupta, Tanya (11 November 2005). "How Brighton beat Dutch Elm menace". BBC News, South East. 23. ^ Isle of Man elms, geocomputation.org 24. ^ Coleman, M.; A’Hara, S.W.; Tomlinson, P.R.; Davey, P.J. (2016). "Elm clone identification and the conundrum of the slow spread of Dutch Elm Disease on the Isle of Man". New Journal of Botany. 6 (2–3): 79–89. doi:10.1080/20423489.2016.1271612. S2CID 90001207. 25. ^ prolandscapermagazine.com 24 February 2017 26. ^ Coleman, Max, ed., Wych Elm (Edinburgh 2009) 27. ^ edinburgh.gov.uk/info/20064/parks_and_green_spaces/256/trees_and_woodlands 28. ^ Coleman, Max (2009). Wych Elm. Royal Botanic Gardens Edinburgh. p. 47. ISBN 978-1-906129-21-7. 29. ^ Ulmus 'Nanguen' www.foretpriveefrancaise.com [http://www.foretpriveefrancaise.com/data/info/127219-P.pdf [https://web.archive.org/web/20150924014610/http://www.foretpriveefrancaise.com/data/info/127219-P.pdf Archived 24 September 2015 at the Wayback Machine] 30. ^ Life, 11 September 1944, p. 58 31. ^ Baulch, Vivian (20 December 2001). "How Detroit lost its stately elms". Detroit News. 32. ^ New York Times, 5 December 1989, nytimes.com nytimes.com/1989/12/05/science/new-varieties-of-elm-raise-hope-of-rebirth-for-davastated-tree.html?sec=health&spon=&pagewanted=all 33. ^ Sherald, James L (December 2009). Elms for the Monumental Core: History and Management Plan (PDF). Washington, D.C.: Center for Urban Ecology, National Capital Region, National Park Service. Natural Resource Report NPS/NCR/NRR--2009/001. Archived from the original (PDF) on 29 November 2010. Retrieved 14 October 2010. 34. ^ Beaucher, Serge (Autumn 2009). "Québec, terre des ormes". Contact (in French). Laval University. 28 (1). 35. ^ CFIA annual pest survey report. 1999 Summary of Plant Quarantine Pest and Disease Situations in Canada (report available upon demand at the Canadian Food Inspection Agency: http://publications.gc.ca/site/eng/9.831610/publication.html) 36. ^ "Dutch Elm Disease". Alberta Agriculture and Rural Development. Retrieved 14 December 2014. 37. ^ "Hydro contractors snubbing Winnipeg elm-pruning ban, group suspects". CBC News. 26 July 2017. Retrieved 26 July 2019. 38. ^ Agriculture, Alberta; Forestry (11 April 2018). "Elm pruning ban now in place". Alberta Farmer Express. Retrieved 26 July 2019. 39. ^ "Pruning ban on elm trees starts April 1". CTV News Regina. Retrieved 26 July 2019. 40. ^ "Pruning ban on elm trees starts April 1". CTV News Regina. Retrieved 26 July 2019. 41. ^ Semeschuk, Darci. "Majestic Elms marked for removal". Souris Plaindealer. Retrieved 26 July 2019. 42. ^ Release, Stopded (14 November 2016). "Elm pruning ban over until March". Alberta Farmer Express. Retrieved 26 July 2019. 43. ^ "Elm Bark Beetle Control Program" (PDF). City of Winnipeg. 2009.[permanent dead link] 44. ^ a b Rumbolt, Colin (17 November 2009). "Dutch elm vaccine tested in Winnipeg". the Manitoban. 45. ^ "Dutch Elm Disease". Biosecurity New Zealand. 26 May 2008. Archived from the original on 5 December 2012. Retrieved 1 October 2012. 46. ^ "Elm disease strikes out south". Manukau Courier. Fairfax NZ News. 18 August 2013. 47. ^ Auckland's elms, bts.nzpcn.org.nz/bts_pdf/ABJ58(1)2003-38-45-Elms.pdf 48. ^ a b Benton, Allen H. (January 1951). "Effects on Wildlife of DDT Used for Control of Dutch Elm Disease". The Journal of Wildlife Management. 15 (1): 20–7. doi:10.2307/3796765. JSTOR 3796765. 49. ^ Dempsey, Dave (2001). Ruin & Recovery: Michigan's Rise as a Conservation Leader. University of Michigan Press. p. 126. ISBN 978-0-472-06779-4. 50. ^ Carson, Rachel (2002). Silent Spring. pp. 105–115. ISBN 978-0-618-24906-0. 51. ^ Berlau, John (2006). Eco-Freaks: why Environmentalism Is Hazardous to Your Health. p. 33. ISBN 1-59555-067-4. 52. ^ "New Fungicide Fights Dutch Elm Disease". Chem. Eng. News. 42 (37): 29–31. 1964. doi:10.1021/cen-v042n037.p029. 53. ^ About Dutch Trig® Archived 2010-11-17 at the Wayback Machine 54. ^ "Archived copy". Archived from the original on 15 June 2013. Retrieved 5 August 2013.CS1 maint: archived copy as title (link) 55. ^ Ghelardini, L. (2007) Bud Burst Phenology, Dormancy Release & Susceptibility to Dutch Elm Disease in Elms (Ulmus spp.). Doctoral Thesis No. 2007:134. Faculty of natural Resources and Agricultural Services, Swedish University of Agricultural Sciences, Uppsala, Sweden 56. ^ Mittempergher, L; Santini, A (2004). "The history of elm breeding" (PDF). Investigacion Agraria: Sistemas y Recursos Forestales. 13 (1): 161–177. 57. ^ a b Brookes, A.H. (2013). "Disease-resistant elm cultivars, Butterfly Conservation trials report, 3rd revision" (PDF). Lulworth UK: Butterfly Conservation. Archived from the original (PDF) on 29 May 2014. 58. ^ Institut National de la Recherche Agronomique. Lutèce, a resistant variety, brings elms back to Paris [1], Paris, France 59. ^ Santini, A.; Fagnani, A.; Ferrini, F.; Mittempergher, L.; Brunetti, M.; Crivellaro, A.; Macchioni, N. (2004). "Elm breeding for DED resistance, the Italian clones and their wood properties" (PDF). Invest Agrar: Sist Recur for. 13 (1): 179–184. Archived from the original (PDF) on 26 October 2007. 60. ^ Santini, A.; Fagnani, A.; Ferrini, F.; Mittempergher, L. (2002). "San Zanobi and Plinio elm trees". HortScience. American Society for Horticultural Science. 37 (7): 1139–41. doi:10.21273/HORTSCI.37.7.1139. 61. ^ "Elm Recovery Project". Guelph, Ontario, Canada: University of Guelph Arboretum. Archived from the original on 22 November 2019. Retrieved 22 November 2019. 62. ^ Sticklen, Mariam B.; Sherald, James L. (1993). Chapter 13: Strategies for the Production of Disease-Resistant Elms. Mariam B.; Sherald, James L. (eds.). Dutch Elm Disease Research: Cellular and Molecular Approaches. New York: Springer-Verlag. pp. 171–183. ISBN 9781461568728. LCCN 93017484. OCLC 851736058. Retrieved 22 November 2019 – via Google Books. 63. ^ Newhouse, AE; Schrodt, F; Liang, H; Maynard, CA; Powell, WA (2007). "Transgenic American elm shows reduced Dutch elm disease symptoms and normal mycorrhizal colonization". Plant Cell Rep. 26 (7): 977–987. doi:10.1007/s00299-007-0313-z. PMID 17310333. S2CID 21780088. 64. ^ Martín-Benito, D.; García-Vallejo, M.; Pajares, J.; López, D. (2005). "Triterpenes in elms in Spain" (PDF). Can. J. For. Res. 35: 199–205. doi:10.1139/x04-158. Archived from the original (PDF) on 28 June 2007. 65. ^ Screening European Elms for resistance to 'Ophiostoma novo-ulmi' (Forest Science 2005) [2] 66. ^ ‘Spanish Clones’ (Oct. 2013) resistantelms.co.uk 67. ^ Δoκιμή ανθεκτικότητας ελληνικών γενoτύπων πεδινής φτελιάς (Ulmus minor) κατά της Oλλανδικής ασθένειας, Σ. Διαμαντής και X. Περλέρου (:Resistance test of Greek Field Elm against Dutch Elm Disease, by S. Diamantis and H. Perlerou) [3] 68. ^ '"Super tree" from Northamptonshire helping to fight Dutch Elm Disease and repopulate woodlands', northamptonchron.co.uk [4] 69. ^ "'Young elms return to London', conservationfoundation.co.uk". Archived from the original on 2 December 2013. Retrieved 16 November 2013. 70. ^ Coleman 2009 71. ^ 'First Genetically Modified Dutch Elm Trees Grown', unisci.com 72. ^ resistantelms.co.uk, FAQ 'Disease Control' 73. ^ Coleman 2009, p. 17 74. ^ "The mid-Holocene Ulmus decline: a new way to evaluate the pathogen hypothesis". Archived from the original on 28 September 2011. Retrieved 4 November 2011. 75. ^ Oliver Rackham, The History of the Countryside (London 1986), pp. 242–243, 232 76. ^ Meulemans, M.; Parmentier, C. (1983). Burdekin, D.A. (ed.). "Studies on Ceratocystis ulmi in Belgium" (PDF). Forestry Commission Bulletin (Research on Dutch Elm Disease in Europe). London: HMSO (60): 86–95. 77. ^ Vaclav Vetvička, Trees and Shrubs (London 1985) 78. ^ Oliver Rackham, The History of the Countryside (London 1986), p.242-3 ## Further reading[edit] * Walter E. Burton "Army of Experts Wage War on Dutch Elm Disease" Popular Science Monthly, May 1937 ## External links[edit] * resistantelms.co.uk * Dutchelmdisease.org * Elm Recovery Project – Guelph University, Canada * Dutch elm disease at Government of British Columbia * Dutch elm disease – gallery of pests * Species profile – Dutch elm disease (Ophiostoma ulmi and Ophiostoma novo-ulmi), National Invasive Species Information Center, United States National Agricultural Library. Lists general information and resources for Dutch elm disease. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Dutch elm disease

None

wikipedia

https://en.wikipedia.org/wiki/Dutch_elm_disease

{"wikidata": ["Q845598"]}

X-ray of 2-month-old female child with ulnar dimelia Ulnar dimelia, also referred to simply as mirror hand, is a very rare congenital disorder characterized by the absence of the radial ray, duplication of the ulna, duplication of the carpal, metacarpal, and phalanx bones, and symmetric polydactyly. In some cases surgical amputation is performed to remove the duplicate carpals, metacarpals and phalanges. As of 2015, approximately 70 cases have been recorded in the medical literature. Bone deformity may also accompany nervous and arterial anomalies in some cases due to the duplication of the ulnar nerve, the presence of abnormal arterial arches, the duplication of the ulnar artery, the shortening of the radial nerve, and the absence of the radial artery. The diagnosis of ulnar dimelia is based on laboratory tests of frontal and sagittal planes in individuals suspected of the condition. There are two types of ulnar dimelia noted in medical journals: Type 1 ulnar dimelia entails one lunate and one trapezoid bone as well as one index finger, while type 2 ulnar dimelia has two lunate and two trapezoid bones as well as two index fingers. The American Society for Surgery of the Hand and the International Federation of Societies for Surgery of the Hand classified ulnar dimelia in the third group of congenital hand deformities in accordance with the characteristics proposed in the Swanson classification (1976). ## References[edit] * Tomaszewski, Ryszard; Bulandra, Andrzej (2015). "Ulnar dimelia-diagnosis and management of a rare congenital anomaly of the upper limb". Journal of Orthopaedics. 12 (Suppl 1): S121–S124. doi:10.1016/j.jor.2015.01.027. PMC 4674541. PMID 26719621. * Namdev, Rupesh. "Ulnar dimelia | Radiology Reference Article | Radiopaedia.org". radiopaedia.org. * Chinegwundoh, J. O. M.; Gupta, M.; Scott, W. A. (1 February 1997). "Ulnar dimelia: Is it a true duplication of the ulna?". Journal of Hand Surgery. 22 (1): 77–79. doi:10.1016/S0266-7681(97)80024-1. PMID 9061533. * Jameel, Javed; Khan, Abdul Qayyum; Ahmad, Sohail; Abbas, Mazhar (2011). "Ulnar dimelia variant: a case report". Journal of Orthopaedics and Traumatology. 12 (3): 163–165. doi:10.1007/s10195-011-0146-y. PMC 3163772. PMID 21769660. ## Further reading[edit] *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Ulnar dimelia

c0265585

wikipedia

https://en.wikipedia.org/wiki/Ulnar_dimelia

{"umls": ["C0265585"], "wikidata": ["Q55648731"]}

Chen and D'Souza (1990) described a family in which 3 girls had congenital glaucoma and tetralogy of Fallot. The mother also had congenital glaucoma, but had no heart defect. Cardiac \- Tetralogy of Fallot Eyes \- Congenital glaucoma Inheritance \- Autosomal dominant ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

TETRALOGY OF FALLOT AND GLAUCOMA

c1861234

omim

https://www.omim.org/entry/187501

{"mesh": ["C536501"], "omim": ["187501"]}

Musicians experience a number of health problems related to the practice and performance of music. ## Contents * 1 Health Conditions * 2 See also * 3 References * 4 External links ## Health Conditions[edit] The most common injury type suffered by musicians is repetitive strain injury (RSIs). A survey of orchestral performers found that 64–76% had significant RSIs.[1] Other types of musculoskeletal disorders, such as carpal tunnel syndrome and focal dystonia, are also common.[2][3] Non-musculoskeletal problems include contact dermatitis, hearing problems such as tinnitus, hearing loss, hyperacusis and diplacusis[1] respiratory disorders or pneumothorax, increased intraocular pressure, gastroesophageal reflux disease, and psychological issues such as performance anxiety.[2] Musicians may suffer tinnitus and hearing disorders due to exposure to loud music, such as hyperacusis or diplacusis.[4][5][6] They also are at an increased risk of having problems with the stomatognathic system, in particular mouth and teeth, which may in some cases lead to permanent injuries that prevent the musicians from playing.[7] There is little consistency across the hearing healthcare sector with respect to care of musicians' hearing and provision of hearing protection.[8] However, the American Academy of Audiology has published a consensus document regarding best practices for hearing loss prevention with musicians.[9] Playing a brass or woodwind instrument puts the musician at greater risk of inguinal hernia.[10] Woodwind instrumentalists, in rare cases, suffer a condition known as hypersensitivity pneumonitis, also referred to as saxophone lung, can be caused by Exophiala infection. It is held that this can occur if instruments are not cleaned properly.[11] ## See also[edit] * Performing Arts Medicine * Safe-In-Sound award ## References[edit] 1. ^ Mitchell T (2010). Longyear S (ed.). "A painful melody: repetitive strain injury among musicians" (PDF). Pittsburg State University. 2. ^ a b Heinan M (April 2008). "A review of the unique injuries sustained by musicians". JAAPA. 21 (4): 45–6, 48, 50 passim. doi:10.1097/01720610-200804000-00015. PMID 18468369. S2CID 36408486. 3. ^ Blanco-Piñeiro, Patricia; Díaz-Pereira, M. Pino; Martínez, Aurora (2017). "Musicians, postural quality and musculoskeletal health: A literature's review". Journal of Bodywork and Movement Therapies. 21 (1): 157–172. doi:10.1016/j.jbmt.2016.06.018. ISSN 1532-9283. PMID 28167172. 4. ^ Kardous CA, Themann CL, Morata TC, Reynolds J, Afanuh S (2015). "Workplace Solutions: Reducing the Risk of Hearing Disorders among Musicians" (PDF). National Institute for Occupational Safety and Health. Retrieved 12 July 2016. 5. ^ Behar A, Chasin M, Mosher S, Abdoli-Eramaki M, Russo FA (2018). "Noise exposure and hearing loss in classical orchestra musicians: A five-year follow-up". Noise & Health. 20 (93): 42–46. doi:10.4103/nah.NAH_39_17 (inactive 11 December 2020). PMC 5926315. PMID 29676294.CS1 maint: DOI inactive as of December 2020 (link) 6. ^ Di Stadio, Arianna; Dipietro, Laura; Ricci, Giampietro; Della Volpe, Antonio; Minni, Antonio; Greco, Antonio; de Vincentiis, Marco; Ralli, Massimo (2018). "Hearing Loss, Tinnitus, Hyperacusis, and Diplacusis in Professional Musicians: A Systematic Review". International Journal of Environmental Research and Public Health. 15 (10): 2120. doi:10.3390/ijerph15102120. ISSN 1660-4601. PMC 6209930. PMID 30261653. 7. ^ Rodríguez-Lozano FJ, Sáez-Yuguero MR, Bermejo-Fenoll A (September 2011). "Orofacial problems in musicians: a review of the literature". Medical Problems of Performing Artists. 26 (3): 150–6. doi:10.21091/mppa.2011.3024. PMID 21987070. 8. ^ McGinnity, Siobhan; Beach, Elizabeth Francis; Mulder, Johannes; Cowan, Robert (2018). "Caring for musicians' ears: insights from audiologists and manufacturers reveal need for evidence-based guidelines". International Journal of Audiology. 57 (sup1): S12–S19. doi:10.1080/14992027.2017.1405288. ISSN 1708-8186. PMID 29192525. S2CID 24276596. 9. ^ "Musicians and Music Industry". Audiology. 19 November 2019. Retrieved 13 October 2020. 10. ^ Okoshi, Kae; Minami, Taro; Masahiro, Kikuchi; Tomizawa, Yasuko (2017). "Musical Instrument-Associated Health Issues and Their Management". The Tohoku Journal of Experimental Medicine. 243 (1): 49–56. Retrieved 31 December 2020. 11. ^ Lallanilla M (8 November 2013). "What Is Saxophone Lung?". Live Science. Retrieved 16 January 2017. ## External links[edit] * Okoshi, Kae; Minami, Taro; Masahiro, Kikuchi; Tomizawa, Yasuko (2017). "Musical Instrument-Associated Health Issues and Their Management". The Tohoku Journal of Experimental Medicine. 243 (1): 49–56. doi:10.1620/tjem.243.49. Retrieved 31 December 2020. * Okoshi, Kae; Minami, Taro; Masahiro, Kikuchi; Tomizawa, Yasuko. "Musical Instrument-Associated Health Issues and Their Management". National Library of Medicine. National Center for Biotechnology Information. PMID 28931767. Retrieved 31 December 2020. Abstract, link to the article, and links to similar articles. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Health problems of musicians

None

wikipedia

https://en.wikipedia.org/wiki/Health_problems_of_musicians

{"wikidata": ["Q17619740"]}

Waardenburg Syndrome Type 4A Other namesShah-Waardenburg Syndrome Waardenburg Syndrome Type 4A is an extremely rare congenital disorder caused by a mutation in an endothelin receptor gene. It results in common Waardenburg syndrome symptoms such as abnormal hair and skin pigmentation and heterochromia, but also present with symptoms of Hirschsprung’s disease.[citation needed] Symptoms include abdominal pain and bowel obstruction. Waardenburg Syndrome Type 4A is the rarest among the types, appearing only once in about every 1,000,000 individuals. There have only been a total of 50 cases reported in total as of 2016.[1] ## Contents * 1 Presentation * 2 Genetics * 3 Diagnosis * 4 Management * 5 History * 6 References ## Presentation[edit] The blue irises seen in the image present a common phenotype seen by patient of Type 4A Waardenburg Syndrome. However, patients of the Shah-Waardenburg Syndrome do not display signs of dystopia canthorum as seen in other types of Waardenburg Syndromes. Similar to other types of Waardenburg Syndrome, Shah-Waardenburg Syndrome patients present with some facial features such the abnormal pigmentation in the hair and premature graying, observed as white forelock. Their eyes also present abnormal pigmentation such as heterochromia iridis or uncharacteristic blue eyes.[1] The study conducted by Shah reported additional physical features such as white eyebrows and eyelashes as well, which is not seen in other types of Waardenburg Syndromes.[citation needed]These patients also lack some key features from the Waardenburg syndrome, noted by the lack of dystopia canthorum, the broad nasal root, as well as the lack of white skin pigmentation around the body. Studies have also shown that hearing loss due to EDNRB mutation such as the ones that cause Type 4A, have a 53.3% prevalence in patients.[2] The biggest difference noted is the additional symptoms caused by the additional HSCR which included intestinal obstruction and colonic aganglionosis.[citation needed] Colonic aganglionic indicates that some of the nerves in the intestines are nonfunctional in the patients, causing abnormal bowel obstruction and abdominal pain to occur. It can also lead to constipation and blockage in the body[3]Type 4A leads to early mortality, as observed in the original Shah study, where the 12 infants in question died within 3–38 days after birth.[citation needed] ## Genetics[edit] The mutations in the EDNRB gene results in abnormalities in the neural tube and specification of the enteric nervous system precursors that are present in the gut. Type 4 Waardenburg Syndrome is inherited in an autosomal dominant manner, but it has also been reported in recessive autosomal. The mode of inheritance is still unclear, researchers concluded that it depends on the type of mutation that affected the EDNRB gene.[1] The abnormalities seen are caused in mutation such as the studied deletion of the endothelin‐B receptor gene, which is located at chromosome 13q22.1-q31.3.[4] There is some variation in the size of the deletion in some patients studied. The longer deletions actually led to more severe phenotypes such as retardation and bilateral hearing loss.[2] EDNRB is found in the neural tube early development, and assist in the migration and specification of the enteric nervous system precursors that are present in the gut. The homozygous mutation of this gene results in deafness and abnormal cell migration in the cell as described in the Shah-Waardenburg Syndrome.[1] Variation of mutation for the EDNRB gene can be hard to assist appropriately due to low penetrance and variation in dosages of the product. Mutation in both copies of the gene results in full phenotypes presented by patients. On the other hand, heterzygous can display isolated or minor HSCR symptoms rather than Shah-Waardenburg symptoms.[5] ## Diagnosis[edit] Physicians assess the patient for the typical phenotypes of Waardenburg Syndrome such as the white forelock or heterochromia. But in addition to that, hearing loss is considered as well as side effects of the HSCR disease. That includes multiple issues with the intestines and the gut resulting in symptoms such as constipation or abdominal pain.[3] ## Management[edit] Due to the unfortunate early mortality expected with Shah-Waardenburg Syndrome, it is essential to detect the symptoms as early as possible. The physical features provided by the phenotypes of Waardenburg Syndrome actually work to the benefit of the patient as they work as physical markers for possible detection of the disease.There is no current cure for Waardenburg Syndrome, however, the symptoms are managed by a variety of methods. Some of the hearing loss can be addressed by some aid depending on the specific mutation and the patient. Patients are also encouraged to seek specialists to assist and seek resources and methods to manage the disease.[citation needed] ## History[edit] Shah-Waardenburg Syndrome was first described by Krishnakumar N. Shah in 1981. The discovery focused on 12 babies with abnormal eye pigmentation, white forelock, and exhibited symptoms of Hirschsprung's disease, they presented an unclear relation to Waardenburg syndrome.[citation needed]The babies lacked dystopia canthorum which is the physical marker used to diagnose Waardenburg Syndrome. It is unclear if they had suffered from hearing loss since they died in neonatal age before they were able to conduct the test. The combination of the symptoms of Hirschsprung 's disease and Waardenburg was then named Shah-Waardenburg Syndrome. The main cause of this syndrome is the mutation of the endothelin receptor type B gene (noted as EDNRB).[6] ## References[edit] 1. ^ a b c d Chandra Mohan, Setty. L. N. (2018-09-01). "Case of Waardenburg Shah syndrome in a family with review of literature". Journal of Otology. 13 (3): 105–110. doi:10.1016/j.joto.2018.05.005. ISSN 1672-2930. PMC 6291636. PMID 30559775. 2. ^ a b Song, J.; Feng, Y.; Acke, F. R.; Coucke, P.; Vleminckx, K.; Dhooge, I. J. (2016). "Hearing loss in Waardenburg syndrome: a systematic review". Clinical Genetics. 89 (4): 416–425. doi:10.1111/cge.12631. ISSN 1399-0004. PMID 26100139. 3. ^ a b "Waardenburg syndrome type 4 | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2020-05-01. 4. ^ Tüysüz, Beyhan; Collin, Anna; Arapoğlu, Müjde; Suyugül, Nezir (2009). "Clinical variability of Waardenburg–Shah syndrome in patients with proximal 13q deletion syndrome including the endothelin-B receptor locus". American Journal of Medical Genetics Part A. 149A (10): 2290–2295. doi:10.1002/ajmg.a.33031. ISSN 1552-4833. PMID 19764031. 5. ^ Syrris, Petros; Carter, Nicholas D.; Patton, Michael A. (1999). "Novel nonsense mutation of the endothelin-B receptor gene in a family with Waardenburg-Hirschsprung disease". American Journal of Medical Genetics. 87 (1): 69–71. doi:10.1002/(SICI)1096-8628(19991105)87:1<69::AID-AJMG14>3.0.CO;2-R. ISSN 1096-8628. PMID 10528251. 6. ^ Pingault, Véronique; Ente, Dorothée; Dastot-Le Moal, Florence; Goossens, Michel; Marlin, Sandrine; Bondurand, Nadège (April 2010). "Review and update of mutations causing Waardenburg syndrome". Human Mutation. 31 (4): 391–406. doi:10.1002/humu.21211. ISSN 1098-1004. PMID 20127975. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Waardenburg Syndrome Type 4A

c1848519

wikipedia

https://en.wikipedia.org/wiki/Waardenburg_Syndrome_Type_4A

{"mesh": ["C536467"], "umls": ["C1848519"], "orphanet": ["897"], "wikidata": ["Q32145171"]}

## Clinical Features Gordon et al. (1976) reported 2 sons, of consanguineous parents, who had ostensibly nonprogressive spastic paraplegia, retinitis pigmentosa, and mental retardation. This may be a distinct disorder. It occurred in an inbred Old American kindred of southern Maryland in which the original cases of the Crigler-Najjar syndrome (218800) were found and homocystinuria (236200), Morquio syndrome (253000), Seckel dwarfism (see 210600), metachromatic leukodystrophy (250100), and other recessive disorders have been observed. Inheritance Consanguinity and affected sibs in the family reported by Gordon et al. (1976) support autosomal recessive inheritance of the disorder. Eyes \- Visual loss \- Retinitis pigmentosa Inheritance \- Autosomal recessive Neuro \- Mental retardation \- Spastic quadriplegia Ears \- Hearing loss ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SPASTIC QUADRIPLEGIA, RETINITIS PIGMENTOSA, AND MENTAL RETARDATION

c1849112

omim

https://www.omim.org/entry/270950

{"mesh": ["C564808"], "omim": ["270950"], "orphanet": ["3011"]}

A rare lymphoma characterized by the concurrent occurrence of two or more histologic types of lymphoma involving the same anatomic site. Composite lymphomas can be combinations of two non-Hodgkin lymphomas or of a non-Hodgkin and a Hodgkin lymphoma. In many cases, the tumors are clonally related. Clinical presentation and treatment are determined by the more aggressive component. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Composite lymphoma

c0545080

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=168966

{"mesh": ["D058617"], "umls": ["C0545080", "C1266191"], "synonyms": ["Composite Hodgkin and non-Hodgkin lymphoma"]}

Mansonelliasis Other namesMansonellosis SpecialtyInfectious disease Mansonelliasis is the condition of infection by the nematode Mansonella. The disease exists in Africa and tropical Americas, spread by biting midges or blackflies. It is usually asymptomatic. ## Contents * 1 Symptoms * 2 Causes * 3 Vectors and life cycle * 4 Pathogenesis * 5 Diagnosis * 6 Prevention * 7 Treatment * 8 Epidemiology * 9 History * 10 See also * 11 References * 12 Further reading ## Symptoms[edit] Infections by Mansonella perstans, while often asymptomatic, can be associated with angioedema, pruritus, fever, headaches, arthralgias, and neurologic manifestations. Mansonella streptocerca can manifest on the skin via pruritus, papular eruptions and pigmentation changes. Mansonella ozzardi can cause symptoms that include arthralgias, headaches, fever, pulmonary symptoms, adenopathy, hepatomegaly, and pruritus.[1] Eosinophilia is often prominent in all cases of Mansonelliasis. M. perstans can also present with Calabar-like swellings, hives, and a condition known as Kampala, or Ugandan eye worm.[2] This occurs when adult M. perstans invades the conjunctiva or periorbital connective tissues in the eye. M. perstans can also present with hydrocele in South America.[2] However, it is often hard to distinguish between the symptoms of Mansonelliasis and other nematode infections endemic to the same areas.[3][4] ## Causes[edit] Mansonelliasis is caused by nematodes (roundworms) in the Mansonella genus that reside in the skin or certain body cavities. The specific species are M. perstans, M. streptocerca and M. ozzardi.[2] ## Vectors and life cycle[edit] Life Cycles of Various Mansonella During a blood meal, an infected midge (genus Culicoides) or blackfly (genus Simulium) introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound. They develop into adults that reside in body cavities, most commonly the peritoneal cavity or pleural cavity, but also occasionally in the pericardium (M. perstans), subcutaneous tissue (M. ozzardi) or dermis (M. steptocerca).[1] In M. perstans, size range for female worms is 70 to 80 mm long and 120 μm in diameter, and the males measure approximately 45 mm by 60 μm. In M. steptocerca, the females measure approximately 27 mm long. Their diameter is 50 μm at the level of the vulva (anteriorly) and ovaries (near the posterior end), and up to 85 μm at the mid-body. Males measure 50 μm in diameter. In M. ozzardi, adult worms are rarely found in humans. The size range for females worms is 65 to 81 mm long and 0.21 to 0.25 mm in diameter but unknown for males. Adult worms recovered from experimentally infected Patas monkeys measured 24 to 28 mm long and 70 to 80 μm in diameter (males) and 32 to 62 mm long and .130 to .160 mm in diameter (females).[1] Adults produce unsheathed and non-periodic (sub-periodic in M. perstans) microfilariae that reach the blood stream. A midge or black fly ingests microfilariae during a blood meal. After ingestion, the microfilariae migrate from the midgut through the hemocoel to the thoracic muscles of the arthropod. There the microfilariae develop into first-stage larvae and later into third-stage infective larvae. The third-stage infective larvae migrate to the arthropod’s proboscis where they can then infect another human when the midge or blackfly takes a blood meal.[1] Asymptomatic humans serve as a significant reservoir for the disease. Little is known about other reservoirs of the disease.[citation needed] ## Pathogenesis[edit] Mansonelliasis infection has been considered a minor filariasis, remaining asymptomatic in most infected subjects. Larvae develop in the subject and migrate to their respective regions in the skin or body cavities. It is likely that aside from being caused by the worm itself, some of the pathological changes observed are induced by the immune response to the infection leading to some of the various symptoms mentioned above.[5] However, Mansonelliasis is little studied compared to other forms of filariasis so there is not as much information known regarding its specific pathogenesis.[citation needed] ## Diagnosis[edit] Examination of blood samples will allow identification of microfilariae of M. perstans, and M. ozzardi based.[1] This diagnosis can be made on the basis of the morphology of the nuclei distribution in the tails of the microfilariae.[2][4] The blood sample can be a thick smear, stained with Giemsa or hematoxylin and eosin.[6][1] For increased sensitivity, concentration techniques can be used. These include centrifugation of the blood sample lyzed in 2% formalin (Knott's technique), or filtration through a Nucleopore membrane.[1] Examination of skin snips will identify microfilariae of Onchocerca volvulus and M. streptocerca. Skin snips can be obtained using a corneal-scleral punch, or more simply a scalpel and needle. It is important that the sample be allowed to incubate for 30 minutes to 2 hours in saline or culture medium and then examined. This allows for the microfilariae that would have been in the tissue to migrate to the liquid phase of the specimen.[1] Additionally, to differentiate the skin-dwelling filariae M. streptocerca and Onchocerca volvulus, a nested polymerase chain reaction (PCR) assay was developed using small amounts of parasite material present in skin biopsies.[3] ## Prevention[edit] Prevention can be partially achieved through limiting contact with vectors through the use of DEET and other repellents, but due to the predominantly relatively mild symptoms and the infection being generally asymptomatic, little has formally been done to control the disease.[citation needed] ## Treatment[edit] There is no consensus on optimal therapeutic approach. The most commonly used drug is diethylcarbamazine (DEC), but it is, however, often ineffective.[5] Although other drugs have been tried such as praziquantel, ivermectin, and albendozole, none has proven to be reliably and rapidly effective.[5] Mebendazole appeared more active than DEC in eliminating the infection, and had comparable overall responses. Thiabendazole evidenced a small, but significant activity against the infection. A combination of treatments, DEC plus mebendazole, was much more effective than single drug doses.[5][7] ## Epidemiology[edit] Areas where Mansonelliasis is endemic Mansonelliasis is found in Latin America from the Yucatán peninsula to northern Argentina, in the Caribbean, and in Africa from Senegal to Kenya and south to Angola and Zimbabwe. M. ozzardi is found only in the New World, M. steptocerca is found only in the Congo basin, and M. perstans is found in both the previously described areas of Africa and Latin America. Prevalence rates vary from a few percent to as much as 90% in areas like Trinidad, Guyana and Colombia.[2] Infection is more common and has a higher microfilarial dose with age,[6] though studies have found microfilarial dose not to be correlated with symptoms.[5] In parts of rural South America, men have been found more susceptible than women, possibly due to more outdoors work by males as children, and possibly due to cooking fires serving as deterrents to vectors for women who perform more domestic duties.[6] One study in central Africa found M. perstans to be a much more common cause of filariasis symptoms compared to Loa loa and Wuchereria bancrofti.[8] Since most Mansonelliasis is asymptomatic, it has been considered a relatively minor filarial disease,[5] and has a very low, if any, mortality,[9] though there is little data on which to base estimates. ## History[edit] Mansonelliasis, in the form of M. ozzardi, was first documented in 1897.[6] ## See also[edit] * Filariasis * Mansonella ## References[edit] 1. ^ a b c d e f g h i "Filariasis". 2019-02-04. Archived from the original on February 20, 2009. 2. ^ a b c d e f John, David T.; Petri, William (2013). "Mansonella ozzardi". Markell and Voge's Medical Parasitology (9th ed.). Saunders Elsevier. pp. 292–4. ISBN 978-0-323-27764-8. 3. ^ a b c Fischer P, Büttner DW, Bamuhiiga J, Williams SA (June 1998). "Detection of the filarial parasite Mansonella streptocerca in skin biopsies by a nested polymerase chain reaction-based assay". The American Journal of Tropical Medicine and Hygiene. 58 (6): 816–20. doi:10.4269/ajtmh.1998.58.816. PMID 9660471. 4. ^ a b c Post RJ, Adams Z, Shelley AJ, Maia-Herzog M, Luna Dias AP, Coscarón S (July 2003). "The morphological discrimination of microfilariae of Onchocerca volvulus from Mansonella ozzardi" (PDF). Parasitology. 127 (Pt 1): 21–7. doi:10.1017/S003118200300324X. PMID 12885185. 5. ^ a b c d e f g Bregani ER, Tantardini F, Rovellini A (June 2007). "La filariosi da Mansonella perstans" [Mansonella perstans filariasis]. Parassitologia (in Italian). 49 (1–2): 23–6. PMID 18416002. 6. ^ a b c d e Kozek WJ, D'Alessandro A, Silva J, Navarette SN (November 1982). "Filariasis in Colombia: prevalence of mansonellosis in the teenage and adult population of the Colombian bank of the Amazon, Comisaria del Amazonas". The American Journal of Tropical Medicine and Hygiene. 31 (6): 1131–6. doi:10.4269/ajtmh.1982.31.1131. PMID 6756176. 7. ^ a b "Filariasis" (PDF). 2019-02-04. Archived from the original (PDF) on August 27, 2010. Retrieved February 27, 2009. 8. ^ a b Bregani ER, Balzarini L, Mbaïdoum N, Rovellini A (July 2007). "Prevalence of filariasis in symptomatic patients in Moyen Chari district, south of Chad". Tropical Doctor. 37 (3): 175–7. doi:10.1258/004947507781524629. PMID 17716512. 9. ^ a b "Mansonelliasis".[full citation needed] ## Further reading[edit] * Marinkelle CJ, German E (March 1970). "Mansonelliasis in the Comisaría del Vaupes of Colombia". Tropical and Geographical Medicine. 22 (1): 101–11. PMID 5435931. * Cohen JM, Ribeiro JA, Martins M (2008). "Acometimento ocular em pacientes com mansonelose" [Ocular manifestations in mansonelliasis]. Arquivos Brasileiros de Oftalmologia (in Portuguese). 71 (2): 167–71. doi:10.1590/S0004-27492008000200007. PMID 18516413. * Linley JR, Hoch AL, Pinheiro FP (July 1983). "Biting midges (Diptera: Ceratopogonidae) and human health" (PDF). Journal of Medical Entomology. 20 (4): 347–64. doi:10.1093/jmedent/20.4.347. PMID 6312046. * v * t * e Parasitic disease caused by helminthiases Flatworm/ platyhelminth infection Fluke/trematode (Trematode infection) Blood fluke * Schistosoma mansoni / S. japonicum / S. mekongi / S. haematobium / S. intercalatum * Schistosomiasis * Trichobilharzia regenti * Swimmer's itch Liver fluke * Clonorchis sinensis * Clonorchiasis * Dicrocoelium dendriticum / D. hospes * Dicrocoeliasis * Fasciola hepatica / F. gigantica * Fasciolosis * Opisthorchis viverrini / O. felineus * Opisthorchiasis Lung fluke * Paragonimus westermani / P. kellicotti * Paragonimiasis Intestinal fluke * Fasciolopsis buski * Fasciolopsiasis * Metagonimus yokogawai * Metagonimiasis * Heterophyes heterophyes * Heterophyiasis Cestoda (Tapeworm infection) Cyclophyllidea * Echinococcus granulosus / E. multilocularis * Echinococcosis * Taenia saginata / T. asiatica / T. solium (pork) * Taeniasis / Cysticercosis * Hymenolepis nana / H. diminuta * Hymenolepiasis Pseudophyllidea * Diphyllobothrium latum * Diphyllobothriasis * Spirometra erinaceieuropaei * Sparganosis * Diphyllobothrium mansonoides * Sparganosis Roundworm/ Nematode infection Secernentea Spiruria Camallanida * Dracunculus medinensis * Dracunculiasis Spirurida Filarioidea (Filariasis) * Onchocerca volvulus * Onchocerciasis * Loa loa * Loa loa filariasis * Mansonella * Mansonelliasis * Dirofilaria repens * D. immitis * Dirofilariasis * Wuchereria bancrofti / Brugia malayi / |B. timori * Lymphatic filariasis Thelazioidea * Gnathostoma spinigerum / G. hispidum * Gnathostomiasis * Thelazia * Thelaziasis Spiruroidea * Gongylonema Strongylida (hookworm) * Hookworm infection * Ancylostoma duodenale / A. braziliense * Ancylostomiasis / Cutaneous larva migrans * Necator americanus * Necatoriasis * Angiostrongylus cantonensis * Angiostrongyliasis * Metastrongylus * Metastrongylosis Ascaridida * Ascaris lumbricoides * Ascariasis * Anisakis * Anisakiasis * Toxocara canis / T. cati * Visceral larva migrans / Toxocariasis * Baylisascaris * Dioctophyme renale * Dioctophymosis * Parascaris equorum Rhabditida * Strongyloides stercoralis * Strongyloidiasis * Trichostrongylus spp. * Trichostrongyliasis * Halicephalobus gingivalis Oxyurida * Enterobius vermicularis * Enterobiasis Adenophorea * Trichinella spiralis * Trichinosis * Trichuris trichiura (Trichuriasis / Whipworm) * Capillaria philippinensis * Intestinal capillariasis * C. hepatica *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Mansonelliasis

c0024759

wikipedia

https://en.wikipedia.org/wiki/Mansonelliasis

{"gard": ["8216"], "mesh": ["D008368"], "umls": ["C0024759"], "orphanet": ["2459"], "wikidata": ["Q4280605"]}

For a general phenotypic description and a discussion of genetic heterogeneity of chondrodysplasia punctata, see CDPX2 (302960). Clinical Features Sheffield et al. (1976) reported several children from Australia with a mild form of chondrodysplasia punctata. The patients presented during infancy with abnormal facies, and punctate calcification in the calcanerum and sometimes other sites. Growth and developmental progress improved during childhood, and the final phenotype seemed to include low-normal height and intelligence with persistence of the typical facies. Illnesses during pregnancy were frequent, and anticonvulsants taken during pregnancy may have had an etiologic role in some patients. Happle (1981) suggested that cataracts are consistently absent in the autosomal dominant form of chondrodysplasia punctata. Rittler et al. (1990) referred to the mild 'Sheffield-type' of chondrodysplasia punctata and suggested possible autosomal dominant inheritance. They noted that patients with this form had characteristic face and symmetric stippling of upper and/or lower limbs that disappeared with age. A female patient observed by Silverman (1961, 1969) had a similarly affected brother and apparently a male cousin with the same disorder. Their fathers appeared unaffected, but this was not unexpected since the bone changes disappear during childhood. The brother of the original patient reported by Silverman (1961) had a daughter who was similarly affected (Vinke and Duffy, 1974). ### Vitamin K Deficiency or Warfarin Teratogenicity Several different modes of vitamin K-related teratogenicity have been shown to cause chondrodysplasia punctata. The best described of these is warfarin embryopathy. Hall et al. (1980) placed the critical period for warfarin effects on the fetus as 6 to 9 weeks following conception. Warfarin inhibits synthesis of gamma-carboxyglutamic acid, which is involved in both clotting and calcification. See review by Gallop et al. (1980). Ingestion of warfarin during pregnancy can result in hypoplasia of the nasal bones to produce koala bear facies (Becker et al., 1975; Pettifor and Benson, 1975; Shaul et al., 1975). In addition to severe hypoplasia of the nose, sometimes with choanal atresia, stippled epiphyses and coronal vertebral clefts have also been observed. In addition, various vitamin K antagonists produce this picture. The only difference from chondrodysplasia punctata may be the absence of skin and hair changes. Harrod and Sherrod (1981) reported 2 sibs from pregnancies during which their mother took warfarin for thrombophlebitis who showed signs of chondrodysplasia punctata, and a third sib from a pregnancy without warfarin ingestion who was unaffected. Pauli et al. (1985) described a boy with the phenotype of warfarin embryopathy including nasal hypoplasia and, in infancy, cartilage stippling by x-ray, who also had combined deficiency of vitamin K-dependent coagulation factors. These observations were interpreted to mean that warfarin embryopathy is not due to hemorrhage but rather to inhibition of carboxylation of osteocalcins and/or other vitamin K-dependent bone proteins. Embryopathy due to vitamin K deficiency as a result of various maternal intestinal abnormalities leading to malabsorption was described by Menger et al. (1997) and Nivelon-Chevallier (1998). Eash et al. (2003) described a male infant with brachytelephalangic chondrodysplasia punctata who had multiple serious medical problems and striking physical abnormalities. These included cervical spine stenosis with resultant quadriplegia, severe nasal hypoplasia, and brachytelephalangy. Radiographs taken shortly after birth demonstrated extensive epiphyseal and vertebral stippling, and distal phalangeal hypoplasia. Mutation analysis excluded the ARSE gene. The 25-year-old mother's pregnancy had been complicated by severe bouts of intractable vomiting caused by a small bowel obstruction secondary to a severe high-grade synovial carcinoma. Prenatal problems began at 3 weeks of gestation with severe anemia, dehydration, prerenal failure, and weight loss. Between 5 and 18 weeks' gestation she received total parenteral nutrition on several occasions. She received no chemotherapeutic agents or warfarin. She experienced hypocalcemia and hypoalbuminemia at 17 weeks and hypokalemia at 18 weeks' gestation. Eash et al. (2003) concluded that the severity of the phenotype in this case may have been influenced by vitamin K deficiency. Limbs \- Limb asymmetry \- Talipes equinovarus Radiology \- Predominantly epiphyseal, frequently asymmetric calcifications and dysplastic skeletal changes Inheritance \- Autosomal dominant Spine \- Scoliosis Eyes \- Cataracts Skel \- Chondrodysplasia punctata Head \- Frontal bossing Facies \- Koala bear facies \- Nasal bone hypoplasia Joints \- Flexion contractures of hips and knees Misc \- Relatively good prognosis Hair \- Sparse hair \- Coarse hair Growth \- Moderate growth deficiency Skin \- Hyperkeratosis with erythema ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

CHONDRODYSPLASIA PUNCTATA, AUTOSOMAL DOMINANT

c1861578

omim

https://www.omim.org/entry/118650

{"mesh": ["C563248"], "omim": ["118650"]}

Cleft palate- short stature- vertebral anomalies is a multiple congenital anomalies syndrome described in a father and son characterized by the association of cleft palate, peculiar facies (asymmetrical appearance, inner epicanthal folds, short nose, anteverted nostrils, low and back-oriented ears, thin upper lip and micrognathism), short stature, short neck , vertebral anomalies and intellectual disability. The transmission is presumed to be autosomal dominant. There have been no further descriptions in the literature since 1993. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Cleft palate-short stature-vertebral anomalies syndrome

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2015

{"gard": ["1392"], "icd-10": ["Q87.0"], "synonyms": ["Mathieu-De Broca-Bony syndrome"]}

Multiple endocrine neoplasia type 2b Other namesMEN2B, Mucosal neuromata with endocrine tumors, Multiple endocrine neoplasia type 3 ,Wagenmann–Froboese syndrome[1] Micrograph of medullary thyroid carcinoma, as may be seen in MEN 2b. H&E stain. SpecialtyEndocrinology Multiple endocrine neoplasia type 2B is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands. It is the most severe type of multiple endocrine neoplasia,[2] differentiated by the presence of benign oral and submucosal tumors in addition to endocrine malignancies. It was first described by Wagenmann in 1922,[3] and was first recognized as a syndrome in 1965-1966 by E.D. Williams and D.J. Pollock.[4][5] MEN 2B typically manifests before a child is 10 years old. Affected individuals tend to be tall and lanky, with an elongated face and protruding, blubbery lips. Benign tumors (neoplasms) develop in the mouth, eyes, and submucosa of almost all organs in the first decade of life.[6] Medullary thyroid cancer almost always occurs, sometimes in infancy. It is often aggressive. Cancer of the adrenal glands (pheochromocytoma) occurs in 50% of cases. A variety of eponyms have been proposed for MEN 2B, such as Williams-Pollock syndrome, Gorlin-Vickers syndrome, and Wagenmann-Froboese syndrome. However, none ever gained sufficient traction to merit continued use, and they are no longer used in the medical literature.[7] The prevalence of MEN2B is not well established, but has been derived from other epidemiological considerations as 1 in 600,000[8] to 1 in 4,000,000.[9] The annual incidence has been estimated at 4 per 100 million per year.[10] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 3.1 Differential diagnosis * 4 Treatment * 5 Abraham Lincoln hypothesis * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] The most common clinical features of MEN2B are:[citation needed] * a tall, thin, "marfanoid" body build, in which long bones are disproportionately elongated; * masses beneath mucosal surfaces in the mouth, lips, and eyes (discussed below); * low muscle mass, sometimes with myopathy; * gastrointestinal complaints, especially constipation; * symptoms derived from medullary carcinoma of the thyroid; * symptoms derived from pheochromocytoma; * craniosynostosis; * dry eyes or lack of tears; * delayed puberty. A patient with Multiple endocrine neoplasia type 2B, presenting with mucosal neuromas. Unlike Marfan syndrome, the cardiovascular system and the lens of the eye are unaffected.[citation needed] Mucosal neuromas are the most consistent and distinctive feature, appearing in 100% of patients.[11] Usually there are numerous yellowish-white, sessile, painless nodules on the lips or tongue, with deeper lesions having normal coloration. There may be enough neuromas in the body of the lips to produce enlargement and a "blubbery lip" appearance. Similar nodules may be seen on the sclera and eyelids.[citation needed] Histologically, neuromata contain a characteristic adventitious plaque of tissue composed of hyperplastic, interlacing bands of Schwann cells and myelinated fibers overlay the posterior columns of the spinal cord.[12] Mucosal neuromas are made up of nerve cells, often with thickened perineurium, intertwined with one another in a plexiform pattern. This tortuous pattern of nerves is seen within a background of loose endoneurium-like fibrous stroma.[citation needed] ## Causes[edit] Variations in the RET proto-oncogene cause MEN2B. In recent decades no case of MEN2B has been reported that lacks such a variation. The M918T variant alone is responsible for approximately 95% of cases.[13] All DNA variants that cause MEN2B are thought to enhance signaling through the RET protein, which is a receptor molecule found on cell membranes, whose ligands are part of the transforming growth factor beta signaling system.[citation needed] About half of cases are inherited from a parent as an autosomal dominant trait. The other half appear to be spontaneous mutations,[2] usually arising in the paternal allele,[14] particularly from older fathers.[2] The sex ratio in de novo cases is also uneven: sons are twice as likely to develop MEN 2B as daughters.[2] ## Diagnosis[edit] ### Differential diagnosis[edit] DNA testing is now the preferred method of establishing a diagnosis for MEN 2B, and is thought to be almost 100% sensitive and specific. Gordon et al. reported cases of a difference disease—the "multiple mucosal neuroma syndrome"—having the physical phenotype of MEN2B, but without variations in the RET gene and without malignancy.[15] MEN2B should be entertained as a diagnosis whenever a person is found to have either medullary thyroid carcinoma or pheochromocytoma. Before DNA testing became available, measurement of serum calcitonin was the most important laboratory test for MEN2B. Calcitonin is produced by the "C" cells of the thyroid, which, because they are always hyperplastic or malignant in MEN2B, produce more calcitonin than normal. Calcitonin levels remain a valuable marker to detect recurrence of medullary thyroid carcinoma after thyroidectomy.[citation needed] Luxol fast blue staining identifies myelin sheathing of some fibers, and lesional cells react immunohistochemically for S-100 protein, collagen type IV, vimentin, NSE, and neural filaments. More mature lesions will react also for EMA, indicating a certain amount of perineurial differentiation. Early lesions, rich in acid mucopolysaccharides, stain positively with alcian blue. When medullary thyroid cancer is present, levels of the hormone calcitonin are elevated in serum and urine.[13] Under the microscope, tumors may closely resemble traumatic neuroma, but the streaming fascicles of mucosal neuroma are usually more uniform and the intertwining nerves of the traumatic neuroma lack the thick perineurium of the mucosal neuroma.[16] Inflammatory cells are not seen in the stroma and dysplasia is not present in the neural tissues. ## Treatment[edit] Without treatment, persons with MEN2B die prematurely. Details are lacking, owing to the absence of formal studies, but it is generally assumed that death in the 30s is typical unless prophylactic thyroidectomy and surveillance for pheochromocytoma are performed (see below). The range is quite variable, however: death early in childhood can occur, and a few untreated persons have been diagnosed in their 50s.[17] Recently, a larger experience with the disease "suggests that the prognosis in an individual patient may be better than previously considered."[18] Thyroidectomy is the mainstay of treatment, and should be performed without delay as soon as a diagnosis of MEN2B is made, even if no malignancy is detectable in the thyroid. Without thyroidectomy, almost all patients with MEN2B develop medullary thyroid cancer, in a more aggressive form than MEN 2A.[13][19] The ideal age for surgery is 4 years old or younger, since cancer may metastasize before age 10.[14] Pheochromocytoma \- a hormone secreting tumor of the adrenal glands \- is also present in 50% of cases.[14] Affected individuals are encouraged to get yearly screenings for thyroid and adrenal cancer.[citation needed] Because prophylactic thyroidectomy improves survival, blood relatives of a person with MEN2B should be evaluated for MEN2B, even if lacking the typical signs and symptoms of the disorder.[citation needed]The mucosal neuromas of this syndrome are asymptomatic and self-limiting, and present no problem requiring treatment. They may, however, be surgically removed for aesthetic purposes or if they are being constantly traumatized. ## Abraham Lincoln hypothesis[edit] In 2007, Dr. John Sotos proposed that President Abraham Lincoln suffered from MEN2B.[20] This theory suggests Lincoln had all the major features of the disease: a marfan-like body habitus, large, bumpy lips, constipation, muscular hypotonia, a history compatible with cancer and a family history of the disorder - his sons Eddie, Willie, and Tad, and probably his mother. The "mole" on Lincoln's right cheek, the asymmetry of his face, his large jaw, his drooping eyelid, and "pseudo-depression" are also suggested as manifestations of MEN2B. Lincoln's longevity (dying at 56 of a gunshot wound and without any apparent suggestion of ill health otherwise) is the principal challenge to the MEN2B theory, which could be proven by DNA testing.[21][22] ## See also[edit] * Multiple endocrine neoplasia * Multiple endocrine neoplasia type 1 * Multiple endocrine neoplasia type 2a ## References[edit] 1. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 858. ISBN 978-1-4160-2999-1. 2. ^ a b c d Carlson KM, Bracamontes J, Jackson CE, et al. (December 1994). "Parent-of-origin effects in multiple endocrine neoplasia type 2B". Am. J. Hum. Genet. 55 (6): 1076–82. PMC 1918453. PMID 7977365. 3. ^ Wagenmann A. (1922). "Multiple neurome des Auges und der Zunge". Ber Dtsch Ophthalmol Ges. 43: 282–5{{inconsistent citations}} 4. ^ Williams ED (1965). "A review of 17 cases of carnicoma of the thyroid and phaeochromocytoma". J Clin Pathol. 18 (3): 288–292. doi:10.1136/jcp.18.3.288. PMC 472926. PMID 14304238. 5. ^ Williams, E. D., Pollock, D. J. (1966). "Multiple mucosal neuromata with endocrine tumours: a syndrome allied to von Recklinghausen's disease". J. Pathol. Bacteriol. 91 (1): 71–80. doi:10.1002/path.1700910109. PMID 4957444.CS1 maint: multiple names: authors list (link) 6. ^ Fryns JP, Chrzanowska K (October 1988). "Mucosal neuromata syndrome (MEN type IIb (III))". J. Med. Genet. 25 (10): 703–6. doi:10.1136/jmg.25.10.703. PMC 1051565. PMID 2906373. 7. ^ Schimke RN, Hartmann WH, Prout TE, Rimoin DL (1968). "Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma and multiple neuromas. A possible regulatory defect in the differentiation of chromaffin tissue". N. Engl. J. Med. 279 (1): 1–7. doi:10.1056/NEJM196807042790101. PMID 4968712. 8. ^ Marx, Stephen J (2011). "Chapter 41: Multiple endocrine neoplasia". In Melmed, Shlomo (ed.). Williams Textbook of Endocrinology, 12th ed. pp. 1728–1767. 9. ^ Moline J, Eng C (2011). "Multiple endocrine neoplasia type 2: an overview". Genetics in Medicine. 13 (9): 755–764. doi:10.1097/GIM.0b013e318216cc6d. PMID 21552134. S2CID 22402472. 10. ^ Martino Ruggieri (2005). Neurocutaneous Disorders : The Phakomatoses. Berlin: Springer. ISBN 978-3-211-21396-4. \- Chapter: Multiple Endocrine Neoplasia Type 2B by Electron Kebebew, Jessica E. Gosnell and Emily Reiff. Pages 695-701. [1] This reference quotes a prevalence of 1 in 40,000, but this figure is inconsistent with the same reference's calculated incidence of 4 per 100 million per year for MEN2B. 11. ^ Pujol RM, Matias-Guiu X, Miralles J, Colomer A, de Moragas JM (August 1997). "Multiple idiopathic mucosal neuromas: a minor form of multiple endocrine neoplasia type 2B or a new entity?". J. Am. Acad. Dermatol. 37 (2 Pt 2): 349–52. doi:10.1016/S0190-9622(97)70025-2. PMID 9270546. 12. ^ Dyck, PJ (October 1979). "Multiple endocrine neoplasia, type 2b: phenotype recognition; neurological features and their pathological basis". Annals of Neurology. 6 (4): 302–314. doi:10.1002/ana.410060404. PMID 554522. S2CID 24328061{{inconsistent citations}} 13. ^ a b c Sperling, Mark A. (2008). Pediatric Endocrinology (3 ed.). Elsevier Health Sciences. pp. 246–7. ISBN 978-1-4160-4090-3{{inconsistent citations}} 14. ^ a b c Morrison PJ, Nevin NC (September 1996). "Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome)". J. Med. Genet. 33 (9): 779–82. doi:10.1136/jmg.33.9.779. PMC 1050735. PMID 8880581. 15. ^ Gordon CM, Majzoub JA, Marsh DJ, Mulliken JB, Ponder BA, Robinson BG, Eng C (Jan 1998). "Four cases of mucosal neuroma syndrome: multiple endocrine neoplasm 2B or not 2B?". J Clin Endocrinol Metab. 83 (1): 17–20. doi:10.1210/jc.83.1.17. PMID 9435410.CS1 maint: multiple names: authors list (link) 16. ^ R. L. Miller; N. J. Burzynski; B. L. Giammara (1977). "The ultrastructure of oral neuromas in multiple mucosal neuromas, pheochromocytoma, medullary thyroid carcinoma syndrome". Journal of Oral Pathology & Medicine. 6 (5): 253–63. doi:10.1111/j.1600-0714.1977.tb01647.x. PMID 409817. Archived from the original on 2012-10-13{{inconsistent citations}} 17. ^ Sizemore GW, Carney JA, Gharib H, Capen CC (1992). "Multiple endocrine neoplasia type 2B: eighteen-year follow-up of a four-generation family". Henry Ford Hosp Med J. 40 (3–4): 236–244. PMID 1362413. 18. ^ Hoff, AO; Gagel, RF (2006). "Chapter 192: Multiple endocrine neoplasia type 2". In DeGroot, LJ; Jameson, JL (eds.). Endocrinology (5th ed.). Philadelphia: Elsevier-Saunders. pp. 3533–3550. ISBN 978-0721603766. 19. ^ Lester W. Burket; Martin S. Greenberg; Michaël Glick; Jonathan A. Ship (2008). Burket's oral medicine (11 ed.). PMPH-USA. p. 141. ISBN 978-1-55009-345-2{{inconsistent citations}} 20. ^ Sotos, JG (2008). The Physical Lincoln: Finding the Genetic Cause of Abraham Lincoln's Height, Homeliness, Pseudo-Depression, and Imminent Cancer Death. Mount Vernon, VA: Mt. Vernon Book Systems. 21. ^ Scientist Wants to Test Abraham Lincoln's Bloodstained Pillow for Cancer Discover Magazine April 20, 2009 22. ^ Lincoln's Shroud of Turin, Philadelphila Inquirer, April 13, 2009 ## External links[edit] Classification D * OMIM: 162300 * MeSH: D018814 * DiseasesDB: 22784 * v * t * e Disorders involving multiple endocrine glands * Autoimmune polyendocrine syndrome * APS1 * APS2 * Carcinoid syndrome * Multiple endocrine neoplasia * 1 * 2A * 2B * Progeria * Werner syndrome * Acrogeria * Metageria * Woodhouse–Sakati syndrome * v * t * e Tumours of endocrine glands Pancreas * Pancreatic cancer * Pancreatic neuroendocrine tumor * α: Glucagonoma * β: Insulinoma * δ: Somatostatinoma * G: Gastrinoma * VIPoma Pituitary * Pituitary adenoma: Prolactinoma * ACTH-secreting pituitary adenoma * GH-secreting pituitary adenoma * Craniopharyngioma * Pituicytoma Thyroid * Thyroid cancer (malignant): epithelial-cell carcinoma * Papillary * Follicular/Hurthle cell * Parafollicular cell * Medullary * Anaplastic * Lymphoma * Squamous-cell carcinoma * Benign * Thyroid adenoma * Struma ovarii Adrenal tumor * Cortex * Adrenocortical adenoma * Adrenocortical carcinoma * Medulla * Pheochromocytoma * Neuroblastoma * Paraganglioma Parathyroid * Parathyroid neoplasm * Adenoma * Carcinoma Pineal gland * Pinealoma * Pinealoblastoma * Pineocytoma MEN * 1 * 2A * 2B *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Multiple endocrine neoplasia type 2B

c0025269

wikipedia

https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_2B

{"gard": ["10225"], "mesh": ["D018814"], "umls": ["C0025269"], "orphanet": ["247709", "653"], "wikidata": ["Q624748"]}

A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1E can be caused by mutation in the cardiac sodium channel gene SCN5A (600163). For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200). Clinical Features Greenlee et al. (1986) reported a large family of German and Swiss ancestry with dilated cardiomyopathy, conduction defect, and arrhythmia. The phenotype included sinus node dysfunction in adolescence, supraventricular tachyarrhythmia, and progressive atrial ventricular and intraventricular conduction delay that led to permanent pacing in most cases. The phenotype was also characterized by a progression toward atrial dilation, frequently followed by right ventricular dilation and, in some cases, led to ventricular dilation and dysfunction. Cheng et al. (2010) described 2 families with dilated cardiomyopathy (CMD) and arrhythmias. Pedigree A was a non-Hispanic white family, previously studied by Hershberger et al. (2008) (family C.3), with early-onset CMD occurring at approximately 29 years of age and prominent conduction system disease. The proband and his 2 affected sibs required implantable cardiac defibrillators (ICDs) at ages 32, 31, and 23 years, respectively. The proband's son had asymptomatic premature ventricular complexes (PVCs) detected during screening at 10 years of age and was diagnosed with CMD at age 17. Pedigree B was an African American family with CMD, also previously studied by Hershberger et al. (2008) (family C.7), in which the asymptomatic proband was diagnosed with CMD at 31 years of age after a screening echocardiogram showed left ventricular enlargement and low-normal ejection fraction. At 37 years of age, he developed symptoms of heart failure, with a 15-mm increase in left ventricular end-diastolic size and an ejection fraction that had decreased to 10%. An ICD was placed 1 year later, and he died suddenly at 42 years of age. His mother, who had a history of conduction system disease, was diagnosed with CMD at age 53 and died 5 years later of 'sudden cardiac death and arrhythmia,' according to her death certificate. His 72-year-old maternal aunt had cardiac arrhythmias including atrial fibrillation, first-degree atrioventricular block, and premature atrial contractions (PACs); she had an ejection fraction of 65% with left ventricular enlargement and tachyarrhythmias, but was not diagnosed with CMD. Laurent et al. (2012) studied 21 affected individuals from 3 unrelated 3-generation families with multifocal ectopic Purkinje-related premature contractions and CMD. Age at diagnosis ranged from 24 weeks of gestation to 62 years (mean age, 20 years). Symptoms included palpitations, dyspnea, and syncope. Patients exhibited paroxysmal atrial arrhythmia, atrial flutter, and atrial fibrillation, as well as PVC rates ranging from 3,500 to 86,000 per 24-hour period. Six patients were diagnosed with CMD, and 4 patients required placement of ICDs. Sudden death was reported in 5 individuals. The electrocardiographic phenotype was remarkably consistent, with narrow sinus and junctional QRS complexes competing with various complexes showing an RBBB or LBBB pattern, corresponding to PVCs with superior or inferior axes. There was no QT prolongation or ST segment elevation. Electrophysiologic studies demonstrated that the PVCs originated from the Purkinje tissue. Mann et al. (2012) studied a large kindred with CMD and multiple arrhythmias, including PVCs of variable morphologies. A striking feature of the EKG tracings from affected family members was the relative paucity of normally conducted sinus beats, with the majority of beats being PVCs, including narrow PVCs of probably high septal origin that had varying morphology and axis, as well as wide PVCs of left and right bundle branch type. PACs and accelerated junctional rhythms were also seen. Of the 16 affected individuals, 6 had documented atrial fibrillation, and 3 received pacemakers for symptomatic bradycardia or complete heart block in later life. Electrophysiologic studies done in 4 individuals uniformly showed multiple PVC foci in the left and right ventricles, with no inducible ventricular arrhythmias. Five patients had prophylactic placement of ICDs. Eight individuals had a diagnosis of CMD, including 2 asymptomatic young men who were diagnosed only as a result of family screening; in all other cases, the diagnosis was preceded by a history of palpitations. CMD was present in 7 of 9 affected males but in only 1 of 7 affected females. There was 1 clinically unaffected mutation carrier in this family (see MOLECULAR GENETICS), a 56-year-old man with a normal EKG and echocardiogram. Mann et al. (2012) noted that affected family members who had shown little or no benefit from standard heart failure therapy who, after genetic diagnosis, were switched to drugs with sodium channel-blocking properties, exhibited dramatic reductions in numbers of PVCs, with recovery of normal left ventricular function over approximately 6 months. Mapping Olson and Keating (1996) studied the family reported by Greenlee et al. (1986) with dilated cardiomyopathy associated with sinus node dysfunction, supraventricular tachyarrhythmias, conduction delay, and stroke. Linkage to D3S2303 was identified with a 2-point lod score of 6.09 at a recombination fraction of 0.00. Haplotype analyses mapped this locus to a 30-cM region of 3p25-p22, excluding candidate genes encoding a G protein, GNAI2 (139360), a calcium channel, CACNL1A2 (114206), a sodium channel, SCN5A (600163), and an inositol-triphosphate receptor, ITPR1 (147265). Molecular Genetics In affected members of the family with dilated cardiomyopathy reported by Greenlee et al. (1986), McNair et al. (2004) identified heterozygosity for an asp1275-to-asn mutation (D1275N; 600163.0034) in the SCN5A gene. Groenewegen et al. (2003) had found the same D1275N mutation, coinherited with polymorphisms in the atrial-specific junction channel protein connexin-40 (GJA5; 121013), in a family with atrial standstill (ATRST1; 108770). None of the affected members in this family had dilated cardiomyopathy, leading Groenewegen and Wilde (2005) to question the relationship of the SCN5A mutation to dilated cardiomyopathy in the family reported by McNair et al. (2004). McNair et al. (2005) responded that the younger age of the affected members studied by Groenewegen et al. (2003) as well as additional genetic or environmental factors may account for the difference between the 2 families. Olson et al. (2005) analyzed the SCN5A gene in 156 unrelated patients with dilated cardiomyopathy who were negative for mutations in several known CMD genes and identified 5 different heterozygous mutations in 4 probands from multigenerational families segregating CMD and cardiac arrhythmias and in 1 patient with a de novo mutation (see, e.g., 600163.0027, 600163.0038-600163.0039). All of the mutations altered highly conserved residues in the transmembrane domains of SCN5A, and each was found to segregate with disease in the respective family. Among individuals with an SCN5A mutation, 27% had early features of CMD, 38% had CMD, and 43% had atrial fibrillation. In affected members of 2 unrelated families with CMD and conduction system disease, Hershberger et al. (2008) identified heterozygosity for 2 different missense mutations in the SCN5A gene, R222Q (600163.0046) and I1835T (600163.0047), respectively. In 3 unrelated families with multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy, Laurent et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene, which was fully penetrant and strictly segregated with the cardiac phenotype in each family. The mutation was not found in 600 control chromosomes, and haplotype analysis showed that a founder effect for these 3 families was very unlikely. In vitro studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. Because only 6 of the 19 patients carrying the R222Q mutation had CMD, and the cardiomyopathy recovered at least partially with antiarrhythmia treatment and a reduction in the number of premature ventricular contractions, Laurent et al. (2012) suggested that CMD might be a consequence of the arrhythmia and not directly linked to the mutation. In affected members of a 3-generation Canadian family with CMD and junctional escape ventricular capture bigeminy, Nair et al. (2012) identified the R222Q mutation in the SCN5A gene. All 6 patients had cardiac arrhythmias and 5 had left ventricular dysfunction, which was mild in 1 individual; the proband's brother, who carried the mutation, had only an ectopic atrial rhythm with normal left ventricular systolic function. Catheterization and mapping revealed that there was no consistent evidence of bundle branch reentry or fascicular potentials preceding ectopic beats, and there was no single site suitable for ablation. The results were consistent with the triggered activity originating from variable regions of the septum, most likely the left fascicle or possibly Purkinje muscle junctions and transitional cells. The bigeminy was suppressed by intravenous administration of the sodium channel blocker lidocaine. Patch-clamp studies demonstrated differential leftward voltage-dependent shifts in activation and inactivation of mutant channels, consistent with increasing channel excitability at precisely the voltages corresponding to the resting membrane potential of cardiomyocytes. Nair et al. (2012) stated that their results supported the notion that patients harboring the R222Q mutation develop cardiomyopathy as a result of the arrhythmia. In 16 affected members over 3 generations of a large kindred with CMD and multiple arrhythmias, including PVCs of variable morphologies, Mann et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene. The mutation was also identified in 1 clinically unaffected family member, a 56-year-old man with a normal EKG and echocardiogram, but was not found in 200 control chromosomes. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Palpitations \- Syncope \- Dilated cardiomyopathy (in some patients) \- Left ventricular enlargement \- Reduced systolic function (in some patients) \- Sinus node dysfunction \- Conduction system defects \- Conduction delay \- Right bundle branch block \- Left bundle branch block \- Supraventricular tachyarrhythmias \- Atrial standstill \- Atrial fibrillation \- Atrial flutter \- Atrioventricular block \- Premature atrial contractions \- Premature ventricular contractions (with variable morphologies some arising from Purkinje fibers) \- Junctional escape ventricular capture bigeminy (in some patients) MISCELLANEOUS \- Patients may require implantable cardioverter defibrillators \- May result in sudden death MOLECULAR BASIS \- Caused by mutation in the alpha subunit of the type V voltage-gated sodium channel gene (SCN5A, 600163.0034 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

CARDIOMYOPATHY, DILATED, 1E

c0340427

omim

https://www.omim.org/entry/601154

{"doid": ["0110433"], "mesh": ["C536231"], "omim": ["601154"], "orphanet": ["154"], "synonyms": ["Alternative titles", "CARDIOMYOPATHY, DILATED, WITH CONDUCTION DISORDER AND ARRHYTHMIA", "CARDIOMYOPATHY, DILATED, WITH CONDUCTION DEFECT 2"], "genereviews": ["NBK1309"]}

22q11.2 duplication is a condition caused by an extra copy of a small piece of chromosome 22. The duplication occurs near the middle of the chromosome at a location designated q11.2. The features of this condition vary widely, even among members of the same family. Affected individuals may have developmental delay, intellectual disability, slow growth leading to short stature, and weak muscle tone (hypotonia). Many people with the duplication have no apparent physical or intellectual disabilities. ## Frequency The prevalence of the 22q11.2 duplication in the general population is difficult to determine. Because many individuals with this duplication have no associated symptoms, their duplication may never be detected. Most people tested for the 22q11.2 duplication have come to medical attention as a result of developmental delay or other problems affecting themselves or a family member. In one study, about 1 in 700 people tested for these reasons had the 22q11.2 duplication. Overall, more than 60 individuals with the duplication have been identified. ## Causes People with 22q11.2 duplication have an extra copy of some genetic material at position q11.2 on chromosome 22. In most cases, this extra genetic material consists of a sequence of about 3 million DNA building blocks (base pairs), also written as 3 megabases (Mb). The 3 Mb duplicated region contains 30 to 40 genes. For many of these genes, little is known about their function. A small percentage of affected individuals have a shorter duplication in the same region. Researchers are working to determine which duplicated genes may contribute to the developmental delay and other problems that sometimes affect people with this condition. ### Learn more about the chromosome associated with 22q11.2 duplication * chromosome 22 ## Inheritance Pattern The inheritance of 22q11.2 duplication is considered autosomal dominant because the duplication affects one of the two copies of chromosome 22 in each cell. About 70 percent of affected individuals inherit the duplication from a parent. In other cases, the duplication is not inherited and instead occurs as a random event during the formation of reproductive cells (eggs and sperm) or in early fetal development. These affected people typically have no history of the disorder in their family, although they can pass the duplication to their children. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

22q11.2 duplication

c2675369

medlineplus

https://medlineplus.gov/genetics/condition/22q112-duplication/

{"gard": ["10557"], "mesh": ["C567224"], "omim": ["608363"], "synonyms": []}

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a progressive disorder of the nervous system (neurodegeneration) characterized by problems with movement and vision that begin during childhood or adolescence. Changes in the way a person walks (gait) and frequent falls are usually the first noticeable signs of FAHN. Affected individuals gradually develop extreme muscle stiffness (spasticity) and exaggerated reflexes. They typically have involuntary muscle cramping (dystonia), problems with coordination and balance (ataxia), or both. The movement problems worsen over time, and some people with this condition eventually require wheelchair assistance. People with FAHN often develop vision problems, which occur due to deterioration (atrophy) of the nerves that carry information from the eyes to the brain (the optic nerves) and difficulties with the muscles that control eye movement. Affected individuals may have a loss of sharp vision (reduced visual acuity), decreased field of vision, impaired color perception, eyes that do not look in the same direction (strabismus), rapid involuntary eye movements (nystagmus), or difficulty moving the eyes intentionally (supranuclear gaze palsy). Speech impairment (dysarthria) also occurs in FAHN, and severely affected individuals may lose the ability to speak. People with this disorder may also have difficulty chewing or swallowing (dysphagia). In severe cases, they may develop malnutrition and require a feeding tube. The swallowing difficulties can lead to a bacterial lung infection called aspiration pneumonia, which can be life-threatening. As the disorder progresses, some affected individuals experience seizures and a decline in intellectual function. Magnetic resonance imaging (MRI) of the brain in people with FAHN shows signs of iron accumulation, especially in an area of the brain called the globus pallidus, which is involved in regulating movement. Similar patterns of iron accumulation are seen in certain other neurological disorders such as infantile neuroaxonal dystrophy and pantothenate kinase-associated neurodegeneration. All these conditions belong to a class of disorders called neurodegeneration with brain iron accumulation (NBIA). ## Frequency FAHN is a rare disorder; only a few dozen cases have been reported. ## Causes Mutations in the FA2H gene cause FAHN. The FA2H gene provides instructions for making an enzyme called fatty acid 2-hydroxylase. This enzyme modifies fatty acids, which are building blocks used to make fats (lipids). Specifically, fatty acid 2-hydroxylase adds a single oxygen atom to a hydrogen atom at a particular point on a fatty acid to create a 2-hydroxylated fatty acid. Certain 2-hydroxylated fatty acids are important in forming normal myelin; myelin is the protective covering that insulates nerves and ensures the rapid transmission of nerve impulses. The part of the brain and spinal cord that contains myelin is called white matter. The FA2H gene mutations that cause FAHN reduce or eliminate the function of the fatty acid 2-hydroxylase enzyme. Reduction of this enzyme's function may result in abnormal myelin that is prone to deterioration (demyelination), leading to a loss of white matter (leukodystrophy). Leukodystrophy is likely involved in the development of the movement problems and other neurological abnormalities that occur in FAHN. Iron accumulation in the brain is probably also involved, although it is unclear how FA2H gene mutations lead to the buildup of iron. People with FA2H gene mutations and some of the movement problems seen in FAHN were once classified as having a separate disorder called spastic paraplegia 35. People with mutations in this gene resulting in intellectual decline and optic nerve atrophy were said to have a disorder called FA2H-related leukodystrophy. However, these conditions are now generally considered to be forms of FAHN. ### Learn more about the gene associated with Fatty acid hydroxylase-associated neurodegeneration * FA2H ## Inheritance Pattern This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Fatty acid hydroxylase-associated neurodegeneration

c3496228

medlineplus

https://medlineplus.gov/genetics/condition/fatty-acid-hydroxylase-associated-neurodegeneration/

{"gard": ["10810"], "mesh": ["C567311"], "omim": ["612319"], "synonyms": []}

CT scan of the chest showing bilateral lymphadenopathy in the mediastinum due to sarcoidosis. Bilateral hilar lymphadenopathy is a bilateral enlargement of the lymph nodes of pulmonary hila. It is a radiographic term for the enlargement of mediastinal lymph nodes and is most commonly identified by a chest x-ray. ## Causes[edit] The following are causes of BHL:[1] * Sarcoidosis[2] * Infection * Tuberculosis[2] * Fungal infection[2] * Mycoplasma * Intestinal Lipodystrophy (Whipple's disease)[3][4] * Malignancy * Lymphoma[2] * Carcinoma * Mediastinal tumors * Inorganic dust disease * Silicosis[5][6][7] * Berylliosis[7] * Extrinsic allergic alveolitis * Such as bird fancier's lung * Less common causes also exist:[citation needed] * Eosinophilic granulomatosis with polyangiitis * Human immunodeficiency virus * Extrinsic allergic alveolitis * Adult-onset Still's disease[8] ## References[edit] 1. ^ M. Longmore; I. Wilkinson; T. Turmezei; CK. Cheug (2007). Oxford Handbook of Clinical Medicine 7th Edition. United States, New York: Oxford University Press. p. 179. ISBN 978-0-19-856837-7. 2. ^ a b c d Criado, E; Sánchez, M; Ramírez, J; Arguis, P; De Caralt, TM; Perea, RJ; Xaubet, A (October 2010). "Pulmonary sarcoidosis: typical and atypical manifestations at high-resolution CT with pathologic correlation". Radiographics. 30 (6): 1567–1586. doi:10.1148/rg.306105512. PMID 21071376. 3. ^ Urbanksi, G; Rivereau, P; Artru, L; Fenollar, F; Raoult, D; Puéchal, X (June 2012). "Whipple disease revealed by lung involvement: a case report and literature review". Chest. 141 (6): 1595–1598. doi:10.1378/chest.11-1812. PMID 22670021. 4. ^ Beers, Mark (2006). The Merck Manual. 5. ^ Suwatanapongched, T; Gierada, DS (December 2006). "CT of thoracic lymph nodes. Part II: diseases and pitfalls". The British Journal of Radiology. 79 (948): 999–1000. doi:10.1259/bjr/82484604. PMID 16641412. 6. ^ Leung, CC; Yu, IT; Chen, W (May 2012). "Silicosis". The British Journal of Radiology. 379 (9830): 2008–2018. doi:10.1016/S0140-6736(12)60235-9. PMID 22534002. S2CID 208793253. 7. ^ a b Chong, S; Lee, KS; Chung, MJ; Han, J; Kwon, OJ; Kim, TS (January–February 2006). "Pneumoconiosis: comparison of imaging and pathologic findings". Radiographics. 26 (1): 59–77. doi:10.1148/rg.261055070. PMID 16418244. 8. ^ Owlia, MB; Mehrpoor, G (May 2009). "Adult-onset Still's disease: a review" (PDF). Indian Journal of Medical Sciences. 63 (5): 207–221. doi:10.4103/0019-5359.53169. PMID 19584494. This medical sign article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Bilateral hilar lymphadenopathy

c0456973

wikipedia

https://en.wikipedia.org/wiki/Bilateral_hilar_lymphadenopathy

{"umls": ["C0456973"], "wikidata": ["Q16841927"]}

A rare T-cell non-Hodgkin lymphoma characterized by a proliferation of cytotoxic T-cells, usually gamma delta T-cells, with involvement of the liver and spleen, but without involvement of lymph nodes. The bone marrow is consistently affected. Patients typically present during adolescence or young adulthood with hepatosplenomegaly, pancytopenia, and systemic symptoms. Peripheral blood involvement may develop later in the disease course. There is a clear male preponderance. The disease often occurs in the context of long-term immunosuppression. The course is aggressive with poor therapy response. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hepatosplenic T-cell lymphoma

c1333984

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86882

{"umls": ["C1333984"], "icd-10": ["C86.1"]}

Roth et al. (1978) described a family with many cases of painful callosities over pressure points in the hands and feet. There were several instances of male-to-male transmission and affected persons were present in 5 generations. Dupre et al. (1979) suggested that the disorder is not rare. In France the condition is referred to as 'keratoderma palmo-plantaire disseminee type Brauer' or 'type Buschke-Fischer.' Successful treatment with aromatic tretinoin by mouth was noted. Rachid et al. (1987) described a large Brazilian kindred with plantar callosities that begin with walking and persist life-long. They are present over pressure points of the soles with excessive walking. Bullae, which form at the edge of the callosities, are filled with a foul-smelling fluid. Thirty-one affected persons were observed. Four affected males transmitted the gene to 7 sons and 9 daughters. Normal persons had only normal children. No instance of palmar callosities was mentioned, even in persons engaged in heavy labor. Baden et al. (1984) reported a family. Though Rachid et al. (1987) claimed that the disorder they described was distinct from that reported by Roth et al. (1978), this is by no means clear. Inheritance \- Autosomal dominant Skin \- Painful callosities over pressure points of hands and feet \- Fluid-filled bullae at edges of foot callosities ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

CALLOSITIES, HEREDITARY PAINFUL

c1861964

omim

https://www.omim.org/entry/114140

{"mesh": ["C566180"], "omim": ["114140"], "orphanet": ["79141"], "synonyms": ["Alternative titles", "CALLOSITIES, PAINFUL PLANTAR"]}

Hypertensive disease of pregnancy Other namesMaternal hypertensive disorder Frequency20.7 million (2015)[1] Deaths46,900 (2015)[2] Hypertensive disease of pregnancy, also known as maternal hypertensive disorder, is a group of high blood pressure disorders that include preeclampsia, preeclampsia superimposed on chronic hypertension, gestational hypertension, and chronic hypertension.[3] Maternal hypertensive disorders occurred in about 20.7 million women in 2013.[1] About 10% of pregnancies globally are complicated by hypertensive diseases.[4] In the United States hypertensive disease of pregnancy affect about 8% to 13% of pregnancies.[3] Rates have increased in the developing world.[3] They resulted in 29,000 deaths in 2013 down from 37,000 deaths in 1990.[5] They are one of the three major causes of death in pregnancy (16%) along with post partum bleeding (13%) and puerperal infections (2%).[6] ## Contents * 1 Signs and symptoms * 2 Risks * 3 Diagnosis * 3.1 Classification * 3.2 Preeclampsia * 4 Prevention * 5 Prognosis * 6 Epidemiology * 7 References ## Signs and symptoms[edit] Although many pregnant women with high blood pressure have healthy babies without serious problems, high blood pressure can be dangerous for both the mother and baby. Women with pre-existing, or chronic, high blood pressure are more likely to have certain complications during pregnancy than those with normal blood pressure. However, some women develop high blood pressure while they are pregnant (often called gestational hypertension).[7] Chronic poorly-controlled high blood pressure before and during pregnancy puts a pregnant woman and her baby at risk for problems. It is associated with an increased risk for maternal complications such as preeclampsia, placental abruption (when the placenta separates from the wall of the uterus), and gestational diabetes. These women also face a higher risk for poor birth outcomes such as preterm delivery, having an infant small for his/her gestational age, and infant death.[8] ## Risks[edit] Some women have a greater risk of developing hypertension during pregnancy. These are: * Women with chronic hypertension (high blood pressure before becoming pregnant). * Women who developed high blood pressure or preeclampsia during a previous pregnancy, especially if these conditions occurred early in the pregnancy. * Women who are obese prior to pregnancy. * Pregnant women under the age of 20 or over the age of 40. * Women who are pregnant with more than one baby. * Women with diabetes, kidney disease, rheumatoid arthritis, lupus, or scleroderma.[7] ## Diagnosis[edit] There is no single test to predict or diagnose preeclampsia. Key signs are increased blood pressure and protein in the urine (proteinuria). Other symptoms that seem to occur with preeclampsia include persistent headaches, blurred vision or sensitivity to light, and abdominal pain.[7] All of these sensations can be caused by other disorders; they can also occur in healthy pregnancies. Regular visits are scheduled to track blood pressure and level of protein in urine, to order and analyze blood tests that detect signs of preeclampsia, and to monitor fetal development more closely.[7] ### Classification[edit] A classification of hypertensive disorders of pregnancy uses 4 categories as recommended by the U.S. National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy:[9] 1. Chronic hypertension; 2. Preeclampsia-eclampsia; 3. Preeclampsia superimposed on chronic hypertension; 4. Gestational hypertension (transient hypertension of pregnancy or chronic hypertension identified in the latter half of pregnancy). This terminology is preferred over the older but widely used term pregnancy-induced hypertension (PIH) because it is more precise.[9] The newer terminology reflects simply relation of pregnancy with either the onset or first detection of hypertension and that the question of causation, while pathogenetically interesting, is not the important point for most health care purposes. This classification treats HELLP syndrome as a type of preeclampsia rather than a parallel entity.[9] ### Preeclampsia[edit] Preeclampsia is a condition that typically starts after the 20th week of pregnancy and is related to increased blood pressure and protein in the mother's urine (as a result of kidney problems). Preeclampsia affects the placenta, and it can affect the mother's kidney, liver, and brain. When preeclampsia causes seizures, the condition is known as eclampsia--the second leading cause of maternal death in the U.S. Preeclampsia is also a leading cause of fetal complications, which include low birth weight, premature birth, and stillbirth.[7] There is no proven way to prevent preeclampsia. Most women who develop signs of preeclampsia, however, are closely monitored to lessen or avoid related problems. The only way to "cure" preeclampsia is to deliver or abort the baby.[7] ## Prevention[edit] Blood pressure control can be accomplished before pregnancy. Medications can control blood pressure. Certain medications may not be ideal for blood pressure control during pregnancy such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AII) receptor antagonists.[7] Controlling weight gain during pregnancy can help reduce the risk of hypertension during pregnancy.[10] There is limited evidence to suggest that calcium supplementation may reduce the risk of pre-eclampsia or stillbirth but it is unclear if it has other benefits.[11] ## Prognosis[edit] The effects of high blood pressure during pregnancy vary depending on the disorder and other factors. Preeclampsia does not in general increase a woman's risk for developing chronic hypertension or other heart-related problems. Women with normal blood pressure who develop preeclampsia after the 20th week of their first pregnancy, short-term complications, including increased blood pressure, usually go away within about six weeks after delivery.[7] Some women, however, may be more likely to develop high blood pressure or other heart disease later in life. More research is needed to determine the long-term health effects of hypertensive disorders in pregnancy and to develop better methods for identifying, diagnosing, and treating women at risk for these conditions.[citation needed] Even though high blood pressure and related disorders during pregnancy can be serious, most women with high blood pressure and those who develop preeclampsia have successful pregnancies. Obtaining early and regular prenatal care for pregnant women is important to identity and treat blood pressure disorders.[7] ## Epidemiology[edit] High blood pressure problems occur in six percent to eight percent of all pregnancies in the U.S., about 70 percent of which are first-time pregnancies. In 1998, more than 146,320 cases of preeclampsia alone were diagnosed.[7] Although the proportion of pregnancies with gestational hypertension and eclampsia has remained about the same in the U.S. over the past decade, the rate of preeclampsia has increased by nearly one-third. This increase is due in part to a rise in the numbers of older mothers and of multiple births, where preeclampsia occurs more frequently. For example, in 1998 birth rates among women ages 30 to 44 and the number of births to women ages 45 and older were at the highest levels in three decades, according to the National Center for Health Statistics. Furthermore, between 1980 and 1998, rates of twin births increased about 50 percent overall and 1,000 percent among women ages 45 to 49; rates of triplet and other higher-order multiple births jumped more than 400 percent overall, and 1,000 percent among women in their 40s.[7] ## References[edit] 1. ^ a b GBD 2015 Disease and Injury Incidence and Prevalence, Collaborators. (8 October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC 5055577. PMID 27733282. 2. ^ GBD 2015 Mortality and Causes of Death, Collaborators. (8 October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC 5388903. PMID 27733281. 3. ^ a b c Lo, JO; Mission, JF; Caughey, AB (April 2013). "Hypertensive disease of pregnancy and maternal mortality". Current Opinion in Obstetrics and Gynecology. 25 (2): 124–32. doi:10.1097/gco.0b013e32835e0ef5. PMID 23403779. 4. ^ WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia (PDF). 2011. ISBN 978-92-4-154833-5. 5. ^ GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604. PMID 25530442. 6. ^ "40". Williams obstetrics (24th ed.). McGraw-Hill Professional. 2014. ISBN 9780071798938. 7. ^ a b c d e f g h i j k "High Blood Pressure in Pregnancy - NHLBI, NIH". www.nhlbi.nih.gov. Archived from the original on 2017-07-10. Retrieved 2017-11-08. This article incorporates text from this source, which is in the public domain. 8. ^ "Pregnancy Complications | Pregnancy | Maternal and Infant Health | CDC". www.cdc.gov. Retrieved 2017-11-09. This article incorporates text from this source, which is in the public domain. 9. ^ a b c Mammaro, A; et al. (2009), "Hypertensive disorders of pregnancy", J Prenat Med, 3 (1): 1–5, PMC 3279097, PMID 22439030. 10. ^ "Proper Nutrition During Pregnancy". State of Israel Ministry of Health. Retrieved 8 November 2017. 11. ^ Hofmeyr, GJ; Manyame, S; Medley, N; Williams, MJ (16 September 2019). "Calcium supplementation commencing before or early in pregnancy, for preventing hypertensive disorders of pregnancy". The Cochrane Database of Systematic Reviews. 9: CD011192. doi:10.1002/14651858.CD011192.pub3. PMC 6745517. PMID 31523806. * Magee, Laura (2016). The FIGO textbook of pregnancy hypertension : an evidence-based guide to monitoring, prevention and management. City: Global Library of Women's Medicine. ISBN 978-0-9927545-5-6. [1]==External links== * Hypertensive disease of pregnancy at Curlie * v * t * e Pathology of pregnancy, childbirth and the puerperium Pregnancy Pregnancy with abortive outcome * Abortion * Ectopic pregnancy * Abdominal * Cervical * Interstitial * Ovarian * Heterotopic * Embryo loss * Fetal resorption * Molar pregnancy * Miscarriage * Stillbirth Oedema, proteinuria and hypertensive disorders * Gestational hypertension * Pre-eclampsia * HELLP syndrome * Eclampsia Other, predominantly related to pregnancy Digestive system * Acute fatty liver of pregnancy * Gestational diabetes * Hepatitis E * Hyperemesis gravidarum * Intrahepatic cholestasis of pregnancy Integumentary system / dermatoses of pregnancy * Gestational pemphigoid * Impetigo herpetiformis * Intrahepatic cholestasis of pregnancy * Linea nigra * Prurigo gestationis * Pruritic folliculitis of pregnancy * Pruritic urticarial papules and plaques of pregnancy (PUPPP) * Striae gravidarum Nervous system * Chorea gravidarum Blood * Gestational thrombocytopenia * Pregnancy-induced hypercoagulability Maternal care related to the fetus and amniotic cavity * amniotic fluid * Oligohydramnios * Polyhydramnios * Braxton Hicks contractions * chorion / amnion * Amniotic band syndrome * Chorioamnionitis * Chorionic hematoma * Monoamniotic twins * Premature rupture of membranes * Obstetrical bleeding * Antepartum * placenta * Circumvallate placenta * Monochorionic twins * Placenta accreta * Placenta praevia * Placental abruption * Twin-to-twin transfusion syndrome Labor * Amniotic fluid embolism * Cephalopelvic disproportion * Dystocia * Shoulder dystocia * Fetal distress * Locked twins * Nuchal cord * Obstetrical bleeding * Postpartum * Pain management during childbirth * placenta * Placenta accreta * Preterm birth * Postmature birth * Umbilical cord prolapse * Uterine inversion * Uterine rupture * Vasa praevia Puerperal * Breastfeeding difficulties * Low milk supply * Cracked nipples * Breast engorgement * Childbirth-related posttraumatic stress disorder * Diastasis symphysis pubis * Postpartum bleeding * Peripartum cardiomyopathy * Postpartum depression * Postpartum psychosis * Postpartum thyroiditis * Puerperal fever * Puerperal mastitis Other * Concomitant conditions * Diabetes mellitus * Systemic lupus erythematosus * Thyroid disorders * Maternal death * Sexual activity during pregnancy * Category 1. ^ Tinawi, Mohammad (8 January 2020). "Hypertension in Pregnancy". Archives of Internal Medicine Research. 3 (1): 10–17. doi:10.26502/aimr.0018. Retrieved 11 April 2020. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hypertensive disease of pregnancy

c0341934

wikipedia

https://en.wikipedia.org/wiki/Hypertensive_disease_of_pregnancy

{"mesh": ["D046110"], "icd-9": ["642.00"], "wikidata": ["Q19001368"]}

Carey et al. (1990) reported a possible causal relationship between maternal diabetes and hallucal polydactyly, with a very unusual proximal placement of the extra digit. They suggested that this was a useful diagnostic marker of teratogenic effects in infants with multiple congenital abnormalities. Slee and Goldblatt (1997) reported a child with multiple skeletal abnormalities, including preaxial polydactyly, who was born to a woman with poorly controlled insulin-dependent diabetes. The proximal placement of the duplicated hallux was illustrated. Limbs \- Preaxial hallucal polydactyly \- Proximal placement of extra digit Misc \- Maternal insulin-dependent diabetes mellitus Inheritance \- ? Diabetes teratogenicity ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

PREAXIAL HALLUCAL POLYDACTYLY

c1866339

omim

https://www.omim.org/entry/601759

{"mesh": ["C566632"], "omim": ["601759"], "orphanet": ["1926"], "synonyms": []}

One of the late complications of pelvic inflammatory disease Tubo-ovarian abscesses(TOA) Other namesTDA Drawing showing the sites of Tubo-ovarian abscess SpecialtyUrology Tubo-ovarian abscesses are one of the late complications of pelvic inflammatory disease (PID) and can be life-threatening if the abscess ruptures and results in sepsis. It consists of an encapsulated or confined 'pocket of pus' with defined boundaries that forms during an infection of a fallopian tube and ovary. These abscesses are found most commonly in reproductive age women and typically result from upper genital tract infection.[1][2] It is an inflammatory mass involving the fallopian tube, ovary and, occasionally, other adjacent pelvic organs. A TOA can also develop as a complication of a hysterectomy.[3]:103 Patients typically present with fever, elevated white blood cell count, lower abdominal-pelvic pain, and/or vaginal discharge. Fever and leukocytosis may be absent. TOAs are often polymicrobial with a high percentage of anaerobic bacteria. The cost of treatment in the United States is approximately $2,000 per patient, which equals about $1.5 billion annually.[1] Though rare, TOA can occur without a preceding episode of PID or sexual activity.[4][5] ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Cause * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 Epidemiology * 7 References * 8 External links ## Signs and symptoms[edit] Bacteroides fragilis The signs and symptoms of tubo-ovarian abscess (TOA) are the same as with pelvic inflammatory disease (PID) with the exception that the abscess can be found with magnetic resonance imaging (MRI), sonography and x-ray.[1] It also differs from PID in that it can create symptoms of acute-onset pelvic pain.[6] Typically this disease is found in sexually active women.[4][7] Tubo-ovarian abscess can mimic abdominal tumours.[8] ### Complications[edit] Further information: Perioperative mortality Complications of TOA are related to the possible removal of one or both ovaries and fallopian tubes. Without these reproductive structures, fertility can be affected. Surgical complications can develop and include:[citation needed] * Allergic shock due to anesthetics * A paradoxical reaction to a drug * Infection ## Cause[edit] The development of TOA is thought to begin with the pathogens spreading from the cervix to the endometrium, through the salpinx, into the peritoneal cavity and forming the tubo-ovarian abscess with (in some cases) pelvic peritonitis. TOA can develop from the lymphatic system with infection of the parametrium from an intrauterine device (IUD).[1] Bacteria recovered from TOAs are Escherichia coli, Bacteroides fragilis, other Bacteroides species, Peptostreptococcus, Peptococcus, and aerobic streptococci.[9] Long term IUD use is associated with TOA.[10] Actinomyces is also recovered from TOA.[10] Genus species Gram stain form genome sequenced reference Neisseria gonorrhoeae spp. + cocci [1][11] Chlamydia trachomatis spp. + intracellular [1][11] Mycoplasma genitalium spp. + bacillus [11] Mycoplasma hominis [11] Ureaplasma urealyticum + bacillus [11] Escherichia coli + bacillus X .[4][9][11] Corynebacterium jeikeium + bacillus X [11] Bacteroides fragilis + bacillus X [9][11] Lactobacillus jensenii + bacillus [11] Cutibacterium acnes + bacillus [11] Haemophilus influenzae + bacillus [11] Streptococcus pneumoniae + cocci [11] Streptococcus constellatus + cocci [9][11] Prevotella bivia + bacillus [11] Fusobacterium nucleatum + bacillus [11] Enterococcus faecium + cocci [11] Actinomyces neuii + bacillus X [11] Lactobacillus delbrueckii + bacillus [11] Streptococcus intermedius + cocci [9][11] Eikenella corrodens + bacillus X [11] Abiotrophia + bacillus X [4] Granulicatella + bacillus X [4] ## Diagnosis[edit] Laparoscopy and other imaging tools can visualize the abscess. Physicians are able to make the diagnosis if the abscess ruptures when the woman begins to have lower abdominal pain that then begins to spread. The symptoms then become the same as the symptoms for peritonitis. Sepsis occurs, if left untreated.[3]:103 Ultrasonography is a sensitive enough imaging tool that it can accurately differentiate between pregnancy, hemorrhagic ovarian cysts, endometriosis, ovarian torsion, and tubo-ovarian abscess. Its availability, the relative advancement in the training of its use, its low cost, and because it does not expose the woman (or fetus) to ionizing radiation, ultrasonography an ideal imaging procedure for women of reproductive age.[6] ## Prevention[edit] Risk factors have been identified which indicate what women will be more likely to develop TOA. These are: increased age, IUD insertion, chlamydia infection, and increased levels of certain proteins (CRP and CA-125) and will alert clinicians to follow up on unresolved symptoms of PID.[12] ## Treatment[edit] Treatment for TOA differs from PID in that some clinicians recommend patients with tubo-ovarian abscesses have at least 24 hours of inpatient parenteral treatment with antibiotics, and that they may require surgery.[1][13] If surgery becomes necessary, pre-operative administration of broad-spectrum antibiotics is started and removal of the abscess, the affected ovary and fallopian tube is done. After discharge from the hospital, oral antibiotics are continued for the length of time prescribed by the physician.[3]:103 Treatment is different if the TOA is discovered before it ruptures and can be treated with IV antibiotics. During this treatment, IV antibiotics are usually replaced with oral antibiotics on an outpatient basis. Patients are usually seen three days after hospital discharge and then again one to two weeks later to confirm that the infection has cleared.[3]:103 Ampicillin/sulbactam plus doxycycline is effective against C. trachomatis, N. gonorrhoeae, and anaerobes in women with tubo-ovarian abscess. Parenteral Regimens described by the Centers for Disease Control and prevention are Ampicillin/Sulbactam 3 g IV every 6 hours and Doxycycline 200 mg orally or IV every 24 hours, though other regiments that are used for pelvic inflammatory disease have been effective.[14] ## Epidemiology[edit] The epidemiology of TOA is closely related to that of pelvic inflammatory disease which is estimated to one million people yearly.[15] ## References[edit] 1. ^ a b c d e f g Pelvic inflammatory disease. American Family Physician, Vol. 85, No. 8. (15 April 2012), pp. 791-796 by Margaret Gradison 2. ^ "CDC - Pelvic Inflammatory Disease - 2010 STD Treatment Guidelines". Retrieved 2015-05-16. 3. ^ a b c d Hoffman, Barbara (2012). Williams gynecology. New York: McGraw-Hill Medical. ISBN 9780071716727. 4. ^ a b c d e Goodwin, K.; Fleming, N.; Dumont, T. (2013). "Tubo-ovarian Abscess in Virginal Adolescent Females: A Case Report and Review of the Literature". Journal of Pediatric and Adolescent Gynecology. 26 (4): e99–e102. doi:10.1016/j.jpag.2013.02.004. ISSN 1083-3188. PMID 23566794. 5. ^ Ho, Jeh Wen; Angstetra, D.; Loong, R.; Fleming, T. (2014). "Tuboovarian Abscess as Primary Presentation for Imperforate Hymen". Case Reports in Obstetrics and Gynecology. 2014: 1–3. doi:10.1155/2014/142039. ISSN 2090-6684. PMC 4009186. PMID 24822139. 6. ^ a b Dupuis, Carolyn S.; Kim, Young H. (2015). "Ultrasonography of adnexal causes of acute pelvic pain in pre-menopausal non-pregnant women". Ultrasonography. 34 (4): 258–267. doi:10.14366/usg.15013. ISSN 2288-5919. PMC 4603210. PMID 26062637. 7. ^ Cho, Hyun-Woong; Koo, Yu-Jin; Min, Kyung-Jin; Hong, Jin-Hwa; Lee, Jae-Kwan (2015). "Pelvic Inflammatory Disease in Virgin Women with Tubo-ovarian Abscess: A Single-center Experience and Literature Review". Journal of Pediatric and Adolescent Gynecology. 30 (2): 203–208. doi:10.1016/j.jpag.2015.08.001. ISSN 1083-3188. PMID 26260586. 8. ^ Lim, Andy; Pourya, Pouryahya; Lim, Alvin (2020). "Tubo-ovarian Abscess Masquerading as Dual Tumours". OSP Journal of Case Reports. 2 (2). doi:10.26180/5ed852773f47e. Retrieved 4 June 2020. 9. ^ a b c d e Landers, D. V.; Sweet, R. L. (1983). "Tubo-ovarian Abscess: Contemporary Approach to Management". Clinical Infectious Diseases. 5 (5): 876–884. doi:10.1093/clinids/5.5.876. ISSN 1058-4838. PMID 6635426. 10. ^ a b Lentz, Gretchen (2013). Comprehensive gynecology. Philadelphia: Mosby Elsevier. p. 558. ISBN 9780323069861. 11. ^ a b c d e f g h i j k l m n o p q r s t Dessein, Rodrigue; Giraudet, Géraldine; Marceau, Laure; Kipnis, Eric; Galichet, Sébastien; Lucot, Jean-Philippe; Faure, Karine; Munson, E. (2015). "Identification of Sexually Transmitted Bacteria in Tubo-Ovarian Abscesses through Nucleic Acid Amplification: TABLE 1". Journal of Clinical Microbiology. 53 (1): 357–359. doi:10.1128/JCM.02575-14. ISSN 0095-1137. PMC 4290956. PMID 25355760. 12. ^ Lee, Suk Woo; Rhim, Chae Chun; Kim, Jang Heub; Lee, Sung Jong; Yoo, Sie Hyeon; Kim, Shin Young; Hwang, Young Bin; Shin, So Young; Yoon, Joo Hee (2015). "Predictive Markers of Tubo-Ovarian Abscess in Pelvic Inflammatory Disease". Gynecologic and Obstetric Investigation. 81 (2): 97–104. doi:10.1159/000381772. ISSN 0378-7346. PMID 25926103. S2CID 27186672. 13. ^ Lentz, Gretchen (2013). Comprehensive gynecology. Philadelphia: Mosby Elsevier. p. 584. ISBN 9780323069861. 14. ^ https://www.cdc.gov/std/treatment/2010/pid.htm 15. ^ "PID Epidemiology". Center for Disease Control. Retrieved 2015-05-21. ## External links[edit] Classification D * ICD-10: N70 -N77 * ICD-9-CM: 614.2-616 * MeSH: D000292 * DiseasesDB: 9748 External resources * MedlinePlus: 000888 * eMedicine: emerg/410 * v * t * e Female diseases of the pelvis and genitals Internal Adnexa Ovary * Endometriosis of ovary * Female infertility * Anovulation * Poor ovarian reserve * Mittelschmerz * Oophoritis * Ovarian apoplexy * Ovarian cyst * Corpus luteum cyst * Follicular cyst of ovary * Theca lutein cyst * Ovarian hyperstimulation syndrome * Ovarian torsion Fallopian tube * Female infertility * Fallopian tube obstruction * Hematosalpinx * Hydrosalpinx * Salpingitis Uterus Endometrium * Asherman's syndrome * Dysfunctional uterine bleeding * Endometrial hyperplasia * Endometrial polyp * Endometriosis * Endometritis Menstruation * Flow * Amenorrhoea * Hypomenorrhea * Oligomenorrhea * Pain * Dysmenorrhea * PMS * Timing * Menometrorrhagia * Menorrhagia * Metrorrhagia * Female infertility * Recurrent miscarriage Myometrium * Adenomyosis Parametrium * Parametritis Cervix * Cervical dysplasia * Cervical incompetence * Cervical polyp * Cervicitis * Female infertility * Cervical stenosis * Nabothian cyst General * Hematometra / Pyometra * Retroverted uterus Vagina * Hematocolpos / Hydrocolpos * Leukorrhea / Vaginal discharge * Vaginitis * Atrophic vaginitis * Bacterial vaginosis * Candidal vulvovaginitis * Hydrocolpos Sexual dysfunction * Dyspareunia * Hypoactive sexual desire disorder * Sexual arousal disorder * Vaginismus * Urogenital fistulas * Ureterovaginal * Vesicovaginal * Obstetric fistula * Rectovaginal fistula * Prolapse * Cystocele * Enterocele * Rectocele * Sigmoidocele * Urethrocele * Vaginal bleeding * Postcoital bleeding Other / general * Pelvic congestion syndrome * Pelvic inflammatory disease External Vulva * Bartholin's cyst * Kraurosis vulvae * Vestibular papillomatosis * Vulvitis * Vulvodynia Clitoral hood or clitoris * Persistent genital arousal disorder * v * t * e Sexually transmitted infections (STI) Bacterial * Chancroid (Haemophilus ducreyi) * Chlamydia, lymphogranuloma venereum (Chlamydia trachomatis) * Donovanosis (Klebsiella granulomatis) * Gonorrhea (Neisseria gonorrhoeae) * Mycoplasma hominis infection (Mycoplasma hominis) * Syphilis (Treponema pallidum) * Ureaplasma infection (Ureaplasma urealyticum) Protozoal * Trichomoniasis (Trichomonas vaginalis) Parasitic * Crab louse * Scabies Viral * AIDS (HIV-1/HIV-2) * Cancer * cervical * vulvar * penile * anal * Human papillomavirus (HPV) * Genital warts (condyloma) * Hepatitis B (Hepatitis B virus) * Herpes simplex * HSV-1 & HSV-2 * Molluscum contagiosum (MCV) General inflammation female Cervicitis Pelvic inflammatory disease (PID) male Epididymitis Prostatitis either Proctitis Urethritis/Non-gonococcal urethritis (NGU) *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Tubo-ovarian abscess

c0041343

wikipedia

https://en.wikipedia.org/wiki/Tubo-ovarian_abscess

{"umls": ["C0041343"], "icd-9": ["614.2"], "icd-10": ["N70"], "wikidata": ["Q19972185"]}

Papillary thyroid carcinoma is a form of cancer that occurs due to abnormal and uncontrolled cell growth of certain cells (follicular cells) of the thyroid. Many people with papillary thyroid carcinoma have no signs or symptoms of the condition. When present, symptoms may include a small lump at the base of the neck, hoarseness, difficulty swallowing, trouble breathing, and pain in the neck or throat. Although people of all ages may be diagnosed with the condition, women between ages 30 and 50 are most commonly affected. The cause of papillary thyroid carcinoma is currently unknown. Risks for developing thyroid cancer include a history of high-dose external radiation treatments to the neck and radiation exposure during nuclear plant disasters. The best treatment options depend on many factors, but may include surgery, radiation therapy (including radioactive iodine therapy), chemotherapy and thyroid hormone therapy. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Papillary thyroid carcinoma

c0238463

gard

https://rarediseases.info.nih.gov/diseases/12027/papillary-thyroid-carcinoma

{"mesh": ["D000077273"], "omim": ["188550"], "umls": ["C0238463 "], "orphanet": ["146"], "synonyms": ["Familial nonmedullary thyroid cancer, papillary", "Nonmedullary thyroid carcinoma, papillary"]}

Copper toxicity Other namesCopperiedus A Kayser-Fleischer ring, copper deposits found in the cornea, is an indication the body is not metabolizing copper properly. SpecialtyToxicology Copper toxicity is a type of metal poisoning caused by an excess of copper in the body. Copperiedus can occur from eating acidic foods cooked in uncoated copper cookware, an IUD, or from exposure to excess copper in drinking water and other environmental sources . ## Contents * 1 Signs and symptoms * 1.1 Toxicity * 1.2 EPA cancer data * 2 Cause * 2.1 Cookware * 2.2 Non-sparking tools * 2.3 Drinking water * 2.4 Birth control * 3 Pathophysiology * 3.1 Indian childhood cirrhosis * 3.2 Wilson's disease * 3.3 Alzheimer's disease * 4 Diagnosis * 4.1 ICD-9-CM * 4.2 ICD-10-CM * 4.3 SNOMED * 5 Treatment * 6 Aquatic life * 7 Bacteria * 8 References * 9 External links ## Signs and symptoms[edit] Acute symptoms of copper poisoning by ingestion include vomiting, hematemesis (vomiting of blood), hypotension (low blood pressure), melena (black "tarry" feces), coma, jaundice (yellowish pigmentation of the skin), and gastrointestinal distress.[1] Individuals with glucose-6-phosphate deficiency may be at increased risk of hematologic effects of copper.[1] Hemolytic anemia resulting from the treatment of burns with copper compounds is infrequent.[1] Chronic (long-term) copper exposure can damage the liver and kidneys.[2] Mammals have efficient mechanisms to regulate copper stores such that they are generally protected from excess dietary copper levels.[2][3] Those same protection mechanisms can cause milder symptoms, which are often misdiagnosed as psychiatric disorders. There is a lot of research on the function of the Cu/Zn ratio in neurological, endocrinological, and psychological conditions.[4][5][6] Many of the substances that protect us from excess copper perform important functions in our neurological and endocrine systems, leading to diagnostic difficulties. When they are used to bind copper in the plasma, to prevent it from being absorbed in the tissues, their own function may go unfulfilled. Such symptoms often include mood swings, irritability, depression, fatigue, excitation, difficulty focusing, and feeling out of control. To further complicate diagnosis, some symptoms of excess copper are similar to those of a copper deficit. The U.S. Environmental Protection Agency's Maximum Contaminant Level (MCL) in drinking water is 1.3 milligrams per liter.[1][7] The MCL for copper is based on the expectation that a lifetime of consuming copper in water at this level is without adverse effect (gastrointestinal). The US EPA lists copper as a micronutrient and a toxin.[8] Toxicity in mammals includes a wide range of animals and effects such as liver cirrhosis, necrosis in kidneys and the brain, gastrointestinal distress, lesions, low blood pressure, and fetal mortality.[9][10][11] The Occupational Safety and Health Administration (OSHA) has set a limit of 0.1 mg/m3 for copper fumes (vapor generated from heating copper) and 1 mg/m3 for copper dusts (fine metallic copper particles) and mists (aerosol of soluble copper) in workroom air during an eight-hour work shift, 40-hour work week.[12] Toxicity to other species of plants and animals is noted to varying levels.[8] ### Toxicity[edit] Copper in the blood and blood stream exists in two forms: bound to ceruloplasmin (85–95%), and the rest "free", loosely bound to albumin and small molecules. Nutritionally, there is a distinct difference between organic and inorganic copper, according to whether the copper ion is bound to an organic ligand.[13][14] ### EPA cancer data[edit] The EPA lists no evidence for human cancer incidence connected with copper, and lists animal evidence linking copper to cancer as "inadequate". Two studies in mice have shown no increased incidence of cancer. One of these used regular injections of copper compounds, including cupric oxide. One study of two strains of mice fed copper compounds found a varying increased incidence of reticulum cell sarcoma in males of one strain, but not the other (there was a slightly increased incidence in females of both strains). These results have not been repeated.[15] ## Cause[edit] ### Cookware[edit] Cookware in which copper is the main structural element (as opposed to copper clad, copper sandwiched or copper colored) is sometimes manufactured without a lining when intended to be used for any of a number of specific culinary tasks, such as preparing preserves or meringues. Otherwise, copper cookware is lined with a non-reactive metal to prevent contact between acidic foods and the structural copper element of the cookware. Excepting for acute or chronic conditions, exposure to copper in cooking is generally considered harmless.[16] According to Paracelsus, dosage makes the poison; as this pertains to copper "a defense mechanism has apparently evolved as a consequence of which toxicity in man is very unusual."[17] Acute exposure and attendant copper toxicity is possible when cooking or storing highly acidic foods in unlined copper vessels for extended periods, or by exposing foodstuffs to reactive copper salts (copper corrosion, or verdigris). Continuous, small ("chronic") exposures of acidic foods to copper may also result in toxicity in cases where either surface area interaction potentials are significant, pH is exceptionally low and concentrated (in the case of cooking with, for example, vinegar or wine), or both, and insufficient time elapses between exposures for normal homeostatic elimination of excess copper. Exceptions to the above may be observed in the case of jam, jelly and preserve -making, wherein unlined copper vessels are used to cook (not to store) acidic preparations, in this case of fruit. Methods of jamming and preserving specify sugar as chemically necessary to the preserving (antibacterial) action, which has the additional effect of mediating (buffering) the interaction of fruit acid with copper,[18] permitting the use of the metal for its efficient thermal transfer properties.[19] ### Non-sparking tools[edit] OSHA has set safety standards for grinding and sharpening copper and copper alloy tools, which are often used in nonsparking applications. These standards are recorded in the Code of Federal Regulations 29 CFR 1910.134 and 1910.1000.[20] Note: The most important nonsparking copper alloy is beryllium copper, and can lead to beryllium poisoning. ### Drinking water[edit] With an LD50 of 30 mg/kg in rats, "gram quantities" of copper sulfate are potentially lethal in humans.[21] The suggested safe level of copper in drinking water for humans varies depending on the source, but tends to be pegged at 1.3 mg/l.[22] ### Birth control[edit] There are conditions in which an individual's copper metabolism is compromised to such an extent that birth control may cause an issue with copper accumulation. They include toxicity or just increased copper from other sources, as well as the increased copper level of the individual's mother via the placenta before birth.[23] ## Pathophysiology[edit] A significant portion of the toxicity of copper comes from its ability to accept and donate single electrons as it changes oxidation state. This catalyzes the production of very reactive radical ions, such as hydroxyl radical in a manner similar to Fenton chemistry.[24] This catalytic activity of copper is used by the enzymes with which it is associated, thus is only toxic when unsequestered and unmediated. This increase in unmediated reactive radicals is generally termed oxidative stress, and is an active area of research in a variety of diseases where copper may play an important but more subtle role than in acute toxicity. Some of the effects of aging may be associated with excess copper.[25] ### Indian childhood cirrhosis[edit] One manifestation of copper toxicity, cirrhosis of the liver in children (Indian childhood cirrhosis), has been linked to boiling milk in copper cookware. The Merck Manual states that recent studies suggest that a genetic defect is associated with this particular cirrhosis.[26] ### Wilson's disease[edit] An inherited condition called Wilson's disease causes the body to retain copper, since it is not excreted by the liver into the bile. This disease, if untreated, can lead to brain and liver damage, and bis-choline tetrathiomolybdate is under investigation as a therapy against Wilson's disease. ### Alzheimer's disease[edit] Elevated free copper levels exist in Alzheimer's disease,[27] which has been hypothesized to be linked to inorganic copper consumption.[28] Copper and zinc are known to bind to amyloid beta proteins in Alzheimer's disease.[29] This bound form is thought to mediate the production of reactive oxygen species in the brain.[30] ## Diagnosis[edit] ### ICD-9-CM[edit] ICD-9-CM code 985.8 Toxic effect of other specified metals includes acute & chronic copper poisoning (or other toxic effect) whether intentional, accidental, industrial etc. * In addition, it includes poisoning and toxic effects of other metals including tin, selenium, nickel, iron, heavy metals, thallium, silver, lithium, cobalt, aluminum and bismuth. Some poisonings, e.g. zinc phosphide, would/could also be included as well as under 989.4 Poisoning due to other pesticides, etc. * Excluded are toxic effects of mercury, arsenic, manganese, beryllium, antimony, cadmium, and chromium. ### ICD-10-CM[edit] Code Term T56.4X1D Toxic effect of copper and its compounds, accidental (unintentional), subsequent encounter T56.4X1S Toxic effect of copper and its compounds, accidental (unintentional), sequela T56.4X2D Toxic effect of copper and its compounds, intentional self-harm, subsequent encounter T56.4X2S Toxic effect of copper and its compounds, intentional self-harm, sequela T56.4X3D Toxic effect of copper and its compounds, assault, subsequent encounter T56.4X3S Toxic effect of copper and its compounds, assault, sequela T56.4X4D Toxic effect of copper and its compounds, undetermined, subsequent encounter T56.4X4S Toxic effect of copper and its compounds, undetermined, sequela ### SNOMED[edit] Concept ID Term 46655005 Copper 43098002 Copper fever 49443005 Phytogenous chronic copper poisoning 50288007 Chronic copper poisoning 73475009 Hepatogenous chronic copper poisoning 875001 Chalcosis of eye 90632001 Acute copper poisoning ## Treatment[edit] In cases of suspected copper poisoning, penicillamine is the drug of choice, and dimercaprol, a heavy metal chelating agent, is often administered. Vinegar is not recommended to be given, as it assists in solubilizing insoluble copper salts. The inflammatory symptoms are to be treated on general principles, as are the nervous ones.[citation needed] There is some evidence that alpha-lipoic acid (ALA) may work as a milder chelator of tissue-bound copper.[31] Alpha lipoic acid is also being researched for chelating other heavy metals, such as mercury.[32] ## Aquatic life[edit] Too much copper in water may damage marine and freshwater organisms such as fish and molluscs.[33] Fish species vary in their sensitivity to copper, with the LD50 for 96-h exposure to copper sulphate reported to be in the order of 58 mg per litre for Tilapia (Oreochromis niloticus) and 70 mg per litre for catfish (Clarias gariepinus) [34] The chronic effect of sublethal concentrations of copper on fish and other creatures is damage to gills, liver, kidneys and the nervous system. It also interferes with the sense of smell in fish, thus preventing them from choosing good mates or finding their way to mating areas.[35] Copper-based paint is a common marine antifouling agent.[36] In the United States, copper-based paint replaced tributyltin, which was banned due to its toxicity, as a way for boats to control organic growth on their hulls. In 2011, Washington state became the first U.S. state to ban the use of copper-based paint for boating, although it only applied to recreational boats.[37] California has also pursued initiatives to reduce the effect of copper leaching, with the U.S. EPA pursuing research.[38] Copper is an essential elemental for metabolic processes in marine algae. It is required for electron transport in photosynthesis and by various enzyme systems. Too much copper can also affect phytoplankton or marine algae in both marine and freshwater ecosystems. It has been show to inhibit photosynthesis, disrupt electron transport in photosystem 2, reduce pigment concentrations, restrict growth, reduce reproduction, etc. [39] The toxicity of Copper is widely recognized and is used to help prevent algal blooms. The effect of Copper is solely dependent on the free Copper the water is receiving. It's determined by the relative solubility and the concentration of the Copper binding ligands. Based on that, they can look at both natural and anthropogenic situations. They have done studies to show that Copper concentrations are toxic when marine phytoplankton are confined to areas that are heavily impacted by anthropogenic emissions. [40] Some of the studies have used a marine amphipod to show how Copper affects it. This particular study said that the juveniles were 4.5 more times sensitive to the toxins than the adults.[41] Another study used 7 different algal species. They found that one species was more sensitive than the others, which was Synechococcus, and that another species was more sensitive in seawater, which wasThalassiosira weissflogii. [42] One study used cyanobacteria, diatoms, coccolithophores, and dinoflagellates. This study showed that cyanobacteria was the most sensitive, diatoms were the least sensitive, and the coccolithophores and dinoflagellates were intermediate. They used copper ion in a buffer system and controlled it at different levels. They found that cyanobacteria reproduction rates were reduced while other algae had maximum reproduction rates. They found that Copper may influence seasonal successions of species. [43] ## Bacteria[edit] Copper and copper alloys such as brass have been found to be toxic to bacteria via the oligodynamic effect. The exact mechanism of action is unknown, but common to other heavy metals. Viruses are less susceptible to this effect than bacteria. Associated applications include the use of brass doorknobs in hospitals, which have been found to self-disinfect after eight hours, and mineral sanitizers, in which copper can act as an algicide. Overuse of copper sulfate as an algicide has been speculated to have caused a copper poisoning epidemic on Great Palm Island in 1979.[44] ## References[edit] 1. ^ a b c d Casarett, L.; Casarett, L.J.; Amdur, M.O.; Doull, J. (1996). Casarett & Doull's Toxicology, The Basic Science of Poisons (5th ed.). McGraw-Hill. p. 715. ISBN 0071054766. 2. ^ a b "Copper: Health Information Summary" (PDF). Environmental Fact Sheet. New Hampshire Department of Environmental Services. 2005. ARD-EHP-9. 3. ^ Lutsenko, Svetlana; Barnes, Natalie L.; Bartee, Mee Y.; Dmitriev, Oleg Y. (2007). "Function and Regulation of Human Copper-Transporting ATPases". Physiological Reviews. 87 (3): 1011–46. doi:10.1152/physrev.00004.2006. PMID 17615395. 4. ^ Desai, Vishal; Kaler, Stephen G. (2008). "Role of copper in human neurological disorders". The American Journal of Clinical Nutrition. 88 (3): 855S–8S. doi:10.1093/ajcn/88.3.855S. PMID 18779308. Retrieved 20 December 2015. 5. ^ Kaplan, Bonnie J.; Crawford, Susan G.; Gardner, Beryl; Farrelly, Geraldine (2002). "Treatment of Mood Lability and Explosive Rage with Minerals and Vitamins: Two Case Studies in Children". Journal of Child and Adolescent Psychopharmacology. 12 (3): 205–219. doi:10.1089/104454602760386897. PMID 12427294. 6. ^ Faber, Scott; Zinn, Gregory M.; Kern Ii, John C.; Skip Kingston, H. M. (2009). "The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders". Biomarkers. 14 (3): 171–180. doi:10.1080/13547500902783747. PMID 19280374. S2CID 205770002. 7. ^ Federal Register / Vol. 65, No. 8 / Wednesday, January 12, 2000 / Rules and Regulations. pp. 1976. 8. ^ a b US EPA Region 5 (2011-12-28). "Ecological Toxicity Information". US EPA. Retrieved 17 June 2015. 9. ^ "Toxicological Profile for Copper". Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services. Retrieved 17 June 2015. 10. ^ Kabata-Pendias, Alina (2010). Trace Elements in Soils and Plants, Fourth Edition (4th ed.). Taylor & Francis. ISBN 9781420093681. Archived from the original on 16 July 2015. Retrieved 17 June 2015. 11. ^ Ware, George W. (1983). Pesticides: Theory and application. New York: W.H. Freeman. OCLC 669712126. 12. ^ Occupational Safety and Health Administration, U.S. Department of Labor, Copper, Available Online at: https://www.osha.gov/SLTC/metalsheavy/copper.html 13. ^ Batley, G.E.; Florence, T.M. (1976). "Determination of the chemical forms of dissolved cadmium, lead and copper in seawater". Marine Chemistry. 4 (4): 347–363. doi:10.1016/0304-4203(76)90020-7. 14. ^ Van Den Berg, C.M. (1984). "Organic and inorganic speciation of copper in the Irish Sea". Marine Chemistry. 14 (3): 201–212. doi:10.1016/0304-4203(84)90042-2. 15. ^ EPA results for copper and cancer. Accessed March 11, 2011 16. ^ "The Dispatch - Google News Archive Search". 17. ^ Sternlieb, Irmin (June 1967). "Gastrointestinal Copper Absorption in Man". Gastroenterology. 52 (6): 1038–1041. doi:10.1016/S0016-5085(67)80160-4. PMID 6026483. 18. ^ "Jam Making 101: The Tools and Techniques for Success". 19. ^ Escoffier, Auguste; Gilbert, Pliléas (1961). Larousse Gastronomique. New York: Crown. p. 546. 20. ^ "Occupational Safety and Health Standards". Retrieved 2012-09-18. 21. ^ "Pesticide Information Profile for Copper Sulfate". Cornell University. Retrieved 2008-07-10. 22. ^ "The Water Supply (Water Quality) Regulations 2000". 23. ^ McArdle HJ, Andersen HS, Jones H, Gambling L (2008). "Copper and iron transport across the placenta: regulation and interactions". Journal of Neuroendocrinology. 20 (4): 427–31. doi:10.1111/j.1365-2826.2008.01658.x. PMID 18266949. S2CID 12395297. 24. ^ Held KD; et al. (May 1996). "Role of Fenton chemistry in thiol-induced toxicity and apoptosis". Radiat. Res. 145 (5): 542–53. Bibcode:1996RadR..145..542H. doi:10.2307/3579272. JSTOR 3579272. PMID 8619019. 25. ^ Brewer GJ (February 2007). "Iron and copper toxicity in diseases of aging, particularly atherosclerosis and Alzheimer's disease". Exp. Biol. Med. (Maywood). 232 (2): 323–35. PMID 17259340. 26. ^ "Copper". Merck Manuals — Online Medical Library. Merck. November 2005. Retrieved 2008-07-19. 27. ^ Brewer GJ (Apr 2010). "Copper toxicity in the general population". Clin Neurophysiol. 121 (4): 459–60. doi:10.1016/j.clinph.2009.12.015. PMID 20071223. S2CID 43106197. 28. ^ Brewer GJ (June 2009). "The risk of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer's disease". J. Am. Coll. Nutr. 28 (3): 238–42. doi:10.1080/07315724.2009.10719777. PMID 20150596. S2CID 21630019. 29. ^ Faller P (2009-12-14). "Copper and zinc binding to amyloid-beta: coordination, dynamics, aggregation, reactivity and metal-ion transfer". ChemBioChem. 10 (18): 2837–45. doi:10.1002/cbic.200900321. PMID 19877000. S2CID 35130040. 30. ^ Hureau C, Faller P (October 2009). "Abeta-mediated ROS production by Cu ions: structural insights, mechanisms and relevance to Alzheimer's disease". Biochimie. 91 (10): 1212–7. doi:10.1016/j.biochi.2009.03.013. PMID 19332103. 31. ^ Marangon, Karine; Devaraj, Sridevi; Tirosh, Oren; Packer, Lester; Jialal, Ishwarlal (November 1999). "Comparison of the effect of α-lipoic acid and α-tocopherol supplementation on measures of oxidative stress". Free Radical Biology and Medicine. 27 (9–10): 1114–1121. doi:10.1016/S0891-5849(99)00155-0. PMID 10569644. 32. ^ "Mercury toxicity and antioxidants: part I: role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity. (Mercury Toxicity)". Thorne Research Inc. 2002. Archived from the original on 22 December 2015. Retrieved 20 December 2015. 33. ^ Van Genderen EJ, Ryan AC, Tomasso JR, Klaine SJ (February 2005). "Evaluation of acute copper toxicity to larval fathead minnows (Pimephales promelas) in soft surface waters". Environ. Toxicol. Chem. 24 (2): 408–14. doi:10.1897/03-494.1. PMID 15720002. 34. ^ Ezeonyejiaku, CD, Obiakor, MO and Ezenwelu, CO (2011). "Toxicity of copper sulphate and behavioural locomotor response of tilapia (Oreochromis niloticus) and catfish (Clarias gariepinus) species". Online J. Anim. Feed Res. 1 (4): 130–134.CS1 maint: multiple names: authors list (link) 35. ^ C. A. Flemming; J. T. Trevors (1989). "Copper toxicity and chemistry in the environment: a review". Water, Air, & Soil Pollution. 44 (1–2): 143–158. Bibcode:1989WASP...44..143F. doi:10.1007/BF00228784. S2CID 98175996. 36. ^ Earley, Patrick J.; Swope, Brandon L.; Barbeau, Katherine; Bundy, Randelle; McDonald, Janessa A.; Rivera-Duarte, Ignacio (2014-01-01). "Life cycle contributions of copper from vessel painting and maintenance activities". Biofouling. 30 (1): 51–68. doi:10.1080/08927014.2013.841891. ISSN 0892-7014. PMC 3919178. PMID 24199998. 37. ^ "Is Copper Bottom Paint Sinking? - BoatUS Magazine". Retrieved 2016-09-22. 38. ^ "Marine Coatings: Making Sense of U.S., State, and Local Mandates of Copper-Based Antifouling Regulations". American Coatings Association. Retrieved 2016-09-22. 39. ^ https://www.researchgate.net/profile/Murray_Brown/publication/228052466_The_toxicity_of_copper_II_species_to_marine_with_particular_reference_to_macroalgae/links/5954f3990f7e9b2da1b3bce0/The-toxicity-of-copper-II-species-to-marine-with-particular-reference-to-macroalgae.pdf 40. ^ Lopez, Johann S.; Lee, Lillian; Mackey, Katherine R. M. (2019-01-24). "The Toxicity of Copper to Crocosphaera watsonii and Other Marine Phytoplankton: A Systematic Review". Frontiers in Marine Science. 5: 511. doi:10.3389/fmars.2018.00511. ISSN 2296-7745. 41. ^ Ahsanullah, M.; Florence, T. M. (1984-12-01). "Toxicity of copper to the marine amphipod Allorchestes compressa in the presence of water-and lipid-soluble ligands". Marine Biology. 84 (1): 41–45. doi:10.1007/BF00394525. ISSN 1432-1793. 42. ^ Quigg, Antonietta; Reinfelder, John R.; Fisher, Nicholas S. (2006). "Copper uptake kinetics in diverse marine phytoplankton". Limnology and Oceanography. 51 (2): 893–899. doi:10.4319/lo.2006.51.2.0893. ISSN 1939-5590. 43. ^ Brand, Larry E.; Sunda, William G.; Guillard, Robert R. L. (1986-05-01). "Reduction of marine phytoplankton reproduction rates by copper and cadmium". Journal of Experimental Marine Biology and Ecology. 96 (3): 225–250. doi:10.1016/0022-0981(86)90205-4. ISSN 0022-0981. 44. ^ Prociv P (September 2004). "Algal toxins or copper poisoning—revisiting the Palm Island "epidemic"". Med. J. Aust. 181 (6): 344. doi:10.5694/j.1326-5377.2004.tb06316.x. PMID 15377259. S2CID 22054004. ## External links[edit] Classification D * ICD-10: T56.4 * ICD-9-CM: 985.8 External resources * MedlinePlus: 002496 * v * t * e * Poisoning * Toxicity * Overdose History of poison Inorganic Metals Toxic metals * Beryllium * Cadmium * Lead * Mercury * Nickel * Silver * Thallium * Tin Dietary minerals * Chromium * Cobalt * Copper * Iron * Manganese * Zinc Metalloids * Arsenic Nonmetals * Sulfuric acid * Selenium * Chlorine * Fluoride Organic Phosphorus * Pesticides * Aluminium phosphide * Organophosphates Nitrogen * Cyanide * Nicotine * Nitrogen dioxide poisoning CHO * alcohol * Ethanol * Ethylene glycol * Methanol * Carbon monoxide * Oxygen * Toluene Pharmaceutical Drug overdoses Nervous * Anticholinesterase * Aspirin * Barbiturates * Benzodiazepines * Cocaine * Lithium * Opioids * Paracetamol * Tricyclic antidepressants Cardiovascular * Digoxin * Dipyridamole Vitamin poisoning * Vitamin A * Vitamin D * Vitamin E * Megavitamin-B6 syndrome Biological1 Fish / seafood * Ciguatera * Haff disease * Ichthyoallyeinotoxism * Scombroid * Shellfish poisoning * Amnesic * Diarrhetic * Neurotoxic * Paralytic Other vertebrates * amphibian venom * Batrachotoxin * Bombesin * Bufotenin * Physalaemin * birds / quail * Coturnism * snake venom * Alpha-Bungarotoxin * Ancrod * Batroxobin Arthropods * Arthropod bites and stings * bee sting / bee venom * Apamin * Melittin * scorpion venom * Charybdotoxin * spider venom * Latrotoxin / Latrodectism * Loxoscelism * tick paralysis Plants / fungi * Cinchonism * Ergotism * Lathyrism * Locoism * Mushrooms * Strychnine 1 including venoms, toxins, foodborne illnesses. * Category * Commons * WikiProject *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Copper toxicity

None

wikipedia

https://en.wikipedia.org/wiki/Copper_toxicity

{"icd-9": ["985.8"], "icd-10": ["T56.4"], "wikidata": ["Q5168803"]}

Ophthalmoplegia-intellectual disability-lingua scrotalis syndrome is a rare, genetic, syndromic intellectual disability disorder characterized by congenital, external, nuclear ophthalmoplegia, lingua scrotalis, progressive chorioretinal sclerosis and intellectual disability. Bilateral ptosis, bilateral facial weakness, Parinaud's syndrome, convergence paresis and myopia may be associated. There have been no further descriptions in the literature since 1975. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Ophthalmoplegia-intellectual disability-lingua scrotalis syndrome

c1833835

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2743

{"gard": ["3236"], "mesh": ["C563498"], "omim": ["165150"], "umls": ["C1833835"], "synonyms": ["Levic-Stefanovic-Nikolic syndrome"]}

Syndrome that causes episodes of increased activity of the sympathetic nervous system Paroxysmal sympathetic hyperactivity SpecialtyNeurology Paroxysmal sympathetic hyperactivity (PSH) is a syndrome that causes episodes of increased activity of the sympathetic nervous system. Hyperactivity of the sympathetic nervous system can manifest as increased heart rate, increased respiration, increased blood pressure, diaphoresis, and hyperthermia.[1] Previously, this syndrome has been identified as general dysautonomia but now is considered a specific form of it. It has also been referred to as paroxysmal sympathetic instability with dystonia, or PAID, and sympathetic storm. Recently, however, studies have adopted the name paroxysmal sympathetic hyperactivity to ensure specificity.[2] PSH is observed more in younger patients than older ones. It is also seen more commonly in men than women.[2] There is no known reason why this is the case, although it is suspected pathophysiological links may exist. In patients surviving traumatic brain injury, the occurrence of these episodes is one in every three. PSH can also be associated with severe anoxia, subarachnoid and intracerebral hemorrhage, and hydrocephalus.[3] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 5.1 Medication * 5.1.1 Morphine * 5.1.2 Beta-blockers * 5.1.3 Others * 6 Prognosis * 7 History * 8 References * 9 External links ## Signs and symptoms[edit] Characteristics of paroxysmal sympathetic hyperactivity include:[3] * fever * tachycardia * hypertension * tachypnea * hyperhidrosis or diaphoresis * dystonic posturing * pupillary dilation * flushing In cases where PSH episodes develop post-injury, specifically traumatic brain injury, symptoms typically develop quickly, usually within a week. Symptom onset has been seen to average 5.9 days post-injury.[2] Episodes vary in duration and occurrence. Episodes can last as little as a few minutes or as long as ten hours, and they can occur multiple times a day. Episode duration has been seen to average 30.8 minutes and occur five to six times a day.[2] Episodes can occur naturally or arise from external triggers. Common triggers include pain or stimulation, body turning or movements, and bladder distention. Bladder distention has been observed in patients being treated in intensive care units with the concurrent use of catheters.[3] Symptoms of PSH can last from weeks to years following initial onset. As episodes persist over time, they have been found to become less frequent in occurrence but last for prolonged periods.[3] ## Causes[edit] The number of events that can lead to the development of PSH symptoms is many. The exact pathways or causes for the development of the syndrome are not known. Traumatic brain injury, hypoxia,[4] stroke, anti-NMDA receptor encephalitis (although further associations are being explored),[5] injury of the spinal cord,[1] and many other forms of brain injury can cause onset of PSH. Even more obscure diseases such as intracranial tuberculoma have been seen to cause onset of paroxysmal sympathetic hyperactivity.[6] It is observed that these injuries lead to the development of PSH or are seen in conjunction with PSH, but the pathophysiology behind these diseases and the syndrome is not well understood. ## Pathophysiology[edit] A considerable number of theories exist as to the pathophysiology: * Epileptiform discharges in the diencephalon, or the interbrain, are a potential theory for PSH.[2] These discharges can be identified using electroencephalography. * Increased intracranial pressure is another theory.[2] Currently, this theory seems to be less likely than the others. Intracranial pressure has been seen to have no correlation to PSH episodes. * Disconnection via lesions of the inhibitory efferent pathways from cortical and subcortical areas of the brain is a potential theory.[2] This theory deals with inhibitory pathways being ablated or malfunctioning post-injury. This leads to sympathetic pathways from the cortical and subcortical areas being less controlled, resulting in a 'sympathetic storm'. * Excitatory-inhibitory models suggest that lesions in the mesencephalic area lessen inhibition pathways from the brain. This is thought to lead to pathways that are usually non-nociceptive becoming nociceptive, which results in the peripheral sympathetic nervous system being over activated.[2] * Another theory deals with malfunction of the brainstem, specifically excitatory centers in the brainstem.[1] In this case, rather than inhibitory pathways malfunctioning and allowing sympathetic pathways to propagate unhindered, excitatory centers are up-regulated, increasing sympathetic activity. There are many theories dealing with the pathophysiology of paroxysmal sympathetic hyperactivity. It is possible that none or multiple of these theories are correct. Research that is being conducted on PSH is focused on figuring out these pathways. ## Diagnosis[edit] Diagnosing PSH can be very difficult due to the lack of common terminology in circulation and a lack of diagnostic criteria.[7] Different systems for diagnosis have been proposed, but a universal system has not been embraced. One example of a proposed system of diagnosis requires observation confirmation for four of the six following symptoms: fever greater than 38.3 degrees Celsius, tachycardia classified as a heart rate of 120 bpm or higher, hypertension classified as a systolic pressure higher than 160 mmHg or a pulse pressure higher than 80 mmHg, tachypnea classified as respiration rate higher than 30 breaths per minute, excess sweating, and severe dystonia.[3] Ruling out other diseases or syndromes that show similar symptoms is imperative to diagnosis as well. Sepsis, encephalitis, neuroleptic malignant syndrome,[8] malignant hyperthermia,[8] lethal catatonia, spinal cord injury (not associated with PSH), seizures, and hydrocephalus (this can be associated with PSH) are examples of diagnoses that should be considered due to the manifestation of similar symptoms before confirming a diagnosis of PSH.[3] PSH has no simple radiological features that can be observed or detected on a scan. ## Treatment[edit] Various methods are used to treat PSH. Medications are used to end episodes or prevent their occurrence. Hyperbaric oxygen therapy has been explored as well.[9] Other treatments have been used, but their success is measured on a case-by-case basis. Successful treatments with qualitative results or efficacy for wider ranges of patients have not been developed. ### Medication[edit] The two most common medications used in the treatment of paroxysmal sympathetic hyperactivity are morphine sulfate and beta-blockers.[3] Morphine is useful in helping halt episodes that have started to occur. Beta-blockers are helpful in preventing the occurrence of 'sympathetic storms'. Other drugs that have been used and have in some cases been helpful are dopamine agonists, other various opiates, benzodiazepines, clonidine, and baclofen.[10] Chlorpromazine and haloperidol, both dopamine antagonists, in some cases have worsened PSH symptoms.[3] These drugs are in use currently for treatment; exact pathways are not known and wide-range helpfulness is speculative. #### Morphine[edit] Morphine has been found to be effective in aborting episodes; sometimes it is the only medication that can combat the sympathetic response. Morphine helps lower respiration rates and hypertension. It is given in doses of two milligrams to eight milligrams but can be administered up to twenty milligrams. Nausea and vomiting are common side effects. Withdrawal is sometimes seen in patients.[3] #### Beta-blockers[edit] Non-selective beta-blockers are the most effective in reducing the frequency and severity of PSH episodes. They help decrease the effect of circulating catecholamines and lower metabolic rates, which are high in patients during PSH episodes. Beta-blockers also help in reducing fever, diaphoresis, and in some cases dystonia. Propanolol is a common beta-blocker administered due to the fact that it penetrates the blood-brain barrier relatively well. Typically it is administered in doses of twenty milligrams to sixty milligrams every four to six hours in the treatment of PSH.[3] #### Others[edit] Clonidine is an alpha receptor agonist that helps reduces sympathetic activity leaving the hypothalamus and reduces circulating catecholamines. It is helpful in lowering blood pressure and heart rate, but it does not show much of an effect on other symptoms. It may also increase sympathetic inhibition in the brainstem. Bromocriptine is a dopamine agonist that helps lower blood pressure. Its effects are modest, but they are not well understood. Baclofen is a GABA agonist that helps control muscle spasms, proving to be helpful in treating dystonia. Benzodiazepines bind to GABA receptors and work as muscle relaxants. Benzodiazepines also combat high blood pressure and respiratory rates; however, they are associated with glaucoma, which is a rather serious side effect. Gabapentin inhibits neurotransmitter release in the dorsal horn of the spinal cord and various areas of the central nervous system. It helps treat mild symptoms and can be tolerated for longer periods of time compared to other drug treatments. Dantrolene helps combat dystonia and fever by affecting muscle contraction and relaxation cycles. It hinders the release of calcium from the sarcoplasmic reticulum, inhibiting muscle contraction. It causes decreases in respiration, but it can be very dangerous for the liver.[3] Again, these treatments are seen case by case and treat symptoms well. They do not treat the syndrome as a whole or preventatively. Efficacy varies patient to patient, as symptoms do. ## Prognosis[edit] Patients who develop PSH after traumatic injury have longer hospitalization and longer durations in intensive care in cases where ICU treatment is necessary. Patients often are more vulnerable to infections and spend longer times on ventilators, which can lead to an increased risk of various lung diseases. PSH does not affect mortality rate, but it increases the amount of time it takes a patient to recover from injury, compared to patients with similar injuries who do not develop PSH episodes. It often takes patients who develop PSH longer to reach similar levels of the brain activity seen in patients who do not develop PSH, although PSH patients do eventually reach these same levels.[2] ## History[edit] The first published case of paroxysmal sympathetic hyperactivity was Wilder Penfield's case report of a 41-year-old woman, JH, published in 1929. She had a third ventricle cholesteatoma. She displayed increased respiration, increased heart rate, diaphoresis, and increased blood pressure. She also displayed minor symptoms: pupillary dilation, hiccups, and lacrimation. At the time, her episodes were termed 'diencephalic autonomic epilepsy'. It was believed that both her sympathetic and parasympathetic nervous systems were showing overactivity.[1] The future may hold non-pharmacologic solutions such as renal sympathetic denervation.[11] ## References[edit] 1. ^ a b c d Perkes, Iain; Baguley, Ian J.; Nott, Melissa T.; Menon, David K. (2010). "A review of paroxysmal sympathetic hyperactivity after acquired brain injury". Annals of Neurology. 68 (2): 126–135. doi:10.1002/ana.22066. ISSN 0364-5134. 2. ^ a b c d e f g h i Fernandez-Ortega, JF; Prieto-Palomino, MA; Garcia-Caballero, M; Galeas-Lopez, JL; Quesada-Garcia, G; Baguley, I (May 2012). "Paroxysmal Sympathetic Hyperactivity after Traumatic Brain Injury: Clinical and Prognostic Implications". Journal of Neurotrauma. 29 (7): 1364–70. doi:10.1089/neu.2011.2033. 3. ^ a b c d e f g h i j k Rabinstein, AA; Benarroch, EE (March 2008). "Treatment of paroxysmal sympathetic hyperactivity". Current Treatment Options in Neurology. 10 (2): 151–7. doi:10.1007/s11940-008-0016-y. PMID 18334137. 4. ^ Perkes, IE; Menon, DK; Nott, MT; Baguley, IJ (September 2011). "Paroxysmal sympathetic hyperactivity after acquired brain injury: A review of diagnostic criteria". Brain Injury. 25 (10): 925–932. doi:10.3109/02699052.2011.589797. 5. ^ Hinson, HE; Takahashi, C; Altowaijri, G; Baguley, I; Bourdette, D (April 2013). "Anti-NMDA receptor encephalitis with paroxysmal sympathetic hyperactivity: an under-recognized association?". Clinical Autonomic Research. 23 (2): 109–111. doi:10.1007/s10286-012-0184-4. 6. ^ Singh, DK; Singh, N (September 2011). "Paroxysmal Autonomic Instability with Dystonia in a Child: Rare Manifestation of an Interpeduncular Tuberculoma". Pediatr Neurosurg. 47: 275–278. doi:10.1159/000334276. 7. ^ Hinson, HE; Ling, G; Vandenbark, M; Baguley, I; Schreiber, M (August 2013). "Quantifying Paroxysmal Sympathetic Hyperactivity in Traumatic Brain Injury". Journal of Neurotrauma. 30 (15): A38-A38. doi:10.1089/neu.2013.9938. 8. ^ a b Blackman, James A.; Patrick, Peter D.; Buck, Marcia L.; Rust, Jr, Robert S. (2004). "Paroxysmal Autonomic Instability With Dystonia After Brain Injury". Archives of Neurology. 61 (3): 321. doi:10.1001/archneur.61.3.321. ISSN 0003-9942. 9. ^ Lv, LQ; Hou, LJ; Yu, MK; Ding, XH; Qi, XQ; Lu, YC (September 2011). "Hyperbaric Oxygen Therapy in the Management of Paroxysmal Sympathetic Hyperactivity After Severe Traumatic Brain Injury: A Report of 6 Cases". Archives of Physical Medicine and Rehabilitation. 92 (9): 1515–18. doi:10.1016/j.apmr.2011.01.014. 10. ^ Choi, HA; Jeon, SB; Samuel, S; Allison, T; Lee, K (June 2013). "Paroxysmal Sympathetic Hyperactivity After Acute Brain Injury". Curr Neurol Neurosci Rep. 13 (370). doi:10.1007/s11910-013-0370-3. 11. ^ Renal Sympathetic Denervation, From Wikipedia, the free encyclopedia12/7/2014 ## External links[edit] Classification D * ICD-10: G90 * ICD-9-CM: 337.9 * v * t * e Diseases of the autonomic nervous system General * Dysautonomia * Autonomic dysreflexia * Autonomic neuropathy * Pure autonomic failure Hereditary * Hereditary sensory and autonomic neuropathy * Familial dysautonomia * Congenital insensitivity to pain with anhidrosis Orthostatic intolerance * Orthostatic hypotension * Postural orthostatic tachycardia syndrome Other * Horner's syndrome * Multiple system atrophy *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Paroxysmal sympathetic hyperactivity

c4285793

wikipedia

https://en.wikipedia.org/wiki/Paroxysmal_sympathetic_hyperactivity

{"wikidata": ["Q17156972"]}

Hemiplegic migraine Other namesFamilial or sporadic hemiplegic migraine[1] Hemiplegic migraine is inherited via autosomal dominant manner ## Contents * 1 Cause * 2 Symptoms * 3 Diagnosis * 3.1 Classification * 3.2 Familial hemiplegic migraine * 3.3 Sporadic hemiplegic migraine * 4 Screening * 5 Management * 6 Epidemiology * 7 References * 8 External links ## Cause[edit] This section is empty. You can help by adding to it. (July 2017) ## Symptoms[edit] Hemiplegia (Greek 'hemi' = Half), is condition that affects one side of the body. Signs of a hemiplegic migraine attack are similar to what would be presented in a stroke that typically includes sudden severe headache on one side of the brain, weakness of half the body, ataxia and aphasia which can last for hours, days or weeks. [2] ## Diagnosis[edit] ### Classification[edit] The ICHD classification and diagnosis of migraine distinguish 6 subtypes of hemiplegic migraine.[3] Familial hemiplegic migraine (FHM) can be loosely divided into two categories: with and without cerebellar signs. Cerebellar signs refer to ataxia, sometimes episodic and other times progressive, that can accompany FHM1 mutations and is caused by degeneration of the cerebellum. These cerebellar signs result in a phenotypic overlap between FHM and both episodic ataxia and spinocerebellar ataxia. This is unsurprising as subtypes of these disorders (FHM1, EA2 and SCA6) are allelic, i.e., they result from mutations in the same gene. The other forms of FHM seem to be distinguishable only on the basis of their genetic cause.[citation needed] ### Familial hemiplegic migraine[edit] Main article: Familial hemiplegic migraine Familial hemiplegic migraine is a form of hemiplegic migraine headache that runs in families.[4] ### Sporadic hemiplegic migraine[edit] Main article: Sporadic hemiplegic migraine There are also non-familial cases of hemiplegic migraine, termed sporadic hemiplegic migraine. These cases seem to have the same causes as the familial cases and represent de novo mutations. Sporadic cases are also clinically identical to familial cases with the exception of a lack of family history of attacks.[5] ## Screening[edit] Prenatal screening is not typically done for FHM, however it may be performed if requested. As penetrance is high, individuals found to carry mutations should be expected to develop signs of FHM at some point in life. ## Management[edit] See the equivalent section in the main migraine article. People with FHM are encouraged to avoid activities that may trigger their attacks. Minor head trauma is a common attack precipitant, so FHM sufferers should avoid contact sports. Acetazolamide or standard drugs are often used to treat attacks, though those leading to vasoconstriction should be avoided due to the risk of stroke. ## Epidemiology[edit] Migraine itself is a very common disorder, occurring in 15–20% of the population. Hemiplegic migraine, be it familial or spontaneous, is less prevalent, 0.01% prevalence according to one report.[6] Women are three times more likely to be affected than males. ## References[edit] 1. ^ RESERVED, INSERM US14 -- ALL RIGHTS. of diseases=Familial-or-sporadic-hemiplegic-migraine&title=Familial-or-sporadic-hemiplegic-migraine&search=Disease_Search_Simple "Orphanet: Familial or sporadic hemiplegic migraine" Check `|url=` value (help). www.orpha.net. Retrieved 20 July 2017. 2. ^ "What is hemiplegia? | HemiHelp: for children and young people with hemiplegia (hemiparesis)". www.hemihelp.org.uk. Retrieved 2019-07-09. 3. ^ Website The International Classification of Headache Disorders 3rd edition (Beta version). Retrieved 29. August 2016. 4. ^ "familial hemiplegic migraine". Genetics Home Reference. Genetics Home Reference. Retrieved 19 June 2017. 5. ^ "sporadic hemiplegic migraine". Genetics Home Reference. Genetics Home Reference. Retrieved 19 June 2017. 6. ^ Lykke Thomsen, L; Kirchmann Eriksen, M; Faerch Romer, S; Andersen, I; Ostergaard, E; Keiding, N; Olesen, J; Russell, MB (June 2002). "An epidemiological survey of hemiplegic migraine". Cephalalgia. 22 (5): 361–375. doi:10.1046/j.1468-2982.2002.00371.x. PMID 12110112. S2CID 22040734. ## External links[edit] Classification D * ICD-10: ICD-10: G43.1 * OMIM: 141500 External resources * Orphanet: 569 * v * t * e Diseases of the nervous system, primarily CNS Inflammation Brain * Encephalitis * Viral encephalitis * Herpesviral encephalitis * Limbic encephalitis * Encephalitis lethargica * Cavernous sinus thrombosis * Brain abscess * Amoebic Brain and spinal cord * Encephalomyelitis * Acute disseminated * Meningitis * Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders * Basal ganglia disease * Parkinsonism * PD * Postencephalitic * NMS * PKAN * Tauopathy * PSP * Striatonigral degeneration * Hemiballismus * HD * OA * Dyskinesia * Dystonia * Status dystonicus * Spasmodic torticollis * Meige's * Blepharospasm * Athetosis * Chorea * Choreoathetosis * Myoclonus * Myoclonic epilepsy * Akathisia * Tremor * Essential tremor * Intention tremor * Restless legs * Stiff-person Dementia * Tauopathy * Alzheimer's * Early-onset * Primary progressive aphasia * Frontotemporal dementia/Frontotemporal lobar degeneration * Pick's * Dementia with Lewy bodies * Posterior cortical atrophy * Vascular dementia Mitochondrial disease * Leigh syndrome Demyelinating * Autoimmune * Inflammatory * Multiple sclerosis * For more detailed coverage, see Template:Demyelinating diseases of CNS Episodic/ paroxysmal Seizures and epilepsy * Focal * Generalised * Status epilepticus * For more detailed coverage, see Template:Epilepsy Headache * Migraine * Cluster * Tension * For more detailed coverage, see Template:Headache Cerebrovascular * TIA * Stroke * For more detailed coverage, see Template:Cerebrovascular diseases Other * Sleep disorders * For more detailed coverage, see Template:Sleep CSF * Intracranial hypertension * Hydrocephalus * Normal pressure hydrocephalus * Choroid plexus papilloma * Idiopathic intracranial hypertension * Cerebral edema * Intracranial hypotension Other * Brain herniation * Reye syndrome * Hepatic encephalopathy * Toxic encephalopathy * Hashimoto's encephalopathy Both/either Degenerative SA * Friedreich's ataxia * Ataxia–telangiectasia MND * UMN only: * Primary lateral sclerosis * Pseudobulbar palsy * Hereditary spastic paraplegia * LMN only: * Distal hereditary motor neuronopathies * Spinal muscular atrophies * SMA * SMAX1 * SMAX2 * DSMA1 * Congenital DSMA * Spinal muscular atrophy with lower extremity predominance (SMALED) * SMALED1 * SMALED2A * SMALED2B * SMA-PCH * SMA-PME * Progressive muscular atrophy * Progressive bulbar palsy * Fazio–Londe * Infantile progressive bulbar palsy * both: * Amyotrophic lateral sclerosis * v * t * e Headache Primary ICHD 1 * Migraine * Familial hemiplegic * Retinal migraine ICHD 2 * Tension * Mixed tension migraine ICHD 3 * Cluster * Chronic paroxysmal hemicrania * SUNCT ICHD 4 * Hemicrania continua * Thunderclap headache * Sexual headache * New daily persistent headache * Hypnic headache Secondary ICHD 5 * Migralepsy ICHD 7 * Ictal headache * Post-dural-puncture headache ICHD 8 * Hangover * Medication overuse headache ICHD 13 * Trigeminal neuralgia * Occipital neuralgia * External compression headache * Cold-stimulus headache * Optic neuritis * Postherpetic neuralgia * Tolosa–Hunt syndrome Other * Vascular *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hemiplegic migraine

c0270862

wikipedia

https://en.wikipedia.org/wiki/Hemiplegic_migraine

{"gard": ["10768"], "orphanet": ["569"], "synonyms": [], "wikidata": ["Q30587719"]}

This article is an orphan, as no other articles link to it. Please introduce links to this page from related articles; try the Find link tool for suggestions. (January 2017) Centurion syndrome SpecialtyDermatology Centurion syndrome is characterized by anterior malposition of the medial part of the lid, with displacement of puncta out of the lacus lacrimalis due to a prominent nasal bridge.[1][2] ## References[edit] 1. ^ Garg (2009). Instant Clinical Diagnosis in Ophthalmology: Oculoplasty & Reconstructive Surgery. Jaypee Brothers Publishers. pp. 12–. ISBN 978-81-8448-403-8. 2. ^ Suresh D Isloor (30 May 2014). Lacrimal Drainage Surgery. JP Medical Ltd. p. 51. ISBN 978-93-5090-650-7. * v * t * e Medicine Specialties and subspecialties Surgery * Cardiac surgery * Cardiothoracic surgery * Colorectal surgery * Eye surgery * General surgery * Neurosurgery * Oral and maxillofacial surgery * Orthopedic surgery * Hand surgery * Otolaryngology * ENT * Pediatric surgery * Plastic surgery * Reproductive surgery * Surgical oncology * Transplant surgery * Trauma surgery * Urology * Andrology * Vascular surgery Internal medicine * Allergy / Immunology * Angiology * Cardiology * Endocrinology * Gastroenterology * Hepatology * Geriatrics * Hematology * Hospital medicine * Infectious disease * Nephrology * Oncology * Pulmonology * Rheumatology Obstetrics and gynaecology * Gynaecology * Gynecologic oncology * Maternal–fetal medicine * Obstetrics * Reproductive endocrinology and infertility * Urogynecology Diagnostic * Radiology * Interventional radiology * Nuclear medicine * Pathology * Anatomical * Clinical pathology * Clinical chemistry * Cytopathology * Medical microbiology * Transfusion medicine Other * Addiction medicine * Adolescent medicine * Anesthesiology * Dermatology * Disaster medicine * Diving medicine * Emergency medicine * Mass gathering medicine * Family medicine * General practice * Hospital medicine * Intensive care medicine * Medical genetics * Narcology * Neurology * Clinical neurophysiology * Occupational medicine * Ophthalmology * Oral medicine * Pain management * Palliative care * Pediatrics * Neonatology * Physical medicine and rehabilitation * PM&R * Preventive medicine * Psychiatry * Addiction psychiatry * Radiation oncology * Reproductive medicine * Sexual medicine * Sleep medicine * Sports medicine * Transplantation medicine * Tropical medicine * Travel medicine * Venereology Medical education * Medical school * Bachelor of Medicine, Bachelor of Surgery * Bachelor of Medical Sciences * Master of Medicine * Master of Surgery * Doctor of Medicine * Doctor of Osteopathic Medicine * MD–PhD Related topics * Alternative medicine * Allied health * Dentistry * Podiatry * Pharmacy * Physiotherapy * Molecular oncology * Nanomedicine * Personalized medicine * Public health * Rural health * Therapy * Traditional medicine * Veterinary medicine * Physician * Chief physician * History of medicine * Book * Category * Commons * Wikiproject * Portal * Outline This cutaneous condition article is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Centurion syndrome

None

wikipedia

https://en.wikipedia.org/wiki/Centurion_syndrome

{"wikidata": ["Q28458440"]}

Axial spondylometaphyseal dysplasia is a genetic disorder of bone growth. The term “axial” means towards the center of the body. “Sphondylos” is a Greek term meaning vertebra. “Metaphyseal dysplasia” refers to abnormalities at the ends of long bones. Axial spondylometaphyseal dysplasia primarily affects the bones of the chest, pelvis, spine, upper arms and upper legs, and results in shortened stature. For reasons not well understood, this rare skeletal dysplasia is also associated with early and progressive vision loss. The underlying genetic cause of axial spondylometaphyseal dysplasia is currently unknown. It is thought to be inherited in an autosomal recessive fashion. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Axial spondylometaphyseal dysplasia

c1865695

gard

https://rarediseases.info.nih.gov/diseases/8720/axial-spondylometaphyseal-dysplasia

{"mesh": ["C535795"], "omim": ["602271"], "umls": ["C1865695"], "orphanet": ["168549"], "synonyms": ["Axial SMD", "Spondylometaphyseal dysplasia axial type", "SMD Axial"]}

A number sign (#) is used with this entry because glutaric acidemia I (GA1) is caused by homozygous or compound heterozygous mutation in the gene encoding glutaryl-CoA dehydrogenase (GCDH; 608801) on chromosome 19p13. Description Glutaric acidemia I is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). Hedlund et al. (2006) provided a detailed review of the clinical and biochemical aspects of glutaric acidemia type I. Clinical Features Goodman et al. (1974) described glutaric aciduria and acidemia in a brother and sister with a neurodegenerative disorder beginning at about 6 months of age and characterized by opisthotonos, dystonia, and athetoid posturing. The glutaric aciduria was increased by oral administration of L-lysine, which is metabolized through glutaryl-CoA, and was decreased by reduced protein intake. Metabolism of radioactive glutaryl-CoA was deficient in white cells, a result compatible with inherited deficiency of glutaryl-CoA dehydrogenase (Goodman et al., 1975). Brandt et al. (1978) described a 10-year-old girl with progressive dystonic cerebral palsy. The urine contained large amounts of glutaric acid. From a review of this and 4 cases reported earlier, the authors concluded that disorders in the metabolism of organic acids should be sought in patients with progressive dystonic palsy. Lysed leukocytes from their patient showed severe impairment in the ability to metabolize glutaryl-CoA. Amir et al. (1987) described 2 pairs of sibs with this disorder. All had a unique pattern of frontotemporal atrophy on computerized tomography (CT). Remarkably, in both sib pairs, 1 child was asymptomatic. All 12 previously reported patients had a homogeneous phenotype presenting in infancy with debilitating dystonia and choreoathetosis. In an affected infant with glutaric aciduria, Mandel et al. (1991) described CT findings of dilatation of the insular cisterns, regression of the temporal lobes, with 'bat wings' dilatation of the Sylvian fissures and hypodensity of the lenticular nuclei. CT changes preceded the onset of symptoms by 3 months. Improvement in the temporal lobe atrophy was observed after a period of treatment, coincident with marked clinical improvement. In 14 children with type I glutaric aciduria from the Old Order Amish community in Lancaster County, Pennsylvania, Morton et al. (1991) noted a remarkably variable clinical picture ranging from acute infantile encephalopathy and sudden death to static extrapyramidal cerebral palsy. In 10 patients, the disorder was first manifest between 3 and 18 months during an acute infectious illness. Four of these children died in early childhood, also during acute illnesses. However, there had been little progression of the neurologic disorder after age 5 years in the surviving children, and intellect was usually preserved even in children with severe spastic paralysis. They suggested that restriction of dietary protein and limitation of protein catabolism, dehydration, and acidosis during illnesses may prevent the onset or progression of neurologic disease in Amish patients with this disorder. Morton et al. (1991) presented a pedigree chart tracing both parents of all except one case to John Lapp and his wife, who immigrated to the United States in the 1730s. The oldest patient was a 28-year-old man who was normal until age 3 months when, after a period of irritability and poor feeding on day 7 of a varicella infection, he experienced an acute, afebrile episode of tonic posturing and thereafter became flaccid and unresponsive. After recovery from the acute episode, which was diagnosed as varicella encephalitis, he was left with a residual spastic diplegia, partial bulbar palsy, and choreoathetosis. GA I was diagnosed based on a urinary glutaric acid level of 166 mg/g creatinine. Despite spastic diplegia and moderate choreoathetosis, he had normal intelligence and regularly worked in a carriage and harness repair shop. There had been no apparent progression of his neurologic disease since the single damaging illness at age 3 months. Kyllerman et al. (1994) reported 12 new cases, aged 9 months to 16 years, comprising all known cases of GA I in Sweden and Norway. Ten had a severe dystonic-dyskinetic disorder, 1 had a mild hyperkinetic disorder, and 1 was asymptomatic. Two children died in a state of hyperthermia. Carnitine deficiency and malnutrition developed in patients with severe dystonia and dysphagia, which necessitated replacement therapy and gastrostomy. A slowly progressive dyskinetic disorder developed in 1 subject despite adequate early dietary treatment. Macrocephaly was found in 3. Computed tomography and magnetic resonance investigations in 10 showed deep bitemporal spaces in 7. Neuropsychologic testing of 8 of 12 subjects demonstrated receptive language function to be superior to expressive language and motor function, although cognitive functions were less affected than motor functions. A review of 57 pooled cases demonstrated that a severe dystonic syndrome developed in 77% and a mild extrapyramidal syndrome in 10%, while 12% were asymptomatic. Hoffmann et al. (1995) presented the clinical findings in more than 21 patients with GCDH deficiency. Seventy-six percent of the patients presented with an acute encephalopathic crisis, mostly associated with an upper respiratory and/or gastrointestinal infection between the ages of 2 and 37 months. The metabolic symptoms, such as hypoglycemia and metabolic acidosis, were minimal. After recovery the children had lost most motor skills and functioned at a 1- to 2-month-old level. At that point, the very distinctive clinical picture of a severe dystonic-dyskinetic syndrome in alert-looking children with relatively well-preserved intellectual functions and a prominent forehead could be recognized. About one-fourth of the patients never suffered encephalopathic crisis but presented with subacute motor delay. These patients showed developmental delay from birth and a progressive dystonic 'cerebral palsy.' Hoffmann et al. (1995) observed that, whereas in most patients with GCDH deficiency there is often remarkable discrepancy between the severe motor impairment and the normal or near-normal intellectual functions until late in the disease process, children who never develop normally are more likely to be impaired mentally. Forty-three percent of this series showed macrocephaly at birth and 67% showed macrocephaly in infancy. Profuse sweating was noted in 35%. Merinero et al. (1995) described 7 new patients with severe deficiency of glutaryl-CoA dehydrogenase in cultured skin fibroblasts, only 3 of which excreted high levels of glutaric acid in the urine. High levels of glutaric acid were seen in the spinal fluid of all these patients. The patients presented between 6 months and 2 years of age with either seizures or hypotonia and dystonia. All but 1 had severe impairment of psychomotor development and abnormalities on T2-weighted MRI, chiefly bilateral hyperdensities of basal ganglia, atrophy of the temporal lobe, or extensive white matter hypodensities. Bjugstad et al. (2000) performed a forward, stepwise, multiple regression analysis to find predictors for outcome in 115 previously described patients with glutaric acidemia type I. The analyses showed that in patients who did not have a precipitating illness before the first appearance of motor symptoms, the age at onset was significantly associated with the severity of motor impairments and overall clinical outcome. In patients who had a precipitating illness, the age at onset did not predict the outcome. In both groups of patients, basal ganglia degeneration, enlargement of spaces containing cerebrospinal fluid, and white matter abnormalities were indicative of a poorer prognosis. Treatment given after the appearance of symptoms was not associated with a better clinical outcome or fewer motor deficits. In a discussion of the natural history of GA I, Strauss et al. (2003) commented that micrencephalic macrocephaly is a distinctive radiologic feature of GA I. In most neonates, an enlarged head circumference is the only presenting sign of the disorder. The authors pointed to radiologic signs of large fluid collections in the middle cranial fossae. Veins could be seen stretching tenuously across this space, where they are subject to distortion and rupture. Acute subdural hemorrhage can occur after minor head trauma and in some instances is accompanied by retinal hemorrhages. Investigation of child abuse preceded a correct metabolic diagnosis in some non-Amish children. Strauss et al. (2003) summarized the clinical characteristics of 37 Amish and 40 non-Amish patients with GA I. Of the Amish patients, 17 were identified retrospectively and 20 were treated prospectively following diagnosis through screening of asymptomatic newborns. In all groups, basal ganglia degeneration was the major determinant of functional disability. The incidence of basal ganglia injury was 85% in non-Amish patients and 94% in retrospectively identified Amish children. In the other 20 Amish children, most of them diagnosed by neonatal screening, prospective management was accompanied by a basal ganglia injury rate of 35%. Acute striatal necrosis was the major cause of morbidity and mortality, and dystonia caused chronic medical and surgical complications. In older patients, exercise intolerance, hypoglycemia, and seizures often developed. Strauss et al. (2003) stated that fasting hypoglycemia probably has 2 distinct causes in GA I: nonketosis and hypoketosis. The former results from carnitine deficiency, which can also give rise to myopathy, cardiomyopathy, and Reye-like hepatocerebral crisis, and the latter can occur during intercurrent illness even in carnitine-supplemented children. Bahr et al. (2002) reported a previously healthy 19-year-old woman who presented with recurrent headaches, oculomotor symptoms, and a severe leukoencephalopathy on MRI. Subsequent evaluation revealed increased urinary glutaric acid and compound heterozygosity for mutations in the GCDH gene. Kulkens et al. (2005) reported 2 unrelated patients who developed neurologic signs at ages 35 and 15 years, respectively. The first patient had onset of headaches at age 35, developed tremor of both arms at age 50, and had 6 tonic-clonic seizures between ages 54 and 62. At age 63, he developed ataxia, progressive dementia, and speech problems. The other patient developed headache, vertigo, and gait disturbance at age 15 years following an upper respiratory tract infection. Both patients had macrocephaly from birth and showed supratentorial leukoencephalopathy. Genetic analysis confirmed glutaryl-CoA dehydrogenase deficiency. Clinical treatment resulted in improvement and full recovery, respectively. Despite early diagnosis, one-third of Amish infants with glutaryl-CoA dehydrogenase deficiency developed striatal lesions that leave them permanently disabled. To better understand mechanisms of striatal degeneration, Strauss et al. (2007) retrospectively studied imaging results from 25 Amish patients homozygous for the 1296C-T mutation in GCDH (608801.0002). Asymptomatic infants had reduced glucose tracer uptake and increased blood volume throughout the gray matter, which may signify predisposition to brain injury. Striatal lesions developed in 9 children (36%): 3 had sudden motor regression during infancy, whereas 6 had insidious motor delay associated with striatal lesions of undetermined onset. Acute striatal necrosis consisted of 3 stages: (1) an acute stage within 24 hours of motor regression, characterized by cytotoxic edema within the basal ganglia, cerebral oligemia, and rapid transit of blood throughout the gray matter; (2) a subacute stage, 4 to 5 days after the onset of clinical symptoms, characterized by reduced striatal perfusion and glucose uptake, and supervening vasogenic edema; and (3) a chronic stage of striatal atrophy. Strauss et al. (2007) suggested that intravenous fluid and dextrose therapy for illnesses during the first 2 years of life was the only intervention that was clearly neuroprotective in these patients. Marti-Masso et al. (2012) reported 2 adult Spanish sisters with onset in infancy of a severe progressive form of dystonia affecting the upper and lower limbs, face, neck, and trunk, and resulting in severe speech impairment and the inability to walk by the teenage years. Neither had macrocephaly, organomegaly, cognitive impairment, or acute encephalopathy in childhood. Whole-exome sequence analysis identified a homozygous mutation in the GCDH gene (V400M; 608801.0008), consistent with glutaric acidemia. Laboratory studies showed decreased long-chain acylcarnitines and high excretion of 3-hydroxyglutaric acid, but urinary glutaric acid excretion was normal. Brain imaging showed increased signals in the lenticular nuclei. The findings implicated mitochondrial fatty acid metabolism as an important pathway in the development of dystonia, and Marti-Masso et al. (2012) concluded that GCDH mutation analysis should be considered in the differential diagnosis of progressive forms of early-onset generalized dystonia. Clinical Management Heringer et al. (2010) summarized the guidelines published by Kolker et al. (2007) for the management of glutaryl-CoA dehydrogenase deficiency. Recommendations included a lysine-restricted diet to reduce the accumulation of the neurotoxic metabolites glutaric acid, 3-hydroxyglutaric acid, and glutaryl-CoA deriving from the precursor amino acid lysine; the supplementation of carnitine to prevent secondary carnitine depletion, to facilitate production of the nontoxic C5DC, and to replenish the intracellular free coenzyme A pool; and the intermittent and stepwise intensification of metabolic treatment using a high-calorie, low- or no-protein emergency treatment protocol during putatively threatening episodes such as infectious disease to prevent striatal injury. Heringer et al. (2010) assessed the outcome of 52 patients identified by a newborn screen in Germany from 1999 to 2009. Outcome was evaluated in relationship to therapy and therapy-independent parameters. According to following the guidelines of Kolker et al. (2007), Heringer et al. (2010) found that outcome was best in glutaric aciduria-1 patients who were treated in full accordance with treatment recommendations (n = 37; 5% had movement disorder (MD)). Deviations from recommended basic metabolic treatment (low-lysine diet, carnitine) resulted in an intermediate outcome (n = 9; 44% MD), whereas disregard of emergency treatment recommendations was associated with a poor outcome (n = 6; 100% MD). Treatment regimens deviating from recommendations significantly increased the risk for movement disorder (OR, 35; 95% CI, 5.88-208.39) and acute encephalopathic crises (OR, 51.32; 95% CI, 2.65-993.49). Supervision by a metabolic center improved the outcome (18% vs 57% MD; OR, 6.17; 95% CI, 1.15-33.11), whereas migrational background and biochemical phenotype (high vs low excretor status) had no significant effect. Diagnosis Kyllerman et al. (1994) noted that glutaric aciduria may go undetected in patients with cerebral palsy and mental retardation. In patients suspected of having the disorder, repeated examinations of organic acids in the urine and enzyme assay may be necessary to confirm the diagnosis. Tortorelli et al. (2005) found that the urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric acidemia I in patients with inconclusive biochemical findings. ### Prenatal Diagnosis Goodman et al. (1980) monitored 2 pregnancies at risk for glutaric acidemia type I. In 1 case in which the fetus was unaffected, glutaric acid was not detected in the amniotic fluid at amniocentesis (15 weeks) and the glutaryl-CoA dehydrogenase activity of cultured amniotic cells was normal. In the other case, there was a marked increase of glutaric acid in the amniotic fluid as well as a deficiency of glutaryl-CoA dehydrogenase in cultured amniotic cells. The pregnancy was terminated, and postmortem studies confirmed the diagnosis of glutaric acidemia. Christensen (1994) described experience with chorionic villus sampling for first-trimester diagnosis of this disorder. Among 16 pregnancies, 4 were predicted to represent an affected fetus; in 3 of the affected cases, GCDH activity was measured in both uncultured and cultured chorionic cells and the correct diagnosis was established by both measurements. Molecular Genetics In a Navajo child with glutaric acidemia type I, Biery and Goodman (1992) and Goodman et al. (1995) identified homozygosity for a mutation in the GCDH gene (608801.0001). Among 64 unrelated patients with glutaric acidemia type I, Biery et al. (1996) identified 12 mutations and several polymorphisms in 7 exons of the GCDH gene (see, e.g., 608801.0007-608801.0009). Several mutations were found in more than one patient, but no one prevalent mutation was detected in the general population. However, a single mutation was found as the cause of glutaric acidemia in the Old Order Amish of Lancaster County, Pennsylvania (A421V; 608801.0002). Population Genetics Morton et al. (1989, 1991) described type I glutaric aciduria in 14 children from the Old Order Amish community in Lancaster County, Pennsylvania. The authors estimated a 10% carrier frequency for this disorder among the Lancaster County Old Order Amish. Among 48 individuals with confirmed GCDH deficiency, Zschocke et al. (2000) identified a total of 38 different mutations. R402W (608801.0004) was the most common mutation in Europeans, accounting for 40% of alleles in patients of German origin. Glutaric acidemia type I occurs in about 1 in 100,000 infants worldwide (Hedlund et al., 2006). INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive HEAD & NECK Head \- Macrocephaly ABDOMEN Liver \- Hepatomegaly NEUROLOGIC Central Nervous System \- Dystonia \- Hypotonia \- Rigidity \- Choreoathetosis \- Opisthotonus \- Seizures (less common) \- Infantile encephalopathy \- Spastic diplegia \- Frontotemporal atrophy \- Dilation of lateral ventricles \- Widening of cortical sulci \- Delayed myelination \- Symmetrical progressive demyelination \- Hypodensity of lenticular nuclei \- Hypodensity of caudate \- Striatal necrosis LABORATORY ABNORMALITIES \- Glutaricaciduria \- Glutaryl-CoA dehydrogenase deficiency \- Metabolic acidosis \- Ketonemia \- Ketonuria \- Hypoglycemia MISCELLANEOUS \- Variable clinical presentation ranging from acute onset to normal adult \- Prevalent in Old Order Amish of Lancaster County, Pennsylvania and Saulteaux/Ojibway Indians of Canada \- Onset of illness often associated with acute infection \- Worldwide frequency of 1 in 100,000 infants MOLECULAR BASIS \- Caused by mutation in the glutaryl-CoA dehydrogenase gene (GCDH, 608801.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

GLUTARIC ACIDEMIA I

c0268595

omim

https://www.omim.org/entry/231670

{"doid": ["0111254"], "mesh": ["C536833"], "omim": ["231670"], "icd-10": ["E72.3"], "orphanet": ["25"], "synonyms": ["Alternative titles", "GLUTARIC ACIDURIA I", "GA I", "GLUTARYL-CoA DEHYDROGENASE DEFICIENCY"]}

Purpura haemorrhagica is a rare complication of equine strangles and is caused by bleeding from capillaries which results in red spots on the skin and mucous membranes together with oedema (swelling) of the limbs and the head.[1] Purpura hemorrhagica is more common in younger animals.[1] ## Contents * 1 Pathophysiology * 2 Clinical signs * 3 Treatment * 4 Prognosis * 5 Prevention * 6 See also * 7 References ## Pathophysiology[edit] Horses that develop purpura hemorrhagica usually have a recent history of strangles (infection with Streptococcus equi subsp. equi) or vaccination (intramuscular or intranasal) for strangles. It is thought to be caused by an auto-immune reaction where antibodies against the S. equi M- or R-protein cross-react with proteins on endothelial cells. This results in vasculitis, leading to subsequent severe peripheral edema in the legs and ventral abdomen, as well as petechiation or ecchymoses over the mucous membranes.[2] Purpura hemorrhagica can also rarely be seen after infection with S. equi subsp.zooepidemicus,[3] Rhodococcus equi,[3] Corynebacterium pseudotuberculosis (causative agent of pigeon fever),[3] equine influenza virus, or equine herpes virus type 1, or without any apparent infection.[3] ## Clinical signs[edit] The most common clinical sign is subcutaneous edema of the limbs and hemorrhages on mucous membranes. Other clinical signs include depression, anorexia, fever, elevated heart and respiratory rate, reluctance to move, drainage from lymph nodes, exudation of serum from the skin, colic, epistaxis and weight loss.[3] Rarely, horses may also develop disseminated intravascular coagulation (DIC), leading to infarction of various organs,[4] or chronic myositis and muscle atrophy.[2] ## Treatment[edit] Treatment usually involves high doses of steroids such as dexamethasone. While high doses of steroids may risk laminitis, low doses are associated with refractory cases.[2] Antibiotics are used to treat any residual nidus of S. equi. Non-steroidal anti-inflammatory drugs (NSAIDs), such as phenylbutazone or flunixin, may be useful to reduce fever and relieve pain. Intravenous DMSO is sometimes used as a free-radical scavenger and anti-inflammatory. Additionally, wrapping the legs may reduce edema and skin sloughing.[2] Supportive care with oral or IV fluids may also be required. ## Prognosis[edit] Prognosis is good with early, aggressive treatment (92% survival in one study).[3] ## Prevention[edit] Purpura hemorrhagica may be prevented by proper management during an outbreak of strangles. This includes isolation of infected horses, disinfection of fomites, and good hygiene by caretakers. Affected horses should be isolated at least one month following infection. Exposed horses should have their temperature taken daily and should be quarantined if it becomes elevated. Prophylactic antimicrobial treatment is not recommended.[5] Vaccination can reduce the incidence and severity of the disease. However, horses with high SeM antibody titers are more likely to develop purpura hemorrhagica following vaccination and so these horses should not be vaccinated.[5] Titers may be measured by ELISA. ## See also[edit] * Purpura \- in humans ## References[edit] 1. ^ a b "Strangles - Complications". 2. ^ a b c d MacLeay, JM (February 2000). "Purpura hemorrhagica". Journal of Equine Veterinary Science. 20 (2): 101. doi:10.1016/S0737-0806(00)80451-7. 3. ^ a b c d e f Pusterla, N; Watson, JL; Affolter, VK; Magdesian, KG; Wilson, WD; Carlson, GP (26 July 2003). "Purpura haemorrhagica in 53 horses". The Veterinary Record. 153 (4): 118–21. doi:10.1136/vr.153.4.118. PMID 12918829. 4. ^ Kaese, HJ; Valberg, SJ; Hayden, DW; Wilson, JH; Charlton, P; Ames, TR; Al-Ghamdi, GM (1 June 2005). "Infarctive purpura hemorrhagica in five horses". Journal of the American Veterinary Medical Association. 226 (11): 1893–8, 1845. doi:10.2460/javma.2005.226.1893. PMID 15934258. 5. ^ a b Taylow, S. D.; Wilson, W. D. (September 2006). "Streptococcus equi subsp. equi (Strangles) Infection". Clinical Techniques in Equine Practice. 5 (3): 211–217. doi:10.1053/j.ctep.2006.03.016. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Purpura haemorrhagica

c0376362

wikipedia

https://en.wikipedia.org/wiki/Purpura_haemorrhagica

{"mesh": ["D011695"], "wikidata": ["Q7261507"]}

eye condition "Snow blindness" redirects here. For other uses, see Snowblind (disambiguation). This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (May 2017) (Learn how and when to remove this template message) Photokeratitis SpecialtyOphthalmology Photokeratitis or ultraviolet keratitis is a painful eye condition caused by exposure of insufficiently protected eyes to the ultraviolet (UV) rays from either natural (e.g. intense sunlight) or artificial (e.g. the electric arc during welding) sources. Photokeratitis is akin to a sunburn of the cornea and conjunctiva. The injury may be prevented by wearing eye protection that blocks most of the ultraviolet radiation, such as welding goggles with the proper filters, a welder's helmet, sunglasses rated for sufficient UV protection, or appropriate snow goggles. The condition is usually managed by removal from the source of ultraviolet radiation, covering the corneas, and administration of pain relief. Photokeratitis is known by a number of different terms including: snow blindness, arc eye, welder's flash, bake eyes, corneal flash burns, sand man's eye, flash burns, niphablepsia, potato eye, or keratoconjunctivitis photoelectrica. ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 See also * 7 References * 8 External links ## Signs and symptoms[edit] Common symptoms include pain, intense tears, eyelid twitching, discomfort from bright light,[1] and constricted pupils. ## Cause[edit] Any intense exposure to UV light can lead to photokeratitis.[2] Common causes include welders who have failed to use adequate eye protection such as an appropriate welding helmet or welding goggles. This is termed arc eye, while photokeratitis caused by exposure to sunlight reflected from ice and snow, particularly at elevation, is commonly called snow blindness.[3] It can also occur due to using tanning beds without proper eyewear. Natural sources include bright sunlight reflected from snow or ice or, less commonly, from sea or sand.[4] Fresh snow reflects about 80% of the UV radiation compared to a dry, sandy beach (15%) or sea foam (25%). This is especially a problem in polar regions and at high altitudes,[3] as with every thousand feet (approximately 305 meters) of elevation (above sea level), the intensity of UV rays increases by four percent.[5] ## Diagnosis[edit] Fluorescein dye staining will reveal damage to the cornea under ultraviolet light.[6] ## Prevention[edit] Snow goggles traditionally used by the Inuit Photokeratitis can be prevented by using sunglasses or eye protection that transmits 5–10% of visible light and absorbs almost all UV rays. Additionally, these glasses should have large lenses and side shields to avoid incidental light exposure. Sunglasses should always be worn, even when the sky is overcast, as UV rays can pass through clouds.[7] The Inuit, Yupik, and other Arctic peoples carved snow goggles from materials such as driftwood or caribou antlers to help prevent snow blindness. Curved to fit the user's face with a large groove cut in the back to allow for the nose, the goggles allowed in a small amount of light through a long thin slit cut along their length. The goggles were held to the head by a cord made of caribou sinew.[8] In the event of missing sunglass lenses, emergency lenses can be made by cutting slits in dark fabric or tape folded back onto itself.[9] The SAS Survival Guide recommends blackening the skin underneath the eyes with charcoal (as the ancient Egyptians did) to avoid any further reflection.[10][11] ## Treatment[edit] The pain may be temporarily alleviated with anaesthetic eye drops for the examination; however, they are not used for continued treatment,[12] as anaesthesia of the eye interferes with corneal healing, and may lead to corneal ulceration and even loss of the eye.[13] Cool, wet compresses over the eyes and artificial tears may help local symptoms when the feeling returns. Nonsteroidal anti-inflammatory drug (NSAID) eyedrops are widely used to lessen inflammation and eye pain, but have not been proven in rigorous trials. Systemic (oral) pain medication is given if discomfort is severe. Healing is usually rapid (24–72 hours) if the injury source is removed. Further injury should be avoided by isolation in a dark room, removing contact lenses, not rubbing the eyes, and wearing sunglasses until the symptoms improve.[3] ## See also[edit] * Actinic conjunctivitis * Albedo * Glare (vision) * Over-illumination * Health effects of sun exposure * Selective yellow * Eye black * Solar Retinopathy ## References[edit] 1. ^ "Arc eye – General Practice Notebook". 2007-03-25. Archived from the original on 2007-03-25. Retrieved 2012-02-07. 2. ^ Porter, Daniel (February 16, 2019). "What is Photokeratitis — Including Snow Blindness?". American Academy of Ophthalmology. Retrieved November 22, 2019. 3. ^ a b c Brozen, Reed; Christian Fromm (February 4, 2008). "Ultraviolet Keratitis". eMedicine. Retrieved November 19, 2008. 4. ^ "Snow blindness". General Practice Notebook. Retrieved November 19, 2008. 5. ^ "Sun Safety". University of California, Berkeley. April 2005. Retrieved November 19, 2008. 6. ^ Reed Brozen (15 April 2011). "Ultraviolet Keratitis". Medscape.com. Retrieved 9 August 2012. 7. ^ Butler Jr, Frank. "Base Camp MD – Guide to High Altitude Medicine". Retrieved November 19, 2008. 8. ^ Mogens Norn (1996). Eskimo Snow Goggles in Danish and Greenlandic Museums, Their Protective and Optical Properties. Museum Tusculanum Press. pp. 3–. ISBN 978-87-635-1233-6. 9. ^ Henry, Jeff. Survive: Snow Country. p. 107. 10. ^ Wiseman, John (2004). "Climate & Terrain". SAS Survival Guide: How to survive in the wild, in any climate on land or at sea. Harper Collins. p. 45. ISBN 0-00-718330-5. 11. ^ "Egyptian Make Up". King-tut.org.uk. 2007-05-29. Archived from the original on 2012-01-26. Retrieved 2012-02-07. 12. ^ "Photokeratitis (Ultraviolet [UV] burn, Arc eye, Snow Blindness)". The College of Optometrists. April 4, 2018. Retrieved November 22, 2019. 13. ^ Khakshoor, Hamid (October 2012). "Anesthetic keratopathy presenting as bilateral Mooren-like ulcers". Clinical Ophthalmology. 6: 1719–1722. doi:10.2147/OPTH.S36611. PMC 3484722. PMID 23118524. ## External links[edit] Classification D * ICD-10: H16.1 * ICD-10-CM: H16.13 * ICD-9-CM: 370.24 * DiseasesDB: 31147 * SNOMED CT: 1714005 External resources * eMedicine: emerg/759 * v * t * e * Diseases of the human eye Adnexa Eyelid Inflammation * Stye * Chalazion * Blepharitis * Entropion * Ectropion * Lagophthalmos * Blepharochalasis * Ptosis * Blepharophimosis * Xanthelasma * Ankyloblepharon Eyelash * Trichiasis * Madarosis Lacrimal apparatus * Dacryoadenitis * Epiphora * Dacryocystitis * Xerophthalmia Orbit * Exophthalmos * Enophthalmos * Orbital cellulitis * Orbital lymphoma * Periorbital cellulitis Conjunctiva * Conjunctivitis * allergic * Pterygium * Pseudopterygium * Pinguecula * Subconjunctival hemorrhage Globe Fibrous tunic Sclera * Scleritis * Episcleritis Cornea * Keratitis * herpetic * acanthamoebic * fungal * Exposure * Photokeratitis * Corneal ulcer * Thygeson's superficial punctate keratopathy * Corneal dystrophy * Fuchs' * Meesmann * Corneal ectasia * Keratoconus * Pellucid marginal degeneration * Keratoglobus * Terrien's marginal degeneration * Post-LASIK ectasia * Keratoconjunctivitis * sicca * Corneal opacity * Corneal neovascularization * Kayser–Fleischer ring * Haab's striae * Arcus senilis * Band keratopathy Vascular tunic * Iris * Ciliary body * Uveitis * Intermediate uveitis * Hyphema * Rubeosis iridis * Persistent pupillary membrane * Iridodialysis * Synechia Choroid * Choroideremia * Choroiditis * Chorioretinitis Lens * Cataract * Congenital cataract * Childhood cataract * Aphakia * Ectopia lentis Retina * Retinitis * Chorioretinitis * Cytomegalovirus retinitis * Retinal detachment * Retinoschisis * Ocular ischemic syndrome / Central retinal vein occlusion * Central retinal artery occlusion * Branch retinal artery occlusion * Retinopathy * diabetic * hypertensive * Purtscher's * of prematurity * Bietti's crystalline dystrophy * Coats' disease * Sickle cell * Macular degeneration * Retinitis pigmentosa * Retinal haemorrhage * Central serous retinopathy * Macular edema * Epiretinal membrane (Macular pucker) * Vitelliform macular dystrophy * Leber's congenital amaurosis * Birdshot chorioretinopathy Other * Glaucoma / Ocular hypertension / Primary juvenile glaucoma * Floater * Leber's hereditary optic neuropathy * Red eye * Globe rupture * Keratomycosis * Phthisis bulbi * Persistent fetal vasculature / Persistent hyperplastic primary vitreous * Persistent tunica vasculosa lentis * Familial exudative vitreoretinopathy Pathways Optic nerve Optic disc * Optic neuritis * optic papillitis * Papilledema * Foster Kennedy syndrome * Optic atrophy * Optic disc drusen Optic neuropathy * Ischemic * anterior (AION) * posterior (PION) * Kjer's * Leber's hereditary * Toxic and nutritional Strabismus Extraocular muscles Binocular vision Accommodation Paralytic strabismus * Ophthalmoparesis * Chronic progressive external ophthalmoplegia * Kearns–Sayre syndrome palsies * Oculomotor (III) * Fourth-nerve (IV) * Sixth-nerve (VI) Other strabismus * Esotropia / Exotropia * Hypertropia * Heterophoria * Esophoria * Exophoria * Cyclotropia * Brown's syndrome * Duane syndrome Other binocular * Conjugate gaze palsy * Convergence insufficiency * Internuclear ophthalmoplegia * One and a half syndrome Refraction * Refractive error * Hyperopia * Myopia * Astigmatism * Anisometropia / Aniseikonia * Presbyopia Vision disorders Blindness * Amblyopia * Leber's congenital amaurosis * Diplopia * Scotoma * Color blindness * Achromatopsia * Dichromacy * Monochromacy * Nyctalopia * Oguchi disease * Blindness / Vision loss / Visual impairment Anopsia * Hemianopsia * binasal * bitemporal * homonymous * Quadrantanopia subjective * Asthenopia * Hemeralopia * Photophobia * Scintillating scotoma Pupil * Anisocoria * Argyll Robertson pupil * Marcus Gunn pupil * Adie syndrome * Miosis * Mydriasis * Cycloplegia * Parinaud's syndrome Other * Nystagmus * Childhood blindness Infections * Trachoma * Onchocerciasis *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Photokeratitis

c0155078

wikipedia

https://en.wikipedia.org/wiki/Photokeratitis

{"umls": ["C0155078"], "wikidata": ["Q829876"]}

Parana hard skin syndrome is a rare genetic skin disorder characterized by very early-onset of progressive skin thickening over the entire body (except for eyelids, neck and ears), progressively limited joint mobility with gradual freezing of joints, and eventual severe chest and abdomen movement restriction, manifesting with restrictive pulmonary disease, which may lead to death. Additional features include severe growth restriction and osteoporosis. There have been no further descriptions in the literature since 1974. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Parana hard skin syndrome

c1850079

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2812

{"gard": ["2598"], "mesh": ["C564905"], "omim": ["260530"], "umls": ["C1850079"], "icd-10": ["L91.8"], "synonyms": ["Hard skin syndrome, Parana type"]}

Dysembryoplastic neuroepithelial tumour DNET SpecialtyNeurosurgery Dysembryoplastic neuroepithelial tumour (DNT, DNET) is a type of brain tumor. Most commonly found in the temporal lobe, DNTs have been classified as benign tumours.[1] These are glioneuronal tumours comprising both glial and neuron cells and often have ties to focal cortical dysplasia.[2] Varying subclasses of DNTs have been presently identified, with dispute existing in the field on how to properly group these classes.[3] The identification of possible genetic markers to these tumours is currently underway.[4] With DNTs often causing epileptic seizures, surgical removal is a common treatment, providing high rates of success.[4] ## Contents * 1 Signs and symptoms * 2 Pathogenesis * 3 Diagnosis * 3.1 Classification * 3.2 Complications in diagnosis * 4 Treatment * 5 Outcomes * 6 Epidemiology * 7 History * 8 See also * 9 References * 10 External links ## Signs and symptoms[edit] Seizures and epilepsy are the strongest ties to dysembryoplastic neuroepithelial tumours.[4] The most common symptom of DNTs are complex partial seizures.[2] Simple DNTs more frequently manifest generalized seizures.[2] In children, DNTs are considered to be the second leading cause of epilepsy.[3] A headache is another common symptom.[2] Other neurological impairments besides seizures are not common.[2] ## Pathogenesis[edit] Dysembryoplastic neuroepithelial tumours are largely glioneuronal tumours, meaning they are composed of both glial cells and neurons.[2] Three subunits of DNTs have been commonly identified:[2] * Simple: Specific glioneuronal elements are the sole components of simple DNTs.[2] * Complex: Glial nodules and/or type 3b focal cortical dysplasia (FCD), in addition to the glioneuronal elements are present in complex DNTs.[4] Both the nodules and FCD can be present within the same tumour, though only 47% of complex DNTs are linked to FCD.[2] * Nonspecific: Nonspecific DNTs are lacking the glioneuronal elements common to DNTs but will show glial nodules and/or type 3b FCD.[2] Eighty-five percent of nonspecific case of DNTs show this FCD.[2] There currently exists some debate over where to make the proper division for the subunits of DNTs. A fourth subunit is sometimes noted as a mixed subunit. This mixed subunit expresses the glial nodules and components of ganglioglioma.[1] Other findings suggest that DNTs require a reclassification to associate them with oligodendrogliomas, tumours that arise from solely glial cells.[3] These reports suggest that the neurons found within DNTs are much rarer than previously reported. For the neurons that are seen in the tumours, it is suggested that they had been trapped within the tumor upon formation, and are not a part of the tumour itself.[3] ## Diagnosis[edit] Dysembryoplastic neuroepithelial tumour, MRI FLAIR. A dysembryoplastic neuroepithelial tumour is commonly diagnosed in patients who are experiencing seizures with magnetic resonance imaging (MRI), electroencephalogram (EEG).[4] A DNT is most commonly diagnosed in children who are experiencing seizures, and when given medication do not respond to them. When an MRI is taken there are lesions located in the temporal parietal region of the brain.[4] Typical DNTs can be detected in an EEG scan when there are rapid repetitive spikes against a contrasted background.[4] EEG are predominantly localized with DNT location in the brain, however there are nonspecific cases in which the location of the tumour is abnormal and not localized.[4] ### Classification[edit] Dysembryoplastic neuroepithelial tumours are classified as a benign tumour, Grade I of the World Health Organization (WHO) classification of brain tumours.[1] This classification by WHO only covers the simple and complex subunits. Groups lacking glioneuronal elements were not considered to have fallen in the same group and have thusly not yet been classified.[1] ### Complications in diagnosis[edit] Dysembryoplastic neuroepithelial tumours are often described as a low grade tumour because about 1.2% people under the age of twenty are affected and about 0.2% over the age of twenty are affected by this tumour.[5] Since its prevalence is small among the population, it often goes misdiagnosed or even at times goes undiagnosed. ## Treatment[edit] The most common course of treatment of DNT is surgery. About 70-90% of surgery are successful in removing the tumour.[4] Since the tumour is most often benign, and does not impose immediate threat, aggressive treatments such as chemotherapy and radiation are not needed, and therefore patients especially children and young adults do not have to go through the side effects of these treatments.[5] In order for the seizures to completely be stopped the tumour needs to be completely removed. For the tumor to be completely removed doctors need to perform resections consisting an anterior temporal lobectomy or amygdalo-hippocampectomy.[4] It has been found that if the tumour is removed by performing resections patients are then recognized as seizure free. On the other hand, if resections are not performed, and the tumour is not completely removed, then the patient is still at risk of experiencing the seizures.[4] In a study done by Bilginer et al., 2009, looking at patients whose tumour was not completely removed, and saw that they were still experiencing seizures, concluding that the incomplete resection as a being a failure.[4] This then causes the patient to undergo a second surgery and remove the tumour in which case causing a complete resection. ## Outcomes[edit] Recurrence of the tumour is highly unlikely if the patient undergoes a complete resection since the tumour is completely taken out.[5] Most of the tumours observed in patients are benign tumours, and once taken out do not cause neurological deficits. However, there have been incidents where the tumour was malignant.[5] There have been cases where the malignant tumour has made a reoccurrence, and this happens at the site of the residual tumour in which an incomplete resection has been done.[4] In this case, a second operation has to be done in order to completely remove the malignant tumour. In a study done with Daumas Duport and Varlet, 2003, they have found that there has been one case so far that the tumour has come back, however, in that particular case the patient underwent an incomplete resection, which led them to perform a second surgery in order to remove it completely.[4] This evidence shows that surgery and complete resections are one of the better approaches in treating dysembryoplastic neuroepithelial tumours. Furthermore, a longer period of epilepsy, and patients older in age are less likely to have a full recovery and remain seizure free. This is the case because their body is not able to recover as quickly, as it would for a child who has had one seizure before.[5] Therefore, it is crucial to diagnose and perform the surgery early in order to make a full recovery. ## Epidemiology[edit] Children are much more prone to exhibit these dysembryoplastic neuroepithelial tumours than adults.[1] The mean age of onset of seizures for children with DNTs is 8.1 years old.[1] Few other neurological deficits are associated with DNTs, so that earlier detection of the tumour before seizure symptoms are rare.[2] DNTs are found in the temporal lobe in 84% of reported cases.[1] In children, DNTs account for 0.6% of diagnosed central nervous system tumours.[2] It has been found that males have a slightly higher risk of having these tumours.[2] Some familial accounts of DNTs have been documented, though the genetic ties have not yet been fully confirmed.[2] ## History[edit] Dysembryoplastic neuroepithelial tumours were usually found during investigation of patients who underwent multiple seizures.[2] The tumours were encountered when the patient required surgery to help with the epilepsy to help with the seizures. The term DNT was first introduced in 1988 by Daumas-Duport, terming it dysembryoplastic, suggesting a dysembryoplastic origin in early onset seizures, and neuroepithelial to allow the wide range of possible varieties of tumours to be put into the category.[2] In 2003 and 2007, DNT was made into further subsets of categories based upon the displayed elements within the tumour.[2] ## See also[edit] * Pilocytic astrocytoma * Oligodendroglioma * Focal cortical dysplasia ## References[edit] 1. ^ a b c d e f g Thom, Maria; Toma, Ahmed; An, Shu; Martinian, Lillian; Hadjivassiliou, George; Ratilal, Bernardo; Dean, Andrew; McEvoy, Andrew; Sisodiya, Sanjay M. (2011-10-01). "One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature". Journal of Neuropathology and Experimental Neurology. 70 (10): 859–878. doi:10.1097/NEN.0b013e3182302475. ISSN 1554-6578. PMID 21937911. 2. ^ a b c d e f g h i j k l m n o p q r Suh, Yeon-Lim (2015-11-01). "Dysembryoplastic Neuroepithelial Tumors". Journal of Pathology and Translational Medicine. 49 (6): 438–449. doi:10.4132/jptm.2015.10.05. ISSN 2383-7837. PMC 4696533. PMID 26493957. 3. ^ a b c d Komori, Takashi; Arai, Nobutaka (2013-08-01). "Dysembryoplastic neuroepithelial tumor, a pure glial tumor? Immunohistochemical and morphometric studies". Neuropathology. 33 (4): 459–468. doi:10.1111/neup.12033. ISSN 1440-1789. PMID 23530928. 4. ^ a b c d e f g h i j k l m n Chassoux, Francine; Daumas-Duport, Catherine (2013-12-01). "Dysembryoplastic neuroepithelial tumors: Where are we now?". Epilepsia. 54: 129–134. doi:10.1111/epi.12457. ISSN 1528-1167. PMID 24328886. 5. ^ a b c d e Shen, JunK; Guduru, Harsha; Lokannavar, HarishS (2012-01-01). "A Rare Case of Dysembryoplastic Neuroepithelial Tumor". Journal of Clinical Imaging Science. 2 (1): 60. doi:10.4103/2156-7514.102057. PMC 3515966. PMID 23230542. ## External links[edit] Classification D * ICD-O: 9413/0 * v * t * e Tumours of the nervous system Endocrine Sellar: * Craniopharyngioma * Pituicytoma Other: * Pinealoma CNS Neuroepithelial (brain tumors, spinal tumors) Glioma Astrocyte * Astrocytoma * Pilocytic astrocytoma * Pleomorphic xanthoastrocytoma * Subependymal giant cell astrocytoma * Fibrillary astrocytoma * Anaplastic astrocytoma * Glioblastoma multiforme Oligodendrocyte * Oligodendroglioma * Anaplastic oligodendroglioma Ependyma * Ependymoma * Subependymoma Choroid plexus * Choroid plexus tumor * Choroid plexus papilloma * Choroid plexus carcinoma Multiple/unknown * Oligoastrocytoma * Gliomatosis cerebri * Gliosarcoma Mature neuron * Ganglioneuroma: Ganglioglioma * Retinoblastoma * Neurocytoma * Dysembryoplastic neuroepithelial tumour * Lhermitte–Duclos disease PNET * Neuroblastoma * Esthesioneuroblastoma * Ganglioneuroblastoma * Medulloblastoma * Atypical teratoid rhabdoid tumor Primitive * Medulloepithelioma Meninges * Meningioma * Hemangiopericytoma Hematopoietic * Primary central nervous system lymphoma PNS: * Nerve sheath tumor * Cranial and paraspinal nerves * Neurofibroma * Neurofibromatosis * Neurilemmoma/Schwannoma * Acoustic neuroma * Malignant peripheral nerve sheath tumor Other * WHO classification of the tumors of the central nervous system Note: Not all brain tumors are of nervous tissue, and not all nervous tissue tumors are in the brain (see brain metastasis). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Dysembryoplastic neuroepithelial tumour

c1266177

wikipedia

https://en.wikipedia.org/wiki/Dysembryoplastic_neuroepithelial_tumour

{"gard": ["10640"], "umls": ["C1266177"], "orphanet": ["251946"], "wikidata": ["Q824595"]}

Thyroid dyshormonogenesis Other namesDyshormogenetic goiter Thyroid dyshormonogenesis is inherited in an autosomal recessive manner SpecialtyEndocrinology Thyroid dyshormonogenesis is a rare condition due to genetic defects in the synthesis of thyroid hormones.[1][2] Patients develop hypothyroidism with a goiter. It is due to either deficiency of thyroid enzymes, inability to concentrate, or ineffective binding. ## Contents * 1 Cause * 2 Diagnosis * 2.1 Types * 3 Treatment * 4 References * 5 External links ## Cause[edit] This is due to inability to produce thyroid hormones due to congenital absence of peroxidase or dehalogenase enzymes[citation needed] ## Diagnosis[edit] ### Types[edit] One particular familial form is associated with sensorineural deafness (Pendred's syndrome).[citation needed] OMIM includes the following: Type OMIM Gene Type 1 274400 SLC5A5 Type 2A 274500 TPO Type 2B 274600 (Pendred) SLC26A4 Type 3 274700 TG Type 4 274800 IYD Type 5 274900 DUOXA2 Type 6 607200 DUOX2 ## Treatment[edit] These patients respond well to levothyroxine (synthetic T4) and the goiter may decrease in size if any. They may not require surgery at any time.[citation needed] ## References[edit] 1. ^ Avbelj M, Tahirovic H, Debeljak M, et al. (May 2007). "High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis". Eur. J. Endocrinol. 156 (5): 511–9. doi:10.1530/EJE-07-0037. PMID 17468186. 2. ^ Kumar PG, Anand SS, Sood V, Kotwal N (December 2005). "Thyroid dyshormonogenesis" (PDF). Indian Pediatr. 42 (12): 1233–5. PMID 16424561. ## External links[edit] Classification D * ICD-10: E07.1 * ICD-9-CM: 246.1 * MeSH: C564766 * DiseasesDB: 9771 External resources * Orphanet: 95716 * v * t * e Thyroid disease Hypothyroidism * Iodine deficiency * Cretinism * Congenital hypothyroidism * Myxedema * Myxedema coma * Euthyroid sick syndrome * Signs and symptoms * Queen Anne's sign * Woltman sign * Thyroid dyshormonogenesis * Pickardt syndrome Hyperthyroidism * Hyperthyroxinemia * Thyroid hormone resistance * Familial dysalbuminemic hyperthyroxinemia * Hashitoxicosis * Thyrotoxicosis factitia * Thyroid storm Graves' disease * Signs and symptoms * Abadie's sign of exophthalmic goiter * Boston's sign * Dalrymple's sign * Stellwag's sign * lid lag * Griffith's sign * Möbius sign * Pretibial myxedema * Graves' ophthalmopathy Thyroiditis * Acute infectious * Subacute * De Quervain's * Subacute lymphocytic * Palpation * Autoimmune/chronic * Hashimoto's * Postpartum * Riedel's Enlargement * Goitre * Endemic goitre * Toxic nodular goitre * Toxic multinodular goiter * Thyroid nodule * Colloid nodule * v * t * e Congenital endocrine disorders Pituitary * Congenital hypopituitarism Thyroid * Thyroid disease * Persistent thyroglossal duct * Thyroglossal cyst * Congenital hypothyroidism * Thyroid dysgenesis * Thyroid dyshormonogenesis * Pendred syndrome Parathyroid * Congenital absence of parathyroid Adrenal * Absent adrenal gland * v * t * e Genetic disorder, membrane: Solute carrier disorders 1-10 * SLC1A3 * Episodic ataxia 6 * SLC2A1 * De Vivo disease * SLC2A5 * Fructose malabsorption * SLC2A10 * Arterial tortuosity syndrome * SLC3A1 * Cystinuria * SLC4A1 * Hereditary spherocytosis 4/Hereditary elliptocytosis 4 * SLC4A11 * Congenital endothelial dystrophy type 2 * Fuchs' dystrophy 4 * SLC5A1 * Glucose-galactose malabsorption * SLC5A2 * Renal glycosuria * SLC5A5 * Thyroid dyshormonogenesis type 1 * SLC6A19 * Hartnup disease * SLC7A7 * Lysinuric protein intolerance * SLC7A9 * Cystinuria 11-20 * SLC11A1 * Crohn's disease * SLC12A3 * Gitelman syndrome * SLC16A1 * HHF7 * SLC16A2 * Allan–Herndon–Dudley syndrome * SLC17A5 * Salla disease * SLC17A8 * DFNA25 21-40 * SLC26A2 * Multiple epiphyseal dysplasia 4 * Achondrogenesis type 1B * Recessive multiple epiphyseal dysplasia * Atelosteogenesis, type II * Diastrophic dysplasia * SLC26A4 * Pendred syndrome * SLC35C1 * CDOG 2C * SLC39A4 * Acrodermatitis enteropathica * SLC40A1 * African iron overload see also solute carrier family This article about an endocrine, nutritional, or metabolic disease is a stub. You can help Wikipedia by expanding it. * v * t * e *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Thyroid dyshormonogenesis

c1848805

wikipedia

https://en.wikipedia.org/wiki/Thyroid_dyshormonogenesis

{"mesh": ["C564766"], "umls": ["C1848805"], "icd-9": ["246.1"], "icd-10": ["E07.1"], "orphanet": ["95716"], "wikidata": ["Q7799748"]}

Mounier-Kuhn syndrome is a lung disorder that causes the respiratory tract to dilate or enlarge. People with this condition develop frequent respiratory tract infections and recurrent cough. The condition can be diagnosed by lung function tests, bronchoscopy, and a chest CT scan. The cause of Mounier-Kuhn syndrome is unknown, although cigarette smoke and air pollutants may act as irritating factors. Some cases are associated with connective tissue diseases such as Ehlers-Danlos syndrome, Marfan syndrome, and cutis laxa and may be inherited. Treatment typically involves chest physical therapy and antibiotics to treat infections. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Mounier-Kuhn syndrome

c0040587

gard

https://rarediseases.info.nih.gov/diseases/3793/mounier-kuhn-syndrome

{"mesh": ["D014137"], "omim": ["275300"], "orphanet": ["3347"], "synonyms": ["Congenital tracheobronchomegaly", "Mounier Kuhn syndrome"]}

Transient myeloproliferative syndrome is a leukemoid reaction that occurs in some newborn infants with Down syndrome and rarely in phenotypically normal infants (Seibel et al., 1984). In 9 Down syndrome patients with transient myeloproliferative syndrome, Niikawa et al. (1991) found that the mode of inheritance of centromeric chromosomal markers was compatible with duplication of one parental chromosome 21. Therefore, they proposed a hypothesis of 'disomic homozygosity' of a mutant gene on chromosome 21 as the causative mechanism (Abe et al., 1989). Niikawa et al. (1991) observed a Down syndrome patient who had an inversion of one chromosome 21; by studies with DNA polymorphic markers in 5 other patients, they obtained results suggesting that the putative gene (which they symbolized TMS) was located at 21q11.2. Cytogenetic and molecular studies demonstrated that in Down syndrome associated with transient abnormal myelopoiesis, trisomy 21 had arisen much more frequently through mitotic (or meiosis II) nondisjunctions than through meiosis I errors (Shen et al., 1995). This supported the notion of 'disomic homozygosity' of a certain locus on chromosome 21 in 21-trisomic cells. In these patients there was no evidence of maternal age effect (Iselius et al., 1990). Like Niikawa et al. (1991), Shen et al. (1995) mapped the putative TAM gene to the pericentromeric region, 21q11.1-q11.2. In the 7-day-old male with Down syndrome and TAM reported by Niikawa et al. (1991), Ohta et al. (1996) isolated a cosmid clone corresponding to the inv(21) breakpoint, on the presumption that in this patient the putative TAM gene was disrupted by the break. The mother had the same inversion, and the father had a normal karyotype. The leukemoid reaction disappeared spontaneously several months after birth. Ohta et al. (1996) noted there was no evidence of imprinting on chromosome 21; thus, they speculated that disruption of a putative TAM gene may be the basis of the abnormality. The existence of a fusion gene is unlikely because almost no cases of TAM in Down syndrome had been reported with a rearranged chromosome 21 such as was observed in this critical case. Inheritance \- Possible disomic homozygosity at 21q11.2 Misc \- Usually in newborns with Down syndrome \- rarely in normals Lab \- Leukocytosis Heme \- Transient myeloproliferative syndrome ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MYELOPROLIFERATIVE SYNDROME, TRANSIENT

c1834582

omim

https://www.omim.org/entry/159595

{"doid": ["0060888"], "mesh": ["C563551"], "omim": ["159595"], "orphanet": ["420611"], "synonyms": ["Alternative titles", "MST", "LEUKEMIA, TRANSIENT", "TRANSIENT ABNORMAL MYELOPOIESIS"]}

For the abnormal fear of women, see Gynophobia. Gymnophobia SpecialtyPsychiatry SymptomsFear of nudity Gymnophobia is a fear (phobia) of nudity. ## Contents * 1 Symptoms * 2 Terminology * 3 See also * 4 References ## Symptoms[edit] Gymnophobics experience anxiety from nudity, even if they realize their fear is irrational. They may worry about seeing others naked, being seen naked, or both. Their fear may stem from a general anxiety about sexuality, from a fear that they are physically inferior, or from a fear that their nakedness leaves them exposed and unprotected.[1] Gymnophobia refers to an actual fear of nudity, but most sufferers with the condition learn how to function in general society despite the condition. They may, for example, avoid changing rooms, washrooms, showers, and beaches. However, the condition can be regarded as an anxiety disorder if the person cannot control the phobia or it is interfering with their daily life.[2] Gymnophobia has been likened to the fictional condition "never-nude" portrayed in the comedy series Arrested Development.[3][4][5][6][7] ## Terminology[edit] The term gymnophobia comes from the Greek γυμνός - gumnos, "naked"[8] and φόβος - phobos, "fear".[9] A phobia that has a significant amount of overlap with gymnophobia is dishabiliophobia, which is the fear of undressing in front of others.[10] ## See also[edit] * Sex-negativity * List of phobias * Nudity portal ## References[edit] 1. ^ "Gymnophobia". MedicineNet. 2. ^ Edmund J. Bourne (2005-05-01). The Anxiety & Phobia Workbook. New Harbinger Publications Incorporated. ISBN 978-1-57224-413-9. 3. ^ Nick Haslam (23 May 2013). "No more cover-up: bared bodies and never nudes exposed". The Conversation. 4. ^ Meghan Holohan. "Gymnophobics are real-life 'never-nudes'". NBC News. 5. ^ "Tobias Fünke's "nevernude" problem is real. It's called "gymnophobia," or the fear of nude bodies". Mental Floss. Archived from the original on 2013-12-30. Retrieved 2013-12-30. 6. ^ Tracie Egan Morrissey. "'Never Nude' Is Actually a Real Condition". Jezebel. 7. ^ "Here's a timely reminder that "never-nudes" aren't just something Arrested Development made up". 8. ^ γυμνός, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus 9. ^ φόβος, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus 10. ^ Greene, Elliot (2013). The Psychology of the Body. p. 240. Look up gymnophobia in Wiktionary, the free dictionary. * v * t * e Nudity Naturism * Christian naturism * Freikörperkultur * Gay naturism * Gymnosophy * Naturist magazines * Naturist resort * Anarchist naturism Nude recreation * Nude beach * Nude swimming * Streaking * Naked yoga * Public bathing * Sauna * Massage * Naked party * Nude wedding * Nude beaches * Clothing-optional events Depictions of nudity * Nude (art) * Body painting * Naked News * Nude modeling (art) * Nudity in film * Nude photography * Nude photography (art) * Glamour photography * Nudity in American television * Nudity in music videos * Nudity in advertising * Nude calendar Nudity and sexuality * Intimate part * Exhibitionism * Voyeurism * Anasyrma * Candaulism * Mooning * Striptease * Stripper * feminist stripper * Softcore pornography * Erotic photography * Sexual objectification * Clothed female, naked male * Clothed male, naked female Issues in social nudity * Indecent exposure * Obscenity * Toplessness * Topfreedom * Wardrobe malfunction * Nudity and protest * Sex segregation * Breastfeeding in public * Dress code * Clothing laws by country * Modesty * Nudity in religion * Awrah * Strip search * Undress code * Barefoot By location * Africa * Asia * Europe * North America * Oceania * South America Social nudity advocates * Kurt Barthel * Lee Baxandall * Paul Bindrim * Ilsley Boone * Henry S. Huntington * Heinrich Pudor * Elton Raymond Shaw * Richard Ungewitter See also * History of nudity * Timeline of non-sexual social nudity * Nudity in combat * Nudity clause * Imagery of nude celebrities * Social nudity organizations *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Gymnophobia

None

wikipedia

https://en.wikipedia.org/wiki/Gymnophobia

{"wikidata": ["Q1010522"]}