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For a general phenotypic description and a discussion of genetic heterogeneity of basal cell carcinoma, see BCC1 (605462). Mapping In a genomewide association study of 3,473 basal cell carcinoma (BCC) cases and 37,915 controls of European ancestry, Stacey et al. (2009) detected significant association of the A allele of a single-nucleotide polymorphism (SNP) on chromosome 12q13, rs11170164 with risk of BCC (odds ratio = 1.35; combined P value 2.1 x 10(-9)). This SNP encodes a nonconservative gly-to-glu substitution at codon 138 (G138E) in the keratin-5 gene (KRT5; 148040). There was no evidence of association of the rs11170164 variant with cutaneous melanoma or pigmentary traits. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

BASAL CELL CARCINOMA, SUSCEPTIBILITY TO, 4

c2751602

omim

https://www.omim.org/entry/613061

{"omim": ["613061"]}

Myotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Although myotonia can affect any skeletal muscles, including muscles of the face and tongue, it occurs most often in the legs. Myotonia causes muscle stiffness that can interfere with movement. In some people the stiffness is very mild, while in other cases it may be severe enough to interfere with walking, running, and other activities of daily life. These muscle problems are particularly noticeable during movement following a period of rest. Many affected individuals find that repeated movements can temporarily alleviate their muscle stiffness, a phenomenon known as the warm-up effect. The two major types of myotonia congenita are known as Thomsen disease and Becker disease. These conditions are distinguished by the severity of their symptoms and their patterns of inheritance. Becker disease usually appears later in childhood than Thomsen disease and causes more severe muscle stiffness, particularly in males. People with Becker disease often experience temporary attacks of muscle weakness, particularly in the arms and hands, brought on by movement after periods of rest. They may also develop mild, permanent muscle weakness over time. This muscle weakness is not seen in people with Thomsen disease. ## Frequency Myotonia congenita is estimated to affect 1 in 100,000 people worldwide. This condition is more common in northern Scandinavia, where it occurs in approximately 1 in 10,000 people. ## Causes Mutations in the CLCN1 gene cause myotonia congenita. The CLCN1 gene provides instructions for making a protein that is critical for the normal function of skeletal muscle cells. For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contraction and relaxation are controlled by the flow of charged atoms (ions) into and out of muscle cells. Specifically, the protein produced from the CLCN1 gene forms a channel that controls the flow of negatively charged chlorine atoms (chloride ions) into these cells. The main function of this channel is to stabilize the cells' electrical charge, which prevents muscles from contracting abnormally. Mutations in the CLCN1 gene alter the usual structure or function of chloride channels. The altered channels cannot properly regulate ion flow, reducing the movement of chloride ions into skeletal muscle cells. This disruption in chloride ion flow triggers prolonged muscle contractions, which are the hallmark of myotonia. ### Learn more about the gene associated with Myotonia congenita * CLCN1 ## Inheritance Pattern The two forms of myotonia congenita have different patterns of inheritance. Thomsen disease 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 most cases, an affected person has one parent with the condition. Becker disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition. Because several CLCN1 mutations can cause either Becker disease or Thomsen disease, doctors usually rely on characteristic signs and symptoms to distinguish the two forms of myotonia congenita. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Myotonia congenita

c2936781

medlineplus

https://medlineplus.gov/genetics/condition/myotonia-congenita/

{"gard": ["12301"], "mesh": ["D009224"], "omim": ["160800", "255700"], "synonyms": []}

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with severe motor impairment and absent language (NEDMIAL) is caused by heterozygous mutation in the DHX30 gene (DHX30; 616423) on chromosome 3p21. Description NEDMIAL is a neurodevelopmental disorder characterized by severely delayed psychomotor development and hypotonia apparent from early infancy, resulting in feeding difficulties, ataxic gait or inability to walk, minimal or absent speech development, and severe intellectual disability, often with behavioral abnormalities, such as hand-flapping. Additional common features may include sleep disorder, nonspecific dysmorphic facial features, and joint hyperlaxity (summary by Lessel et al., 2017). Clinical Features Lessel et al. (2017) reported 12 unrelated patients, ranging in age from 3 to 17 years, with a severe neurodevelopmental disorder apparent from early infancy. Most of the patients were Caucasian of European descent, although 2 were of Hispanic descent, 1 was Turkish, and 1 was of Yemenite/Tripolitan Jewish descent. The patients presented in infancy with delayed psychomotor development, hypotonia, and feeding difficulties. All had severe intellectual disability. Many had behavioral abnormalities, including autistic features, aggressive behavior, low frustration tolerance, and stereotypies, although some were described as pleasant or smiling. All but 2 patients were nonverbal and had very poor or absent communication skills, although a few had some nonverbal gestures and sounds. Six patients never achieved independent ambulation and 4 walked with an ataxic gait. Three patients had seizures and 1 had hearing loss. Brain imaging was normal in some patients, but showed nonspecific abnormalities in others, including cerebral atrophy, cerebellar atrophy, enlarged ventricles, and delayed myelination. Additional common features included sleep abnormalities, bruxism, joint hypermobility, persistent fingerpads, tapering fingers, flat feet, poor fine motor skills, and involuntary movements, such as dystonia or chorea. Many patients had variable dysmorphic facial features, such as small head, strabismus, epicanthal folds, synophrys, high palate, low-set ears, orofacial hypotonia, full eyelids, and eversion of the lower lip. The patients were severely disabled; none attended school, many had no purposeful hand movements and had impaired fine motor skills, and at least 1 patient was noted to be doubly incontinent at age 13 years. Two of the patients (probands F and G) had previously been reported by Eldomery et al. (2017) as part of a large study of patients who underwent exome sequencing. Inheritance The DHX30 mutations in all 12 patients with NEDMIAL reported by Lessel et al. (2017) occurred de novo. Molecular Genetics In 12 unrelated patients with NEDMIAL, Lessel et al. (2017) identified 6 different de novo heterozygous missense mutations in the DHX30 gene (616423.0001-616423.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. All mutations occurred within the helicase core region, which is predicted to mediate either ATP binding/hydrolysis or RNA recognition. In vitro cellular expression studies showed that all 5 variants that occurred in the ATP binding motifs II or VI (616423.0002-616423.0006) showed markedly reduced ATPase activities compared to wildtype. The 1 remaining variant (R493H; 616423.0001), located in the putative RNA-binding motif Ia, did not alter RNA-dependent activity of DHX30, but did interfere with the binding capacity toward some target RNAs. Transfection of the mutations into a human cell line (U2OS) showed that the mutant proteins accumulated abnormally in cytoplasmic stress granules, which was associated with a global decrease in protein synthesis. Lessel et al. (2017) hypothesized that the DHX30 variants generate a chronic stress condition whereby pervasive and pronounced stress granule assembly induces impairments in the local regulation of translation, thus adversely affecting neurodevelopmental processes. INHERITANCE \- Autosomal dominant HEAD & NECK Head \- Small head circumference Face \- Dysmorphic facial features, variable \- Orofacial hypotonia Ears \- Low-set ears Eyes \- Strabismus \- Synophrys \- Epicanthal folds \- Full eyelids Mouth \- High-arched palate \- Everted lower lip \- Bruxism ABDOMEN Gastrointestinal \- Feeding difficulties SKELETAL \- Joint hypermobility Hands \- Tapering fingers Persistent fetal fingerpads Feet \- Flat feet MUSCLE, SOFT TISSUES \- Hypotonia NEUROLOGIC Central Nervous System \- Global developmental delay \- Intellectual disability \- Absent speech \- Delayed walking \- Inability to walk \- Ataxia \- Poor fine motor skills \- Seizures (in some patients) \- Involuntary movements \- Dystonia \- Chorea \- Sleep disorder \- Brain imaging abnormalities (in some patients) \- Cerebral atrophy \- Cerebellar atrophy \- Enlarged ventricles \- Delayed myelination Behavioral Psychiatric Manifestations \- Behavioral abnormalities, variable \- Autistic features MISCELLANEOUS \- Onset in infancy \- Variable dysmorphic features \- Patients are severely impaired \- De novo mutation MOLECULAR BASIS \- Caused by mutation in the DEAH box polypeptide 30 gene (DHX30, 616423.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

NEURODEVELOPMENTAL DISORDER WITH SEVERE MOTOR IMPAIRMENT AND ABSENT LANGUAGE

c4540496

omim

https://www.omim.org/entry/617804

{"omim": ["617804"]}

A rare, primary immunodeficiency characterized by variable combination of enteropathy, hypogammaglobulinemia, recurrent respiratory infections, granulomatous lymphocytic interstitial lung disease, lymphocytic infiltration of non-lymphoid organs (intestine, lung, brain, bone marrow, kidney), autoimmune thrombocytopenia or neutropenia, autoimmune hemolytic anemia and lymphadenopathy. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency

c4015214

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=436159

{"gard": ["12316"], "omim": ["616100"], "icd-10": ["D84.8"], "synonyms": ["ALPS due to CTLA4 haploinsuffiency", "CHAI", "CTLA-4 haploinsufficiency with autoimmune infiltration disease"]}

## Description Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease that usually affects middle-aged women and eventually leads to liver failure (summary by Kaplan, 1996). For a discussion of genetic heterogeneity of primary biliary cirrhosis (PBC), see PBC1 (109720). Mapping To replicate the findings of Hirschfield et al. (2009) and to evaluate the relevance of identified loci to PBC susceptibility, Hirschfield et al. (2010) tested an additional independent cohort of 857 individuals with PBC and 3,198 controls, all of European descent, for PBC associations with 36 SNPs across 24 loci. The combination of these replication results and the prior genomewide association data yielded a genetic dataset derived from 1,351 PBC cases and 4,700 controls. The locus on chromosome 7q32 near the IRF5 (607218)-TNPO3 (610032) genes was confirmed by this analysis (SNP rs10488631, replication dataset p = 1.13 x 10(-8), OR = 1.58; combined dataset p = 8.66 x 10(-13), OR = 1.57). Fine mapping at this locus showed that the strongest signals were from rs12539741 and rs2070197 alleles. These variants map to just 3-prime of the IRF5 coding region and are in tight linkage disequilibrium with one another, and their associations with PBC reached fine-mapping p values of 1.65 x 10(-10) (odds ratio = 1.63) and 3.74 x 10(-10) (odds ratio = 1.62), respectively. Liu et al. (2010) identified rs10488631 at chromosome 7q32 as a risk allele for primary biliary cirrhosis with an odds ratio of 1.63, p = 2.78 x 10(-10). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

BILIARY CIRRHOSIS, PRIMARY, 4

c0008312

omim

https://www.omim.org/entry/614220

{"doid": ["12236"], "mesh": ["D008105"], "omim": ["614220"], "orphanet": ["186"]}

Mitochondrial DNA depletion syndrome, encephalomyopathic form is a group of mitochondrial DNA maintenance syndrome diseases characterized by predominantly neuromuscular manifestations with typically infantile onset of hypotonia, lactic acidosis, psychomotor delay, progressive hyperkinetic-dystonic movement disorders, external ophtalmoplegia, sensosineural hearing loss, generalized seizures and variable renal tubular dysfunction. It may be associated with a broad range of other clinical features. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Mitochondrial DNA depletion syndrome, encephalomyopathic form

c2749864

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=254803

{"omim": ["612073", "612075"], "icd-10": ["E88.8"], "synonyms": ["mtDNA depletion syndrome, encephalomyopathic form"]}

A form of focal dystonia, affecting the lower part of the face and jaws. It is characterized by sustained or repetitive involuntary jaw and tongue movements and facial grimacing caused by involuntary spasms of the masticatory, facial, pharyngeal, lingual, and lip muscles. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Oromandibular dystonia

c0393607

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93958

{"umls": ["C0393607"], "icd-10": ["G24.4"]}

Megaesophagus Other namesEsophageal dilatation Chagas megaseophagus SpecialtyGastroenterology Megaesophagus, also known as esophageal dilatation, is a disorder of the esophagus in humans and other mammals, whereby the esophagus becomes abnormally enlarged. Megaesophagus may be caused by any disease which causes the muscles of the esophagus to fail to properly propel food and liquid from the mouth into the stomach (that is, a failure of peristalsis). Food can become lodged in the flaccid esophagus, where it may decay, be regurgitated, or may be inhaled into the lungs (leading to aspiration pneumonia). ## Contents * 1 Humans * 2 Other animals * 2.1 Dogs * 2.1.1 Diagnosis * 2.1.2 Affected breeds * 2.2 Cats * 2.3 Horses * 3 References * 4 External links ## Humans[edit] Megaesophagus may occur secondary to diseases such as achalasia or Chagas disease. Achalasia is caused by a loss of ganglion cells in the myenteric plexus. There is a marked lack of contraction within the muscles involved in peristalsis with a constant contraction of the lower esophageal sphincter. Dilation of the esophagus results in difficulty swallowing. Retention of food bolus is also noted.[1] ## Other animals[edit] ### Dogs[edit] An x-ray of the thorax of a dog with megaoesophagus. The edges of the esophagus are shown by the yellow arrows. (In this image, the head end of the dog is to the right, and the tail end is to the left Megaesophagus can also be a symptom of the disease myasthenia gravis. Myasthenia gravis is a neuromuscular disease where the primary symptom is weakness in various body parts of the dog. However, when myasthenia gravis occurs in older dogs it is thought of as an immune-mediated disease. Often when myasthenia gravis is diagnosed in older dogs the first symptom the dog may manifest is megaesophagus. Myasthenia gravis occurs when acetylcholine receptors (nicotinic acetylcholine receptors) fail to function properly, so that the muscle is not stimulated to contract. There is an invention known as the "bailey chair" that uses the force of gravity to push down liquids and food into the dog's stomach. Usually dogs are known to understand when it's time to eat in their bailey chair, and this helps prevent issues. Bailey chairs can be made and are sold. In two unrelated incidents in Latvia and Australia megaesophagus developed in dogs that had eaten certain brands of dog food, however no agent that could have caused the disorder has been found in lab tests of the food.[2][3][4] #### Diagnosis[edit] An important distinction in recognizing megaesophagus is the difference between when a dog regurgitates or vomits. When a dog regurgitates there is usually not as much effort involved as when a dog vomits. Often when regurgitating, the dog will tip its head down and the liquid and/or food will almost appear to "spill out" of its throat. One of the primary dangers to a dog with megaesophagus is aspiration pneumonia. Because the food stays lodged in the throat, it can often be inhaled into the lungs causing aspiration pneumonia. One way to avoid this is to make sure that every time the dog eats or drinks anything, that the dog sits for at least 10 minutes afterwards or is held in a sitting up or begging position. This disorder has a guarded prognosis, however a successful management technique is vertical feeding in a Bailey Chair.[5] #### Affected breeds[edit] * Chihuahua * Basset Fauve de Bretagne * Bernese Mountain Dog * Bichon Frise * Boston Terrier * Dachshund * English Springer Spaniel * French Bulldog * German Shepherd * Golden Retriever * Great Dane * Greyhound * Yorkshire Terrier * Irish Setter * Irish Wolfhound * Italian Greyhound * Labrador Retriever * Miniature Schnauzer * Newfoundland dog * Rottweiler * Shar Pei * Shih Tzu * Welsh Corgi * Welsh Terrier * Wire Fox Terrier * Cocker Spaniel ### Cats[edit] Affected breeds: * American Shorthair * Persian (cat) * Siamese (cat) ### Horses[edit] Megaesophagus is rare in horses.[6] It is more frequently reported in Friesian horses than in other breeds.[7] Congenital megaesophagus is usually identified when a foal begins to eat solid food from the ground; prior to this, as the foal nurses milk from its mother, the milk passes easily down into the stomach.[8] The most common signs are difficulty swallowing (dysphagia) and inhalational pneumonia.[8] ## References[edit] 1. ^ Lewandowski, A. (2009). "Diagnostic criteria and surgical procedure for megaesophagus--a personal experience". Diseases of the Esophagus. 22 (4): 305–309. doi:10.1111/j.1442-2050.2008.00897.x. ISSN 1442-2050. PMID 19207550. 2. ^ Mičāne, Ingrīda. "Jauns 'megaesophagus' uzliesmojuma precedents suņiem – šoreiz Austrālijā". Latvijas Avīze. Retrieved 30 March 2018. 3. ^ Matīse-VanHoutana, Ilze. "I did my research, blew the whistle and found myself at war". YouTube. Retrieved 13 December 2018. 4. ^ DONNELLAN, ANGELIQUE; SCOPELIANOS, SARAH. "Pet food Advance Dermocare linked to megaesophagus outbreak, research shows". Retrieved 13 December 2018.[permanent dead link] 5. ^ "Megaesophagus". vca_corporate. Retrieved 2019-12-29. 6. ^ Broekman, LE; Kuiper, D (December 2002). "Megaesophagus in the horse. A short review of the literature and 18 own cases". The Veterinary Quarterly. 24 (4): 199–202. doi:10.1080/01652176.2002.9695136. PMID 12540136. 7. ^ Ploeg, M; Gröne, A; Saey, V; de Bruijn, CM; Back, W; van Weeren, PR; Scheideman, W; Picavet, T; Ducro, BJ; Wijnberg, I; Delesalle, C (November 2015). "Esophageal dysfunction in Friesian horses: morphological features". Veterinary Pathology. 52 (6): 1142–7. doi:10.1177/0300985814556780. PMID 25367366. 8. ^ a b McAuliffe, Siobhan Brid (2013). "Esophageal dilatation/megaesophagus". Knottenbelt and Pascoe's color atlas of diseases and disorders of the horse (2nd ed.). Elsevier Saunders. pp. 23–24. ISBN 9780723436607. ## External links[edit] Classification D * ICD-9-CM: 530.0 * DiseasesDB: 31519 * Canine megaesophagus * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Megaesophagus

c0025164

wikipedia

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

{"mesh": ["D004931"], "umls": ["C0025164"], "icd-9": ["530.0"], "wikidata": ["Q1713499"]}

A number sign (#) is used with this entry because spastic ataxia of the Charlevoix-Saguenay type (SACS, or ARSACS) is caused by homozygous or compound heterozygous mutation in the gene encoding the sacsin protein (SACS; 604490) on chromosome 13q12 For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600). Description Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a complex neurodegenerative disorder usually characterized by early childhood onset of cerebellar ataxia, pyramidal tract signs, and peripheral neuropathy. Most patients become wheelchair-bound; cognitive function is usually not affected. Some patients may have atypical features, such as later onset or initial presentation of peripheral neuropathy (summary by Baets et al., 2010). Clinical Features In French Canada, Bouchard et al. (1978) identified a distinctive form of early-onset spastic ataxia. They examined 42 patients from 24 sibships and knew of 24 other affected persons. None of the patients ever walked normally. The disease had a long course with little progression after age 20 years. The oldest patient was aged 52 years. Features include ataxia, dysarthria, spasticity, distal muscle wasting, nystagmus, defect in conjugate pursuit ocular movements, retinal striation (from prominent retinal nerves) obscuring the retinal blood vessels in places, and the frequent presence (57%) of mitral valve prolapse. The disorder bore some similarity to Troyer syndrome (275900). However, nystagmus and abnormal pursuit movements were not noted in Troyer syndrome. Inheritance was clearly autosomal recessive. Bouchard et al. (1978) suggested that the gene originated from a couple that lived in Quebec City about 1650 and was also ancestral to many cases of typical Friedreich ataxia (229300). Bouchard et al. (1979) defined electromyographic differences from Friedreich ataxia. In ARSACS (an acronym suggested by Bouchard et al., 1979), more EMG signs of denervation were found and nerve conduction was slower. In the 2 conditions an identical and important abnormality of sensory nerve conduction was found. Bouchard (1985) knew of almost 200 patients with ARSACS and commented on 'the remarkable increased visibility of the retinal nerve fibers, which is characteristic of the disease.' Bouchard et al. (1979) pointed to greater incidence of EEG changes and lower IQ in ARSACS than in Friedreich ataxia. By CT scan and/or pneumoencephalography, Langelier et al. (1979) found in all 9 cases studied cerebellar atrophy limited in the main to the superior part of the vermis and anterior lobes. Richter et al. (1999) commented on the clinical homogeneity of ARSACS with early-onset spastic ataxia, with prominent myelinated retinal nerve fibers as a particularly distinctive feature. More than 300 patients had been identified by their group; most of the families originated in the Charlevoix-Saguenay region of northeastern Quebec, where the carrier prevalence had been estimated to be 1/22. ### Clinical Variability El Euch-Fayache et al. (2003) reported 4 Tunisian families, 3 of which were consanguineous, with autosomal recessive ataxia showing linkage to the ARSACS locus. Mean age at onset was 4.5 years, and the clinical phenotype was homogeneous, with progressive cerebellar ataxia, a pyramidal syndrome with brisk knee reflexes and absent ankle reflexes, and a peripheral neuropathy. Several patients had pes cavus, hammertoes, and/or scoliosis. The authors commented on the phenotypic similarities to ARSACS, but noted that fundi with prominent retinal myelinated fibers were rarely encountered in their patients. Criscuolo et al. (2004) and Grieco et al. (2004) reported 4 patients from Italy, 2 of whom were sibs, with ARSACS. All patients had typical signs and symptoms associated with the disorder, but retinal striation was either mild or not observed. Ogawa et al. (2004) reported 2 Japanese sibs with ARSACS who also had mild retinal striation. The combined findings of the 3 reports broadened the worldwide distribution of the disorder and suggested variability in severity of retinal striation among different ethnic groups. Shimazaki et al. (2005) reported 2 Japanese brothers with ARSACS confirmed by genetic analysis (604490.0009). The phenotype was unique in that neither patient had spasticity or hyperreflexia, although both had extensor plantar responses, indicating pyramidal tract dysfunction. The authors hypothesized that the severe peripheral nerve degeneration found on sural nerve biopsy may have masked any spasticity. The younger brother had mildly decreased IQ scores. Muona et al. (2015) reported 2 unrelated patients with ARSACS, confirmed by genetic analysis, who were ascertained from a cohort of 84 patients with progressive myoclonic epilepsy who underwent exome sequencing. One patient had ataxia in early infancy, delayed motor development, intellectual disability, and absence seizures at age 3 years. She developed progressive myoclonic epilepsy with action myoclonus at age 14 years. The other patient had onset of myoclonus at age 13 years, seizures at age 15, mild learning disability, and progressive ataxia. She was wheelchair-bound at age 22 years. Muona et al. (2015) noted that progressive myoclonic epilepsy had not previously been described in ARSACS. Both patients were compound heterozygous for missense mutations; functional studies of the variants were not performed. Armour et al. (2016) reevaluated 2 male twins who were originally reported by Fitzsimmons and Guilbert (1987) as having early-onset slowly progressive spastic paraplegia, dysarthria, and low-normal intellectual capacity. In addition, both patients had skeletal abnormalities of the hands and feet: brachydactyly, cone-shaped epiphyses, and an abnormal metaphyseal-phalangeal pattern profile. Fitzsimmons and Guilbert (1987) concluded that the patients had a novel syndrome, which was later designated 'Fitzsimmons-Guilbert syndrome;' however, exome sequencing performed by Armour et al. (2016) found that the patients were compound heterozygous for mutations in the SACS gene, resulting in the correct diagnosis of autosomal recessive spastic ataxia-6. In addition, the patients carried a heterozygous truncating mutation in the TRPS1 gene (604386), consistent with a diagnosis of type I trichorhinophalangeal syndrome (190350), a rare disorder associated with brachydactyly. Thus, the patients had 2 different genetic diseases that explained the unusual phenotype. Mapping Consistent with the hypothesis of a founder effect (see POPULATION GENETICS), Richter et al. (1999) observed excess shared homozygosity at 13q11 among patients in a genomewide scan of 12 families. Analysis of 19 pedigrees demonstrated very tight linkage between the ARSACS locus and an intragenic polymorphism of the gamma-sarcoglycan gene (SGCG; 608896), which maps to 13q12, but genomic DNA sequence analysis of all 8 exons of SGCG revealed no disease-causing mutation. On the basis of haplotypes composed of 7 marker loci that span 11.1 cM, the most likely position of the ARSACS locus was 0.42 cM distal to the SGCG polymorphism. Two groups of ARSACS-associated haplotypes were identified: a large group that carried a common SGCG allele and a small group that carried a rare SGCG allele. The haplotype groups did not appear to be closely related. Therefore, although chromosomes within each haplotype group may harbor a single ARSACS mutation identical by descent, the 2 mutations could have independent origins. In a large Tunisian family with autosomal recessive cerebellar ataxia associated with a pyramidal syndrome and peripheral neuropathy, Mrissa et al. (2000) demonstrated linkage to chromosome 13q11-q12, the same locus as ARSACS. Molecular Genetics Engert et al. (2000) identified 2 mutations in the SACS gene (604490.0001, 604490.0002), which resides on chromosome 13q11, in ARSACS families that lead to protein truncation. The 2 different mutations corresponded to the 2 different haplotypes previously identified. In 4 Tunisian families with autosomal recessive ataxia phenotypically similar to ARSACS, 3 of which were consanguineous, El Euch-Fayache et al. (2003) identified 4 mutations in the SACS gene (604490.0003-604490.0006). Criscuolo et al. (2004) and Ogawa et al. (2004) identified mutations in the SACS gene in ARSACS patients from southern Italy and Japan, respectively (see 604490.0007 and 604490.0008). Breckpot et al. (2008) reported a Belgian patient with ARSACS who was found to be compound heterozygous for a point mutation in the SACS gene and a de novo 1.54-Mb microdeletion on chromosome 13q12.12 involving 6 genes, including the SACS gene. The microdeletion was detected using array comparative genomic hybridization, and was postulated to result from nonallelic homologous recombination. The patient had typical clinical features of ARSACS with the addition of moderate perceptive hearing loss. Baets et al. (2010) identified homozygous or compound heterozygous mutations in the SACS gene in 11 (12.9%) of 85 index patients with phenotypes suggestive of ARSACS. Eighteen different mutations were identified, including 11 missense, 5 frameshift, 1 nonsense, and 1 in-frame deletion. A founder allele was identified in 4 unrelated Belgian families. Five patients had onset after age 20 years, including 1 with onset at age 40. In addition, some patients presented with predominant features of a peripheral neuropathy, although most eventually developed the classic signs of the disorder, such cerebellar ataxia and pyramidal signs. Only 1 of 17 patients had mild mental retardation, and 2 had reduced IQ. There were no clear genotype/phenotype correlations. Heterogeneity Bouhlal et al. (2008) reported an unusual, highly consanguineous Tunisian family in which 11 individuals had autosomal recessive ataxia caused by 3 distinct gene defects. Seven patients who also had low vitamin E levels were all homozygous for the common 744delA mutation in the TTPA gene (600415.0001), consistent with a diagnosis of AVED (277460). Two patients with normal vitamin E levels were homozygous for a mutation in the FXN gene (606829.0001), consistent with a diagnosis of FRDA (229300). The final 2 patients with normal vitamin E levels carried a mutation in the SACS gene (604490), consistent with a diagnosis of ARSACS. The clinical phenotype was relatively homogeneous, although the 2 patients with SACS mutations had hyperreflexia of the knee. One asymptomatic family member was compound heterozygous for the TTPA and FXN mutations. Bouhlal et al. (2008) emphasized the difficulty of genetic counseling in deeply consanguineous families. Population Genetics De Braekeleer et al. (1993) estimated that the incidence at birth of this spastic ataxia syndrome in French Canadians of the Saguenay-Lac-Saint-Jean (SLSJ) region was 1/1,932, giving a carrier frequency of 1/21, for the period 1941-1985. The mean inbreeding coefficient was twice higher and the mean kinship coefficient 3 times higher among affected families than among control families. In the SLSJ region, the birth places of the ARSACS individuals and their parents did not show a clustered distribution. The genealogy of the families suggested that the high incidence of ARSACS in SLSJ and Charlevoix is likely to be the result of a founder effect and that a unique mutation accounts for most, if not all, of the ARSACS cases known in these regions. De Braekeleer and Gauthier (1996) calculated the inbreeding coefficient of 567 probands from the Saguenay-Lac-Saint-Jean region of northeastern Quebec who suffered from one of the autosomal recessive disorders that are unusually frequent there. At least 2 of them with spastic ataxia of the Charlevoix-Saguenay type and sensorimotor polyneuropathy with or without agenesis of the corpus callosum (218000) were found almost only in that population. The mean inbreeding coefficient of the group containing all 567 probands was 2.73 times higher than that of the matched controls. Parental consanguinity was found in 75 of 567 probands (13%), but only 5% were born to matings between spouses related as second-degree cousins or closer. No marriage between uncle and niece and only 2 marriages between first-degree cousins were identified in the disorder group. These results strongly suggested that the high incidence of the autosomal recessive disorders in that region of Quebec is the result of founder effect. Vermeer et al. (2008) identified pathogenic mutations in the SACS gene in 16 (37%) of 43 Dutch probands with early-onset ataxia before age 25 years. Sixteen novel mutations were identified. The phenotype was homogeneous and similar to that reported for other patients with this disorder. History Hennekam (1994) reported a girl with slowly progressive difficulties in walking, dysarthria, growth retardation, brachydactyly, and cone-shaped epiphyses, and suggested the eponym Fitzsimmons syndrome because the phenotype was reminiscent of that reported by Fitzsimmons and Guilbert (1987). Lacassie et al. (1999) reported monozygotic female twins, aged 62 years, with mental retardation, dysarthria, progressive spastic paraplegia, and brachydactyly type E who had been institutionalized since age 33 years. Differences from the patients reported by Fitzsimmons and Guilbert (1987) included more severe mental retardation and a different metacarpal-phalangeal pattern profile, suggesting either an expanded phenotype of the Fitzsimmons-Guilbert syndrome or a different entity. In a follow-up, Armour et al. (2016) stated that the patient reported by Hennekam (1994) was lost to follow-up and the sisters reported by Lacassie et al. (1999) had both died. Thus, it was not possible to perform genetic studies of these 3 patients, as was done in the patients originally reported by Fitzsimmons and Guilbert (1987). INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Retinal striation \- Hypermyelinated retinal fibers \- Nystagmus \- Impaired smooth pursuit GENITOURINARY Bladder \- Urinary urgency SKELETAL Hands \- Swan neck-like deformities of the fingers Feet \- Pes cavus \- Hammertoes MUSCLE, SOFT TISSUES \- Distal muscle weakness due to peripheral neuropathy NEUROLOGIC Central Nervous System \- Delayed walking development \- Increased falls \- Gait ataxia, progressive \- Truncal ataxia, progressive \- Spasticity \- Dysarthria \- Scanning speech \- Dysmetria \- Corticospinal tract dysfunction \- Hyperreflexia \- Extensor plantar responses \- Absent ankle reflexes \- Amyotrophy, distal, severe \- Distal muscle weakness \- Mental retardation (2 patients) \- Cerebellar vermis atrophy \- Loss of Purkinje cells in the cerebellar vermis Peripheral Nervous System \- Distal sensory loss, especially vibratory sense \- Decreased sensory nerve conduction velocities (NCV) \- Decreased motor NCV \- Loss of large myelinated fibers MISCELLANEOUS \- Onset usually in infancy or early childhood \- Later onset has been reported \- Most patients become wheelchair-bound \- High prevalence in Charlevoix-Saguenay region of northeastern Quebec \- Estimated carrier frequency in Charlevoix-Saguenay region is 1/22 MOLECULAR BASIS \- Caused by mutation in the sacsin gene (SACS, 604490.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SPASTIC ATAXIA, CHARLEVOIX-SAGUENAY TYPE

c1849140

omim

https://www.omim.org/entry/270550

{"doid": ["0050946"], "mesh": ["C536787"], "omim": ["270550"], "orphanet": ["98"], "synonyms": ["Alternative titles", "SPASTIC ATAXIA 6, AUTOSOMAL RECESSIVE", "CHARLEVOIX-SAGUENAY SPASTIC ATAXIA", "AUTOSOMAL RECESSIVE SPASTIC ATAXIA OF CHARLEVOIX-SAGUENAY"], "genereviews": ["NBK1255"]}

A severe form of congenital disorders of N-linked glycosylation characterized by severe developmental and psychomotor delay, muscular hypotonia, intractable early-onset seizures, and microcephaly. Additional features include altered blood coagulation with a high probability of hemorrhages or thromboses, nephrotic syndrome, ascites, hepatomegaly, cardiomyopathy, ocular manifestations (strabismus, nystagmus), and immunodeficiency. The disease is caused by loss-of-function mutations in the gene ALG1 (16p13.3). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ALG1-CDG

c2931005

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79327

{"gard": ["9838"], "mesh": ["C535749"], "omim": ["608540"], "umls": ["C2931005"], "icd-10": ["E77.8"], "synonyms": ["CDG syndrome type Ik", "CDG-Ik", "CDG1K", "Carbohydrate deficient glycoprotein syndrome type Ik", "Congenital disorder of glycosylation type 1k", "Congenital disorder of glycosylation type Ik", "Mannosyltransferase 1 deficiency"]}

A severe type of RAEB characterized by cytopenias and the following hematological parameters: uni- or multilineage dysplasia, 5% to 9% blasts in bone marrow or 2% to 4% in peripheral blood, and no Auer rods (abnormal, needle-shaped or round inclusions in the cytoplasm of myeloblasts and promyelocytes). Median survival has been reported to be 18 months. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Refractory anemia with excess blasts type 1

c1318550

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=100019

{"umls": ["C1318550"], "icd-10": ["D46.2"], "synonyms": ["RAEB-1"]}

A number sign (#) is used with this entry because autosomal recessive dyskeratosis congenita-2 (DKCB2) is caused by homozygous or compound heterozygous mutation in the NOLA2 gene (606470), also known as NHP2, on chromosome 5q35. Description Dyskeratosis congenita is a multisystem disorder caused by defective telomere maintenance. Clinical manifestations include mucocutaneous abnormalities, bone marrow failure, and an increased predisposition to cancer, among other variable features (summary by Vulliamy et al., 2008). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550). Clinical Features Vulliamy et al. (2008) reported a Turkish man with nail dystrophy, thrombocytopenia, testicular atrophy, opportunistic infections, growth and mental retardation, liver cirrhosis, and intracranial calcification. His parents were asymptomatic and unrelated. Another unrelated Turkish boy presented with dyskeratosis congenita at age 12 years. He had the classic mucocutaneous triad of nail dystrophy, leukoplakia, and reticulate skin pigmentation and developed peripheral pancytopenia due to progressive bone marrow failure. No other somatic abnormalities were reported. His parents were asymptomatic. Both patients had shortened telomeres and decreased levels of serum TERC (602322) RNA. Molecular Genetics In 2 unrelated Turkish patients with autosomal recessive dyskeratosis congenita, Vulliamy et al. (2008) identified biallelic mutations in the NOLA2 gene (606470.0001-606470.0003). The 2 patients were identified from a larger group of 117 patients with the disorder; no other pathogenic NOLA2 variants and no mutations in the GAR1 gene (606468) were identified. INHERITANCE \- Autosomal recessive GROWTH Other \- Poor growth HEAD & NECK Mouth \- Leukoplakia ABDOMEN Liver \- Liver cirrhosis GENITOURINARY External Genitalia (Male) \- Testicular atrophy SKIN, NAILS, & HAIR Skin \- Leukoplakia \- Reticulate skin pigmentation Nails \- Nail dystrophy NEUROLOGIC Central Nervous System \- Mental retardation (1 patient) \- Intracranial calcifications (1 patient) HEMATOLOGY \- Bone marrow failure \- Pancytopenia \- Thrombocytopenia IMMUNOLOGY \- Opportunistic infections LABORATORY ABNORMALITIES \- Shortened telomeres MISCELLANEOUS \- Two unrelated patients have been reported (as of May 2011) MOLECULAR BASIS \- Caused by mutation in the nucleolar protein family A, member 2 gene (NOLA2, 606470.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE 2

c0265965

omim

https://www.omim.org/entry/613987

{"doid": ["0070017"], "mesh": ["D019871"], "omim": ["613987"], "orphanet": ["1775"], "genereviews": ["NBK22301"]}

A number sign (#) is used with this entry because of evidence that arrhythmogenic right ventricular dysplasia-8 (ARVD8) is caused by heterozygous mutation in the gene encoding desmoplakin (DSP; 125647) on chromosome 6p24. Description ARVD8 is characterized by progressive degeneration of the right ventricular myocardium. Patients may experience life-threatening cardiac arrhythmias and show depolarization, conduction, and repolarization defects on electrocardiography (Rampazzo et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of ARVD, see 107970. Clinical Features Rampazzo et al. (2002) reported a 4-generation Italian family in which the proband experienced cardiac arrest at age 18 due to ventricular fibrillation during physical effort. Cardiac evaluation revealed depolarization, conduction, and repolarization abnormalities as well as right ventricular kinetic alterations, and he had ventricular arrhythmias including fibrillation and premature contractions. Familial analysis revealed 10 additional family members who all exhibited repolarization abnormalities as well as various other cardiac abnormalities, including sustained ventricular tachycardia in 2 patients. Cardiac symptoms ranged from mild to severe among the family members; there were 2 sudden deaths, at ages 15 and 65 years, and 1 patient died of heart failure at age 68 years. None of the family members exhibited woolly hair or skin changes. Christensen et al. (2010) studied a patient (family L) with ARVD, who developed cardiac symptoms at age 22 years, including palpitations and syncope. He had depolarization and repolarization abnormalities on electrocardiography, as well as arrhythmias. Left ventricular ejection fraction was slightly decreased, at 50%; structural and/or functional alterations were tabulated but not reported in detail. There was no family history of similar cardiac disease, and hair and skin findings in the proband were not reported. Mapping Rampazzo et al. (2002) reported on a genome scan in an Italian family in which the disorder appeared unlinked to any of the previously reported ARVD loci. Significantly positive linkage was detected for several markers on the short arm of chromosome 6 (maximum lod = 4.32 at theta = 0 for marker D6S309). All patients in the family shared a common haplotype. Since the novel 6p24 locus described by Rampazzo et al. (2002) was the eighth reported for ARVD, they named the locus ARVD8. Penetrance was approximately 50%. Population Genetics ARVD8 is probably an infrequent form of ARVD, at least in northeast Italy; among 16 families in which Rampazzo et al. (2002) firmly established linkage with ARVD loci, this was the only family linked to 6p. Molecular Genetics In affected members of an Italian family with ARVD mapping to 6p, Rampazzo et al. (2002) identified heterozygosity for a missense mutation in the desmoplakin gene (S299R; 125647.0003). They focused on the DSP gene because a homozygous DSP nonsense mutation had been reported to cause a biventricular dilated cardiomyopathy associated with keratoderma and woolly hair (605676) in an Ecuadorian family. Rampazzo et al. (2002) noted that the involvement of DSP and JUP (173325) in 2 different ARVD clinical phenotypes, ARVD8 and Naxos disease (601214), suggests that some ARVDs may result from defects in intercellular connections. Mutations in the cardiac ryanodine receptor (RYR2; 180902) cause dominant ARVD2 (600996), thus supporting the hypothesis of a key pathogenic role played by altered intracellular calcium concentration in these disorders. Yang et al. (2006) analyzed 66 probands with ARVD and identified heterozygosity for variants in the DSP gene in 4 patients (see, e.g., R2834H, 125647.0012). In a cohort of 65 patients with ARVD, Christensen et al. (2010) screened 5 desmosomal genes as well as the TGFB3 gene (190230) and identified 1 patient (family L) who was heterozygous for a splice site mutation in the DSP gene (125647.0024). This splice site mutation had previously been identified in a family with striate palmoplantar keratoderma (see PPKS2, 612908). From the same ARVD cohort, Christensen et al. (2010) also identified a patient from a consanguineous Danish family (family H) who was homozygous for a missense mutation in DSP and exhibited palmar keratoderma in addition to cardiac abnormalities. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Cardiomyopathy, right ventricular \- Ventricular arrhythmia (PVC, VT, and VF) \- Sudden cardiac death \- Heart failure MISCELLANEOUS \- Genetic heterogeneity MOLECULAR BASIS \- Caused by mutation in the desmoplakin gene (DSP, 125647.0003 ) ▲ 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, 8

c1862511

omim

https://www.omim.org/entry/607450

{"doid": ["0110076"], "mesh": ["C566254"], "omim": ["107970", "607450"], "orphanet": ["217656"], "synonyms": ["Familial isolated ARVD", "Familial isolated ARVC", "Alternative titles", "Familial isolated arrhythmogenic ventricular dysplasia", "Familial isolated arrhythmogenic ventricular cardiomyopathy", "Familial isolated arrhythmogenic right ventricular cardiomyopathy", "ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY 8"], "genereviews": ["NBK1131"]}

Epidermolytic ichthyosis (EI) is a rare, genetic skin disorder. It becomes apparent at birth, or shortly after birth, with reddening, scaling, and severe blistering of the skin. Hyperkeratosis (thickening of the skin) develops within months and worsens over time. Blister formation decreases, but may still occur after skin trauma or during summer months. Skin can be itchy and smelly, and prone to infection. Other features may include reduced sweating; nail abnormalities; and in severe cases, growth failure. EI is caused by changes (mutations) in the KRT1 or KRT10 genes. About half of cases are due to new mutations and are not inherited from a parent (sporadic). Other cases are usually inherited in an autosomal dominant manner, and rarely, in an autosomal recessive manner. Treatment aims at alleviating and preventing symptoms and may include topical moisturizers or medications, and antiseptic washes. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Epidermolytic ichthyosis

c0079153

gard

https://rarediseases.info.nih.gov/diseases/1039/epidermolytic-ichthyosis

{"mesh": ["D017488"], "omim": ["113800"], "orphanet": ["312"], "synonyms": ["Bullous congenital ichthyosiform erythroderma", "epidermolytic hyperkeratosis", "EHK", "Congenital bullous ichthyosiform erythroderma", "BCIE", "Bullous ichthyosiform erythroderma congenita", "Bullous ichthyosiform erythroderma", "Bullous erythroderma ichthyosiformis congenita of Brocq"]}

Arteriolosclerosis Right breast mammograms showing several calcified arterioles. Patient 94 years old. SpecialtyCardiology Arteriolosclerosis is a form of cardiovascular disease involving hardening and loss of elasticity of arterioles or small arteries and is most often associated with hypertension and diabetes mellitus.[1] Types include hyaline arteriolosclerosis and hyperplastic arteriolosclerosis,[2] both involved with vessel wall thickening and luminal narrowing that may cause downstream ischemic injury. The following two terms whilst similar, are distinct in both spelling and meaning and may easily be confused with arteriolosclerosis. * Arteriosclerosis is any hardening (and loss of elasticity) of medium or large arteries (from the Greek arteria, meaning artery, and sclerosis, meaning hardening) * Atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque. The term atherogenic is used for substances or processes that cause atherosclerosis. Micrograph showing hyaline arteriolosclerosis in the kidney. PAS stain. ## Contents * 1 Hyaline arteriolosclerosis * 2 Hyperplastic arteriolosclerosis * 3 References * 4 External links ## Hyaline arteriolosclerosis[edit] Also arterial hyalinosis and arteriolar hyalinosis refers to thickening of the walls of arterioles by the deposits that appear as homogeneous pink hyaline material in routine staining.[3] It is a type of arteriolosclerosis, which refers to thickening of the arteriolar wall and is part of the ageing process.[4] Associations It is associated with aging, hypertension, diabetes mellitus[5] and may be seen in response to certain drugs (calcineurin inhibitors).[6] It is often seen in the context of kidney pathology.[4]:284 In hypertension only the afferent arteriole is affected, while in diabetes mellitus, both the afferent and efferent arteriole are affected. Cause Lesions reflect leakage of plasma components across vascular endothelium and excessive extracellular matrix production by smooth muscle cells, usually secondary to hypertension.[7] Hyaline arteriolosclerosis is a major morphologic characteristic of benign nephrosclerosis, in which the arteriolar narrowing causes diffuse impairment of renal blood supply, with loss of nephrons.[5] The narrowing of the lumen can decrease renal blood flow and hence glomerular filtration rate leading to increased renin secretion and a perpetuating cycle with increasing blood pressure and decreasing kidney function. ## Hyperplastic arteriolosclerosis[edit] "Onion-skin" renal arteriole This is a type of arteriolosclerosis involving a narrowed lumen.[4] The term "onion-skin" is sometimes used to describe this form of blood vessel[8] with thickened concentric smooth muscle cell layer and thickened, duplicated basement membrane. In malignant hypertension these hyperplastic changes are often accompanied by fibrinoid necrosis of the arterial intima and media. These changes are most prominent in the kidney and can lead to ischemia and acute kidney failure. Cause It can be caused by malignant hypertension.[4][9] ## References[edit] 1. ^ Robbins, Stanley L.; Kumar, Vinay (2007). Robbins basic pathology. Saunders/Elsevier. p. 343. ISBN 978-0-8089-2366-4. 2. ^ "Arteriolosclerosis" at Dorland's Medical Dictionary 3. ^ Gamble CN (March 1986). "The pathogenesis of hyaline arteriolosclerosis". Am. J. Pathol. 122 (3): 410–20. PMC 1888226. PMID 2420184. 4. ^ a b c d Thomas H. McConnell (2007). The Nature of Disease: Pathology for the Health Professions. Lippincott Williams & Wilkins. pp. 277–. ISBN 978-0-7817-5317-3. 5. ^ a b Robbins, Stanley L.; Kumar, Vinay (2007). Robbins basic pathology. Saunders/Elsevier. p. 356. ISBN 978-0-8089-2366-4. 6. ^ Yagisawa T, Omoto K, Shimizu T, Ishida H, Tanabe K (2015). "Arteriosclerosis in zero-time biopsy is a risk factor for tacrolimus-induced chronic nephrotoxicity". Nephrology (Carlton). 20 Suppl 2: 51–7. doi:10.1111/nep.12461. PMID 26031587. 7. ^ Eva Brehmer-Andersson (2006-08-02). Dermatopathology. Springer Science & Business Media. pp. 75–. ISBN 978-3-540-30244-5. 8. ^ "Pathology Education". Archived from the original on 2006-09-01. Retrieved 2009-01-12. 9. ^ "Atherosclerosis". Retrieved 2009-01-12. ## External links[edit] Classification D * MeSH: D050379 * 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]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Arteriolosclerosis

c0878486

wikipedia

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

{"mesh": ["D050379"], "umls": ["C0878486"], "wikidata": ["Q4797547"]}

A number sign (#) is used with this entry because alacrima, achalasia, and mental retardation syndrome (AAMR) is caused by homozygous mutation in the GMPPA gene (615495) on chromosome 2q35. Description Alacrima, achalasia, and mental retardation syndrome (AAMR) is an autosomal recessive disorder characterized by onset of these 3 main features at birth or in early infancy. More variable features include hypotonia, gait abnormalities, anisocoria, and visual or hearing deficits. The disorder shows similarity to the triple A syndrome (231550), but patients with AAMR do not have adrenal insufficiency (summary by Koehler et al., 2013). See also 300858 for a phenotypically similar disorder that shows X-linked inheritance. Clinical Features Koehler et al. (2013) reported 13 patients from 9 unrelated families with alacrima, achalasia, and mental retardation. The families originated from several different regions, including Pakistan, Turkey, Palestine, and Morocco, and most were consanguineous. The patients presented at birth or in the first years of life with alacrima, feeding difficulties due to achalasia, and delayed psychomotor development with speech delay. Most also had muscular hypotonia. More variable features included gait abnormalities, spasticity, nasal speech, visual problems, and hearing impairment. A few patients had autonomic problems, such as decreased sweating, postural hypotension, and anisocoria. Affected members of 1 family had hyperkeratosis. None had signs of adrenal insufficiency. Koehler et al. (2013) noted the considerable clinical overlap with triple A syndrome, but none of the patients had mutations in the AAAS gene (605378). Inheritance The transmission pattern of AAMR in the families reported by Koehler et al. (2013) was consistent with autosomal recessive inheritance. Molecular Genetics In 13 patients from 9 unrelated families with AAMR, Koehler et al. (2013) identified 9 different homozygous mutations in the GMPPA gene (see, e.g., 615495.0001-615495.0005). The mutation in the first family was found by linkage analysis and whole-exome sequencing. The subsequent families were identified by sequencing of the GMPPA gene in 63 families with alacrima and achalasia who were negative for mutations in the AAAS gene. Immunoblot analysis of patient cells with missense mutations showed lower levels of GMPPA compared to controls, consistent with a loss of function. However, GDP-mannose levels were significantly higher in patient cells compared to controls, whereas other nucleotide diphosphate sugars were unchanged. There was no evidence of alterations in N-glycosylation profiles in patients: serum transferrin, immunoglobulin G, and serum Apo-CIII glycosylation profiles were similar to those in controls. Koehler et al. (2013) suggested that changes induced by GDP-mannose overload might only be significant in restricted cell types or affect other glycosylation types, or may lead to perturbations in the levels of other guanine nucleotides. Alternatively, GMPPA might serve as a regulatory subunit. The clinical features of the patients with mutations indicated that GMPPA is important in neurons and autonomic nerve fibers innervating the distal esophageal sphincter or the lacrimal glands. INHERITANCE \- Autosomal recessive HEAD & NECK Ears \- Hearing impairment (in some patients) Eyes \- Alacrima \- Visual problems (in some patients) \- Nystagmus (in some patients) \- Strabismus (in some patients) \- Anisocoria (in some patients) CARDIOVASCULAR Vascular \- Postural hypotension (in some patients) ABDOMEN Gastrointestinal \- Achalasia \- Dysphagia \- Feeding difficulties SKIN, NAILS, & HAIR Skin \- Hyperkeratosis (in some patients) \- Hypohidrosis (in some patients) MUSCLE, SOFT TISSUES \- Hypotonia (in some patients) NEUROLOGIC Central Nervous System \- Delayed psychomotor development \- Intellectual disability \- Gait abnormalities (in some patients) \- Autonomic dysfunction Peripheral Nervous System \- Sensory impairment (in some patients) VOICE \- Nasal voice (in some patients) ENDOCRINE FEATURES \- No adrenal insufficiency LABORATORY ABNORMALITIES \- Normal serum transferrin profiles MISCELLANEOUS \- Onset at birth or in infancy MOLECULAR BASIS \- Caused by mutation in the GDP-mannose pyrophosphorylase A gene (GMPPA, 615495.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ALACRIMA, ACHALASIA, AND MENTAL RETARDATION SYNDROME

c0271742

omim

https://www.omim.org/entry/615510

{"mesh": ["C536008"], "omim": ["615510"], "orphanet": ["869"]}

A number sign (#) is used with this entry because of evidence that neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (NEDMEHM) is caused by compound heterozygous mutation in the MTHFS gene (604197) on chromosome 15q25. Clinical Features Rodan et al. (2018) reported 2 unrelated patients, aged 8 and 11 years, with a similar neurodevelopmental disorder. The patients presented at birth or in early infancy with microcephaly, short stature, exaggerated startle response, poor feeding, and global developmental delay with delayed walking and spasticity. Both patients developed seizures around 2 to 3 years of age. Patient 1 had well-controlled seizures, spastic quadriparesis managed with a baclofen pump, a feeding tube, and cortical visual impairment. Patient 2 had refractory seizures and recurrent episodes of hyperthermia that responded to lamotrigine. He walked at age 4 and could speak, but had limited vocabulary and articulation difficulties. Serial brain imaging in both patients showed delayed myelination, hypomyelination, enlarged ventricles, and cerebellar atrophy. Both patients had low-normal levels of 5-methyl-tetrahydrofolate (5-MTHF) in the CSF, but other laboratory values were normal. Clinical Management Rodan et al. (2018) reported that treatment with folinic and folic acid in a patient with low-normal 5-methyl-tetrahydrofolate (5-MTHF) levels in the CSF was unsuccessful. Treatment with oral levomefolic acid (L-5-methyltetrahydrofolate), a usable reduced form of folate, and methylcobalamin resulted in subjective improvement and increased CSF 5-MTHF. Inheritance The transmission pattern of NEDMEHM in the families reported by Rodan et al. (2018) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 unrelated boys with NEDMEHM, Rodan et al. (2018) identified compound heterozygous mutations in the MTHFS gene (604197.0001-604197.0003). The mutations, which were found by exome sequencing, segregated with the disorder in the families. Fibroblasts derived from patient 1 showed no MTHFS enzymatic activity, and there was a 30-fold increase in the MTHFS substrate 5-formyl-THF (folinic acid). Rodan et al. (2018) concluded that accumulation of folinic acid may act as a toxic metabolite, but also noted that the phenotype, particularly abnormal myelination, was consistent with cerebral folate deficiency syndromes. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature HEAD & NECK Head \- Microcephaly Eyes \- Cortical visual impairment (1 patient) ABDOMEN Gastrointestinal \- Poor feeding \- Tube feeding NEUROLOGIC Central Nervous System \- Global developmental delay \- Poor speech \- Spasticity \- Exaggerated startle response \- Seizures \- Delayed myelination \- Hypomyelination \- Enlarged ventricles \- Cerebellar atrophy LABORATORY ABNORMALITIES \- Low-normal CSF levels of 5-methyl-tetrahydrofolate (5-MTHF) MISCELLANEOUS \- Onset at birth or early infancy \- Two unrelated patients have been reported (last curated March 2019) MOLECULAR BASIS \- Caused by mutation in the 5,10-methenyltetrahydrofolate synthetase gene (MTHFS, 604197.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, EPILEPSY, AND HYPOMYELINATION

None

omim

https://www.omim.org/entry/618367

{"omim": ["618367"]}

Tricho-hepato-enteric syndrome Other namesIntractable diarrhea of infancy with facial dysmorphism[1] Typical facial abnormalities with prominent forehead and cheeks, broad nasal root and wide-spaced eyes. Abnormal hairs are woolly, easily removed and poorly pigmented. Tricho-hepato-enteric syndrome (THE), also known as syndromic or phenotypic diarrhea, is an extremely rare congenital bowel disorder which manifests itself as intractable diarrhea in infants with intrauterine growth retardation, hair and facial abnormalities.[2] Many also have liver disease and abnormalities of the immune system.[2] The associated malabsorption leads to malnutrition and failure to thrive.[2] It is thought to be a genetic disorder with an autosomal recessive inheritance pattern, although responsible genes have not been found and the exact cause remains unknown. Prognosis is poor; many patients die before the age of 5 (mainly from infections or cirrhosis), although most patients nowadays survive with intravenous feeding (parenteral nutrition). ## Contents * 1 Symptoms * 2 Genetics * 3 Diagnosis * 3.1 Facial features * 3.2 Liver * 3.3 Small bowel * 3.4 Hair * 3.5 Platelets * 3.6 Other * 4 Treatment * 5 Epidemiology * 6 Footnotes * 7 References * 8 External links ## Symptoms[edit] Tricho-hepato-enteric syndrome is one particular form of intractable diarrhea of infancy, presenting typically in the first month of life. These babies were usually born small for their age and continue to experience failure to thrive, usually with a final short stature. Typical facial features include prominent forehead and cheeks, a broad nasal root and widely spaced eyes (hypertelorism). Their hairs are woolly, easily removed and poorly pigmented. Liver disease is mainly present as cirrhosis or fibrosis, and staining might reveal high iron content of the liver cells (consistent with hemochromatosis).[3] Most evaluated patients had some degree of decrease in intelligence.[citation needed] ## Genetics[edit] The syndrome appears to be due to mutations in the gene tetratricopeptide repeat domain 37 (TTC37) which encodes the protein Thespin or the SKIV2L gene.[4][5] This gene is expressed is in the adrenal gland, amniotic fluid, bladder, blood, bone, bone marrow, brain, cervix, connective tissue, ear, epididymis, eye, heart, intestine, kidney, liver, lung, lymph nodes, mammary glands, mouth, muscle, nerve, oesophagus, ovary, pancreas, pharynx, placenta, prostate, pituitary gland, salivary gland, testis, thyroid, tonsil, thymus, trachea, skin, uterus, spleen, spinal cord, stomach and vascular tissue. It is also expressed in ascites and various embryonic tissues. It is expressed at high level in the intestine, lung, lymph nodes, pituitary and vascular tissues. This gene is also known as KIAA0372, MGC32587 and TPR repeat protein 37.[citation needed] This gene is located on the Crick (minus) strand of the long arm of chromosome 5 (5q15). The gene is 91,113 bases in length and encodes a protein of 1564 amino acid residues with twenty tetratricopeptide repeats. It has 43 exons of which exons 1, 2 and 3 are non coding. The predicted molecular weight of the protein is 175.486 kiloDaltons and its predicted pI is 7.47. Its function is unknown but it may have adenylate cyclase activity and calcium- and calmodulin-responsive adenylate cyclase activity. A homolog has been identified in the frog (Xenopus tropicalis), the mouse (Mus musculus) and the rat (Rattus norvegicus). In the mouse this gene is located on chromosome 13.[citation needed] ## Diagnosis[edit] Microscopic analysis of the hair shaft showing breaks located at nodes in the hair (trichorrhexis nodosa) and longitudinal breaks. Small intestine biopsy of a patient with THE syndrome showing severe villous atrophy with intense mononuclear cell infiltration in the lamina propria. (Courtesy of Prof. Michel Peuchmaur, Hôpital Robert Debré, Paris, France) ### Facial features[edit] The typical facial features are low-set ears, prominent eyes with hypertelorism, broad flat nose, prominent forehead and large mouth.[citation needed] ### Liver[edit] There may be fibrosis with bile duct proliferation, occasional giant cells and regenerative parenchymal nodules. Siderosis is common.[citation needed] ### Small bowel[edit] Microscopic examination of a biopsy of the small bowel in these patients shows villous atrophy with low or no mononuclear cell infiltration of the lamina propria nor specific abnormalities involving the epithelium. The amount of villous atrophy does not explain the severity of the diarrhea.[citation needed] Studies of enterocyte brush-border ion transporter proteins (sodium-hydrogen exchanger 2, sodium-hydrogen exchanger 3, aquaporin 7, sodium iodide symporter and hydrogen potassium adenosine triphosphatase) showed reduced expression or mislocalization in all patients with different profiles for each.[6] ### Hair[edit] Microscopic analysis of the hair shows twisted hairs of unequal size and different shapes (pili torti, aniso- and poikilotrichosis), longitudinal breaks and breaks located at nodes (trichorrhexis nodosa). Scanning electron microscopy might reveal hair budding (trichorrhexis blastysis). Biochemical analysis may reveal sulfur-deficient brittle hair (trichothiodystrophy; note that disulfide bonds determine hair waviness).[citation needed] ### Platelets[edit] Platelets may be enlarged. The membrane surface connected canalicular system is disrupted with prominent tubules and small membranous vesicles. Alpha granules may be missing from the platelets. Despite these abnormalities there is no increased tendency to bleed in this syndrome.[citation needed] ### Other[edit] More than 90% of patients present immune defects. Low immunoglobulin level, a defect in antibody production after vaccination, monoclonal hyper IgA, and low lymphocyte count have been reported. In these cases, some patients may need immunoglobulin supplementation.[7] ## Treatment[edit] No specific treatment or cure exists. Affected children usually need total parenteral nutrition through a central venous catheter. Further worsening of liver damage should however be avoided if possible. Diarrhea will likely continue even though food stops passing through the gastrointestinal system.[8] They can subsequently be managed with tube feeding, and some may be weaned from nutritional support during adolescence.[citation needed] ## Epidemiology[edit] Tricho-hepato-enteric syndrome is estimated to affect 1 in 300,000 to 400,000 live births in Western Europe. This syndrome was first reported in 1982 with a report on 2 siblings,[9] and as of 2008 there were around 25 published cases in medical journals. There seem to be no racial differences in its occurrence. It might be more common, as many genetic diseases, in areas with high levels of consanguinity.[citation needed] ## Footnotes[edit] 1. ^ Fabre A, André N, Breton A, Broué P, Badens C, Roquelaure B (March 2007). "Intractable diarrhea with "phenotypic anomalies" and tricho-hepato-enteric syndrome: two names for the same disorder". Am. J. Med. Genet. A. 143 (6): 584–8. doi:10.1002/ajmg.a.31634. PMID 17318842. 2. ^ a b c Goulet O, Vinson C, Roquelaure B, Brousse N, Bodemer C, Cézard JP (2008). "Syndromic (phenotypic) diarrhea in early infancy". Orphanet J Rare Dis. 3: 6. doi:10.1186/1750-1172-3-6. PMC 2279108. PMID 18304370. 3. ^ Verloes A, Lombet J, Lambert Y, et al. (February 1997). "Tricho-hepato-enteric syndrome: further delineation of a distinct syndrome with neonatal hemochromatosis phenotype, intractable diarrhea, and hair anomalies". Am. J. Med. Genet. 68 (4): 391–5. doi:10.1002/(SICI)1096-8628(19970211)68:4<391::AID-AJMG3>3.0.CO;2-P. PMID 9021008. 4. ^ Fabre A, Martinez-Vinson C, Roquelaure B, Missirian C, André N, Breton A, Lachaux A, Odul E, Colomb V, Lemale J, Cézard JP, Goulet O, Sarles J, Levy N, Badens C (2011). "Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome" (PDF). Hum Mutat. 32 (3): 277–281. doi:10.1002/humu.21420. PMID 21120949.CS1 maint: multiple names: authors list (link) 5. ^ Vardi I, Barel O, Sperber M, Schvimer M, Nunberg M, Field M, Ouahed J, Marek-Yagel D, Werner L, Haberman Y, Lahad A, Anikster Y, Rechavi G, Barshack I, McElwee JJ, Maranville J, Somech R, Snapper SB, Weiss B, Shouval DS (May 2018). "Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome". Dig Dis Sci. 63 (5): 1192–1199. doi:10.1007/s10620-018-4983-x. PMC 6167312. PMID 29484573.CS1 maint: multiple names: authors list (link) 6. ^ Hartley JL, Zachos NC, Dawood B, Donowitz M, Forman J, Pollitt RJ, Morgan NV, Tee L, Gissen P, Kahr WH, Knisely AS, Watson S, Chitayat D, Booth IW, Protheroe S, Murphy S, de Vries E, Kelly DA, Maher ER (2010). "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy)". Gastroenterology. 138 (7): 2388–2398. doi:10.1053/j.gastro.2010.02.010. PMC 3166659. PMID 20176027.CS1 maint: multiple names: authors list (link) 7. ^ Fabre, A., Martinez-Vinson, C., Goulet, O. et al. Syndromic diarrhea/Tricho-hepato-enteric syndrome. Orphanet J Rare Dis 8, 5 (2013). https://doi.org/10.1186/1750-1172-8-5 8. ^ Girault D, Goulet O, Le Deist F, et al. (July 1994). "Intractable infant diarrhea associated with phenotypic abnormalities and immunodeficiency". J. Pediatr. 125 (1): 36–42. doi:10.1016/S0022-3476(94)70118-0. PMID 8021782. 9. ^ Stankler L, Lloyd D, Pollitt RJ, Gray ES, Thom H, Russell G (March 1982). "Unexplained diarrhoea and failure to thrive in 2 siblings with unusual facies and abnormal scalp hair shafts: a new syndrome". Arch. Dis. Child. 57 (3): 212–6. doi:10.1136/adc.57.3.212. PMC 1627586. PMID 7073301. ## References[edit] * Goulet O, Vinson C, Roquelaure B, Brousse N, Bodemer C, Cézard JP (2008). "Syndromic (phenotypic) diarrhea in early infancy". Orphanet J Rare Dis. 3: 6. doi:10.1186/1750-1172-3-6. PMC 2279108. PMID 18304370. ## External links[edit] Classification D * OMIM: 222470 External resources * Orphanet: 84064 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Tricho-hepato-enteric syndrome

c1857276

wikipedia

https://en.wikipedia.org/wiki/Tricho-hepato-enteric_syndrome

{"gard": ["5258"], "mesh": ["C565627"], "umls": ["C1857276"], "orphanet": ["84064"], "wikidata": ["Q7840696"]}

A number sign (#) is used with this entry because of evidence that ectodermal dysplasia-4 (ECTD4) is caused by homozygous mutation in the KRTHB5 gene (KRT85; 602767) on chromosome 12q13. Description Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Ectodermal dysplasia of the hair/nail type is a rare congenital condition characterized by hypotrichosis and nail dystrophy without nonectodermal or other ectodermal manifestations. Clinical Features Calzavara-Pinton et al. (1991) reported a family with an autosomal recessive form of hidrotic ectodermal dysplasia involving the hair and nails. Affected members had scalp, beard, axillary, and pubic hairs 1 to 10 mm long. The hair was brittle and easily broken, and showed twisting on scanning electron microscopy (EM). Eyebrows, eyelashes, and body hair were completely absent. Nails were distally dystrophic. No teeth abnormalities were found. Naeem et al. (2006) described a large consanguineous Pakistani family in which 4 males and 4 females had ectodermal dysplasia of the hair and nails with total alopecia and nail dystrophy present at birth. Affected individuals were born completely devoid of eyebrows and eyelashes, had no scalp, face, chest, arm, or leg hair, and never developed axillary or pubic hair. The nails of all digits were dystrophic. Affected individuals were in good general health, sweated normally, and were of normal intelligence. Shimomura et al. (2010) analyzed 2 consanguineous Pakistani families with hair and nail ectodermal dysplasia. In family A, affected individuals showed sparse hair and diffuse follicular papules on the scalp, and facial and body hair was less dense overall. The scalp hair was brittle and showed inconsistent thickness of the hair shaft on scanning EM. In family B, affected individuals displayed complete alopecia with diffuse follicular papules on the scalp. Facial and body hair was also absent, and the tips of the nails showed severe deformities. Affected individuals in both families showed normal facial features, teeth, and sweating, and they did not show palmoplantar hyperkeratosis. Inheritance The disorder in the families reported by Calzavara-Pinton et al. (1991) and Naeem et al. (2006) segregated in an autosomal recessive fashion; obligate carriers had normal hair and nails. Mapping Using a candidate gene approach, Naeem et al. (2006) performed linkage analysis in a large consanguineous Pakistani family with ectodermal dysplasia of the hair and nails and found linkage at the type II keratin gene cluster on chromosome 12q13.13. A maximum 2-point lod score of 4.54 was obtained at D12S398 (theta = 0); multipoint analysis yielded a lod score of 8.2 at that marker. The 3-unit support interval and region of homozygosity was flanked by markers D12S291 and D12S90, defining a 16.6-cM (15.0-Mb) region known to contain 6 type II hair keratin genes. Molecular Genetics In a large consanguineous Pakistani family with ectodermal dysplasia that had been mapped to a 15.0-Mb region on chromosome 12q13.13, Naeem et al. (2006) sequenced 6 candidate type II hair keratin genes and identified homozygosity for a missense mutation in the KRTHB5 gene (602767.0001) in all affected individuals. The mutation was present in heterozygosity in obligate carriers within the family and was not found in 200 chromosomes from Pakistani controls. In 2 consanguineous Pakistani families with hair and nail ectodermal dysplasia mapping to a 1.26-Mb region on chromosome 12, Shimomura et al. (2010) identified homozygous mutations in the KRT85 gene: the same missense mutation (602767.0001) identified by Naeem et al. (2006) and a truncating mutation (602767.0002). The family with the truncating mutation (family A) had a less severe phenotype. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Absent eyebrows \- Absent eyelashes Teeth \- Normal teeth SKIN, NAILS, & HAIR Skin \- Normal sweating Nails \- Onychodystrophy \- Micronychia \- Onycholysis Hair \- Alopecia \- Brittle hair (in some patients) \- Pili torti (in some patients) \- Sparse body hair (in some patients) \- Absent body hair NEUROLOGIC Central Nervous System \- No mental retardation METABOLIC FEATURES \- Normal sweating MISCELLANEOUS \- Three families described (last curated January 2014) MOLECULAR BASIS \- Caused by mutation in the keratin 85 gene (KRT85, 602767.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ECTODERMAL DYSPLASIA 4, HAIR/NAIL TYPE

c1865951

omim

https://www.omim.org/entry/602032

{"mesh": ["C566592"], "omim": ["602032"], "orphanet": ["69084"], "synonyms": ["Alternative titles", "ECTODERMAL DYSPLASIA, 'PURE' HAIR/NAIL TYPE"]}

Chromium deficiency Chromium SpecialtyEndocrinology Chromium deficiency is described as the consequence of an insufficient dietary intake of the mineral chromium. Chromium was first proposed as an essential element for normal glucose metabolism in 1959,[1] and was widely accepted as being such by the 1990s.[2] Cases of deficiency were described in people who received all of their nutrition intravenously for long periods of time.[3] The essentiality of chromium has been challenged.[4][5][6] Whereas the authorities in the European Union do not recognize chromium as an essential nutrient,[7] those in the United States do, and identify an adequate intake for adults as between 25 and 45 μg/day, depending on age and sex.[8] Dietary supplements containing chromium are widely available in the United States, with claims for benefits for fasting plasma glucose, hemoglobin A1C and weight loss. Reviews report the changes as modest, and without scientific consensus that the changes have a clinically relevant impact.[9][10] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Dietary recommendations * 3.1 Sources * 4 Diabetes * 5 Supplementation * 5.1 Government-approved health claims * 6 See also * 7 References * 8 Further reading * 9 External links ## Signs and symptoms[edit] The claimed symptoms of chromium deficiency caused by long-term total parenteral nutrition are severely impaired glucose tolerance, weight loss, peripheral neuropathy and confusion.[11][8] ## Diagnosis[edit] According to the Dietary Reference Intake review, neither plasma nor urine concentrations can serve as useful clinical indicators of chromium status. Before chromium became a standard ingredient in total parenteral nutrition (TPN), people getting TPN as their sole source of nutrition developed symptoms that were reversed within two week after chromium was added.[8] ## Dietary recommendations[edit] The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for chromium in 2001. For chromium there was not sufficient information to set EARs and RDAs, so needs are described as estimates for Adequate Intakes (AIs). The current AIs for chromium for women ages 14 and up is 25 μg/day up to age 50 and 20 μg/day for older. AI for pregnancy is 30 μg/day. AI for lactation is 45 μg/day. For men ages 14 and up 35 μg/day up to age 50 and 30 μg/day for older. For infants to children ages 1–13 years the AI increases with age from 0.2 to 25 μg/day. As for safety, the IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of chromium there is not yet enough information and hence no UL. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).[8] Japan designate chromium as an essential nutrient, identifying 10 μg/day as an Adequate Intake for adults.[12] The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL defined the same as in United States. The EFSA does not consider chromium to be an essential nutrient, and so has not set PRIs, AIs or ULs. Chromium is the only mineral for which the United States and the European Union disagree on essentiality.[7][13] For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For chromium labeling purposes 100% of the Daily Value was 120 μg, but as of May 27, 2016 it was revised to 35 μg to bring it into agreement with the RDA.[14][15] Compliance with the updated labeling regulations was required by 1 January 2020, for manufacturers with $10 million or more in annual food sales, and by 1 January 2021 for manufacturers with less than $10 million in annual food sales.[16][17][18] During the first six months following the 1 January 2020 compliance date, the FDA plans to work cooperatively with manufacturers to meet the new Nutrition Facts label requirements and will not focus on enforcement actions regarding these requirements during that time.[16] A table of the old and new adult Daily Values is provided at Reference Daily Intake. ### Sources[edit] Approximately 2% of ingested chromium(III) is absorbed, with the remainder being excreted in the feces. Amino acids, vitamin C and niacin may enhance the uptake of chromium from the intestinal tract.[19] After absorption, this metal accumulates in the liver, bone, and spleen. Trivalent chromium is found in a wide range of foods, including whole-grain products, processed meats, high-bran breakfast cereals, coffee, nuts, green beans, broccoli, spices, and some brands of wine and beer.[19] Most fruits and vegetables and dairy products contain only low amounts.[3] ## Diabetes[edit] Given the evidence for chromium deficiency causing problems with glucose management in the context of intravenous nutrition products formulated without chromium,[20] research interest turned to whether chromium supplementation for people who have type 2 diabetes but are not chromium deficient could benefit. Looking at the results from four meta-analyses, one reported a statistically significant decrease in fasting plasma glucose levels (FPG) and a non-significant trend in lower hemoglobin A1C (HbA1C).[21] A second reported the same,[22] a third reported significant decreases for both measures,[23] while a fourth reported no benefit for either.[24] A review published in 2016 listed 53 randomized clinical trials that were included in one or more of six meta-analyses. It concluded that whereas there may be modest decreases in FPG and/or HbA1C that achieve statistical significance in some of these meta-analyses, few of the trials achieved decreases large enough to be expected to be relevant to clinical outcome. The authors also mentioned that trial design was for chromium as an addition to standard glycemic control medications, and so did not evaluate chromium as a first treatment for type 2 diabetes, or for prevention of progression from pre-diabetes to diabetes. The conclusion was that "...there is still little reason to recommend chromium dietary supplements to achieve clinically meaningful improvements in glycemic control."[9] The American Diabetes Association publishes a standards of care review every year. The 2018 review makes no mention of chromium supplementation as a possible treatment.[25] ## Supplementation[edit] Chromium supplementation in general is subject to a certain amount of controversy as it is by no means clear that chromium is an essential element in human biology.[26] Nevertheless, chromium is an ingredient in total parenteral nutrition, along with other trace minerals.[20] It is also in nutritional products for preterm infants.[27] Many chromium-containing products, including chromium chloride, chromium citrate, chromium(III) picolinate, chromium(III) polynicotinate are sold as non-prescription dietary supplements.[28] ### Government-approved health claims[edit] In 2005, the U.S. Food and Drug Administration approved a Qualified Health Claim for chromium picolinate with a requirement for very specific label wording: "One small study suggests that chromium picolinate may reduce the risk of insulin resistance, and therefore possibly may reduce the risk of type 2 diabetes. FDA concludes, however, that the existence of such a relationship between chromium picolinate and either insulin resistance or type 2 diabetes is highly uncertain."[29] In 2010, chromium(III) picolinate was approved by Health Canada to be used in dietary supplements. Approved labeling statements included: "...provides support for healthy glucose metabolism."[30] The European Food Safety Authority (EFSA) approved claims in 2010 that chromium contributed to normal macronutrient metabolism and maintenance of normal blood glucose concentration.[31] ## See also[edit] * Chromium toxicity ## References[edit] 1. ^ SCHWARZ, K; MERTZ, W (November 1959). "Chromium(III) and the glucose tolerance factor". Archives of Biochemistry and Biophysics. 85: 292–295. doi:10.1016/0003-9861(59)90479-5. PMID 14444068. 2. ^ Mertz, W (April 1993). "Chromium in human nutrition: a review". The Journal of Nutrition. 123 (4): 626–633. doi:10.1093/jn/123.4.626. PMID 8463863. 3. ^ a b Expert group on Vitamins and Minerals (August 2002). "Review of Chromium" (PDF). Archived from the original (PDF) on 7 February 2012. Retrieved 24 February 2013. 4. ^ Vincent, John B. (2010). "Chromium: celebrating 50 years as an essential element?". Dalton Transactions. 39 (16): 3787–3794. doi:10.1039/B920480F. PMID 20372701. 5. ^ Jeejeebhoy, Khursheed N. (1999). "The role of chromium in nutrition and therapeutics and as a potential toxin". Nutrition Reviews. 57 (11): 329–335. doi:10.1111/j.1753-4887.1999.tb06909.x. PMID 10628183. 6. ^ Vincent, JB (2013). "Chromium: is it essential, pharmacologically relevant, or toxic?". Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences. 13. pp. 171–198. doi:10.1007/978-94-007-7500-8_6. ISBN 978-94-007-7499-5. PMID 24470092. 7. ^ a b "Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies" (PDF). 2017. 8. ^ a b c d Chromium. IN: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Chromium, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Chromium National Academy Press. 2001, PP.197-223. 9. ^ a b Costello RB, Dwyer JT, Bailey RL (2016). "Chromium supplements for glycemic control in type 2 diabetes: limited evidence of effectiveness". Nutr. Rev. 74 (7): 455–468. doi:10.1093/nutrit/nuw011. PMC 5009459. PMID 27261273. 10. ^ Onakpoya I, Posadzki P, Ernst E (2013). "Chromium supplementation in overweight and obesity: a systematic review and meta-analysis of randomized clinical trials". Obes Rev. 14 (6): 496–507. doi:10.1111/obr.12026. PMID 23495911. 11. ^ Freund, Herbert; Atamian, Susan; Fischer, Josef E. (February 1979). "Chromium deficiency during total parenteral nutrition". JAMA. 241 (5): 496–498. doi:10.1001/jama.1979.03290310036012. PMID 104057. 12. ^ Overview of Dietary Reference Intakes for Japanese (2015) 13. ^ Tolerable Upper Intake Levels For Vitamins And Minerals (PDF), European Food Safety Authority, 2006 14. ^ "Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982" (PDF). 15. ^ "Daily Value Reference of the Dietary Supplement Label Database (DSLD)". Dietary Supplement Label Database (DSLD). Retrieved 16 May 2020. 16. ^ a b "FDA provides information about dual columns on Nutrition Facts label". U.S. Food and Drug Administration (FDA). 30 December 2019. Retrieved 16 May 2020. This article incorporates text from this source, which is in the public domain. 17. ^ "Changes to the Nutrition Facts Label". U.S. Food and Drug Administration (FDA). 27 May 2016. Retrieved 16 May 2020. This article incorporates text from this source, which is in the public domain. 18. ^ "Industry Resources on the Changes to the Nutrition Facts Label". U.S. Food and Drug Administration (FDA). 21 December 2018. Retrieved 16 May 2020. This article incorporates text from this source, which is in the public domain. 19. ^ a b Lukaski, Henry C. (1999). "Chromium as a supplement". Annual Review of Nutrition. 19 (1): 279–302. doi:10.1146/annurev.nutr.19.1.279. PMID 10448525. 20. ^ a b Stehle P, Stoffel-Wagner B, Kuhn KS (2016). "Parenteral trace element provision: recent clinical research and practical conclusions". Eur J Clin Nutr. 70 (8): 886–893. doi:10.1038/ejcn.2016.53. PMC 5399133. PMID 27049031. 21. ^ San Mauro-Martin I, Ruiz-León AM, et al. (2016). "[Chromium supplementation in patients with type 2 diabetes and high risk of type 2 diabetes: a meta-analysis of randomized controlled trials]". Nutr Hosp (in Spanish). 33 (1): 27. doi:10.20960/nh.27. PMID 27019254. 22. ^ Abdollahi M, Farshchi A, Nikfar S, Seyedifar M (2013). "Effect of chromium on glucose and lipid profiles in patients with type 2 diabetes; a meta-analysis review of randomized trials". J Pharm Pharm Sci. 16 (1): 99–114. doi:10.18433/j3g022. PMID 23683609. 23. ^ Suksomboon N, Poolsup N, Yuwanakorn A (2014). "Systematic review and meta-analysis of the efficacy and safety of chromium supplementation in diabetes". J Clin Pharm Ther. 39 (3): 292–306. doi:10.1111/jcpt.12147. PMID 24635480. 24. ^ Bailey CH (January 2014). "Improved meta-analytic methods show no effect of chromium supplements on fasting glucose". Biol Trace Elem Res. 157 (1): 1–8. doi:10.1007/s12011-013-9863-9. PMID 24293356. 25. ^ Standards of Medical Care for Diabetes - 2018 Diabetes Care 2008:41:Supplement 1. 26. ^ Maret, Wolfgang (2019). "Chapter 9. Chromium Supplementation in Human Health, Metabolic Syndrome, and Diabetes". In Sigel, Astrid; Freisinger, Eva; Sigel, Roland K. O.; Carver, Peggy L. (Guest editor) (eds.). Essential Metals in Medicine:Therapeutic Use and Toxicity of Metal Ions in the Clinic. Metal Ions in Life Sciences. 19. Berlin: de Gruyter GmbH. pp. 231–251. doi:10.1515/9783110527872-015. ISBN 978-3-11-052691-2. PMID 30855110. 27. ^ Finch, C. W (2015). "Review of trace mineral requirements for preterm infants: What are the current recommendations for clinical practice?". Nutrition in Clinical Practice. 30 (1): 44–58. CiteSeerX 10.1.1.957.4763. doi:10.1177/0884533614563353. PMID 25527182. 28. ^ "Chromium". Office of Dietary Supplements, US National Institutes of Health. 2016. Retrieved 26 June 2016. 29. ^ FDA Qualified Health Claims: Letters of Enforcement Discretion, Letters of Denial U.S. Food and Drug Administration, Docket #2004Q-0144 (August 2005). 30. ^ "Monograph: Chromium (from Chromium picolinate)". Health Canada. 9 December 2009. Retrieved 24 March 2015. 31. ^ Scientific Opinion on the substantiation of health claims related to chromium and contribution to normal macronutrient metabolism (ID 260, 401, 4665, 4666, 4667), maintenance of normal blood glucose concentrations (ID 262, 4667), contribution to the maintenance or achievement of a normal body weight (ID 339, 4665, 4666), and reduction of tiredness and fatigue (ID 261) pursuant to Article 13(1) of Regulation (EC) No 1924/2006 European Food Safety Authority EFSA J 2010;8(10)1732. ## Further reading[edit] * A "possible resolution of controversies in chromium biology" is suggested by Wolfgang Maret in chapter 9, pp 246-248 of Essential Metals in Medicine: Therapeutic Use and Toxicity of Metal Ions in the Clinic. edited by Astrid Sigel, Eva Freisinger, Roland K. O. Sigel and Peggy L. Carver; de Gruyter GmbH (publisher), 2019 Berlin. * "Dietary Supplement Fact Sheet: Chromium". Office of Dietary Supplements, National Institutes of Health. Retrieved 24 February 2013. * Chromium in glucose metabolism ## External links[edit] Classification D * ICD-10: E61.4 * DiseasesDB: 2625 * v * t * e Malnutrition Protein-energy malnutrition * Kwashiorkor * Marasmus * Catabolysis Vitamin deficiency B vitamins * B1 * Beriberi * Wernicke–Korsakoff syndrome * Wernicke's encephalopathy * Korsakoff's syndrome * B2 * Riboflavin deficiency * B3 * Pellagra * B6 * Pyridoxine deficiency * B7 * Biotin deficiency * B9 * Folate deficiency * B12 * Vitamin B12 deficiency Other * A: Vitamin A deficiency * Bitot's spots * C: Scurvy * D: Vitamin D deficiency * Rickets * Osteomalacia * Harrison's groove * E: Vitamin E deficiency * K: Vitamin K deficiency Mineral deficiency * Sodium * Potassium * Magnesium * Calcium * Iron * Zinc * Manganese * Copper * Iodine * Chromium * Molybdenum * Selenium * Keshan disease Growth * Delayed milestone * Failure to thrive * Short stature * Idiopathic General * Anorexia * Weight loss * Cachexia * Underweight *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Chromium deficiency

c0268093

wikipedia

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

{"umls": ["C0268093"], "icd-10": ["E61.4"], "wikidata": ["Q5113829"]}

Autosomal recessive spastic paraplegia type 55 (SPG 55) is a rare, complex type of hereditary spastic paraplegia characterized by childhood onset of progressive spastic paraplegia associated with optic atrophy (with reduced visual acuity and central scotoma), ophthalmoplegia, reduced upper-extremity strength and dexterity, muscular atrophy in the lower extremities, and sensorimotor neuropathy. SPG55 is caused by mutations in the C12ORF65 gene (12q24.31) encoding probable peptide chain release factor C12orf65, mitochondrial. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Autosomal recessive spastic paraplegia type 55

c3539506

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=320375

{"omim": ["615035"], "icd-10": ["G11.4"], "synonyms": ["SPG55"]}

Laron syndrome is a condition that occurs when the body is unable to utilize growth hormone. It is primarily characterized by short stature. Other signs and symptoms vary but may include reduced muscle strength and endurance; hypoglycemia in infancy; delayed puberty; short limbs (arms and legs); and obesity. It is often caused by changes (mutations) in the GHR gene and is inherited in an autosomal recessive manner. Treatment is focused on improving growth and generally includes injections of insulin-like growth factor 1 (IGF-1). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Laron syndrome

c0271568

gard

https://rarediseases.info.nih.gov/diseases/6859/laron-syndrome

{"mesh": ["D046150"], "omim": ["262500"], "umls": ["C0271568"], "orphanet": ["633"], "synonyms": ["Growth hormone insensitivity syndrome", "Pituitary dwarfism II", "Growth hormone receptor deficiency", "Primary growth hormone resistance", "Primary growth hormone insensitivity", "Laron dwarfism", "Laron type pituitary dwarfism I"]}

## Description Adiposis dolorosa, also known as Dercum disease, is characterized by generalized obesity and pronounced, disabling, and chronic pain in the adipose tissue of the proximal extremities, trunk, pelvic area, and buttocks; the face and hands are usually spared. There are a number of associated symptoms, including multiple lipomas, generalized weakness, fatigue, sleep disturbances, constipation, and psychiatric abnormalities. It is 5 to 30 times more common in women than men, and usually presents between 35 and 50 years of age (summary by Campen et al., 2001; review by Hansson et al., 2012). Based on a review of the literature and studies of 111 patients, Hansson et al. (2012) proposed a classification of Dercum disease into 4 types: (I) generalized diffuse form without clear lipomas, (II) generalized nodular form with multiple lipomas, (III) localized nodular form, and (IV) juxtaarticular form with solitary fatty deposits near joints. Clinical Features This disorder, which was first described by Dercum (1892), is characterized by painful subcutaneous lipomas in a background of obesity. Severe asthenia has been emphasized as a feature by some (Wohl and Pastor, 1938). Campen et al. (2001) reported a family in which 9 individuals spanning 2 generations had highly variable manifestations of lipomatosis. Seven individuals were studied in detail. The most severely affected male proband presented with over 20 painful lipomas on the abdomen, back, buttocks, and extremities, with onset at age 25 years. Another sister had 4 painful lipomas on the arm, also with onset at age 25. These 2 individuals were the only family members who reported pain associated with the lipomas; both were also obese, consistent with adiposis dolorosa. Both of these individuals reportedly had multiple birthmarks as children, and both were found to have several cafe-au-lait spots; 1 also had freckling. Obesity was present in many, but not all, affected relatives. One individual had only 1 painless lipoma on the patella that developed at age 39 years. Histopathologic analysis of the tumors from the 2 patients with painful lesions showed typical lipomas consisting of mature adipocytes. Entrapped nerves were not observed, and the tumors had well-defined margins. Genetic analysis excluded the mitochondrial DNA 8344A-G mutation in the MTTK gene (590060.0001), which has occasionally been found in patients with multiple symmetric lipomatosis (MSL; 151800). Campen et al. (2001) suggested that adiposis dolorosa may be an expression of MSL or familial multiple lipomas (FML; 151900). In an extensive review of Dercum disease, Hansson et al. (2012) noted that several reports had described unusual symptoms, but it was unclear whether these were truly manifestations of the disorder. Some of these symptoms, such as tissue necrosis, hydronephrosis, and pain on the scalp or neck, may have resulted secondarily from compression of the fatty tissue on other structures. ### Clinical Variability Kyllerman et al. (2002) reported a 2-generation family in which a man and his 3 teenaged sons presented with variable neurologic abnormalities in early childhood. Features included dysarthria, disturbed ocular motility, rigidity, and delayed motor development. Brain imaging showed progressive bilateral cystic lesions in the putamen. The father developed painful lipomas on the trunk as an adult. His father reportedly had similar symptoms at the same age. The painful lipomas were reminiscent of Dercum disease, but neither the father, his father, nor 2 of his sons were obese; 1 son was described as 'slightly obese' at age 13 years. None of the sons had lipomas. Kyllerman et al. (2002) suggested that this family had a variant of Dercum disease, but Hansson et al. (2012) noted that it was unclear whether these patients truly fulfilled the diagnostic criteria. Diagnosis Hansson et al. (2012) suggested that the diagnostic criteria for Dercum disease should include generalized overweight or obesity and chronic pain in the adipose tissue present for over 3 months. The differential diagnosis is large and can include fibromyalgia, lipedema, panniculitis, lipomatosis, and endocrine abnormalities. Inheritance The majority of cases of Dercum disease occur sporadically (review by Hansson et al., 2012). However, there have been rare reports of familial occurrence consistent with autosomal dominant inheritance. Lynch and Harlan (1963) observed the disease in 4 members of 3 generations of 1 family and in 2, possibly 4, persons in 2 generations of a second family. Autosomal dominant inheritance was suggested by the families reported by Campen et al. (2001) and Cantu et al. (1973). INHERITANCE \- Autosomal dominant GROWTH Weight \- Obesity ABDOMEN Gastrointestinal \- Constipation \- Bloating SKELETAL \- Arthralgia SKIN, NAILS, & HAIR Skin \- Subcutaneous lipomas, well-circumscribed and painful \- Mature adipocytes MUSCLE, SOFT TISSUES \- Painful adipose tissue \- Muscle aches NEUROLOGIC Central Nervous System \- Chronic pain \- Fatigue \- Sleep disturbances Behavioral Psychiatric Manifestations \- Depression \- Anxiety \- Difficulty concentrating \- Impaired memory \- Anxiety MISCELLANEOUS \- Adult onset \- Female to male ratio 5:1 \- Pain most commonly affects the trunk, extremities, pelvic region, buttocks \- Variable severity ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ADIPOSIS DOLOROSA

c0001529

omim

https://www.omim.org/entry/103200

{"doid": ["3928"], "mesh": ["D000274"], "omim": ["103200"], "icd-10": ["E88.2"], "orphanet": ["36397"], "synonyms": ["Alternative titles", "DERCUM DISEASE"]}

A number sign (#) is used with this entry because of evidence that Loeys-Dietz syndrome-3 (LDS3) is caused by heterozygous mutation in the SMAD3 gene (603109) on chromosome 15q. For a general phenotypic description and a discussion of genetic heterogeneity of Loeys-Dietz syndrome, see LDS1A (609192). Clinical Features Van de Laar et al. (2011) studied 3 unrelated Dutch families with arterial aneurysms, dissections, and/or early-onset osteoarthritis. The largest family was a 4-generation pedigree in which 12 of 22 affected individuals presented with aneurysms of the aorta, primarily at the sinus of Valsalva, but also involving the abdominal aorta and/or other arteries such as the splenic, common iliac, mesenteric, renal, vertebral, or main pulmonary artery. There was a strong history of sudden death between 35 and 69 years of age, primarily due to dissection and/or rupture of the aorta, which sometimes occurred in mildly dilated aortas. Arterial tortuosity of the cerebral, thoracic, and/or abdominal arterial tree was present in the majority of cases. Other congenital heart disease was present as well, including mitral valve abnormalities, and 5 normotensive individuals had idiopathic mild to moderate predominantly concentric left ventricular hypertrophy. Craniofacial abnormalities in affected individuals were mild and included hypertelorism, abnormal palate and/or uvula, and dental malocclusion. In contrast to other aneurysm syndromes, most affected individuals also presented with early-onset osteoarthritis, with radiologically proven osteoarthritis of 1 or more joints at a mean age of 42 years, primarily involving the knees, spine, and/or thumb base. Intervertebral disc abnormalities of the cervical and lumbar discs were commonly seen, and were detected as early as 12 years of age. The osteoarthritic changes in the hands and wrists involved the scaphotrapeziotrapecoidal, first carpometacarpal, and occasionally the metacarpophalangeal joints; in contrast with classic hand osteoarthritis, the proximal and distal interphalangeal joints were not affected. In addition, umbilical and/or inguinal hernias, velvety skin, and striae were recurring features. Varices or thread veins presented at a young age and were resistant to therapy. Ophthalmologic examination in 10 cases revealed no abnormalities. Aortic tissue that was obtained at surgery or postmortem from affected individuals in 2 of the families showed a variable degree of disorganization of the tunica media with fragmentation and loss of elastic fibers, as well as characteristic mucoid medial degeneration and accumulation of collagen in the media. The authors designated the disorder aneurysms-osteoarthritis syndrome (AOS). Regalado et al. (2011) reported 5 families with mutation in the SMAD3 gene. One family, TAA549, had been reported by Regalado et al. (2011). That family had a frameshift mutation in exon 5 of the SMAD3 gene (603109.0004). Regalado et al. (2011) identified 3 additional SMAD3 mutations in 4 families. These families all segregated thoracic aortic aneurysm as an autosomal dominant trait. Some members of the family also had abdominal aortic aneurysms, iliac artery aneurysms, and intracranial aneurysms. Only 2 of 6 who were imaged had arterial tortuosity of the cerebral vessels. Seven of 25 patients reported osteoarthritis, and 2 of 25 reported degenerative disc or joint disease. In the 5 families, there were 31 individuals carrying SMAD3 mutations and 11 obligate carriers. Among these 42 individuals, 21 individuals presented with thoracic aortic aneurysm and/or dissection, 4 with intracranial aneurysm or subarachnoid hemorrhage, 2 with abdominal aortic aneurysm, and 2 with bilateral iliac aneurysms. The average age at presentation of disease was 45.1 years (42 years for thoracic aortic dissection and 51 years for intracranial aneurysms or subarachnoid hemorrhage). Regalado et al. (2011) concluded that SMAD3 mutations are responsible for 2% of familial thoracic aortic aneurysms with dissection. Van de Laar et al. (2012) presented clinical data on 45 patients with aneurysms-osteoarthritis syndrome from 8 families with 8 different SMAD3 mutations. The 45 patients had a mean age of 45 years, including 6 children aged 9 to 17 years. All had at least 1 sign of the disorder. Among adult patients, 54% had presented with joint complaints with age of onset 18 to 61 years, and 46% presented with cardiovascular abnormalities with an age range of 20 to 66 years. Sudden death, aortic aneurysms, and severe mitral valve insufficiency were the most common presentation. In 3 patients the diagnosis of Marfan syndrome (154700) was made at the time of presentation on the basis of revised Ghent criteria. All 6 children were referred for initial evaluation after the disorder had been diagnosed in the family. Among the children, a 12-year-old patient presented with knee and lower back pain and imaging showed agenesis of the anterior cruciate ligaments, osteochondritis dissecans of the knee, and severe intervertebral disc degeneration. A 17-year-old boy also showed severe intervertebral disc degeneration at multiple levels, and a 16-year-old boy had tenodesis of the first metacarpophalangeal joint. Overall, 89% of patients had cardiovascular anomalies, including aneurysm or tortuosity (83%), ventricular hypertrophy (18%), atrial fibrillation (24%), mitral valve anomalies (50%), and congenital heart malformation (9%), including atrial septal defect, persistent ductus arteriosus, pulmonary valve stenosis, and bicuspid aortic valve. Osteoarthritis in at least 1 joint was present in 96% with variable joints involved; however, 77% presented with spine osteoarthritis, 92% with intervertebral disc degeneration, 56% with osteochondritis dissecans, and 85% with painful joints. Pes planus was present in 91%, and scoliosis in 61%. A minority had other skeletal anomalies associated with this phenotype, including dolichostenomelia, long slender fingers, camptodactyly, pectus deformity, and protrusio acetabulae. Hypertelorism was present in 31%; abnormal palate in 54%; abnormal uvula in 52%; velvety skin in 62%; migraine or severe headache in 50%; and varices in 58%. Other anomalies were present in a minority of patients. Van de Laar et al. (2012) noted that atrial fibrillation and ventricular hypertrophy had not previously been reported in LDS and that both are uncommon in Marfan syndrome. They suggested that patients presenting with arterial tortuosity and symptoms of osteoarthritis, as well as those with osteoarthritis who have a family history of arterial disease or sudden death should have SMAD3 as the first gene screened. They recommended x-ray examination of the knees, total spine, and hands, particularly in thoracic aortic aneurysm disease patients with a family history of joint complaints or abnormalities. Mapping In a 4-generation Dutch family in which 22 individuals had arterial aneurysms and dissections and/or early-onset osteoarthritis, van de Laar et al. (2011) performed genomewide linkage analysis and obtained a lod score of 3.6 on chromosome 15q. Fine mapping narrowed the gene locus to a 12.8-Mb region between markers D15S155 and D15S980. Molecular Genetics In a 4-generation Dutch family with arterial aneurysms and dissections and/or early-onset osteoarthritis mapping to chromosome 15q22.2-q24.2, van de Laar et al. (2011) analyzed the candidate gene SMAD3 and identified heterozygosity for a missense mutation (603109.0001) that segregated with the disease. Analysis of SMAD3 in 99 patients with thoracic aortic aneurysms and dissections and Marfan-like features, who were known to be negative for mutation in the FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes, revealed 2 additional probands with heterozygous SMAD3 mutations (603109.0002; 603109.0003). Regalado et al. (2011) reported 4 new mutations in SMAD3 in 5 families with thoracic aortic and other aneurysms with dissection. Van de Laar et al. (2012) screened 393 patients with aneurysms but without mutation in FBN1, TGFBR1, or TRGBR2 for mutations in SMAD3 and identified 45 patients from 8 families with 8 different SMAD3 mutations, 5 of which were novel. The novel mutations included 1 nonsense, 2 missense, and 2 frameshift mutations. INHERITANCE \- Autosomal dominant HEAD & NECK Eyes \- Hypertelorism Mouth \- Abnormal uvula \- High-arched palate \- Cleft palate (rare) Teeth \- Dental malocclusion CARDIOVASCULAR Heart \- Mitral valve prolapse \- Mitral valve regurgitation \- Aortic insufficiency \- Left ventricular hypertrophy \- Atrial fibrillation \- Pulmonary valve stenosis (rare) Vascular \- Aortic aneurysm \- Aortic dissection \- Arterial aneurysm \- Arterial tortuosity \- Persistent ductus arteriosus (rare) \- Varices \- Veins, spider CHEST Ribs Sternum Clavicles & Scapulae \- Pectus deformity ABDOMEN External Features \- Umbilical hernia \- Inguinal hernia Gastrointestinal \- Bowel prolapse GENITOURINARY Internal Genitalia (Female) \- Uterine prolapse Bladder \- Bladder prolapse SKELETAL \- Osteoporosis (rare) Spine \- Intervertebral disc degeneration \- Facet joint osteoarthritis \- Uncovertebral (C3-C7) joint osteoarthritis \- Dural ectasia \- Scoliosis \- Spondylysis \- Spondylolisthesis Pelvis \- Hip osteoarthritis \- Protrusio acetabuli Limbs \- Long bone overgrowth (dolichostenomelia) \- Osteochondritis dissecans \- Knee osteoarthritis \- Meniscal lesions \- Wrist osteoarthritis \- Ankle osteoarthritis \- Joint laxity Hands \- Hand osteoarthritis \- Arachnodactyly \- Camptodactyly Feet \- Foot osteoarthritis \- Pes planus SKIN, NAILS, & HAIR Skin \- Skin velvety \- Striae \- Easy bruisability \- Atrophic scarring MOLECULAR BASIS \- Caused by mutation in the mothers against decapentaplegic, Drosophila, homolog of, 3 gene (SMAD3, 603109.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

LOEYS-DIETZ SYNDROME 3

c3151087

omim

https://www.omim.org/entry/613795

{"doid": ["0070237"], "omim": ["613795"], "orphanet": ["284984"], "synonyms": ["ANEURYSMS-OSTEOARTHRITIS SYNDROME", "Alternative titles", "LOEYS-DIETZ SYNDROME WITH OSTEOARTHRITIS", "LOEYS-DIETZ SYNDROME, TYPE 1C, FORMERLY"], "genereviews": ["NBK1133"]}

A number sign (#) is used with this entry because of evidence that sick sinus syndrome-2 (SSS2) is caused by heterozygous mutation in the cardiac pacemaker channel gene HCN4 (605206) on chromosome 15q24. For a general description and a discussion of genetic heterogeneity of sick sinus syndrome (SSS), see 608567. Clinical Features Bacos et al. (1960) presented a family in which 9 members of 3 generations exhibited nodal rhythm with bradycardia and tended to develop paroxysms of atrial fibrillation in the fourth decade of life. Surawicz and Hariman (1988) provided a follow-up of this family. As predicted by Bacos et al. (1960), individuals in subsequent generations manifested slow heart rate with regular rhythm from birth and developed intermittent atrial fibrillation with established atrial fibrillation requiring chronic treatment later. Surawicz and Hariman (1988) found that some members of the third and fourth generations suffered from more symptomatic bradycardia at a younger age than their parents which led, in some cases, to pacemaker implantation. Sudden death, presumably of cardiac origin, had occurred in 1 member of the third generation. Lehmann and Klein (1978) reported a large family with sinus node dysfunction spanning 3 generations as an autosomal dominant trait. In some affected members, there was an association between the grade of mental retardation and the severity of the sinoatrial disorder. In another family, described in 140450, brachydactyly was combined. Mackintosh and Chamberlain (1979) described sinus node disease affecting both parents and both children in 1 family. Beyer et al. (1993) described a family in which a 10-year-old boy and his 20-year-old sister were found to have atrial fibrillation and bradyarrhythmia. Their father and grandfather, as well as their great-grandmother, had the same. This is clearly the same family as that reported later by Bertram et al. (1996). The 10-year-old proband had shown intrauterine and postnatal bradycardia, and atrial fibrillation was first documented electrocardiographically at 16 months of age. No structural heart defect was evident. A permanent ventricular demand pacemaker was implanted at the age of 10 years after syncope due to severe bradyarrhythmia. Idiopathic atrial fibrillation known since childhood was documented in 3 close relatives. A high-grade AV block resulting in bradyarrhythmia and the occurrence of ST-T changes in precordial leads could be demonstrated in all affected family members, suggesting a diffuse general conduction abnormality. Nof et al. (2007) studied 8 affected and 8 unaffected members of a 4-generation family with asymptomatic sinus bradycardia. Affected individuals had an average heart rate of less than 55 bpm on 24-hour ECG with a minimum of less than 36 bpm, whereas unaffected individuals had an average heart rate greater than 63 bpm and a minimum rate greater than 49 bpm. Exercise testing demonstrated normal chronotropic and exercise capacity, and all had a normally structured heart on echocardiography. There was no history of dizziness, syncope, or sudden cardiac death in the family. Electrophysiologic testing of 2 affected family members confirmed significant sinus node dysfunction, with prolonged average and corrected sinus node recovery times. ### Clinical Variability Milano et al. (2014) reported a large Dutch family (family A) in which affected individuals exhibited sinus bradycardia and left ventricular noncompaction (LVNC). The proband, who had a history of bradycardia with rates as low as 31 beats per minute (bpm), experienced out-of-hospital cardiac arrest due to ventricular fibrillation at age 57 years and underwent placement of an implantable cardioverter-defibrillator (ICD). Review of her previous echocardiograms showed LVNC. The proband had 3 sibs and 2 nephews who also had bradycardia and LVNC. Sinus bradycardia was detected in utero in 1 of the nephews, and he and 2 of the affected sibs had pacemakers implanted due to symptomatic bradycardia. In addition, 2 of the proband's sibs underwent mitral valve reconstruction due to mitral valve prolapse (MVP). Milano et al. (2014) studied 3 more families with a similar phenotype. The 53-year-old proband of family B presented after she collapsed in the shower, and cardiovascular examination revealed bradycardia, LVNC, and myxoid degeneration of the mitral valve. She also had polymorphic ventricular extrasystoles during exercise, and later developed atrial fibrillation. Her son was also affected. In family C, the 74-year-old proband presented with atrial fibrillation and LVNC. His 2 sons had bradycardia and LVNC; 1 son had severe bradycardia documented on Holter monitoring, involving 12 episodes of standstill with a maximum duration of 2.88 seconds. Both sons also exhibited left ventricular hypertrophy, with interventricular septa measuring 13 mm. In the fourth family (family D), a 36-year-old man had severe sinus bradycardia and LVNC as well as moderate aortic valve regurgitation. His mother had a pacemaker for bradycardia, but echocardiography reports were unavailable. Schweizer et al. (2014) studied a 4-generation German family with sinus node dysfunction and myocardial noncompaction, in which the index patient was a 23-year-old man who had syncope resulting in a car accident. He was aware of bradycardia since childhood, with dizziness, fatigue, and palpitations. Resting ECG showed sinus bradycardia and first-degree atrioventricular block, and Holter monitor revealed heart rates as low as 21 bpm, with an average heart rate of 34 bpm. Echocardiography showed LVNC as well as MVP. The proband's mother and his 16-year-old sister also had sinus node dysfunction, LVNC, and MVP. His deceased maternal grandmother, granduncle, and great-grandfather all had a history of sinus bradycardia and congestive heart failure, for which they had received pacemakers in the fifth decade of life. Schweizer et al. (2014) noted that the presence of marked hypertrabeculations and MVP in the 2 youngest patients supported a congenital origin for the structural defects. Vermeer et al. (2016) reported a family with bradycardia, LVNC, and MVP due to a mutation in the HCN4 gene, in which 6 of 7 affected individuals studied also exhibited dilation of the ascending aorta. Review of the patients described by Milano et al. (2014) and Schweizer et al. (2014) revealed dilation of the ascending aorta in 13 of the 18 patients who had images of sufficient quality to be assessed, for an overall detection rate of 77%. Multiple regression analysis showed that HCN4 mutation carriers have a significantly larger age-related increase in aortic diameter than control individuals, and Vermeer et al. (2016) suggested that aortic diameter should be monitored in HCN4 mutation carriers. Molecular Genetics In a 66-year-old woman with marked sinus bradycardia (41 bpm) and intermittent atrial fibrillation who suffered a severe syncopal episode, Schulze-Bahr et al. (2003) identified heterozygosity for a 1-bp deletion (605206.0002) in the pacemaker channel gene HCN4. Family history was unremarkable, and the mutation was not found in her 3 unaffected children or in 362 control chromosomes. In a 43-year-old woman with syncope and a 24-hour ECG showing severe bradycardia (39 bpm on average), cardiac arrest for 40 seconds followed by polymorphic ventricular tachycardia and torsade de pointes, Ueda et al. (2004) identified heterozygosity for a mutation (D553N; 605206.0003) in the HCN4 gene. The patient's resting ECG showed flat T waves and a QTc of 670 ms. The mutation was also found in her affected sister and son, but was not present in 380 control chromosomes. Milanesi et al. (2006) screened the HCN4 gene in 52 patients with bradycardia and identified a mutation (S672R; 605206.0001) in affected members of a 3-generation Italian family with asymptomatic sinus bradycardia. In 8 affected members of a 4-generation family with asymptomatic sinus bradycardia, Nof et al. (2007) identified a heterozygous mutation in the HCN4 gene (G480R; 605206.0004). The mutation was not found in 8 unaffected family members or 100 unrelated control chromosomes. Schweizer et al. (2010) screened 416 patients with cardiac arrhythmias for mutation in 7 candidate genes and identified a 45-year-old German woman with marked sinus bradycardia who was heterozygous for a 13-bp insertion in the HCN4 gene (605206.0007). Pedigree analysis identified 7 additional family members with bradycardia and sinus arrhythmias who were also heterozygous for the insertion. Schweizer et al. (2010) noted that the mutation carriers exhibited an intact capability to accelerate heart rate according to physiologic needs, and stated that these patients had no structural cardiac anomalies. However, Schweizer et al. (2014) reevaluated the cardiac morphology of 5 affected family members and observed that although left ventricular ejection fraction was preserved and there were no overt structural anomalies, comprehensive echocardiography and/or cardiac magnetic resonance imaging revealed biventricular hypertrabeculation and mitral valve prolapse in all 5 patients. In a large Dutch family with bradycardia and LVNC, Milano et al. (2014) performed exome sequencing and identified heterozygosity for a missense mutation in the HCN4 gene (G482R; 605206.0008) that segregated fully with disease. Analysis of the HCN4 gene in 3 additional families with bradycardia and LVNC revealed heterozygosity for 2 mutations: a Y481H substitution (605206.0009) in affected members of 2 families, which were shown to share a common ancestral haplotype, and an A414G mutation (605206.0010) in an affected father and 2 sons in the third family. The mutations were not found in 500 Dutch controls or in public variant databases. The probands from all 4 families were negative for mutations in 13 LVNC-associated genes. In a German mother and 2 children with sinus node dysfunction, LVNC, and MVP, Schweizer et al. (2014) analyzed 79 cardiomyopathy- and cardiac arrhythmia-associated candidate genes and identified heterozygosity for the G482R mutation in the HCN4 gene. In addition, the mother was homozygous and the 2 children heterozygous for a variant of unknown significance in the CSRP3 gene (W4R; see 600824.0001); the authors stated that this variant was unlikely to be a primary cause of the cardiac noncompaction phenotype, but suggested that it might make a modifying contribution. Screening of a cohort of 85 additional unrelated probands identified 2 more probands with heterozygous mutations in HCN4: 1 was the proband of the German family previously studied by Schweizer et al. (2010) with a 13-bp insertion (see 605206.0007), and 1 was a sporadic patient with an HCN4 missense mutation. The CSRP3 W4R variant was not present in either of the latter 2 patients or their families, and all of the patients with HCN4 mutations exhibited LVNC and MVP. In a family with sinus bradycardia, LVNC, MVP, and dilation of the ascending aorta, Vermeer et al. (2016) identified the Y481H mutation in the HCN4 gene. Analysis of 46 cardiomyopathy-associated genes and 15 aortic dilation-associated genes revealed no additional mutations. Vermeer et al. (2016) reviewed multimodal imaging studies available from previously described patients with HCN4 mutations (Milano et al., 2014; Schweizer et al., 2014) and detected dilation of the ascending aorta in 13 of 18 patients with adequate studies, for an overall detection rate of 77%. INHERITANCE \- Autosomal dominant CARDIOVASCULAR Heart \- Sinus bradycardia \- Atrial fibrillation (in some patients) \- Ventricular fibrillation (in some patients) \- Cardiac arrest (rare) \- Left ventricular noncompaction (in some patients) \- Biventricular hypertrabeculation (in some patients) \- Left ventricular hypertrophy (in some patients) \- Mitral valve prolapse (in some patients) \- Mitral valve myxoid degeneration (in some patients) \- Aortic valve regurgitation (in some patients) Vascular \- Dilation of ascending aorta (in some patients) MISCELLANEOUS \- Onset in utero or at birth MOLECULAR BASIS \- Caused by mutation in the hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 gene (HCN4, 605206.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SICK SINUS SYNDROME 2

c0037052

omim

https://www.omim.org/entry/163800

{"doid": ["13884"], "mesh": ["D012804"], "omim": ["163800"], "orphanet": ["166282"], "synonyms": ["Alternative titles", "SICK SINUS SYNDROME 2 WITH OR WITHOUT CARDIAC NONCOMPACTION AND/OR ASCENDING AORTA DILATION", "ATRIAL FIBRILLATION WITH BRADYARRHYTHMIA", "SINUS NODE DISEASE, FAMILIAL, AUTOSOMAL DOMINANT", "SINUS BRADYCARDIA SYNDROME, FAMILIAL, AUTOSOMAL DOMINANT"]}

A number sign (#) is used with this entry because single-nucleotide variation in the promoter region of the MSMB gene (157145) has been associated with the development of prostate cancer. For a general discussion of hereditary prostate cancer, see 176807. Molecular Genetics In a large 2-stage genomewide association study of prostate cancer, Thomas et al. (2008) identified a SNP, rs10993994 (157145.0001), in the proximal promoter of the MSMB gene on chromosome 10q11.2 that was significantly associated with prostate cancer risk (7.31 x 10(-13)). The MSMB gene encodes beta-microseminoprotein (MSP), a member of the immunoglobulin binding factor family synthesized by epithelial cells of the prostate and secreted into seminal plasma. MSP and its binding protein in serum, PSPBP (PI16), have been proposed as serum markers for early detection of high grade prostate cancer. Although its expression has been noted in both normal and neoplastic prostate tissue, MSMB can be silenced by EZH2 (601573) in advanced, androgen-insensitive prostate cancer. Buckland et al. (2005) found that the rs10993994 SNP of MSMB functionally altered in vitro gene expression. Eeles et al. (2008) conducted a genomewide association study using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA; see 176820) concentration (less than 0.5 ng/ml). Analysis of these samples for 541,129 SNPs was performed using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. Eeles et al. (2008) identified a SNP in the MSMB gene, rs10993994, that was significantly associated with prostate cancer (8.7 x 10(-29)). The SNP rs10993994 is 2 basepairs upstream of the transcription start site of MSMB. The risk allele, T, affects multiple predicted binding sites for transcription and splicing factors. Putative androgen and estrogen binding sites lie less than 50 kb upstream from this SNP. Loss of expression of MSMB is associated with recurrence after radical prostatectomy (Reeves et al., 2006). By fine-mapping analysis of a 65-kb region on chromosome 10q including rs10993994 in 6,118 prostate cancer cases and 6,105 controls of European origin, Lou et al. (2009) found rs10993994 remained the SNP most strongly associated with prostate cancer risk (p = 8.8 x 10(-18); heterozygous odds ratio (OR) of 1.20, homozygous OR of 1.64). Lou et al. (2009) stated that the SNP was located at position -57. In vitro functional analysis showed that the T allele was associated with decreased transcriptional activity and that the C allele preferentially bound to the CREB transcription factor (123810). Analysis of tumor cell lines with a CC or CT genotype revealed a higher level of MSMB gene expression compared to cell lines with a TT genotype. Lou et al. (2009) suggested that regulation of MSMB expression is a plausible mechanism accounting for the association with prostate cancer identified at this locus. Yeager et al. (2009) sequenced a 97-kb region of chromosome 10q11.2 including the area surrounding the MSMB gene and the NCOA4 gene (601984) in 70 unrelated individuals, including 36 with prostate cancer. They identified a 51-kb block of linkage disequilibrium (LD) containing rs10993994 and the proximal promoter of the MSMB gene. No additional variants in LD with rs10993994 were identified, suggesting that this is the probable variant that accounts for the association with prostate cancer. In total, 241 novel polymorphisms were identified in the 97-kb region, but none were in the exons of the MSMB gene. No polymorphic sites were found in the first 6 exons of the NCOA4 gene, but several were observed in exons 7 through 10. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

PROSTATE CANCER, HEREDITARY, 13

c2931456

omim

https://www.omim.org/entry/611928

{"doid": ["10283"], "mesh": ["C537243"], "omim": ["611928"], "orphanet": ["1331"]}

Condition in which tumours stimulate excessive gastric acid production Zollinger–Ellison syndrome Other namesgastrinoma, pancreatic ulcerogenic tumor syndrome, ZES, Z-E syndrome[1] Endoscopy image of multiple small ulcers in the distal duodenum in a patient with Zollinger–Ellison syndrome SpecialtyEndocrinology CausesGastrinoma Zollinger–Ellison syndrome (Z-E syndrome) is a disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea. The syndrome is caused by a gastrinoma, a neuroendocrine tumor that secretes a hormone called gastrin.[2] Too much gastrin in the blood (hypergastrinemia) results in the overproduction of gastric acid by parietal cells in the stomach. Gastrinomas most commonly arise in the duodenum, pancreas or stomach. In 75% of cases Zollinger-Ellison syndrome occurs sporadically, while in 25% of cases it occurs as part of an autosomal dominant syndrome called multiple endocrine neoplasia type 1 (MEN 1).[3] ## Contents * 1 Signs and symptoms * 2 Pathophysiology * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 History * 7 References * 8 External links ## Signs and symptoms[edit] Patients with Zollinger–Ellison syndrome may experience abdominal pain and diarrhea.[2] The diagnosis is also suspected in patients who have severe ulceration of the stomach and small bowel, especially if they fail to respond to treatment.[citation needed] * Chronic diarrhea, including steatorrhea (fatty stools) * Pain in the esophagus, especially between and after meals at night * Nausea * Wheezing * Vomiting blood * Malnourishment * Loss of appetite * Malabsorption Gastrinomas may occur as single tumors or as multiple small tumors. About one-half to two-thirds of single gastrinomas are malignant tumors that most commonly spread to the liver and to lymph nodes near the pancreas and small bowel.[citation needed] Nearly 25 percent of patients with gastrinomas have multiple tumors as part of a condition called multiple endocrine neoplasia type 1 (MEN 1). MEN I patients have tumors in their pituitary gland and parathyroid glands, in addition to tumors of the pancreas.[4][citation needed] ## Pathophysiology[edit] Gastrin works on the parietal cells of the gastric glands, causing them to secrete more hydrogen ions into the stomach lumen. In addition, gastrin acts as a trophic factor for parietal cells, causing parietal cell hyperplasia. Normally, hydrogen ion secretion is controlled by a negative feedback loop by gastric cells to maintain a suitable pH, however, the neuroendocrine tumor that is present in individuals with Zollinger-Ellison Syndrome has no regulation, resulting in excessively large amounts of secretion.[5][6] Thus, there is an increase in the number of acid-secreting cells, and each of these cells produces acid at a higher rate. The increase in acidity contributes to the development of peptic ulcers in the stomach, duodenum (first portion of the small bowel) and occasionally the jejunum (second portion of the small bowel)-- the last of which is an 'atypical' ulcer.[7] ## Diagnosis[edit] Zollinger–Ellison syndrome may be suspected when the above symptoms prove resistant to treatment, when the symptoms are especially suggestive of the syndrome, or when endoscopy is suggestive. The diagnosis is made through several laboratory tests and imaging studies:[8] * Secretin stimulation test, which measures evoked gastrin levels. Note that the mechanism underlying this test is in contrast to the normal physiologic mechanism whereby secretin inhibits gastrin release from G cells. Gastrinoma cells release gastrin in response to secretin stimulation,[9][10] thereby providing a sensitive means of differentiation. * Fasting gastrin levels on at least three occasions[11] * Gastric acid secretion and pH (normal basal gastric acid secretion is less than 10 mEq/hour; in Zollinger–Ellison patients, it is usually more than 15 mEq/hour)[12] * An increased level of chromogranin A is a common marker of neuroendocrine tumors. In addition, the source of the increased gastrin production must be determined using MRI or somatostatin receptor scintigraphy.[13] ## Treatment[edit] Proton pump inhibitors (such as omeprazole and lansoprazole) and histamine H2-receptor antagonists (such as famotidine and ranitidine) are used to slow acid secretion. Once gastric acid is suppressed, symptoms normally improve. Surgery to remove peptic ulcers or tumors might also be considered.[14] ## Epidemiology[edit] The condition most commonly affects people between the ages of 30 and 60.[15] The prevalence is unknown, but estimated to be about 1 in 100,000 people.[16] ## History[edit] Sporadic reports of unusual cases of peptic ulceration in the presence of pancreatic tumors occurred prior to 1955, but R. M. Zollinger and E. H. Ellison, surgeons at The Ohio State University, were the first to postulate a causal relationship between these findings. The American Surgical Association meeting in Philadelphia in April 1955 heard the first public description of the syndrome, and Zollinger and Ellison subsequently published their findings in Annals of Surgery.[17] ## References[edit] 1. ^ "Zollinger Ellison syndrome". NORD. Retrieved 16 July 2018. 2. ^ a b "Zollinger-Ellison syndrome". Mayo Clinic. Retrieved 2017-02-27. 3. ^ Rt, Jensen; B, Niederle; E, Mitry; Jk, Ramage; T, Steinmuller; V, Lewington; A, Scarpa; A, Sundin; A, Perren (2006). "Gastrinoma (Duodenal and Pancreatic)". Neuroendocrinology. 84 (3): 173–82. doi:10.1159/000098009. PMID 17312377. S2CID 5096249. 4. ^ Thakker, Rajesh V. (June 2010). "Multiple endocrine neoplasia type 1 (MEN1)". Best Practice & Research Clinical Endocrinology & Metabolism. 24 (3): 355–370. doi:10.1016/j.beem.2010.07.003. ISSN 1521-690X. PMID 20833329. 5. ^ Cho MS, Kasi A. Zollinger Ellison Syndrome. [Updated 2020 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537344/ 6. ^ Cho, Min S.; Kasi, Anup. "Zollinger Ellison Syndrome". In: StatPearls [Internet]. StatPearls Publishing. Retrieved 1 December 2020. 7. ^ Meko, M.D, J. B.; Norton, M.D, J. A. (February 1995). "Management of Patients with Zollinger-Ellison Syndrome". Annual Review of Medicine. 46 (1): 395–411. doi:10.1146/annurev.med.46.1.395. ISSN 0066-4219. PMID 7598474. 8. ^ Hennen, Georges (2001-10-03). Endocrinologie (in French). De Boeck Supérieur. ISBN 9782804138165. 9. ^ Bradley, E L; Galambos, J T (1976). "Diagnosis of gastrinoma by the secretin suppression test". Surgery, Gynecology & Obstetrics. 143 (5): 784–8. PMID 982259. 10. ^ Chiba, T; Yamatani, T; Yamaguchi, A; Morishita, T; Nakamura, A; Kadowaki, S; Fujita, T (1989). "Mechanism for increase of gastrin release by secretin in Zollinger-Ellison syndrome". Gastroenterology. 96 (6): 1439–44. doi:10.1016/0016-5085(89)90510-6. PMID 2565843. 11. ^ "Zollinger-Ellison Syndrome. Information about ZES Syndrome". Patient.info. Retrieved 14 January 2018. 12. ^ Elizabeth D Agabegi; Agabegi, Steven S (2008). Step-Up to Medicine. Step-Up. Hagerstwon, MD: Lippincott Williams & Wilkins. p. 192. ISBN 978-0-7817-7153-5. 13. ^ Jensen RT (2004). "Gastrinomas: advances in diagnosis and management". Neuroendocrinology. 80 Suppl 1: 23–7. doi:10.1159/000080736. PMID 15477712. S2CID 44311651. 14. ^ "Zollinger-Ellison syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-04-17. 15. ^ "Zollinger Ellison Syndrome - NORD (National Organization for Rare Disorders)". Rarediseases.org. Retrieved 14 January 2018. 16. ^ "Orphanet: Zollinger Ellison syndrome". Orpha.net. Retrieved 14 January 2018. 17. ^ Zollinger RM, Ellison EH (1955). "Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas". Ann. Surg. 142 (4): 709–23, discussion, 724–8. doi:10.1097/00000658-195510000-00015. PMC 1465210. PMID 13259432. ## External links[edit] Classification D * ICD-10: E16.4 * ICD-9-CM: 251.5 * MeSH: D015043 External resources * MedlinePlus: 000325 * eMedicine: med/2437 ped/2472 * Patient UK: Zollinger–Ellison syndrome * v * t * e Diseases of the digestive system Upper GI tract Esophagus * Esophagitis * Candidal * Eosinophilic * Herpetiform * Rupture * Boerhaave syndrome * Mallory–Weiss syndrome * UES * Zenker's diverticulum * LES * Barrett's esophagus * Esophageal motility disorder * Nutcracker esophagus * Achalasia * Diffuse esophageal spasm * Gastroesophageal reflux disease (GERD) * Laryngopharyngeal reflux (LPR) * Esophageal stricture * Megaesophagus * Esophageal intramural pseudodiverticulosis Stomach * Gastritis * Atrophic * Ménétrier's disease * Gastroenteritis * Peptic (gastric) ulcer * Cushing ulcer * Dieulafoy's lesion * Dyspepsia * Pyloric stenosis * Achlorhydria * Gastroparesis * Gastroptosis * Portal hypertensive gastropathy * Gastric antral vascular ectasia * Gastric dumping syndrome * Gastric volvulus * Buried bumper syndrome * Gastrinoma * Zollinger–Ellison syndrome Lower GI tract Enteropathy Small intestine (Duodenum/Jejunum/Ileum) * Enteritis * Duodenitis * Jejunitis * Ileitis * Peptic (duodenal) ulcer * Curling's ulcer * Malabsorption: Coeliac * Tropical sprue * Blind loop syndrome * Small bowel bacterial overgrowth syndrome * Whipple's * Short bowel syndrome * Steatorrhea * Milroy disease * Bile acid malabsorption Large intestine (Appendix/Colon) * Appendicitis * Colitis * Pseudomembranous * Ulcerative * Ischemic * Microscopic * Collagenous * Lymphocytic * Functional colonic disease * IBS * Intestinal pseudoobstruction / Ogilvie syndrome * Megacolon / Toxic megacolon * Diverticulitis/Diverticulosis/SCAD Large and/or small * Enterocolitis * Necrotizing * Gastroenterocolitis * IBD * Crohn's disease * Vascular: Abdominal angina * Mesenteric ischemia * Angiodysplasia * Bowel obstruction: Ileus * Intussusception * Volvulus * Fecal impaction * Constipation * Diarrhea * Infectious * Intestinal adhesions Rectum * Proctitis * Radiation proctitis * Proctalgia fugax * Rectal prolapse * Anismus Anal canal * Anal fissure/Anal fistula * Anal abscess * Hemorrhoid * Anal dysplasia * Pruritus ani GI bleeding * Blood in stool * Upper * Hematemesis * Melena * Lower * Hematochezia Accessory Liver * Hepatitis * Viral hepatitis * Autoimmune hepatitis * Alcoholic hepatitis * Cirrhosis * PBC * Fatty liver * NASH * Vascular * Budd–Chiari syndrome * Hepatic veno-occlusive disease * Portal hypertension * Nutmeg liver * Alcoholic liver disease * Liver failure * Hepatic encephalopathy * Acute liver failure * Liver abscess * Pyogenic * Amoebic * Hepatorenal syndrome * Peliosis hepatis * Metabolic disorders * Wilson's disease * Hemochromatosis Gallbladder * Cholecystitis * Gallstone / Cholelithiasis * Cholesterolosis * Adenomyomatosis * Postcholecystectomy syndrome * Porcelain gallbladder Bile duct/ Other biliary tree * Cholangitis * Primary sclerosing cholangitis * Secondary sclerosing cholangitis * Ascending * Cholestasis/Mirizzi's syndrome * Biliary fistula * Haemobilia * Common bile duct * Choledocholithiasis * Biliary dyskinesia * Sphincter of Oddi dysfunction Pancreatic * Pancreatitis * Acute * Chronic * Hereditary * Pancreatic abscess * Pancreatic pseudocyst * Exocrine pancreatic insufficiency * Pancreatic fistula Other Hernia * Diaphragmatic * Congenital * Hiatus * Inguinal * Indirect * Direct * Umbilical * Femoral * Obturator * Spigelian * Lumbar * Petit's * Grynfeltt-Lesshaft * Undefined location * Incisional * Internal hernia * Richter's Peritoneal * Peritonitis * Spontaneous bacterial peritonitis * Hemoperitoneum * Pneumoperitoneum * v * t * e Paraneoplastic syndromes Endocrine * Hypercalcaemia * SIADH * Zollinger–Ellison syndrome * Cushing's syndrome Hematological * Multicentric reticulohistiocytosis * Nonbacterial thrombotic endocarditis Neurological * Paraneoplastic cerebellar degeneration * Encephalomyelitis * Limbic encephalitis * Opsoclonus * Polymyositis * Transverse myelitis * Lambert–Eaton myasthenic syndrome * Anti-NMDA receptor encephalitis Musculoskeletal * Dermatomyositis * Hypertrophic osteopathy Mucocutaneous reactive erythema * Erythema gyratum repens * Necrolytic migratory erythema papulosquamous * Acanthosis nigricans * Ichthyosis acquisita * Acrokeratosis paraneoplastica of Bazex * Extramammary Paget's disease * Florid cutaneous papillomatosis * Leser-Trélat sign * Pityriasis rotunda * Tripe palms Other * Febrile neutrophilic dermatosis * Pyoderma gangrenosum * Paraneoplastic pemphigus *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Zollinger–Ellison syndrome

c0043515

wikipedia

https://en.wikipedia.org/wiki/Zollinger%E2%80%93Ellison_syndrome

{"gard": ["7918"], "mesh": ["D015043"], "umls": ["C0043515"], "icd-9": ["251.5"], "orphanet": ["913"], "wikidata": ["Q218712"]}

Provisional name given to any recently discovered coronavirus of medical significance This article is about the naming of newly discovered coronaviruses. For the 2019 virus, see Severe acute respiratory syndrome coronavirus 2. For the ongoing pandemic, see COVID-19 pandemic. Look up nCoV in Wiktionary, the free dictionary. Novel coronavirus (nCoV) is a provisional name given to coronaviruses of medical significance before a permanent name is decided upon. Although coronaviruses are endemic in humans and infections normally mild, such as the common cold (caused by human coronaviruses in ~15% of cases), cross-species transmission has produced some unusually virulent strains which can cause viral pneumonia and in serious cases even acute respiratory distress syndrome and death.[1][2][3][4] ## Contents * 1 Species * 2 Etymology * 3 See also * 4 References ## Species[edit] The following viruses could initially be referred to as "novel coronavirus", before being formally named: Human pathogenic novel coronaviridae species Official name Other names Original host[a] Place (date) of discovery Disease caused Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[b][4][5] 2019-nCoV; SARS virus 2; Human coronavirus 2019 (HCoV-19) bats, pangolins Wuhan, China (2019) coronavirus disease 2019 (COVID-19)[c][4][6] Middle East respiratory syndrome-related coronavirus (MERS-CoV)[d] Middle East virus; MERS virus; camel flu virus camels, bats Jeddah, Saudi Arabia (2012) Middle East respiratory syndrome (MERS) Human coronavirus HKU1 (HCoV-HKU1) New Haven virus mice Hong Kong (2005) unnamed, extremely rare, usually mild variant of coronavirus respiratory syndrome Severe acute respiratory syndrome coronavirus (SARS-CoV-1)[b] SARS virus civets, bats Foshan, China (2002) severe acute respiratory syndrome (SARS) 1. ^ Host jump capability may not persist 2. ^ a b This virus is not a distinct species, but rather a strain of the species SARSr-CoV 3. ^ Synonyms include 2019 coronavirus pneumonia and Wuhan respiratory syndrome 4. ^ Strains include HCoV-EMC/2012 and London1 novel CoV/2012 All four viruses are part of the Betacoronavirus genus within the coronavirus family. ## Etymology[edit] The word "novel" indicates a "new pathogen of a previously known type" (i.e. known family) of virus. Use of the word conforms to best practices for naming new infectious diseases published by the World Health Organization (WHO) in 2015. Historically, pathogens have sometimes been named after locations, individuals, or specific species.[7] However, this practice is now explicitly discouraged by the WHO.[8] A study published in 2020 suggested that referring to the novel coronavirus (COVID-19) as the "Chinese virus" was stigmatizing and could hinder public health efforts.[9] The official permanent names for viruses and for diseases are determined by the ICTV and the WHO's ICD, respectively. ## See also[edit] * Coronavirus * Coronavirus disease * Coronavirus 229E * Coronavirus OC43 * Coronavirus NL63 * Bat SARS-like coronavirus WIV1 * Bat-borne viruses ## References[edit] 1. ^ Murray and Nadel (2010). Chapter 31. 2. ^ Cunha (2010). pp. 6–18. 3. ^ Melmed (2011). p. 636 4. ^ a b c "The 2019–2020 Novel Coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2) Pandemic: A Joint American College of Academic International Medicine‑World Academic Council of Emergency Medicine Multidisciplinary COVID‑19 Working Group Consensus Paper". ResearchGate. Retrieved May 16, 2020. 5. ^ "Coronavirus disease named Covid-19". BBC News.. 6. ^ According to ICD-10 the disease is referred to as "2019-new coronavirus acute respiratory disease [temporary name]". It is not listed in ICD-11. 7. ^ Ghosh R, Das S. A Brief Review of the Novel Coronavirus (2019-Ncov) Outbreak. Global Journal for Research Analysis. 2020; 9 (2). 8. ^ World Health Organization Best Practices for the Naming of New Human Infectious Diseases. World Health Organization. May 2015. 9. ^ Budhwani, Henna; Sun, Ruoyan (2020). "Creating COVID-19 Stigma by Referencing the Novel Coronavirus as the "Chinese virus" on Twitter: Quantitative Analysis of Social Media Data". Journal of Medical Internet Research. 22 (5): e19301. doi:10.2196/19301. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Novel coronavirus

None

wikipedia

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

{"wikidata": ["Q84497971"]}

Saal Bulas syndrome is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). This means that Saal Bulas syndrome, or a subtype of Saal Bulas syndrome, affects fewer than 200,000 people in the US population. ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Treatment * 4 History * 5 References * 6 External links ## Signs and symptoms[edit] This syndrome consists of ectrodactyly or lobster-like hands, diaphragmatic hernia and absence of the corpus callosum.[1] In addition to these the following problems may also be present. * abnormal alimentary tract * cardiac septal defect * low hair line in front * oligodactyly or missing fingers * respiratory distress * stillbirth/neonatal death ## Diagnosis[edit] This section is empty. You can help by adding to it. (February 2018) ## Treatment[edit] This section is empty. You can help by adding to it. (February 2018) ## History[edit] The syndrome was first described by American paediatricians Howard M. Saal and Dorothy I. Bulas in 1995.[2] ## References[edit] 1. ^ Bissonnette, Bruno (2006). Syndromes: Rapid Recognition and Perioperative Implications. McGraw Hill Professional. ISBN 9780071354554. Retrieved 7 March 2018. 2. ^ Saal, HM; Bulas, DI (July 1995). "Ectrodactyly, diaphragmatic hernia, congenital heart defect, and agenesis of the corpus callosum". Clinical Dysmorphology. 4 (3): 246–50. PMID 7551162. ## External links[edit] * Orpha.net - A listing of Rare diseases * National Institute of Health - Office for Rare Diseases *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Saal Bulas syndrome

c2931439

wikipedia

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

{"gard": ["311"], "mesh": ["C537193"], "umls": ["C2931439"], "wikidata": ["Q7395633"]}

A number sign (#) is used with this entry because Duane-radial ray syndrome (DRRS) is caused by heterozygous mutation in the SALL4 gene (607343) on chromosome 20q13. The IVIC syndrome (147750) is an allelic disorder with a similar phenotype. Description Duane-radial ray syndrome, also known as Okihiro syndrome, is an autosomal dominant disorder characterized by upper limb anomalies, ocular anomalies, and, in some cases, renal anomalies. The combination of the 3 findings was earlier referred to as 'acro-renal-ocular syndrome.' The ocular anomalies usually include Duane anomaly (see 126800), but this finding may be absent in some patients (Kohlhase et al., 2003). Similarly, renal anomalies are not always seen and may not have been investigated, particularly in cases reported before routine renal imaging (Aalfs et al., 1996). Other less common features include sensorineural deafness and gastrointestinal anomalies, such as imperforate anus. The Holt-Oram syndrome (142900), caused by mutation in the TBX5 gene (601620) on chromosome 12q24, shows similar anomalies of the upper limb, but can be differentiated from Duane-radial ray syndrome by the absence of ocular and renal anomalies and the presence of severe congenital heart defects (Kohlhase, 2003). Clinical Features Ferrell et al. (1966) reported a family in which a father and 3 of his 5 children had radial defects in an autosomal dominant pattern of inheritance. The father and 1 child also had Duane anomaly, 1 child had atrial septal defect without Duane anomaly, and the third had radial defects only. Radial malformations in this family ranged from hypoplasia of the thenar musculature to absence of the thumb and first metacarpal. Ferrell et al. (1966) suggested that the family had both the Duane anomaly and a heart-hand syndrome (likely Holt-Oram syndrome). Okihiro et al. (1977) reported a family who showed Duane anomaly and hypoplasia of the thenar eminence in 5 persons in 3 generations. One of the 5 had Hirschsprung disease and another was congenitally deaf. A sixth person, without Duane anomaly, had more extensive malformation of the upper limbs and unilateral deafness. Temtamy et al. (1975) and Temtamy and McKusick (1978) described father and son with some combination of Duane anomaly, radial defects, and kidney anomalies. The father had Duane anomaly, bilateral thenar and thumb hypoplasia with syndactyly of the index finger and unilateral club hand deformity, and malrotation of both kidneys with partial horseshoe anomaly. The son had apparently normal eyes, bilateral club hand with absent thumbs, and absent right kidney with malrotation of the left kidney. Other features included malformed pinnas, pectoral and upper limb hypoplasia, facial nerve weakness, and congenital deafness. Halal et al. (1984) reported a French-Canadian family in which 7 persons in 3 generations had various combinations of acral, renal, and ocular defects. The acral anomalies varied from mild hypoplasia of the distal part of the thumb with limitation of motion at the interphalangeal joint to severe thumb hypoplasia and preaxial polydactyly. Renal anomalies varied from mild malrotation to crossed renal ectopia without fusion; other urinary tract anomalies were vesicoureteral reflux and bladder diverticula. Ocular features included 'complete' coloboma, coloboma of the optic nerve, ptosis, and Duane anomaly. The disorder showed autosomal dominant inheritance with high penetrance but variable expressivity. Dermatoglyphic abnormalities were described. Halal et al. (1984) noted the considerable phenotypic overlap in their family with the disorder reported by Temtamy and McKusick (1978), but also noted that it differed from the latter family by the absence of pectoral and upper limb involvement. Hayes et al. (1985) gave the designation Okihiro syndrome to the combination of Duane anomaly, radial ray abnormalities, and deafness. They reported a family in which the proband had fusion of C2 and C3, in addition to Duane anomaly, bilateral hypoplasia of the thenar eminence with inability to flex the interphalangeal joint of the thumb, and severe bilateral sensorineural hearing loss. A sister had hemifacial microsomia, cervical abnormalities, and hypoplasia of the thenar eminence. Four other relatives had thenar hypoplasia; a fifth had preaxial polydactyly. Duane anomaly was present in 2 distant relatives. MacDermot and Winter (1987) reported a family in which a mother and 2 of her 3 children, a son and a daughter, had bilateral radial defects and absent thumbs transmitted in an autosomal dominant pattern. In addition, Duane anomaly was present in both offspring, one of whom also had anal stenosis. Pierquin et al. (1991) described another case of acrorenoocular syndrome. Aalfs et al. (1996) reported an affected family from the Dutch Antilles. The proband had hypoplasia of the right thumb and absence of the left thumb, hypoplastic left forearm, microphthalmia, microcornea, coloboma of iris and choroid, cataract, and left-crossed renal ectopia with fusion. His mother had hypoplastic left thumb and cataract (possibly due to diabetes mellitus). The sister of the proband demonstrated absence of both thumbs, radii and ulnae, and bilateral chorioretinal scars between optic disc and fovea. Urologic investigations could not be done in the proband's mother and sister. The clinical picture in this family was consistent with the acrorenoocular syndrome. Becker et al. (2002) reported 2 families with an overlapping phenotype of Okihiro syndrome and acrorenoocular syndrome. In 1 family, the proband had severe radial ray defects and Duane anomaly, whereas her mother had radial ray defects, a small left kidney, and sensorineural hearing loss. In the other family, the proband had abnormal thumbs, Duane anomaly, mild hearing loss, and renal anomalies, including pelvicalyceal dilatation and vesicoureteric reflux. Her father had radial ray defects, Duane anomaly, and optic disc hypoplasia. Mutation analysis of the PAX2 gene (167409) showed no mutations. Becker et al. (2002) suggested that Okihiro syndrome and the acrorenoocular syndrome are the same entity. Kohlhase et al. (2003) observed hypertelorism and epicanthic folds in 2 of their patients and reported previously undescribed slit-like openings of the external auditory meatus. They suggested that this feature may help discriminate Okihiro syndrome from Holt-Oram syndrome if no Duane anomaly is present. They also described characteristic flat feet and large sandal gaps in both affected members of 1 family. As indicated by patients reported by Kohlhase et al. (2003), the diagnosis of this disorder is often missed because the associated Duane anomaly is overlooked in combination with striking limb anomalies, which suggest Holt-Oram syndrome. Molecular Genetics Based on the phenotypic overlap between some patients with Okihiro syndrome and those with Townes-Brocks syndrome (107480), Kohlhase et al. (2002) postulated that Okihiro syndrome might result from mutations in a member of the human SALL gene family (see, e.g., SALL1; 602218). In affected members of 5 families with the Okihiro syndrome, Kohlhase et al. (2002) identified 5 different mutations in the SALL4 gene (see, e.g., 607343.0001-607343.0003). In affected members of the family with Duane-radial ray syndrome originally reported by Okihiro et al. (1977), Al-Baradie et al. (2002) identified a nonsense mutation in the SALL4 gene (R865X; 605343.0005). They also identified 2 additional SALL4 mutations (607343.0004; 607343.0006) in 2 other affected families. The authors suggested that SALL4 plays a critical role in abducens motoneuron development. There is phenotypic overlap between Okihiro syndrome and Holt-Oram syndrome. Patients with presumed HOS were found by Brassington et al. (2003) to have mutations in the SALL4 gene. In one of these patients, after a mutation in SALL4 was found, the primary care physician reexamined the patient and noted the presence of ophthalmoplegia, making the diagnosis of Okihiro syndrome (Bamshad, 2003). Bamshad (2003) also stated that he had not considered kidney defects typical of HOS and 1 of the 2 SALL4 cases had a pelvic kidney. Kohlhase (2003) did not consider severe congenital heart defects such as those observed in HOS to be part of the Duane-radial ray syndrome. Kohlhase et al. (2003) found a mutation in the SALL4 gene (607343.0005) in family 1 reported by Becker et al. (2002). The patient had Duane anomaly in addition to the limb and renal changes, indicating that the appropriate diagnosis was Okihiro syndrome. In affected members of family 2 reported by Becker et al. (2002) as having acrorenoocular syndrome, Borozdin et al. (2004) identified a heterozygous deletion of at least 135 kb, including the entire SALL4 gene (607343.0010). In an Italian child with a mild form of Duane-radial ray syndrome originally reported by Parentin and Perissutti (2003), Miertus et al. (2006) identified a heterozygous missense mutation in the SALL4 gene (H888R; 607343.0012). The mutation was present in the affected father and maternal grandmother, but not in the unaffected mother or twin sister of the proband. The proband had mild features of Duane-radial ray syndrome as well as cranial midline defects, including facial dysmorphism, pituitary hypoplasia, and a single central incisor. Nomenclature Temtamy (1986) preferred the designation DR syndrome because she and her colleagues (Temtamy et al., 1975; Temtamy and McKusick, 1978) described and named the disorder earlier than Okihiro et al. (1977) and because D is a mnemonic for Duane and deafness and R for radial and renal. The designation Duane-radial ray syndrome may be preferable to the Okihiro eponymic designation because it indicates that the disorder represents a combination of Duane anomaly and radial ray abnormalities. Use of the hyphen indicates that Duane anomaly and radial ray abnormalities are separate manifestations of the syndrome, not that this is a second syndrome described by Duane. History Duane anomaly with associated deformity of the upper extremities was reported by Crisp (1918), Mennerich (1923), and Gifford (1926). INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Facial weakness \- Facial asymmetry Ears \- Sensorineural deafness \- Abnormal pinnae \- Slit-like openings of the exterior auditory meatus \- External ear malformations Eyes \- Duane anomaly (less common) \- Congenital strabismus \- Impaired ocular abduction \- Impaired ocular adduction \- Globe retraction and deviation on adduction \- Palpebral fissure narrowing on adduction \- Impaired convergence \- Optic disc hypoplasia \- Optic disc dysplasia \- Retinal coloboma \- Iris coloboma \- Epicanthal folds, mild \- Hypertelorism, mild \- Microphthalmia \- Cataracts CARDIOVASCULAR Heart \- Atrial septal defect (rare) \- Ventricular septal defect (rare) RESPIRATORY Nasopharynx \- Choanal stenosis \- Choanal atresia ABDOMEN Gastrointestinal \- Gastrointestinal anomalies (less common) \- Hirschsprung disease \- Anal stenosis \- Imperforate anus GENITOURINARY Kidneys \- Renal anomalies (less common) \- Hypoplastic kidney \- Renal agenesis \- Abnormally placed kidney (dystopic) \- Ectopic kidney with fusion \- Malrotation of the kidney \- Horseshoe kidney \- Hydronephrosis \- Pelvicalyceal dilatation \- Vesicoureteric reflux SKELETAL Spine \- Fused cervical vertebrae \- Scoliosis \- Spina bifida occulta Limbs \- Radial ray abnormalities, highly variable \- Hypoplastic radius \- Absent radius \- Hypoplastic humerus \- Hypoplastic ulna Hands \- Preaxial polydactyly \- Hypoplastic thumb(s) \- Absent thumb(s) \- Triphalangeal thumb(s) \- Absent metacarpal(s) \- Syndactyly \- Thenar hypoplasia \- Radial deviation of hands \- Clubbed hand Feet \- Flat feet \- 'Sandal gap' between first and second toes MUSCLE, SOFT TISSUES \- Thenar eminence hypoplasia \- Pectoralis hypoplasia \- Upper limb muscle hypoplasia MISCELLANEOUS \- Highly variable phenotype \- Duane anomaly is not always present \- Renal anomalies are not always present \- Gastrointestinal anomalies are not always present \- Allelic disorder to the IVIC syndrome ( 147750 ) MOLECULAR BASIS \- Caused by mutation in the sal-like 4 gene (SALL4, 607323.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

DUANE-RADIAL RAY SYNDROME

c1623209

omim

https://www.omim.org/entry/607323

{"doid": ["0060747"], "mesh": ["D004370"], "omim": ["607323"], "orphanet": ["93293", "959"], "synonyms": ["Alternative titles", "OKIHIRO SYNDROME", "DUANE ANOMALY WITH RADIAL RAY ABNORMALITIES AND DEAFNESS", "DR SYNDROME", "ACRORENOOCULAR SYNDROME"], "genereviews": ["NBK1373"]}

Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare immunodeficiency syndrome, characterized by a narrow vulnerability to poorly virulent mycobacteria, such as bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM), and defined by severe, recurrent infections, either disseminated or localized. ## Epidemiology The prevalence is unknown. ## Clinical description MSMD due to autosomal recessive (AR) complete interferon gamma receptor 1 (IFN-gammaR1) and receptor 2 (IFN-gammaR2) deficiencies (see these terms), the most serious variants, develop in early childhood with first infections generally occurring around the age of 3. Serious, disseminated infections with BCG and EM are observed and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Other infections with Salmonella spp., Listeria monocytogenes and viruses have been reported. MSMD due to partial IFN-gammaR1, partial IFN-gammaR2, complete IL-12R-beta1, complete IL12B, complete ISG15, partial STAT1 and partial IRF8 deficiencies and MSMD due to partial X-linked recessive (XR) mutations (see these terms) are usually less severe. They have minor symptoms and some occur after the age of 3 to adulthood. Patients are vulnerable to Mycobacterium tuberculosis. Severe diseases caused by non-typhoidal Salmonella species have been reported in half of patients, especially in those with IL-12R-beta1 or IL12B deficiencies. ## Etiology Only about half of patients with MSMD have an identified genetic etiology. Nine genes are known to be responsible for MSMD. Seven of them are inherited autosomally (IFNGR1, IFNGR2, STAT1, IL12B , IL12RB1 and more recently IRF8 and ISG15) and 2 are X-linked (IKBKG and CYBB). MSMD is heterogeneous and thought to be mendelian based on the large number of consanguineous and/or multiplex kindred identified and/or X-linked heritance. The genetic defects impair IL-12 dependent IFN-gamma immunity. The high allelic heterogeneity results in 17 genetic disorders according to the mode of transmission, impact on function, association of a lack of protein expression or expression of an abnormal protein, and the specific function affected. Molecular and cellular mechanisms remain largely unknown. ## Diagnostic methods Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA, after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. High plasma concentrations of IFN-gamma suggest a complete IFN-gammaR deficiency. Mutational analysis is necessary to identify the exact causative genes involved. ## Differential diagnosis Chronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency should be excluded as well as complete defects in IRF8 or STAT1 and TyK2 (see these terms). ## Antenatal diagnosis Antenatal diagnosis can be offered to those families with the often fatal complete IFNGR deficiencies. ## Genetic counseling MSMD can be inherited in an AD, AR or X-linked manner. Genetic counseling is possible when a specific mutation is identified within a family. ## Management and treatment BCG vaccination should be avoided in those with MSMD. Patients with IL-12B, IL-12R-beta1 or ISG15 deficiencies and partial IFN-gammaR, IRF8 and STAT1 deficiencies respond well to antibiotic therapy and can also be treated with IFN-g therapy. Abdominal lymph node resection may be needed in some cases. Hematopoietic stem cell transplantation (HSCT) should be considered in those with complete IFN-gammaR1 and IFN-gammaR2 deficiencies but rates of rejection are high, probably due to high levels of IFN-gamma detected in the serum of these patients. ## Prognosis Prognosis depends on the specific mutation involved and the corresponding associated disorder. Some cases are fatal while others resolve with antibiotic therapy. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Mendelian susceptibility to mycobacterial diseases

c3266863

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=748

{"gard": ["12977"], "mesh": ["D009165"], "umls": ["C3266863"], "icd-10": ["D84.8"], "synonyms": ["Idiopathic infection caused by BCG or atypical mycobacteria", "MSMD", "Mendelian susceptibility to atypical mycobacteria", "Mendelian susceptibility to mycobacterial infections"]}

Autoimmune skin condition Discoid lupus erythematosus Other namesDLE or Discoid lupus Discoid lupus erythematosus lesion on the face of musician Seal. SpecialtyDermatology Discoid lupus erythematosus is the most common type of chronic cutaneous lupus (CCLE), an autoimmune skin condition on the lupus erythematosus spectrum of illnesses.[1][2] It presents with red, inflamed, coin-shaped patches of skin with a scaling and crusty appearance, most often on the scalp, cheeks, and ears. Hair loss may occur if the lesions are on the scalp.[3] The lesions can then develop severe scarring, and the centre areas may appear lighter in color with a rim darker than the normal skin.[3] These lesions can last for years without treatment.[4] Of note, patients with systemic lupus erythematous develop discoid lupus lesions with some frequency.[4] However, patients who present initially with discoid lupus infrequently develop systemic lupus.[3] Discoid lupus can be divided into localized, generalized, and childhood discoid lupus.[3] The lesions are diagnosed by biopsy.[5] Patients are first treated with sunscreen and topical steroids.[5] If this does not work, an oral medication—most likely hydroxychloroquine or a related medication—can be tried.[5] ## Contents * 1 Signs and symptoms * 1.1 Morphology of Lesions * 1.2 Location of lesions * 1.3 Special characteristics of some lesions * 1.3.1 Scalp lesions * 1.3.2 Lip lesions * 1.4 Other symptoms * 1.5 Complications * 2 Causes * 3 Mechanism * 4 Diagnosis * 4.1 Classification * 4.1.1 Localized * 4.1.2 Generalized * 4.1.3 Childhood * 4.1.4 Special Types of discoid lupus lesions * 4.1.4.1 Hypertrophic lupus * 4.1.4.2 Lupus profundus * 4.1.5 Systemic lupus erythematosus with discoid lupus lesions * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 Society and culture * 9 Other Animals * 10 See also * 11 References * 12 External links ## Signs and symptoms[edit] ### Morphology of Lesions[edit] Discoid lupus erythematosus (DLE) skin lesions first present as dull or purplish red, disc-shaped flat or raised and firm areas of skin.[3][5] These lesions then develop increasing amounts of white, adherent scale.[3][5] Finally, the lesions develop extensive scarring and/or atrophy, as well as pigment changes.[3] They may also have overlying dried fluid, known as crust.[4] On darker skin, the lesions often lose skin pigmentation in the center and develop increased, dark skin pigmentation around the rim.[3] On lighter skin, the lesions often develop a gray color or have very little color change.[3] More rarely, the lesions may be bright red and look like hives.[3] ### Location of lesions[edit] The skin lesions are most often in sun-exposed areas localized above the neck, with favored sites being the scalp, bridge of the nose, upper cheeks, lower lip, and ear and hands [3][5] 24% of patients also have lesions in the mouth (most often the palate), nose, eye, or vulva, which are all mucosal parts of the body.[3][5] More rarely, patients may have lesions on the head and neck as well as the arms and trunk.[3] ### Special characteristics of some lesions[edit] #### Scalp lesions[edit] When discoid lupus is on the scalp, it starts as a red flat or raised area of skin that then loses hair and develops extensive scarring.[3] The lesions often lose skin pigment and become white with areas of increased skin pigment, with or without areas of redness, and have a sunken appearance.[3] They can have a smooth surface or have visible, dilated hair follicles on the surface.[3] #### Lip lesions[edit] When discoid lupus is on the lip, it often has a gray or red color with a thickened top layer of skin (known as hyperkeratosis), areas where the top layer has worn away (known as erosion), and a surrounding rim of redness.[3] ### Other symptoms[edit] Patients may state that their lesions are itchy, tender, or asymptomatic.[3][5] In addition to their skin lesions, they may also have swelling and redness around their eyes, as well as blepharitis.[3][6] ### Complications[edit] Darker-skinned patients are often left with severe scarring and skin color changes even after the lesions get better.[5] In addition, these patients have an increased, though still small, risk for aggressive skin squamous cell carcinoma.[3] ## Causes[edit] Sun exposure triggers lesions in people with discoid lupus erythematous (DLE).[5] Evidence does not clearly demonstrate a genetic component to DLE; however, genetics may predispose certain people to disease.[5] ## Mechanism[edit] Most experts consider DLE an autoimmune disease since pathologists see antibodies when they biopsy the lesions and look at the tissue under the microscope.[5] However, scientists do not understand the connection between these antibodies and the lesions seen in discoid lupus.[5] Possibly, UV light damages skin cells, which then release material from their nuclei.[5] This material diffuses to the dermoepidermal junction, where it binds to circulating antibodies, thereby leading to a series of inflammatory reactions by the immune system.[5] Alternatively, dysfunctional T cells may lead to the disease.[5] ## Diagnosis[edit] When a patient initially presents with discoid lupus, the doctor should ensure that the patient does not have systemic lupus erythematosus.[5] The doctor will order tests to check for anti-nuclear antibodies in the patient's serum, low white blood cell levels, and protein and/or blood in the urine.[3][5] In order to help with diagnosis, the doctor may peel off the top layer of scale from a patient's lesions in order to look at its underside.[3] If the patients does indeed have discoid lupus, the doctor may see tiny spines of keratin that look like carpet tacks and are called langue au chat.[3] Diagnosis is confirmed through biopsy.[5] Typical biopsy findings include deposits of IgG and IgM antibodies at the dermoepidermal junction on direct immunofluorescence.[3][5] This finding is 90% sensitive; however, false positives can occur with biopsies of facial lesions.[5] In addition, pathologists often see groups of white blood cells, particularly T helper cells, around the follicles and blood vessels in the dermis.[3][5] The epidermis appears thin and has effaced rete ridges as well as excess amounts of keratin clogging the openings of the follicles.[3][5] The basal layer of the epidermis sometimes appears to have holes in it since some of the cells in this layer have broken apart.[5] The remains of skin cells that have died through a process called apoptosis are visible in the upper layer of the dermis and the basal layer of the epidermis.[3] The differential diagnosis includes actinic keratoses, sebborheic dermatitis, lupus vulgaris, sarcoidosis, drug rash, Bowen’s disease, lichen planus, tertiary syphilis, polymorphous light eruption, lymphocytic infiltration, psoriasis, and systemic lupus erythematosus.[3][5] ### Classification[edit] Discoid lupus can be broadly classified into localized discoid lupus and generalized discoid lupus based on the location of the lesions.[3] Patients who develop discoid lupus in childhood also have their own sub-type of disease.[3] Hypertrophic lupus and lupus profundus are two special types of discoid lupus distinguished by their characteristic morphological findings.[4] Finally, many patients with systemic lupus also develop discoid lupus lesions.[4] #### Localized[edit] Most people with discoid lupus only have lesions above the neck and therefore have localized discoid lupus erythematosus.[3] #### Generalized[edit] Rarely, patients may have lesions above and below the neck; these patients have generalized discoid lupus erythematosus.[3][5] In addition to lesions in the typical above-the-neck locations, patients with generalized discoid lupus often have lesions on the thorax and the arms.[3] These patients are often bald, with abnormal skin pigment on their scalp, and have severe scarring of the face and arms.[3] Patients with generalized discoid lupus often have abnormal lab tests, such as an elevated ESR or a low white blood cell count.[3] They also often have auto-antibodies, such as ANA or anti-ssDNA antibody.[3] #### Childhood[edit] When patients develop discoid lupus in childhood, it differs from typical discoid lupus in several ways. Boys and girls are equally affected, and these patients later develop SLE more often.[3] These patients also typically do not have any abnormal sensitivity to the sun.[3] #### Special Types of discoid lupus lesions[edit] ##### Hypertrophic lupus[edit] Some experts consider hypertrophic lupus erythematosus—which consists of lesions covered by a very thick, keratin-filled scale—an unusual subset of discoid lupus.[4] Others consider it a distinct entity.[3] ##### Lupus profundus[edit] If a patient has discoid lupus lesions on top of lupus panniculitis, they have lupus profundus.[4] These patients have firm, nontender nodules with defined borders underneath their discoid lupus lesions.[3] #### Systemic lupus erythematosus with discoid lupus lesions[edit] In general, patients with discoid lupus who have only skin disease and no systemic symptoms have a genetically distinct disease from patients with SLE.[5] However, 25% of patients with SLE get discoid lupus lesions at some point as part of their disease.[4] ## Treatment[edit] Treatment for discoid lupus erythematosus includes smoking cessation and a sunscreen that protects against both UVA and UVB light as well as very strong topical steroids or steroids injected into the lesions.[5] Other topical treatments, tacrolimus or pimecrolimus can also be used.[2][7] If this does not help the patient, his or her physician can prescribe an antimalarial medication such as oral hydroxychloroquine or chloroquine.[5] Other oral medications used to treat discoid lupus include retinoids (isotretinoin or acitretin), dapsone, thalidomide (teratogenic, side effects include peripheral neuropathy), azathioprine, methotrexate, or gold.[2][5] The topical steroid fluocinonide is more effective than hydrocortisone in the treatment of discoid lupus erythematosus.[8] For oral treatment, hydroxychloroquine and acitretin are equally effective; however, acitretin was associated with more adverse effects.[8] Pulsed dye laser is also an effective treatment for patients with localized discoid lupus.[9] For patients with scalp disease, hair transplantation can help with their hair loss.[10] ## Prognosis[edit] Discoid lupus erythematosus is a chronic condition, and lesions will last for several years without treatment.[4][5] 50% of patients will eventually get better on their own.[5] If a patient does not have any signs of systemic lupus erythematosus, such as generalized hair loss, ulcers in the mouth or nose, Raynaud's phenomenon, arthritis, or fever at the time that they develop discoid lupus, they will most likely only have discoid lupus and will never develop systemic lupus erythematosus.[3][5] ## Epidemiology[edit] Discoid lupus has an unknown incidence, although it is two to three times more common than systemic lupus erythematosus.[5][6] The disease tends to affect young adults, and women are affected more than men in a 2:1 ratio.[3] ## Society and culture[edit] The musician Seal has this skin condition.[11] Singer Michael Jackson was reportedly diagnosed with discoid lupus in 1984; the condition might have damaged his nasal cartilage and led to some of his cosmetic surgery.[12] ## Other Animals[edit] Dogs and horses can also get discoid lupus.[13][14] ## See also[edit] * Lupus erythematosus * List of cutaneous conditions associated with increased risk of nonmelanoma skin cancer * List of people with lupus ## References[edit] 1. ^ "Cutaneous Lupus Erythematosus | American Skin Association". www.americanskin.org. Retrieved 2018-12-11. 2. ^ a b c Wollina, Uwe; Hansel, Gesina; Koch, André; Abdel-Naser, Mohamed Badawy (2006). "Topical pimecrolimus for skin disease other than atopic dermatitis". Expert Opinion on Pharmacotherapy. 7 (14): 1967–1975. doi:10.1517/14656566.7.14.1967. PMID 17020422. 3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.) Saunders. Chapter 8. ISBN 0-7216-2921-0. 4. ^ a b c d e f g h i editor., Fitzpatrick, James E., 1948- editor. Morelli, Joseph G. Dermatology secrets plus. OCLC 1010741108.CS1 maint: extra text: authors list (link) 5. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah author., Marks, James G., Jr. (2019). Lookingbill and Marks' principles of dermatology. ISBN 9780323430425. OCLC 1024315813. 6. ^ a b Malagola, R.; Abicca, I.; Abbouda, A.; Arrico, L. (2015). "Ocular Complications in Cutaneous Lupus Erythematosus: A Systematic Review with a Meta-Analysis of Reported Cases". Journal of Ophthalmology. 2015: 254260. doi:10.1155/2015/254260. PMC 4480931. PMID 26171240. 7. ^ Kouvelas, Dimitrios; Tzellos, Thrasivoulos George (2008-04-01). "Topical tacrolimus and pimecrolimus in the treatment of cutaneous lupus erythematosus: an evidence-based evaluation". European Journal of Clinical Pharmacology. 64 (4): 337–341. doi:10.1007/s00228-007-0421-2. ISSN 1432-1041. PMID 18157526. 8. ^ a b Jessop, Sue; Whitelaw, David A; Grainge, Matthew J; Jayasekera, Prativa (2017-05-05). "Drugs for discoid lupus erythematosus". Cochrane Database of Systematic Reviews. 5: CD002954. doi:10.1002/14651858.CD002954.pub3. ISSN 1465-1858. PMC 6481466. PMID 28476075. 9. ^ Erceg, Angelina; De Jong, Elke M.J.G.; Van De Kerkhof, Peter C.M.; Seyger, Marieke M.B. (2013). "Journal of the American Academy of Dermatology". Journal of the American Academy of Dermatology. 69 (4): 609–615.e8. doi:10.1016/j.jaad.2013.03.029. PMID 23711766. Retrieved 2018-12-14. 10. ^ Ekelem, Chloe; Pham, Christine; Atanaskova Mesinkovska, Natasha (2018-09-05). "A Systematic Review of the Outcome of Hair Transplantation in Primary Scarring Alopecia". Skin Appendage Disorders. 5 (2): 65–71. doi:10.1159/000492539. ISSN 2296-9195. PMC 6388556. PMID 30815438. 11. ^ Finn, Robin (June 5, 1996). "At Lunch With: Seal; From a Crucible Of Early Pain Comes the Gold Of Stardom". The New York Times. 12. ^ Alyssa Rosenberg (Feb. 2, 2016). Opinion:To understand Michael Jackson and his skin, you have to go beyond race, The Washington Post, 30 May 2020 13. ^ Olivry, Thierry; Linder, Keith E.; Banovic, Frane (2018-04-18). "Cutaneous lupus erythematosus in dogs: a comprehensive review". BMC Veterinary Research. 14 (1): 132. doi:10.1186/s12917-018-1446-8. ISSN 1746-6148. PMC 5907183. PMID 29669547. 14. ^ Rosenkrantz, Wayne (2013-12-01). "Immune-Mediated Dermatoses". Veterinary Clinics of North America: Equine Practice. 29 (3): 607–613. doi:10.1016/j.cveq.2013.08.001. ISSN 0749-0739. PMID 24267678. ## External links[edit] Classification D * ICD-10: L93.0 (ILDS L93.020) * ICD-9-CM: 695.4 * MeSH: D008179 * DiseasesDB: 29595 External resources * Orphanet: 90281 Wikimedia Commons has media related to Discoid lupus erythematosus. * v * t * e Cutaneous keratosis, ulcer, atrophy, and necrobiosis Epidermal thickening * keratoderma: Keratoderma climactericum * Paraneoplastic keratoderma * Acrokeratosis paraneoplastica of Bazex * Aquagenic keratoderma * Drug-induced keratoderma * psoriasis * Keratoderma blennorrhagicum * keratosis: Seborrheic keratosis * Clonal seborrheic keratosis * Common seborrheic keratosis * Irritated seborrheic keratosis * Seborrheic keratosis with squamous atypia * Reticulated seborrheic keratosis * Dermatosis papulosa nigra * Keratosis punctata of the palmar creases * other hyperkeratosis: Acanthosis nigricans * Confluent and reticulated papillomatosis * Callus * Ichthyosis acquisita * Arsenical keratosis * Chronic scar keratosis * Hyperkeratosis lenticularis perstans * Hydrocarbon keratosis * Hyperkeratosis of the nipple and areola * Inverted follicular keratosis * Lichenoid keratosis * Multiple minute digitate hyperkeratosis * PUVA keratosis * Reactional keratosis * Stucco keratosis * Thermal keratosis * Viral keratosis * Warty dyskeratoma * Waxy keratosis of childhood * other hypertrophy: Keloid * Hypertrophic scar * Cutis verticis gyrata Necrobiosis/granuloma Necrobiotic/palisading * Granuloma annulare * Perforating * Generalized * Subcutaneous * Granuloma annulare in HIV disease * Localized granuloma annulare * Patch-type granuloma annulare * Necrobiosis lipoidica * Annular elastolytic giant-cell granuloma * Granuloma multiforme * Necrobiotic xanthogranuloma * Palisaded neutrophilic and granulomatous dermatitis * Rheumatoid nodulosis * Interstitial granulomatous dermatitis/Interstitial granulomatous drug reaction Foreign body granuloma * Beryllium granuloma * Mercury granuloma * Silica granuloma * Silicone granuloma * Zirconium granuloma * Soot tattoo * Tattoo * Carbon stain Other/ungrouped * eosinophilic dermatosis * Granuloma faciale Dermis/ localized CTD Cutaneous lupus erythematosus * chronic: Discoid * Panniculitis * subacute: Neonatal * ungrouped: Chilblain * Lupus erythematosus–lichen planus overlap syndrome * Tumid * Verrucous * Rowell's syndrome Scleroderma/ Morphea * Localized scleroderma * Localized morphea * Morphea–lichen sclerosus et atrophicus overlap * Generalized morphea * Atrophoderma of Pasini and Pierini * Pansclerotic morphea * Morphea profunda * Linear scleroderma Atrophic/ atrophoderma * Lichen sclerosus * Anetoderma * Schweninger–Buzzi anetoderma * Jadassohn–Pellizzari anetoderma * Atrophoderma of Pasini and Pierini * Acrodermatitis chronica atrophicans * Semicircular lipoatrophy * Follicular atrophoderma * Linear atrophoderma of Moulin Perforating * Kyrle disease * Reactive perforating collagenosis * Elastosis perforans serpiginosa * Perforating folliculitis * Acquired perforating dermatosis Skin ulcer * Pyoderma gangrenosum Other * Calcinosis cutis * Sclerodactyly * Poikiloderma vasculare atrophicans * Ainhum/Pseudo-ainhum *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Discoid lupus erythematosus

c0024138

wikipedia

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

{"mesh": ["D008179"], "umls": ["C0024138"], "icd-9": ["695.4"], "icd-10": ["L93.0"], "orphanet": ["90281"], "wikidata": ["Q1228801"]}

Domestic sheep lamb once each year and most breeds have 1 or 2 lambs at each lambing. The Booroola Merino is of particular interest because it frequently has litter sizes of 3 or more and the exceptional reproductive performance segregates as a single gene. Merino sheep carrying this mutation were identified and selected by 2 commercial sheep breeders, the Seears brothers of 'Booroola,' Cooma, New South Wales, Australia. The Booroola fecundity gene was named FecB by the Committee on Genetic Nomenclature of Sheep and Goats. The effect of the FecB mutation is additive for ovulation rate (the number of ova shed at each ovulatory cycle) and partially dominant for litter size. On average, one copy of the FecB mutation increases litter size by 1 extra lamb. Montgomery et al. (1993) identified linkage between the ovine mutation and 2 microsatellite markers and epidermal growth factor (EGF; 131530) which in the human are located at 4q25. The ovine mutation was also linked to secreted phosphoprotein-1 (SPP1; 166490) which maps to 4q21-q23 in the human. By partial sheep/hamster somatic cell hybridization analysis, Montgomery et al. (1994) reported that the Booroola mutation is located within a conserved syntenic group that maps to sheep chromosome 6. The linkage group with the FecB locus includes the genes for platelet-derived growth factor receptor alpha (PDGFRA; 173490) and alpha casein (CSN1; 115450), providing evidence that a large syntenic group from human chromosome 4q is conserved in sheep. The high ovulation rate and litter size of the Booroola strain of Australian Merino sheep is due to the action of the FecB(B) allele of the FecB gene. By genetic analysis of 31 informative half-sib families from heterozygous sires, Mulsant et al. (2001) showed that the FecB locus is situated in the region of ovine chromosome 6 corresponding to human chromosome 4q22-q23 that contains the bone morphogenetic protein receptor IB gene (BMPR1B; 603248). They found a nonconservative substitution in the BMPR1B coding sequence to be associated fully with the hyperprolificacy phenotype of Booroola ewes. In vitro, ovarian granulosa cells from ewes homozygous for the B allele were less responsive than granulosa cells from ewes homozygous for the wildtype allele to the inhibitory effect on steroidogenesis of GDF5 (601146) and BMP4 (112262), natural ligands of BMPR1B. Mulsant et al. (2001) suggested that ewes homozygous for the B allele would have partial inactivation of BMPR1B, leading to an advanced differentiation of granulosa cells and an advanced maturation of ovulatory follicles. Duffy et al. (2001) investigated the possibility that a gene in the 4q21-q25 region predisposes to human dizygotic twinning (276400). They collected DNA from 169 pairs and 17 sets of 3 sisters (trios) from Australia and New Zealand who had each had spontaneous DZ twins, mostly before the age of 35, and from a replication sample of 111 families (92 affected sister pairs) from the Netherlands. Exclusion mapping was carried out after typing 26 markers on chromosome 4, of which 8 spanned the region likely to contain the human homolog of the sheep FecB gene. Exclusion of linkage to markers led them to conclude that if there is a gene influencing dizygotic twinning on chromosome 4, its effect must be minor. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

FECUNDITY GENE, BOOROOLA, OF SHEEP, HOMOLOG OF

c1851318

omim

https://www.omim.org/entry/134720

{"omim": ["134720"], "synonyms": ["Alternative titles", "FECB"]}

GRN-related frontotemporal lobar degeneration is a progressive brain disorder that can affect behavior, language, and movement. The symptoms of this disorder usually become noticeable in a person's fifties or sixties, and affected people typically survive 7 to 13 years after the appearance of symptoms. However, symptoms can begin as early as a person's thirties or as late as a person's eighties. The features of this condition vary significantly, even among affected members of the same family. Behavioral changes are the most common early signs of GRN-related frontotemporal lobar degeneration. These include marked changes in personality, judgment, and insight. It may become difficult for affected individuals to interact with others in a socially appropriate manner. Affected people may also become easily distracted and unable to complete tasks. They increasingly require help with personal care and other activities of daily living. Many people with GRN-related frontotemporal lobar degeneration develop progressive problems with speech and language (aphasia). Affected individuals may have trouble speaking, remembering words and names (dysnomia), and understanding speech. Over time, they may completely lose the ability to communicate (mutism). People with this condition also experience a decline in intellectual function (dementia). Some people with GRN-related frontotemporal lobar degeneration also develop movement disorders, such as parkinsonism and corticobasal syndrome. The signs and symptoms of these disorders include tremors, muscle stiffness (rigidity), unusually slow movement (bradykinesia), walking problems (gait disturbance), involuntary muscle spasms (myoclonus), uncontrolled muscle tensing (dystonia), and an inability to carry out purposeful movements (apraxia). ## Frequency The prevalence of GRN-related frontotemporal lobar degeneration varies worldwide. It affects an estimated 3 to 15 per 100,000 people aged 45 to 64. ## Causes GRN-related frontotemporal lobar degeneration results from mutations (pathogenic variants) in the GRN gene. This gene provides instructions for making a protein called progranulin. Progranulin is active in many different tissues in the body, where it helps control the growth, division, and survival of cells. Progranulin's function in the brain is not well understood, although it appears to play an important role in the survival of nerve cells (neurons). Most mutations in the GRN gene prevent any progranulin from being produced from one copy of the gene in each cell. As a result, cells make only half the usual amount of progranulin. It is unclear how a shortage of this protein leads to the features of GRN-related frontotemporal lobar degeneration. However, studies have shown that the disorder is characterized by the buildup of a protein called TAR DNA-binding protein 43 (TDP-43) in certain brain cells. The TDP-43 protein forms clumps (aggregates) that may interfere with cell functions and ultimately lead to cell death. Researchers are working to determine how mutations in the GRN gene, and the resulting loss of progranulin, are related to a buildup of TDP-43 in the brain. The features of GRN-related frontotemporal lobar degeneration result from the gradual loss of neurons in regions near the front of the brain called the frontal and temporal lobes. The frontal lobes are involved in reasoning, planning, judgment, and problem-solving, while the temporal lobes help process hearing, speech, memory, and emotion. The death of neurons in these areas causes problems with many critical brain functions. However, it is unclear why the loss of neurons occurs in the frontal and temporal lobes more often than other brain regions in people with GRN-related frontotemporal lobar degeneration. ### Learn more about the gene associated with GRN-related frontotemporal lobar degeneration * GRN ## Inheritance Pattern GRN-related frontotemporal lobar degeneration has a pattern of inheritance known as incomplete autosomal dominance. This means having one copy of the altered gene generally results in milder signs and symptoms than having both copies of the altered gene. People with a mutation in one copy of the GRN gene in each cell (heterozygotes) have some functional progranulin protein and develop GRN-related frontotemporal lobar degeneration. Usually, people with a mutation in both copies of the GRN gene in each cell (homozygotes) do not produce any functional progranulin protein. These individuals have the signs and symptoms of another condition called CLN11 disease, in which movement and neurological problems begin in adolescence or early adulthood. However, some people with two GRN gene mutations that allow the production of some functional progranulin protein have GRN-related frontotemporal lobar degeneration. In most cases of GRN-related frontotemporal lobar degeneration, an affected person has a parent and other family members with the condition. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

GRN-related frontotemporal lobar degeneration

c1843792

medlineplus

https://medlineplus.gov/genetics/condition/grn-related-frontotemporal-lobar-degeneration/

{"omim": ["607485"], "synonyms": []}

Harding ataxia Other namesEarly onset cerebellar ataxia with retained reflexes (EOCARR) Harding ataxia has an autosomal recessive pattern of inheritance. SpecialtyNeurology Harding ataxia is an autosomal recessive cerebellar ataxia originally described by Harding in 1981.[1] This form of cerebellar ataxia is similar to Friedreich ataxia including that it results in poor reflexes and balance, but differs in several ways, including the absence of diabetes mellitus, optic atrophy, cardiomyopathy, skeletal abnormalities, and the fact that tendon reflexes in the arms and knees remain intact.[2] This form of ataxia is characterized by onset in the first 20 years, and is less severe than Friedreich ataxia. Additional cases were diagnosed in 1989,[3] 1990,[4] 1991,[5] and 1998.[6] ## Contents * 1 Cases * 2 See also * 3 References * 4 External links ## Cases[edit] 40 cases were diagnosed in northern Italy between 1940 and 1990. The gene frequency for this autosomal recessive condition was estimated at 1 in 218.[7] In 1989, 16 cases on EOCA were diagnosed in children with a mean onset age of 7.1[3] In 1990, 20 patients affected by EOCA were studied. It was found that the ataxia of this study's participants affected the pyramidal tracts and peripheral nerves.[4] ## See also[edit] * Cerebellar ataxia * Friedreich ataxia ## References[edit] 1. ^ Harding, A. E. (1981). "Early onset cerebellar ataxia with retained tendon reflexes: a clinical and genetic study of a disorder distinct from Friedreich's ataxia". Journal of Neurology, Neurosurgery, and Psychiatry. 44 (6): 503–508. doi:10.1136/jnnp.44.6.503. PMC 491030. PMID 7276963. 2. ^ Brusse, E.; Maat-Kievit, J.A.; van Swieten, J.C. (January 2007). "Diagnosis and management of early- and late-onset cerebellar ataxia". Clinical Genetics. 71 (1): 12–24. doi:10.1111/j.1399-0004.2006.00722.x. PMID 17204042. 3. ^ a b Ozeren, A.; Arac, N.; ulku, A. (December 1989). "Early-onset cerebellar ataxia with retained tendon reflexes". Acta Neurologica Scandinavica. 80 (6): 593–597. doi:10.1111/j.1600-0404.1989.tb03933.x. PMID 2618587. 4. ^ a b Filla et at. (1990). "Clinical and genetic heterogeneity in early onset cerebellar ataxia with retained tendon reflexes". Journal of Neurology, Neurosurgery, and Psychiatry. 53 (8): 667–670. doi:10.1136/jnnp.53.8.667. PMC 488168. PMID 2213043. 5. ^ Klockgether, T.; Petersen, D.; Grodd, W.; Dichgans, J. (1991). "Early onset cerebellar ataxia with retained tendon reflexes. Clinical, electrophysiological and MRI observations in comparison with Friedreich's ataxia". Brain. 114 (4): 1559–73. doi:10.1093/brain/114.4.1559. PMID 1884166. 6. ^ Mielke; et al. (July 1998). "Early-onset cerebellar ataxia (EOCA) with retained reflexes: reduced cerebellar benzodiazepine-receptor binding, progressive metabolic and cognitive impairment". Movement Disorders. 13 (4): 739–745. doi:10.1002/mds.870130423. PMID 9686785. 7. ^ Chio; et al. (1993). "Early onset cerebellar ataxia with retained tendon reflexes: prevalence and gene frequency in an Italian population". Clinical Genetics. 43 (4): 207–211. doi:10.1111/j.1399-0004.1993.tb04450.x. PMID 8330454. ## External links[edit] Classification D * ICD-10: none * ICD-9-CM: none * OMIM: 212895 * MeSH: C535633 * Harding ataxia at the Office of Rare Diseases Research * 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]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Harding ataxia

c0393520

wikipedia

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

{"gard": ["2600"], "mesh": ["C535633"], "umls": ["C0393520"], "icd-9": [], "icd-10": [], "orphanet": ["1177"], "wikidata": ["Q5656137"]}

Pityriasis rosea Other namesPityriasis rosea Gibert[1] Pityriasis rosea on the back showing a "christmas tree" pattern SpecialtyDermatology, Infectious disease SymptomsSingle red and slightly scaly area, followed Usual onset10 to 35 years old[2] DurationLess than three months[2] CausesUnclear[3] Diagnostic methodBased on symptoms[2] Differential diagnosisTinea corporis, viral rash, pityriasis versicolor, nummular eczema[3] TreatmentSupportive care[3][2] Frequency1.3% (at some point in time)[3] Pityriasis rosea is a type of skin rash.[2] Classically, it begins with a single red and slightly scaly area known as a "herald patch".[2] This is then followed, days to weeks later, by a rash of many similar but smaller round or oval lesions, mainly on the trunk and upper limbs.[3] About 20% of cases show atypical deviations from this pattern.[3] It usually lasts less than three months and goes away without treatment.[3] Sometimes malaise or a fever may occur before the start of the rash or itchiness, but often there are few other symptoms.[3] While the cause is not entirely clear, it is believed to be related to human herpesvirus 6 (HHV6) or human herpesvirus 7 (HHV7).[3] It does not appear to be contagious.[3] Certain medications may result in a similar rash.[3] Diagnosis is based on the symptoms.[2] Evidence for specific treatment is limited.[3] About 1.3% of people are affected at some point in time.[3] It most often occurs in those between the ages of 10 and 35.[2] The condition was described at least as early as 1798.[1] ## Contents * 1 Signs and symptoms * 2 Causes * 3 Diagnosis * 4 Treatment * 5 Prognosis * 6 Epidemiology * 7 See also * 8 References * 9 External links ## Signs and symptoms[edit] Pityriasis rosea on torso The symptoms of this condition include: * Recent upper respiratory tract infections in 8–69% of patients have been reported by some studies.[4][5] * Occasionally, prodromal flu-like symptoms, including headache, joint pain, mild fever, and fatigue, as well as gastrointestinal symptoms such as nausea, diarrhea, or vomiting, and feeling generally unwell, precede other symptoms.[6][7] * In most cases, a single, 2 to 10cm (1" to 4") oval red "herald" patch appears, classically on the trunk or neck, having an appearance similar to ringworm.[8] Occasionally, the herald patch may occur in a hidden position (in the armpit, for example) and not be noticed immediately. The herald patch may also appear as a cluster of smaller oval spots, and be mistaken for acne. Rarely, it does not become present at all. * After the herald patch appears, usually some days or weeks later, a rash of many small (5–10 mm; ¼" to ½") pink or red, flaky, oval or round spots appear. They are mostly situated on the trunk and upper limbs. They follow the skin's cleavage lines, which on the upper chest and back produce a characteristic "christmas-tree" distribution.[8] * In 6% of cases an "inverse" distribution may occur, with rash mostly on the extremities.[9] In children, presentation can be atypical or inverse, and the course is typically milder.[10][11] * About one in four people with PR have mild to severe symptomatic itching. (Moderate itching due to skin over-dryness is much more common, especially if soap is used to cleanse the affected areas.) The itching is often non-specific, and worsens if scratched. This tends to fade as the rash develops and does not usually last through the entire course of the disease.[12] About a fifth of cases have an atypical form, with significant variations in symptoms including the size, distribution, morphology, and evolution of the lesions.[13][14] In addition to typical papules and scales, forms appearing as very large plaques (pityriasis rosea gigantea), urticaria, large blisters, patches resembling erythema multiforme, oral lesions, and various other appearances have been noted.[7] A vesicular form can mimic chicken pox.[14][7] Variations in distribution include inverted forms, with rashes on the face or extremities without appearing on the trunk, as well as more uncommon versions localized to the armpits, groin, or extremities (pityriasis rosea circinata et marginata of Vidal) or unilateral spread.[7] ## Causes[edit] The cause of pityriasis rosea is not certain, but its clinical presentation and immunologic reactions suggest a viral infection as a cause. Some believe it to be a reactivation[15] of herpes viruses 6 and 7, which cause roseola in infants,[16][17][18][19] though some investigations have found no evidence of this.[20] ## Diagnosis[edit] A herald patch of pityriasis rosea which started before the rest of the lesion and was initially mistaken for a fungal infection Experienced practitioners may make the diagnosis clinically.[21] Classical symptoms are usually straightforward to recognize, but the wide range of atypical forms may cause difficulty for the clinician in diagnosing some cases.[13] Misdiagnosis by nondermatologists is not uncommon.[6] If the diagnosis is in doubt, tests may be performed to rule out similar conditions such as Lyme disease, ringworm, guttate psoriasis, nummular or discoid eczema, drug eruptions, other viral exanthems.[21][22] The clinical appearance of pityriasis rosea in some cases is similar to that of secondary syphilis, and rapid plasma reagin testing should be performed if there is any clinical concern for syphilis.[23] A biopsy of the lesions will show extravasated erythrocytes within dermal papillae and dyskeratotic cells within the dermis.[21] A set of validated diagnostic criteria for pityriasis rosea[24][25] is as follows: A patient is diagnosed as having pityriasis rosea if: 1. On at least one occasion or clinical encounter, he / she has all the essential clinical features and at least one of the optional clinical features, and 2. On all occasions or clinical encounters related to the rash, he / she does not have any of the exclusional clinical features. The essential clinical features are the following:[citation needed] 1. Discrete circular or oval lesions, 2. Scaling on most lesions, and 3. Peripheral collarette scaling with central clearance on at least two lesions. The optional clinical features are the following:[citation needed] 1. Truncal and proximal limb distribution, with less than 10% of lesions distal to mid-upper-arm and mid-thigh, 2. Orientation of most lesions along skin cleavage lines, and 3. A herald patch (not necessarily the largest) appearing at least two days before eruption of other lesions, from history of the patient or from clinical observation. The exclusional clinical features are the following:[citation needed] 1. Multiple small vesicles at the centre of two or more lesions, 2. Two or more lesions on palmar or plantar skin surfaces, and 3. Clinical or serological evidence of secondary syphilis. ## Treatment[edit] The condition usually resolves on its own, and treatment is not required.[26] Oral antihistamines or topical steroids may be used to decrease itching.[21] Steroids do provide relief from itching, and improve the appearance of the rash, but they also cause the new skin that forms (after the rash subsides) to take longer to match the surrounding skin color. While no scarring has been found to be associated with the rash, scratching should be avoided. It's possible that scratching can make itching worse and an itch-scratch cycle may develop with regular scratching (that is, you itch more because you scratch, so you scratch more because you itch, and so on). Irritants such as soaps with fragrances, hot water, wool, and synthetic fabrics should be avoided. Lotions that help stop or prevent itching may be helpful.[26][27] Direct sunlight makes the lesions resolve more quickly.[21] According to this principle, medical treatment with ultraviolet light has been used to hasten resolution,[28] though studies disagree whether it decreases itching[28] or not.[29] UV therapy is most beneficial in the first week of the eruption.[28] A 2007 meta-analysis concluded that there is insufficient evidence for the effectiveness of most treatments.[30] Oral erythromycin was found to be effective for treating the rash and relieving the itch based on one early trial; however, a later study could not confirm these results.[5][30][31] ## Prognosis[edit] In most patients, the condition lasts only a matter of weeks; in some cases it can last longer (up to six months). The disease resolves completely without long-term effects. In a ten-year epidemiological study of 939 people in the United States, less than two percent had a recurrence.[32] ## Epidemiology[edit] The overall prevalence of PR in the United States has been estimated to be 0.13% in men and 0.14% in women. It most commonly occurs between the ages of 10 and 35.[21] It is more common in spring.[21] PR is not viewed as contagious,[33][34] though there have been reports of small epidemics in fraternity houses and military bases, schools and gyms.[21] ## See also[edit] * Pityriasis circinata \- a localized form of pityriasis rosea that affects the axillae and groin * Pityriasis \- for list of similarly named flaky skin conditions * List of cutaneous conditions ## References[edit] 1. ^ a b Bolognia, Jean L.; Jorizzo, Joseph L.; Rapini, Ronald P. (2003). Dermatology. Mosby. p. 183. ISBN 9789997638991. 2. ^ a b c d e f g h "Pityriasis Rosea". NORD (National Organization for Rare Disorders). 2015. Retrieved 10 November 2017. 3. ^ a b c d e f g h i j k l m Eisman, S; Sinclair, R (29 October 2015). "Pityriasis rosea". BMJ (Clinical Research Ed.). 351: h5233. doi:10.1136/bmj.h5233. PMID 26514823. S2CID 33609874. 4. ^ CHUANG, TSU-YI; PERRY, H.O.; ILSTRUP, D.M.; KURLAND, L.T. (May 1983). "Recent upper respiratory tract infection and pityriasis rosea: a case-control study of 249 matched pairs". British Journal of Dermatology. 108 (5): 587–591. doi:10.1111/j.1365-2133.1983.tb01061.x. PMID 6849825. S2CID 11253684. 5. ^ a b Sharma PK, Yadav TP, Gautam RK, Taneja N, Satyanarayana L (2000). "Erythromycin in pityriasis rosea: A double-blind, placebo-controlled clinical trial". Journal of the American Academy of Dermatology. 42 (2 Pt 1): 241–4. doi:10.1016/S0190-9622(00)90132-4. PMID 10642679. 6. ^ a b Drago, Francesco; Ciccarese, Giulia; Rebora, Alfredo; Broccolo, Francesco; Parodi, Aurora (2016). "Pityriasis Rosea: A Comprehensive Classification". Dermatology. 232 (4): 431–437. doi:10.1159/000445375. PMID 27096928. 7. ^ a b c d Parsons, Jerome M. (1986-08-01). "Pityriasis rosea update: 1986". Journal of the American Academy of Dermatology. 15 (2): 159–167. doi:10.1016/S0190-9622(86)70151-5. ISSN 0190-9622. PMID 3528239. 8. ^ a b González, Lenis M.; Allen, Robert; Janniger, Camila Krysicka; Schwartz, Robert A. (2005-09-01). "Pityriasis rosea: An important papulosquamous disorder". International Journal of Dermatology. 44 (9): 757–764. doi:10.1111/j.1365-4632.2005.02635.x. ISSN 1365-4632. PMID 16135147. 9. ^ Tay YK, Goh CL (1999). "One-year review of pityriasis rosea at the National Skin Centre, Singapore". Annals of the Academy of Medicine, Singapore. 28 (6): 829–31. PMID 10672397. 10. ^ Trager, Jonathan D. K. (2007-04-01). "What's your diagnosis? Scaly pubic plaques in a 2-year-old girl--or an "inverse" rash". Journal of Pediatric and Adolescent Gynecology. 20 (2): 109–111. doi:10.1016/j.jpag.2006.12.005. ISSN 1083-3188. PMID 17418397. 11. ^ Chuh, Antonio A. T. (2003-11-01). "Quality of life in children with pityriasis rosea: a prospective case control study". Pediatric Dermatology. 20 (6): 474–478. doi:10.1111/j.1525-1470.2003.20603.x. ISSN 0736-8046. PMID 14651563. 12. ^ "Pityriasis rosea". American Academy of Dermatology. 2003. Archived from the original on 2009-06-21. Retrieved 2009-06-04. 13. ^ a b Urbina, Francisco; Das, Anupam; Sudy, Emilio (2017). "Clinical variants of pityriasis rosea". World Journal of Clinical Cases. 5 (6): 203–211. doi:10.12998/wjcc.v5.i6.203. PMC 5480068. PMID 28685133. 14. ^ a b Bilgili, Serap Güneş; Karadağ, Ayşe Serap; Çalka, Ömer; Şimşek, Gülçin Güler (2012). "Two Cases with Vesicular Pityriasis Rosea" (PDF). Journal of the Turkish Academy of Dermatology. 6 (4). S2CID 73748192. Retrieved 15 June 2020. 15. ^ Board basics : an enhancement to MKSAP 17. Alguire, Patrick C. (Patrick Craig), 1950-, Paauw, Douglas S. (Douglas Stephen), 1958-, American College of Physicians (2003- ). [Philadelphia, Pa.]: American College of Physicians. 2015. ISBN 978-1938245442. OCLC 923566113.CS1 maint: others (link) 16. ^ Drago F, Broccolo F, Javor S, Drago F, Rebora A, Parodi A (2014). "Evidence of human herpesvirus-6 and -7 reactivation in miscarrying women with pityriasis rosea". Journal of the American Academy of Dermatology. 71 (1): 198–9. doi:10.1016/j.jaad.2014.02.023. PMID 24947696. 17. ^ http://www.dermnetnz.org/viral/pityriasis-rosea.html[full citation needed] 18. ^ Pityriasis Rosea at eMedicine 19. ^ Cynthia M. Magro; A. Neil Crowson; Martin C. Mihm (2007). The Cutaneous Lymphoid Proliferations: A Comprehensive Textbook of Lymphocytic Infiltrates of the Skin. John Wiley and Sons. pp. 36–. ISBN 978-0-471-69598-1. Retrieved 10 November 2010. 20. ^ Kempf W, Adams V, Kleinhans M, Burg G, Panizzon RG, Campadelli-Fiume G, Nestle FO (1999). "Pityriasis rosea is not associated with human herpesvirus 7". Archives of Dermatology. 135 (9): 1070–2. doi:10.1001/archderm.135.9.1070. PMID 10490111. 21. ^ a b c d e f g h Habif, Thomas P (2004). Clinical Dermatology: A Clinical Guide to Diagnosis and Therapy (4th ed.). Mosby. pp. 246–8. ISBN 978-0-323-01319-2. 22. ^ Horn T, Kazakis A (1987). "Pityriasis rosea and the need for a serologic test for syphilis". Cutis. 39 (1): 81–2. PMID 3802914. 23. ^ Board basics : an enhancement to MKSAP 17. Alguire, Patrick C. (Patrick Craig), 1950-, Paauw, Douglas S. (Douglas Stephen), 1958-, American College of Physicians (2003- ). Philadelphia, Pa.: American College of Physicians. 2015. ISBN 978-1938245442. OCLC 923566113.CS1 maint: others (link) 24. ^ Chuh AA (2003). "Diagnostic criteria for pityriasis rosea: a prospective case control study for assessment of validity". Journal of the European Academy of Dermatology and Venereology. 17 (1): 101–3. doi:10.1046/j.1468-3083.2003.00519_4.x. PMID 12602987. 25. ^ Chuh A, Zawar V, Law M, Sciallis G (2012). "Gianotti-Crosti syndrome, pityriasis rosea, asymmetrical periflexural exanthem, unilateral mediothoracic exanthem, eruptive pseudoangiomatosis, and papular-purpuric gloves and socks syndrome: a brief review and arguments for diagnostic criteria". Infectious Disease Reports. 4 (1): e12. doi:10.4081/idr.2012.e12. PMC 3892651. PMID 24470919. 26. ^ a b Chuh, A.; Zawar, V.; Sciallis, G.; Kempf, W. (2016-10-01). "A position statement on the management of patients with pityriasis rosea". Journal of the European Academy of Dermatology and Venereology: JEADV. 30 (10): 1670–1681. doi:10.1111/jdv.13826. ISSN 1468-3083. PMID 27406919. 27. ^ Browning, John C. (2009-08-01). "An update on pityriasis rosea and other similar childhood exanthems". Current Opinion in Pediatrics. 21 (4): 481–485. doi:10.1097/MOP.0b013e32832db96e. ISSN 1531-698X. PMID 19502983. S2CID 20224657. 28. ^ a b c Arndt KA, Paul BS, Stern RS, Parrish JA (1983). "Treatment of pityriasis rosea with UV radiation". Archives of Dermatology. 119 (5): 381–2. doi:10.1001/archderm.119.5.381. PMID 6847217. 29. ^ Leenutaphong V, Jiamton S (1995). "UVB phototherapy for pityriasis rosea: a bilateral comparison study". Journal of the American Academy of Dermatology. 33 (6): 996–9. doi:10.1016/0190-9622(95)90293-7. PMID 7490372. 30. ^ a b Chuh, AA; Dofitas, BL; Comisel, GG; Reveiz, L; Sharma, V; Garner, SE; Chu, F (18 April 2007). "Interventions for pityriasis rosea". The Cochrane Database of Systematic Reviews (2): CD005068. doi:10.1002/14651858.CD005068.pub2. PMID 17443568. 31. ^ Rasi A, Tajziehchi L, Savabi-Nasab S (2008). "Oral erythromycin is ineffective in the treatment of pityriasis rosea". J Drugs Dermatol. 7 (1): 35–38. PMID 18246696. 32. ^ Chuang TY, Ilstrup DM, Perry HO, Kurland LT (1982). "Pityriasis rosea in Rochester, Minnesota, 1969 to 1978". Journal of the American Academy of Dermatology. 7 (1): 80–9. doi:10.1016/s0190-9622(82)80013-3. PMID 6980904. 33. ^ "Pityriasis rosea". American Osteopathic College of Dermatology. Retrieved 26 Jan 2010. 34. ^ "Pityriasis rosea". DERMAdoctor.com. Archived from the original on 2009-04-08. Retrieved 26 Jan 2010. ## External links[edit] Classification D * ICD-10: L42 * ICD-9-CM: 696.3 * MeSH: D017515 * DiseasesDB: 24698 External resources * MedlinePlus: 000871 * eMedicine: derm/335 emerg/426 ped/1815 * Patient UK: Pityriasis rosea * DermNet viral/pityriasis-rosea * American Academy of Dermatology - Pityriasis Rosea * American Osteopathic College of Dermatology * v * t * e Diseases of the skin and appendages by morphology Growths Epidermal * Wart * Callus * Seborrheic keratosis * Acrochordon * Molluscum contagiosum * Actinic keratosis * Squamous-cell carcinoma * Basal-cell carcinoma * Merkel-cell carcinoma * Nevus sebaceous * Trichoepithelioma Pigmented * Freckles * Lentigo * Melasma * Nevus * Melanoma Dermal and subcutaneous * Epidermal inclusion cyst * Hemangioma * Dermatofibroma (benign fibrous histiocytoma) * Keloid * Lipoma * Neurofibroma * Xanthoma * Kaposi's sarcoma * Infantile digital fibromatosis * Granular cell tumor * Leiomyoma * Lymphangioma circumscriptum * Myxoid cyst Rashes With epidermal involvement Eczematous * Contact dermatitis * Atopic dermatitis * Seborrheic dermatitis * Stasis dermatitis * Lichen simplex chronicus * Darier's disease * Glucagonoma syndrome * Langerhans cell histiocytosis * Lichen sclerosus * Pemphigus foliaceus * Wiskott–Aldrich syndrome * Zinc deficiency Scaling * Psoriasis * Tinea (Corporis * Cruris * Pedis * Manuum * Faciei) * Pityriasis rosea * Secondary syphilis * Mycosis fungoides * Systemic lupus erythematosus * Pityriasis rubra pilaris * Parapsoriasis * Ichthyosis Blistering * Herpes simplex * Herpes zoster * Varicella * Bullous impetigo * Acute contact dermatitis * Pemphigus vulgaris * Bullous pemphigoid * Dermatitis herpetiformis * Porphyria cutanea tarda * Epidermolysis bullosa simplex Papular * Scabies * Insect bite reactions * Lichen planus * Miliaria * Keratosis pilaris * Lichen spinulosus * Transient acantholytic dermatosis * Lichen nitidus * Pityriasis lichenoides et varioliformis acuta Pustular * Acne vulgaris * Acne rosacea * Folliculitis * Impetigo * Candidiasis * Gonococcemia * Dermatophyte * Coccidioidomycosis * Subcorneal pustular dermatosis Hypopigmented * Tinea versicolor * Vitiligo * Pityriasis alba * Postinflammatory hyperpigmentation * Tuberous sclerosis * Idiopathic guttate hypomelanosis * Leprosy * Hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized * Drug eruptions * Viral exanthems * Toxic erythema * Systemic lupus erythematosus Localized * Cellulitis * Abscess * Boil * Erythema nodosum * Carcinoid syndrome * Fixed drug eruption Specialized * Urticaria * Erythema (Multiforme * Migrans * Gyratum repens * Annulare centrifugum * Ab igne) Nonblanchable Purpura Macular * Thrombocytopenic purpura * Actinic/solar purpura Papular * Disseminated intravascular coagulation * Vasculitis Indurated * Scleroderma/morphea * Granuloma annulare * Lichen sclerosis et atrophicus * Necrobiosis lipoidica Miscellaneous disorders Ulcers * Hair * Telogen effluvium * Androgenic alopecia * Alopecia areata * Systemic lupus erythematosus * Tinea capitis * Loose anagen syndrome * Lichen planopilaris * Folliculitis decalvans * Acne keloidalis nuchae Nail * Onychomycosis * Psoriasis * Paronychia * Ingrown nail Mucous membrane * Aphthous stomatitis * Oral candidiasis * Lichen planus * Leukoplakia * Pemphigus vulgaris * Mucous membrane pemphigoid * Cicatricial pemphigoid * Herpesvirus * Coxsackievirus * Syphilis * Systemic histoplasmosis * Squamous-cell carcinoma * v * t * e Papulosquamous disorders Psoriasis Pustular * Generalized pustular psoriasis (Impetigo herpetiformis) * Acropustulosis/Pustulosis palmaris et plantaris (Pustular bacterid) * Annular pustular psoriasis * Localized pustular psoriasis Other * Guttate psoriasis * Psoriatic arthritis * Psoriatic erythroderma * Drug-induced psoriasis * Inverse psoriasis * Napkin psoriasis * Seborrheic-like psoriasis Parapsoriasis * Pityriasis lichenoides (Pityriasis lichenoides et varioliformis acuta, Pityriasis lichenoides chronica) * Lymphomatoid papulosis * Small plaque parapsoriasis (Digitate dermatosis, Xanthoerythrodermia perstans) * Large plaque parapsoriasis (Retiform parapsoriasis) Other pityriasis * Pityriasis rosea * Pityriasis rubra pilaris * Pityriasis rotunda * Pityriasis amiantacea Other lichenoid Lichen planus * configuration * Annular * Linear * morphology * Hypertrophic * Atrophic * Bullous * Ulcerative * Actinic * Pigmented * site * Mucosal * Nails * Peno-ginival * Vulvovaginal * overlap synromes * with lichen sclerosus * with lupus erythematosis * other: * Hepatitis-associated lichen planus * Lichen planus pemphigoides Other * Lichen nitidus * Lichen striatus * Lichen ruber moniliformis * Gianotti–Crosti syndrome * Erythema dyschromicum perstans * Idiopathic eruptive macular pigmentation * Keratosis lichenoides chronica * Kraurosis vulvae * Lichen sclerosus * Lichenoid dermatitis * Lichenoid reaction of graft-versus-host disease *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Pityriasis rosea

c0032026

wikipedia

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

{"mesh": ["D017515"], "umls": ["C0032026"], "wikidata": ["Q1125160"]}

Goodman et al. (1980) reported the cases of 2 Ashkenazi Jewish brothers with a 'new' syndrome of white forelock (poliosis), distinctive facial features and congenital malformations of the ocular, cardiopulmonary and skeletal systems. Ocular hypertelorism, atrial septal defect, prominent thoracic and abdominal veins, hypoplastic or absent terminal phalanges of toes, and segmental bronchomalacia with atelectasis were features. Eyes \- Hypertelorism Inheritance \- Autosomal recessive Limbs \- Absent/hypoplastic terminal phalanges of toes Hair \- White forelock (poliosis) Skin \- Prominent thoracic and abdominal veins Cardiac \- Atrial septal defect Pulmonary \- Segmental bronchomalacia with atelectasis ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

WHITE FORELOCK WITH MALFORMATIONS

c1848463

omim

https://www.omim.org/entry/277740

{"mesh": ["C536700"], "omim": ["277740"], "orphanet": ["2475"]}

Ulbright-Hodes syndrome is characterised by renal dysplasia, growth retardation, phocomelia or mesomelia, radiohumeral fusion, rib abnormalities, anomalies of the external genitalia and a potter-like facies. The syndrome has been described in three infants (one pair of sibs and an unrelated case), all of whom died shortly after birth from respiratory distress resulting from pulmonary hypoplasia and oligohydramnios caused by renal dysplasia. The mode of transmission appears to be autosomal recessive. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Ulbright-Hodes syndrome

c1849438

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3404

{"gard": ["5394"], "mesh": ["C537754"], "omim": ["266910"], "umls": ["C1849438"], "icd-10": ["Q87.8"], "synonyms": ["Renal dysplasia-limb defects syndrome", "Renal dysplasia-mesomelia-radiohumeral fusion syndrome"]}

## Description This EEG variant is characterized by almost complete absence of alpha waves except, in some cases, for a few seconds after the eyes are closed and after hyperventilation (summary by Vogel and Motulsky, 1986). Inheritance An autosomal dominant mode of inheritance was established for low-voltage EEG by Vogel (see review by Vogel and Motulsky, 1986). Population Genetics Vogel and Fujiya (1969) found it in about 5% of the adult German and Japanese populations. Mapping In a study of 17 families, Steinlein et al. (1992) found evidence of close linkage of EEGV1 with the highly polymorphic marker D20S19 located on 20q13.2-q13.3. The gene for benign neonatal seizures (BFNC; 121200) maps to the same region. However, epileptic seizures had not been observed in the families of Steinlein et al. (1992), and no low-voltage patterns were reported in families with benign neonatal convulsions. Data on the families indicated heterogeneity; the maximum likelihood estimate for the proportion of linked families was 0.33 and for the recombination fraction in linked families, 0.0. The linkage between BFNC and D20S19 was confirmed by Malafosse et al. (1990, 1992) and Ryan et al. (1991). Low voltage EEG, benign neonatal convulsions, and Fanconi anemia (FA; 227650) are all linked to the VNTR marker CMM6 (D20S19). Steinlein et al. (1992) examined this region of 20q by pulsed field gel electrophoresis and determined the orientation and order of 4 probes, including CMM6. Comparisons of genetic distances with physical distances showed that the latter were markedly shorter. This discrepancy between physical distance and genetic distance indicates that the EEGV1, BFNC, and FA genes lie in a region of enhanced recombination such as is often found near the end of chromosomes. Clusters of rare cutter sites around CMM6 pointed to at least 4 closely related CpG islands. Lab \- Low-voltage EEG \- Absent EEG alpha waves Inheritance \- Autosomal dominant (20q) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ELECTROENCEPHALOGRAM, LOW-VOLTAGE

c1851759

omim

https://www.omim.org/entry/130180

{"omim": ["130180"], "synonyms": ["Alternative titles", "EEG, LOW-VOLTAGE", "ELECTROENCEPHALOGRAPHIC VARIANT PATTERN 1"]}

A number sign (#) is used with this entry because of evidence that progressive familial intrahepatic cholestasis-3 (PFIC3) is caused by mutation in the gene encoding the class III multidrug resistance (MDR3) P-glycoprotein (ABCB4; 171060). For a general phenotypic description and a discussion of genetic heterogeneity of PFIC, see PFIC1 (211600). Clinical Features De Vree et al. (1998) reported 2 unrelated patients with PFIC3. The first patient was a Turkish boy, born of consanguineous parents, who had recurrent bouts of jaundice from the age of 3 months, when he presented with severe icterus, diarrhea, fever, and pruritus. At the age of 3 years, he showed hepatosplenomegaly, elevated serum liver enzymes, increased gamma-glutamyltransferase (GGT1; 612346) activity (6 times normal), and a high serum bile acid concentration (50 times normal). Liver biopsy showed nonspecific portal inflammation, extensive portal fibrosis, and cirrhosis. There was no response to treatment with ursodeoxycholate (UDCA). Orthotopic liver transplantation was performed at the age of 3.5 years. The second patient was a North African boy, born of first-cousin parents, who had recurrent episodes of severe pruritus from the age of 8 months. At age 3 years, he had hepatosplenomegaly, elevated serum GGT1 activity (38 times normal), and increased serum bile acids (16 times normal), whereas other liver enzymes were only mildly elevated. Liver histology showed ductular proliferation and extensive portal fibrosis. Liver transplantation was performed at the age of 9 years. The mother of the affected child experienced recurrent episodes of intrahepatic cholestasis of pregnancy (ICP3; 614972). Deleuze et al. (1996) found lack of MDR3 (ABCB4) mRNA in the livers of patients with PFIC and increased serum GGT1 levels. Molecular Genetics In 2 unrelated patients with PFIC and high serum GGT1, de Vree et al. (1998) identified 2 different homozygous mutations in the ABCB4 gene (171060.0001; 171060.0002). In a patient with severe PFIC3 requiring liver transplant at the age of 6 years, Jacquemin et al. (1999) identified a homozygous mutation in the ABCB4 gene (171060.0003). Six women in the family with intrahepatic cholestasis of pregnancy were heterozygous for the mutation. Degiorgio et al. (2007) identified 29 distinct mutations in the ABCB4 gene, including 25 novel mutations (see, e.g., 171060.0009; 171060.0010), in 18 probands with PFIC3. The findings indicated high allelic variability in the disorder with a high prevalence of mutations in exon 17 of the ABCB4 gene. Nomenclature Hadchouel (1998) questioned the designation PFIC3 for this type of cholestasis. Noting that there are at least 2 other types of PFIC, she suggested that PFIC3 should be referred to as 'MDR3 deficiency.' INHERITANCE \- Autosomal recessive ABDOMEN Liver \- Intrahepatic cholestasis \- Jaundice \- Hepatomegaly \- Nonspecific portal inflammation shown on biopsy \- Abnormal bile duct proliferation shown on biopsy \- Portal fibrosis shown on biopsy \- Cirrhosis \- End-stage liver disease before adulthood Spleen \- Splenomegaly Gastrointestinal \- Diarrhea \- Malabsorption of fat and fat-soluble vitamins SKIN, NAILS, & HAIR Skin \- Jaundice \- Pruritus LABORATORY ABNORMALITIES \- Increased serum gamma-GGT ( 231950 ) \- Abnormal liver function tests \- Increased serum bile acids MISCELLANEOUS \- Genetic heterogeneity (see PFIC1, 211600 ) \- Onset in early infancy \- Carrier females may develop intrahepatic cholestasis of pregnancy (ICP, 147480 ) MOLECULAR BASIS \- Caused by mutation in the ATP-binding cassette, subfamily B, member 4 gene (ABCB4, 171060.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 3

c0268312

omim

https://www.omim.org/entry/602347

{"doid": ["0070223"], "omim": ["602347"], "orphanet": ["172", "79305"], "synonyms": ["Alternative titles", "MDR3 DEFICIENCY", "CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, WITH ELEVATED SERUM GAMMA-GLUTAMYLTRANSFERASE"]}

Oligoarthritis SpecialtyRheumatology Oligoarthritis (from Greek oligos \- 'few') is defined as arthritis affecting two to four joints during the first six months of disease.[1] ## Types[edit] Two subcategories are recognized:[1][2] * Persistent oligoarthritis: Affecting not more than 4 joints throughout the disease course * Extended oligoarthritis: Affecting a total of more than 4 joints after the first 6 months of disease ## Notes[edit] 1. ^ a b Petty RE, Southwood TR, Manners P, et al. (February 2004). "International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001". J. Rheumatol. 31 (2): 390–2. PMID 14760812. 2. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1. ## References[edit] * Medical Glossary of the Spondylitis Association of America * Pauciarticular juvenile rheumatoid arthritis (oligoarthritis) * About Oligoarthritis * v * t * e Diseases of joints General * Arthritis * Monoarthritis * Oligoarthritis * Polyarthritis Symptoms * Joint pain * Joint stiffness Inflammatory Infectious * Septic arthritis * Tuberculosis arthritis Crystal * Chondrocalcinosis * CPPD (Psudogout) * Gout Seronegative * Reactive arthritis * Psoriatic arthritis * Ankylosing spondylitis Other * Juvenile idiopathic arthritis * Rheumatoid arthritis * Felty's syndrome * Palindromic rheumatism * Adult-onset Still's disease Noninflammatory * Hemarthrosis * Osteoarthritis * Heberden's node * Bouchard's nodes * Osteophyte *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Oligoarthritis

c0409702

wikipedia

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

{"umls": ["C0409702"], "wikidata": ["Q3350500"]}

Hemoglobin SC disease, is a type of sickle cell disease, which means it affects the shape of the red blood cells. Red blood cells contain a protein called hemoglobin, which is responsible for carrying blood throughout the body. People with hemoglobin SC disease have red blood cells that are differently shaped and therefore do not carry oxygen as effectively. Symptoms of hemoglobin SC disease include anemia and episodes of fatigue and extreme pain (vaso-occlusive crisis). The severity of the symptoms can vary from person to person. Hemoglobin SC disease is caused by mutations in the gene that tells our bodies how to make hemoglobin. These mutations cause changes in the shape of the red blood cells. People affected by hemoglobin SC disease need to be especially careful to avoid infection and should be checked regularly by doctors to make sure all of the organs in the body are functioning properly. In times when the anemia becomes severe, a person affected by hemoglobin SC disease may require a blood transfusion. A bone marrow transplant may also be recommended depending on the severity of the symptoms. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hemoglobin SC disease

c0019034

gard

https://rarediseases.info.nih.gov/diseases/6584/hemoglobin-sc-disease

{"mesh": ["D006450"], "umls": ["C0019034"], "orphanet": ["251365"], "synonyms": ["Sickle cell - hemoglobin C disease", "HbSC disease", "Sickle cell-hemoglobin C disease syndrome"]}

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-18 (SPG18) is caused by homozygous mutation in the ERLIN2 gene (611605) on chromosome 8p11. Description Spastic paraplegia-18 is a severe autosomal recessive neurologic disorder characterized by onset in early childhood of progressive spastic paraplegia resulting in motor disability. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures (summary by Alazami et al., 2011 and Yildirim et al., 2011). Clinical Features Al-Yahyaee et al. (2006) reported 2 unrelated consanguineous Omani families with autosomal recessive complicated SPG. In 1 family (family B), 3 affected individuals presented with walking difficulties between ages 4 and 6 years. Physical examination showed lower limb spasticity primarily affecting the hamstring and posterior tibial muscles. Two of the children also had epilepsy; all had normal brain CT scans and normal mental development. Affected individuals from the second family (family A) had early-onset spasticity, mental retardation, and thin corpus callosum on brain MRI. Family A was later found by Schuurs-Hoeijmakers et al. (2012) to have SPG54 (615033), caused by mutation in the DDHD2 gene (615003) on chromosome 8p11. Alazami et al. (2011) reported a consanguineous Saudi family with a complicated form of SPG. One of 2 affected sibs was described in detail. At age 30 months, he developed progressive tightening of the lower extremities with later involvement of the upper extremities, rendering him wheelchair-bound at age 4 years. He had a history of delayed early motor development and intellectual disability, and failed to acquire language. He also developed seizures at age 7 years, and EEG was severely abnormal, with generalized slowing of background and generalized slow spike and wave activities compatible with atypical absence epilepsy. Brain MRI was normal. His younger sister had a similar disease course, except without seizures. Three maternal uncles, who were not examined, reportedly had severe intellectual disability, aphasia, and marked hypertonia, all without seizures. Yildirim et al. (2011) reported a very large, highly consanguineous family from eastern Turkey with a neurologic disorder that the authors termed 'intellectual disability, motor dysfunction, and joint contractures' (IDMDC). Affected individuals presented between ages 6 months and 2 years with an arrest and regression of motor function. Nine patients had infantile febrile seizures. Distal limb deformities became evident after the age of 1 or 2 years and progressed very slowly, but each child finally assumed a specific fixed position. Contractures seemed to begin from the feet and spread in an ascending manner, involving the ankles, knees, and elbows, and finally involving the spine and the neck. Examination of 11 patients between ages 4 and 22 years revealed that none of the patients could walk or crawl; only 2 were still able to sit. All had severe intellectual disability, and none could speak, read, or write. Features suggestive of spasticity included hyperactive reflexes, ankle clonus, and extensor plantar responses, but the neurologic examination was difficult to perform in most. Muscle biopsy of 2 patients, EMG of 4 patients, and brain imaging of 3 patients were all normal. Electron microscopy of white blood cells from 2 affected sibs showed large membrane-bound vacuoles containing flocculent material in 7 to 10% of cells, and these vacuoles appeared to be associated with the endoplasmic reticulum. Al-Saif et al. (2012) reported 4 sibs, born of consanguineous parents from the central region of the Arabian peninsula, with a clinical diagnosis of severe juvenile primary lateral sclerosis. The patients showed difficulty in crawling and limb spasticity around 8 months of age. The motor problems were progressive: patients had delayed motor development, required crutches and walkers at age 5 to 6 years, were wheelchair-bound at age 11 to 12 years, and were bedridden by age 15. Speech and articulation regressed after age 2 years, and the patients were unable to communicate verbally. Cognition was difficult to assess, but was apparently delayed. Other features included kyphosis, scoliosis, high-arched palate, abnormal smooth pursuit, and pseudobulbar palsy as manifest by increased jaw and glabellar reflexes and weak cough. There was distal muscle weakness, overall decreased muscle bulk, and increased muscle tone with hyperreflexia and extensor plantar responses. Seizures were not reported, and brain MRI showed no significant abnormalities. Inheritance The transmission pattern of the neurologic disease in the families reported by Yildirim et al. (2011) and Al-Saif et al. (2012) was consistent with autosomal recessive inheritance. Mapping By genomewide linkage analysis in 2 unrelated Omani families with SPG, Al-Yahyaee et al. (2006) identified a candidate disease locus, referred to here as SPG18, on chromosome 8p12-p11.21 (2-point maximum lod score of 5.91 at D8S1820; combined multipoint lod score of 7.08 at D8S505). Haplotype analysis of both families delineated a 9-cM candidate region between D8S1820 and D8S532. The locus did not overlap with SPG5A (270800). One of the families (family A) was later found to have SPG54, which also maps to 8p11 (Schuurs-Hoeijmakers et al., 2012). By autozygosity mapping of a consanguineous Saudi family with complicated SPG, Alazami et al. (2011) found linkage to an 18.2-Mb interval on chromosome 8p12-q11.22 (maximum lod score of 4.205), which overlapped with the SPG18 locus delineated by Al-Yahyaee et al. (2006). Cytogenetics By autozygosity mapping followed by candidate gene sequencing in a consanguineous Saudi family with complicated SPG, Alazami et al. (2011) identified a homozygous 20-kb deletion on chromosome 8, with the distal breakpoint near physical position 37,694,857 (NCBI36) and the proximal breakpoint near 37,714,575 immediately upstream of exon 2 of the ERLIN2 gene (611605). This 20-kb interval spans 2 protein-coding genes, ERLIN2 and FLJ34378. RT-PCR analysis of patient lymphoblasts showed loss of ERLIN2 transcription, consistent with a null allele. Alazami et al. (2011) noted that ERLIN2 is involved in the endoplasmic reticulum degradation (ERAD) pathway, and postulated that loss of ERLIN2 may result in persistent activation of IP3 signaling and neuronal channel activity since ERAD normally degrades IP3 receptors (see, e.g., ITPR1, 147265). Alazami et al. (2011) also concluded that ERLIN2 depletion caused the phenotype, although they could not exclude a role for FLJ34378. Molecular Genetics In affected members of a consanguineous Turkish family with autosomal recessive intellectual disability, motor dysfunction, and contractures, Yildirim et al. (2011) identified a homozygous truncation mutation in the ERLIN2 gene (611605.0001). The mutation was found by linkage analysis followed by candidate gene sequencing. In 4 sibs, born of consanguineous parents from the central region of the Arabian peninsula, with a clinical diagnosis of juvenile primary lateral sclerosis, Al-Saif et al. (2012) identified a homozygous splice site mutation in the ERLIN2 gene (611605.0002). The mutation was found by homozygosity mapping followed by candidate gene sequencing and segregated with the disorder in the family. Analysis of patient cells demonstrated that the mutation caused premature termination and a decrease in levels of ERLIN2 mRNA (about 15% of controls), and that the mutant transcript underwent nonsense-mediated mRNA decay, resulting in a loss of function. Knockdown of ERLIN2 in mouse neuronal cells resulted in decreased cellular growth compared to controls, supporting a deleterious effect of loss of Erlin2 in patient neurons. INHERITANCE \- Autosomal recessive HEAD & NECK Eyes \- Squint \- Abnormal smooth pursuit Mouth \- High-arched palate SKELETAL \- Contractures, progressive, severe Spine \- Scoliosis \- Kyphosis Feet \- Pes cavus MUSCLE, SOFT TISSUES \- Lower limb muscle weakness \- Global muscle weakness \- Muscle atrophy \- Increased muscle tone NEUROLOGIC Central Nervous System \- Delayed walking \- Abnormal gait \- Lower limb spasticity \- Upper limb spasticity, mild \- Extensor plantar responses \- Hyperreflexia \- Lack of speech \- Mental retardation (in most patients) \- Seizures (in some patients) MISCELLANEOUS \- Onset in infancy or childhood (range 1 to 6 years) \- Regression in infancy (in some patients) \- Progressive disorder \- Results in severe motor disability and loss of independent ambulation MOLECULAR BASIS \- Caused by mutation in the endoplasmic reticulum lipid raft-associated protein 2 gene (ERLIN2, 611605.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SPASTIC PARAPLEGIA 18, AUTOSOMAL RECESSIVE

c2749936

omim

https://www.omim.org/entry/611225

{"doid": ["0110771"], "mesh": ["C567628"], "omim": ["611225"], "orphanet": ["209951"], "synonyms": ["Alternative titles", "INTELLECTUAL DISABILITY, MOTOR DYSFUNCTION, AND JOINT CONTRACTURES"]}

Split hand foot malformation (SHFM) is a type of birth defect that consists of missing digits (fingers and/or toes), a deep cleft down the center of the hand or foot, and fusion of remaining digits. The severity of this condition varies widely among affected individuals. SHFM is sometimes called ectrodactyly; however, this is a nonspecific term used to describe missing digits. SHFM may occur by itself (isolated) or it may be part of a syndrome with abnormalities in other parts of the body. At least six different forms of isolated SHFM have been described. Each type is associated with a different underlying genetic cause. SHFM1 has been linked to chromosome 7, and SHFM2 is linked to the X chromosome. SHFM3 is caused by a duplication of chromosome 10 at position 10q24. Changes (mutations) in the TP63 gene cause SHFM4. SHFM5 is linked to chromosome 2, and SHFM6 is caused by mutations in the WNT10B gene. SHFM may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Split hand split foot malformation autosomal recessive

None

gard

https://rarediseases.info.nih.gov/diseases/4965/split-hand-split-foot-malformation-autosomal-recessive

{"synonyms": []}

Combined immunodeficiency due to MALT1 deficiency is a rare, genetic form of primary immunodeficiency characterized by growth retardation, early recurrent pulmonary infections leading to bronchiectasis, inflammatory gastrointestinal disease, and other symptoms, such as rash, dermatitis, skin infections. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Combined immunodeficiency due to MALT1 deficiency

c3809583

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=397964

{"omim": ["615468"], "icd-10": ["D81.8"]}

A rare, inflammatory eye disease characterized by IgG4-immunopositive lymphocyte and plasmacyte infiltration and collagenous fibrosis of affected tissue and elevated serum levels of IgG4. Clinical presentation includes mass lesion or swelling of the involved structures, commonly involving lacrimal gland and duct, infraorbital and supraorbital nerves, extraocular muscles and orbital soft tissues. A systemic involvement is common. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

IgG4-related ophthalmic disease

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=449563

{"icd-10": ["H05.1"]}

A number sign (#) is used with this entry because of evidence that Bailey-Bloch congential myopathy (MYPBB) is caused by homozygous or compound heterozygous mutation in the STAC3 gene (615521) on chromosome 12q13. Description Bailey-Bloch congenital myopathy, also known as Native American myopathy (NAM), is an autosomal recessive disorder characterized by congenital weakness and arthrogryposis, cleft palate, ptosis, myopathic facies, short stature, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia provoked by anesthesia. It was first reported in the Lumbee Indian tribe in North Carolina (summary by Stamm et al., 2008). Clinical Features Bailey and Bloch (1987) first described Native American myopathy in a 3-month-old American Indian infant of Lumbee descent with multiple congenital anomalies including cleft palate, micrognathia, talipes equinus, and arthrogryposis. The Lumbee population are a mixture of Cheraw Indian, English settlers, and African American ancestry and originate from the Lumber River region of south-central North Carolina (Stamm et al., 2008). Stewart et al. (1988) described 6 Lumbee Indian children with congenital weakness, cleft palate, and multiple skeletal anomalies. All had ptosis and kyphosis/scoliosis. By photograph, the configuration of the sternum was that found in Noonan syndrome (163950). Myopathic facies was also demonstrated by the illustrations. Malignant hyperthermia occurred in 1 patient in whom cleft palate was undergoing repair and was aborted during the initial stages of anesthesia in another. Stewart et al. (1988) noted the similarities to King syndrome (see 145600). All 6 came from the same ethnic group; 3 were known to be related as brother, sister, and first cousin. All parents were normal and there were no known instances of consanguinity although remote consanguinity is likely. The Lumbee Indians, said to number more than 30,000, are thought to have ancestors that are a mixture of coastal Indians and English colonists (Berry, 1963). Stamm et al. (2008) reported 14 Lumbee individuals with Native American myopathy. All had myopathic facies, and most had ptosis, downturned corners of the mouth, high-arched palate, or cleft palate. Other dysmorphic features included downslanting or short palpebral fissures, telecanthus, and micrognathia. The patients had generalized muscle weakness and atrophy, congenital joint contractures, diminished reflexes, and a high frequency of foot deformities. Most also had oral hypotonia, poor feeding, progressive scoliosis, and variable restrictive respiratory insufficiency. Three died within the first year of life. Four (29%) had malignant hyperthermia. Despite significantly delayed motor development, all had normal cognition. Muscle biopsies showed small type I and II fibers in some, and fiber-type disproportion in others. Grzybowski et al. (2017) reported a 19-year-old man, born of unrelated Turkish parents, with a congenital myopathy. He presented in the neonatal period with hypotonia, poor feeding, talipes, and some dysmorphic features, such as low-set ears, micrognathia, and high-arched palate. He walked at age 30 months and later showed proximal muscle weakness with positive Gowers sign, absent deep tendon reflexes, marked scoliosis, mild contractures of the ankles, and facial weakness with mild ptosis and downturned corners of the mouth. The muscle weakness was progressive, but he was able to walk; he also had short stature. EMG showed a myopathic pattern, muscle biopsy showed nonspecific myopathic changes with increased intermyofibrillar and subsarcolemmal lipid droplets, and MRI of the lower limbs showed fatty degeneration of the muscles. Creatine kinase was normal. Telegrafi et al. (2017) reported 4 patients from 2 unrelated families with congenital myopathy. One family was consanguineous from Qatar and the other was nonconsanguineous of Puerto Rican origin. The patients had hypotonia, growth delay with short stature, cleft palate, myopathic facies, and kyphoscoliosis. They had delayed motor development, but were able to walk in childhood and had no cognitive impairment. Dysmorphic features included small head circumference, brachycephaly, long face with bitemporal narrowing, midface hypoplasia, downslanting palpebral fissures, ptosis, epicanthal folds, downturned corners of the mouth, open mouth with tented upper lip, and kyphoscoliosis. One patient had malignant hyperthermia and 2 had conductive hearing loss. More variable features included respiratory insufficiency, short trunk, pectus excavatum, and decreased skin creases on the palms and soles. One patient had a tracheostomy and feeding tube at age 16 years, but intelligence was normal. Telegrafi et al. (2017) noted that the initial clinical diagnoses in these patients included Moebius syndrome (MBS; 157900) and Carey-Fineman-Ziter syndrome (CFZS; 254940). Inheritance Native American myopathy is transmitted in an autosomal recessive pattern; several affected individuals have been born of consanguineous parents, and presumed carrier parents are unaffected (Stamm et al., 2008). Mapping By homozygosity mapping of 5 Lumbee families with Native American myopathy, Stamm et al. (2008) identified a common homozygous 5.6-Mb region on chromosome 12q13.13-q14.1 between markers D12S398 and rs3842936 in affected individuals. Mutation screening of 4 candidate genes, ITGA7 (600536), PIP5K2C, PDE1B (171891), and MLC1SA (609930), failed to identify pathogenic changes. Molecular Genetics Horstick et al. (2013) sequenced the coding regions of the STAC3 gene in a cohort of 5 families with Native American myopathy that included 5 affected and 13 unaffected individuals. All affected individuals were homozygous for a missense mutation (W284S; 615521.0001), whereas all obligate carriers were heterozygous for the mutation. The mutation was not found in 3 unaffected, unrelated Lumbee individuals, in 13 Caucasian control individuals, or in the 1000 Genomes Project database. Horstick et al. (2013) created zebrafish with the W284S mutation, which exhibited decreased Ca(2+) transients. Conversely, expression of the normal human STAC3 gene in mutant fish rescued their phenotype. In a 19-year-old man, born of unrelated Turkish parents, with MYPBB, Grzybowski et al. (2017) identified compound heterozygous mutations in the STAC3 gene (615521.0002 and 615521.0003). The mutations, which were identified by next-generation sequencing of a panel of genes and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function. In 2 sibs, born of consanguineous parents from Qatar with MYPBB, Telegrafi et al. (2017) identified a homozygous W284S mutation. Two sibs from Puerto Rico with the same phenotype were found to be compound heterozygous for the W284S mutation and a 4-bp deletion (c.763_766delCTCT; 615521.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the report demonstrated that the W284S mutation is not restricted to the Native American population. INHERITANCE \- Autosomal recessive GROWTH Height \- Short stature Other \- Poor overall growth HEAD & NECK Head \- Small head circumference \- Brachycephaly Face \- Myopathic facies \- Micrognathia \- Oral hypotonia \- Midface hypoplasia Ears \- Low-set ears \- Hearing loss, conductive Eyes \- Ptosis \- Downslanting palpebral fissures \- Short palpebral fissures \- Telecanthus Mouth \- Downturned mouth \- High-arched palate \- Cleft palate RESPIRATORY \- Restrictive respiratory insufficiency ABDOMEN Gastrointestinal \- Poor feeding GENITOURINARY External Genitalia (Male) \- Cryptorchidism SKELETAL \- Joint contractures Spine \- Kyphoscoliosis Feet \- Talipes deformities MUSCLE, SOFT TISSUES \- Muscle weakness, congenital \- Muscle wasting NEUROLOGIC Central Nervous System \- Delayed motor development \- Mental retardation (rare) \- Enlarged ventricles (in some) Peripheral Nervous System \- Hyporeflexia METABOLIC FEATURES \- Malignant hyperthermia LABORATORY ABNORMALITIES \- Serum creatine kinase may be increased \- Increased prevalence among the Native American Lumbee Indians MOLECULAR BASIS \- Caused by mutation in the SH3 and cysteine-rich domains 3 gene (STAC3, 615521.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MYOPATHY, CONGENITAL, BAILEY-BLOCH

c1850625

omim

https://www.omim.org/entry/255995

{"doid": ["0060346"], "mesh": ["C538343"], "omim": ["255995"], "orphanet": ["168572"], "synonyms": ["Alternative titles", "NATIVE AMERICAN MYOPATHY", "MYOPATHY, CONGENITAL, WITH MYOPATHIC FACIES, SCOLIOSIS, AND MALIGNANT HYPERTHERMIA"], "genereviews": ["NBK542808"]}

Apert syndrome is a genetic disorder characterized by skeletal abnormalities. A key feature of Apert syndrome is the premature closure of the bones of the skull (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face. In addition, a varied number of fingers and toes are fused together (syndactyly). Craniosynostosis causes many of the characteristic facial features of Apert syndrome. Premature fusion of the skull bones prevents the head from growing normally, which leads to a sunken appearance in the middle of the face (midface hypoplasia), a beaked nose, a wrinkled forehead, and an opening in the roof of the mouth (a cleft palate). In individuals with Apert syndrome, an underdeveloped upper jaw can lead to dental problems, such as missing teeth, irregular tooth enamel, and crowded teeth. Many individuals with Apert syndrome have vision problems due to eye abnormalities, which can include bulging eyes (exophthalmos), wide-set eyes (hypertelorism), outside corners of the eyes that point downward (downslanting palpebral fissures), eyes that do not look in the same direction (strabismus), and shallow eye sockets (ocular proptosis). Some people with Apert syndrome have hearing loss or recurrent ear infections due to malformed ear structures. Abnormal development of structures in the face and head can also cause partial blockage of the airways and lead to breathing difficulties in people with Apert syndrome. Craniosynostosis also affects development of the brain, which can disrupt intellectual development. Cognitive abilities in people with Apert syndrome range from normal to mild or moderate intellectual disability. Individuals with Apert syndrome have syndactyly of the fingers and toes. The severity of the fusion varies, although the hands tend to be more severely affected than the feet. Most commonly, three digits on each hand and foot are fused together. In the most severe cases, all of the fingers and toes are fused. Rarely, people with Apert syndrome may have extra fingers or toes (polydactyly). Some people with Apert syndrome have abnormalities in the bones of the elbows or shoulders. These bone problems can restrict movement and impede everyday activities. In some people, abnormalities occur in both sides of the body, but in others, only one side is affected. Additional signs and symptoms of Apert syndrome can include unusually heavy sweating (hyperhidrosis), oily skin with severe acne, or patches of missing hair in the eyebrows. ## Frequency Apert syndrome affects an estimated 1 in 65,000 to 88,000 newborns. Although parents of all ages can have a child with Apert syndrome, the risk is increased in older fathers. ## Causes Mutations in a gene known as FGFR2 cause Apert syndrome. This gene provides instructions for making a protein called fibroblast growth factor receptor 2 (FGFR2). Among its multiple functions, the FGFR2 protein plays a key role in development before birth by signaling immature cells to become bone cells. A mutation in a specific part of the FGFR2 gene alters the protein, increasing its signaling. The abnormal signaling causes the cell to mature too quickly and promotes the premature fusion of bones in the skull, hands, and feet. ### Learn more about the gene associated with Apert syndrome * FGFR2 ## Inheritance Pattern Apert syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Nearly all cases of this condition result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or in early embryonic development. These cases 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

Apert syndrome

c0001193

medlineplus

https://medlineplus.gov/genetics/condition/apert-syndrome/

{"gard": ["5833"], "mesh": ["D000168"], "omim": ["101200"], "synonyms": []}

Malum perforans Other namesNeurotrophic ulcer and Trophic ulcer Diabetic foot ulcer SpecialtyDermatology Malum perforans is a long-lasting, usually painless ulcer that penetrates deep into or through the skin, usually on the sole of the foot (in which case it may be called malum perforans pedis). It is often a complication in diabetes mellitus and other conditions affecting the nerves.[1] ## Contents * 1 Presentation * 2 Cause * 3 Pathophysiology * 4 Diagnosis * 5 Treatment * 6 See also * 7 References * 8 External links ## Presentation[edit] A 47-year-old diabetic patient with profound peripheral neuropathy developed a blister on the plantar aspect of her right heel that became recalcitrant to conservative treatment. These ulcers have punched-out edge and slough in floor, resembling gummatous ulcer. Surrounding area might have loss of sensation. ## Cause[edit] This condition results from denervation of areas exposed to day-to-day friction of bony prominences. The denervation may be result of any of the following diseases: * Spinal injuries * Leprosy * Peripheral nerve injury * Diabetic neuropathy * Tabes dorsalis * Transverse myelitis * Meningomyelocele ## Pathophysiology[edit] Normal pressure and pain sensations are essential for protecting the foot from excessive and prolonged pressures over bony prominences. In insensitive foot, such as in diabetic neuropathy, soft tissues are exposed to excessive pressures without knowledge of the individual. In other words, by nerve damage in the feet, the patients get no feedback on the impact of the feet when walking. These ulcers start with callosity under which suppuration takes place. The pus comes out and a hole forms under which the lesion grows deeper. This leads to punched-out, painless ulcers usually under metatarsal heads, tip of toe, proximal interphalangeal joint of a hammertoe or on the heel.[2] In non-ambulatory patients, these ulcers are found on buttocks and back of heel. ## Diagnosis[edit] Diagnosis is clinical. Sensation is tested using graded monofilament.[2] ## Treatment[edit] Underlying cause of neuropathy is first treated. Necrotic portions of the wound are removed and wound is kept moist at all occasions. Infected ulcers are administered antibiotics. Skin grafting is one of the options. It has been shown that ultrasound may increase the acceptance of graft at trophic ulcer sites.[3] ## See also[edit] * List of cutaneous conditions ## References[edit] 1. ^ Siebel, R; Baumgartner, R; Greitemann, B; Junker, Th. (6 December 2012). "The Treatment of Malum Perforans Pedis". In Altmeyer, Peter; Hoffmann, Klaus; el Gammal, Stephan; et al. (eds.). Wound Healing and Skin Physiology. Springer Science & Business Media. p. 423. ISBN 978-3-642-77882-7. 2. ^ a b Degowin, Richard L.; Leblond, Richard F.; Brown, Donald D. (2004). DeGowin's Diagnostic Examination 8th ed. pp. 157. ISBN 9780071409230. 3. ^ Hill, C. R.; Bamber, J. C.; Ter Haar, G. R. (2004). Physical principles of medical ultrasonics. p. 421. ISBN 9780471970026. ## External links[edit] Classification D * ICD-10: L97 (ILDS L97) *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Malum perforans

c4523969

wikipedia

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

{"icd-10": ["L97"], "wikidata": ["Q1764657"]}

Hemorrhagic disease due to alpha-1-antitrypsin Pittsburg mutation is a rare, genetic, constitutional coagulation factor defect disorder characterized by a bleeding tendancy of variable severity due to methionine 358 to arginine replacement (Pittsburgh mutation) in the alpha-1-antitrypsin protein. Patients present with spontaneous hematomas, hematomas following minor trauma or surgery and, in female patients, ovarian hematomas after ovulation. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=178396

{}

Protamine P4 is a minor basic protein of human sperm nuclei. (Human sperm contains 4 protamines whereas most mammalian species contain only 1.) The human protamines fall into 2 families. One family contains only 1 molecular species, HP1, which shows structural relatedness to other mammalian protamines P1. The second family is represented by 3 proteins: P2, P3, and the minor protein P4. The first family shows high concentration of arginine, cysteine, and tyrosine; the second family, high amounts of arginine, cysteine and histidine. Arkhis et al. (1991) presented the complete amino acid sequence of human protamine P4 which differs from P2 and P3 only by an amino-terminal extension of 1 and 4 residues, respectively. The possibility was raised that the nuclear basic protein HPI1, which is present in low amounts in human testis and can still be detected in mature sperm nuclei, is the precursor for the 3 polypeptides P2, P3, and P4. HPI1 was cloned by Martinage et al. (1990). It is possible that there is only one gene, that encoding HPI1, and that P2, P3, and P4 are derived therefrom. If so, the gene is presumably the one called PRM2, which has been mapped to 16p13.3 (182890). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SPERM PROTAMINE P4

c1866801

omim

https://www.omim.org/entry/182882

{"omim": ["182882"]}

A reproductive system disease is any disease of the reproductive system. ## Contents * 1 Types * 1.1 Infections * 1.2 Congenital abnormalities * 1.3 Examples of cancers * 1.4 Examples of functional problems * 1.5 Endocrine * 2 References ## Types[edit] ### Infections[edit] Reproductive tract infection (RTI) are infections that affect the reproductive tract, which is part of the Reproductive System. For females, reproductive tract infections can affect the upper reproductive tract (fallopian tubes, ovary and uterus) and the lower reproductive tract (vagina, cervix and vulva); for males these infections affect the penis, testicles, urethra or the vas deferens. The three types of reproductive tract infections are endogenous infections, iatrogenic infections and the more commonly known sexually transmitted infections.[1] Each has its own specific causes and symptoms, caused by a bacterium, virus, fungus or other organism. Some infections are easily treatable and can be cured, some are more difficult, and some are non curable such as AIDS and herpes.[2] ### Congenital abnormalities[edit] Examples of congenital abnormalities of the reproductive system include: * Kallmann syndrome \- Genetic disorder causing decreased functioning of the sex hormone-producing glands caused by a deficiency of one or both testes from the scrotum. * Androgen insensitivity syndrome \- A genetic disorder causing people who are genetically male (i.e. XY chromosome pair) to develop sexually as a female due to an inability to utilize androgen. * Intersexuality \- A person who has genitalia and/or other sexual traits which are not clearly male or female. ### Examples of cancers[edit] Examples of cancers of the reproductive system include: * Prostate cancer \- Cancer of the prostate gland * Breast cancer \- Cancer of the mammary gland. * Ovarian cancer \- Cancer of the ovary. * Penile cancer \- Cancer of the penis. * Uterine cancer \- Cancer of the uterus. * Testicular cancer \- Cancer of the testicle/(plural:testes). * Cervical cancer \- Cancer of the cervix. * Benign Prostatic Hypertrophy ### Examples of functional problems[edit] Examples of functional problems of the reproductive system include: * Impotence \- The inability of a male to produce or maintain an erection. * Hypogonadism \- A lack of function of the gonads, in regards to either hormones or gamete production. * Ectopic pregnancy \- When a fertilized ovum is implanted in any tissue other than the uterine wall. * Female sexual arousal disorder \- A condition of decreased, insufficient, or absent lubrication in females during sexual activity * Premature ejaculation \- A lack of voluntary control over ejaculation. * Dysmenorrhea \- Is a medical condition of pain during menstruation that interferes with daily activities[3] ### Endocrine[edit] It is also known that disruption of the endocrine system by certain chemicals adversely affects the development of the reproductive system and can cause vaginal cancer.[4] Many other reproductive diseases have also been link to exposure to synthetic and environmental chemicals. Common chemicals with known links to reproductive disorders include: lead, dioxins and dioxin-like compounds, styrene, toluene, BPA (Bisphenol A) and pesticides.[5] ## References[edit] 1. ^ Reproductive Tract Infections: An Introductory Overview, from Population Council. Retrieved January 2013 2. ^ HIV, AIDS, and Sexually Transmitted Infections, at EngenderHealth. Retrieved January 2017 3. ^ Reproductive System Diseases : Types, Signs and Symptoms and Causes 4. ^ "Endocrine Disruptors" (PDF). National Institute of Environmental Health Sciences. 2006. Archived from the original (PDF) on 2008-02-27. Retrieved 2007-11-29. 5. ^ Infertility and Related Reproductive Disorders. 2003\. Ted Schettler, MD. The collaborative on health and the environment. * v * t * e Male diseases of the pelvis and genitals Internal Testicular * Orchitis * Hydrocele testis * Testicular cancer * Testicular torsion * Male infertility * Aspermia * Asthenozoospermia * Azoospermia * Hyperspermia * Hypospermia * Oligospermia * Necrospermia * Teratospermia Epididymis * Epididymitis * Spermatocele * Hematocele Prostate * Prostatitis * Acute prostatitis * Chronic bacterial prostatitis * Chronic prostatitis/chronic pelvic pain syndrome * Asymptomatic inflammatory prostatitis * Benign prostatic hyperplasia * Prostate cancer Seminal vesicle * Seminal vesiculitis External Penis * Balanoposthitis / Balanitis * Balanitis plasmacellularis * Pseudoepitheliomatous keratotic and micaceous balanitis * Phimosis * Paraphimosis * Priapism * Sexual dysfunction * Erectile dysfunction * Peyronie's disease * Penile cancer * Penile fracture * Balanitis xerotica obliterans Other * Hematospermia * Retrograde ejaculation * Postorgasmic illness syndrome * 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 Reproductive health Rights * Compulsory sterilization * Contraceptive security * Genital integrity * Circumcision controversies * Genital modification and mutilation * Intersex Education * Genetic counseling * Pre-conception counseling * Sex education Planning * Assisted reproductive technology * Birth control * Childfree/Childlessness * Parenting * Adoption * Childbirth * Foster care * Safe sex Health * Men's * Women's * Vulvovaginal * Research * Self-report sexual risk behaviors Pregnancy * Abortion * Birth spacing * Maternal health * Obstetrics * Options counseling * Pregnancy from rape * Pregnant patients' rights * Prenatal care * Teenage pregnancy * Preteen pregnancy * Unintended pregnancy Medicine * Andrology * Genitourinary medicine * Gynaecology * Obstetrics and gynaecology * Reproductive endocrinology and infertility * Sexual medicine Disorder * Disorders of sex development * Infertility * Reproductive system disease * Sexual dysfunction * Sexually transmitted infection * Clinic By country * China * India * Iran * Ireland * Pakistan * Philippines * Singapore * United Kingdom * Teen * United States * Teen pregnancy * Birth control History * Birth control movement in the United States * History of condoms * Social hygiene movement * Timeline of reproductive rights legislation Policy * One-child policy * Two-child policy * Financial * Baby bonus * Bachelor tax * Child benefit * Tax on childlessness * v * t * e Women's health Reproductive & Sexual health Reproductive health Reproductive tract * External female genitalia (vulva) * Clitoris * Clitoral hood * Labia minora * Labia majora * Vagina * Cervix * Uterus * Fallopian tube * Ovary * Reproductive system disease Maternal health * Pregnancy * Unintended pregnancy * Gravidity and parity * Obstetrics * Antenatal care * Adolescent pregnancy * Complications of pregnancy * Hyperemesis gravidarum * Ectopic pregnancy * Miscarriage * Obstetrical bleeding * Gestational diabetes * Hypertension * Preeclampsia * Eclampsia * Childbirth * Midwifery * Preterm birth * Multiple births * Oxytocin * Obstructed labor * Cesarian section * Retained placenta * Obstetrical fistulae * Vesicovaginal fistula * Rectovaginal fistula * Episiotomy * husband stitch * Postpartum care * Postpartum confinement * Maternal deaths * Perinatal mortality * Stillbirths * Abortion * Mother-to-child transmission * Sterilization * Compulsory sterilization * Breastfeeding and mental health Reproductive life plan * Infertility * Childlessness * Assisted reproductive technology * In vitro fertilization * Parenting * Adoption * Fostering Contraception & Family planning * Unsafe sex * Intrauterine devices * Oral contraceptives * Condoms * Contraceptive prevalence * Contraceptive security * Planned parenthood * Fertility awareness Menstruation * Culture and menstruation * Feminine hygiene * Menarche * Menstrual cycle * Menstrual aids * Cloth menstrual pad * Menstrual cup * Tampon * Sanitary pad * Dysmenorrhea * Menorrhagia * Amenorrhoea * Menopause * Hormone replacement therapy Sexual health Sexually transmitted infections * HIV * Human papilloma virus * HPV vaccine * Pelvic inflammatory disease * Female genital mutilation * Clitoridectomy * Infibulation * Breast ironing * Child marriage * Forced marriage * Leblouh * Polygamy * Sexual intercourse * Orgasm * Dyspareunia * Sex differences * Sex education * Puberty * Breast health * Gynaecological disorders * Vaginitis Non-reproductive health Violence against women * Abuse during childbirth * Domestic violence * Intimate partner violence * Misogyny * Sexual harassment * Sexual assault * Rape * Femicide * Gender discrimination Non-communicable diseases Cancer * Lung cancer * Breast cancer * Uterine cancer * Endometrial cancer * Cervical cancer * Papanicolaou test * Ovarian cancer * Cardiovascular disease * Dementia * Alzheimer's disease * Bone health * Osteoporosis * Hip fracture * Anaemia * Mental health * Anxiety * Depression * Major depressive disorder * Urinary tract * Urethra * Urinary tract infection * Urinary incontinence Sociocultural factors * Poverty * Disadvantaged * Gender equality * Healthcare inequality * Gender disparities in health * Social determinants of health * Reproductive justice * Women's empowerment Politics, Research & Advocacy United Nations * The Convention on the Elimination of All Forms of Discrimination against Women * Declaration on the elimination of violence against women * International Day of the Girl Child * Commission on the Status of Women * UN Women United States * Office of Research on Women's Health * Women's Health Initiative * International Center for Research on Women * Nurses' Health Study * Black Women's Health Study * Cartwright Inquiry * Society for Women's Health Research Women's health by country * Women's health in China * Women's health in Ethiopia * Women's health in India * Family planning * Birth control in the United States * Category * Commons * WikiProject *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Reproductive system disease

c0178829

wikipedia

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

{"umls": ["C0178829"], "wikidata": ["Q7314317"]}

Osteogenesis imperfecta (OI) is a group of genetic disorders that mainly affect the bones. People with this condition have bones that break easily, often from little or no trauma, however, severity varies among affected people. Multiple fractures are common, and in severe cases, can even occur before birth. Milder cases may involve only a few fractures over a person's lifetime. People with OI also have dental problems (dentinogenesis imperfecta) and hearing loss in adulthood. Other features may include muscle weakness, loose joints, and skeletal malformations. There are various recognized forms of OI which are distinguished by their features and genetic causes. Depending on the genetic cause, OI may be inherited in an autosomal dominant (more commonly) or autosomal recessive manner. Treatment is supportive and aims to decrease the number of fractures and disabilities. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Osteogenesis imperfecta

c0029434

gard

https://rarediseases.info.nih.gov/diseases/1017/osteogenesis-imperfecta

{"mesh": ["D010013"], "umls": ["C0029434"], "orphanet": ["666"], "synonyms": ["OI", "Brittle bone disease", "Vrolik disease", "Fragilitas ossium", "Lobstein disease", "Osteopsathyrosis", "Porak and Durante disease"]}

Paraphilia in which a subject derives gratification from giving pain This article is about the medical condition involving unwilling victims. For consensual sadomasochism, see BDSM. Sexual sadism disorder SpecialtyPsychiatry Sexual sadism disorder is the condition of experiencing sexual arousal in response to the extreme pain, suffering or humiliation of others.[1] Several other terms have been used to describe the condition, and the condition may overlap with other conditions that involve inflicting pain. It is distinct from situations in which consenting individuals use mild or simulated pain or humiliation for sexual excitement.[2] The words sadism and sadist are derived from Marquis de Sade. ## Contents * 1 Related terms and conditions * 1.1 Current terminology * 1.2 Previous terminology * 2 Features * 3 Typology * 4 See also * 5 References * 6 External links ## Related terms and conditions[edit] ### Current terminology[edit] Sexual sadism disorder is the term employed by the current version of the Diagnostic and Statistical Manual (DSM-5) of the American Psychiatric Association.[3] It refers to the "recurrent and intense sexual arousal from the physical or psychological suffering of another person, as manifested by fantasies, urges, or behaviors" (p. 696). It is classified as one of the paraphilias, called an "algolagnic disorder" (p. 685), which is one of the "anomalous activity preferences" (p. 685). The formal diagnosis of Sexual Sadism Disorder would apply if the individual has acted on these urges with a nonconsenting person or if the urges cause significant distress to the individual. Sadomasochism appears in the current version of the International Classification of Diseases (ICD-10) of the World Health Organization.[4] It refers to the "preference for sexual activity that involves bondage or the infliction of pain or humiliation" (p. 172), and divides sadomasochism into sadism and masochism according to whether the individual prefers to be the provider or recipient of it. The ICD-10 specifies that mild forms of sadomasochism "are commonly used to enhance otherwise normal sexual activity" (p. 172), and that the diagnosis would apply only if the behavior is preferred or required for sexual gratification. The condition is classified as one of the disorders of sexual preference, which includes the paraphilias (p. 170). Paraphilic coercive disorder refers to the preference for non-consenting over consenting sexual partners.[5] It differs from sexual sadism disorder in that although the individual with this disorder may inflict pain or threats of pain in order to gain the compliance of the victim, the infliction of pain is not the actual goal of the individual. The condition is typically described as a paraphilia and continues to undergo research, but does not appear in the current DSM or ICD. Alternate terms for the condition have included Biastophilia,[6] Coercive Paraphilic Disorder,[7] and Preferential Rape.[8] BDSM or "bondage/discipline dominance/submission sadomasochism" is a colloquial term referring to the subculture of individuals who willingly engage in consenting forms of mild or simulated pain or humiliation.[9] It is not currently a diagnosable condition in either the DSM or ICD system. Alternative terms have included Bondage and Discipline (B&D), Domination and Submission (D&S), and Sadism and Masochism (S&M). In scientific research, this sexual preference has also been called the hyperdominance pattern of sexual behavior.[10] Unlike individuals with sexual sadism disorder or paraphilic coercive disorder, individuals with hyperdominance seek to provoke pleasure in their partner(s) with the pain/humiliation.[6] ### Previous terminology[edit] Sexual sadism is the term previously employed by the DSM-III-R,[11] DSM-IV,[12] and DSM-IV-TR,[13] where it was classified as a paraphilia. In these versions of the DSM, sexual sadism pertained only to the infliction of real (not simulated) suffering (p. 530). The condition was renamed sexual sadism disorder in DSM-5. Sexual sadism was the term employed in the DSM-III,[14] classifying the condition as a paraphilia. The DSM-III noted that "the imagery in a Paraphilia, such as simulated bondage, may be playful and harmless and acted out with a mutually consenting partner….In more extreme form, paraphilic imagery is acted out with a nonconsenting partner, and is noxious and injurious to the partner" (p. 267). In DSM-III, sexual sadism could be diagnosed if: 1. the person repeatedly and intentionally inflicted suffering on a nonconsenting person, to experience sexual excitement 2. repeatedly or exclusively preferred simulated or mild suffering with a consenting sexual partner 3. employs extensive, permanent, or potentially fatal suffering to achieve sexual excitement, regardless of the consent of the other person. Sadism was the term employed by the DSM-II.[15] In that manual, the condition was classified as a sexual deviation, which was used to describe "individuals whose sexual interests are directed primarily toward…coitus performed under bizarre circumstances" (p. 44). The term "paraphilia" did not exist in the DSM-II, and diagnoses did not have specific criteria until DSM-III. Sexual sadism was the phrase mentioned in DSM-I as one of the sexual deviations[16] (p. 39), but neither it (nor any of the other sexual deviations) received a specific label or diagnostic criteria. The term paraphilia did not exist in the DSM-II, and diagnoses did not have specific criteria until DSM-III. Sadistic personality disorder does not actually refer to any sexual interest, and instead refers to the pervasive disregard for the well-being of others. It is usually associated with a history of violence and criminality (which can include, but is not limited to sexual crimes).[citation needed] ## Features[edit] With paraphilic coercive disorder, the individual employs enough force to subdue a victim, but with sexual sadism disorder, the individual often continues to inflict harm regardless of the compliance of the victim, which sometimes escalates not only to the death of the victim,[17] but also to the mutilation of the body. What is experienced by the sadist as sexual does not always appear obviously sexual to non-sadists: sadistic rapes do not necessarily include penile penetration of the victim. In a survey of offenses, 77% of cases included sexual bondage, 73% included anal rape, 60% included blunt force trauma, 57% included vaginal rape, and 40% included penetration of the victim by a foreign object.[17] In 40% of cases, the offender kept a personal item of the victim as a souvenir.[17] On personality testing, sadistic rapists apprehended by law enforcement have shown elevated traits of impulsivity, hypersexuality, callousness, and psychopathy.[18] Although there appears to be a continuum of severity from mild (hyperdominance or BDSM) to moderate (paraphilic coercive disorder) to severe (sexual sadism disorder), it is not clear if they are genuinely related or only appear related superficially.[6] Very little is known about how sexual sadism disorder develops.[3] Most of the people diagnosed with sexual sadism disorder come to the attention of authorities by committing sexually motivated crimes.[19] Surveys have also been conducted to include people who are interested in only mild and consensual forms of sexual pain/humiliation (BDSM).[19] Most of the people with full-blown sexual sadism disorder are male, whereas the sex ratio of people interested in BDSM is closer to 2:1 male-to-female.[20][21][22] People with sexual sadism disorder are at an elevated likelihood of having other paraphilic sexual interests.[3] ## Typology[edit] Criminologist Lee Mellor created a six typology of sexually sadistic homicide offenders, based upon a combination of three binary factors:[23] Destructive versus Preservative: Destructive sex sadists mutilate the bodies of their living victims, while Preservative sex sadists do not. Prolonged versus Brief: The Prolonged sex sadist tortures their victim for an hour or more, while the Brief sex sadist does so over less time. Elaborate versus Simple: Where Simple sex sadists tend to use one or two methods of torture, Elaborate sadists have three of the following four characteristics, (i) variation in torture methods, (ii) complex torture apparatus, (iii) psychological torture, (iv) record making (e.g., using notes/media to document the process).[23] This renders eight possible categories, six of which Mellor was able to find multiple criminal offenders to exemplify: Mellor's (2016) Typology of Homicidal Sexual Sadists[23] Category Destructive Prolonged Elaborate Examples 1 Y Y Y Dean Corll 2 N Y Y Paul Bernardo 3 Y Y N Chicago Rippers 4 N Y N Keith Jesperson 5 Y N N Andrei Chikatilo 6 N N N Dennis Rader 7 N N Y No examples (hypothetical) 8 Y N Y No examples (hypothetical) This typology is compatible with the necrophilia typology, producing hybrid categories which help to understand the totality of the offender's paraphilic desires.[23] ## See also[edit] * Sexual masochism disorder * Biastophilia * Lust murder * Marquis de Sade, after whom sadism is named * Sadistic personality disorder ## References[edit] 1. ^ American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. 2. ^ Freund, K., & Blanchard, R. (1986). The concept of courtship disorder. Journal of Sex & Marital Therapy, 12, 79-92. 3. ^ a b c American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA: American Psychiatric Publishing. 4. ^ World Health Organization. (2007). International statistical classification of diseases and related health problems (10th rev., version for 2007). Retrieved from http://apps.who.int/classifications/apps/icd/icd10online/index.htm?gf60.htm 5. ^ Thornton, D. (2010). Evidence regarding the need for a diagnostic category for a coercive paraphilia. Archives of Sexual Behavior, 39, 411-418. 6. ^ a b c Cantor, J. M., & Sutton, K. S. (2014). Paraphilia, gender dysphoria, and hypersexuality. In P. H. Blaney & T. Millon (Eds.), Oxford textbook of psychopathology (3rd ed.) (pp. 589–614). New York: Oxford University Press. 7. ^ Quiney, V. L. (2010). Coersive paraphilic disorder. Archives of Sexual Behavior, 39, 405-410. 8. ^ Freund, K., & Seto, M. C. (1998). Preferential rape in the theory of courtship disorder. Archives of Sexual Behavior, 27, 433-443. 9. ^ Aggrawal, A. (2009). Forensic and medico-legal aspects of sexual crimes and unusual sexual practices. New York: Taylor & Francis. p. 145. 10. ^ Freund, K., Scher, H., & Hucker, S. (1983). The courtship disorders. Archives of Sexual Behavior, 12, 369-379. 11. ^ American Psychiatric Association. (1987). Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised). Washington, DC: Author. 12. ^ American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders (4th ed.). Washington, DC: Author. 13. ^ American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.). Washington, DC: Author. 14. ^ American Psychiatric Association. (1980). Diagnostic and Statistical Manual of Mental Disorders (3rd ed.). Washington, DC: Author. 15. ^ American Psychiatric Association. (1968). Diagnostic and Statistical Manual of Mental Disorders (2nd ed.). Washington, DC: Author. 16. ^ American Psychiatric Association. (1952). Diagnostic and Statistical Manual: Mental Disorders. Washington, DC: Author. 17. ^ a b c Dietz, P. E., Hazelwood, R. R., & Warren, J. (1990). The sexually sadistic criminal and his offenses. Bulletin of the American Academy of Psychiatry and the Law, 18, 163-178. 18. ^ Barbaree, H. E., Seto, M. C., Serin, R. C., Amos, N. L., & Preston, D. L. (1994). Comparisons between sexual and nonsexual rapist subtypes: Sexual arousal to rape, offense precursors, and offense characteristics. Criminal Justice and Behavior, 21, 95-114. 19. ^ a b Krueger, R. B. (2010). The DSM diagnostic criteria for sexual sadism. Archives of Sexual Behavior, 39, 325-345. 20. ^ Hunt, M. (1974). Sexual behavior in the 1970s. Chicago: Playboy Press. 21. ^ Kinsey, A., Pomeroy, W. B., Martin, C. E., & Gebhard, P. H. (1953). Sexual behavior in the human female. Philadelphia, PA: W. B. Saunders. 22. ^ Breslow, N., Evans, L., & Langley, J. (1985). On the prevalence and roles of females in the sadomasochistic subculture: Report of an empirical study. Archives of Sexual Behavior, 14, 303-317. 23. ^ a b c d Mellor, Lee (2016). Homicide: A Forensic Psychology Casebook. Boca Raton, FL: CRC Press. pp. 136–139. ## External links[edit] Classification D * ICD-10: F65.5 * MeSH: D012448 * v * t * e Psychopathy Contexts * In fiction * In the workplace Characteristics * Anti-social behaviour * Bold * Callous * Diminished empathy * Disinhibited * Grandiose * Impulsive * Lack of guilt * Manipulative * Pathological lying * Remorseless * Shallow affect * Superficially charming Related topics * Antisocial personality disorder * Conduct disorder * Dark triad * Flying monkeys * History of psychopathy * Juvenile delinquency * Machiavellianism * Macdonald triad * Narcissism * Psychopathic Personality Inventory * Psychopathy Checklist * Sadistic personality disorder * Sexual sadism disorder * Sociopathy Notable theorists * Hervey M. Cleckley * George E. Partridge * Robert D. Hare *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Sexual sadism disorder

c0036039

wikipedia

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

{"mesh": ["D012448"], "wikidata": ["Q5507613"]}

Trichiasis SpecialtyOphthalmology Diagnostic methodSlit lamp Trichiasis (/trɪkiˈeɪsɪs/ trik-ee-AY-sis, /trɪˈkaɪəsɪs/ tri-KEYE-ə-sis)[1] is a medical term for abnormally positioned eyelashes that grow back toward the eye, touching the cornea or conjunctiva. This can be caused by infection, inflammation, autoimmune conditions, congenital defects, eyelid agenesis and trauma such as burns or eyelid injury. It is the leading cause of infectious blindness in the world.[2] Standard treatment involves removal or destruction of the affected eyelashes with electrology, specialized laser, or surgery. In many cases, removal of the affected eyelashes with forceps resolves the symptoms, although the problem often recurs in a few weeks when the eyelashes regrow. Severe cases may cause scarring of the cornea and lead to vision loss if untreated. Mild cases may not require treatment. Repeated cases of trachoma infection may cause trichiasis.[3] Posterior misdirection of normal lashes most frequently affects lower lid. ## Contents * 1 In Dogs * 2 Complications * 3 See also * 4 References * 5 External links ## In Dogs[edit] Trichiasis in dogs is hair from the eyelid growing in the wrong direction and rubbing on the eye, causing irritation. It usually occurs at the lateral upper eyelid, especially in the English Cocker Spaniel.[4] Trichiasis also refers to hair from a nasal fold rubbing on the eye. This type of trichiasis can be flattened by rubbing petroleum jelly onto it, but surgery is sometimes necessary for permanent correction. ## Complications[edit] * Inferior punctate epitheliopathy * Corneal ulceration * Pannus ## See also[edit] * Distichiasis * Madarosis * Trachoma ## References[edit] 1. ^ https://www.lexico.com/definition/trichiasis 2. ^ Burton M, Habtamu E, Ho D, Gower EW (2015). "Interventions for trachoma trichiasis". Cochrane Database Syst Rev. 11: CD004008. doi:10.1002/14651858.CD004008.pub3. PMC 4661324. PMID 26568232.CS1 maint: multiple names: authors list (link) 3. ^ Rabiu M, Alhassan MB, Ejere HOD, Evans JR (2012). "Environmental sanitary interventions for preventing active trachoma". Cochrane Database Syst Rev. 2: CD004003. doi:10.1002/14651858.CD004003.PUB4. PMC 4422499. PMID 22336798. 4. ^ Gelatt, Kirk N., ed. (1999). Veterinary Ophthalmology (3rd ed.). Lippincott, Williams & Wilkins. ISBN 0-683-30076-8. ## External links[edit] Classification D * ICD-10: H02.0 (ILDS H02.010) * ICD-9-CM: 374.05 * MeSH: D058457 * DiseasesDB: 31305 External resources * eMedicine: oph/609 * 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

Trichiasis

c0221259

wikipedia

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

{"mesh": ["D058457"], "umls": ["C0221259"], "icd-9": ["374.05"], "icd-10": ["H02.0"], "wikidata": ["Q1852755"]}

A number sign (#) is used with this entry because of evidence that progressive encephalopathy with amyotrophy and optic atrophy (PEAMO) is caused by homozygous or compound heterozygous mutation in the TBCE gene (604934) on chromosome 1q42. Biallelic mutation in the TBCE gene can also cause hypoparathyroidism-retardation-dysmorphism syndrome (HRDS; 241410) and Kenny-Caffey syndrome (KCS1; 244460). Description PEAMO is a severe autosomal recessive neurodegenerative disorder characterized by delayed development with hypotonia apparent in infancy and subsequent motor regression. Most affected individuals are unable to or lose the ability to sit and show distal amyotrophy and weakness of all 4 limbs. The patients are cognitively impaired and unable to speak or have severe dysarthria. Additional features include optic atrophy, thin corpus callosum, and cerebellar atrophy (summary by Sferra et al., 2016). Clinical Features Sferra et al. (2016) reported 6 patients from 4 apparently unrelated families originating from the same geographic area in Italy near Naples with a similar infantile-onset neurodegenerative disorder. The patients ranged from 6 to 20 years of age. They presented between birth and 14 months of age with delayed psychomotor development and hypotonia, followed by progression of the disorder and regression of motor skills. Most lost the ability to sit and developed distal amyotrophy of all 4 limbs, with foot drop, ataxia, and spastic tetraplegia. Additional features included optic atrophy, severe dysarthria or inability to speak, and scoliosis. Cognitive impairment ranged from mild to severe. Only 1 patient had overt seizures: she developed partial seizures at age 12, which progressed to refractory seizures by age 18. Electrophysiologic and electromyographic studies in all patients were consistent with a motor neuropathy, and muscle biopsy showed denervation atrophy. Fibrillation potentials were found only in distal muscles. Brain imaging showed cerebellar atrophy and thin corpus callosum. Patients in the second decade had iron accumulation in the pallidum and substantia nigra, a pattern similar to that observed in NBIA (see, e.g., NBIA1, 234200). None of the patients had growth defects, endocrine abnormalities, or hypoparathyroidism, thus distinguishing this disorder from both HRDS and KCS1. Inheritance The transmission pattern of PEAMO in the family reported by Sferra et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 5 patients from 3 unrelated Italian families with PEAMO, Sferra et al. (2016) identified a homozygous missense mutation in the TCBE gene (I155N; 604934.0004). The mutation in 2 families was found by whole-exome sequencing and confirmed by Sanger sequencing; the mutation in a pair of affected monozygotic twins in the third family was found by mutation scan of the TBCE gene. Another patient (patient 2518864) with the disorder was found to be compound heterozygous for the I155N mutation and a frameshift mutation (604934.0005). The mutations segregated with the disorder in all families, and haplotype analysis of the families indicated a founder effect for I155N. Western blot analysis of patient fibroblasts showed significantly reduced amounts of mutant TBCE protein compared to controls, with lower levels in the patient with compound heterozygous mutations. RNA analysis of patient cells showed normal levels in the patient homozygous for I155N but decreased amounts of RNA in the compound heterozygous patient, suggesting that the 1-bp deletion resulted in nonsense-mediated mRNA decay. Patient cells showed decreased levels of polymerized alpha-tubulin (see 602529) and altered microtubule dynamics with decreased nucleation and markedly delayed microtubule repolymerization; microtubules were less abundant and strongly disorganized in both early and late stages of repolymerization, and there was loss of compaction in the Golgi apparatus. There was also abnormal mitotic morphology with abnormal mitotic spindles and disorganized microtubule arrangement. Sferra et al. (2016) concluded that the I155N allele is hypomorphic. The phenotype was similar to that of pmn/pmn mice who have a homozygous missense mutation in the Tbce gene (see ANIMAL MODEL). Animal Model Mice that are homozygous with respect to the progressive motor neuronopathy (pmn) mutation on chromosome 13 develop a progressive caudiocranial degeneration of their motor axons from the age of 2 weeks and die 4 to 6 weeks after birth (Schmalbruch et al., 1991). The mutation is fully penetrant and expressivity does not depend on the genetic background. Martin et al. (2002) identified the pmn mutation as a trp524-to-gly (W524G) substitution at the last residue of the Tbce protein that leads to decreased protein stability. Electron microscopy of the sciatic and phrenic nerves of affected mice showed a reduced number of microtubules, probably due to defective stabilization. Transgenic complementation with a wildtype Tbce cDNA restored a normal phenotype in mutant mice. The observations indicated that Tbce is critical for the maintenance of microtubules in mouse motor axons, and suggested that altered function of tubulin cofactors might be implicated in human motor neuron diseases. Bommel et al. (2002) independently identified a point mutation resulting in the trp524-to-gly substitution in the Tbce protein in pmn mice. Homozygous pmn mice have a severe motor neuron disease characterized by motor axon dying back and progressive loss of motor units. In pmn mice, Schaefer et al. (2007) found that axonal microtubule loss in the phrenic and sciatic nerves first manifested distally and progressed proximally, in parallel with the axonal dying back neuronopathy. Studies of cultured pmn neurons showed loss of Tbce from the Golgi apparatus in motor neuron cells and in Schwann cells, microtubule loss resulting from defective axonal routing of tubulin from the Golgi, and impaired tubulin folding and dimerization. Similar results were found with knockdown of the Tbce gene in cultured motor neurons. The findings indicated that destabilization of Tbce in motor neurons is responsible for the axonal dying back process in pmn mice. INHERITANCE \- Autosomal recessive GROWTH Other \- Normal growth HEAD & NECK Eyes \- Optic atrophy SKELETAL Spine \- Scoliosis MUSCLE, SOFT TISSUES \- Hypotonia, severe \- Distal amyotrophy, all four limbs \- Neurogenic pattern seen on EMG \- Denervation atrophy seen on muscle biopsy NEUROLOGIC Central Nervous System \- Encephalopathy \- Delayed psychomotor development \- Motor regression \- Spinal muscular atrophy \- Intellectual disability (variable severity) \- Inability to sit \- Foot drop \- Ataxia \- Spastic tetraplegia \- Seizures (rare) \- Dysarthria \- Absence of speech \- Cerebellar atrophy \- Thin corpus callosum \- Iron accumulation in the pallidum and substantia nigra (in some patients in the second decade) Peripheral Nervous System \- Axonal peripheral neuropathy ENDOCRINE FEATURES \- No endocrine abnormalities MISCELLANEOUS \- Infantile onset \- Progressive disorder MOLECULAR BASIS \- Caused by mutation in the tubulin-specific chaperone E gene (TBCE, 604934.0004 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ENCEPHALOPATHY, PROGRESSIVE, WITH AMYOTROPHY AND OPTIC ATROPHY

c4310667

omim

https://www.omim.org/entry/617207

{"omim": ["617207"], "orphanet": ["496756"], "synonyms": []}

A number sign (#) is used with this entry because familial partial lipodystrophy type 2 (FPLD2) is caused by heterozygous mutation in the gene encoding lamin A/C (LMNA; 150330) on chromosome 1q21. Description Familial partial lipodystrophy is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution beginning in late childhood or early adult life. Affected individuals gradually lose fat from the upper and lower extremities and the gluteal and truncal regions, resulting in a muscular appearance with prominent superficial veins. In some patients, adipose tissue accumulates on the face and neck, causing a double chin, fat neck, or cushingoid appearance. Metabolic abnormalities include insulin-resistant diabetes mellitus with acanthosis nigricans and hypertriglyceridemia; hirsutism and menstrual abnormalities occur infrequently. Familial partial lipodystrophy may also be referred to as lipoatrophic diabetes mellitus, but the essential feature is loss of subcutaneous fat (review by Garg, 2004). The disorder may be misdiagnosed as Cushing disease (see 219080) (Kobberling and Dunnigan, 1986; Garg, 2004). ### Genetic Heterogeneity of Familial Partial Lipodystrophy Familial partial lipodystrophy is a clinically and genetically heterogeneous disorder. Types 1 and 2 were originally described as clinical subtypes: type 1 (FPLD1; 608600), characterized by loss of subcutaneous fat confined to the limbs (Kobberling et al., 1975), and FPLD2, characterized by loss of subcutaneous fat from the limbs and trunk (Dunnigan et al., 1974; Kobberling and Dunnigan, 1986). No genetic basis for FPLD1 has yet been delineated. FPLD3 (604367) is caused by mutation in the PPARG gene (601487) on chromosome 3p25; FPLD4 (613877) is caused by mutation in the PLIN1 gene (170290) on chromosome 15q26; FPLD5 (615238) is caused by mutation in the CIDEC gene (612120) on chromosome 3p25; FPLD6 (615980) is caused by mutation in the LIPE gene (151750) on chromosome 19q13; and FPLD7 (606721) is caused by mutation in the CAV1 gene (601047) on chromosome 7q31. Clinical Features Dunnigan et al. (1974) described an autosomal dominant disorder in 2 families from the same region of northern Scotland. Features were symmetric lipoatrophy of the trunk and limbs with rounded, full face, tuberoeruptive xanthomata, acanthosis nigricans, and insulin-resistant hyperinsulinism. In 1 family, 6 females, 3 of whom were personally examined by the authors, were affected in 4 generations. In the other family, which was probably related to the first, 6 females in 3 generations were affected. This syndrome is distinct from congenital generalized lipodystrophy (see 608594), from progressive partial lipodystrophy (see 613779), which is a sporadic disorder associated with decreased levels of complement component C3, and from the acquired generalized lipodystrophy described by Lawrence (1946). Greene et al. (1970) and Ozer et al. (1973) described a condition of fat accumulation around the neck, shoulders, upper back, and genitalia associated with lean muscular limbs, phlebectasia, insulin resistance, hyperglycemia, and type IV hyperlipoproteinemia. Affected members in the family of Greene et al. (1970) also had hyperuricemia. Successive generations were affected, but only females appeared to have the full-blown disorder. Davidson and Young (1975) reported a family with familial partial lipodystrophy characterized by absence of subcutaneous fat from the limbs and lower trunk with sparing of the face and upper trunk. Although lipodystrophy was not seen in males, 5 males were diabetic. The authors suggested X-linked dominant inheritance of the disorder. See also the pedigree analysis of Wettke-Schafer and Kantner (1983), who discussed the possibility of X-linked dominant inheritance with lethality in hemizygous males. Burn and Baraitser (1986) reported a family in which 5 members, including 1 male, were affected with familial partial lipodystrophy in an autosomal dominant pattern of inheritance. Clinical features included lipoatrophy of the limbs and trunk, with sparing of the face and neck. Affected members had muscular definition with variable muscular hypertrophy and prominent peripheral veins. Acanthosis nigricans and xanthomata were present. Laboratory studies showed hyperinsulinemia, hyperlipidemia, and insulin resistance. Reardon et al. (1990) described partial lipodystrophy in a 2-year-old boy. There was complete absence of fat on the body and limbs, but the face and feet were spared and the hands were puffy. Classification of the case was considered difficult, but the distribution of loss of subcutaneous fat corresponded to that of FPLD type 2 (Dunnigan type) described in adults. To investigate whether there is a unique pattern of fat distribution in men and women with FPLD, Garg et al. (1999) performed whole-body magnetic resonance imaging (MRI) in 1 male and 3 female patients from 2 pedigrees. MRI studies confirmed the clinical findings of near-total absence of subcutaneous fat from all extremities. Reduction in subcutaneous adipose tissue from the truncal area was more prominent anteriorly than posteriorly. Increased fat stores were observed in the neck and face. The authors concluded that FPLD results in a characteristic absence of subcutaneous fat from the extremities, with preservation of intermuscular fat stores. The clinical features in families studied by Jackson et al. (1998) included a dramatic absence of adipose tissue in the limbs and trunk, more evident in females than in males, with fat retained on the face, in the retroorbital space, and at periserous sites. Jackson et al. (1998) noted that a syndrome with similar metabolic abnormalities, including insulin resistance, hyperinsulinemia, and dyslipidemia, has been referred to as 'metabolic syndrome X' (Reaven, 1988); see 605552. Garg (2000) compared the anthropometric variables and prevalence of diabetes mellitus, dyslipidemia, hypertension, and atherosclerotic vascular disease among 17 postpubertal males and 22 females with FPLD from 8 pedigrees. All individuals completed a questionnaire, and fasting blood was analyzed for glucose, insulin, and lipoprotein concentrations. Both affected men and women had similar patterns of fat loss. Compared with the affected men, women had a higher prevalence of diabetes (18% and 50%, respectively; P = 0.05) and atherosclerotic vascular disease (12% and 45%, respectively; P = 0.04), and had higher serum triglycerides (median values, 2.27 and 4.25 mmol/L, respectively; P = 0.02) and lower HDL cholesterol concentrations (age-adjusted means, 0.94 and 0.70 mmol/L, respectively; P = 0.04). The prevalence of both hypertension and fasting serum insulin concentrations were similar. Garg (2000) concluded that females with FPLD are more severely affected with metabolic complications of insulin resistance than are males. The common insulin resistance syndrome of obesity, dyslipidemia, hyperglycemia, and hypertension has a well-recognized association with atherosclerosis. Hegele (2001) studied the prevalence of coronary artery disease in a group of individuals with Dunnigan-type familial partial lipodystrophy, all of whom had mutations in the LMNA gene. All individuals had insulin resistance, with significantly more type II diabetes mellitus, hypertension, and dyslipidemia than in normal family control subjects. Eight of 23 individuals (35%) had identifiable endpoints of coronary artery disease (angina pectoris, myocardial infarction, or coronary artery bypass surgery); 1 of these individuals had also developed occlusive peripheral vascular disease. Only 1 control individual had coronary artery disease. Hegele (2001) concluded that Dunnigan-type familial partial lipodystrophy represents a single-gene model for the more common insulin resistance syndrome. Caux et al. (2003) reported a 27-year-old man with generalized lipodystrophy, hepatic steatosis, insulin-resistant diabetes, hypertrophic cardiomyopathy, and leukomelanodermic papules. He had been diagnosed with hepatic steatosis at the age of 21 years, hypertriglyceridemia at 22 years, and diabetes at 25 years. The patient's appearance included square jaw, thin lips, high forehead, marked thinning of the eyebrows, pectus excavatum, and narrow shoulders. Generalized atrophy of subcutaneous fat resulted in sunken cheeks and muscular pseudohypertrophy of the 4 limbs. Multiple whitish papules on pigmented skin were present on the neck, trunk, and upper limbs and to a lesser extent on the lower limbs. The patient mentioned that his subcutaneous body fat progressively disappeared from the age of 14 years, after the onset of puberty. The development of the skin lesions occurred simultaneously. No acanthosis nigricans was present. Gray hair had been present since the age of 17 years. Muscular strength was normal, and no neurologic defects were detected. Cardiac involvement included concentric hypertrophy of the left ventricle without cavity dilatation, associated with thickened and regurgitant valves, aortic fibrotic nodules, and calcification of the posterior annulus. Doppler echocardiographic findings were similar to those described in aged patients. Abdominal MRI revealed an absence of body fat at both the subcutaneous and visceral levels. Osteopoikilosis, acroosteolysis, hypoplastic clavicles, wide sutures, and mandibular hypoplasia, previously described in mandibuloacral dysplasia (MAD; 248370), were not identified by bone x-rays. Typical symptoms of Werner syndrome (277700), such as cataracts, short stature, and skeletal anomalies, were absent. Family members were unaffected, and no consanguinity was reported. Genetic analysis identified a heterozygous mutation in the LMNA gene (R133L; 150330.0027). Vigouroux et al. (2003) emphasized that a striking feature in the patient reported by Caux et al. (2003) was muscular hypertrophy of the limbs, which contrasts with the muscular atrophy usually present in Werner syndrome. Muscular hypertrophy, along with insulin-resistant diabetes and hypertriglyceridemia, is more often associated with LMNA-linked Dunnigan lipodystrophy. Fibroblasts from this patient showed nuclear abnormalities identical to those described in Dunnigan lipodystrophy (Vigouroux et al., 2001). Spuler et al. (2007) reported 13 FPLD2 patients with neuromuscular involvement. Twelve had muscle hypertrophy, 9 had severe myalgias, and 8 had multiple nerve entrapment syndromes. Skeletal muscle biopsies showed marked hypertrophy of type 1 and type 2 muscle fibers and nonspecific myopathic changes. Sural nerve biopsies showed numerous paranodal myelin swellings, or tomacula. Skeletal muscle myostatin (MSTN; 601788) mRNA was decreased in patients compared to controls, but no MSTN gene mutations were detected. FPLD2 muscle specimens had a large number of SMAD (see, e.g., 601595) molecules adhered to the nuclear membrane and not found within the nucleus, compared to normal muscle or muscle from a patient with a non-FPLD LMNA disease. Spuler et al. (2007) concluded that neuromuscular features of FPLD2 may result from disrupted SMAD-MSTN signaling. Vantyghem et al. (2008) compared the fertility and occurrence of obstetric complications of women with familial partial lipodystrophy due to LMNA mutations with those of unaffected relatives, women from the general population, and women with polycystic ovary syndrome (PCOS). Data were obtained from clinical follow-up of 7 families with patients exhibiting mutations in LMNA (14 affected among 48 women). The mean number of live children per woman was 1.7 in affected patients versus 2.8 in nonaffected relatives. Fifty-four percent of LMNA-mutated women exhibited a clinical phenotype of PCOS, 28% suffered from infertility, 50% experienced at least one miscarriage, 36% developed gestational diabetes, and 14% experienced eclampsia and fetal death. Vantyghem et al. (2008) concluded that in these LMNA-linked lipodystrophic patients, the prevalence of PCOS, infertility, and gestational diabetes was higher than in the general population. Moreover, the prevalence of gestational diabetes and miscarriages was higher in lipodystrophic LMNA-mutated women than previously reported in PCOS women with similar body mass index. Women with lipodystrophies due to LMNA mutations are at high risk of infertility, gestational diabetes, and obstetrical complications and require reinforced gynecologic and obstetric care. Inheritance Although X-linked dominant inheritance had been suggested, affected pedigrees reported by Robbins et al. (1982), Jackson et al. (1997), and Peters et al. (1998) showed clear autosomal dominant inheritance. Mapping In a genomewide scan using highly polymorphic short tandem repeats (STRs) in individuals from 5 well-characterized FPLD pedigrees, Peters et al. (1998) mapped the disease locus to 1q21-q22. The maximum 2-point lod score obtained with a highly polymorphic microsatellite at D1S2624 at theta (max) = 0.0 was 5.84. Multipoint linkage analysis yielded a peak lod score of 8.25 between D1S305 and D1S1600. There was no evidence for genetic heterogeneity in these pedigrees. Anderson et al. (1999) performed linkage and haplotype analysis with highly polymorphic microsatellite markers on a large, multigenerational Caucasian kindred of German ancestry with the Dunnigan form of familial partial lipodystrophy. The family showed affected members through at least 4 generations. The results yielded a maximum 2-point lod score of 4.96 at theta = 0 for marker D1S2721 and a maximum multipoint lod score of 6.27 near the same marker. The results of the haplotype analysis supported the minimal candidate region reported by Peters et al. (1998). Jackson et al. (1998) ascertained 2 multigenerational families, with a combined total of 18 individuals with partial lipodystrophy. A genomewide linkage search using microsatellite markers provided conclusive evidence of linkage to 1q21 (D1S498, maximum lod score = 6.89 at theta = 0.00), with no evidence of heterogeneity. Haplotype and multipoint analysis supported the location of the locus (which they symbolized PLD, for partial lipodystrophy) within a 21.2-cM chromosomal region flanked by markers D1S2881 and D1S484. Molecular Genetics In 5 Canadian FPLD families, Cao and Hegele (2000) identified heterozygosity for a mutation in the lamin A/C gene (R482Q; 150330.0010). There were no differences in age, gender, or body mass index in Q482/R482 heterozygotes compared with R482/R482 homozygotes (normals) from these families; however, there were significantly more Q482/R482 heterozygotes who had definite partial lipodystrophy and frank diabetes. Also compared with the normal homozygotes, heterozygotes had significantly higher serum insulin and C-peptide (see 176730) levels. The LMNA heterozygotes with diabetes were significantly older than heterozygotes without diabetes. In 6 families and 3 isolated cases of partial lipodystrophy, Shackleton et al. (2000) found heterozygosity for an R482W missense mutation in the LMNA gene (150330.0011), in the same codon as the R482Q mutation found in Canadian families by Cao and Hegele (2000). Shackleton et al. (2000) identified a third mutation in that codon, R482L (150330.0012), in another family with partial lipodystrophy. Speckman et al. (2000) analyzed the LMNA gene in 15 families with partial lipodystrophy and identified the R482Q mutation in 5, the R482W mutation in 7, and a G465D mutation (150330.0015) in 1. Schmidt et al. (2001) identified a family with partial lipodystrophy carrying the R482W missense mutation in the LMNA gene. Clinically, the loss of subcutaneous fat and muscular hypertrophy, especially of the lower extremities, started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. Characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. Lanktree et al. (2007) analyzed the LMNA gene in 3 unrelated patients with FPLD2 and identified heterozygosity for 3 different missense mutations, all affecting only the lamin A isoform and each changing a conserved residue. Two of the mutations, D230N (150330.0042) and R399C (150330.0043), were 5-prime to the nuclear localization signal, which is not typical of LMNA mutations in FPLD2. Genotype/Phenotype Correlations In a family with an atypical form of FPLD, Speckman et al. (2000) identified an R582H mutation (150330.0016) in the LMNA gene. In a follow-up of this same family, Garg et al. (2001) reported that 2 affected sisters showed less severe loss of subcutaneous fat from the trunk and extremities with some retention of fat in the gluteal region and medial parts of the proximal thighs compared to women with typical FPLD2. Neither of the sisters with atypical FPLD2 had acanthosis nigricans or hirsutism, and only 1 had diabetes mellitus, borderline hypertriglyceridemia, and irregular menstrual periods. The sisters also tended to have lower serum triglycerides and higher HDL cholesterol concentrations compared to those with typical FPLD2. Both types had similar excess of fat deposition in the neck, face, intraabdominal, and intermuscular regions. Noting that the R582H mutation interrupts only the lamin A protein, Garg et al. (2001) suggested that in typical FPLD2, interruption of both lamins A and C causes a more severe phenotype than that seen in atypical FPLD2, in which only lamin A is altered. Pathogenesis Araujo-Vilar et al. (2009) studied 7 patients from 1 kindred with FPLD2 caused by an R482W mutation in the LMNA gene (150330.0011). Two had type 2 diabetes mellitus. As a group, the patients with FPLD2 were found to have significantly higher insulin resistance compared to 10 controls. The expression of LMNA in abdominal and peripheral adipose tissues was similar in both groups. In patients with FPLD2, thigh adipose tissue, but not abdomen adipose tissue, showed significantly decreased expression of PPARG2 (601487), RB1 (614041), cyclin D3 (CCND3; 123834), and LPL (609708) (67%, 25%, 38%, and 66%, respectively) compared to controls. There was an accumulation of prelamin A in the nuclear envelope of peripheral adipose tissue of patients with FPLD2. Electron microscopic analysis of adipocytes of patients with FPLD2 showed defects in the peripheral heterochromatin and a nuclear fibrous dense lamina. Collectively, the findings indicated that transcriptional activity of several genes involved in adipogenesis is altered in affected tissues of patients with FPLD2. INHERITANCE \- Autosomal dominant HEAD & NECK Face \- Normal or increased facial adipose tissue \- Round, full face Neck \- Normal or increased adipose tissue around the neck CARDIOVASCULAR Vascular \- Prominent superficial veins \- Atherosclerosis \- Hypertension ABDOMEN Liver \- Hepatomegaly \- Hepatic steatosis Pancreas \- Pancreatitis, acute in some GENITOURINARY External Genitalia (Female) \- Labial pseudohypertrophy \- Polycystic ovary disease (uncommon) SKIN, NAILS, & HAIR Skin \- Prominent superficial veins \- Xanthomata \- Acanthosis nigricans (uncommon) Hair \- Hirsutism (uncommon) MUSCLE, SOFT TISSUES \- Partial lipodystrophy (abnormal distribution of subcutaneous adipose tissue) \- Loss of subcutaneous truncal adipose tissue \- Loss of subcutaneous adipose tissue in limbs \- Loss of adipose tissue occurs around puberty \- No lipodystrophy in face and neck \- Muscular appearance \- Muscular hypertrophy \- Myalgia \- Increased intramuscular fat \- Increased intraabdominal fat \- Skeletal muscle biopsy shows hypertrophy of type 1 and 2 muscle fibers \- Nonspecific myopathic changes NEUROLOGIC Peripheral Nervous System \- Nerve compression \- Nerve entrapment syndromes \- Enlarged peripheral nerves \- Tomaculae (paranodal myelin swellings) ENDOCRINE FEATURES \- Insulin-resistant diabetes mellitus (onset around puberty) LABORATORY ABNORMALITIES \- Hyperglycemia \- Hyperinsulinemia \- Increased serum triglycerides \- Decreased HDL cholesterol MISCELLANEOUS \- Onset of clinical features around puberty MOLECULAR BASIS \- Caused by mutation in the lamin A/C gene (LMNA, 150330.0003 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

LIPODYSTROPHY, FAMILIAL PARTIAL, TYPE 2

c1720860

omim

https://www.omim.org/entry/151660

{"doid": ["0070202"], "mesh": ["D052496"], "omim": ["151660"], "orphanet": ["2348"], "synonyms": ["Alternative titles", "FPL2", "LIPODYSTROPHY, FAMILIAL PARTIAL, DUNNIGAN TYPE", "LIPODYSTROPHY, FAMILIAL, OF LIMBS AND LOWER TRUNK", "LIPODYSTROPHY, REVERSE PARTIAL", "LIPOATROPHIC DIABETES"]}

Reed’s syndrome Other namesFamilial leiomyomatosis cutis et uteri Micrograph showing the characteristic hyalinized papillary cores found in some hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinomas. H&E stain. Reed’s syndrome is a rare inherited condition characterised by multiple cutaneous leiomyomas and, in women, uterine leiomyomas. It predisposes for renal cell cancer, an association denominated hereditary leiomyomatosis and renal cell cancer,[1][2] and it is also associated with increased risk of uterine leiomyosarcoma.[3] The syndrome is caused by a mutation in the fumarate hydratase gene, which leads to an accumulation of fumarate. The inheritance pattern is autosomal dominant. ## Contents * 1 Signs and symptoms * 1.1 Associated conditions * 2 Cause * 3 Pathogenesis * 4 Diagnosis * 4.1 Histology * 4.2 Differential diagnosis * 5 Treatment * 6 Prognosis * 7 History * 8 Notes * 9 References * 10 External links ## Signs and symptoms[edit] Almost all women present with uterine fibroids, approximately 76% with dermal manifestations and 10-16% with renal tumors.[3] The uterine fibroids tend to occur at younger age and larger and more numerous than in general population. They may be distinguishable from sporadic fibroids by special histological features such as prominent nucleoli with perinucleolar halos.[4] The skin presentation is of asymmetrical, reddish-brown nodules or papules with a firm consistency, predominantly located on the limbs (multiple cutaneous leiomyoma), although they may occur anywhere, including the face. The lesions, which are typically painful and most often present during the third decade of life, are piloleiomyomata—a benign smooth muscle tumour arising from the arrectores pilorum muscles of the skin. These tumours may also arise in the tunica dartos of the scrotum and the mammillary muscle of the nipple (genital leiomyoma), the smooth muscle of blood vessels (angioleiomyoma) and the lung (pulmonary lymphangioleiomyomatosis).[5] A pseudo-Darier sign may be present. The renal cell carcinoma tends to be of the papillary (type 2) form and tends to occur more commonly in women than men with this syndrome. These cancers present earlier than is usual for renal cell carcinomas (typically in the twenties and thirties) and to be at relatively advanced stages at presentation. Tumours have rarely been reported in children. These tumours occur in ~20% of those with this mutation suggesting that other factors are involved in the pathogenesis. ### Associated conditions[edit] Other relatively rare conditions have been reported in association with this disease. It is not yet known if these associations are fortuitous or manifestations of the condition itself. Cerebral cavernomas and massive, macronodular adrenocortical disease have also been reported in association with this syndrome.[6][7] A case of cutis verticis gyrata, disseminated collagenoma and Charcot-Marie-Tooth disease in association with a mutation in the fumarate hydratase gene has also been reported.[8] Two cases of ovarian mucinous cystadenoma have also been reported with this mutation.[9] ## Cause[edit] The fumarate hydratase gene, located on the long arm of chromosome 1 (1q42.3-43), spans 22 kilobases and has 10 exons. The first exon codes for a signal peptide. ## Pathogenesis[edit] While the pathogenetic mechanisms underlying the lesions remain unclear, it has been suggested that the accumulation of fumarate may lead to overexpression of the aldo-keto reductase enzyme, AKR1B10.[10] It has also been found that fumarate is present in the mitochondria and in the cytoplasm. The cytoplasmic form appears to have a role in the protection of DNA from molecular injury.[11] Fumarate has been shown to be a competitive inhibitor of prolyl hydroxylase. This inhibition leads to the stabilisation of a number of hypoxia-inducible factors which are thought to predispose to tumorigenesis. An alternative pathway for the metabolism of fumarate in the presence of these mutations has been described.[12] Other genes involved affected by this mutation are Keap1, Nrf2 and HMOX1.[13] ## Diagnosis[edit] The diagnosis is made either by testing of the fumarate hydratase activity in cultured skin fibroblasts or lymphoblastoid cells and demonstrating reduced activity (≤60%) or by molecular genetic testing.[3] Special histologic features of fibroids may allow an early diagnosis in absence of other symptoms.[4] ### Histology[edit] The skin lesions may be difficult to diagnose clinically but a punch biopsy will usually reveal a Grenz zone [1] separating the tumour from the overlying skin. Histological examination shows dense dermal nodules composed of elongated cells with abundant eosinophilic cytoplasm arranged in fascicles (spindle cells). The nuclei are uniform, blunt-ended and cigar-shaped with only occasional mitoses. Special stains that may be of use in the diagnosis include Masson's trichrome, Van Gieson's stain and phosphotungstic acid–haematoxylin. The renal cell carcinomas have prominent eosinophilic nucleoli surrounded by a clear halo. ### Differential diagnosis[edit] Differential diagnosis of this condition includes the Birt-Hogg-Dubé syndrome and tuberous sclerosis. As the skin lesions are typically painful, it is also often necessary to exclude other painful tumors of the skin (including blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomus tumor and granular cell tumor; the mnemonic "BLEND-AN-EGG" may be helpful). Other skin lesions that may need to be considered include cylindroma, lipoma, poroma and trichoepithelioma; these tend to be painless and have other useful distinguishing features. ## Treatment[edit] Uterine fibroids can be treated with the same methods like sporadic uterine fibroids including antihormonal treatment, surgery or embolisation. Substantially elevated risk of progression to or independent development of uterine leiomyosarcoma has been reported which may influence treatment methods.[3] The predisposition to renal cell cancer calls for screening and, if necessary, urological management. The skin lesions may be difficult to treat as they tend to recur after excision or destructive treatment. Drugs which affect smooth muscle contraction, such as doxazosin, nitroglycerine, nifedipine and phenoxybenzamine, may provide pain relief. Topical lidocaine patches have been reported to decrease in severity and frequency of pain cutaneous leiomyomas.[14] ## Prognosis[edit] A 2006 review stated that RS often leads renal cancer between ages 30-50. Renal cancer kills about 1 in 3 people, but 5-year survival rates improved between 1974-1976 and 1995-2000, from 52% to 64%.[15] ## History[edit] The syndrome was first described by Reed et al in 1973.[16] The link with the fumarate hydratase gene was uncovered in 2002.[17] ## Notes[edit] A database of the mutations of the fumarate hydratase gene is available.[18] Autosomal recessive mutations cause a serious neurological disease known as fumarase deficiency, which is associated with a variety of congenital lesions in the brain. ## References[edit] 1. ^ Tolvanen, J.; Uimari, O.; Ryynanen, M.; Aaltonen, L. A.; Vahteristo, P. (2012). "Strong family history of uterine leiomyomatosis warrants fumarate hydratase mutation screening". Human Reproduction. 27 (6): 1865–9. doi:10.1093/humrep/des105. PMID 22473397. 2. ^ Toro, J.; Nickerson, M.; Wei, M.; Warren, M.; Glenn, G.; Turner, M.; Stewart, L.; Duray, P.; Tourre, O.; Sharma, N.; Choyke, P.; Stratton, P.; Merino, M.; Walther, M. M.; Linehan, W. M.; Schmidt, L. S.; Zbar, B. (2003). "Mutations in the Fumarate Hydratase Gene Cause Hereditary Leiomyomatosis and Renal Cell Cancer in Families in North America". The American Journal of Human Genetics. 73 (1): 95–106. doi:10.1086/376435. PMC 1180594. PMID 12772087. 3. ^ a b c d Pithukpakorn, M.; Toro, J. R. (2010) [2006]. Pagon, R. A.; Adam, M. P.; Bird, T. D.; Dolan, C. R.; Fong, C. T.; Stephens, K. (eds.). "Hereditary Leiomyomatosis and Renal Cell Cancer". GeneReviews. PMID 20301430. 4. ^ a b Garg, K.; Tickoo, S. K.; Soslow, R. A.; Reuter, V. E. (2011). "Morphologic Features of Uterine Leiomyomas Associated with Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome". The American Journal of Surgical Pathology. 35 (8): 1235–1237. doi:10.1097/PAS.0b013e318223ca01. PMID 21753700. 5. ^ Kogan, E. A.; Mikhaĭlov, O. I.; Sekamova, S. M.; Kornev, B. M.; Osipova, I. N.; Osipenko, V. I.; Romanova, E. A.; Mukhin, N. A. (2001). "Combination of pulmonary lymphangioleiomyomatosis with skin leiomyomatosis and uterine leiomyoma". Arkhiv Patologii. 63 (6): 39–44. PMID 11810925. 6. ^ Campione, E.; Terrinoni, A.; Orlandi, A.; Codispoti, A.; Melino, G.; Bianchi, L.; Mazzotta, A.; Garaci, F. G.; Ludovici, A.; Chimenti, S. (2007). "Cerebral Cavernomas in a Family with Multiple Cutaneous and Uterine Leiomyomas Associated with a New Mutation in the Fumarate Hydratase Gene". Journal of Investigative Dermatology. 127 (9): 2271–2273. doi:10.1038/sj.jid.5700851. PMID 17476294. 7. ^ Matyakhina, L.; Freedman, R. J.; Bourdeau, I.; Wei, M. H.; Stergiopoulos, S. G.; Chidakel, A.; Walther, M.; Abu-Asab, M.; Tsokos, M.; Keil, M.; Toro, J.; Linehan, W. M.; Stratakis, C. A. (2005). "Hereditary Leiomyomatosis Associated with Bilateral, Massive, Macronodular Adrenocortical Disease and Atypical Cushing Syndrome: A Clinical and Molecular Genetic Investigation". Journal of Clinical Endocrinology & Metabolism. 90 (6): 3773–3779. doi:10.1210/jc.2004-2377. PMID 15741255. 8. ^ Marque, M.; Gardie, B.; Bressac De Paillerets, B.; Rustin, P.; Guillot, B.; Richard, S.; Bessis, D. (2010). "Novel FH mutation in a patient with cutaneous leiomyomatosis associated with cutis verticis gyrata, eruptive collagenoma and Charcot-Marie-Tooth disease". British Journal of Dermatology. 163 (6): 1337–1339. doi:10.1111/j.1365-2133.2010.09912.x. PMID 20560959. 9. ^ Ylisaukko-Oja, S. K.; Cybulski, C.; Lehtonen, R.; Kiuru, M.; Matyjasik, J.; Szymañska, A.; Szymañska-Pasternak, J.; Dyrskjot, L.; Butzow, R.; Orntoft, T. F.; Launonen, V.; Lubiñski, J.; Aaltonen, L. A. (2006). "Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma". European Journal of Human Genetics. 14 (7): 880–883. doi:10.1038/sj.ejhg.5201630. PMID 16639410. 10. ^ Ooi, A.; Wong, J. C.; Petillo, D.; Roossien, D.; Perrier-Trudova, V.; Whitten, D.; Min, B. W. H.; Tan, M. H.; Zhang, Z.; Yang, X. J.; Zhou, M.; Gardie, B.; Molinié, V.; Richard, S. P.; Tan, P. H.; Teh, B. T.; Furge, K. A. (2011). "An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma". Cancer Cell. 20 (4): 511–523. doi:10.1016/j.ccr.2011.08.024. PMID 22014576. 11. ^ Yogev, O.; Yogev, O.; Singer, E.; Shaulian, E.; Goldberg, M.; Fox, T. D.; Pines, O. (2010). Elledge, Steve (ed.). "Fumarase: A Mitochondrial Metabolic Enzyme and a Cytosolic/Nuclear Component of the DNA Damage Response". PLoS Biology. 8 (3): e1000328. doi:10.1371/journal.pbio.1000328. PMC 2834712. PMID 20231875. 12. ^ Frezza, C.; Zheng, L.; Folger, O.; Rajagopalan, K. N.; MacKenzie, E. D.; Jerby, L.; Micaroni, M.; Chaneton, B.; Adam, J.; Hedley, A.; Kalna, G.; Tomlinson, I. P. M.; Pollard, P. J.; Watson, D. G.; Deberardinis, R. J.; Shlomi, T.; Ruppin, E.; Gottlieb, E. (2011). "Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase". Nature. 477 (7363): 225–228. Bibcode:2011Natur.477..225F. doi:10.1038/nature10363. PMID 21849978. 13. ^ Kinch, L.; Grishin, N. V.; Brugarolas, J. (2011). "Succination of Keap1 and Activation of Nrf2-Dependent Antioxidant Pathways in FH-Deficient Papillary Renal Cell Carcinoma Type 2". Cancer Cell. 20 (4): 418–420. doi:10.1016/j.ccr.2011.10.005. PMC 3226726. PMID 22014567. 14. ^ Hsu, Tina (2017). "Treatment of cutaneous leiomyomas with 5% lidocaine patches in a patient with hereditary leiomyomatosis and renal cell cancer (Reed syndrome)". JAAD Case Reports. 3 (5): 406–407. doi:10.1016/j.jdcr.2017.06.007. PMC 5581856. PMID 28884140. 15. ^ Laber, Damian A. (2006). "Risk factors, classification, and staging of renal cell cancer". Medical Oncology. 23 (4): 443–454. doi:10.1385/MO:23:4:443. ISSN 1357-0560. PMID 17303902. 16. ^ Reed, W. B.; Walker, R.; Horowitz, R. (1973). "Cutaneous leiomyomata with uterine leiomyomata". Acta Dermato-venereologica. 53 (5): 409–416. PMID 4127477. 17. ^ Tomlinson, I. P. M.; Alam, N. A.; Rowan, A. J.; Barclay, E.; Jaeger, E. E. M.; Kelsell, D.; Leigh, I.; Gorman, P.; Lamlum, H.; Rahman, S.; Roylance, R. R.; Olpin, S.; Bevan, S.; Barker, K.; Hearle, N.; Houlston, R. S.; Kiuru, M.; Lehtonen, R.; Karhu, A.; Vilkki, S.; Laiho, P. I.; Eklund, C.; Vierimaa, O.; Aittomäki, K.; Hietala, M.; Sistonen, P.; Paetau, A.; Salovaara, R.; Herva, R.; Launonen, V. (2002). "Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer". Nature Genetics. 30 (4): 406–410. doi:10.1038/ng849. PMID 11865300. 18. ^ Bayley, J. P.; Launonen, V.; Tomlinson, I. P. (2008). "The FH mutation database: An online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency". BMC Medical Genetics. 9: 20. doi:10.1186/1471-2350-9-20. PMC 2322961. PMID 18366737. ## External links[edit] Classification D * OMIM: 150800 136850 * MeSH: C537112 * DiseasesDB: 34278 * Reed syndrome and Hereditary leiomyomatosis and renal cell cancer at the Genetic and Rare Diseases Information Center (GARD) *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hereditary leiomyomatosis and renal cell cancer syndrome

c1708350

wikipedia

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

{"gard": ["10096"], "mesh": ["C535516"], "umls": ["C1708350"], "icd-10": ["D23"], "orphanet": ["523"], "wikidata": ["Q3270312"]}

Root fracture of the tooth is a dentine cementum fracture involving the pulp. Traumatic root fracture occurs most often in the middle third of the roots of fully erupted and fully formed teeth. However, root treated teeth are more susceptible to root fracture, as this involves removing root dentine, thereby weakening the tooth.[1] Objectives of the treatment is to reposition the coronal fragments to allow revascularisation of the tooth, therefore maintaining aesthetics and functional integrity.[2] ## Contents * 1 Vertical root fracture * 1.1 Signs and symptoms * 1.2 Predisposing factors * 1.3 Treatment * 2 Horizontal root fracture * 2.1 Detection * 2.2 Treatment * 3 References ## Vertical root fracture[edit] Vertical Root Fractures are longitudinally orientated fractures of the root. They extend from the root canal to the periodontium. They are usually seen in root filled teeth, however they can also be seen in non-restored teeth.[3] The fractures can involve the whole length of the root or only a section of it. When un-recognised they lead to frustration and inappropriate endodontic therapy. The time between a root filling and a fracture is around 39 months, but they can occur during the treatment.[3] Diagnosis is tricky as there as signs and symptoms are frequently delayed and no single clinical feature indicates a root fracture is present.[3] ### Signs and symptoms[edit] They often present with discomfort/soreness which may be associated with an infection. Pain is usually mild to moderate in its intensity. Patients may also report a pain on biting. Another characteristic feature is the repetitive and frequent dislodgement of an apparently well-fitting post.[3] ### Predisposing factors[edit] * Root Canal Anatomy: Roots narrower in mesio-distal dimension are more susceptible to fracture. * Dentin Characteristics: Dentine of pulpless teeth is stiffer and more susceptible to fracture * Corrosion: Corrosion of pins and posts can contribute * Use of a spreader: The wedging effect of the spreader during lateral condensation can lead to it.[4] ### Treatment[edit] A clinician should remember that whilst a root fracture remains, bone around the tooth is continuing to be lost, compromising the success of any future potential implants. Anterior teeth with a vertical root fracture have a very poor prognosis and treatment is mainly extraction. Multi-rooted teeth can be successfully treated by removing the fractured root, either by root amputation or hemisection.[3] ## Horizontal root fracture[edit] Horizontal root fracture is when the fracture line is perpendicular or oblique to the long axis of the tooth. It can occur in the apical, middle or coronal portion of the root. Horizontal root fracture accounts for only 3% of all dental injuries.[5] ### Detection[edit] Horizontal root fractures can often be identified by taking a peri-apical radiograph.[2] Now, with the introduction of cone beam computed tomography (CBCT), it is possible to view root fractures three-dimensionally.[5] ### Treatment[edit] The treatment of horizontally root-fractured teeth involves re-positioning, stabilisation and occlusion adjustment, with a good chance of survival.[6] The exception to this is when the horizontal fracture affects the coronal third of the root, in which case extraction is necessary in 80% of cases.[7] In this case of pulpal necrosis, which occurs in 20-44% of root fracture cases,[8] this can be treated through root canal treatment or endodontic surgery.[6] When the coronal fragment of the tooth is stable, then splinting is unnecessary.[9] However, in the case that the fracture affects the coronal third of the root, is in close-proximity to the cemento-enamel junction, and it is almost impossible to prevent the contents of the oral cavity contacting the fracture, then splinting for at least 2 months is required.[8][10] ## References[edit] 1. ^ Principles of operative dentistry. Qualtrough, A. J. E. Oxford, UK: Blackwell Pub. 2005. pp. 83, 90. ISBN 9781405118217. OCLC 56956075.CS1 maint: others (link) 2. ^ a b "root-fracture". www.dentalcare.com. Retrieved 2018-02-09. 3. ^ a b c d e Moule AJ, Kahler B (June 1999). "Diagnosis and management of teeth with vertical root fractures". Australian Dental Journal. 44 (2): 75–87. doi:10.1111/j.1834-7819.1999.tb00205.x. PMID 10452161. 4. ^ Khasnis SA, Kidiyoor KH, Patil AB, Kenganal SB (March 2014). "Vertical root fractures and their management". Journal of Conservative Dentistry. 17 (2): 103–10. doi:10.4103/0972-0707.128034. PMC 4001262. PMID 24778502. 5. ^ a b Churlinov, Mil. "Horizontal root fracture in permanent dentition: double case report" (PDF). Retrieved 24 March 2019. 6. ^ a b Hovland, E. J. (April 1992). "Horizontal root fractures. Treatment and repair". Dental Clinics of North America. 36 (2): 509–525. ISSN 0011-8532. PMID 1572511. 7. ^ Cvek, M.; Andreasen, J. O.; Borum, M. K. (April 2001). "Healing of 208 intra-alveolar root fractures in patients aged 7-17 years". Dental Traumatology. 17 (2): 53–62. doi:10.1034/j.1600-9657.2001.017002053.x. ISSN 1600-4469. PMID 11475947. 8. ^ a b Andreasen, J. O.; Andreasen, F. M.; Mejare, I.; Cvek, M. (August 2004). "Healing of 400 intra-alveolar root fractures. 1. Effect of pre-injury and injury factors such as sex, age, stage of root development, fracture type, location of fracture and severity of dislocation". Dental Traumatology. 20 (4): 192–202. doi:10.1111/j.1600-9657.2004.00279.x. ISSN 1600-4469. PMID 15245518. 9. ^ Andreasen, J. O.; Andreasen, F. M.; Mejàre, I.; Cvek, M. (August 2008). "Healing of 400 intra-alveolar root fractures. 2. Effect of treatment factors such as treatment delay, repositioning, splinting type and period and antibiotics". Dental Traumatology. 20 (4): 203–211. doi:10.1111/j.1600-9657.2004.00278.x. ISSN 1600-4469. PMID 15245519. 10. ^ Andreasen, Jens Ove; Ahrensburg, Søren Steno; Tsilingaridis, Georgios (October 2012). "Root fractures: the influence of type of healing and location of fracture on tooth survival rates - an analysis of 492 cases". Dental Traumatology. 28 (5): 404–409. doi:10.1111/j.1600-9657.2012.01132.x. ISSN 1600-9657. PMID 22443169. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Root fracture

c0347822

wikipedia

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

{"umls": ["C0347822"], "wikidata": ["Q49001435"]}

Dennie–Marfan syndrome SpecialtyNeurology Dennie–Marfan syndrome is a syndrome in which there is association of spastic paraplegia of the lower limbs and mental retardation in children with congenital syphilis.[1] Both sexes are affected, and the onset of the disease can be acute or insidious, with slow progression from weakness to quadriplegia. Epilepsy, cataract, and nystagmus may also be found. The syndrome was described by Charles Clayton Dennie in 1929,[2] and Antoine Marfan in 1936.[3] ## References[edit] 1. ^ M.D, Mark E. Williams (2009). Geriatric Physical Diagnosis: A Guide to Observation and Assessment. McFarland. p. 56. ISBN 9780786451609. 2. ^ Dennie CC. Partial paralysis of the lower extremities in children, accompanied by backward mental development. Am J Syphilis 1929; 13: 157–163 3. ^ Marfan AB. Paraplégie spasmodique avec troubles cérébraux d’origine hérédo-syphilitique chez les grands enfants. Revue Franc Pédiat 1936; 12: 1–16 ## External links[edit] * Dennie-Marfan syndrome at Who Named It? * v * t * e Symptoms and signs relating to infectious diseases Bacterial disease * syphilis * Hutchinson's teeth * Hutchinson's triad * Westphal's sign * Clutton's joints * Dennie–Marfan syndrome Viral disease * measles * Koplik's spots Parasitic disease * African trypanosomiasis * Winterbottom's sign General * Meningism * Fever * Liebermeister's rule * Faget sign * v * t * e Symptoms and signs relating to the nervous system Neurological examination · Cranial nerve examination Central nervous system Head * Battle's sign * Kernig's sign * Macewen's sign * Myerson's sign * Stroop test * Hirano body Other * increased intracranial pressure * Cushing's triad * Lhermitte's sign * Charcot's neurologic triad Peripheral nervous system Reflexes Combination * Jendrassik maneuver Legs * Plantar reflex * Chaddock reflex * Oppenheim's sign * Westphal's sign Arms * Hoffmann's sign Other Arms * Froment's sign * carpal tunnel syndrome * Tinel sign * Phalen maneuver Legs * Gowers' sign * Hoover's sign * Lasègue's sign * Trendelenburg's sign Torso * Beevor's sign General * Pain stimulus This article about a medical condition affecting the nervous 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

Dennie–Marfan syndrome

None

wikipedia

https://en.wikipedia.org/wiki/Dennie%E2%80%93Marfan_syndrome

{"icd-10": ["A50.45"], "wikidata": ["Q5258099"]}

A number sign (#) is used with this entry because pseudohypoaldosteronism type IIC (PHA2C) is caused by heterozygous mutation in the WNK1 gene (605232) on chromosome 12p13. For a phenotypic description and a discussion of genetic heterogeneity of PHAII, see PHA2A (145260). Clinical Features Disse-Nicodeme et al. (2000) analyzed a large French pedigree in which 12 affected members over 3 generations confirmed autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range, 5.2-6.2 mmol/liter), hyperchloremia (range, 100-109 mmol/liter), normal plasma creatinine, and low renin (179820) levels. Wilson et al. (2001) studied a new PHAII kindred that included 10 living members with typical features of PHAII, including hypertension, hyperkalemia (mean serum potassium, 6.2 mM), normal glomerular filtration rate, suppressed plasma renin activity, normal or elevated aldosterone levels, hyperchloremia (mean serum chloride, 112 mM), and reduced bicarbonate (mean serum bicarbonate, 17.5 mM). These features were absent in unaffected kindred members, and inheritance of the trait was consistent with autosomal dominant transmission with high penetrance. Mapping In a 3-generation French pedigree with 12 affected members with PHAII, Disse-Nicodeme et al. (2000) excluded genetic linkage for the 2 previously mapped PHAII loci as well as for the thiazide-sensitive sodium-chloride cotransporter gene (SLC12A3; 600968) on chromosome 16q. A genomewide screen using 383 microsatellite markers showed strong linkage to 12p13 (PHA2C). Haplotype analysis using 10 additional polymorphic markers led to a minimal 13-cM interval. Analysis of 2 obvious candidate genes, SCNN1A (600228) and GNB3 (139130), located within the interval showed no deleterious mutation. Wilson et al. (2001) performed genomic sequence analysis of linkage in a 3-generation PHAII kindred, which demonstrated complete linkage of the phenotype to the most telomeric 2-cM segment of chromosome 12p, with a multipoint lod score of 5.07. Molecular Genetics Wilson et al. (2001) found that members of a family with PHAII carried a deletion in the interval between D12S341 and D12S91. Further evaluation indicated that affected family members had a heterozygous 41-kb deletion within intron 1 of the WNK1 gene (605232.0001). Both deletion endpoints occur within Alu repetitive elements. Wilson et al. (2001) also identified a deletion in the WNK1 gene (605232.0002) in the family reported by Disse-Nicodeme et al. (2000). Boyden et al. (2012) studied a cohort of 52 PHAII kindreds including 126 affected subjects with renal hyperkalemia and otherwise normal renal function; hypertension and acidosis were present in 71% and 82%, respectively. The authors identified 2 kindreds with PHAII caused by WNK1 mutation. There were 23 affected individuals in those 2 kindreds. Mean age at diagnosis was 36 +/- 20 years with a mean potassium of 5.8 +/- 0.8 and a mean bicarbonate 22.4 +/- 4.6, and only 13% developed hypertension by 18 years of age. Genotype/Phenotype Correlations Boyden et al. (2012) observed that families with PHAII due to mutation in the WNK1 gene (PHA2C) are significantly less severely affected than those with mutation in WNK4 (PHA2B; 614491) or dominant or recessive mutation in the KLHL3 gene (605775; PHA2D, 614495), and all are less severely affected than those with dominant mutation in the CUL3 gene (603136; PHA2E, 614496). INHERITANCE \- Autosomal dominant CARDIOVASCULAR Vascular \- Hypertension METABOLIC FEATURES \- Hyperchloremic metabolic acidosis, mild, in some cases (HCO3 22.4 +/- 4.6 mM) LABORATORY ABNORMALITIES \- Hyperkalemia (5.8 +/- 0.8 mM) \- Hyperchloremia (mean 109 mM) MISCELLANEOUS \- 23 patients from 2 kindreds reported (as of February 2012) \- Age at diagnosis 36 +/- 20 years \- Only 13% develop hypertension at 18 years of age or less \- Responsive to thiazide diuretics MOLECULAR BASIS \- Caused by mutation in the WNK lysine deficient protein kinase 1 gene (WNK1, 605232.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

PSEUDOHYPOALDOSTERONISM, TYPE IIC

c1840391

omim

https://www.omim.org/entry/614492

{"mesh": ["C564162"], "omim": ["614492"], "orphanet": ["88940", "757"], "genereviews": ["NBK65707"]}

A number sign (#) is used with this entry because X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism is caused by mutation in the NR0B1 gene (300473). Description Congenital adrenal hypoplasia (AHC) is a rare disorder that can be inherited in an X-linked or autosomal recessive (see 240200) pattern. In X-linked AHC, primary adrenocortical failure occurs because the adrenal glands lack the permanent adult cortical zone. The remaining cells are termed 'cytomegalic' because they are larger than typical fetal adrenal cells (Hay et al., 1981; Reutens et al., 1999). Patients with AHC usually present in early infancy with primary adrenal failure. Hypogonadotropic hypogonadism (HHG) is a hallmark of the disorder, and is recognized during adolescence because of the absence or interruption of normal pubertal development. Abnormal spermatogenesis has also been observed in these patients. Milder forms of the disease have been described, with adrenal insufficiency sometimes occurring in childhood or even early adulthood. A few cases of partial HHG have been reported (summary by Raffin-Sanson et al., 2013). Transient precocious sexual development in infancy or early childhood can be a prominent feature of AHC (Landau et al., 2010). A contiguous gene syndrome involving a combination of congenital adrenal hypoplasia, glycerol kinase deficiency (307030), and Duchenne muscular dystrophy (DMD; 310200) is caused by deletion of multiple genes on chromosome Xp21 (see 300679). Clinical Features Weiss and Mellinger (1970) described an X-linked form of congenital adrenal hypoplasia in 3 of 4 brothers, each of whom had a different father. Histologically, there was hypoplasia of the adrenal cortex and lack of organization of the cortex into cords, as well as clumps of large pale-staining cells. Several other families consistent with X-linked inheritance had been reported (e.g., Boyd and MacDonald, 1960; Uttley, 1968; Stempfel and Engel, 1960). Brochner-Mortensen (1956) described Addison disease in 2 brothers and 2 of their maternal uncles. Three of the patients had died at ages 19, 26, and 33 years. In brothers reported by Meakin et al. (1959), the diagnosis was made in the elder at 9 years of age and in the second at 6 years of age. Congenital adrenal hypoplasia with hypogonadotropic hypogonadism (HHG) was observed by Hay (1977), who suggested that hypogonadism might be a consequence of absence of adrenal androgen secretion. Hay et al. (1981) described 5 boys with cytomegalic adrenocortical hypoplasia who had been followed for many years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty, and when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone and inadequate pituitary reserve of gonadotropin. Treatment with either testosterone or gonadotropin resulted in advances in pubertal staging in all 5 patients. Hay et al. (1981) noted that the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia is a common finding. Prader et al. (1975), Golden et al. (1977), and Zachmann et al. (1980) also described this association. Martin (1971) described a pair of brothers in whom the signs of Addison disease developed at age 5. Gonadotropin deficiency was later demonstrated in both brothers (Martin, 1980). An extensive Greenlandic pedigree was reported by Petersen et al. (1982). Over 5 generations, 11 boys had died with a clinical picture of adrenocortical insufficiency within 3 weeks of birth. In 3 treated males who survived, the adrenal glands could not be identified by computed tomography. Pubertal development was delayed in 2 patients aged 14 years. Subsequently, Schwartz et al. (1997) identified a missense mutation (300473.0008) in the DAX1 gene in 3 affected members of this Greenlandic family. Reutens et al. (1999) described the clinical features and genetic alterations in 6 families with AHC. Most patients presented within the first year of life with variable signs and symptoms, including hyperpigmentation, salt-wasting crisis, vomiting, and malaise. One patient had a delayed presentation at the age of 7 years, after a hypotensive episode and hyponatremia during an acute asthma attack. A review of the literature showed an apparent bimodal distribution for age at diagnosis. The majority of patients were diagnosed within the first 2 months of life, and another group of patients were diagnosed from 1 to 11 years. Nonsense mutations in the DAX1 gene were identified in 3 cases, and frameshift mutations resulting in a premature stop codon were found in the other 3 families. There were no obvious genotype/phenotype correlations. The authors concluded that the clinical presentation of DAX1 mutations is variable and emphasized the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked AHC. The review of Kletter et al. (1991) suggested that gonadotropin deficiency is an integral part of X-linked cytomegalic adrenocortical hypoplasia. Zachmann et al. (1992) found progressive high frequency hearing loss developing at about the age of 14 years in 3 brothers with X-linked congenital adrenal hypoplasia associated with gonadotropin deficiency. All 3, aged 22, 20, and 18 years, had developed progressive high frequency hearing loss at about 14 years of age. They were doing well on replacement therapy with hydrocortisone, fluorohydrocortisone, and long-acting testosterone. High resolution chromosomal analysis showed no structural anomalies. Although no statement was made concerning the sense of smell, the gonadotropin deficiency may have represented Kallmann syndrome (308700). Jones et al. (1995) reported the case of a Hispanic boy with congenital adrenal hypoplasia who had coal-black hyperpigmentation at birth. Both parents were of light complexion. Usually hyperpigmentation in this condition appears gradually over a period of months to years. Following steroid therapy, the patient's color began to lighten, and at week 7 of life the infant had pigmentation intermediate between coal-black and the color of his Hispanic mother. By 6 months of age, the infant's skin color was similar to that of his mother. ### Clinical Variability Tabarin et al. (2000) reported an unusually mild case in a man who presented with apparently isolated adrenal insufficiency at 28 years of age. Examination revealed partial pubertal development (Tanner stage 3) and undiagnosed incomplete HHG. The patient noted that puberty had occurred at about age 16, and that he had impaired libido and infrequent erections. Severe oligospermia was detected. A mutation in the DAX1 gene (300473.0020) was found, extending the clinical spectrum of the disease to include a milder disorder with delayed onset of symptoms. Domenice et al. (2001) reported a 2-year-old Brazilian boy with a DAX1 mutation (300473.0024). Initial clinical manifestation was isosexual gonadotropin-independent precocious puberty. He presented with pubic hair, enlarged penis and testes, and advanced bone age. Testosterone levels were elevated, whereas basal and GnRH-stimulated LH levels were compatible with a prepubertal pattern. Chronic GnRH agonist therapy did not reduce testosterone levels, supporting the diagnosis of gonadotropin-independent precocious puberty. Surprisingly, steroid replacement therapy induced a clear decrease in testicular size and testosterone levels to the prepubertal range. The authors concluded that chronic excessive ACTH levels resulting from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty in some boys with DAX1 gene mutations. Salvi et al. (2002) reported a 25-year-old man with a complex rearrangement in the DAX1 gene (300473.0026) who was diagnosed with adrenal failure at 6 weeks of age, but who experienced transient recovery of adrenal function of several months' duration later in infancy. He subsequently failed to undergo puberty because of hypogonadotropic hypogonadism (HHG) that was demonstrated to be of pituitary origin, with no pituitary gonadotropin secretion upon stimulation by low-dose pulsatile GnRH or by acute administration of GnRH by intravenous bolus. The patient was also diagnosed with schizophrenia in early adulthood. Salvi et al. (2002) noted that heterogeneity both in age at diagnosis and in severity of the adrenal syndrome is a well-recognized feature of AHC, and that variability in the HHG syndrome that classically accompanies AHC has also been reported. They stated that there was evidence in the literature supporting a purely hypothalamic origin of the defect, a pituitary origin, or both, and noted that the results obtained in their patient did not exclude a hypothalamic component to the HHG. Landau et al. (2010) studied 12 patients with AHC from 5 Israeli families. Six patients from 2 families had a contiguous gene deletion involving NR0B1, and those patients also exhibited developmental delay ranging from mild to severe. The remaining 6 patients had point mutations, resulting in a nonsense mutation, a missense mutation, and a splice site mutation, respectively. Signs of transient precocious sexual development were documented in infancy and childhood in 5 patients from 4 families, with enlarged penis in all 5 patients and increased testicular volume in 2 brothers. All 5 patients later exhibited HHG at the age of puberty. Landau et al. (2010) noted that the clinical spectrum of disease in X-linked AHC is quite variable, and that precocious sexual development can be a prominent feature. Raffin-Sanson et al. (2013) studied a family in which 3 male relatives were hemizygous for a nonsense mutation in the NR0B1 gene (W39X; see MOLECULAR GENETICS), with different adrenal consequences. The proband, 47 years old at the time of the report, had been diagnosed at age 19 years with adrenal insufficiency and with oligospermia at age 23. Evaluation at 32 years of age showed normal external genitalia, and he reported spontaneous onset of puberty at age 13, with normal virilization, growth spurt, and testicular growth. CT scan showed bilateral adrenal atrophy. Over 25 years of follow-up, his LH pulsatile secretion and testosterone level remained normal, consistent with LH-driven preservation of Leydig cell function. However, his sperm counts fell from 4 x 10(6) at age 23 to 0.05 x 10(6) by age 37, and inhibin B (see 147290) levels also decreased, indicating impaired Sertoli cell function. He fathered 1 child by in vitro fertilization at age 33 and another by spontaneous conception 2 years later. Evaluation of the proband's younger brother at age 36 years revealed complete virilization with normal penile length and testicular volume, but low testosterone level and azoospermia. He also exhibited an abnormal cortisol response to the standard-dose cortrosyn test and was diagnosed with mild asymptomatic adrenal insufficiency. In addition, their sister gave birth to a boy who underwent adrenal crisis during the second week of life. All 3 patients carried the recurrent W39X mutation, which Raffin-Sanson et al. (2013) stated had previously been reported in patients with mild phenotypes. Diagnosis ### Differential Diagnosis Adrenoleukodystrophy (ALD; 300100) is a well-established X-linked disorder. Since adrenal insufficiency can precede neurologic symptoms by several years in ALD, and may in fact be the only manifestation in one form of the disorder, some reported cases of X-linked Addison disease may represent that disorder. For example, Sadeghi-Nejad and Senior (1990) looked for signs of adrenomyeloneuropathy, a biochemically identical but milder and more slowly progressive variant of adrenoleukodystrophy, in 8 male patients with childhood-onset Addison disease. In 5 of the patients, elevated plasma hexacosanoic acid concentrations were found, confirming the diagnosis, and in all 5, magnetic resonance imaging showed evidence of brain involvement. Reexploration of the family histories showed additional missed cases. In the family reported by O'Neill et al. (1982), clinically apparent Addison disease without neurologic involvement was the expression of adrenoleukodystrophy in males, and spastic paraplegia and sphincter disturbances occurred in female carriers. Again, Addison disease in young males should prompt consideration of ALD as the underlying abnormality. The achalasia-Addisonian syndrome (231550), which appears to be autosomal recessive, is another example of combined adrenal and neurologic (autonomic) involvement. Like ALD, glycerol kinase deficiency (GKD; 307030) is an X-linked systemic disorder with adrenal insufficiency. Clinical Management Cohen et al. (1982) reported treatment failure in a 19-year-old male with familial cytomegalic adrenocortical hypoplasia and associated hypogonadotropism with the adrenal androgen dehydroepiandrosterone sulfate. A 1-year course did not induce puberty. Kikuchi et al. (1987) reported failure to induce puberty in an 18-year-old patient by pulsatile administration of low-dose gonadotropin-releasing hormone (GNRH; 152760). Mapping Hammond et al. (1985) suggested that the locus for glycerol kinase and that for X-linked adrenal hypoplasia are in the segment Xp21-p11.2. The suggestion was based on the finding of an interstitial Xp deletion with breakpoints at p11.2 and p21 in the phenotypically normal mother of a male infant who died at 36 hrs of cytomegalic adrenal hypoplasia with glyceroluria (indicating glycerol kinase deficiency) and deficiency of ornithine carbamoyltransferase (OTC; 300461) in the liver (see Xp21 deletion syndrome, 300679). Yates et al. (1987) found a deletion of Xp21 causing congenital adrenal hypoplasia without glycerol kinase deficiency. This indicated that the AHC locus is situated distal to GK. The studies using DNA markers were performed on a patient with adrenal hypoplasia but no excess glycerol in the urine and no evidence of Duchenne muscular dystrophy. Molecular Genetics Muscatelli et al. (1994) demonstrated that mutations in the DAX1 gene give rise to X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism. In 14 patients with AHC, AHC and glycerol kinase deficiency, and AHC-GKD-DMD, DAX1 was deleted. In 11 AHC families, and 1 sporadic case, point mutations were found in the coding region of the DAX1 gene (see, e.g., 300473.0001-300473.0005). All AHC patients over 14 years of age and with only point mutations in DAX1 were also found to have hypogonadotropic hypogonadism. However, in 4 sporadic cases and a single familial case of AHC, no point mutations were found, suggesting genetic heterogeneity. Zhang et al. (1998) identified 14 new mutations in 17 families with AHC, bringing the total number of families with AHC studied to 48 and the number of reported mutations to 42; 1 family showed gonadal mosaicism. In a patient who presented at 28 years of age with hypogonadotropic hypogonadism but no clinical evidence of adrenal dysfunction and who was shown to have compensated primary adrenal failure by biochemical testing, Mantovani et al. (2002) identified a missense mutation in the NR0B1 gene (Y380D; 300473.0025), which caused partial loss of function in transient gene expression assays. The authors concluded that partial loss-of-function mutations in DAX1 can present with HHG and covert adrenal failure in adulthood. In a 20-year-old male with an unusual form of AHC manifest as late-onset adrenal insufficiency and gonadal failure, Ozisik et al. (2003) identified a nonsense mutation in the NR0B1 gene (Q37X; 300473.0029). Using a combination of in vitro translation assays and transfection studies, the authors demonstrated that the mutation, which was predicted to cause severe truncation of the protein, was associated with a milder phenotype due to the expression of a partially functional DAX1 protein generated from an alternate in-frame translation start site. In a family in which 3 affected male relatives had variable adrenal-related phenotypes, Raffin-Sanson et al. (2013) identified hemizygosity for a nonsense mutation in the NR0B1 gene (W39X; 300473.0031). The proband was diagnosed with adrenal insufficiency at 19 years of age and with oligospermia at age 23, and his brother had azoospermia and mild asymptomatic adrenal insufficiency diagnosed at 36 years of age. In contrast, their nephew underwent adrenal crisis during the second week of life. Raffin-Sanson et al. (2013) stated that this was the first report of an NR0B1 mutation in a patient with documented normal gonadotrope function, and noted that the association between a normal gonadotrope axis and severe testicular dysfunction suggested that NR0B1 deficiency could cause progressive alteration of the testicular germinal epithelium, independently of gonadotropin and testosterone production. The authors also stated that W39X was a recurrent NR0B1 mutation that had been previously associated with mild phenotypes, as had the nearby Q37X amino-terminal nonsense mutation. ### Associations Pending Confirmation In an 11-year-old prepubertal Dutch boy with a mild form of congenital adrenal hypoplasia involving prominent hypoaldosteronism without clear evidence of glucocorticoid insufficiency, Verrijn Stuart et al. (2007) identified a missense mutation in the NR0B1 gene (W105C; 300473.0030) that was also detected in 3 asymptomatic male relatives. Mou et al. (2015) screened for NR0B1 mutations in 776 Han Chinese men with nonobstructive azoospermia and identified 1 man with a missense mutation (V385L) that showed reduced inhibition of the androgen receptor (AR; 313700) compared to wildtype and was not found in 709 ethnically matched controls. The patient had a low-normal testosterone level with normal LH and FSH values and normal testicular volume; testicular histology showed arrest of spermatogenesis at the spermatocyte stage. Adrenocortical hormone analysis was not reported. INHERITANCE \- X-linked recessive GROWTH Other \- Failure to thrive GENITOURINARY External Genitalia (Male) \- Hypogonadotropic hypogonadism Internal Genitalia (Male) \- Cryptorchidism \- Oligospermia \- Azoospermia SKIN, NAILS, & HAIR Skin \- Hyperpigmentation METABOLIC FEATURES \- Dehydration ENDOCRINE FEATURES \- Primary adrenocortical failure \- Adrenal insufficiency \- Hypoplastic adrenal glands \- 'Cytomegalic' cells (large, pale) in adrenal glands \- Glucocorticoid insufficiency \- Mineralocorticoid insufficiency \- Salt-wasting \- Gonadotropin insufficiency \- Absence of pubertal development \- Delayed puberty \- Precocious puberty LABORATORY ABNORMALITIES \- Hyponatremia \- Decreased serum cortisol \- Decreased serum luteinizing hormone (LH) \- Decreased serum follicle-stimulating hormone (FSH) \- Decreased serum androgens \- Decreased serum testosterone \- Increased adrenocorticotropic hormone (ACTH) MISCELLANEOUS \- Clinical variability \- Onset usually within first weeks of life \- Later onset may occur (1 to 11 years) \- Transient recovery of adrenal function may occur in childhood \- Poor gonadotropin response to gonadotropin releasing hormone (GnRH) \- Autosomal recessive form ( 240220 ) \- May be seen in combination with Duchenne muscular dystrophy (DMD, 310200 ) and/or glycerol kinase deficiency ( 307030 ) as part of a contiguous gene deletion syndrome MOLECULAR BASIS \- Caused by mutation in the nuclear receptor subfamily 0, group B, member 1 gene (NR0B1, 300473.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ADRENAL HYPOPLASIA, CONGENITAL

c0220766

omim

https://www.omim.org/entry/300200

{"doid": ["0080156"], "omim": ["300200"], "orphanet": ["95702"], "synonyms": ["Alternative titles", "ADRENAL HYPOPLASIA, CONGENITAL, WITH HYPOGONADOTROPIC HYPOGONADISM", "ADDISON DISEASE, X-LINKED", "AHC WITH HHG", "CYTOMEGALIC ADRENOCORTICAL HYPOPLASIA", "AHC WITH ISOLATED GONADOTROPIN DEFICIENCY"], "genereviews": ["NBK1431"]}

Chromosome 16 Trisomy 16 is a chromosomal abnormality in which there are 3 copies of chromosome 16 rather than two.[1] It is the most common trisomy leading to miscarriage and the second most common chromosomal cause of it, closely following X-chromosome monosomy.[2] About 6% of miscarriages have trisomy 16.[3] Those mostly occur between 8 and 15 weeks after the last menstrual period.[3] It is not possible for a child to be born alive with an extra copy of this chromosome present in all cells (full trisomy 16).[4] It is possible, however, for a child to be born alive with the mosaic form.[5][6] ## Contents * 1 Chromosome 16 * 2 Screening * 3 Full trisomy 16 * 4 Mosaic trisomy 16 * 4.1 Prenatal diagnosis * 5 References * 6 External links ## Chromosome 16[edit] Normally humans have 2 copies of chromosome 16, one inherited by each parent. This chromosome represents almost 3% of all DNA in cells.[7] ## Screening[edit] Micrograph showing chorionic villi-the tissue that is collected in CVS. During pregnancy, women can be screened by chorionic villus sampling and amniocentesis to detect trisomy 16. With the advent of noninvasive techniques for detecting aneuploidy, prenatal screening with tests using Next Generation Sequencing can be utilised prior to invasive techniques. This can cause fetal growth retardation.[8] ## Full trisomy 16[edit] Full trisomy 16 is incompatible with life and most of the time it results in miscarriage during the first trimester. This occurs when all of the cells in the body contain an extra copy of chromosome 16.[8] ## Mosaic trisomy 16[edit] Mosaic trisomy 16, a rare chromosomal disorder, is compatible with life, therefore a baby can be born alive. This happens when only some of the cells in the body contain the extra copy of chromosome 16. Some of the consequences include slow growth before birth.[9] ### Prenatal diagnosis[edit] During prenatal diagnosis the levels of trisomy in fetal-placental tissues can be analyzed. These levels can be predictors of outcomes in mosaic trisomy 16 pregnancies. In a study of prenatal diagnosis cases, there were 66% live births with an average 35.7 weeks gestational age. About 45% of them had malformations. The most common malformations were CSD, ASD, and hypospadias.[7] However, confined placental trisomy 16 does not always result in anatomical abnormalities.[9] ## References[edit] 1. ^ Mary Kugler, R.N. (2005-08-20). "Chromosome 16 Disorders". About.com:Rare Diseases. About, Inc. Retrieved 2008-01-30. 2. ^ DeCherney, Alan H.; Nathan, Lauren; Goodwin, T. Murphy; Laufer, Neri, eds. (2007). Current diagnosis & treatment: Obstetrics & gynecology (10th ed.). New York: McGraw-Hill. ISBN 978-0-07-143900-8. 3. ^ a b Benn, Peter (1998-09-01). "Trisomy 16 and trisomy 16 mosaicism: A review". American Journal of Medical Genetics. 79 (2): 121–133. doi:10.1002/(SICI)1096-8628(19980901)79:2<121::AID-AJMG8>3.0.CO;2-T. ISSN 1096-8628. 4. ^ Seller, MJ; Fear, C; Kumar, A; Mohammed, S (2004). "Trisomy 16 in a mid-trimester IVF foetus with multiple abnormalities". Clinical Dysmorphology. 13 (3): 187–190. doi:10.1097/01.mcd.0000133498.91871.1b. ISSN 0962-8827. OCLC 196772467. PMID 15194958. BL Shelfmark 3286.273700. 5. ^ Simensen, RJ; Colby, RS; Corning, KJ (2003). "A prenatal counseling conundrum: mosaic trisomy 16. A case study presenting cognitive functioning and adaptive behavior". Genetic Counselling. 14 (3): 331–6. ISSN 1015-8146. OCLC 210520912. PMID 14577678. BL Shelfmark 4111.845000. 6. ^ Langlois S, Yong PJ, Yong SL; Yong, P J; Yong, S L; Barrett, I; Kalousek, D K; Miny, P; Exeler, R; Morris, K; Robinson, W P; et al. (2006). "Postnatal follow-up of prenatally diagnosed trisomy 16 mosaicism". Prenatal Diagnosis. 26 (6): 548–558. doi:10.1002/pd.1457. OCLC 108807898. PMID 16683298. BL Shelfmark 6607.646000.CS1 maint: multiple names: authors list (link) 7. ^ a b Yong, PJ; Barrett, IJ; Kalousek, DK; Robinson, WP (2003). "Clinical aspects, prenatal diagnosis, and pathogenesis of trisomy 16 mosaicism". Journal of Medical Genetics. 40 (3): 175–82. doi:10.1136/jmg.40.3.175. PMC 1735382. PMID 12624135. 8. ^ a b Groli, C; Cerri, V; Tarantini, M; Bellotti, D; Jacobello, C; Gianello, R; Zanini, R; Lancetti, S; Zaglio, S (1996). "Maternal serum screening and trisomy 16 confined to the placenta". Prenatal Diagnosis. 16 (8): 685–9. doi:10.1002/(SICI)1097-0223(199608)16:8<685::AID-PD907>3.0.CO;2-2. PMID 8878276. 9. ^ a b Kontomanolis, EN; Lambropoulou, M; Georgiadis, A; Gramatikopoulou, I; Deftereou, TH; Galazios, G (2012). "The challenging trisomy 16: A case report". Clinical and Experimental Obstetrics & Gynecology. 39 (3): 412–3. PMID 23157062. ## External links[edit] * Disorders of Chromosome 16 Foundation * v * t * e Chromosome abnormalities Autosomal Trisomies/Tetrasomies * Down syndrome * 21 * Edwards syndrome * 18 * Patau syndrome * 13 * Trisomy 9 * Tetrasomy 9p * Warkany syndrome 2 * 8 * Cat eye syndrome/Trisomy 22 * 22 * Trisomy 16 Monosomies/deletions * (1q21.1 copy number variations/1q21.1 deletion syndrome/1q21.1 duplication syndrome/TAR syndrome/1p36 deletion syndrome) * 1 * Wolf–Hirschhorn syndrome * 4 * Cri du chat syndrome/Chromosome 5q deletion syndrome * 5 * Williams syndrome * 7 * Jacobsen syndrome * 11 * Miller–Dieker syndrome/Smith–Magenis syndrome * 17 * DiGeorge syndrome * 22 * 22q11.2 distal deletion syndrome * 22 * 22q13 deletion syndrome * 22 * genomic imprinting * Angelman syndrome/Prader–Willi syndrome (15) * Distal 18q-/Proximal 18q- X/Y linked Monosomy * Turner syndrome (45,X) Trisomy/tetrasomy, other karyotypes/mosaics * Klinefelter syndrome (47,XXY) * XXYY syndrome (48,XXYY) * XXXY syndrome (48,XXXY) * 49,XXXYY * 49,XXXXY * Triple X syndrome (47,XXX) * Tetrasomy X (48,XXXX) * 49,XXXXX * Jacobs syndrome (47,XYY) * 48,XYYY * 49,XYYYY * 45,X/46,XY * 46,XX/46,XY Translocations Leukemia/lymphoma Lymphoid * Burkitt's lymphoma t(8 MYC;14 IGH) * Follicular lymphoma t(14 IGH;18 BCL2) * Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) * Anaplastic large-cell lymphoma t(2 ALK;5 NPM1) * Acute lymphoblastic leukemia Myeloid * Philadelphia chromosome t(9 ABL; 22 BCR) * Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) * Acute promyelocytic leukemia t(15 PML,17 RARA) * Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other * Ewing's sarcoma t(11 FLI1; 22 EWS) * Synovial sarcoma t(x SYT;18 SSX) * Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) * Myxoid liposarcoma t(12 DDIT3; 16 FUS) * Desmoplastic small-round-cell tumor t(11 WT1; 22 EWS) * Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Other * Fragile X syndrome * Uniparental disomy * XX male syndrome/46,XX testicular disorders of sex development * Marker chromosome * Ring chromosome * 6; 9; 14; 15; 18; 20; 21, 22 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Trisomy 16

c1519651

wikipedia

https://en.wikipedia.org/wiki/Trisomy_16

{"gard": ["7060"], "mesh": ["C538041"], "orphanet": ["1708"], "synonyms": ["Mosaic trisomy chromosome 16", "Trisomy 16 mosaicism"], "wikidata": ["Q503642"]}

Severe combined immunodeficiencies (SCID) are inherited immune system disorders characterized by abnormalities with responses of both T cells and B cells (specific types of white blood cells needed for immune system function). Common signs and symptoms include an increased susceptibility to infections including ear infections; pneumonia or bronchitis; oral thrush; and diarrhea. Due to recurrent infections, children with SCID do not grow and gain weight as expected (failure to thrive). SCID may be caused by mutations in any of several genes and can be inherited in an X-linked recessive (most commonly) or autosomal recessive manner. The most common type of SCID is called X-linked severe combined immunodeficiency (XSCID). Another form of SCID is caused by a deficiency of the enzyme adenosine deaminase (ADA). Infections are treated with specific antibiotic, antifungal, and antiviral agents and administration of intravenous (IV) immunoglobulin. The most effective treatment is transplantation of blood-forming stem cells from the bone marrow of a healthy person. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Severe combined immunodeficiency

c0085110

gard

https://rarediseases.info.nih.gov/diseases/7628/severe-combined-immunodeficiency

{"mesh": ["D016511"], "orphanet": ["183660"], "synonyms": ["SCID"]}

Cancer in adolescents and young adults SpecialtyOncology Cancer in adolescents and young adults is cancer which occurs in those between the ages of 15 and 39.[1] This occurs in about 70,000 people a year in the United States—accounting for about 5 percent of cancers. This is about six times the number of cancers diagnosed in children ages 0–14.[1] Globally, nearly 1 million young adults between the ages of 20 and 39 were diagnosed with cancer in 2012, and more than 350,000 people in this age range died from cancer.[2] Young adults are more likely than either younger children or older adults to be diagnosed with certain cancers, such as Hodgkin lymphoma, testicular cancer, and some types of sarcomas. In adolescents and young adults 15 to 24 years old, lymphoma, testicular cancer, and thyroid cancer are the most common types, while among 25- to 39-year-olds, breast cancer and melanoma are more common.[1][3] ## Contents * 1 Definition * 2 Types * 3 Treatment * 3.1 Fertility * 3.1.1 Females * 3.1.2 Males * 4 Prognosis * 4.1 Differences * 4.2 Education * 4.3 Employment * 4.4 Relationships * 5 Epidemiology * 6 References ## Definition[edit] People who are diagnosed with cancer between the ages of 15 and 39 fit the definition of “adolescent and young adults” according to the Report of the Adolescent and Young Adult Oncology Progress Review Group.[4] While this age range is commonly used in the United States, age ranges used to characterize adolescent and young adult populations in terms of cancer care and research may vary by country, region, or study.[2][5] For example, throughout much of Europe and in Australia, adolescence and young adulthood in terms of cancer is defined as ages 15 through 24, while the age range accepted by the Canadian Cancer Society is 15 through 29.[6][7] ## Types[edit] The most common cancers among 15- to 39-year-olds worldwide in 2018, determined by estimated age-standardized incidence rates, were:[8] * Breast cancer * Cervical cancer * Thyroid cancer * Testicular cancer * Ovarian cancer * Leukemia * Non-Hodgkin Lymphoma * Colorectal cancer * Brain and other CNS tumors * Liver cancer * Oral cancer * Hodgkin lymphoma * Uterine cancer * Melanoma * Stomach cancer ## Treatment[edit] For some types of cancer, young adults may have better outcomes if treated with pediatric, rather than adult, treatment regimens. Young adults who have a cancer that typically occurs in children and adolescents, such as brain tumors, leukemia, osteosarcoma, and Ewing sarcoma, may fare better if treated by a pediatric oncologist. For example, adolescents and young adults with acute lymphoblastic leukemia (ALL) may have better outcomes if they are treated with pediatric treatment protocols rather than adult treatment protocols. The 5-year survival rates for 15- to 19-year-olds with ALL has risen to 74% as of 2007-2013, from survival rates of around 50% in the early 1990s. This may be due to greater use of treatment protocols for children.[9] Young adults who have cancers that are more common in adults, such as breast cancer and melanoma, may be better treated by a medical oncologist.[10] ### Fertility[edit] Cancer treatments can affect a person's fertility, with these changes being temporary or permanent. Whether fertility is affected depends on factors such as a person's baseline fertility, age at the time of treatment, the type of cancer and treatment(s), the amount (dose) of treatment, the duration of treatment, the amount of time that has passed since cancer treatment, and other personal health factors.[11] Cancer treatments may harm reproductive organs and glands that control fertility. Chemotherapy (especially alkylating agents) can affect a female's ovaries, causing them to stop releasing eggs and estrogen, and can damage sperm and sperm-forming cells (germ cells) in young men. Radiation therapy to or near the abdomen, pelvis, or spine can harm nearby reproductive organs. Radiation therapy to the brain can damage the pituitary gland, which controls the function of most other endocrine glands. Surgery for cancers of the reproductive system and for cancers in the pelvic region can harm nearby reproductive tissues and/or nerves or lymph nodes. Hormone therapy (also called endocrine therapy) used to treat cancer can disrupt the menstrual cycle, which may affect female fertility. Hematopoietic stem cell transplantation involves receiving high doses of chemotherapy and/or radiation that may damage a female's ovaries and a male's sperm and sperm-forming cells.[11][12] The American Society of Clinical Oncology encourages oncologists to discuss the possibility of treatment-related infertility, as well as options for preserving fertility, with all people of reproductive age and to provide them with referrals to reproductive specialists.[13] #### Females[edit] Females with cancer have fertility preservation options such as oocyte cryopreservation (also called egg cryopreservation or egg freezing), embryo cryopreservation (also called embryo banking or embryo freezing), ovarian shielding (also called gonadal shielding), ovarian tissue cryopreservation (also called ovarian tissue freezing), ovarian transposition (also called oophoropexy), and radical trachelectomy (also called radical cervicectomy).[11] #### Males[edit] Males with cancer have fertility preservation options such as semen cryopreservation (also called sperm banking); testicular shielding (also called gonadal shielding), a procedure in which a protective cover is placed on the outside of the body to shield the testicles from scatter radiation to the pelvis when other parts of the body are being treated with radiation; testicular sperm extraction (TESE), a procedure for males who are not able to produce a semen sample; and testicular tissue freezing (also called testicular tissue cryopreservation) which, for boys who have not gone through puberty and are at high risk of infertility, may be an option.[12] ## Prognosis[edit] Adolescents and young adults with cancer have not attained the same improvements in overall survival as either younger children or older adults.[14] The 5-year survival rate for all invasive adolescent and young adult cancers diagnosed from 2002 to 2006 in the United States was 82.5%.[15] While this survival rate is comparable to those for children and older adults with cancer during the same time period, survival figures favor younger people with cancer with several cancer types common in both children and adolescent and young adult populations, including acute lymphomas, rhabdomyosarcoma, and Ewing sarcoma. Likewise, older people with cancer fared better than adolescents and young adults in terms of 5-year survival for breast cancer, Kaposi sarcoma, and anal cancer.[15] To improve low survival rates for some adolescent and young adult cancers, researchers are studying distinct genetic and biologic features of cancer at different ages, differences in treatment approaches and treatment intensity, and possible differences in compliance to treatment, as well as social, behavioral, or other factors affecting young people with cancer.[14][16] Adolescent and young adult with cancer and survivors of cancer report difficulties related to employment, educational attainment, and financial stability—as well as social relationships.[17] ### Differences[edit] Cancer in adolescents and young adults often differs in terms of signs and symptoms, histology, prognosis, and rates of survivals. Some cancers in adolescents and young adults may have unique genetic and biological features.[18] For example: * Colorectal cancer: Adolescents and young adults tend to have poorer cellular differentiation, differences in histology, more lymphovascular invasion, and signet ring cells. Often, colorectal cancers are found at more advanced tumor stages in AYAs.[19] * Breast cancer: Adolescents and young adults often have higher grade tumors, larger primary tumors, and a greater propensity for triple-negative breast cancer. Adolescents and young adults with breast cancer generally have a worse prognosis than older women.[14] * Acute lymphoblastic leukemia: Genetic alterations found in AYAs are associated with higher rates of treatment failure and relapse. Genomic abnormalities associated with high survivals rates are less likely in AYAs than in younger people, and genetic abnormalities associated with a poorer outcome tend to be more common.[14] * Melanoma: Localized melanoma in AYAs may have clinically different features than in older adults. Adolescents and young adults also tend to have higher stages of melanoma at diagnosis. Younger age at diagnosis and high mitotic rate may correlate with a greater likelihood of metastasis to the lymph nodes.[14] * Sarcoma: Adolescents and young adults often fare worse than young children with the same histologic type of sarcoma. In Ewing sarcoma, survival is inversely related to age and tumor size diagnosis. Adolescents and young adults with rhabdomyosarcoma have a much lower survival rate at 5 years than children, 27% compared with 61%.[14] A stronger understanding of the different biologic and genomic processes seen in some adolescent and young adult cancers will help to develop new and better treatments for these cancers.[18] ### Education[edit] People who reported their cancer treatment was “very intensive” and those who had quit work or school after being diagnosed were more likely to report that cancer negatively affected their work and school after diagnosis, with more than 50% reporting problems with memory and attentiveness. Almost three-quarters of adolescents and young adults with cancer who had been studying or working returned to school or work within one to three years after a diagnosis. Reasons for educational disruption and lower educational attainment given by adolescents and young adults in qualitative interviews included missing school, not taking required tests, and feeling as if they had been “left behind.” [17] ### Employment[edit] Roughly a third of young adults in the United States reported that cancer had a negative impact on their employment plans. In research that compared young people who had survived cancer with their healthy peers, 33% of adolescents and young adults with cancer were not working compared to 27% of controls. In another US study, 23% of adolescents and young adults with cancer reported unemployment due to health issues compared with 14% of controls. Another national study found that adolescents and young adults who had had cancer reported lower family incomes than their peer-age cohorts without cancer.[17] ### Relationships[edit] Social relationships and educational achievements during the formative adolescent and young adult years are very important, and studies in the United States have documented that a cancer experience can negatively affect the attainment of these goals. Marriage rates were lower among young adults with cancer, and they were more likely to have divorced or separated than peers in an age-related control group. Adolescents and young adults also reported fears about sexual attractiveness due to physical changes as well as fertility-related changes caused by cancer. Adolescents and young adults with cancer expressed a strong desire to connect with other young adult with cancer and survivors from cancer who may have gone through similar experiences for support to cope with these challenges.[17] ## Epidemiology[edit] During the period from 2000 to 2011, of 40 cancers that are relatively common in both adolescents and young adults in the United States, 7 increased in frequency: acute lymphoblastic leukemia, colorectal cancer, prostate cancer, kidney cancer, testicular cancer, thyroid cancer, and uterine cancer.[20] Rates of some cancers such as lung cancer and melanoma decreased among adolescents and young adults in the United States during this period. One hypothesis for this decline is the launching of prevention campaigns, such as smoking prevention and skin cancer awareness.[20] Cervical cancer also declined among adolescents and young adults in the United States, which may be attributable to the introduction of the HPV vaccine. In contrast, rates among older adults declined in 26 types of cancer that also affect adolescents and young adults. Rates among older adults increased only in cancers of the thyroid, kidney, liver, and small intestine.[citation needed] ## References[edit] 1. ^ a b c "AYA". National Cancer Institute. 2015-05-15. Retrieved 2018-06-08. 2. ^ a b Fidler, Miranda M; Gupta, Sumit; Soerjomataram, Isabelle; Ferlay, Jacques; Steliarova-Foucher, Eva; Bray, Freddie (2017). "Cancer incidence and mortality among young adults aged 20–39 years worldwide in 2012: a population-based study". The Lancet Oncology. 18 (12): 1579–1589. doi:10.1016/S1470-2045(17)30677-0. ISSN 1470-2045. PMID 29111259. 3. ^ "SEER Cancer Statistics Review, 1975-2015". SEER. Retrieved 2018-11-28. 4. ^ "Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer" (PDF). Report of the Adolescent and Young Adult Oncology Progress Review Group (NIH Publication No. 06-6067). U.S. National Institutes of Health. 2006-08-15. Retrieved 2019-07-08. 5. ^ Smith, Ashley Wilder; Seibel, Nita L.; Lewis, Denise R.; Albritton, Karen H.; Blair, Donald F.; Blanke, Charles D.; Bleyer, W. Archie; Freyer, David R.; Geiger, Ann M. (2016-02-05). "Next steps for adolescent and young adult oncology workshop: An update on progress and recommendations for the future". Cancer. 122 (7): 988–999. doi:10.1002/cncr.29870. ISSN 0008-543X. PMID 26849003. 6. ^ "Cancer in adolescents and young adults in Australia, Table of contents". Australian Institute of Health and Welfare. Retrieved 2019-05-07. 7. ^ "Cancer in young people - Canadian Cancer Society". www.cancer.ca. Retrieved 2019-05-07. 8. ^ "Cancer today: Estimated age-standardized incidence rates (World) in 2018, worldwide, both sexes, ages 15-39". gco.iarc.fr. Retrieved 2019-07-08. 9. ^ Ram, Ron; Wolach, Ofir; Vidal, Liat; Gafter-Gvili, Anat; Shpilberg, Ofer; Raanani, Pia (2012). "Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis". American Journal of Hematology. 87 (5): 472–478. doi:10.1002/ajh.23149. ISSN 1096-8652. PMID 22388572. S2CID 205294792. 10. ^ "Cancer in Children and Adolescents". National Cancer Institute. September 2017. Retrieved 2018-07-16. 11. ^ a b c "Female Fertility Issues". National Cancer Institute. 2017-09-22. Retrieved 2018-10-19. 12. ^ a b "Male Fertility Issues". National Cancer Institute. 2017-09-22. Retrieved 2018-10-19. 13. ^ Oktay, Kutluk; Harvey, Brittany E.; Partridge, Ann H.; Quinn, Gwendolyn P.; Reinecke, Joyce; Taylor, Hugh S.; Wallace, W. Hamish; Wang, Erica T.; Loren, Alison W. (2018-07-01). "Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update". Journal of Clinical Oncology. 36 (19): 1994–2001. doi:10.1200/JCO.2018.78.1914. ISSN 1527-7755. PMID 29620997. S2CID 4633292. 14. ^ a b c d e f Tricoli, James V.; Blair, Donald G.; Anders, Carey K.; Bleyer, W. Archie; Boardman, Lisa A.; Khan, Javed; Kummar, Shivaani; Hayes-Lattin, Brandon; Hunger, Stephen P. (2016-04-01). "Biologic and clinical characteristics of adolescent and young adult cancers: Acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma". Cancer. 122 (7): 1017–1028. doi:10.1002/cncr.29871. ISSN 1097-0142. PMC 4803597. PMID 26849082. 15. ^ a b Keegan, Theresa H. M.; Ries, Lynn A. G.; Barr, Ronald D.; Geiger, Ann M.; Dahlke, Deborah Vollmer; Pollock, Bradley H.; Bleyer, W. Archie; National Cancer Institute Next Steps for Adolescent and Young Adult Oncology Epidemiology Working Group (2016-04-01). "Comparison of cancer survival trends in the United States of adolescents and young adults with those in children and older adults" (PDF). Cancer. 122 (7): 1009–1016. doi:10.1002/cncr.29869. ISSN 1097-0142. PMID 26848927. S2CID 25293817. 16. ^ Tricoli, James V.; Bleyer, Archie (Nov–Dec 2018). "Adolescent and Young Adult Cancer Biology". Cancer Journal (Sudbury, Mass.). 24 (6): 267–274. doi:10.1097/PPO.0000000000000343. ISSN 1540-336X. PMID 30480571. 17. ^ a b c d Warner, Echo L.; Kent, Erin E.; Trevino, Kelly M.; Parsons, Helen M.; Zebrack, Bradley J.; Kirchhoff, Anne C. (2016-04-01). "Social well-being among adolescents and young adults with cancer: A systematic review". Cancer. 122 (7): 1029–1037. doi:10.1002/cncr.29866. ISSN 1097-0142. PMC 5007077. PMID 26848713. 18. ^ a b Bleyer, Archie; Barr, Ronald; Hayes-Lattin, Brandon; Thomas, David; Ellis, Chad; Anderson, Barry; Biology and Clinical Trials Subgroups of the US National Cancer Institute Progress Review Group in Adolescent and Young Adult Oncology (2008). "The distinctive biology of cancer in adolescents and young adults". Nature Reviews. Cancer. 8 (4): 288–298. doi:10.1038/nrc2349. ISSN 1474-1768. PMID 18354417. 19. ^ Tricoli, James V.; Boardman, Lisa A.; Patidar, Rajesh; Sindiri, Sivasish; Jang, Jin S.; Walsh, William D.; McGregor, Paul M.; Camalier, Corinne E.; Mehaffey, Michele G. (2018-03-01). "A mutational comparison of adult and adolescent and young adult (AYA) colon cancer". Cancer. 124 (5): 1070–1082. doi:10.1002/cncr.31136. ISSN 1097-0142. PMC 5821537. PMID 29194591. 20. ^ a b Barr, Ronald D.; Ries, Lynn A. G.; Lewis, Denise R.; Harlan, Linda C.; Keegan, Theresa H. M.; Pollock, Bradley H.; Bleyer, W. Archie; US National Cancer Institute Science of Adolescent and Young Adult Oncology Epidemiology Working Group (2016-04-01). "Incidence and incidence trends of the most frequent cancers in adolescent and young adult Americans, including "nonmalignant/noninvasive" tumors". Cancer. 122 (7): 1000–1008. doi:10.1002/cncr.29867. ISSN 1097-0142. PMID 26848808. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Cancer in adolescents and young adults

None

wikipedia

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

{"wikidata": ["Q4655219"]}

## Summary The purpose of this overview is to increase the awareness of clinicians regarding familial hyperinsulinism (referred to as FHI in this GeneReview) and its genetic causes and management. The following are the goals of this overview. ### Goal 1. Describe the clinical characteristics of FHI. ### Goal 2. Review the genetic causes of FHI. ### Goal 3. Provide an evaluation strategy to identify the genetic cause of FHI in a proband (when possible). ### Goal 4. Inform (when possible) medical management of FHI based on genetic cause and evaluation of relatives at risk. ### Goal 5. Inform risk assessment and surveillance of at-risk relatives for early detection and treatment of FHI. ## Diagnosis ## Clinical Characteristics ## Differential Diagnosis ## Management *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Familial Hyperinsulinism

c3888018

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK1375/

{"mesh": ["D044903"], "synonyms": ["Congenital Hyperinsulinism (CHI)", "Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI)"]}

## Clinical Features Beginning with an infant screened for Sandhoff disease, Alexander et al. (1984) found 5 healthy persons in 3 generations of a Lebanese family with high levels of lysosomal enzymes in the plasma comparable to those found in mucolipidoses II and III (252500, 252600) homozygotes. The same enzymes were within normal limits in other extracellular fluids; in ML II/III, they are elevated in urine and cerebrospinal fluid. As with ML II/III patients, levels of acid phosphatase, alkaline phosphatase and beta-glucuronidase were normal. Two alternative possibilities were considered: (1) a defect in the phosphodiesterase that normally uncovers the mannose 6-phosphate marker, or (2) a defect in the mannose 6-phosphate receptor. One might expect that an enzyme defect would not be expressed in the heterozygote. On the other hand, defects in the LDL receptor (606945) are so expressed. Mutant Chinese hamster ovary cells with altered mannose 6-phosphate receptors were studied by Robbins and Myerowitz (1981). Although the kindred studied was consanguineous, the pattern of inheritance appeared to be autosomal dominant; one instance of male-to-male transmission was noted. Alexander et al. (1986) showed that mannose 6-phosphate receptors in the fibroblasts from a member of this family were functioning normally but the cells had only half-normal levels of phosphodiester glycosidase activity. Pinocytosis into Sandhoff disease fibroblasts of beta-hexosaminidase B secreted by the fibroblasts of this person was 18% of control. Treatment of the abnormal Hex-B with exogenous placental phosphodiester glycosidase (607985) increased its binding to mannose 6-phosphate receptors 3-fold. Secretion rates of 7 lysosomal enzymes from the subject's fibroblasts were, on average, twice as great as rates measured for 2 I-cell disease heterozygote fibroblast lines. Alexander et al. (1986) suggested that an individual homozygous for this enzyme deficiency would develop I-cell disease. Lab \- Elevated plasma lysosomal enzymes \- Normal urinary and CSF lysosoal enzymes \- Normal levels of acid phosphatase, alkaline phosphatase and beta-glucuronidase \- Mannose 6-phosphate receptor recognition defect Inheritance \- Autosomal dominant \- homozygotes expected to have I-cell disease ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MANNOSE 6-PHOSPHATE RECEPTOR RECOGNITION DEFECT, LEBANESE TYPE

c1835134

omim

https://www.omim.org/entry/154570

{"mesh": ["C563601"], "omim": ["154570"], "synonyms": ["Alternative titles", "PHOSPHODIESTER GLYCOSIDE DEFICIENCY"]}

Some women with hirsutism and amenorrhea have an attenuated form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (201910). This form, as in the classic form of congenital adrenal hyperplasia, is linked to HLA and has an autosomal recessive inheritance. Mild forms of 11-hydroxylase deficiency (202010) and of 3-beta-hydroxysteroid dehydrogenase deficiency (201810) also exist. Lee et al. (1987) described a family in which female members presented with premature pubarche, later with hirsutism and amenorrhea, and with evidence of functional adrenal hyperfunction but no evidence of enzyme deficiency. These findings were observed in the proband, her mother, the mother's twin sister, and her maternal great-grandmother. Basal levels of androgen in the first 3 were variably elevated. Neither the proband nor her mother or twin sister had the type of response seen in homozygotes, the attenuated form of congenital adrenal hyperplasia, when ACTH stimulation was tested. Glucocorticoid therapy suppressed adrenal androgen levels; in each of 2 otherwise amenorrheic women, conception occurred twice during such treatment. Lee et al. (1987) showed that the disorder is not linked to HLA and suggested that the condition was either autosomal or X-linked dominant. Endocrine \- Premature pubarche \- Amenorrhea \- Adrenal hyperfunction Hair \- Hirsutism Lab \- Variably elevated androgen levels Inheritance \- Autosomal dominant ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

HYPERSECRETION OF ADRENAL ANDROGENS, FAMILIAL

c1840387

omim

https://www.omim.org/entry/145295

{"mesh": ["C536845"], "omim": ["145295"]}

Maternal uniparental disomy of chromosome 14 is a rare chromosomal anomaly characterized by prenatal and postnatal growth retardation, hypotonia, motor delay, early puberty, obesity, short adult stature, small hands and feet, mild intellectual disability, and mild dysmorphic facial features (frontal bossing, short nose with wide nasal tip, micrognathia, high palate, short philtrum). *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Temple syndrome due to maternal uniparental disomy of chromosome 14

c4015558

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=96184

{"omim": ["616222"], "icd-10": ["Q99.8"], "synonyms": ["UPD(14)mat"]}

Seaver Cassidy syndrome Other namesFacial dysmorphism-shawl scrotum-joint laxity syndrome Seaver Cassidy syndrome is a very rare disorder characterized by certain facial, genital, and skeletal deformities, as well as an unusual susceptibility to bleeding.[1] Seaver Cassidy syndrome was first described in 1991 by Laurie Seaver and Suzanne Cassidy.[2] ## Contents * 1 Signs and symptoms * 2 Diagnosis * 3 Treatment * 4 References * 5 External links ## Signs and symptoms[edit] Signs of Seaver Cassidy syndrome include several facial disorders, including hypertelorism and telecanthus, epicanthal folds, downslanting palpebral fissures, ptosis, a broad nasal bridge, malar hypoplasia, a thin upper lip, a smooth philtrum, and low-set, prominent ears. Males with Seaver Cassidy syndrome may also experience an underdeveloped shawl scrotum and cryptorchidism. Skeletal anomalies, such genu valgum, hyperextended joints, or cubitus valgus, may also be present.[2] ## Diagnosis[edit] This section is empty. You can help by adding to it. (August 2017) ## Treatment[edit] This section is empty. You can help by adding to it. (August 2017) ## References[edit] 1. ^ "Seaver Cassidy syndrome". Check Orphan. Archived from the original on 2013-04-14. Retrieved 2011-09-06. 2. ^ a b Seaver LH, Cassidy SB (December 1991). "New syndrome: mother and son with hypertelorism, downslanting palpebral fissures, malar hypoplasia, and apparently low-set ears associated with joint and scrotal anomalies". American Journal of Medical Genetics. 41 (4): 405–9. doi:10.1002/ajmg.1320410404. PMID 1776627. ## External links[edit] * Seaver Cassidy syndrome at the Office of Rare Diseases Classification D * ICD-10: none * ICD-9-CM: none * MeSH: C537529 External resources * Orphanet: 1778 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

Seaver Cassidy syndrome

c2931522

wikipedia

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

{"gard": ["4778"], "mesh": ["C537529"], "umls": ["C2931522"], "icd-9": [], "icd-10": [], "orphanet": ["1778"], "wikidata": ["Q7442226"]}

Hereditary hypercarotenemia and vitamin A deficiency is an extremely rare metabolic disorder characterized clinically by skin discoloration, elevated levels of carotene and low levels of vitamin A described in fewer than 5 patients to date. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hereditary hypercarotenemia and vitamin A deficiency

c2676023

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=199285

{"mesh": ["C567296"], "omim": ["115300", "277350"], "icd-10": ["E50.8"]}

Hurler syndrome Structure of dermatan sulfate, one of the molecules that accumulates in the lysosomes of Hurler syndrome patients CausesDeficiency of the alpha-L iduronidase enzyme Differential diagnosisHurler-Scheie syndrome; Scheie syndrome; Hunter Syndrome; other mucopolysaccharidoses PrognosisDeath usually occurs before 12 years Frequency1 in 100,0000 Hurler syndrome, also known as mucopolysaccharidosis Type IH (MPS-IH), Hurler's disease, and formerly gargoylism, is a genetic disorder that results in the buildup of large sugar molecules called glycosaminoglycans (AKA GAGs, or mucopolysaccharides) in lysosomes. The inability to break down these molecules results in a wide variety of symptoms caused by damage to several different organ systems, including but not limited to the nervous system, skeletal system, eyes, and heart. The underlying mechanism is a deficiency of alpha-L iduronidase, an enzyme responsible breaking down GAGs.[1]:544 Without this enzyme, a buildup of dermatan sulfate and heparan sulfate occurs in the body. Symptoms appear during childhood, and early death usually occurs. Other, less severe forms of MPS Type I include Hurler-Scheie Syndrome (MPS-IHS) and Scheie Syndrome (MPS-IS). Hurler syndrome is classified as a lysosomal storage disease. It is clinically related to Hunter syndrome (MPS II);[2] however, Hunter syndrome is X-linked, while Hurler syndrome is autosomal recessive. ## Contents * 1 Signs and symptoms * 2 Mechanisms * 3 Genetics * 4 Diagnosis * 4.1 Classification * 5 Treatment * 6 Prognosis * 7 Epidemiology * 8 Research * 8.1 Gene therapy * 9 History * 10 See also * 11 References * 12 External links ## Signs and symptoms[edit] Corneal clouding in a 30-year-old male with MPS VI. Hurler syndrome and other MPS disorders may also present with corneal clouding Children with Hurler syndrome may appear normal at birth and develop symptoms over the first years of life. Symptoms vary between patients. One of the first abnormalities that may be detected is coarsening of the facial features; these symptoms can begin at 3-6 months of age. The head can be large with prominent frontal bones. The skull can be elongated. The nose can have a flattened nasal bridge with continuous nasal discharge. The eye sockets may be widely spaced, and the eyes may protrude from the skull. The lips can be large, and affected children may hold their jaws open constantly. Skeletal abnormalities occur by about age 6 months, but may not be clinically obvious until 10-14 months. Patients may experience debilitating spine and hip deformities, carpal tunnel syndrome, and joint stiffness. Patients may be normal height in infancy, but stop growing by the age of 2 years. They may not reach a height of greater than 4 feet. Other early symptoms may include inguinal and umbilical hernias. These may be present at birth, or they may develop within the first months of life. Clouding of the cornea and retinal degeneration may occur within the first year of life, leading to blindness. Enlarged liver and spleen are common. There is no organ dysfunction, but GAG deposition in these organs may lead to a massive increase in size. Patients may also have diarrhea. Aortic valve disease may occur. Airway obstruction is frequent, usually secondary to abnormal cervical vertebrae.[3] Upper and lower respiratory tract infections can be frequent. Developmental delay may become apparent by age 1-2 years, with a maximum functional age of 2-4 years. Progressive deterioration follows. Most children develop limited language capabilities. Death usually occurs by age 10.[4][5] ## Mechanisms[edit] Heparan sulfate is one of the GAGs that builds up in the lysosomes of people with Hurler Syndrome The IDUA gene is responsible for encoding an enzyme called alpha-L-iduronidase. Through hydrolysis, alpha-L-iduronidase is responsible for breaking down a molecule called unsulfated alpha-L-iduronic acid. This is a uronic acid found in the GAGs dermatan sulfate and heparan sulfate. The alpha-L-iduronidase enzyme is located in lysosomes. Without sufficient enzymatic function, these GAGs cannot be digested properly.[6] ## Genetics[edit] Hurler syndrome has an autosomal recessive pattern of inheritance. Children with Hurler Syndrome carry two defective copies of the IDUA gene, which has been mapped to the 4p16.3 site on chromosome 4. This is the gene which encodes for the protein iduronidase. As of 2018[update], more than 201 different mutations in the IDUA gene have been shown to cause MPS I.[7] Because Hurler syndrome is an autosomal recessive disorder, affected persons have two nonworking copies of the gene. A person born with one normal copy and one defective copy is called a carrier. They will produce less α-L-iduronidase than an individual with two normal copies of the gene. The reduced production of the enzyme in carriers, however, remains sufficient for normal function; the person should not show any symptoms of the disease. ## Diagnosis[edit] Diagnosis often can be made through clinical examination and urine tests (excess mucopolysaccharides are excreted in the urine). Enzyme assays (testing a variety of cells or body fluids in culture for enzyme deficiency) are also used to provide definitive diagnosis of one of the mucopolysaccharidoses. Prenatal diagnosis using amniocentesis and chorionic villus sampling can verify if a fetus either carries a copy of the defective gene or is affected with the disorder. Genetic counseling can help parents who have a family history of the mucopolysaccharidoses determine if they are carrying the mutated gene that causes the disorders. ### Classification[edit] All members of the mucopolysaccharidosis family are also lysosomal storage diseases. Mucopolysaccharidosis type I (MPS I) is divided into three subtypes based on severity of symptoms. All three types result the absence or decreased functioning of the same enzyme. MPS-IH (Hurler syndrome) is the most severe of the MPS I subtypes. The other two types are MPS-IS (Scheie syndrome) and MPS-IHS (Hurler-Scheie syndrome). Because of the substantial overlap between Hurler syndrome, Hurler-Scheie syndrome, and Scheie syndrome, some sources consider these terms to be outdated. Instead, MPS I may be divided into "severe" and "attenuated" forms.[8] ## Treatment[edit] There is currently no cure for Hurler Syndrome. Enzyme replacement therapy with iduronidase (Aldurazyme) may improve pulmonary function and mobility. It can reduce the amount of carbohydrates being improperly stored in organs. Surgical correction of hand and foot deformities may be necessary. Corneal surgery may help alleviate vision problems.[5] Bone marrow transplantation (BMT) and umbilical cord blood transplantation (UCBT) can be used as treatments for MPS I. BMT from siblings with identical HLA genes and from relatives with similar HLA genes can significantly improve survival, cognitive function, and physical symptoms. Patients can develop graft versus host disease; this is more likely in non-sibling donors. In a 1998 study, children with HLA-identical sibling donors had a 5-year survival of 75%; children with non-sibling donors had a 5-year survival of 53%.[9] Children often lack access to a suitable bone marrow donor. In these cases, UCBT from unrelated donors can increase survival, decrease physical signs of the disease, and improve cognition. Complications from this treatment may include graft versus host disease.[10] ## Prognosis[edit] A British study from 2008 found a median estimated life expectancy of 8.7 years for patients with Hurler syndrome. In comparison, the median life expectancy for all forms of MPS type I was 11.6 years. Patients who received successful bone marrow transplants had a 2-year survival rate of 68% and a 10-year survival rate of 64%. Patients who did not receive bone marrow transplants had a significantly reduced lifespan, with a median age of 6.8 years.[4] ## Epidemiology[edit] Hurler syndrome has an overall frequency of one per 100,000.[5] Combined, all of the mucopolysaccharidoses have a frequency of approximately one in every 25,000 births in the United States.[2] ## Research[edit] ### Gene therapy[edit] A great deal of interest exists in treating MPS I with gene therapy. In animal models, delivery of the iduronidase gene has been accomplished with retrovirus, adenovirus, adeno-associated virus, and plasmid vectors. Mice and dogs with MPS I have been successfully treated with gene therapy. Most vectors can correct the disease in the liver and spleen, and can correct brain effects with a high dosage. Gene therapy has improved survival, neurological, and physical symptoms; however, some animals have developed unexplained liver tumors. If safety issues can be resolved, gene therapy may provide an alternative human treatment for MPS disorders in the future.[11] Sangamo Therapeutics, headquartered in Richmond, California, is currently conducting a clinical trial involving gene editing using Zinc Finger Nuclease (ZFN) for the treatment of MPS I.[12] ## History[edit] In 1919, Gertrud Hurler, a German pediatrician, described a syndrome involving corneal clouding, skeletal abnormalities, and mental retardation. A similar disease of "gargoylism" had been described in 1917 by Charles A. Hunter. Hurler did not mention Hunter's paper. Because of the communications interruptions caused by World War I, it is likely that she was unaware of his study. Hurler syndrome now refers to MPS IH, while Hunter syndrome refers to MPS II.[13][14] In 1962, a milder form of MPS I was identified by Scheie, leading to the designation of Scheie syndrome.[4] ## See also[edit] * Hunter syndrome (MPS II) * Sanfilippo syndrome (MPS III) * Morquio syndrome (MPS IV) * Maroteaux-Lamy syndrome (MPS VI) ## References[edit] 1. ^ James WD, Berger TG, et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 978-0-7216-2921-6. 2. ^ a b "Mucopolysaccharidoses Fact Sheet". National Institute of Neurological Disorders and Stroke. 15 Nov 2017. Retrieved 11 May 2018. 3. ^ Myer CM (July 1991). "Airway obstruction in Hurler's syndrome--radiographic features". International Journal of Pediatric Otorhinolaryngology. 22 (1): 91–6. doi:10.1016/0165-5876(91)90101-g. PMID 1917344. 4. ^ a b c Moore D, Connock MJ, Wraith E, Lavery C (September 2008). "The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK". Orphanet Journal of Rare Diseases. 3: 24. doi:10.1186/1750-1172-3-24. PMC 2553763. PMID 18796143. 5. ^ a b c Banikazemi M (12 Oct 2014). "Hurler syndrome, Hurler-Scheie Syndrome, and Scheie Syndrome (Mucopolysaccharidosis Type I)". Medscape. Retrieved 10 May 2018. 6. ^ "IDUA gene". Genetics Home Reference. 11 June 2019. Retrieved 18 June 2019. 7. ^ Chkioua L, Boudabous H, Jaballi I, Grissa O, Turkia HB, Tebib N, Laradi S (May 2018). "Novel splice site IDUA gene mutation in Tunisian pedigrees with hurler syndrome". Diagnostic Pathology. BioMed Central. 13 (1): 35. doi:10.1186/s13000-018-0710-3. PMC 5975427. PMID 29843745. 8. ^ "Mucopolysaccharidosis type I". Genetics Home Reference. Retrieved 10 May 2018. 9. ^ Peters C, Shapiro EG, Anderson J, Henslee-Downey PJ, Klemperer MR, Cowan MJ, et al. (April 1998). "Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group". Blood. 91 (7): 2601–8. doi:10.1182/blood.V91.7.2601. PMID 9516162. 10. ^ Staba SL, Escolar ML, Poe M, Kim Y, Martin PL, Szabolcs P, et al. (May 2004). "Cord-blood transplants from unrelated donors in patients with Hurler's syndrome". The New England Journal of Medicine. 350 (19): 1960–9. doi:10.1056/NEJMoa032613. PMID 15128896. S2CID 43572313. 11. ^ Ponder KP, Haskins ME (September 2007). "Gene therapy for mucopolysaccharidosis". Expert Opinion on Biological Therapy. 7 (9): 1333–45. doi:10.1517/14712598.7.9.1333. PMC 3340574. PMID 17727324. 12. ^ "Ascending Dose Study of Genome Editing by the Zinc Finger Nuclease (ZFN) Therapeutic SB-318 in Subjects With MPS I". clinicaltrials.gov. U.S. National Library of Medicine. Retrieved 7 February 2019. 13. ^ Hurler's syndrome at Who Named It? 14. ^ Hurler, G. (1919). "Über einen Typ multipler Abartungen, vorwiegend am Skelettsystem". Zeitschrift für Kinderheilkunde. 24 (5–6): 220–234. doi:10.1007/BF02222956. S2CID 34471544. ## External links[edit] Classification D * ICD-10: E76.0 * ICD-9-CM: 277.5 * OMIM: 607014 * MeSH: D008059 * DiseasesDB: 6067 External resources * MedlinePlus: 001204 * eMedicine: ped/1031 * GeneReviews: Mucopolysaccharidosis Type I * GeneReview/NIH/UW entry on Mucopolysaccharidosis Type I * v * t * e Lysosomal storage diseases: Inborn errors of carbohydrate metabolism (Mucopolysaccharidoses) Catabolism * MPS I * Hurler Syndrome, Hurler-Scheie Syndrome, Scheie Syndrome * MPS II: Hunter Syndrome * MPS III: Sanfilippo Syndrome * MPS IV: Morquio Syndrome * MPS VI: Maroteaux-Lamy Syndrome * MPS VII: Sly Syndrome * MPS IX: Hyaluronidase deficiency *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hurler syndrome

c0086795

wikipedia

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

{"gard": ["12559"], "mesh": ["D008059"], "orphanet": ["93473"], "wikidata": ["Q25379699"]}

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-26 (COXPD26) is caused by compound heterozygous mutation in the TRMT5 gene (611023) on chromosome 14q23. For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060). Clinical Features Powell et al. (2015) reported 2 unrelated patients with a highly variable phenotype resulting from a defect in mitochondrial respiratory chain activity. One of the patients (patient 73901), previously reported by Haller et al. (1989), was a woman who presented at age 25 years with a life-long history of exercise intolerance with prominent exertional dyspnea. Evaluation showed lactic acidosis and a mitochondrial myopathy associated with a deficiency of complexes III and IV. Over the following years, she developed exocrine insufficiency with malabsorption, glucose intolerance, renal tubulopathy, cirrhosis, spasticity with hyperreflexia and extensor plantar responses, and mild distal paresthesia. The weakness was progressive. A repeat muscle biopsy showed decreased activity of mitochondrial complexes I, III, and IV, whereas values in fibroblasts were normal. Cognitive and cardiac function were normal. She died in her sleep at age 55 years. The second patient (patient 65205) was a 7-year-old boy with early-onset growth retardation, hypotonia, poor feeding, delayed psychomotor development, and hypertrophic nonobstructive cardiomyopathy. He had mild dysmorphic signs, including triangular face with small mouth, blue sclerae, and maxillary fused primary incisor. Brain imaging showed mild brain atrophy and delayed myelination. Serum lactate was increased on several occasions. Muscle biopsy showed myopathic features without ragged-red fibers, decreased activity of mitochondrial complex IV, and borderline low complex I activity; these activities in fibroblasts were normal. Additional features included delayed nerve conduction and gastrointestinal dysmotility. At age 7 years, he had hypotonia with hyporeflexia, was unable to sit, stand, or walk unsupported, and had limited speech. Inheritance The transmission pattern of COXPD26 in the families reported by Powell et al. (2015) was consistent with autosomal recessive inheritance. Molecular Genetics In 2 unrelated patients with variable manifestations of COXPD26, Powell et al. (2015) identified compound heterozygous mutations in the TRMT5 gene (611023.0001-611023.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated within the families according to DNA available from family members. A reverse-transcription primer extension (RT-PEx) assay performed on patient-derived fibroblasts and skeletal muscle tissue indicated that mt-tRNA(Leu-CUN) had decreased G37 modification compared to controls, with a more significant effect on the patient with the more severe phenotype. In addition, neither missense mutation was able to rescue defective mitochondrial respiratory activity in a yeast knockout model, consistent with a loss of function. The findings indicated that TRMT5 is responsible for G37 modification in human mitochondrial tRNA molecules. INHERITANCE \- Autosomal recessive GROWTH Other \- Failure to thrive (patient B) \- Poor overall growth (patient B) HEAD & NECK Face \- Triangular face (patient B) Eyes \- Blue sclerae (patient B) Mouth \- Small mouth (patient B) Teeth \- Fused primary incisor (patient B) CARDIOVASCULAR Heart \- Hypertrophic non-obstructive cardiomyopathy (patient B) RESPIRATORY \- Exertional dyspnea (patient A) ABDOMEN Liver \- Cirrhosis (patient A) Pancreas \- Pancreatic exocrine deficiency (patient A) \- Pancreatic endocrine deficiency (patient A) Gastrointestinal \- Malabsorption (patient A) GENITOURINARY Kidneys \- Renal tubulopathy (patient A) MUSCLE, SOFT TISSUES \- Exercise intolerance (patient A) \- Muscle weakness, lower limbs (patient A) \- Hypotonia (patient B) NEUROLOGIC Central Nervous System \- Delayed psychomotor development (patient B) \- Poor speech (patient B) \- Inability to sit, stand, or walk unsupported (patient B) \- Spasticity (patient A) \- Hyperreflexia (patient A) \- Extensor plantar responses (patient A) \- Brain atrophy, mild (patient B) \- Delayed myelination (patient B) Peripheral Nervous System \- Hyporeflexia (patient B) \- Delayed nerve conduction (patient B) LABORATORY ABNORMALITIES \- Increased serum lactate \- Variable decreased in mitochondrial respiratory complexes I, III, and IV in skeletal muscle MISCELLANEOUS \- Onset in infancy or early childhood \- Highly variable phenotype \- Two unrelated patients have been reported (last curated August 2015) MOLECULAR BASIS \- Caused by mutation in the tRNA methyltransferase 5 gene (TRMT5, 611023.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 26

c4225290

omim

https://www.omim.org/entry/616539

{"omim": ["616539"], "orphanet": ["477684"], "synonyms": ["COXPD26"]}

A number sign (#) is used with this entry because of evidence that myofibrillar myopathy-8 (MFM8) is caused by homozygous or compound heterozygous mutation in the PYROXD1 gene (617220) on chromosome 12p12. Description Myofibrillar myopathy-8 is an autosomal recessive myopathy characterized by childhood onset of slowly progressive proximal muscle weakness and atrophy resulting in increased falls, gait problems, and difficulty running or climbing stairs. Upper and lower limbs are affected, and some individuals develop distal muscle weakness and atrophy. Ambulation is generally preserved, and patients do not have significant respiratory compromise. Muscle biopsy shows a mix of myopathic features, including myofibrillar inclusions and sarcomeric disorganization (summary by O'Grady et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419). Clinical Features O'Grady et al. (2016) reported 9 patients from 5 unrelated families with childhood onset of slowly progressive muscle weakness and atrophy mainly affecting the proximal muscles. Early gross motor skills were largely normal, and all started walking between 9 and 20 months of age. However, some patients had poor head control associated with generalized hypotonia and feeding difficulties in infancy. All patients were still ambulant at 7 to 31 years of age, but had difficulty running and climbing stairs. Some patients had distal muscle involvement, including 2 brothers in their twenties who had marked wasting of the intrinsic hand muscles. Additional variable features included neck weakness, facial weakness, ptosis, high-arched palate, nasal speech, dysphagia, and hypo- or areflexia. Some patients had recurrent respiratory infections and mild restrictive pulmonary function. Only 1 older patient had evidence of cardiac involvement in his late twenties. Cognition was normal, except for 1 patient who had learning difficulties. Laboratory studies showed increased serum creatine kinase. Muscle biopsy, performed in 5 patients, showed variation in fiber size, internal nuclei, increased interstitial connective tissue, central core-like zones devoid of mitochondria, large myofibrillar inclusions, and rare nemaline rods. Electron microscopy showed sarcomeric disorganization and Z-band streaming. Nerve conduction studies of 2 older sibs showed decreased compound muscle action potentials (CMAPs) and decreased sural sensory potentials, suggestive of a mild length-dependent axonal neuropathy. Inheritance The transmission pattern of MFM8 in the families reported by O'Grady et al. (2016) was consistent with autosomal recessive inheritance. Molecular Genetics In 9 patients from 5 unrelated families with MFM8, O'Grady et al. (2016) identified homozygous or compound heterozygous mutations in the PYROXD1 gene (617220.0001-617220.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 2 splice site mutations, 1 frameshift mutation, and 2 missense mutations, including 1 that showed a founder effect in the Turkish families (N155S; 617220.0003). Complementation experiments in yeast showed that the missense mutations caused impaired reductase activity. The findings suggested that altered redox regulation may be a primary cause of congenital muscle disease. Animal Model O'Grady et al. (2016) reported that knockout of Pyroxd1 in mouse was embryonic lethal. Morpholino-mediated knockdown of the zebrafish ortholog, ryroxd1, reduced swimming performance, with lower maximal acceleration in touch-evoked response, compared with controls. Knockdown of ryroxd1 disrupted muscle structure, with mitochondrial infiltration of disintegrated myofibrils, loss of Z-disk and sarcomeric structures, and formation of electron dense bodies. Overexpression of 2 human missense mutations (N155S and Q372H) in zebrafish muscle resulted in occasional thickening of the Z-disk, suggesting the formation of abnormal aggregates. INHERITANCE \- Autosomal recessive GROWTH Height \- Tall stature HEAD & NECK Face \- Facial muscle weakness \- Elongated face \- Micrognathia Eyes \- Ptosis (in some patients) Mouth \- High-arched palate Teeth \- Crowded teeth (in some patients) Neck \- Neck muscle weakness CARDIOVASCULAR Heart \- Decreased ejection fraction (in 1 patient, late-onset) RESPIRATORY \- Respiratory infections \- Decreased vital capacity, mild (in some patients) CHEST Ribs Sternum Clavicles & Scapulae \- Scapular winging ABDOMEN Gastrointestinal \- Dysphagia SKELETAL \- Distal joint laxity (in some patients) Spine \- Scoliosis, mild (in some patients) \- Spinal rigidity (in some patients) Feet \- Pes planus \- Pes cavus MUSCLE, SOFT TISSUES \- Muscle weakness, proximal \- Lower limbs more affected than upper limbs \- Difficulty running \- Difficulty climbing stairs \- Gower sign \- Muscle atrophy, diffuse \- Hypotonia, neonatal (in some patients) \- Easy fatigability \- Distal muscle weakness and atrophy (in some patients) \- Fiber type variation seen on muscle biopsy \- Internalized nuclei \- Myofibrillar inclusions \- Nemaline rods \- Central core lesions devoid of mitochondrial oxidative activity \- Disorganized sarcomeres \- Z-line streaming NEUROLOGIC Central Nervous System \- Normal or mildly delayed early gross motor development \- Gait difficulties due to muscle weakness \- Frequent falls Peripheral Nervous System \- Hyporeflexia \- Areflexia \- Axonal sensory peripheral neuropathy, mild (in 1 family) VOICE \- Nasal speech LABORATORY ABNORMALITIES \- Increased serum creatine kinase MISCELLANEOUS \- Onset in childhood (range infancy to 8 years) \- Slowly progressive MOLECULAR BASIS \- Caused by mutation in the pyridine nucleotide-disulfide oxidoreductase domain-containing protein 1 gene (PYROXD1, 617220.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

MYOPATHY, MYOFIBRILLAR, 8

c4310645

omim

https://www.omim.org/entry/617258

{"omim": ["617258"]}

Hypocholesterolemia Other namesLow cholesterol Formula structure of cholesterol CausesStatins, hyperthyroidism, adrenal insufficiency, malabsorption, malnutrition, etc. Hypocholesterolemia is the presence of abnormally low (hypo-) levels of cholesterol in the blood (-emia). A defect in the body's production of cholesterol can lead to adverse consequences as well. Cholesterol is an essential component of mammalian cell membranes and is required to establish proper membrane permeability and fluidity. It is not clear if a lower than average cholesterol level is directly harmful; however, it is often encountered in particular illnesses. ## Contents * 1 Presentation * 1.1 Role in disease * 1.1.1 Specific disease entities * 1.1.2 Elderly * 1.1.3 Critical illness * 2 Causes * 3 Diagnosis * 3.1 Classification * 4 References * 5 External links ## Presentation[edit] ### Role in disease[edit] Cholesterolemia and mortality for men and women <50 years and >60 years With the increased use of medication to suppress cholesterol, some have expressed concern that lowering cholesterol levels excessively will itself cause disease. #### Specific disease entities[edit] Demographic studies suggest that cholesterol levels form a U-shape curve when plotted against mortality; this suggests that low cholesterol is associated with increased mortality, mainly due to depression, cancer, hemorrhagic stroke, aortic dissection and respiratory diseases.[1] It is possible that whatever causes the low cholesterol level also causes mortality, and that the low cholesterol is simply a marker of poor health.[2] Links with depression have been supported by studies.[3] In contrast, no evidence was found for a link with hemorrhagic stroke (although higher cholesterol levels conferred a relative protection), and neither did statin drugs worsen the risk.[4] The Heart Protection Study found no increase in either respiratory disease or neuropsychiatric illness in a large trial population taking a statin drug.[5] #### Elderly[edit] In the elderly, low cholesterol may confer a health risk that may not be offset by the beneficial effects of cholesterol lowering.[6] Similarly, for elderly patients admitted to hospital, low cholesterol may predict short-term mortality.[7] The prevalence of hypocholesterolemia in the elderly ranges between 2% to 36%, depending on specific cutoff levels and age range investigated.[8] Alerting physicians to hypocholesterolemia may benefit some of their patients who take cholesterol-lowering drugs and decrease the rate of their emergency room visits.[9] #### Critical illness[edit] In the setting of critical illness, low cholesterol levels are predictive of clinical deterioration, and are correlated with altered cytokine levels.[10] ## Causes[edit] Possible causes of low cholesterol are:[citation needed] * statins * hyperthyroidism, or an overactive thyroid gland * adrenal insufficiency * liver disease * malabsorption (inadequate absorption of nutrients from the intestines), such as in celiac disease * malnutrition * abetalipoproteinemia \- a rare genetic disease that causes cholesterol readings below 50 mg/dl. It is found mostly in Jewish populations.[11] * hypobetalipoproteinemia \- a genetic disease that causes cholesterol readings below 50 mg/dl[11] * manganese deficiency * Smith–Lemli–Opitz syndrome * Marfan syndrome * leukemias and other hematological diseases[12] ## Diagnosis[edit] ### Classification[edit] According to the American Heart Association in 1994, only total cholesterol levels below 160 mg/dL or 4.1 mmol/l are to be classified as "hypocholesterolemia".[2] However, this is not agreed on universally and some put the level lower. ## References[edit] 1. ^ Jacobs D, Blackburn H, Higgins M, et al. (1992). "Report of the Conference on Low Blood Cholesterol: Mortality Associations". Circulation. 86 (3): 1046–60. doi:10.1161/01.cir.86.3.1046. PMID 1355411. 2. ^ a b Criqui MH. (1994). Very Low Cholesterol and Cholesterol Lowering. Leaflet 71-0059. American Heart Association. 3. ^ Suarez EC (1 May 1999). "Relations of trait depression and anxiety to low lipid and lipoprotein concentrations in healthy young adult women". Psychosom Med. 61 (3): 273–9. doi:10.1097/00006842-199905000-00004. PMID 10367605. 4. ^ Woo D, Kissela BM, Khoury JC, et al. (2004). "Hypercholesterolemia, HMG-CoA reductase inhibitors, and risk of intracerebral hemorrhage: a case-control study". Stroke. 35 (6): 1360–4. doi:10.1161/01.STR.0000127786.16612.A4. PMID 15087556. 5. ^ Heart Protection Study Collaborative Group (2002). "MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial". Lancet. 360 (9326): 7–22. doi:10.1016/S0140-6736(02)09327-3. PMID 12114036. 6. ^ Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD (2001). "Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study". Lancet. 358 (9279): 351–5. doi:10.1016/S0140-6736(01)05553-2. PMID 11502313. 7. ^ Onder G, Landi F, Volpato S, et al. (2003). "Serum cholesterol levels and in-hospital mortality in the elderly". Am. J. Med. 115 (4): 265–71. doi:10.1016/S0002-9343(03)00354-1. PMID 12967690. 8. ^ Tsabar, Nir; Press, Yan; Rotman, Johanna; Klein, Bracha; Grossman, Yonatan; Vainshtein-Tal, Maya; Eilat-Tsanani, Sophia (2018-01-05). "The low indexes of metabolism intervention trial (LIMIT): design and baseline data of a randomized controlled clinical trial to evaluate how alerting primary care teams to low metabolic values, could affect the health of patients aged 75 or older". BMC Health Services Research. 18 (1): 4. doi:10.1186/s12913-017-2812-0. ISSN 1472-6963. PMC 5755463. PMID 29301522. 9. ^ Tsabar, Nir; Press, Yan; Rotman, Johanna; Klein, Bracha; Grossman, Yonatan; Vainshtein-Tal, Maya; Eilat-Tsanani, Sophia (2019-10-12). "A Randomized Trial of Alerting to Hypocholesterolemia Results of the Low Indexes of Metabolism Intervention Trial-C (LIMIT-C)". Journal of the American Medical Directors Association. 0 (0). doi:10.1016/j.jamda.2019.08.018. ISSN 1525-8610. PMID 31610995. 10. ^ Gordon BR, Parker TS, Levine DM, et al. (2001). "Relationship of hypolipidemia to cytokine concentrations and outcomes in critically ill surgical patients". Crit. Care Med. 29 (8): 1563–8. doi:10.1097/00003246-200108000-00011. PMID 11505128. 11. ^ a b Moutzouri, E; Elisaf, M; Liberopoulos, EN (2011). "Hypocholesterolemia". Current Vascular Pharmacology. 9 (2): 200–12. doi:10.2174/157016111794519354. PMID 20626336. 12. ^ Marini A, Carulli G, Azzarà A, Grassi B, Ambrogi F (1989). "Serum cholesterol and triglycerides in hematological malignancies". Acta Haematol. 81 (2): 75–9. doi:10.1159/000205530. PMID 2496554. ## External links[edit] Classification D * ICD-10: E78.6 * ICD-9-CM: 272.5 * v * t * e Inborn error of lipid metabolism: dyslipidemia Hyperlipidemia * Hypercholesterolemia/Hypertriglyceridemia * Lipoprotein lipase deficiency/Type Ia * Familial apoprotein CII deficiency/Type Ib * Familial hypercholesterolemia/Type IIa * Combined hyperlipidemia/Type IIb * Familial dysbetalipoproteinemia/Type III * Familial hypertriglyceridemia/Type IV * Xanthoma/Xanthomatosis Hypolipoproteinemia Hypoalphalipoproteinemia/HDL * Lecithin cholesterol acyltransferase deficiency * Tangier disease Hypobetalipoproteinemia/LDL * Abetalipoproteinemia * Apolipoprotein B deficiency * Chylomicron retention disease Lipodystrophy * Barraquer–Simons syndrome Other * Lipomatosis * Adiposis dolorosa * Lipoid proteinosis * APOA1 familial renal amyloidosis *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Hypocholesterolemia

c0151718

wikipedia

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

{"umls": ["C0151718"], "wikidata": ["Q10295810"]}

blood film in a patient with hereditary elliptocytosis: approximately 60% to 70% of the RBCs are elliptocytes. Elliptocytes, also known as ovalocytes, are abnormally shaped red blood cells that appear oval or elongated, from slightly egg-shaped to rod or pencil forms. They have normal central pallor with the hemoglobin appearing concentrated at the ends of the elongated cells when viewed through a light microscope. The ends of the cells are blunt and not sharp like sickle cells.[1] ## Causes[edit] Rare elliptocytes (less than 1%) on a peripheral blood smear are a normal finding. These abnormal red blood cells are seen in higher numbers in the blood films of patients with blood disorders such as:[2] * Hereditary elliptocytosis and Southeast Asian ovalocytosis * Thalassemia * Iron deficiency * Myelodysplastic syndrome and myelofibrosis * Megaloblastic anemia ## References[edit] 1. ^ "Ovalocytes/Elliptocytes - LabCE.com, Laboratory Continuing Education". www.labce.com. Retrieved 21 May 2018. 2. ^ Hirschmann, editors, Douglas C. Tkachuk, Jan V. (2007). Wintrobe's atlas of clinical hematology. Philadelphia, PA [etc.]: Lippincott Williams & Wilkins. ISBN 978-0781770231.CS1 maint: extra text: authors list (link) This article about a disease of the blood or immune system is a stub. You can help Wikipedia by expanding it. * v * t * e * v * t * e Blood film findings Red blood cells Size * Anisocytosis * Macrocytosis * Microcytosis Shape * Poikilocytosis * Membrane abnormalities * Acanthocyte * Codocyte * Elliptocyte * Hereditary elliptocytosis * Spherocyte * Hereditary spherocytosis * Dacrocyte * Echinocyte * Schistocyte * Degmacyte * Sickle cell/drepanocyte * Sickle cell disease * Stomatocyte * Hereditary stomatocytosis Colour * Anisochromia * Hypochromic anemia * Polychromasia Inclusion bodies * Developmental * Howell–Jolly body * Basophilic stippling * Pappenheimer bodies * Cabot rings * Hemoglobin precipitation * Heinz body Other * Red cell agglutination * Rouleaux White blood cells Lymphocytes * Reactive lymphocyte * Smudge cell * Russell bodies Granulocytes * Hypersegmented neutrophil * Arneth count * Pelger–Huët anomaly * Döhle bodies * Toxic granulation * Toxic vacuolation * Critical green inclusion * Alder–Reilly anomaly * Jordans' anomaly * Birbeck granules * Left shift Other * Auer rod *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Elliptocyte

None

wikipedia

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

{"umls": ["C0221280"], "wikidata": ["Q3358860"]}

Lesser-known form of OCD involving fewer compulsions Primarily cognitive obsessive-compulsive disorder (also commonly called "primarily obsessional OCD", purely obsessional OCD, Pure-O, OCD without overt compulsions or with covert compulsions)[1] is a lesser-known form or manifestation of OCD. It is not a diagnosis in DSM-5.[2] For people with primarily obsessional OCD, there are fewer observable compulsions, compared to those commonly seen with the typical form of OCD (checking, counting, hand-washing, etc.). While ritualizing and neutralizing behaviors do take place, they are mostly cognitive in nature, involving mental avoidance and excessive rumination.[3] Primarily obsessional OCD takes the form of intrusive thoughts of a distressing or violent nature (e.g., impulsion phobia).[4] According to DSM-5, "The obsessive-compulsive and related disorders differ from developmentally normative preoccupations and rituals by being excessive or persisting beyond developmentally appropriate periods. The distinction between the presence of subclinical symptoms and a clinical disorder requires assessment of a number of factors, including the individual’s level of distress and impairment in functioning."[2] ## Contents * 1 Presentation * 2 Diagnosis * 2.1 Alternatives * 3 Treatment * 4 Notes and references * 5 Bibliography * 6 External links ## Presentation[edit] Primarily obsessional OCD has been called "one of the most distressing and challenging forms of OCD."[5] People with this form of OCD have "distressing and unwanted thoughts pop into [their] head frequently," and the thoughts "typically center on a fear that you may do something totally uncharacteristic of yourself, something... potentially fatal... to yourself or others."[5] The thoughts "quite likely, are of an aggressive or sexual nature."[5] The nature and type of primarily obsessional OCD vary greatly, but the central theme for all sufferers is the emergence of a disturbing, intrusive thought or question, an unwanted/inappropriate mental image, or a frightening impulse that causes the person extreme anxiety because it is antithetical to closely held religious beliefs, morals, or societal norms.[6] The fears associated with primarily obsessional OCD tend to be far more personal and terrifying for the sufferer than what the fears of someone with traditional OCD may be. Pure-O fears usually focus on self-devastating scenarios that the sufferer feels would ruin their life or the lives of those around them. An example of this difference could be that someone with traditional OCD is overly concerned or worried about security or cleanliness. While this is still distressing, it is not to the same level as someone with Pure-O, who may be terrified that they have undergone a radical change in their sexuality (i.e.: might be or might have changed into a pedophile), that they might be a murderer, or that they might cause any form of harm to a loved one or an innocent person, or to themselves, or that they will go insane. They will understand that these fears are unlikely or even impossible but the anxiety felt will make the obsession seem real and meaningful. While those without primarily obsessional OCD might instinctively respond to bizarre, intrusive thoughts or impulses as insignificant and part of a normal variance in the human mind, someone with Pure-O will respond with profound alarm followed by an intense attempt to neutralize the thought or avoid having the thought again. The person begins to ask themselves constantly, "Am I really capable of something like that?" or "Could that really happen?" or "Is that really me?" (even though they usually realize that their fear is irrational, which causes them further distress)[7] and puts tremendous effort into escaping or resolving the unwanted thought. They then end up in a vicious cycle of mentally searching for reassurance and trying to get a definitive answer.[3][8] Common intrusive thoughts/obsessions include themes of: * Responsibility: with an excessive concern over someone's well-being marked specifically by guilt over believing they have harmed or might harm someone, either on purpose or inadvertently.[9] * Sexuality: including recurrent doubt over one's sexual orientation (also called HOCD or "homosexual OCD"). People with this theme display a very different set of symptoms than those actually experiencing an actual crisis in sexuality. One major difference is that people who have HOCD report being attracted sexually towards the opposite sex prior to the onset of HOCD, while homosexual people whether in the closet or repressed have always had such same-sex attractions.[10] The question "Am I gay?"[11] takes on a pathological form. Many people with this type of obsession are in healthy and fulfilling romantic relationships, either with members of the opposite sex, or the same sex (in which case their fear would be "Am I straight?").[6][12][13][14][15][16][17] * Pedophilia: Sexual themes in OCD can also involve the fear that one is a pedophile. This is typically accompanied by significant distress and fear that one might actually act on pedophilic urges.[18] * Violence: which involves a constant fear of harming oneself or loved ones.[12][19] * Religiosity: manifesting as intrusive thoughts or impulses revolving around blasphemous and sacrilegious themes.[19][20] * Health: including consistent fears of having or contracting a disease (different from hypochondriasis) through seemingly impossible means (for example, touching an object that has just been touched by someone with a disease) or mistrust of a diagnostic test.[19][20] * Relationship obsessions (ROCD): in which someone in a romantic relationship endlessly tries to ascertain the justification for being or remaining in that relationship. It includes obsessive thoughts to the tune of "How do I know this is real love?", "How do I know he/she is the one?", "Am I attracted enough to this person?", "Am I in love with this person, or is it just lust?", "Does he/she really love me?", and/or obsessive preoccupation with the perceived flaws of the intimate partner.[21][22] The agony of attempting to arrive at certainty leads to an intense and endless cycle of anxiety because it is impossible to arrive at a definite answer.[23] The partner will have seriously troubling thoughts about what their significant other could be doing, especially in the possible and usual form of cheating. Although these thoughts are not triggered by the sufferer, and are indeed spontaneous, the partner will put them self down for thinking in such a way that makes the other look bad.[1] There is uncontrollable constant guilt, fear, and distressing thoughts of what will happen.[21] In most cases, the significant other will become irritated and part ways. This leads to suicidal rumination and regret by the sufferer, even when it wasn't their fault, because the emotions, thoughts, and impulses were not in their control. * Existential: involving persistent and obsessive questioning of the nature of self, reality, the universe, and/or other philosophical topics.[24] ## Diagnosis[edit] There is no such diagnosis in DSM-5. The only diagnosis existing in DSM-5 is Obsessive–compulsive disorder.[2] According to DSM-5 compulsions can be mental, but they are always repetative actions like "praying, counting, repeating words silently".[25] DSM-5 does not have any information that searching an answer for some question can be associated with OCD.[26] ### Alternatives[edit] Those suffering from primarily obsessional OCD might appear normal and high-functioning, yet spend a great deal of time ruminating, trying to solve or answer any of the questions that cause them distress. Very often, Pure O sufferers are dealing with considerable guilt and anxiety. Ruminations may include trying to think about something 'in the right way' in an attempt to relieve this distress.[3][6] For example, an intrusive thought "I could just kill Bill with this steak knife" is followed by a catastrophic misinterpretation of the thought, i.e. "How could I have such a thought? Deep down, I must be a psychopath."[27] This might lead a person to continually surf the Internet, reading numerous articles on defining psychopathy. This reassurance-seeking ritual will provide no further clarification and could exacerbate the intensity of the search for the answer. There are numerous corresponding cognitive biases present, including thought-action fusion, over-importance of thoughts, and need for control over thoughts.[27] ## Treatment[edit] The most effective treatment for primarily obsessional OCD appears to be cognitive-behavioral therapy.[28] (more specifically exposure and response prevention (ERP)) as well as cognitive therapy (CT)[28][29] which may or may not be combined with the use of medication, such as SSRIs.[3][30][31] People suffering from OCD without overt compulsions are considered by some researchers more refractory towards ERP compared to other OCD sufferers and therefore ERP can prove less successful than CT.[32][33] Exposure and Response Prevention for Pure-O is theoretically based on the principles of classical conditioning and extinction. The spike (intrusive thought) often presents itself as a paramount question or disastrous scenario (e.g., WHAT IF I actually want to harm someone? WHAT IF I committed a sin?). A therapeutic response is one that answers the spike (intrusive thought) in a way that leaves ambiguity. E.g., someone with primarily obsessive OCD might think, "If I don't remember what I had for breakfast yesterday my mother will die of cancer!" Using the antidote procedure, a therapeutic response (one that will help interrupt the cycle of obsessing) would be one in which the subject accepts this possibility and is willing to take the risk of their mother dying of cancer or the question recurring for eternity, rather than attempting to answer the question and reassure oneself that the feared occurrence will not happen. In another example, the spike/intrusive thought would be, "Maybe I said something offensive to my boss yesterday." A recommended response would be, "Maybe I did. I'll live with the possibility and take the risk he'll fire me tomorrow." Although resisting the need to reassure oneself and perform compulsions will initially cause anxiety to increase, refusing to practice compulsions over an extended period of time will eventually cause anxiety around the sufferer's intrusive thoughts to decrease, making them less prevalent (e.g. they will begin to occur less often), and less distressing when they do occur. Using this procedure, it is imperative that the distinction be made between the therapeutic response and rumination. The therapeutic response does not seek to answer the question but to accept the uncertainty of the unsolved dilemma.[34] Acceptance and commitment therapy (ACT) is a newer approach that also is used to treat purely obsessional OCD, as well as other mental disorders such as anxiety and clinical depression. Mindfulness-based stress reduction (MBSR) may also be helpful for breaking out of rumination and interrupting the cycle of obsessing. ## Notes and references[edit] 1. ^ a b Hyman, Bruce and Troy DeFrene. Coping with OCD. 2008. New Harbinger Publications. Page 64. 2. ^ a b c Diagnostic and statistical manual of mental disorders (DSM-5). Arlington: American Psychiatric Publishing. 2013. p. 235. ISBN 978-0-89042-555-8. 3. ^ a b c d Obsessive compulsive disorder By Frederick M. Toates, Olga Coschug-Toates, 2nd Edition 2000, Pages 111-128 4. ^ Julien, Dominic; O'Connor, Kieron P.; Aardema, Frederick (2009-07-01). "Intrusions related to obsessive-compulsive disorder: a question of content or context?". Journal of Clinical Psychology. 65 (7): 709–722. doi:10.1002/jclp.20578. ISSN 1097-4679. PMID 19388059. 5. ^ a b c Hyman, Bruce and Troy DeFrene. Coping with OCD. 2008. New Harbinger Publications. 6. ^ a b c The OCD workbook By Bruce M. Hyman, Cherry Pedrick, Pages 16-23 7. ^ Obsessive-compulsive disorder By Frederick M. Toates, Olga Coschug-Toates, 2nd Edition 2000, Pages 94-96 8. ^ The American Psychiatric Publishing textbook of psychiatry, By Robert E. Hales, Stuart C. Yudofsky, Glen O. Gabbard, American Psychiatric Publishing, includes Purely Obsessional OCD in its definition of O.C.D. 9. ^ http://www.ocdonline.com/articlephillipson2.php 10. ^ "Archived copy". Archived from the original on 2016-01-31. Retrieved 2011-11-11.CS1 maint: archived copy as title (link) 11. ^ Winston, Sally M.; Seif, Martin N. (2017-03-01). Overcoming Unwanted Intrusive Thoughts: A CBT-Based Guide to Getting Over Frightening, Obsessive, or Disturbing Thoughts. New Harbinger Publications. ISBN 978-1-62625-436-7. 12. ^ a b Obsessive-compulsive related disorders By Eric Hollander, pages 140-146 13. ^ Homosexuality Anxiety: A Misunderstood Form of OCD http://www.brainphysics.com/research/HOCD_Williams2008.pdf Archived 2015-09-23 at the Wayback Machine 14. ^ Bhatia, Manjeet S.; Kaur, Jaswinder (January 2015). "Homosexual Obsessive Compulsive Disorder (HOCD): A Rare Case Report". Journal of Clinical and Diagnostic Research. 9 (1): VD01–VD02. doi:10.7860/JCDR/2015/10773.5377. ISSN 2249-782X. PMC 4347158. PMID 25738067. 15. ^ Sebeki, Lennard V. (2008). Leading-Edge Health Education Issues. Nova Publishers. ISBN 978-1-60021-874-3. 16. ^ Williams, Monnica T.; Farris, Samantha G. (2011-05-15). "Sexual orientation obsessions in obsessive–compulsive disorder: Prevalence and correlates". Psychiatry Research. 187 (1): 156–159. doi:10.1016/j.psychres.2010.10.019. ISSN 0165-1781. PMC 3070770. PMID 21094531. 17. ^ Williams, Monnica T.; Crozier, Marjorie; Powers, Mark (2011-02-01). "Treatment of Sexual-Orientation Obsessions in Obsessive-Compulsive Disorder Using Exposure and Ritual Prevention". Clinical Case Studies. 10 (1): 53–66. doi:10.1177/1534650110393732. ISSN 1534-6501. PMC 3230880. PMID 22162667. 18. ^ Bruce SL, Ching TH, Williams MT (February 2018). "Pedophilia-Themed Obsessive-Compulsive Disorder: Assessment, Differential Diagnosis, and Treatment with Exposure and Response Prevention". Arch Sex Behav. 47 (2): 389–402. doi:10.1007/s10508-017-1031-4. PMID 28822003. S2CID 207092958. 19. ^ a b c Akhtar, S., Wig, NA, Verma, VK, Pershad, D., & Verma, SK A phenomenological analysis of symptoms in obsessive-compulsive neurosis. 1975 20. ^ a b Use of factor analysis to detect potential phenotypes in obsessive-compulsive disorder, Psychiatry Research, Volume 128, Issue 3, Pages 273-280 D.Denys, F.de Geus, H.van Megen, H.Westenberg 21. ^ a b Doron, Guy; Derby, D.; Szepsenwol, O.; Talmor, D. (2012). "Flaws and All: Exploring Partner-Focused Obsessive-Compulsive Symptoms". Journal of Obsessive-Compulsive and Related Disorders. 1 (4): 234–243. doi:10.1016/j.jocrd.2012.05.004. 22. ^ Doron, Guy; Derby, D.; Szepsenwol, O.; Talmor, D. (2012). "Tainted Love: exploring relationship-centered obsessive compulsive symptoms in two non-clinical cohorts". Journal of Obsessive-Compulsive and Related Disorders. 1 (1): 16–24. doi:10.1016/j.jocrd.2011.11.002. 23. ^ How Relationship Substantiation can Jeopardize your Romantic Life http://www.obsessivecompulsions.com/rocd 24. ^ "Existential OCD". Intrusive Thoughts. Retrieved 2019-03-04. 25. ^ Diagnostic and statistical manual of mental disorders (DSM-5). Arlington: American Psychiatric Publishing. 2013. p. 237. ISBN 978-0-89042-555-8. 26. ^ Diagnostic and statistical manual of mental disorders (DSM-5). Arlington: American Psychiatric Publishing. 2013. p. 235-264. ISBN 978-0-89042-555-8. 27. ^ a b The Treatment of Obsessions by Stanley Rachman. Oxford University Press, New York, N.Y., 2003 Reviewed by Dean McKay, Ph.D., A.B.P.P. Fordham University, Bronx, New York 28. ^ a b Concepts and Controversies in Obsessive-Compulsive Disorder Source: Springer Science, Business Media Author(s): Abramowitz, Jonathan S.; Houts, Arthur C. 29. ^ G.S. Steketee, R.O. Frost, J. Rhéaume and S. Wilhelm, Cognitive theory and treatment of obsessive-compulsive disorder. In: MA Jenike, L Baer and WE Minichiello (Eds.), Obsessive-Compulsive Disorder: Theory and Management. (3rd ed., pp 368-399) Chicago: Mosby. 30. ^ http://www.ocdonline.com/definecbt.php 31. ^ Understanding and Treating Obsessive-Compulsive Disorder: A Cognitive Behavioral Approach, Lawrence Erlbaum Associates, Inc.; 1 edition (September 2, 2005) 32. ^ Purdon, C.A. & Clark, D.A. (2005). Overcoming Obsessive Thoughts: How to gain control of your OCD. Oakland, CA: New Harbinger. 33. ^ Obsessive Compulsive Disorder Research, By B. E. Ling, 2005. Nova Science Pub Inc. Page 128 34. ^ http://www.ocdonline.com/articlephillipson1.php/ ## Bibliography[edit] * The Imp of the Mind: Exploring the Silent Epidemic of Obsessive Bad Thoughts by Lee Baer, Ph.D. * The Treatment of Obsessions (Medicine) by Stanley Rachman. Oxford University Press, 2003. * Brain lock: Free yourself from obsessive-compulsive behavior: A four-step self-treatment method to change your brain chemistry by Jeffrey Schwartz and Beverly Beyette. New York: Regan Books, 1997. ISBN 0-06-098711-1. * The OCD Workbook by Bruce Hyman and Cherry Pedrick. * Overcoming obsessive thoughts. How to gain control of your OCD by David A. Clark, Ph.D. and Christine Purdon, Ph.D. * Mad Girl by Bryony Gordon. London: Headline, 2016. ISBN 1472232089. ## External links[edit] * Am I Gay? Obsessive-Compulsive Disorder Takes Many Forms * The International OCD Foundation * ROCD Research Unit * v * t * e Obsessive–compulsive disorder History * Yale–Brown Obsessive Compulsive Scale Biology Neuroanatomy * Basal ganglia (striatum) * Orbitofrontal cortex * Cingulate cortex * Brain-derived neurotrophic factor Receptors * 5-HT1Dβ * 5-HT2A * 5-HT2C * μ Opioid * H2 * NK1 * M4 * NMDA Symptoms * Obsessions (associative * diagnostic * injurious * scrupulous * pathogenic * sexual) * Compulsions (impulses, rituals * tics) * Thought suppression (avoidance) * Hoarding (animals, books * possessions) Treatment Serotonergics Selective serotonin reuptake inhibitors * Escitalopram * Fluoxetine * Fluvoxamine * Paroxetine * Sertraline * Citalopram * Nefazodone Serotonin–norepinephrine reuptake inhibitors * Venlafaxine * Desvenlafaxine * Duloxetine Serotonin–norepinephrine–dopamine reuptake inhibitors * Nefazodone Monoamine oxidase inhibitors * Phenelzine * Tranylcypromine Tricyclic antidepressants * Clomipramine Serotonergic psychedelics * Lysergic acid diethylamide * Psilocin Atypical antipsychotics * Aripiprazole * Quetiapine Mu opioidergics * Hydrocodone * Morphine * Tramadol Anticholinergics * Diphenhydramine NMDA glutamatergics * Riluzole NK-1 tachykininergics * Aprepitant Other * Nicotine * Memantine * Tautomycin Behavioral * Cognitive behavioral therapy (Exposure and response prevention) * Inference-based therapy * Metacognitive therapy Organizations * International OCD Foundation Notable people * Edna B. Foa * Stanley Rachman * Adam S. Radomsky * Jeffrey M. Schwartz * Susan Swedo * Emily Colas * Vic Meyer Popular culture Literature/Comics Fictional * Matchstick Men * Plyushkin * Xenocide Nonfiction * Everything in Its Place * Just Checking Media * As Good as It Gets * The Aviator * Matchstick Men * Adrian Monk * "$pringfield" * Straight Up Related * Obsessive–compulsive personality disorder * Obsessional jealousy * PANDAS * Primarily Obsessional OCD * Relationship obsessive–compulsive disorder * Social anxiety disorder * Tourette syndrome *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Primarily obsessional obsessive compulsive disorder

None

wikipedia

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

{"wikidata": ["Q7261173"]}

## Description Hypoglossia with situs inversus is a very rare congenital condition that likely represents a developmental field defect. Only sporadic cases have been reported (Faqeih et al., 2008). Hypoglossia is part of a group of malformation syndromes collectively termed 'oromandibular limb hypogenesis syndromes,' that usually include limb defects. Hall (1971) provided a classification system (see 103300). See also agnathia with holoprosencephaly (202650), which shows hypoglossia and situs inversus in addition to severe neurodevelopmental defects. Clinical Features ### Hypoglossia with Situs Inversus Watkin (1925) reported a girl with congenital absence of the anterior two-thirds of the tongue, small mandible, absence of several teeth, and hypertrophy of the sublingual glands. The latter appeared to have made speech possible. She also had complete situs inversus, with a right-sided heart and left-sided liver. Hussels (1971) reported a 10-year-old girl with microglossia, hypodontia, micrognathia, and situs inversus. At birth, she was noted to have a very small chin and tongue, which caused difficulty in feeding. She developed normally but had disturbed speech. She also had bilateral, primarily conductive, mild hearing loss. Fingers and toes were normal. She had 6 healthy older sibs, and there was no family history of similar disorders. Oulis and Thornton (1982) reported a 14-month-old black male infant with an underdeveloped mandible, severe hypoglossia, low-set ears, and a sloping forehead. He had complete situs inversus with dextrocardia and asplenia. He had feeding and respiratory problems resulting from his small tongue. Physical examination showed absence of the anterior two-thirds of the tongue, high narrow palate, hypodontia, and hypertrophy of the sublingual glands. During pregnancy, the mother had pneumonia treated with antibiotics and underwent chest radiographic studies. There was no relevant family history. Dunham and Austin (1990) reported a black newborn with micrognathia, lingual agenesis, and situs inversus. He presented at birth with upper airway obstruction, cyanosis, and bradycardia. The anterior mandible was short, narrow, and wedge-shaped. He had an arched palate with thickening of the maxillary alveolar ridge. Radiographic studies showed complete situs inversus. He had 1 normal sib, and there was no family history. The case fit into type I of the classification of oromandibular limb hypogenesis syndromes delineated by Hall (1971): hypoglossia without associated limb defects. Jang et al. (1997) reported congenital aglossia, an underdeveloped mandible, and situs inversus totalis in a 10-day-old girl who presented with feeding difficulties and weight loss. There were no limb anomalies and no family history of the disorder. Amor and Craig (2001) described a Vietnamese girl with microstomia, hypoglossia, micrognathia, and situs inversus. The main complications were airway compromise and feeding difficulties requiring tracheostomy and gastrostomy. There were no limb defects. Amor and Craig (2001) postulated that situs inversus with hypoglossia may represent a mild form of agnathia-holoprosencephaly, but also noted that it may be a variant of hypoglossia-hypodactyly without limb defects. In human embryogenesis, the tongue develops near the end of the fourth embryonic week, with the anterior two-thirds arising from the first branchial arch and the posterior third from the third branchial arch. Left-right asymmetry becomes apparent during the fourth embryonic week, although the process begins earlier. The disorder is likely a developmental field defect. Faqeih et al. (2008) reported a 2-year-old male with small oral cavity and tongue, hypoplastic mandible, and situs inversus totalis. He had prominent lower alveolar ridges and low-set ears. He had gross motor delay and underdeveloped speech. ### Isolated Hypoglossia Weingarten et al. (1993) reported a white male infant with marked micrognathia and complete absence of the anterior two-thirds of the tongue with a rudimentary posterior tongue. There were no other anomalies. The child learned how to eat and underwent speech therapy. The phenotype was consistent with type I of Hall's classification. Thorp et al. (2003) described severe microglossia and micrognathia in 5 unrelated South African patients. All had feeding and respiratory difficulties, often requiring a nasogastric feeding tube or tracheostomy at some point. One patient also had extraarticular temporomandibular joint ankylosis. None had limb anomalies or situs inversus. Thorp et al. (2003) classified all affected children as having type V of Hall's classification: the Pierre-Robin syndrome (261800), which is characterized by micrognathia and posterior displacement of the tongue resulting in feeding and respiratory problems. INHERITANCE \- Isolated cases HEAD & NECK Face \- Micrognathia Ears \- Low-set ears Mouth \- Hypoglossia (absence of the anterior two-thirds of the tongue) \- Microglossia \- High-arched palate \- Thickening of the lower alveolar ridge \- Microstomia Teeth \- Hypodontia CARDIOVASCULAR Heart \- Dextrocardia RESPIRATORY \- Respiratory difficulties upper airway obstruction ABDOMEN \- Situs inversus Spleen \- Asplenia \- Polysplenia Gastrointestinal \- Feeding difficulties due to facial obstruction and hypoglossia \- Malnutrition due to poor feeding SKELETAL Skull \- Small mandible NEUROLOGIC Central Nervous System \- Speech delay \- Speech difficulties due to hypoglossia \- Normal development MISCELLANEOUS \- Onset in utero ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

HYPOGLOSSIA WITH SITUS INVERSUS

c2748587

omim

https://www.omim.org/entry/612776

{"mesh": ["C567567"], "omim": ["612776"], "orphanet": ["141152"], "synonyms": []}

A number sign (#) is used with this entry because high molecular weight kininogen deficiency and total kininogen deficiency result from mutations in the kininogen-1 gene (KNG1; 612358). Description High molecular weight kininogen (HMWK) deficiency is an autosomal recessive coagulation defect. It is known by a variety of names, including Fitzgerald trait, Flaujeac trait, and Williams trait. Patients with HWMK deficiency do not have a hemorrhagic tendency, but they exhibit abnormal surface-mediated activation of fibrinolysis. Fitzgerald trait represents a 'true' deficiency of HMWK, whereas Flaujeac and Williams traits represent total kininogen deficiency, in which both HMWK and low molecular weight kininogen (LMWK) are deficient. HMWK and LMWK are both encoded by the KNG1 gene (612358) (Bick, 2002; Takagaki et al., 1985). Clinical Features Lacombe et al. (1975) described deficiency of a procoagulant they called Flaujeac factor, which, like Hageman (F12; 610619) and Fletcher (KLKB1; 229000) factors, participated in the 'contact phase' of coagulation. The deficiency was observed in an asymptomatic French woman born of a consanguineous marriage. Wuepper et al. (1975) showed that 4 children of the proposita had total kininogen antigen about half normal, consistent with autosomal recessive inheritance. Waldmann et al. (1975) and Saito et al. (1975) described a 'new' asymptomatic coagulation factor deficiency in a 71-year-old black man of surname Fitzgerald. The factor seemed to operate at an early stage in the intrinsic coagulation pathway and participated in other Hageman factor-mediated biologic reactions. No family data were presented. His plasma was apparently deficient in a hitherto unrecognized factor needed for expression of the functions of activated Hageman factor. Colman et al. (1975) studied an asymptomatic 64-year-old black woman of the surname Williams, who had severe abnormality of surface-activated intrinsic coagulation, and fibrinolytic and kinin-generating pathways. Fractionation of normal plasma showed that the factor that corrected the defect in Ms. Williams' plasma was kininogen. The proband was ascertained when a prolonged partial thromboplastin time was detected as part of a routine preoperative evaluation of her hemostatic mechanism. Members of her family were not available for study. However, Cheung et al. (1993) had 3 daughters and 1 granddaughter available for study when they reinvestigated the proband. Lefrere et al. (1986) discovered HMWK deficiency in the course of a preoperative hemostasis study of a 23-year-old Portuguese woman without personal or family history of hemorrhage or thrombosis. Family study showed heterozygous HMWK deficiency in the proposita, her father, and 3 of her sibs. Hayashi et al. (1990) studied 4 Japanese families with total kininogen deficiency and 1 with deficiency of HMWK only. Krijanovski et al. (2003) reported a 6-year-old male, born of first-cousin parents, with cerebral artery thrombosis and HMWK deficiency. The previously healthy child had headache and vomiting 10 days after moderate cerebral trauma, followed by loss of consciousness and subsequent visual impairment. CT scan and angiography showed extensive left vertebral-basilar artery thrombosis and a left vertebral artery dissection. The patient had a prolonged activated partial thromboplastin time (APTT) and received fresh frozen plasma before arteriography and then daily for 8 days, which resulted in normalization of the APTT and resolution of neurologic symptoms. There was full neurologic recovery with warfarin anticoagulant therapy for 6 months, and there had been no recurrence after 2 years of follow-up. The child had no high molecular weight kininogen procoagulant activity and antigen (less than 1%). Mapping HMWK deficiency results from mutation in the KNG1 gene, which maps to chromosome 3q26-qter (Fong et al., 1991; Cheung et al., 1992). Molecular Genetics Cheung et al. (1993) demonstrated that Ms. Williams, the patient with total kininogen deficiency reported as Williams trait by Colman et al. (1975), was homozygous for a nonsense mutation in the KNG1 gene (612358.0001). Krijanovski et al. (2003) found that a 6-year-old boy with cerebral artery thrombosis and HMWK deficiency was homozygous for a 1-bp deletion of 1492A in the KNG1 gene (612358.0002), corresponding to amino acid 480 of the mature protein. The mutation resulted in a frameshift and premature termination at amino acid 532 of the mature protein. Each parent and a sib were heterozygous for the mutation. Krijanovski et al. (2003) also identified the causative mutation in Fitzgerald trait as a 17-bp substitution in intron 9 of the KNG1 gene (612358.0003). They provided a diagram comparing the molecular defects of Williams trait (612358.0001), their reported deletion of 1492A, and Fitzgerald trait with normal HMWK. Inheritance \- Autosomal recessive Lab \- Prolonged partial thromboplastin time Heme \- Procoagulant deficiency \- Flaujeac factor deficiency \- Fitzgerald factor deficiency \- Williams factor deficiency \- Kininogen deficiency \- High molecular weight kininogen deficiency \- Total kininogen deficiency ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

HIGH MOLECULAR WEIGHT KININOGEN DEFICIENCY

c0272340

omim

https://www.omim.org/entry/228960

{"mesh": ["C537060"], "omim": ["228960"], "orphanet": ["483"], "synonyms": ["Alternative titles", "HMWK DEFICIENCY", "KININOGEN DEFICIENCY, HIGH MOLECULAR WEIGHT", "FITZGERALD TRAIT"]}

Descending perineum syndrome (also known as levator plate sagging)[1] refers to a condition where the perineum "balloons" several centimeters below the bony outlet of the pelvis during strain, although this descent may happen without straining.[2] The syndrome was first described in 1966 by Parks et al.[3] ## Contents * 1 Signs and symptoms * 2 Cause * 3 Diagnosis * 4 Treatment * 5 Epidemiology * 6 References ## Signs and symptoms[edit] Abnormal descent of the perineum may be asymptomatic, but otherwise the following may feature: * perineodynia (perineal pain) [1] * Colo-proctological symptoms, e.g. obstructed defecation,[4] dyschesia (constipation),[1] or degrees of fecal incontinence[1] * gynaecological symptoms, e.g. cystocele (prolapse of the bladder into the vagina) and rectocele (prolapse of the rectum into the vagina)[1] * lower urinary tract symptoms, e.g. dysuria (painful urination), dyspareunia (pain during sexual intercourse), urinary incontinence and urgency[1] Other researchers concluded that abnormal perineal descent did not correlate with constipation or perineal pain, and there are also conflicting reports of the correlation of fecal incontinence with this condition.[2] ## Cause[edit] One of the main causes is suggested to be excessive and repetitive straining during defecation.[2] Other causes include weakness of the pelvic floor muscles (secondary to age-related neuropathic degeneration or traumatic injury during pregnancy and labor. ## Diagnosis[edit] Diagnosis is by rectal examination. A specialized tool called a "Perineocaliper" can be used to measure the descent of the perineum. A retro anal ultrasound scan may demonstrate the condition.[1] "Anti sagging tests", whereby the abnormal descent is corrected temporarily, may help to show whether symptoms are due to descending perineum syndrome or are in fact due to another condition. Normally, the anal margin lies just below a line drawn between the coccyx (tailbone) and the pubic symphysis. In descending perineum syndrome the anal canal is situated several cm below this imaginary line, or it descends 3–4 cm during straining. Defecography may also demonstrate abnormal perineal descent.[5] ## Treatment[edit] Surgical treatments may be used to treat the condition, and include retro-rectal levatorplasty, post-anal repair, retro-anal levator plate myorrhaphy.[1] ## Epidemiology[edit] The condition mainly occurs in women, and it is thought by some to be one of the main defects encountered problem in perineology.[1] ## References[edit] 1. ^ a b c d e f g h i Beco, Jacques (1 January 2008). "Interest of retro-anal levator plate myorrhaphy in selected cases of descending perineum syndrome with positive anti-sagging test". BMC Surgery. 8 (1): 13. doi:10.1186/1471-2482-8-13. PMC 2533292. PMID 18667056. 2. ^ a b c Broekhuis, Suzan R.; Hendriks, Jan C. M.; Fütterer, Jurgen J.; Vierhout, Mark E.; Barentsz, Jelle O.; Kluivers, Kirsten B. (5 February 2010). "Perineal descent and patients' symptoms of anorectal dysfunction, pelvic organ prolapse, and urinary incontinence". International Urogynecology Journal. 21 (6): 721–729. doi:10.1007/s00192-010-1099-z. PMC 2858277. PMID 20135303. 3. ^ Parks, AG; Porter, NH; Hardcastle, J (June 1966). "The syndrome of the descending perineum". Proceedings of the Royal Society of Medicine. 59 (6): 477–82. doi:10.1177/003591576605900601. PMC 1900931. PMID 5937925. 4. ^ Wexner, edited by Andrew P. Zbar, Steven D. (2010). Coloproctology. New York: Springer. ISBN 978-1-84882-755-4.CS1 maint: extra text: authors list (link) 5. ^ Baek, HN; Hwang, YH; Jung, YH (December 2010). "Clinical Significance of Perineal Descent in Pelvic Outlet Obstruction Diagnosed by using Defecography". Journal of the Korean Society of Coloproctology. 26 (6): 395–401. doi:10.3393/jksc.2010.26.6.395. PMC 3017974. PMID 21221239. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Descending perineum syndrome

c0267602

wikipedia

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

{"umls": ["C0267602"], "wikidata": ["Q5263719"]}

Autosomal dominant (165500), autosomal recessive (258500), X-linked recessive (311050), and mitochondrially-determined forms of hereditary optic atrophy have been described. A negative electroretinogram (ERG) is defined as one in which, at the highest intensity of scotopically presented stimuli, the b-wave amplitude is markedly reduced compared with the a-wave amplitude. Weleber and Miyake (1992) stated that previous studies of inherited forms of optic atrophy had reported normal ERG findings. They described 2 families, each with affected members in 2 generations, who had optic atrophy and bright flash electroretinograms with normal a-wave amplitude and markedly subnormal b-wave amplitude. In affected members, central vision failed in the second to third decade of life. In 1 family, 2 brothers had McArdle disease (232600); only one had optic atrophy. Eyes \- Optic atrophy Lab \- Negative electroretinogram (ERG) Inheritance \- Autosomal dominant form \- also other dominant, autosomal recessive, X-linked recessive, and mitochondrial forms ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

OPTIC ATROPHY WITH NEGATIVE ELECTRORETINOGRAMS

c1833799

omim

https://www.omim.org/entry/165510

{"mesh": ["C563494"], "omim": ["165510"]}

Arginine:glycine amidinotransferase deficiency is an inherited disorder that primarily affects the brain. People with this disorder have mild to moderate intellectual disability and delayed speech development. Some affected individuals develop autistic behaviors that affect communication and social interaction. They may experience seizures, especially when they have a fever. Children with arginine:glycine amidinotransferase deficiency may not gain weight and grow at the expected rate (failure to thrive), and have delayed development of motor skills such as sitting and walking. Affected individuals may also have weak muscle tone and tend to tire easily. ## Frequency The prevalence of arginine:glycine amidinotransferase deficiency is unknown. The disorder has been identified in only a few families. ## Causes Mutations in the GATM gene cause arginine:glycine amidinotransferase deficiency. The GATM gene provides instructions for making the enzyme arginine:glycine amidinotransferase. This enzyme participates in the two-step production (synthesis) of the compound creatine from the protein building blocks (amino acids) glycine, arginine, and methionine. Specifically, arginine:glycine amidinotransferase controls the first step of the process. In this step, a compound called guanidinoacetic acid is produced by transferring a cluster of nitrogen and hydrogen atoms called a guanidino group from arginine to glycine. Guanidinoacetic acid is converted to creatine in the second step of the process. Creatine is needed for the body to store and use energy properly. GATM gene mutations impair the ability of the arginine:glycine amidinotransferase enzyme to participate in creatine synthesis, resulting in a shortage of creatine. The effects of arginine:glycine amidinotransferase deficiency are most severe in organs and tissues that require large amounts of energy, especially the brain. ### Learn more about the gene associated with Arginine:glycine amidinotransferase deficiency * GATM ## 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

Arginine:glycine amidinotransferase deficiency

c2675179

medlineplus

https://medlineplus.gov/genetics/condition/arginineglycine-amidinotransferase-deficiency/

{"gard": ["10323"], "mesh": ["C567192"], "omim": ["612718"], "synonyms": []}

Orbital leiomyoma is a rare benign smooth muscle tumor arising from the walls of orbital vessels characterized by its slow growth and well encapsulated nature. It is usually located in an extraconal position, commonly manifesting with painless proptosis. The tumor is composed of spindle cells arranged in a fibrous stroma rich in dilated sinusoidal capillaries. The nuclei of tumor cells are oval with blunted ends and there are no mitotic figures. Orbital leiomyoma when excised has excellent prognosis for vision and life. One case of orbital leiomyosarcoma that possibly represents sarcomatous change in an orbital leiomyoma following radiation treatment has been reported. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Orbital leiomyoma

c4305000

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=52994

{"icd-10": ["D31.6"]}

A rare form of amyloidosis characterized by accumulation and extensive visceral deposition of anamyloidogenic variant of beta 2 microglobulin leading to progressive gastrointestinal dysfunction, Sjögren syndrome and autonomic neuropathy. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Variant ABeta2M amyloidosis

c4302669

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=314652

{"icd-10": ["E85.1"], "synonyms": ["Autosomal dominant beta2-microglobulinic amyloidosis"]}

A number sign (#) is used with this entry because Bardet-Biedl syndrome-1 (BBS1) is caused by homozygous mutation in the BBS1 gene (209901) on chromosome 11q13. Digenic inheritance has also been reported; see MOLECULAR GENETICS. Description Bardet-Biedl syndrome is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism (summary by Beales et al., 1999). Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014). ### Genetic Heterogeneity of Bardet-Biedl Syndrome BBS1 is caused by mutation in a gene on chromosome 11q13 (209901); BBS2 (615981), by mutation in a gene on 16q13 (606151); BBS3 (600151), by mutation in the ARL6 gene on 3q11 (608845); BBS4 (615982), by mutation in a gene on 15q22 (600374); BBS5 (615983), by mutation in a gene on 2q31 (603650); BBS6 (605231), by the MKKS gene on 20p12 (604896), mutations in which also cause McKusick-Kaufman syndrome (236700); BBS7 (615984), by mutation in a gene on 4q27 (607590); BBS8 (615985), by mutation in the TTC8 gene on 14q32 (608132); BBS9 (615986), by mutation in a gene on 7p14 (607968); BBS10 (615987), by mutation in a gene on 12q (610148); BBS11 (615988), by mutation in the TRIM32 gene on 9q33 (602290); BBS12 (615989), by mutation in a gene on 4q27 (610683); BBS13 (615990), by mutation in the MKS1 gene (609883) on 17q23, mutations in which also cause Meckel syndrome-1 (249000); BBS14 (615991), by mutation in the CEP290 gene (610142) on 12q21, mutations in which also cause Meckel syndrome-4 (611134) and several other disorders; BBS15 (615992), by mutation in the C2ORF86 gene (613580), which encodes a homolog of the Drosophila planar cell polarity gene 'fritz,' on 2p15; BBS16 (615993), by mutation in the SDCCAG8 gene (613524) on 1q43, mutations in which also cause Senior-Loken syndrome-7 (613615); BBS17 (615994), by mutation in the LZTFL1 gene (606568) on 3p21; BBS18 (615995), by mutation in the BBIP1 gene (613605) on 10q25; BBS19 (615996), by mutation in the IFT27 gene (615870) on 22q12; BBS20 (617119), by mutation in the IFT74 gene (608040) on 9p21; and BBS21 (617406), by mutation in the C8ORF37 gene (614477). The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. Although BBS had originally been thought to be a recessive disorder, Katsanis et al. (2001) demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While Katsanis et al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001) suggested the term 'recessive inheritance with a modifier of penetrance.' Mykytyn et al. (2002) found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, Fan et al. (2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (209901.0001). Allelic disorders include nonsyndromic forms of retinitis pigmentosa: RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by ARL6 mutation. Clinical Features Renal abnormalities appear to have a high frequency in the Bardet-Biedl syndrome (Alton and McDonald, 1973). Klein (1978) observed 57 cases of Bardet-Biedl syndrome in Switzerland. Fifteen affected individuals occurred in one inbred pedigree and 7 in a second. Pagon et al. (1982) reported a 12-year-old boy with the Bardet-Biedl syndrome (retinal dystrophy, polydactyly, mental retardation, and mild obesity) who died of renal failure and was found to have hepatic fibrosis. They reviewed both earlier reported cases and other autosomal recessive entities that combine retinal dystrophy, hepatic fibrosis and nephronophthisis. Harnett et al. (1988) evaluated 20 of 30 patients with Bardet-Biedl syndrome identified from ophthalmologic records in Newfoundland. All had some abnormality in renal structure, function, or both. Most had minor functional abnormalities and a characteristic radiologic appearance, but to date (the mean age was 31 years) only 3 of the 20 had end-stage renal disease, with 2 requiring maintenance hemodialysis. Half the subjects had hypertension. Calyceal clubbing or blunting was evident in 18 of 19 patients studied by intravenous pyelography; 13 had calyceal cysts or diverticula. Of the 19 patients, 17 had lobulated renal outlines of the fetal type. Green et al. (1989) examined 32 patients with Bardet-Biedl syndrome for some or all of the cardinal manifestations of the disorder. Of 28 patients examined, all had severe retinal dystrophy, but only 2 had typical retinitis pigmentosa. Polydactyly was present in 18 of 31 patients; syndactyly, brachydactyly, or both were present in all patients. Obesity was present in all but 1 of 25 patients. Only 13 of 32 patients were considered mentally retarded. Scores on verbal subsets of intelligence were usually lower than scores on performance tasks. Of 8 men, 7 had small testes and genitalia, which was not due to hypogonadotropism. All 12 women studied had menstrual irregularities and 3 had low serum estrogen levels (1 of these had hypogonadotropism and 2 had primary gonadal failure). Diabetes mellitus was present in 9 of 20 patients. Renal structural or functional abnormalities were present in all 21 patients studied, and 3 patients had end-stage renal failure. Gershoni-Baruch et al. (1992) emphasized the occurrence of cystic kidney dysplasia in Bardet-Biedl syndrome. They commented on the fact that the combination of cystic kidney dysplasia and polydactyly occurs also in Meckel syndrome (249000) and in the short rib-polydactyly syndromes (see 613091), and that usually these syndromes are easy to differentiate. They observed 3 sibs with cystic kidney dysplasia and polydactyly who were thought to have Meckel syndrome until extinguished responses on electroretinography were detected in one of them, aged 3.5 years. In 19-year-old female twins and their 22-year-old sister, Chang et al. (1981) described hypogonadotropic hypogonadism with primary amenorrhea and lack of secondary sexual development, associated with retinitis pigmentosa. Stoler et al. (1995) described 2 unrelated girls with Bardet-Biedl syndrome who also had vaginal atresia. A similar association was suggested in reports of 11 BBS females who had structural genital abnormalities (some of which were missed in childhood), including persistent urogenital sinus; ectopic urethra; hypoplasia of the uterus, ovaries, and fallopian tubes; uterus duplex; and septate vagina. Mehrotra et al. (1997) observed 2 sisters with the Bardet-Biedl syndrome, 1 of whom had congenital hydrometrocolpos. This infant also had tetramelic postaxial polydactyly, making the diagnosis of Kaufman-McKusick syndrome (236700) a possibility in the neonatal period. However, as a teenager she was evaluated for poor vision and found to have mental deficiency, obesity, poor visual acuity, end gaze nystagmus, tapetoretinal degeneration, and extinguished electroretinogram. Her older sister had similar eye complaints; she likewise was born with tetramelic postaxial polydactyly and was also mentally retarded. David et al. (1999) reported 9 patients who, because of the presence of vaginal atresia and postaxial polydactyly, were diagnosed in infancy with McKusick-Kaufman syndrome; these patients later developed obesity and retinal dystrophy and were diagnosed with Bardet-Biedl syndrome. David et al. (1999) suggested that the phenotypic overlap between McKusick-Kaufman syndrome and Bardet-Biedl syndrome is a diagnostic pitfall, and that all children in whom a diagnosis of McKusick-Kaufman syndrome is made in infancy should be reevaluated for retinitis pigmentosa and other signs of Bardet-Biedl in later childhood. In Bedouin families in the Negev region of Israel, presumably the same kindreds as those studied by Kwitek-Black et al. (1993), Elbedour et al. (1994) performed echocardiographic evaluations of cardiac involvement in BBS. They stated that they found cardiac involvement in 50% of cases, justifying inclusion of echocardiographic examination in the clinical evaluation and follow-up of these patients. However, their Table 1 gives echocardiographic abnormality in only 7 of 22 cases and these included 1 case of bicuspid aortic valve, 1 case of mild thickening of the interventricular septum, 1 case of 'moderate tricuspid regurgitation,' and 1 case of mild pulmonic valve stenosis. The occurrence of renal abnormality in 11 of the 22 patients on kidney ultrasonography was somewhat more impressive than the cardiac involvement. Islek et al. (1996) described a boy with postaxial polydactyly and Hirschsprung disease (142623) found at the age of 3 months. Follow-up examination at the age of 7 years showed obesity, mental retardation, retinitis pigmentosa, microphallus, and cryptorchidism. The diagnosis of Bardet-Biedl syndrome was established. According to Islek et al. (1996), 2 other cases of association of Bardet-Biedl syndrome and Hirschsprung disease have been reported. Beales et al. (1999) reported a study of 109 BBS patients and their families. Average age at diagnosis was 9 years. Postaxial polydactyly was present in 69% of patients at birth, but obesity did not begin to develop until approximately 2 to 3 years of age, and retinal degeneration did not become apparent until a mean age of 8.5 years. As a result of their study, Beales et al. (1999) proposed a set of diagnostic criteria based on primary and secondary features (see DIAGNOSIS). They suggested the use of the term polydactyly-obesity-kidney-eye syndrome in recognition of what they described as the phenotypic overlap between BBS and Laurence-Moon syndrome. In 2 patients with Bardet-Biedl syndrome, Lorda-Sanchez et al. (2000) identified 2 uncommon manifestations: situs inversus in one and Hirschsprung disease in the other. They were unable to determine which of the 5 forms of BBS known at that time was present in these cases. Cox et al. (2003) examined the electrophysiologic responses of carriers of BBS. All carriers had decreased corneal positive potential and 60% had a decreased b-wave sensitivity. The authors postulated that the site of the primary defect in the BBS rod pathway appeared to be proximal to the rod outer segments, most likely before the rod-bipolar cell synapse. Kulaga et al. (2004) showed that individuals with BBS have partial or complete anosmia (107200). To test whether this phenotype is caused by ciliary defects of olfactory sensory neurons, they examined mice with deletions of Bbs1 or Bbs4 (600374) genes. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. By detailed neurologic examination of 9 BBS patients, Tan et al. (2007) observed a noticeable decrease in peripheral sensation affecting all modalities in most patients. Tan et al. (2007) concluded that this may be an underrecognized component of the disorder. In 6 patients with molecularly confirmed BBS, including 1 patient with BBS1, Scheidecker et al. (2015) found a cone-rod pattern of dysfunction. Macular dystrophy was present in all patients, usually with central hypofluorescence surrounded by a continuous hyperfluorescent ring on fundus autofluorescence imaging. Optical coherence tomography confirmed loss of outer retinal structure within the atrophic areas. ### Relationship to Laurence-Moon Syndrome There has been longstanding uncertainty as to the relationship between the Laurence-Moon syndrome (245800) and the Bardet-Biedl syndrome. Solis-Cohen and Weiss (1925) lumped them together as the Laurence-Biedl syndrome. Ammann (1970) concluded that the patients of Laurence and Moon had a distinct disorder with paraplegia and without polydactyly and obesity. As suggested by the study of Ammann (1970), residual heterogeneity may exist even after the Laurence-Moon syndrome is separated; for example, Biemond syndrome II (iris coloboma, hypogenitalism, obesity, polydactyly, and mental retardation; 210350) and Alstrom syndrome (retinitis pigmentosa, obesity, diabetes mellitus, and perceptive deafness; 203800) were considered distinct entities. Schachat and Maumenee (1982) reviewed the nosography of these and related syndromes. In a 22-year prospective cohort study of 46 patients from 26 Newfoundland families with BBS, Moore et al. (2005) found no apparent correlation of clinical or dysmorphic features with genotype. They reported that of 2 patients clinically diagnosed as having Laurence-Moon syndrome, one was from a consanguineous pedigree with linkage to the BBS5 gene (see 615983), and the other was a compound heterozygote for mutations in the MKKS gene (604896.0007 and 604896.0008). Moore et al. (2005) concluded that the features in this population did not support the notion that BBS and LMS are distinct. The patient with mutations in the MKKS gene (NF-B5) had previously been reported by Katsanis et al. (2000) as having BBS6 (605231), thus illustrating the difficulty in distinguishing these 2 disorders. ### Bardet-Biedl Syndrome 1 Beales et al. (1997) observed only subtle phenotypic differences among Bardet-Biedl families mapping to the BBS1, BBS2 (615981), or BBS4 (615982) loci, the most striking of which was the finding of taller affected offspring compared with their parents in the BBS1 category. Affected subjects in the BBS2 and BBS4 groups were significantly shorter than their parents. In more than one-fourth of the pedigrees, linkage to no known locus could be established, suggesting the existence of a fifth BBS locus. ### Reviews Khan et al. (2016) reviewed the clinical spectrum and genetics of BBS, including genotype-phenotype correlations and contribution of each responsible gene to the total BBS mutational load. Inheritance Katsanis et al. (2001) screened 163 BBS families for mutations in both BBS2 and BBS6 and reported the presence of 3 mutant alleles in affected individuals in 4 pedigrees. In addition, Katsanis et al. (2001) detected unaffected individuals in 2 pedigrees who carried 2 BBS2 mutations but not a BBS6 mutation. One of these was found to be homozygous by descent for a BBS1 allele, and the other was found to be homozygous by descent for a BBS4 allele. The identification of the gene most commonly mutated in individuals with BBS (BBS1; 209901) allowed Mykytyn et al. (2002) to examine the hypothesis that 3 mutated alleles are required for penetrance of the BBS phenotype (triallelic inheritance), as had been suggested by Katsanis et al. (2001). They did not find the common M390R mutation (209901.0001) in any of 12 unrelated individuals who had previously been shown to have 2 mutations in BBS2, BBS4, or BBS6 (MKKS). Moreover, complete sequencing of BBS1 in these individuals revealed no coding sequence variations. In addition, they sequenced BBS2, BBS4, and MKKS in 10 unrelated North American individuals who were homozygous with respect to the BBS1 M390R mutation. All sequence alterations identified in affected individuals were also found in controls. Although it is possible that these individuals could harbor an additional mutated allele in an unidentified gene underlying BBS, the fact that the remaining genes account for a very small proportion of Bardet-Biedl syndrome makes this unlikely. Finally, in 6 multiplex families in which affected individuals harbored BBS1 mutations, Mykytyn et al. (2002) did not detect any unaffected individuals with 2 BBS1 mutations. Thus, in the families studied by them, the disorder segregated as an autosomal recessive disease, with no evidence that BBS1 acts in triallelic inheritance. Mykytyn et al. (2003) demonstrated that the common BBS1 M390R mutation accounts for approximately 80% of all BBS1 mutations and is found on a similar genetic background across populations. Abu-Safieh et al. (2012) presented evidence that most cases of BBS are inherited in a classic autosomal recessive pattern, and that the triallelic model is very rare, if it exists at all. The authors conducted a comprehensive sequence analysis of all 14 BBS genes as well as the modifier gene CCDC28B (610162) in a cohort of 29 Arab BBS families. Two pathogenic mutations in trans were identified in affected members of each family, and in no instance was a third allele identified that convincingly acted as a modifier of penetrance supporting the triallelic model of BBS. The massive sequencing effort uncovered a number of novel sequence variants in BBS genes other than the 2 pathogenic mutations per family, but the majority of these variants were noncoding and none of the possible splicing variants were predicted to be pathogenic. Molecular Genetics Muller et al. (2010) screened the BBS1 through BBS12 genes and identified pathogenic mutations in 134 (77%) of 174 BBS families: 117 families had 2 pathogenic mutations in a single gene, and 17 families had a single heterozygous mutation, 8 of which were the BBS1 recurrent mutation M390R (209901.0001). BBS1 and BBS10 were the most frequently mutated genes, each found in 32.6% of families, followed by BBS12, found in 10.4% of families. No mutations were found in BBS11, which has only been identified in 1 consanguineous family. There was a high level of private mutations, and Muller et al. (2010) discussed various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations. In a 53-year-old woman with 'juvenile retinitis pigmentosa-like' retinal features consistent with those seen in other BBS1 patients, but who had no syndromic features, Wang et al. (2013) identified homozygosity for the recurrent M390R mutation in the BBS1 gene. The authors stated that the mutation segregated with disease in the family, and noted that such patients should be followed for the potential development of syndromic features. ### Modifier Genes The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. Putoux et al. (2011) identified 8 different heterozygous missense mutations in the KIF7 gene (611254) in 8 patients with ciliopathies, including Bardet-Biedl syndrome, Meckel syndrome (MKS; 249000), Joubert syndrome (JBTS; 213300), Pallister-Hall syndrome (PHS; 146510), and OFD6 (277170). Four of these patients had additional pathogenic mutations in other BBS genes. Rescue studies of somites in morphant zebrafish embryos demonstrated that the heterozygous KIF7 missense mutations were hypomorphs, and Putoux et al. (2011) concluded that these alleles may contribute to or exacerbate the phenotype of other ciliopathies, particularly BBS. Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene (A229T; 610937.0013) may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations, including BBS. ### Oligogenic Inheritance and Copy Number Variation Lindstrand et al. (2016) found exon-disruptive copy number variants (CNVs) in 17 (18.5%) of 92 probands with various forms of BBS who underwent array CGH of 20 candidate genes and 74 ciliopathy loci. The lesions ranged in size from 700 bp to over 100 kb and contributed recessive alleles. Eleven of the 17 probands carried pathogenic mutations in one or more BBS genes in addition to their driver locus, consistent with significant oligogenic inheritance. The data suggested that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals, and that it remains important to continue the studies of exomes and genomes of affected individuals beyond the discovery of a primary disease driver, as these additional molecular changes may worsen or mitigate the phenotype. Diagnosis Based on a review of 109 BBS patients, Beales et al. (1999) proposed modified diagnostic criteria, requiring the presence of either 4 primary features, including rod-cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism (in males), and/or renal anomalies; or 3 primary plus 2 secondary features, including speech disorder or delay; strabismus, cataracts, or astigmatism; brachydactyly/syndactyly; developmental delay; polyuria/polydipsia (nephrogenic diabetes insipidus); ataxia, poor coordination, or imbalance; mild spasticity, especially of lower limbs; diabetes mellitus; dental crowding, hypodontia, small dental roots, or high-arched palate; left ventricular hypertrophy or congenital heart disease; and/or hepatic fibrosis. Janssen et al. (2011) used a DNA pooling and massively parallel resequencing strategy to screen 132 individuals with BBS from 105 families. This method allowed identification of both disease-causing mutations in 29 (28%) of 105 families. Thirty-five different disease-causing mutations were identified, 18 of which were novel. Genotype/Phenotype Correlations ### BBS Gene Heterozygosity On the basis of a study of 75 relatives in 5 generations of the extended family of 2 adult Bardet-Biedl sibs, Croft and Swift (1990) suggested that heterozygotes have an increased frequency of obesity, hypertension, diabetes mellitus, and renal disease. They pointed out that homozygotes have hepatic disease. Croft et al. (1995) studied obesity and hypertension among nonhomozygous relatives of BBS patients, hypothesizing that BBS heterozygotes might be predisposed to these conditions. Among 34 parents of BBS homozygotes (obligate heterozygotes), a proportion of severely overweight fathers (26.7%) were significantly higher than that in comparably aged U.S. white males (8.9%). They concluded that the BBS gene may predispose male heterozygotes to obesity. If heterozygotes represent 1% of the general population, they estimated that approximately 2.9% of all severely overweight white males carry a single BBS gene. The BBS parents of both sexes were also significantly taller than U.S. white men and women of comparable age. Beales et al. (1999) found renal cell adenocarcinomas in 3 parents of individuals with BBS, and congenital renal malformations in a number of others. They suggested that these findings may be a consequence of heterozygosity for disease-causing mutations in BBS genes. Mapping ### Linkage to 11q13 (BBS1) Leppert et al. (1994) performed linkage analysis in 31 multiplex BBS families and reported linkage with 2 markers on 11q, PYGM (608455) and an anonymous marker, D11S913. The homozygosity testing demonstrated genetic heterogeneity within the set of families. The confidence interval for BBS1, based on a 1 lod difference, extended approximately 1 cM proximal to PYGM and 2 cM distal to PYGM. PYGM is located in band 11q13. Leppert et al. (1994) stated that they had seen families unlinked to either chromosome 16 (BBS2) or chromosome 11. Beales et al. (1997) studied 18 families with 2 or more members affected with Bardet-Biedl syndrome, noting the presence of both major and minor manifestations. They performed linkage studies in the hope of finding phenotypic differences between the 4 linkage categories identified to that time. Eight of the families (44%) were found to be linked to 11q13 (BBS1), and 3 (17%) were linked to 16q21 (BBS2). Only 1 family was linked to 15q22 (BBS4; 600374), and none were linked to 3p12 (BBS3; 608845). They concluded that BBS1 is the major locus among white Bardet-Biedl patients and that BBS3 is extremely rare. Only subtle phenotypic differences were observed, the most striking of which was the finding of taller affected offspring compared with their parents in the BBS1 category. Affected subjects in the BBS2 and BBS4 groups were significantly shorter than their parents. In more than one-fourth of the pedigrees, linkage to no known locus could be established, suggesting the existence of a fifth BBS locus. Katsanis et al. (1999) collected a large number of BBS pedigrees of primarily North American and European origin and performed genetic analysis using microsatellites from all known BBS genomic regions. Heterogeneity analysis established a 40.5% contribution of the 11q13 locus to BBS, and haplotype construction on 11q-linked pedigrees revealed several informative recombinants, defining the BBS1 critical interval between D11S4205 and D11S913, a genetic distance of 2.9 cM, equivalent to approximately 2.6 Mb. Loss of identity by descent in 2 consanguineous pedigrees was also observed in the region, potentially refining the region to 1.8 Mb between D11S1883 and D11S4944. Young et al. (1999) used linkage disequilibrium (LD) mapping in an isolated founder population in Newfoundland to reduce significantly the BBS1 critical region. Extensive haplotype analysis in several unrelated BBS families of English descent revealed that the affected members were homozygous for overlapping portions of a rare, disease-associated ancestral haplotype. The LD data suggested that the BBS1 gene lies in a 1-Mb, sequence-ready region on 11q13. ### Mapping Studies In a study of 19 BBS families of mixed but predominantly European ethnic origin, Bruford et al. (1997) obtained results showing that an estimated 36 to 56% of the families were linked to 11q13. A further 32 to 35% of the families were linked to 15q22.3-q23. Three consanguineous families showed homozygosity for 3 adjacent chromosome 15 markers, consistent with identity by descent for this region. In one of these families haplotype analysis reported a localization for BBS4 between D15S131 and D15S114, a distance of about 2 cM. Weak evidence of linkage to 16q21 was observed in 24 to 27% of families. A fourth group of families, estimated at 8%, were unlinked to all 3 of the above loci. Bruford et al. (1997) found no evidence of linkage to markers on chromosome 3, corresponding to the BBS3 locus, or on chromosome 2 or 17, arguing against the involvement of a BBS locus in a patient with Bardet-Biedl syndrome and a t(2;17) translocation reported by Dallapiccola (1971). The prevalence of BBS in Newfoundland is approximately 10-fold greater than in Switzerland (1 in 160,000) and similar to the prevalence among the Bedouin of Kuwait (1 in 13,500). Woods et al. (1999) performed a population-based genetic survey of 17 BBS families in the island portion of the province of Newfoundland. The families contained a total of 36 well-documented affected individuals; 12 families had 2 or more affected persons. Linkage at each of the 4 then-known loci was tested with 2-point linkage and haplotype analysis. Three of the kindreds showed linkage to 11q (BBS1), 1 to 16q (BBS2), and 1 to 3p (BBS3). The BBS3 family was the first to be identified in a population of northern European descent. Six families remained undetermined because of poor pedigree structure or inconclusive haplotype analyses. Six families were excluded from all 4 then-known BBS loci, including BBS4. Population Genetics Farag and Teebi (1988) concluded that the frequency of both the Bardet-Biedl and the Laurence-Moon syndromes is increased in the Arab population of Kuwait. Farag and Teebi (1989) pointed to a high frequency of the Bardet-Biedl syndrome among the Bedouin; the estimated minimum prevalence was 1 in 13,500. Animal Model Ross et al. (2005) showed that mice with mutations in genes involved in Bardet-Biedl syndrome share phenotypes with planar cell polarity (PCP) mutants including open eyelids, neural tube defects, and disrupted cochlear stereociliary bundles. Furthermore, they identified genetic interactions between BBS genes and a PCP gene in both mouse (LTAP, also called VANGL2; 600533) and zebrafish (vangl2). In zebrafish, the augmented phenotype resulted from enhanced defective convergent extension movements. Ross et al. (2005) also showed that VANGL2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggested that cilia are intrinsically involved in planar cell polarity processes. Davis et al. (2007) generated a knockin mouse model of the BBS1 M390R mutation (209901.0001). Mice homozygous for M390R recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. Morphologic evaluation of Bbs1 mutant brain revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Ultrastructural examination of the ependymal cell cilia that lined the enlarged third ventricle of Bbs1 mutant brains showed that, whereas the 9+2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Davis et al. (2007) concluded that the M390R mutation does not affect axonemal structure, but it may play a role in regulation of cilia assembly and/or function. By immunostaining for axonemal proteins, Tan et al. (2007) demonstrated that mouse dorsal root ganglion neurons contain cilia. Bbs1-null and Bbs4-null mice demonstrated behavioral deficits in thermosensation and mechanosensation associated with alterations in the trafficking of the thermosensory channel Trpv1 (602076) and the mechanosensory channel Stoml3 (608327) within sensory neurons. The findings were replicated in C. elegans lacking Bbs7 or Bbs8. Detailed examination of 9 patients with BBS showed a noticeable decrease in peripheral sensation in most of them. Using mice lacking Bbs2, Bbs4, or Bbs6 and mice with the M390R mutation in Bbs1, Shah et al. (2008) showed that expression of BBS proteins was not required for ciliogenesis, but their loss caused structural defects in a fraction of cilia covering airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia, and this same misshapen appearance was present in airway cilia from all mutant mouse strains. Cilia of Bbs4-null and Bbs1 mutant mice beat at a lower frequency than wildtype cilia. Neither airway hyperresponsiveness nor inflammation increased in Bbs2- or Bbs4-null mice immunized with ovalbumin compared with wildtype mice. Instead, mutant animals were partially protected from airway hyperresponsiveness. INHERITANCE \- Autosomal recessive \- Digenic recessive GROWTH Weight \- Obesity HEAD & NECK Eyes \- Rod-cone dystrophy, onset by end of 2nd decade (major) \- Retinitis pigmentosa \- Retinal degeneration \- Strabismus \- Cataracts Mouth \- High arched palate Teeth \- Dental crowding \- Hypodontia \- Small tooth roots ABDOMEN Liver \- Hepatic fibrosis (rare) Gastrointestinal \- Hirschsprung disease (rare) GENITOURINARY External Genitalia (Male) \- Hypogonadism (major) \- Hypogenitalism Kidneys \- Renal anomalies (major) SKELETAL Hands \- Polydactyly, usually postaxial (major) \- Brachydactyly Feet \- Polydactyly (major) NEUROLOGIC Central Nervous System \- Speech disorder \- Speech delay \- Learning disabilities (major) \- Developmental delay \- Mental retardation \- Ataxia \- Poor coordination MISCELLANEOUS \- Presence of 4 major features or 3 major and 2 minor features establishes the diagnosis \- Clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutation in 1 of the 6 loci plus an additional mutation in a second locus, or triallelic inheritance MOLECULAR BASIS \- Caused by mutation in the BBS1 gene (BBS1, 209901.0001 ) ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

BARDET-BIEDL SYNDROME 1

c0752166

omim

https://www.omim.org/entry/209900

{"doid": ["0110123"], "mesh": ["D020788"], "omim": ["209900"], "orphanet": ["110"], "genereviews": ["NBK1363"]}

Tonoki et al. (1988) described bilateral cryptomicrotia, brachytelomesophalangy, hypoplastic toenails, and excess fingertip arch patterns in a mother and son who were chromosomally and mentally normal. The middle and distal phalanges of digits II through V were abnormally short. The son was noted at birth to have a bifid scrotum and chordee without hypospadias. GU \- Bifid scrotum \- Chordee without hypospadias Neuro \- Normal intelligence Inheritance \- Autosomal dominant Nails \- Hypoplastic toenails Limbs \- Brachytelomesophalangy \- Short middle and distal phalanges of digits II through V Skin \- Excess fingertip arch patterns Ears \- Cryptomicrotia ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

CRYPTOMICROTIA-BRACHYDACTYLY SYNDROME

c1852454

omim

https://www.omim.org/entry/123560

{"mesh": ["C536219"], "omim": ["123560"], "orphanet": ["1547"]}

Machupo mammarenavirus Virus classification (unranked): Virus Realm: Riboviria Kingdom: Orthornavirae Phylum: Negarnaviricota Class: Ellioviricetes Order: Bunyavirales Family: Arenaviridae Genus: Mammarenavirus Species: Machupo mammarenavirus Synonyms[1] Machupo virus Bolivian hemorrhagic fever SpecialtyInfectious disease Bolivian hemorrhagic fever (BHF), also known as black typhus or Ordog Fever, is a hemorrhagic fever and zoonotic infectious disease originating in Bolivia after infection by Machupo mammarenavirus.[2] BHF was first identified in 1963 as an ambisense RNA virus of the Arenaviridae family,[3][4] by a research group led by Karl Johnson. The mortality rate is estimated at 5 to 30 percent. Due to its pathogenicity, Machupo virus requires Biosafety Level Four conditions, the highest level.[5] During the period between February and March 2007, some 20 suspected BHF cases (3 fatal) were reported to the El Servicio Departamental de Salud (SEDES) in Beni Department, Bolivia. In February 2008, at least 200 suspected new cases (12 fatal) were reported to SEDES.[6] In November 2011, a second case was confirmed near the departmental capital of Trinidad, and a serosurvey was conducted to determine the extent of Machupo virus infections in the Department. A SEDES expert involved in the survey expressed his concerns about the expansion of the virus to other provinces outside the endemic regions of Mamoré and Iténez provinces.[7][8] ## Contents * 1 Epidemiology * 1.1 History * 1.2 Vectors * 1.3 Symptoms * 1.4 Prevention * 2 Weaponization * 3 Vaccine research * 4 References * 4.1 Bibliography * 5 External links ## Epidemiology[edit] ### History[edit] The disease was first encountered in 1962, in the Bolivian village of San Joaquín, hence the name "Bolivian" Hemorrhagic Fever. When initial investigations failed to find an arthropod carrier, other sources were sought before finally determining that the disease was carried by infected mice. Although mosquitoes were not the cause as originally suspected, the extermination of mosquitoes using DDT to prevent malaria proved to be indirectly responsible for the outbreak in that the accumulation of DDT in various animals along the food chain led to a shortage of cats in the village; subsequently, a mouse plague erupted in the village, leading to an epidemic.[9] ### Vectors[edit] The vector is the Calomys callosus (large vesper mouse), a rodent indigenous to northern Bolivia. Infected animals are asymptomatic and shed the virus in excreta, thereby infecting humans. Evidence of person-to-person transmission of BHF exists but is believed to be rare.[10] ### Symptoms[edit] The infection has a slow onset with fever, malaise, headache and myalgia, very similar to Malaria symptoms. Petechiae (blood spots) on the upper body and bleeding from the nose and gums are observed when the disease progresses to the hemorrhagic phase, usually within seven days of onset.[10] Severe hemorrhagic or neurologic symptoms are observed in about one third of patients. Neurologic symptoms involve tremors, delirium, and convulsions. The mortality rate is about 25%.[11] ### Prevention[edit] Measures to reduce contact between the vesper mouse and humans may have contributed to limiting the number of outbreaks, with no cases identified between 1973 and 1994. Although there are no cures or vaccine for the disease, a vaccine developed for the genetically related Junín virus which causes Argentine hemorrhagic fever has shown evidence of cross-reactivity to Machupo virus, and may therefore be an effective prophylactic measure for people at high risk of infection. Post infection (and providing that the person survives the infection), those that have contracted BHF are usually immune to further infection of the disease.[10] ## Weaponization[edit] Bolivian hemorrhagic fever was one of three hemorrhagic fevers and one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program in 1969.[12] Albert Nickel, a 53-year old animal caretaker at Fort Detrick, died in 1964 from the disease after being bitten by an infected mouse. Nickel Place, on Fort Detrick, is named in his honor. It was also under research by the Soviet Union, under the Biopreparat bureau.[13] ## Vaccine research[edit] Investigational vaccines exist for Argentine hemorrhagic fever and RVF; however, neither is approved by FDA or commonly available in the United States.[14] The structure of the attachment glycoprotein has been determined by X-ray crystallography and this glycoprotein is likely to be an essential component of any successful vaccine.[15] ## References[edit] 1. ^ "ICTV Taxonomy history: Machupo mammarenavirus" (html). International Committee on Taxonomy of Viruses (ICTV). Retrieved 28 January 2019. 2. ^ Public Health Agency of Canada: Machupo Virus Pathogen Safety Data Sheet, http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/machupo-eng.php, Date Modified: 2011-02-18. 3. ^ "Machupo". Retrieved 2009-01-22. 4. ^ Webb PA, Johnson KM, Mackenzie RB, Kuns ML (July 1967). "Some characteristics of Machupo virus, causative agent of Bolivian hemorrhagic fever". Am. J. Trop. Med. Hyg. 16 (4): 531–8. doi:10.4269/ajtmh.1967.16.531. PMID 4378149. 5. ^ Center for Food Security & Public Health and Institute for International Cooperation in Animal Biologics, Iowa State University: Viral Hemorrhagic Fevers Caused by Arenaviruses, http://www.cfsph.iastate.edu/Factsheets/pdfs/viral_hemorrhagic_fever_arenavirus.pdf, last updated: February 23, 2010. 6. ^ Aguilar PV, Carmago W, Vargas J, Guevara C, Roca Y, Felices V, et al. Reemergence of Bolivian hemorrhagic fever, 2007–2008 [letter]. Emerg Infect Dis [serial on the Internet] 2009 Sep. Available from http://wwwnc.cdc.gov/eid/article/15/9/09-0017.htm. Accessed 2 Dec 2011. 7. ^ "Caso confirmado de fiebre hemorrágica alerta a autoridades benianas," Los Tiempos.com, "Archived copy". Archived from the original on 2012-03-15. Retrieved 2012-11-29.CS1 maint: archived copy as title (link), 16/11/2011. 8. ^ "SEDES movilizado para controlar brote de fiebre hemorrágica en Beni; También se Capacita a Los Comunarios y Estudiantes," Lost Tiempos.com, "Archived copy". Archived from the original on 2011-12-01. Retrieved 2012-11-29.CS1 maint: archived copy as title (link), 30/11/2011. 9. ^ Medical Microbiology 2nd edition; Mims et al. Mosby publishing 1998, p 371 10. ^ a b c Kilgore, et al., (1995). 11. ^ Patterson M, Grant A, Paessler S (2014). "Epidemiology and pathogenesis of Bolivian hemorrhagic fever". Current Opinion in Virology. 5: 82–90. doi:10.1016/j.coviro.2014.02.007. PMC 4028408. PMID 24636947. 12. ^ "Chemical and Biological Weapons: Possession and Programs Past and Present", James Martin Center for Nonproliferation Studies, Middlebury College, April 9, 2002, accessed November 14, 2008. 13. ^ Alibek, Ken and Steven Handelman (1999), Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World - Told from Inside by the Man Who Ran It, Random House, ISBN 0-385-33496-6. 14. ^ Shoemaker T, Choi M. "Travelers' Health: Viral Hemorrhagic Fevers". CDC. CDC. Retrieved 15 September 2020. 15. ^ Bowden, Thomas A.; Crispin, Max; Graham, Stephen C.; Harvey, David J.; Grimes, Jonathan M.; Jones, E. Yvonne; Stuart, David I. (2009-08-15). "Unusual Molecular Architecture of the Machupo Virus Attachment Glycoprotein". Journal of Virology. 83 (16): 8259–8265. doi:10.1128/JVI.00761-09. ISSN 0022-538X. PMC 2715760. PMID 19494008. ### Bibliography[edit] * Kilgore PE, Peters CJ, Mills JN, et al. (1995). "Prospects for the control of Bolivian hemorrhagic fever". Emerging Infect. Dis. 1 (3): 97–100. doi:10.3201/eid0103.950308. PMC 2626873. PMID 8903174. * Medical Microbiology 2nd Edition Mims et al. Mosby Publishing 1998 p 371 ## External links[edit] Classification D * ICD-10: A96.1 * ICD-9-CM: 078.7 * MeSH: D006478 * DiseasesDB: 31899 * v * t * e Zoonotic viral diseases (A80–B34, 042–079) Arthropod -borne Mosquito -borne Bunyavirales * Arbovirus encephalitides: La Crosse encephalitis * LACV * Batai virus * BATV * Bwamba Fever * BWAV * California encephalitis * CEV * Jamestown Canyon encephalitis * Tete virus * Tahyna virus * TAHV * Viral hemorrhagic fevers: Rift Valley fever * RVFV * Bunyamwera fever * BUNV * Ngari virus * NRIV Flaviviridae * Arbovirus encephalitides: Japanese encephalitis * JEV * Australian encephalitis * MVEV * KUNV * Saint Louis encephalitis * SLEV * Usutu virus * West Nile fever * WNV * Viral hemorrhagic fevers: Dengue fever * DENV-1-4 * Yellow fever * YFV * Zika fever * Zika virus Togaviridae * Arbovirus encephalitides: Eastern equine encephalomyelitis * EEEV * Western equine encephalomyelitis * WEEV * Venezuelan equine encephalomyelitis * VEEV * Chikungunya * CHIKV * O'nyong'nyong fever * ONNV * Pogosta disease * Sindbis virus * Ross River fever * RRV * Semliki Forest virus Reoviridae * Banna virus encephalitis Tick -borne Bunyavirales * Viral hemorrhagic fevers: Bhanja virus * Crimean–Congo hemorrhagic fever (CCHFV) * Heartland virus * Severe fever with thrombocytopenia syndrome (Huaiyangshan banyangvirus) * Tete virus Flaviviridae * Arbovirus encephalitides: Tick-borne encephalitis * TBEV * Powassan encephalitis * POWV * Viral hemorrhagic fevers: Omsk hemorrhagic fever * OHFV * Kyasanur Forest disease * KFDV * AHFV * Langat virus * LGTV Orthomyxoviridae * Bourbon virus Reoviridae * Colorado tick fever * CTFV * Kemerovo tickborne viral fever Sandfly -borne Bunyavirales * Adria virus (ADRV) * Oropouche fever * Oropouche virus * Pappataci fever * Toscana virus * Sandfly fever Naples virus Rhabdoviridae * Chandipura virus Mammal -borne Rodent -borne Arenaviridae * Viral hemorrhagic fevers: Lassa fever * LASV * Venezuelan hemorrhagic fever * GTOV * Argentine hemorrhagic fever * JUNV * Brazilian hemorrhagic fever * SABV * Bolivian hemorrhagic fever * MACV * LUJV * CHPV Bunyavirales * Hemorrhagic fever with renal syndrome * DOBV * HTNV * PUUV * SEOV * AMRV * THAIV * Hantavirus pulmonary syndrome * ANDV * SNV Herpesviridae * Murid gammaherpesvirus 4 Bat -borne Filoviridae * BDBV * SUDV * TAFV * Marburg virus disease * MARV * RAVV Rhabdoviridae * Rabies * ABLV * MOKV * DUVV * LBV * CHPV Paramyxoviridae * Henipavirus encephalitis * HeV * NiV Coronaviridae * SARS-related coronavirus * SARS-CoV * MERS-CoV * SARS-CoV-2 Primate -borne Herpesviridae * Macacine alphaherpesvirus 1 Retroviridae * Simian foamy virus * HTLV-1 * HTLV-2 Poxviridae * Tanapox * Yaba monkey tumor virus Multiple vectors Rhabdoviridae * Rabies * RABV * Mokola virus Poxviridae * Monkeypox Taxon identifiers * Wikidata: Q24719427 * Wikispecies: Machupo mammarenavirus * NCBI: 11628 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Bolivian hemorrhagic fever

c0282192

wikipedia

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

{"mesh": ["D006478"], "umls": ["C0282192"], "icd-9": ["078.7"], "icd-10": ["A96.1"], "orphanet": ["319229"], "wikidata": ["Q2700304"]}

Medical condition This article needs attention from an expert in Medicine. The specific problem is: Medical condition and pills details included. WikiProject Medicine may be able to help recruit an expert. (March 2020) Menstrual migraine Other namesCatamenial migraine Menstrual migraine (also called catamenial migraine) is term used to describe both true menstrual migraines and menstrually related migraines. About 7%–14% of women have migraines only at the time of menstruation, these are called true menstrual migraines. Most female migraneurs experience migraine attacks throughout the menstruation cycle with an increased number perimenstrually, these are referred to as menstrually related or menstrually triggered migraine.[1][2] It used to believed that treatments for migraine would work in menstrual migraine but that has not proven to be the case because menstrual migraines are harder to treat. Because of this, menstrual migraines are now considered a separate medical disorder from migraine.[3] In 2008, menstrual migraines were given ICD-9 codes (346.4-346.43) of their own which separate menstrual migraine from other types of migraine. About 40% of women and 20% of men will get a migraine at sometime in their life; most of them will get their first migraine before they are 35-years-old. Menstrual-related migraines happen in more than 50 percent of women who have migraine headaches.[4] Menstrual migraine attacks usually last longer than other migraine attacks,[5] and short-term treatments do not work as well with menstrual migraine as they do in other kinds of migraine. They are usually migraines without aura, but in 2012 a case of menstrual migraine with aura was reported, so it is possible.[6] Auras are a kind of condition which affect certain parts of the brain, usually the parts that control vision but they can also affect the parts of the brain which control the other senses like touch, motor control (moving parts of the body) and the parts of the brain that control speech.[citation needed] ## Contents * 1 Signs and symptoms * 1.1 Warning symptoms * 1.2 Headache * 1.3 Associated conditions * 2 Causes * 3 Diagnosis * 4 Prevention * 5 Treatment * 6 References * 7 External links ## Signs and symptoms[edit] ### Warning symptoms[edit] This is a blister-pack of Levlen®ED birth control pills. These pills contain ethinyloestradiol, one of the three kinds of the hormone estrogen. Stopping use of the pill causes a woman's estrogen levels to drop; that may cause a menstrual migraine in some women.[7] Warning symptoms also called prodrome symptoms often happen before a migraine attack. * Sleepiness * Fatigue * Depression (feeling sad), euphoria (feeling very happy) or irritability * Restlessness * Excessive (too much) yawning * Food cravings especially for sweet or salty foods or loss of appetite * Increased thirst * Diarrhea * Nausea * Bloating: the body retains (keeps) too much water * Neck stiffness * Talkativeness (talking too much) * Feeling light-headed * Uterine pain and cramping ### Headache[edit] A pounding throbbing headache with the pain being on one side of the head (unilateral). The side of the head that has the pain changes from one headache to the next. ### Associated conditions[edit] Often, having one medical condition makes it more likely a person will also have one or more other medical or psychiatric disorders. These other disorders are the "comorbid disorders" or "comorbidities".[8] There are various comorbid medical and psychiatric conditions associated with migraines. The treatment and prognosis (if a disease gets better, worse or stays the same over time)[9] of migraine is affected by the comorbid disorders which may be present and/or the chance of getting comorbid disorders.[10] * Asthma – Premenstrual asthma (PMA): is when asthma symptoms get worse during the premenstrual period. This condition may affect up to 40% of female asthma sufferers. For a diagnosis of PMA to be made it is necessary to have a detailed history of the timing of menstrual cycles along with asthma symptoms experienced, and the peak expiratory flow rate (PMA may cause the PEF to be lowered in the premenstrual period). It is helpful in making a diagnosis to keep a diary of symptoms and peak expiratory flow (PEF) rates.[11][12] * Raynaud's disease: is a circulatory disorder in which the smaller arteries that supply blood to the extremities – most often the hands, but it may also affect the, toes, the tip of the nose and the ears – become narrower reducing blood flow. This causes the extremities to become numb and to be cooler than the core body temperature. It can be triggered by exposure to stress and cold.[13][14] * Epilepsy * Fibromyalgia It is associated with a number of mental health conditions including * Major depressive disorder * Anxiety * Bipolar disorder ## Causes[edit] The exact causes of menstrual migraine are not known for sure but there is a link between falling levels of the female hormone estrogen and the onset of a migraine attack. The estrogen level may fall after bleeding occurs during the menstrual cycle or when external sources of estrogen are no longer taken, like when a woman stops taking birth control pills or hormone pills in hormone replacement therapy.[citation needed] ## Diagnosis[edit] The diagnosis of a menstrual migraine is made by keeping track of when the migraines occur for a period of at least three months. Menstrually related migraine attacks occur usually between 2 days before and 3 days after the start of menstruation in at least 2 out of 3 menstrual cycles (periods) in a row. Pure menstrual migraine and menstrually related migraine are both migraines without auras with one exceptionally rare case with aura reported in 2012. The Menstrual Migraine Assessment Tool (MMAT) is a simple questionnaire with three questions, that has shown to be fairly accurate in diagnosing menstrual migraine (Tepper SJ, 2008).[15] The three questions are: 1. Do migraines occur in the space of time 2 days before the beginning of a woman's period, until the third day after the start of the period. And does this happen in most months. 2. Do headaches that happen during this time become very severe. 3. Does the woman experience photophobia which is when a medical problem cause light to bother a person's eyes. The answer to the first question has to be yes and there has to be at least one yes answer to either question 2 or question 3.[16] In order to keep track of what time of the month the migraines happen it is helpful to use a headache diary. A person uses the headache diary to write down information about their headaches, like when they started, what kind of symptoms they had and how bad the pain was etc. ## Prevention[edit] An estradiol trasdermal patch. Estradiol is one of the three kinds of estrogen. This patch is worn on the skin and the estradiol enters the body through the skin. There are treatments which may decrease the severity or frequency of menstrual migraines. Preventative treatments for menstrual migraine should be tried for at least 3 menstruation cycles to determine effectiveness. Medications used may include: * NSAIDS (nonsteroidal antiinflammatory drugs) such as naproxen[17] * Beta blockers — such as propranolol, nadolol, atenolol, and metoprolol[18] * Tricyclic antidepressants (TCAs) and other kinds of antidepressant medications are often used for migraine prevention. These include amitriptyline, nortriptyline, and doxepin. ## Treatment[edit] Acute treatments (short-term treatment) include drugs called Nonsteroidal anti-inflammatory drugs (NSAIDS) (drugs that help stop inflammation which is redness, swelling, pain, tenderness, heat in parts of the body), triptans such as Frovatriptan, ergotomines which are a kind of drug made from a fungus called ergot, and estrogen transdermal patches, which are patches worn on the skin that have estrogen in them which enters the body through the skin and then into the bloodstream.[19] ## References[edit] 1. ^ Robert A. Davidoff: Migraine:Manifestations, Pathogenesis, and Management: Manifestations p.122 (Oxford University Press, USA; 2nd edition, 2002): ISBN 0195137051 2. ^ Robert B. Daroff, Gerald M Fenichel, Joseph Jankovic, John C Mazziotta. 2012. Bradley's Neurology in clinical practice: the neurological disorders. Volume 2. Editor: Walter George Bradle. Taylor and Francis. p.286 ISBN 1437704344 3. ^ Alice J. Dan, Linda L. Lewis: Menstrual Health in Women's Lives. p.152 (University of Illinois Press, 1991) ISBN 0252062094 4. ^ The Headaches; Editors: Jes Olesen, Peer Tfelt-Hansen, et al. p.331 (Lippincott Williams & Wilkins; Third edition, 2005) ISBN 0781754003 5. ^ Pinkerman, B.; Holroyd, K. (2010). "Menstrual and nonmenstrual migraines differ in women with menstrually-related migraine". Cephalalgia : An International Journal of Headache. 30 (10): 1187–94. doi:10.1177/0333102409359315. PMID 20855364. S2CID 2131220. 6. ^ Chen, J. J.; Hsu, Y. C.; Chen, D. L. (2012). "Pure menstrual migraine with sensory aura: A case report". The Journal of Headache and Pain. 13 (5): 431–3. doi:10.1007/s10194-012-0450-9. PMC 3381070. PMID 22527036. 7. ^ Allais, G.; Bussone, G.; Airola, G.; Borgogno, P.; Gabellari, I. C.; De Lorenzo, C.; Pavia, E.; Benedetto, C. (2008). "Oral contraceptive-induced menstrual migraine. Clinical aspects and response to frovatriptan". Neurological Sciences. 29 (Suppl 1): S186-90. doi:10.1007/s10072-008-0921-6. PMID 18545931. S2CID 5832150. 8. ^ [1]: Free Merriam Webster Dictionary, 2012. Retrieved December 23, 2012 9. ^ prognoses: Free Merriam Webster Dictionary, 2012. Retrieved December 23, 2012 10. ^ Jean Schoenen, David W. Dodick, Peter Sándor, editors: Comorbidity in Migraine; Wiley-Blackwell; 1 edition, 2011 p.vi ISBN 1405185554 11. ^ Tan, K. S. (2001). "Premenstrual asthma: Epidemiology, pathogenesis and treatment". Drugs. 61 (14): 2079–86. doi:10.2165/00003495-200161140-00005. PMID 11735634. S2CID 46963718. 12. ^ Marc A. Fritz, M.D., Leon Speroff: Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins; Eighth edition (2010), p.588 ISBN 0781779685 13. ^ Professional Guide to Diseases Lippincott Williams & Wilkins; Tenth edition, 2012,; p.93 ISBN 1451144601 14. ^ Jonathan M. Borkum: Chronic Headaches: Biology, Psychology, and Behavioral Treatment. Psychology Press; 1 edition, 2007; p.110 ISBN 0805861998 15. ^ Stewart J. Tepper: The Cleveland Clinic Manual of Headache Therapy, Springer; 1st ed. 2011. pp. 15-16 ISBN 146140178X 16. ^ Tepper, S. J.; Zatochill, M.; Szeto, M.; Sheftell, F.; Tepper, D. E.; Bigal, M. (2008). "Development of a simple menstrual migraine screening tool for obstetric and gynecology clinics: The menstrual migraine assessment tool". Headache. 48 (10): 1419–25. doi:10.1111/j.1526-4610.2008.01304.x. PMID 19076645. 17. ^ Egilius L. H. Spierings, Margarita Sánchez del Río – Migraine: A Neuroinflammatory Disease? (Progress in Inflammation Research). Birkhäuser; 1st edition (2002) p.157 ISBN 3764362316 18. ^ Garza, I; Swanson, JW (September 2006). "Prophylaxis of migraine". Neuropsychiatric Disease and Treatment. 2 (3): 281–91. doi:10.2147/nedt.2006.2.3.281. PMC 2671824. PMID 19412475. 19. ^ Dailymed: ESTRADIOL patch ## External links[edit] * Optimizing Management of Menstrual Migraine *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Menstrual migraine

c0269226

wikipedia

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

{"umls": ["C0269226"], "icd-9": ["346.4"], "wikidata": ["Q12859056"]}

This syndrome is characterised by childhood-onset progressive ataxia and cerebellar atrophy. ## Epidemiology Prevalence is unknown. ## Clinical description Exercise intolerance with elevated lactate levels and mild intellectual deficit may also be present. ## Etiology The syndrome is caused by ubiquinone deficiency. Mutations in the ADCK3/CABC1 gene have been detected in affected individuals. This gene is already known to play a role in ubiquinone biosynthesis in yeast. ## Genetic counseling The syndrome is transmitted as an autosomal recessive trait. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Autosomal recessive ataxia due to ubiquinone deficiency

c2677589

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=139485

{"gard": ["10294"], "mesh": ["C567436"], "omim": ["612016"], "umls": ["C2677589"], "icd-10": ["G11.1"], "synonyms": ["ARCA2", "Autosomal recessive ataxia due to coenzyme Q10 deficiency", "Autosomal recessive cerebellar ataxia type 2", "Autosomal recessive spinocerebellar ataxia type 9", "SCAR9"]}

Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine. It is also characterized by poor feeding, vomiting, lack of energy (lethargy), abnormal movements, and delayed development. If untreated, maple syrup urine disease can lead to seizures, coma, and death. Maple syrup urine disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still lead to delayed development and other health problems if not treated. ## Frequency Maple syrup urine disease affects an estimated 1 in 185,000 infants worldwide. The disorder occurs much more frequently in the Old Order Mennonite population, with an estimated incidence of about 1 in 380 newborns. ## Causes Mutations in the BCKDHA, BCKDHB, and DBT genes can cause maple syrup urine disease. These three genes provide instructions for making proteins that work together as part of a complex. The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine, which are present in many kinds of food, particularly protein-rich foods such as milk, meat, and eggs. Mutations in any of these three genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of leucine, isoleucine, and valine. As a result, these amino acids and their byproducts build up in the body. Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious health problems associated with maple syrup urine disease. Researchers are studying other genes related to the same protein complex that may also be associated with maple syrup urine disease. ### Learn more about the genes associated with Maple syrup urine disease * BCKDHA * BCKDHB * DBT Additional Information from NCBI Gene: * PPM1K ## 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

Maple syrup urine disease

c1621920

medlineplus

https://medlineplus.gov/genetics/condition/maple-syrup-urine-disease/

{"gard": ["3228"], "mesh": ["D008375"], "omim": ["248600", "615135"], "synonyms": []}

Hereditary angioedema is a disorder characterized by recurrent episodes of severe swelling (angioedema). The most common areas of the body to develop swelling are the limbs, face, intestinal tract, and airway. Minor trauma or stress may trigger an attack, but swelling often occurs without a known trigger. Episodes involving the intestinal tract cause severe abdominal pain, nausea, and vomiting. Swelling in the airway can restrict breathing and lead to life-threatening obstruction of the airway. About one-third of people with this condition develop a non-itchy rash called erythema marginatum during an attack. Symptoms of hereditary angioedema typically begin in childhood and worsen during puberty. On average, untreated individuals have an attack every 1 to 2 weeks, and most episodes last for about 3 to 4 days. The frequency and duration of attacks vary greatly among people with hereditary angioedema, even among people in the same family. There are three types of hereditary angioedema, called types I, II, and III, which can be distinguished by their underlying causes and levels of a protein called C1 inhibitor in the blood. The different types have similar signs and symptoms. Type III was originally thought to occur only in women, but families with affected males have been identified. ## Frequency Hereditary angioedema is estimated to affect 1 in 50,000 people. Type I is the most common, accounting for 85 percent of cases. Type II occurs in 15 percent of cases, and type III is very rare. ## Causes Mutations in the SERPING1 gene cause hereditary angioedema type I and type II. The SERPING1 gene provides instructions for making the C1 inhibitor protein, which is important for controlling inflammation. C1 inhibitor blocks the activity of certain proteins that promote inflammation. Mutations that cause hereditary angioedema type I lead to reduced levels of C1 inhibitor in the blood, while mutations that cause type II result in the production of a C1 inhibitor that functions abnormally. Without the proper levels of functional C1 inhibitor, excessive amounts of a protein fragment (peptide) called bradykinin are generated. Bradykinin promotes inflammation by increasing the leakage of fluid through the walls of blood vessels into body tissues. Excessive accumulation of fluids in body tissues causes the episodes of swelling seen in individuals with hereditary angioedema type I and type II. Mutations in the F12 gene are associated with some cases of hereditary angioedema type III. This gene provides instructions for making a protein called coagulation factor XII. In addition to playing a critical role in blood clotting (coagulation), factor XII is also an important stimulator of inflammation and is involved in the production of bradykinin. Certain mutations in the F12 gene result in the production of factor XII with increased activity. As a result, more bradykinin is generated and blood vessel walls become more leaky, which leads to episodes of swelling in people with hereditary angioedema type III. The cause of other cases of hereditary angioedema type III remains unknown. Mutations in one or more as-yet unidentified genes may be responsible for the disorder in these cases. ### Learn more about the genes associated with Hereditary angioedema * F12 * SERPING1 ## Inheritance Pattern This condition 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. Other 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

Hereditary angioedema

c1862892

medlineplus

https://medlineplus.gov/genetics/condition/hereditary-angioedema/

{"gard": ["5979"], "mesh": ["D056829"], "omim": ["106100", "610618"], "synonyms": []}

Pulp stones (also denticles or endoliths)[1] are nodular, calcified masses appearing in either or both the coronal and root portion of the pulp organ in teeth. Pulp stones are not painful unless they impinge on nerves. They are classified:[2] A) On the basis of structure 1) True pulp stones: formed of dentin by odontoblasts 2) False pulp stones: formed by mineralization of degenerating pulp cells, often in a concentric pattern B) On the basis of location 1) Free: entirely surrounded by pulp tissue 2) Adherent: partly fused with dentin 3) Embedded: entirely surrounded by dentin ## Contents * 1 Introduction * 2 Etiology * 3 Types/classification * 4 Histopathology * 5 Associations * 6 Prevalence * 7 Clinical implications * 8 References ## Introduction[edit] Pulp stones are discrete calcifications found in the pulp chamber of the tooth which may undergo changes to become diffuse pulp calcifications such as dystrophic calcification. [2] They are usually noticed by radiographic examination and appeared as round or ovoid radiopaque lesions.[3] Clinically, a tooth with a pulp stone has normal appearance like any other tooth.[4] The number of pulp stones in a single tooth may vary from 1 to 12 or more, with varying sizes from minute particles to large masses which tend to occlude the pulpal space. It is reported that pulp stones are more commonly found in the coronal region of pulp, albeit also found in the radicular pulp.[2] It is believed that pulp stones develop around a central nidus of pulp tissue, for instance collagen fibril, ground substance and necrotic cell remnants. Initial calcification occurs around the central nidus and extends outward with regular calcified material in a concentric or radial manner.[5] ## Etiology[edit] The pulp calcifications can arise due to: * pulp degeneration * increasing age * circulatory disturbances within the pulp * long standing local irritants such as dental caries, pulp-capping procedures, healed tooth fractures, tooth injury restorations and periodontal diseases * orthodontic tooth movements * transplantation of teeth * trauma It is shown that pulp stone occurring in adolescents is significantly associated with carious and/or restored teeth, which suggests a causative relationship of chronic pulp irritation to pulp stone formation. A defence reaction in the pulpodentinal complex may be triggered by caries and microleakage around restorations which lead to pulp calcifications. The formation of pulp stone may have a similar mechanism as the tertiary dentine formation near the irritated odontoblasts. Apart from that, with aging, the pulp decreases in size due to the deposition of secondary or tertiary dentine. This subsequently results in favourable conditions for the formation of pulpal calcifications. The other reported etiologic factors also include: * idiopathic factors * consumption of fluoride supplements * hypervitaminosis D * a possible genetic predisposition such as dentinogenesis imperfecta and dentinal dysplasia[4][6] ## Types/classification[edit] Pulp stones can be classified based on different location and structure. [2] Based on location, they can classified into free, embedded and adherent pulp stones. Free pulp stones are found within the pulp tissue and is the most common encounter. The size vary from 50μm in diameter to several millimetres and may occlude the entire pulp chamber. Embedded pulp stone is fully embedded in dentine and most commonly found in the apical portion of the root. Adherent pulp stones are attached to the wall of pulp space but not fully enclosed by dentine. Structurally, pulp stones can be classified as true and false pulp stones. True pulp stones are made up of dentine that is lined by odontoblast. True pulp stones are quite rare. On the other hand, false pulp stones are made up of concentric layers of mineralised tissue around blood thrombi, collagen fibres, or dying and dead cells. ## Histopathology[edit] Histologically, there are two types of stones: (1) stones with regular calcifications (2) stones with irregular calcifications. For regular calcification, the pulp stones are smooth, round or ovoid with concentric laminations. It is commonly found in the coronal pulp. As for irregular calcifications without laminations, pulp stones may have the shape of rods or leaves and the surface is rough. It is more common in the radicular pulp. Pulp stones with regular calcification grow in size by addition of collagen fibrils to their surface, whereas the irregular type of pulp stones are formed by calcification of pre-existing collagen fibres. Pulp stones may also form around epithelial cells such as remnants of Hertwig's epithelial root sheath. It is presumed that epithelial remnants are able to induce adjacent mesenchymal stem cells to differentiate into odontoblasts.[7] ## Associations[edit] A pilot study was done with patients with cardiovascular disease (CVD) and it shows increased incidence of pulp stones in teeth with patients with CVD compared to healthy patients without CVD. [8] There are also researchers which suggest the link between pulpal calcification and carotid artery calcification, despite not having a strong proof on this correlation. [5] Besides cardiovascular disease, other disease such as end stage renal disease, Marfan syndrome, Ehlers-Danlos syndrome, Calcinosis universalis, tumoral calcinosis are also discovered to be in association with pulpal calcifications.[9] Several genetic diseases such as dentin dysplasia and dentinogenesis imperfecta are also accompanied by pulpal calcifications and hence, Marfan syndrome was suspected to be in association with pulp stones due to abnormal dentin formation, leading to the increased frequency of pulpal calcifications in these individuals. [9] Another theory suggests that individuals with Marfan syndrome have connective tissue dysplasia or vascular defects which in the case of tooth pulp, endothelial rupture of the pulp arterioles will lead to hemorrhagic areas in the pulp. It was proposed that these hemorrhagic areas in the pulp will induce mineralization within the pulp. [9] ## Prevalence[edit] Pulpal calcifications can be developed throughout the life and prevalence rates from 8–9% in worldwide population had been reported in studies.It was also found that pulpal stones occurred most frequently over the fourth decade, in advancing age. [10][5] Generally, pulp stones are more frequent to be found in maxillary teeth compared to mandibular teeth. [11] A study in Australia resulted higher occurrences of pulp stones in molars as opposed to premolars, and first molars as opposed to second molars. [12] First molars which were restored and/or with caries showed a higher incidence of pulp stones as compared to intact, unrestored first molars. ## Clinical implications[edit] Pulp stones generally do not have significant clinical implications as they are usually not a source of pain, discomfort or any form of pulpitis. [5][13]However, when the tooth concerned will undergo endodontic treatment such as root canal treatment, presence of large pulp stones will be clinically significant.[13][14] Large pulp stones in the pulp chamber might block the access to canal orifices and prevent the exploring dental instruments from passaging down the canal.[15] In these cases, burs or even ultrasonic instrumentation can be used to remove the blocking pulp stones. [15] During the removal process, sodium hypochlorite which has dissolving action can also be used as a synergistic effect.[16] ## References[edit] 1. ^ Mosby's Medical Dictionary (9th ed.). Elsevier Health Sciences. 2013. p. 507. ISBN 978-0323112581. Retrieved 10 February 2016. 2. ^ a b c d Goga R, Chandler NP, Oginni AO (June 2008). "Pulp stones: a review" (PDF). International Endodontic Journal. 41 (6): 457–68. doi:10.1111/j.1365-2591.2008.01374.x. PMID 18422587. 3. ^ Feng XJ, Luo X, Li R, Dong W, Qi MC (August 2015). "[Multiple pulp stones: report of a case and literature review]". Shanghai Kou Qiang Yi Xue = Shanghai Journal of Stomatology. 24 (4): 511–2. PMID 26383583. 4. ^ a b Berès F, Isaac J, Mouton L, Rouzière S, Berdal A, Simon S, Dessombz A (March 2016). "Comparative Physicochemical Analysis of Pulp Stone and Dentin" (PDF). Journal of Endodontics. 42 (3): 432–8. doi:10.1016/j.joen.2015.11.007. PMID 26794341. 5. ^ a b c d Neville BW, Damm DD, Allen CM, Chi AC (2015-05-13). Oral and maxillofacial pathology (Fourth ed.). St. Louis, MO. ISBN 9781455770526. OCLC 908336985. 6. ^ Kannan S, Kannepady SK, Muthu K, Jeevan MB, Thapasum A (March 2015). "Radiographic assessment of the prevalence of pulp stones in Malaysians". Journal of Endodontics. 41 (3): 333–7. doi:10.1016/j.joen.2014.10.015. PMID 25476972. 7. ^ Cohen's Pathway of Pulp. 8. ^ Edds AC, Walden JE, Scheetz JP, Goldsmith LJ, Drisko CL, Eleazer PD (July 2005). "Pilot study of correlation of pulp stones with cardiovascular disease". Journal of Endodontics. 31 (7): 504–6. doi:10.1097/01.don.0000168890.42903.2b. PMID 15980708. 9. ^ a b c Bauss O, Neter D, Rahman A (December 2008). "Prevalence of pulp calcifications in patients with Marfan syndrome". Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 106 (6): e56–61. doi:10.1016/j.tripleo.2008.06.029. PMID 18805711. 10. ^ Udoye C, Sede M (January 2011). "Prevalence and analysis of factors related to ooccurrence of pulp stone in adult restorative patients". Annals of Medical and Health Sciences Research. 1 (1): 9–14. PMC 3507086. PMID 23209949. 11. ^ Hsieh CY, Wu YC, Su CC, Chung MP, Huang RY, Ting PY, Lai CK, Chang KS, Tsai YW, Shieh YS (June 2018). "The prevalence and distribution of radiopaque, calcified pulp stones: A cone-beam computed tomography study in a northern Taiwanese population". Journal of Dental Sciences. 13 (2): 138–144. doi:10.1016/j.jds.2017.06.005. PMC 6388828. PMID 30895109. 12. ^ Kannan S, Kannepady SK, Muthu K, Jeevan MB, Thapasum A (March 2015). "Radiographic assessment of the prevalence of pulp stones in Malaysians". Journal of Endodontics. 41 (3): 333–7. doi:10.1016/j.joen.2014.10.015. PMID 25476972. 13. ^ a b Goga R, Chandler NP, Oginni AO (June 2008). "Pulp stones: a review". International Endodontic Journal. 41 (6): 457–68. doi:10.1111/j.1365-2591.2008.01374.x. PMID 18422587. 14. ^ Regezi JA, Sciubba J, Jordan RC (2012). "Abnormalities of Teeth". Oral Pathology: Clinical Pathologic Correlations (6th ed.). Elsevier. pp. 373–389. doi:10.1016/b978-1-4557-0262-6.00016-1. ISBN 9781455702626. 15. ^ a b Goga R, Chandler NP, Oginni AO (June 2008). "Pulp stones: a review". International Endodontic Journal. 41 (6): 457–68. doi:10.1111/j.1365-2591.2008.01374.x. PMID 18422587. 16. ^ Ertas ET, Veli I, Akin M, Ertas H, Atici MY (January 2017). "Dental pulp stone formation during orthodontic treatment: A retrospective clinical follow-up study". Nigerian Journal of Clinical Practice. 20 (1): 37–42. doi:10.4103/1119-3077.164357. PMID 27958244. 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HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Pulp stone

c4280546

wikipedia

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

{"mesh": ["D003784"], "umls": ["C4280546", "C1527284", "C4280259", "C0011401"], "wikidata": ["Q7259585"]}

Intestinal pseudo-obstruction is a condition characterized by impairment of the muscle contractions that move food through the digestive tract. The condition may arise from abnormalities of the gastrointestinal muscles themselves (myogenic) or from problems with the nerves that control the muscle contractions (neurogenic). When intestinal pseudo-obstruction occurs by itself, it is called primary or idiopathic (unknown cause) intestinal pseudo-obstruction. The disorder can also develop as a complication of another medical condition; in these cases, it is called secondary intestinal pseudo-obstruction. Individuals with this condition have symptoms that resemble those of an intestinal blockage (obstruction) but without any obstruction. It may be acute or chronic and is characterized by the presence of dilation of the bowel on imaging. The causes may be unknown or due to alterations (mutations) in the FLNA gene, other genes or are secondary to other conditions. It may be inherited in some cases. Intestinal pseudoobstruction neuronal chronic idiopathic X-linked is caused by alterations (mutations) in the FLNA gene which is located in the X chromosome. There is no specific treatment but several medications and procedures may be used to treat the symptoms. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Intestinal pseudoobstruction neuronal chronic idiopathic X-linked

c2746068

gard

https://rarediseases.info.nih.gov/diseases/3017/intestinal-pseudoobstruction-neuronal-chronic-idiopathic-x-linked

{"mesh": ["C535532"], "omim": ["300048"], "synonyms": ["IPOX", "Congenital idiopathic intestinal pseudoobstruction", "CIIP", "CIIP X-linked", "CIIPX"]}

Condition wherein the ductus arteriosus fails to close after birth Patent ductus arteriosus Other namesPersistent ductus arteriosus Diagram of a cross-section through a heart with PDA SpecialtyCardiac surgery, paediatrics SymptomsShortness of breath, failure to thrive, tachycardia, heart murmur ComplicationsHeart failure, Eisenmenger's syndrome, pulmonary hypertension CausesIdiopathic Risk factorsPreterm birth, congenital rubella syndrome, chromosomal abnormalities, genetic conditions Diagnostic methodEchocardiography, Doppler, X-ray PreventionScreening at birth, high index of suspicion in neonates at risk TreatmentNSAIDs, surgery Patent ductus arteriosus (PDA) is a medical condition in which the ductus arteriosus fails to close after birth: this allows a portion of oxygenated blood from the left heart to flow back to the lungs by flowing from the aorta, which has a higher pressure, to the pulmonary artery. Symptoms are uncommon at birth and shortly thereafter, but later in the first year of life there is often the onset of an increased work of breathing and failure to gain weight at a normal rate. With time, an uncorrected PDA usually leads to pulmonary hypertension followed by right-sided heart failure. The ductus arteriosus is a fetal blood vessel that normally closes soon after birth. In a PDA, the vessel does not close, but remains patent (open), resulting in an abnormal transmission of blood from the aorta to the pulmonary artery. PDA is common in newborns with persistent respiratory problems such as hypoxia, and has a high occurrence in premature newborns. Premature newborns are more likely to be hypoxic and have PDA due to underdevelopment of the heart and lungs. If transposition of the great vessels is present in addition to a PDA, the PDA is not surgically closed since it is the only way that oxygenated blood can mix with deoxygenated blood. In these cases, prostaglandins are used to keep the PDA open, and NSAIDs are not administered until surgical correction of the two defects is completed. ## Contents * 1 Signs and symptoms * 2 Risk factors * 3 Diagnosis * 4 Prevention * 5 Treatment * 5.1 Conservative * 5.2 Surgery * 5.3 Prostaglandin inhibitors * 6 Prognosis * 7 History * 8 Adult * 9 See also * 10 References * 11 External links ## Signs and symptoms[edit] Common symptoms include: * dyspnea (shortness of breath) Signs include: * tachycardia (a heart rate exceeding the normal resting rate) * continuous "machine-like" (also described as "rolling-thunder" and "to-and-fro") heart murmur (usually from aorta to pulmonary artery, with higher flow during systole and lower flow during diastole) * cardiomegaly (enlarged heart, reflecting ventricular dilation and volume overload) * left subclavicular thrill * bounding pulse * widened pulse pressure * increased cardiac output * increased systolic pressure * poor growth[1] * differential cyanosis, i.e. cyanosis of the lower extremities but not of the upper body. Patients typically present in good health, with normal respirations and heart rate. If the PDA is moderate or large, widened pulse pressure and bounding peripheral pulses are frequently present, reflecting increased left ventricular stroke volume and diastolic run-off of blood into the (initially lower-resistance) pulmonary vascular bed. [2]Eisenmenger physiology is pulmonary hypertension due to a left-to-right shunt. Prominent suprasternal and carotid pulsations may be noted secondary to increased left ventricular stroke volume. ## Risk factors[edit] Known risk factors include:[citation needed] * Preterm birth * Congenital rubella syndrome * Chromosomal abnormalities (e.g., Down syndrome) * Genetic conditions such as Loeys–Dietz syndrome (would also present with other heart defects), Wiedemann–Steiner syndrome, and CHARGE syndrome. ## Diagnosis[edit] Phonocardiograms from normal and abnormal heart sounds PDA is usually diagnosed using noninvasive techniques. Echocardiography (in which sound waves are used to capture the motion of the heart) and associated Doppler studies are the primary methods of detecting PDA. Electrocardiography (ECG), in which electrodes are used to record the electrical activity of the heart, is not particularly helpful as no specific rhythms or ECG patterns can be used to detect PDA.[3] A chest X-ray may be taken, which reveals overall heart size (as a reflection of the combined mass of the cardiac chambers) and the appearance of blood flow to the lungs. A small PDA most often accompanies a normal-sized heart and normal blood flow to the lungs. A large PDA generally accompanies an enlarged cardiac silhouette and increased blood flow to the lungs. * Illustration of Patent Ductus Arteriosus * Patent ductus arteriosus * An echocardiogram of a stented persisting ductus arteriosus: One can see the aortic arch and the stent leaving. The pulmonary artery is not seen. * An echocardiogram of a coiled persisting ductus arteriosus: One can see the aortic arch, the pulmonary artery, and the coil between them. ## Prevention[edit] Some evidence suggests that indomethacin administration on the first day of life to all preterm infants reduces the risk of developing a PDA and the complications associated with PDA. Indomethacin treatment in premature infants also may reduce the need for surgical intervention.[4] Administering ibuprofen probably helps to prevent PDA and reduce the need for surgery but it probably increases the risk of kidney complications.[5] ## Treatment[edit] Symptomatic PDA can be treated with both surgical and non-surgical methods.[6] ### Conservative[edit] Neonates without adverse symptoms may simply be monitored as outpatients. ### Surgery[edit] Surgically, the DA may be closed by ligation (though support in premature infants is mixed).[7] This can either be performed manually and be tied shut, or with intravascular coils or plugs that leads to formation of a thrombus in the DA. Devices developed by Franz Freudenthal block the blood vessel with woven structures of nitinol wire.[8] ### Prostaglandin inhibitors[edit] Because prostaglandin E2 is responsible for keeping the DA open, NSAIDs (which can inhibit prostaglandin synthesis) such as indomethacin or a special form of ibuprofen have been used to initiate PDA closure.[1][9][10] Recent findings from a systematic review concluded that, for closure of a PDA in preterm and/or low birth weight infants, ibuprofen is as effective as indomethacin. It also causes fewer side effects (such as transient acute kidney injury) and reduces the risk of necrotising enterocolitis.[11] A review and meta-analysis showed that paracetamol may be effective for closure of a PDA in preterm infants.[12] A recent network meta-analysis that compared indomethacin, paracetamol and ibuprofen at different doses and administration schemes among them found that a high dose of oral ibuprofen may offer the highest likelihood of closure in preterm infants.[13] [14]Vasodilator therapy is suitable for patients with Eisenmenger physiology. To assess improvement in Eisenmenger physiology patients, close monitory of toe oxygen saturation is required, for there exists a chance of reversal after a successful right-to-left shunt While indomethacin can be used to close a PDA, some neonates require their PDA be kept open. Keeping a ductus arteriosus patent is indicated in neonates born with concurrent heart malformations, such as transposition of the great arteries. Drugs such as alprostadil, a PGE-1 analog, can be used to keep a PDA open until the primary defect is corrected surgically. ## Prognosis[edit] If left untreated, the disease may progress from left-to-right shunt (acyanotic heart) to right-to-left shunt (cyanotic heart), called Eisenmenger's syndrome. Pulmonary hypertension is a potential long-term outcome, which may require a heart and/or lung transplant. Another complication of PDA is intraventricular hemorrhage. ## History[edit] Robert Edward Gross, MD performed the first successful ligation of a patent ductus arteriosus on a seven-year-old girl at Children's Hospital Boston in 1938.[15] ## Adult[edit] Since PDA is usually identified in infants, it is less common in adults, but it can have serious consequences, and is usually corrected surgically upon diagnosis. ## See also[edit] * George Alexander Gibson ## References[edit] 1. ^ a b MedlinePlus > Patent ductus arteriosus Update Date: 21 December 2009 2. ^ "Medically Sound: Critical Blood Flow Redirection and a Fetus under Pressure – Fetal Heart Defects". Medically Sound. 6 October 2020. Retrieved 1 November 2020. 3. ^ "Tests and Diagnosis". Mayo Clinic. 16 December 2015. Retrieved 1 April 2015. 4. ^ Fowlie, PW; Davis PG; McGuire W (19 May 2010). "Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants (Review)". The Cochrane Database of Systematic Reviews (7): CD000174. doi:10.1002/14651858.CD000174.pub2. PMC 7045285. PMID 20614421. 5. ^ Ohlsson, A; Shah, SS (27 January 2020). "Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants". The Cochrane Database of Systematic Reviews. 1: CD004213. doi:10.1002/14651858.CD004213.pub5. PMC 6984616. PMID 31985838. 6. ^ Zahaka, KG and Patel, CR. "Congenital defects'". Fanaroff, AA and Martin, RJ (eds.). Neonatal-perinatal medicine: Diseases of the fetus and infant. 7th ed. (2002):1120–1139. St. Louis: Mosby. 7. ^ Mosalli R, Alfaleh K, Paes B (July 2009). "Role of prophylactic surgical ligation of patent ductus arteriosus in extremely low birth weight infants: Systematic review and implications for clinical practice". Ann Pediatr Cardiol. 2 (2): 120–6. doi:10.4103/0974-2069.58313. PMC 2922659. PMID 20808624. 8. ^ Alejandra Martins (2 October 2014). "The inventions of the Bolivian doctor who saved thousands of children". BBC Mundo. Retrieved 30 March 2015. 9. ^ circ.ahajournals.org 10. ^ MayoClinic > Patent ductus arteriosus (PDA). 22 Dec. 2009 11. ^ Ohlsson A, Walia R, Shah SS (2015). "Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants". Cochrane Database Syst Rev (2): CD003481. doi:10.1002/14651858.CD003481.pub6. PMID 25692606. 12. ^ Ohlsson, Arne; Shah, Prakeshkumar S. (27 January 2020). "Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants". The Cochrane Database of Systematic Reviews. 1: CD010061. doi:10.1002/14651858.CD010061.pub4. ISSN 1469-493X. PMC 6984659. PMID 31985831. 13. ^ Mitra, Souvik; Florez, Ivan D.; Tamayo, Maria E.; Mbuagbaw, Lawrence; Vanniyasingam, Thuva; Veroniki, Areti Angeliki; Zea, Adriana M.; Zhang, Yuan; Sadeghirad, Behnam (27 March 2018). "Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants". JAMA. 319 (12): 1221–1238. doi:10.1001/jama.2018.1896. ISSN 0098-7484. PMC 5885871. PMID 29584842. 14. ^ "Medically Sound: Diagnosing and treating congenital heart defects". Medically Sound. 6 October 2020. Retrieved 1 November 2020. 15. ^ [1], Robert E. Gross, Harvard Medical School Office for Faculty Affairs. ## External links[edit] * Patent Ductus Arteriosus Causes from US Department of Health and Human Services * Patent Ductus Arteriosus from Merck * Patent ductus arteriosus information for parents. Classification D * ICD-10: Q25.0 * ICD-9-CM: 747.0 * OMIM: 607411 * MeSH: D004374 * DiseasesDB: 9706 External resources * MedlinePlus: 001560 * eMedicine: emerg/358 * Patient UK: Patent ductus arteriosus * v * t * e Congenital vascular defects / Vascular malformation Great arteries/ other arteries Aorta * Patent ductus arteriosus * Coarctation of the aorta * Interrupted aortic arch * Double aortic arch * Right-sided aortic arch * Overriding aorta * Aneurysm of sinus of Valsalva * Vascular ring Pulmonary artery * Pulmonary atresia * Stenosis of pulmonary artery Subclavian artery * Aberrant subclavian artery Umbilical artery * Single umbilical artery Great veins Superior/inferior vena cava * Congenital stenosis of vena cava * Persistent left superior vena cava Pulmonary vein * Anomalous pulmonary venous connection (Total, Partial) * Scimitar syndrome Arteriovenous malformation * Cerebral arteriovenous malformation Authority control * TA98: A12.2.01.221 *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Patent ductus arteriosus

c0013274

wikipedia

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

{"gard": ["7342"], "mesh": ["D004374"], "umls": ["C0013274"], "orphanet": ["706"], "wikidata": ["Q2072063"]}

Epidermolysis bullosa simplex (EBS) is a group of hereditary epidermolysis bullosa (HEB) disorders characterized by skin fragility resulting in intraepidermal blisters and erosions that occur either spontaneously or after physical trauma. ## Epidemiology Reported prevalence ranges from 1/215,000 in the USA to 1/35,000 in Scotland. ## Clinical description Onset is usually at or shortly after birth, although blistering in localized EBS may not develop until late childhood or early adulthood. Along with localized or generalized blistering and erosions, sometimes showing characteristic patterns (herpetiform grouping), cutaneous features may include nail shedding and dystrophy, and, rarely, milia formation. Scarring is mostly absent or minimal (mild atrophic wrinkling and dyspigmentation). Other findings may include congenital absence of the skin, and localized or confluent keratoderma of the palms and soles. The commonest extracutaneous manifestation is blistering of the oral cavity. A variety of additional extracutaneous complications may occur and are age-dependent, with time of onset and cumulative risk of occurrence highly dependent on the EB subtype. Several subtypes exist based on the intraepidermal localization of blisters. In most, blisters occur in the basal layer of the epidermis (autosomal recessive EBS; Dowling-Meara type; Köbner type; EBS - muscular dystrophy; Ogna type; EBS - pyloric atresia; localized EBS; EBS with migratory circinate erythema; EBS with mottled pigmentation). However, 3 subtypes involve suprabasal blistering (EBS due to plakophilin deficiency, EBS superficialis, lethal acantholytic EB; see these terms). ## Etiology EBS is caused by genetic mutations in specific genes depending on the subtype. ## Diagnostic methods Diagnosis is based on determination of the epidermal level within which blisters develop following minor skin traction. Recommended techniques are immunofluorescence antigen mapping (IFM) and transmission electron microscopy (TEM) performed on a skin biopsy sample. Subtypes are then defined on the basis of the mode of transmission, IFM and TEM, and clinical presentation. Cutaneous findings are not reliable diagnostic markers. ## Differential diagnosis Diagnosis is usually straightforward with little need for extensive differential diagnosis. However, in the neonatal period, in utero herpes simplex infection may be considered, especially if there is no family history of blistering disease or if clinical findings are atypical for EB. The differential diagnosis in neonates and small children may include congenital aplasia cutis, neonatal pemphigus, neonatal herpes gestationis, staphylococcal scalded skin syndrome, as well as incontinentia pigmenti, epidermolytic ichthyosis, linear IgA dermatosis, bullous pemphigoid, and bullous impetigo (see these terms). ## Antenatal diagnosis Prenatal testing using fetal DNA from chorionic villi or amniotic fluid cells is possible if the causative gene is known and the pathogenetic mutation(s) identified. ## Genetic counseling Inheritance is either autosomal dominant or autosomal recessive, depending on the subtype. Correct diagnosis of EBS subtype is crucial to proper genetic counseling. ## Management and treatment Management is based on the avoidance of blistering by meticulous protective skin padding and appropriate life-style to avoid trauma, and prevention of secondary infection by careful wound care. Air-conditioning may help in preventing disease worsening in warm weather. Patients with EB subtypes with the highest risk of specific extracutaneous complications need to be monitored closely and appropriate measures implemented to prevent the affected tissues from becoming severely injured. ## Prognosis Prognosis is highly dependent on the subtype. Most patients have a normal life expectancy but significant morbidity and even early death may occur in some subtypes. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Epidermolysis bullosa simplex

c0079298

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=304

{"gard": ["10752"], "mesh": ["D016110"], "umls": ["C0079298"], "icd-10": ["Q81.0"], "synonyms": ["EBS", "EEB"]}

7q31 microdeletion syndrome is a rare chromosomal anomaly characterized by speech and language disorder, predominantly presenting as an apraxia of speech, sometimes associated with oral motor dyspraxia, dysarthria, receptive and expressive language disorder, and hearing loss. Individuals with larger deletions in this region have also been reported to display intellectual disability and autism. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

7q31 microdeletion syndrome

None

orphanet

https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=251061

{"icd-10": ["Q93.5"], "synonyms": ["Del(7)(q31)", "Monosomy 7q31"]}

Hall et al. (1974) reported 2 brothers with mental retardation, absence of eyebrows and eyelashes, progressive spastic quadriplegia, microcephaly, glaucoma, and small, beaked nose. One had had a 'cervical spinal cyst' removed at age 1 year and the second had occipital cranium bifidum occulatum. The parents were unrelated. They and 3 brothers were normal. INHERITANCE \- Autosomal recessive HEAD & NECK Head \- Microcephaly Eyes \- Eyebrows absent \- Glaucoma Nose \- Small nose \- Beaked nose SKELETAL Skull \- Microcephaly \- Cranium bifidum Spine \- Spinal cyst SKIN, NAILS, & HAIR Hair \- Eyebrows absent \- Eyelashes absent ▲ Close *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

ABSENT EYEBROWS AND EYELASHES WITH MENTAL RETARDATION

c0796125

omim

https://www.omim.org/entry/200130

{"mesh": ["C563111"], "omim": ["200130"], "orphanet": ["2985"], "synonyms": ["Alternative titles", "PSEUDOPROGERIA SYNDROME"]}

Chorea gravidarum SpecialtyNeurology, obstetrics Chorea gravidarum is a rare[1] type of chorea which presents with involuntary abnormal movement, characterized by abrupt, brief, nonrhythmic, nonrepetitive movement of any limb, often associated with nonpatterned facial grimaces. It is a complication of pregnancy which can be associated with eclampsia and its effects upon the basal ganglia. It is not a causal or pathologically distinct entity but a generic term for chorea of any cause starting during pregnancy. It is associated with history of Sydenham's chorea. It mostly occurs in young patients; the average age is 22 years.[2][3] Recently there has been a decline in incidence which is probably the result of a decline in rheumatic fever (RF), which was a major cause of chorea gravidarum before the use of antibiotics for streptococcal pharyngitis. ## Contents * 1 Pathophysiology * 2 Diagnosis * 2.1 Differential diagnoses * 3 Treatment * 4 See also * 5 References * 6 Further reading * 7 External links ## Pathophysiology[edit] Several pathogenetic mechanisms for chorea gravidarum have been offered, but none have been proven. History of either rheumatic fever or chorea is suspected:[2][3] the suggestion is that estrogens and progesterone may sensitize dopamine receptors (presumably at a striatal level) and induce chorea in individuals who are vulnerable to this complication by virtue of preexisting pathology in the basal ganglia. The relation to rheumatic fever was strengthened by many studies that showed that women with normal pregnancies before rheumatic fever developed chorea in subsequent pregnancies.[4][5] At least 35% of patients have a definite history of acute rheumatic fever and Sydenham chorea; 4% of those with chorea gravidarum had acute rheumatic fever.[2][3] It has been suggested that use of oral contraceptives is an infrequent cause of chorea. A patient developed this chorea with no definite evidence of previous Sydenham's chorea or recent streptococcal infections, but had anti-basal ganglia antibodies, suggesting immunological basis for the pathophysiology of this chorea.[6][7] ## Diagnosis[edit] ### Differential diagnoses[edit] * Pelizaeus–Merzbacher disease * Pantothenate kinase-associated neurodegeneration * Ramsay Hunt syndrome * Huntington's disease * Striatonigral degeneration * Lesch–Nyhan syndrome * Systemic lupus erythematosus * Lyme disease * Torticollis * Multiple system atrophy * Tourette syndrome and other tic disorders * Neuroacanthocytosis * Viral encephalitis * Neuronal ceroid lipofuscinosis * Wilson's disease * Olivopontocerebellar atrophy * Familial paroxysmal choreoathetosis * Benign hereditary chorea[8] Chorea can also be a manifestation of drug toxicity (for example, anticonvulsants, antiparkinson agents, neuroleptics, steroids, and estrogen), or a result of an infectious disease such as meningovascular syphilis, Lyme disease, viral encephalitis, and many others.[citation needed] ## Treatment[edit] Drug treatment is indicated for patients with severe disabling chorea. It is treated with haloperidol,[9][10][11] chlorpromazine alone or in combination with diazepam, and also pimozide, which is another neuroleptic drug which may have fewer adverse effects than haloperidol.[12] Valproic acid, chloral hydrate, risperidone, or phenobarbital can also be used.[13] ## See also[edit] * Chorea ## References[edit] 1. ^ Zegart, K. N.; Schwarz, R. H. (1968). "Chorea gravidarum". Obstetrics and Gynecology. 32 (1): 24–7. PMID 5742087. 2. ^ a b c Willson, Prentiss (1932). "Chorea Gravidarum". Archives of Internal Medicine. 49 (3): 471–533. doi:10.1001/archinte.1932.00150100128011. 3. ^ a b c Willson, Prentiss (1932). "Chorea Gravidarum". Archives of Internal Medicine. 49 (4): 671–97. doi:10.1001/archinte.1932.00150110134008. 4. ^ Black, M (1900). "Two cases of chorea in pregnancy". Glasgow Medical Journal: 441–4. 5. ^ Matthews, AA (1911). "Chorea complicating pregnancy". Northwest Med. 15: 372. 6. ^ Miranda, M; Cardoso, F; Giovannoni, G; Church, A (2004). "Oral contraceptive induced chorea: Another condition associated with anti-basal ganglia antibodies". Journal of Neurology, Neurosurgery, and Psychiatry. 75 (2): 327–8. doi:10.1136/jnnp.2003.019851. PMC 1738905. PMID 14742621. 7. ^ Archelos, Juan J.; Hartung, Hans-Peter (2000). "Pathogenetic role of autoantibodies in neurological diseases". Trends in Neurosciences. 23 (7): 317–27. doi:10.1016/S0166-2236(00)01575-7. PMID 10856942. 8. ^ Chorea Gravidarum at eMedicine 9. ^ Axley, John (1972). "Rheumatic chorea controlled with haloperidol". The Journal of Pediatrics. 81 (6): 1216–7. doi:10.1016/S0022-3476(72)80272-5. PMID 4643046. 10. ^ Patterson, John F. (1979). "Treatment of Chorea Gravidarum with Haloperidol". Southern Medical Journal. 72 (9): 1220–1. doi:10.1097/00007611-197909000-00044. PMID 472859. 11. ^ Donaldson, J. O. (1982). "Control of chorea gravidarum with haloperidol". Obstetrics and Gynecology. 59 (3): 381–2. PMID 7078886. 12. ^ Shannon, K. M.; Fenichel, G. M. (1990). "Pimozide treatment of Sydenham's chorea". Neurology. 40 (1): 186. doi:10.1212/wnl.40.1.186. PMID 2296371. 13. ^ Chorea Gravidarum~treatment at eMedicine ## Further reading[edit] * Palanivelu, L. M. (2007). "Chorea gravidarum". Journal of Obstetrics & Gynaecology. 27 (3): 310. doi:10.1080/01443610701241134. PMID 17464821. ## External links[edit] Classification D * ICD-10: G25.5, O99.3 * MeSH: D020150 External resources * eMedicine: neuro/61 * 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 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]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Chorea gravidarum

c0264746

wikipedia

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

{"mesh": ["D020150"], "umls": ["C0264746"], "icd-10": ["O99.3", "G25.5"], "wikidata": ["Q5105007"]}

## Summary ### Clinical characteristics. SCN1A seizure disorders encompass a spectrum that ranges from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome are often associated with cognitive decline. Less commonly observed phenotypes include myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, infantile spasms, epilepsy with focal seizures, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A seizure disorders can vary even within the same family. ### Diagnosis/testing. The diagnosis of an SCN1A seizure disorder is established in a proband by identification of a heterozygous pathogenic variant in SCN1A by molecular genetic testing. ### Management. Treatment of manifestations: Care is best provided by a physician (e.g., pediatric epileptologist) familiar with the pharmacotherapy for this disorder. Seizure control is critical to prevent permanent injury and death. Antiepileptic drugs (AEDs): clobazam (can be used for treatment of seizures in Lennox-Gastaut syndrome); stiripentol, benzodiazepines, cannabidiol, topiramate, levetiracetam, valproic acid, and ethosuximide. Levetiracetam is often effective, but may make seizures worse in some individuals. Phenobarbital is effective but poorly tolerated because of its effects on cognition. Use of the ketogenic diet to decrease seizure frequency has been beneficial in some affected individuals. Parents are advised to take a CPR course. Routine seizure and personal safety education is indicated. Prevention of secondary complications: Use of protective helmets by individuals with atonic seizures or myoclonic-astatic epilepsy. Good sleep hygiene should be encouraged. Persons with epilepsy should be made aware of motor vehicle driving laws. Surveillance: Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration; EEG monitoring for new or different seizure types; polysomnography should be considered if obstructive or central sleep apnea is suspected. Agents/circumstances to avoid: AEDs: carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic seizures; phenytoin, which can induce choreoathetosis; rufinamide may exacerbate seizures as well; acetaminophen, which is hepatotoxic. Activities in which a sudden loss of consciousness could lead to injury or death (e.g., bathing, swimming, driving, or working/playing at heights). Sleep deprivation, which can exacerbate seizures, should be avoided. Pregnancy management: Pregnant women should receive counseling regarding the risks and benefits of the use of antiepileptic drugs during pregnancy; the advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily; the effects of pregnancy on anticonvulsant metabolism; and the effect of pregnancy on maternal seizure control. ### Genetic counseling. SCN1A seizure disorders are inherited in an autosomal dominant manner. A proband with an SCN1A seizure disorder may have an inherited or a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants varies by phenotype: the percentage of probands with an SCN1A seizure disorder and an affected parent decreases as the severity of the phenotype in the proband increases; thus, most SCN1A-related severe myoclonic epilepsy in infancy (SCN1A-SMEI) and ICE-GTC are the result of a de novo pathogenic variant. Each child of an individual with an SCN1A seizure disorder has a 50% chance of inheriting the pathogenic variant; however, the risk of developing seizures is less than 100% because of reduced penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known. ## Diagnosis ### Suggestive Findings SCN1A seizure disorders encompass a spectrum of phenotypes that ranges from mild to severe. When the following suggestive features are present, SCN1A molecular genetic testing should be considered: * Precipitation of seizure with fever, warmth, or vaccination * Prolonged or hemiconvulsive seizures * Seizure provocation with overstimulation or flashing/patterned visual stimulus * Worsening of seizures with medications that inhibit sodium channel function as the primary mechanism of action (e.g., carbamazepine, oxcarbazepine, phenytoin, lamotrigine) These features can be seen in any one of several clinical epilepsy syndromes that can occur in individuals with a heterozygous SCN1A pathogenic variant. Clinical epilepsy syndromes reported in individuals with SCN1A seizure disorders (see Clinical Characteristics): * Febrile seizures (simple or complex) may be the first and only manifestation of an SCN1A pathogenic variant, although individuals presenting with febrile seizures can also progress to Dravet syndrome. Febrile seizure onset is typically in the first year of life; seizures are prolonged and multiple. * Febrile seizures plus (FS+) is characterized by seizure onset before age one year, persistence beyond age six years, unusual severity (including status epilepticus), and occurrence of unprovoked (e.g., afebrile) seizures of any kind. * Generalized epilepsy caused by SCN1A pathogenic variants most often involves tonic, clonic, tonic-clonic, myoclonic, or absence seizures. * Generalized epilepsy with febrile seizures plus (GEFS+) * Dravet syndrome * Severe myoclonic epilepsy, borderline (SMEB) * Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) * Infantile partial seizures with variable foci Less common presentations of SCN1A seizure disorders * Epilepsy with focal seizures * Myoclonic-astatic epilepsy (MAE, Doose syndrome) * Lennox-Gastaut syndrome * Infantile spasms * Vaccine-related encephalopathy and seizures ### Establishing the Diagnosis The diagnosis of an SCN1A seizure disorder is established in a proband by identification of a heterozygous pathogenic variant in SCN1A by molecular genetic testing (see Table 1). Because the phenotype of SCN1A seizure disorders is indistinguishable from many other inherited disorders with seizures, the recommended molecular genetic testing is an epilepsy multigene panel. Note: Single-gene testing (sequence analysis of SCN1A, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. * An epilepsy multigene panel that includes SCN1A 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. * Single-gene testing. Sequence analysis of SCN1A 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 first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. ### Table 1. Molecular Genetic Testing Used in SCN1A Seizure Disorders View in own window Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method SCN1ASequence analysis 373%-92% 4 Gene-targeted deletion/duplication analysis 58%-27% 6, 7, 8 1\. See Table A. Genes and Databases for chromosome locus and protein. 2\. See Molecular Genetics for information on allelic variants detected in this gene. 3\. 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. 4\. Estimated value based on subtracting experimental values of deletion frequencies of 8%-27% from 100% (see footnote 5). 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\. Using a variety of methods to identify deletions encompassing the SCN1A locus in individuals with SMEI who did not have an SCN1A pathogenic variant identified on sequence analysis, Madia et al [2006] found deletions in three of 39 (8%), Mulley et al [2006] found deletions in two of 13 (15%), and Suls et al [2006] found deletions in three of 11 (27%). In these three studies a total of eight of 63 (12%) individuals with SMEI who did not have a sequence variant identified on sequence analysis had an identifiable SCN1A deletion. 7\. Marini et al [2009] found that 12.5% of individuals with Dravet syndrome who did not have a pathogenic variant identified on sequence analysis had copy number variations that were detectable by MLPA. 8\. It is not known if the percent of exon and whole-gene deletions is the same for the other phenotypes in the spectrum of SCN1A seizure disorders. ## Clinical Characteristics ### Clinical Description The natural history of SCN1A seizure disorders is strongly influenced by seizure phenotype, which can range from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end [Kimura et al 2005, Mantegazza et al 2005, Fujiwara 2006, Gennaro et al 2006]. The phenotype varies even among family members with the same pathogenic variant (see Figure 1). As a result of this variable expressivity, long-term prognosis is difficult to determine. #### Figure 1. Findings in a family illustrating variable expressivity among individuals with the same pathogenic variant. The proband, a boy (arrow) with febrile convulsions since age seven months, had frequent, difficult-to-control partial seizures beginning at age (more...) Features associated with poor cognitive outcome include early myoclonic and absence seizures [Ragona et al 2011]. Phenotypes with intractable seizures (e.g., Dravet syndrome) usually cause epileptic encephalopathy, a form of progressive dementia. The root cause of the encephalopathy is unknown: the effects on cognition of seizures, the most obvious explanation, cannot be separated from the effects of medication or of an SCN1A pathogenic variant [Riva et al 2009]. In addition to having seizures in response to strong environmental stimuli, individuals with SCN1A seizure disorders often have an ADHD-like phenotype characterized by impulsivity, inattentiveness, and distractibility. Possibly related to the inability of the GABA system to provide negative feedback on extraneous sensory input, these symptoms tend to be less responsive to conventional stimulant medications. The phenotypes in SCN1A seizure disorders include the following (see Table 2). ### Table 2. Distribution of Seizure Phenotypes in SCN1A Seizure Disorders View in own window DisorderDistribution Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC)70% 1 Dravet syndrome33%-90% 2 Generalized epilepsy with febrile seizures plus (GEFS+)5%-10% 3 Febrile seizures plus (FS+)Unknown Simple febrile seizuresUnknown 1\. Fujiwara et al [2003] 2\. Mulley et al [2005] 3\. Marini et al [2007] Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). This phenotype is defined as generalized seizures including absence seizures and generalized tonic-clonic seizures with onset in infancy or childhood. However, partial seizures can occur in up to 13% of affected individuals [Bonanni et al 2004]. Localized epilepsy, either alternating hemiconvulsive or complex partial seizures, may also be seen. Children with frequent generalized tonic-clonic seizures often develop cognitive impairment. The distinction between ICE-GTC and Dravet syndrome is not clear, and the former is not included in the ILAE classification system. Dravet syndrome. Wirrell et al [2017] published guidelines for the clinical diagnosis of Dravet syndrome. Presentation is between age one and 18 months after a period of normal development. Seizures are often prolonged and include recurrent generalized tonic-clonic or hemiconvulsive seizures. Myoclonic seizures are typically seen by age two years. Obtundation status, focal dyscognitive seizures, and atypical absences are often seen after age two years. The seizures are often triggered by hyperthermia (e.g., a hot bath, physical exertion, fever following vaccination), light stimuli, or sodium channel-blocking antiepileptic medications. Status epilepticus is common, and pharmacologic management is difficult. Seizures tend to lessen in severity after puberty; however, they rarely resolve completely. The initial EEGs are often normal or show nonspecific changes such as generalized slowing, but over time epileptiform activity appears. Patterns can include generalized spike and wave discharges, multiple spike and wave (also referred to as polyspike and wave) discharges, and multifocal spikes (see Figure 2). Brain MRI is typically normal or may show mild generalized atrophy and/or hippocampal sclerosis. #### Figure 2. Individuals with Dravet syndrome often have an unusual seizure type that frequently will manifest as obtundation status epilepticus. The EEG during these difficult-to-classify seizures shows an alternation of generalized and focal discharges with variable (more...) The myoclonic seizures that tend to appear later in the course often coincide with the appearance of cognitive dysfunction, ataxia, and psychomotor regression. Some degree of cognitive impairment is always seen, ranging from moderate to severe, often with marked inattention, impulsivity, and distractibility. Anxiety, obsessive personality traits, and autism spectrum disorder are common. Crouched gait, hypotonia, incoordination, and impaired dexterity are typically evident by age three to four years. Parkinsonian features of bradykinesia, tremor, and antecollis have been reported in adults with Dravet syndrome [Rilstone et al 2012, Aljaafari et al 2017]. Individuals with Dravet syndrome often develop a crouched gait. In spite of the gait being commonly described as "ataxic," affected individuals are more mobile than one would expect from how crouched they appear. The gait changes tend to be more prevalent in older children. In one study these changes were absent before age five years, but present in 5/10 children ages 6-12 years and in 8/9 children age 13 years or older [Rodda et al 2012]. In one cohort, 5/10 adults with Dravet syndrome had crouched gait [Rilstone et al 2012]. Decreased passive knee extension, increased external tibial torsion, and pes planovalgus all progressed [Rodda et al 2012]. Hip internal rotation did not show age-related changes. In one study antecollis was present in 9/14 and parkinsonian gait in 8/14 individuals with Dravet syndrome [Aljaafari et al 2017]. The degree of ataxia in affected individuals is greater than would be expected by the use of anticonvulsant medications alone. Pathogenic variants affecting the pore region appear to be more associated with gait changes [Kanai et al 2004, Rilstone et al 2012]. Severe myoclonic epilepsy, borderline (SMEB). This description is sometimes used for children who have some but not all of the features of Dravet syndrome [Fukuma et al 2004]. Generalized epilepsy. This phenotype is otherwise indistinguishable from idiopathic generalized epilepsy with onset in childhood or adolescence. Generalized epilepsies caused by SCN1A pathogenic variants are most often tonic, clonic, tonic-clonic, myoclonic, or absence. Generalized epilepsy with febrile seizures plus (GEFS+). This term refers to the findings in a family rather than an individual [Arzimanoglou et al 2004]. In a family with GEFS+, epilepsy with variable expressivity and incomplete penetrance is inherited in an autosomal dominant manner. It implies a spectrum from mild (such as febrile seizure alone) to severe (including medically treatable generalized epilepsy, intractable generalized epilepsy, or Dravet syndrome). Intermediate phenotypes with myoclonic epilepsy, absence epilepsy, or focal epilepsy are also included. Individuals with GEFS+ often have febrile seizures (or FS+) in early childhood, followed by occasional tonic, clonic, myoclonic, or absence seizures that respond to medication and remit by late childhood or early adolescence. The proportion of children with GEFS+ whose first seizure occurs in the context of immunization appears to be greater than the proportion of children with febrile seizures unrelated to FS+ and GEFS+. Febrile seizures plus (FS+). This subset of febrile seizures (simple or complex) is characerized by any of the following features: * Onset before age one year * Persistence beyond age six years * Unusual severity (including status epilepticus) * Occurrence of unprovoked (i.e., afebrile) seizures of any kind Febrile seizures. These childhood seizures occur only in association with fever. The epidemiologic definition requires the following: * Onset on or after age six months * Resolution by age five years * Fever higher than 38° C (without other evidence of CNS infection) * No other identifiable cause Febrile seizures are divided into simple febrile seizures and complex febrile seizures. Febrile seizures are considered complex if any of the following is present: * Duration longer than 15 minutes * Occurrence of more than one seizure within 24 hours * Presence of any partial (focal) features during the seizure Febrile seizures with the following criteria are associated with a higher risk for developing Dravet syndrome [Hattori et al 2008]: * Febrile seizure onset before age seven months * Five or more febrile seizures * Prolonged seizure(s) lasting more than ten minutes The febrile seizure characteristics include hemiconvulsions, partial seizures, myoclonic seizures, and hot water-induced seizures. Infantile partial seizures with variable foci, also referred to as migrating partial seizures of infancy, cryptogenic focal epilepsy, or severe infantile multifocal epilepsy [Harkin et al 2007]. Multifocal partial seizures are often the first manifestation; however, in some children the first manifestation is febrile seizures. Severity varies and pharmacoresistance is common, but not absolute. Myoclonic seizures are rare but may be precipitated by administration of medications that inactivate the sodium channel, including phenytoin, carbamazepine, or lamotrigine. Cognitive deterioration may occur, especially when seizure control is incomplete. Electroencephalography shows multifocal independent spikes; generalized spike and wave discharges may be seen. Less common phenotypes associated with SCN1A pathogenic variants include the following: * Myoclonic-astatic epilepsy (MAE, also called Doose syndrome).This phenotype is defined as the combination of myoclonic, atonic, and atypical absence seizures. Onset is usually after age two years (range: 7 months - 8 years). Although isolated myoclonic seizures as well as tonic seizures can occur, they are not characteristic of this syndrome (which distinguishes them from Lennox-Gastaut syndrome). Development prior to seizure onset is often normal. The course can range from spontaneous seizure resolution without cognitive impairment to intractable seizures with severe intellectual disability [Arzimanoglou et al 2004]. * Lennox-Gastaut syndrome (LGS). This phenotype is defined as slow spike-waves on EEG, developmental delay, and multiple types of generalized seizures (particularly atypical absence, tonic, and atonic seizures). LGS usually begins during childhood (ages 2-14 years). Any type of seizure can be seen in this syndrome; status epilepticus is common [Arzimanoglou et al 2004]. Only a minority of persons with the LGS phenotype have an SCN1A pathogenic variant, usually in the context of a family in which Dravet syndrome occurs [Singh et al 2001]. This subset remains poorly characterized. It is unclear whether SCN1A-associated LGS differs phenotypically from LGS of other etiologies. * Infantile spasms. This phenotype is defined as clustered seizures that show brief (<1 second) axial contractions associated with a slow-wave transient on EEG, often followed by generalized attenuation of the background. Both findings may be intermixed with fast activity. The resting EEG (between seizures) shows high-voltage slowing and a multifocal spike pattern known as hypsarrhythmia [Arzimanoglou et al 2004]. Association of an SCN1A pathogenic missense variant with infantile spasms has been reported once [Wallace et al 2003]. The single individual represents fewer than 1% of reported cases, although publication bias makes it difficult to estimate the actual proportion. * Vaccine-related encephalopathy and seizures. This phenotype is defined as sudden onset of seizures and encephalopathy in infants 48 hours after immunization. Berkovic et al [2006] identified an SCN1A pathogenic variant in 11/14 children diagnosed with post-vaccine encephalopathy. Tro-Baumann et al [2011] reported that 19 of 70 individuals with an SCN1A pathogenic variant and the Dravet phenotype had a history of seizures following vaccination. Imaging. Brain MRI is most often normal early in the course of the disease; however, it often evolves to show cortical atrophy, cerebellar atrophy, white matter hyperintensity, ventricular enlargement, hippocampal sclerosis, or cortical dysplasia [Striano et al 2007]. Individuals with a more severe phenotype early in life often have more atrophic changes seen on MRI later in life. ### Genotype-Phenotype Correlations Given the variable expressivity of SCN1A disorders, consistent genotype-phenotype correlations have been infrequently identified. Pathogenic nonsense variants and missense variants in the voltage sensor or pore region often lead to a more severe phenotype [Zuberi et al 2011, Meng et al 2015]. A truncation variant, however, does not necessarily result in a severe phenotype [Suls et al 2010, Yu et al 2010]. Affected individuals with missense variants in the pore-forming region and truncations in the SCN1A protein are more likely to have gait changes [Kanai et al 2004, Rilstone et al 2012]. These changes may be due to a direct effect of the SCN1A pathogenic variant in the cerebellar Purkinje cells [Catterall et al 2010]. Variants in SCN9A, CACNA1A, POLG, and CACNB4 have been suggested to play a role in modifying the phenotype of SCN1A seizure disorders [Ohmori et al 2008b, Gaily et al 2013, Ohmori et al 2013, Yang et al 2018]; however, the data are insufficient for use in clinical management or prognosis. ### Nomenclature Generalized epilepsy with febrile seizures plus has been referred to as GEFS+, type 2 related to SCN1A pathogenic variants. Intractable infantile partial seizures has been referred to as ICE-GTC. Dravet syndrome is also known as severe myoclonic epilepsy in infancy (SMEI) or polymorphic myoclonic epilepsy in infancy (PMEI). The term "Dravet syndrome" is preferred over the descriptive names because myoclonic seizures can be absent in children whose seizures are otherwise similar. ### Penetrance SCN1A seizure disorders show incomplete penetrance and variable expressivity. Penetrance varies by phenotype. For example, Bonanni et al [2004] estimated the penetrance to be 70% for the GEFS+ phenotype, whereas Mantegazza et al [2005] reported the penetrance to be 90% for the familial simple febrile seizure phenotype. ### Prevalence Wu et al [2015] reported a population-based estimate of the incidence of Dravet syndrome of 1:15,000. This is supported by similar estimates in Denmark of 1:22,000 [Bayat et al 2015] and a slightly lower number,1:40,900, in the UK [Brunklaus et al 2012]. 2.5% (95%CI:1.3 to 3.6%) of all reported seizures following vaccinations in the first year of life were due to SCN1A Dravet syndrome [Verbeek et al 2013]. ## Differential Diagnosis The phenotypes typically seen in individuals with an SCN1A pathogenic variant are neither necessary nor sufficient to diagnose an SCN1A seizure disorder. Other conditions (including those caused by pathogenic variants in other genes) may be associated with the same phenotypes. It is most important to distinguish SCN1A seizure disorders from potentially treatable conditions, including the following [Arzimanoglou et al 2004, Roger et al 2006]: * Pyridoxine-dependent epilepsy (an autosomal recessive disorder resulting from pathogenic variants in ALDH7A1) and B6-related epilepsies * Inborn errors of metabolism, including mitochondrial dysfunction, which may be diagnosed by the presence of abnormal serum concentrations of lactate, ketones, ammonia, amino acids, and/or abnormal concentrations of urine organic acids (see Mitochondrial Disorders Overview) * Biotinidase deficiency, an autosomal recessive disorder resulting from pathogenic variants in BTD, which is usually identified during newborn screening * Glucose transporter type 1 deficiency syndrome (Glut1 DS), which is diagnosed by low CSF glucose concentrations, and responds to the ketogenic diet. This disorder is caused by mutation of SLC2A1 and is most commonly autosomal dominant. Rarely, Glut1 DS may be inherited in an autosomal recessive manner. * Hepatic porphyrias, which usually demonstrate photosensitive porphyrins in the urine and reduced monopyrrole porphobilinogen (PBG) deaminase in red cells (See Acute Intermittent Porphyria, Familial Porphyria Cutanea Tarda, Hereditary Coproporphyria, and Variegate Porphyria.) If the family history is negative or unavailable, sporadic epilepsies (i.e., those without a genetic cause) need to be included in the differential diagnosis, as does any cause of epilepsy with nonspecific imaging findings. Some general categories of injury to consider include the following [Arzimanoglou et al 2004, Roger et al 2006]: * Trauma * Hypoxia * Sequelae of meningitis or hemorrhage * Infectious or autoimmune cerebritis * Vasculitis * Paraneoplastic syndrome * Toxins (including drug withdrawal) * Endocrinopathy A positive family history for other individuals with epilepsy significantly increases the likelihood of an inherited epilepsy syndrome [Arzimanoglou et al 2004, Roger et al 2006]. See Table 3. ### Table 3. Selected Genes of Interest in the Differential Diagnosis of SCN1A Seizure Disorders View in own window GeneAssociated PhenotypesClinical Features ADNFLEADEAF (ADLTE)BFIEBFNECAEEIEEFEBGEFS+JAEJMENEEOverlapping w/SCN1A seizure disordersDistinguising from SCN1A seizure disorders SCN1A 1+++NANA CHRNA2+Focal seizures may become secondary generalized. * Nocturnal frontal semiology seizures (fast, quick recovery, tonic, hypermotor) * Onset age: <20 yrs CHRNA4+ CHRNB2+ CPA6+Epilepsy can include: * Febrile seizures * Focal seizures w/secondary generalization * Primary generalized seizures * Focal seizures more often auditory, mesiotemporal, or occipitotemporal * Variability can resemble GEFS+, but inheritance pattern is recessive, so pedigree affecting multiple generations is uncommon. * Sodium channel medications can be helpful. CRH+Focal seizures may become secondary generalized. * Nocturnal frontal semiology seizures (fast, quick recovery, tonic, hypermotor) * Onset age: <20 yrs DEPDC5+ ECA2++ * CAE & JAE seen in some individuals w/SCN1A-GEFS+ * JAE may evolve to JME. * Staring seizures only * Absence of DS, GEFS+, intractable epilepsy features EFHC1++ GABRD++++Similar to SCN1A-GEFS+May be clinically indistinguishable from SCN1A epilepsy GABRG2+Febrile seizures / GEFS+ phenotypeMay be clinically indistinguishable from SCN1A epilepsy KCNQ2++Some affected individuals may show both BECTS & neonatal seizures. * Nocturnal GTC * Focal seizures w/face & limb semiology * Absence of DS, GEFS+, intractable epilepsy features * Neonatal onset (rare in SCN1A seizure disorders) GeneAssociated PhenotypesClinical Features ADNFLEADEAF (ADLTE)BFIEBFNECAEEIEEFEBGEFS+JAEJMENEEOverlapping w/SCN1A seizure disordersDistinguishing from SCN1A seizure disorders KCNQ3++ * Focal seizures * Typically benign but may be encephalopathic Neonatal onset (rare in SCN1A seizure disorders) KCNT1+Focal seizures may become secondary generalized. * Nocturnal frontal semiology seizures (fast, quick recovery, tonic, hypermotor) * Onset age: <20 yrs LGI1+Focal seizures may become secondary generalized. * Absence of DS, GEFS+, intractable epilepsy features * Very different seizure semiology (auditory, MTLS-like, or occipitotemporal) MICAL1+Focal seizures may become secondary generalized. * Absence of DS, GEFS+, intractable epilepsy features * Very different seizure semiology (auditory, MTLS-like, or occipitotemporal) PCDH19Phenotype can be quite similar to Dravet syndrome; often respond to the same medications * X-linked * Most symptomatic individuals are female. * Febrile & temperature-induced seizures that tend to occur in clusters * Onset of seizures usually a little later (age ≥12 mos) * May have fewer myoclonic jerks & absence seizures than in SCN1A seizure disorders GeneAssociated PhenotypesClinical Features ADNFLEADEAF (ADLTE)BFIEBFNECAEEIEEFEBGEFS+JAEJMENEEOverlapping w/SCN1A seizure disordersDistinguishing from SCN1A seizure disorders RELN+Focal seizures may become secondary generalized. * Absence of DS, GEFS+, intractable epilepsy features * Very different seizure semiology (auditory, MTLS-like, or occipitotemporal) SCN1B+Febrile seizures / GEFS+ phenotypeLater onset than in SCN1A epilepsy SCN2A++ * Intractable seizures * Occasionally SCN1A epilepsy may show infantile spasms * Response to Na channel blocker * Infantile spasms common SCN8A+ * Ataxic gait * Intractable seizures * Occasionally SCN1A epilepsy may show infantile spasms. * Response to Na channel blocker * Infantile spasms common * SUDEP frequent SCN9A++Dravet syndrome may be seen w/this genotype.May be clinically indistinguishable from SCN1A epilepsy STX1B+Febrile seizures / GEFS+ phenotypeMay be clinically indistinguishable from SCN1A epilepsy but most affected individuals become seizure-free later in childhood. ADLTE = autosomal dominant lateral temporal lobe epilepsy; ADNFLE = autosomal dominant nocturnal frontal lobe epilepsy; ADEAF = autosomal dominant partial epilepsy with auditory features; BECTS = benign epilepsy with centrotemporal spikes; BFIE = benign familial infantile epilepsy; BFNE = benign familial neonatal epilepsy; CAE = childhood absence epilepsy; DS = Dravet syndrome; EIEE = early-infantile epileptic encephalopathy; FEB = familial febrile seizures; FLE = frontal lobe epilepsy; GEFS+ = generalized/genetic epilepsy with febrile seizure plus; GTC = generalized tonic-clonic; JAE = juvenile absence epilepsy; JME = juvenile myoclonic epilepsy; MOI = mode of inheritance; MTLS = mesial temporal lobe seizure; NEE = neonatal epileptic encephalopathy; SUDEP = sudden unexpected death in patients with epilepsy; TLE = temporal lobe epilepsy; XL = X-linked 1\. Topic of this GeneReview; included for comparison Familial epilepsy syndromes with an unknown molecular basis may also be considered in the differential diagnosis of SCN1A seizure disorders. These syndromes include: * Childhood occipital epilepsy, which may be associated with focal seizures that become secondary generalized. Unlike SCN1A seizure disorders, childhood occipital epilepsy is also associated with seizures with visual hallucinations or tonic components (which spread to the frontal lobe) and O1/2 EEG spikes (OMIM 132090). * Epilepsy with photoparoxysmal response. Unlike SCN1A seizure disorders, epilepsy with photoparoxysmal response is associated generalized idiopathic epilepsy without intractability (OMIM 132100). To see loci and additional genes associated with the phenotypes in Table 3, see the following OMIM Phenotypic Series: * Epilepsy, familial temporal lobe * Epilepsy, generalized, with febrile seizures plus (GEFS+) * Epileptic encephalopathy, early infantile * Epileptic encephalopathy, infantile or early childhood * Seizures, benign familial infantile * Seizures, benign familial neonatal * Seizures, familial febrile ## Management ### Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an SCN1A seizure disorder, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: * Neurologic examination * Cognitive neuropsychological evaluation * Behavioral neuropsychological evaluation * Electroencephalogram (EEG), including video EEG telemetry where ictal onset or semiology is unclear * Consideration of polysomnography if obstructive or central sleep apnea is suspected * Consultation with a clinical geneticist and/or genetic counselor ### Treatment of Manifestations Care is best provided by a physician (e.g., pediatric epileptologist) familiar with the pharmacotherapy for this disorder. Seizure control is critical because children with SCN1A seizure disorder are at high risk for sudden unexplained death in epilepsy (SUDEP). In addition, prolonged acute seizures may cause permanent injury [Chipaux et al 2010, Takayanagi et al 2010]. Pharmacologic treatment focuses on the observations that abnormal SCN1A channels disproportionately affect GABA neurons [Yu et al 2006] and that the associated seizures respond optimally to antiepileptic drugs (AEDs) that bind to the GABA receptor: * Clobazam (0.2-1 mg/kg/day) is FDA approved for the treatment of seizures in Lennox-Gastaut syndrome. Stiripentol (30-100 mg/kg/day) is accepted by epileptologists as an effective therapeutic agent in SCN1A seizure disorders. It was FDA approved in 2018. It is part of the early standard of care in Europe, and is used in the US after other conventional anticonvulsants have failed. The evidence of effectiveness in SCN1A epilepsy is based on double-blind evaluation of seizure reduction in Dravet syndrome [Chiron et al 2000]. Thanh et al [2002] demonstrated efficacy of the drug when compared with placebo; only moderate side effects including drowsiness, loss of appetite, and occasional neutropenia in infants and young children were observed. In a recent US survey of 82 children with Dravet syndrome, stiripentol was found to be effective in reducing prolonged seizures [Wirrell et al 2013]. Stiripentol, which acts directly on GABAA receptors [Quilichini et al 2006], is also a potent inhibitor of the hepatic enzymes CYP3A4, CYP1A2, and CYP2C19. As a result, it increases the serum concentration of several common AEDs, including valproic acid, clobazam, and its metabolite nor-clobazam [Thanh et al 2002]. Doses above 50 mg/kg/day are usually not tolerated when used in conjunction with valproic acid and clobazam. Children older than age 12 years may not tolerate stiripentol because of digestive tract side effects and nausea [Thanh et al 2002]. * Benzodiazepines. Individuals taking stiripentol must exercise caution in the use of benzodiazepines [Thanh et al 2002]. A single infusion of diazepam and clonazepam appears to be safe [Thanh et al 2002]. * Cannabidiol. Two double-blind, randomized, placebo-controlled clinical trials demonstrated efficacy in treating seizures associated with Dravet syndrome [Devinsky et al 2017]. Recommended dose is 5 mg/kg/day divided twice a day for 1 week, then 10 mg/kg/day divided twice a day thereafter, and doses above 20 mg/kg/day when indicated. The median reduction of the frequency of convulsive seizures per month was 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo. At least 50% reduction in convulsive seizure frequency was a seen in 43% of the cannabidiol group and 27% of the placebo arm (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). Cannabidiol significantly reduced the frequency of all seizure types combined (P=0.03), but there was no significant reduction specifically in nonconvulsive seizures. The percentage of individuals who became seizure free was 5% with cannabidiol and 0% with placebo (P=0.08). Diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver function tests occurred more frequently in the cannabidiol group than in the placebo group. * Fenfluramine is a serotonergic [Fuller et al 1988] that had been used for the treatment of Dravet syndrome with success in Belgium; it is not FDA approved for use in the United States. Fenfluramine was used previously for the treatment of obesity. Cardiac complications including valve thickening and pulmonary hypertension led to withdrawal from the US market. However, recent preliminary studies found only trivial cardiac valve thickening [Ceulemans et al 2012, Ceulemans et al 2016]. In a study of 12 individuals with Dravet syndrome (11 with SCN1A Dravet syndrome), fenfluramine was combined with valproic acid and in 9/12 individuals it was further combined with benzodiazepines (clobazam, lorazepam), topiramate, lamotrigine, levetiracetam, and ethosuximide. Eight of 12 individuals were seizure-free for more than one year while on fenfluramine (and their other antiepileptic medications). In a five-year follow up of ten individuals with a mean fenfluramine treatment duration of 16.1 years, 7/10 individuals were seizure free longer than two years and 90% of all individuals had an average seizure frequency of less than one seizure per month over the five-year observation period [Ceulemans et al 2016]. * Topiramate [Coppola et al 2002] * Valproic acid (10-30 mg/kg/day) [Thanh et al 2002] * Ethosuximide can be effective for absence seizures. The dose is usually limited by gastrointestinal side effects, which can be minimized by more frequent dosing. * Levetiracetam (20-80 mg/kg/day) is often effective, but may make seizures worse in some individuals [Caraballo et al 2010]. * Potassium bromide is not FDA approved in the US, but widely used in Japan [Tanabe et al 2008] and Europe (it is approved for use in Germany under the DIBRO-BE mark) with reasonable efficacy at doses of up to 100 mg/kg/day. A non-allergic rash is the most common adverse effect, and dose adjustments must be made slowly due to the long half-life. It will cause an artifactual increase in serum chloride measurements on most laboratory instruments in routine clinical use. * Phenobarbital. Although effective, phenobarbital is poorly tolerated because of its effects on cognition. When it is taken in combination with stiripentol, the serum concentration of phenobarbital is increased because stiripentol slows the metabolism and excretion of barbiturates. * Ketogenic diet. Dressler et al [2010] report that seizures were reduced by more than 50% in 62.5% of persons with Dravet syndrome who stayed on the diet for six months. The findings of Nabbout et al [2011] in 15 individuals also support the use of the ketogenic diet in Dravet syndrome. Due to the sedating effects of seizure medications and the possibility of respiratory depression (especially with benzodiazepines and barbiturates), parents are advised to take a CPR course. Routine seizure and personal safety counseling is indicated. Seizures are not always responsive to conventional AEDs. Anecdotal evidence suggests that the following drugs / treatment modalities may be effective for SCN1A Dravet syndrome [Dravet et al 2002]: * Ethosuximide and high-dose piracetam for myoclonic seizures * Corticosteroids * Immunoglobulins Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit. Non-medical interventions that families have reported to be helpful include the following [Nolan et al 2008]: * Placement of an indwelling venous access device * Creating a portable microenvironment * Having a written emergency department protocol * Establishing emergency routines for the family * Assigning a parent on call to lessen the effect on the sibs * Creating personal time to decrease parent stress * Finding respite care * Contacting an internet support group ### Prevention of Secondary Complications Individuals experiencing atonic seizures or myoclonic-astatic epilepsy should be advised to wear a protective helmet. Sleep deprivation and illness can exacerbate SCN1A-associated seizures; thus, good sleep hygiene should be encouraged. Comorbidity with sleep apnea also frequently occurs in individuals with epilepsy [Malow et al 2000], and can influence seizure control, behavior, and cognition. Although immunization may trigger a seizure, it does not affect the natural course of the disorder. McIntosh et al [2010] looked retrospectively at a cohort of 14 individuals with Dravet syndrome and found no effect of immunization on cognitive outcome. These authors suggest that the immunization schedule not be altered and that the risk for fever following immunization could be reduced by providing a scheduled, long-acting NSAID (e.g., naproxen). The treating neurologist may also consider increasing the anticonvulsant dose(s) temporarily around the time of the immunization. ### Surveillance * Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration is appropriate. * Clinical examination for scoliosis and impaired gait at each office visit * EEG monitoring is appropriate when new or different seizure types are suspected. * Polysomnography should be considered if obstructive or central sleep apnea is suspected. ### Agents/Circumstances to Avoid Several AEDs that are effective for most forms of epilepsy can worsen SCN1A-related seizures: * Carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic seizures [Horn et al 1986, Guerrini et al 1998, Ceulemans et al 2004a] * Phenytoin, which may worsen seizures and can induce choreoathetosis [Saito et al 2001] * Rufinamide, which has a pharmacologic mechanism similar to carbamazepine and phenytoin and may exacerbate seizures as well * Acetaminophen, which is hepatotoxic in overdose. Given the possibility of interaction with anticonvulsant medications, especially valproate and topiramate [Nicolai et al 2008], acetaminophen should be avoided. Any of the NSAIDs are effective as antipyretics, and represent much lower risk. Activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights). ### Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. ### Pregnancy Management In addition to the considerations described in Genetic Counseling, other pregnancy-related considerations include the following: * Risk of major malformations (especially due to valproic acid exposure in utero [Samrén et al 1997]) and minor anomalies * Advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily, particularly when women are taking valproic acid or carbamazepine during pregnancy * Effect of in utero exposure to anticonvulsants on future cognitive development [Meador et al 2009] * Effect of anticonvulsants on hormonal methods of birth control * Effects of anticonvulsants on conception; the risk for complications in mothers who are on anticonvulsants * Effect of pregnancy on anticonvulsant metabolism * Effect of pregnancy on maternal seizure control Pregnancy, family planning, and contraception are issues that should be raised with every female near childbearing age who has epilepsy. These considerations are not unique to or (aside from medication selection) significantly influenced by the presence of an SCN1A seizure disorder. See MotherToBaby for further information on medication use during pregnancy. ### Therapies Under Investigation Thalamic deep brain stimulation (DBS) was reported by Andrade et al [2010] in two children with Dravet syndrome with ten-year follow up. One showed "marked improvement" after implantation, whereas the other received no benefit. Lacosamide has not been studied in SCN1A seizure disorders; however, there are theoretic reasons why it may be effective [Curia et al 2009]. Verapamil was reported to help two girls with severe epilepsy resulting from SCN1A pathogenic variants [Iannetti et al 2009]; however, it has not been formally studied. Search ClinicalTrials.gov in the US for access to information on clinical studies for SCN1A seizure disorders and a wide range of other diseases and conditions. Search EU Clinical Trials Register in Europe. ### Other Other cannabis-derived compounds (e.g., tetrahydrocannabinol [THC], cannabidivarin [CBDV], tetrahydrocannabivarin [THCV]) have no proven efficacy. Many anecdotal claims have been made regarding THC and THC:CBD ratios, but the episodic and noisy nature of epilepsy requires any data acquired in a non-blinded way to be viewed with extreme caution. Cannabinoids are bioactive and may have psychotropic and/or systemic side effects; they also may act as an immunosuppressant and an anti-inflammatory in animal models. Clinical trial data regarding safety and efficacy are needed before widespread clinical use is appropriate [Rieder et al 2010, Bergamaschi et al 2011]. Persons with epilepsy should be made aware of local motor vehicle driving laws and physician reporting laws. Hippocampal sclerosis can occur as a secondary feature of SCN1A seizure disorders [Livingston et al 2009], but there is no proven role for surgery given the widespread epileptogenic potential in this disorder. *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

SCN1A Seizure Disorders

None

gene_reviews

https://www.ncbi.nlm.nih.gov/books/NBK1318/

{"synonyms": []}

Ranula SpecialtyOral and maxillofacial surgery A ranula is a mucus extravasation cyst involving a sublingual gland and is a type of mucocele found on the floor of the mouth. Ranulae present as a swelling of connective tissue consisting of collected mucin from a ruptured salivary gland caused by local trauma. If small and asymptomatic further treatment may not be needed, otherwise minor oral surgery may be indicated. ## Contents * 1 Signs and symptoms * 1.1 Complications * 2 Causes * 3 Mechanism * 4 Diagnosis * 4.1 Criteria * 4.2 Classification * 5 Treatment * 6 Epidemiology * 7 Other animals * 8 References * 9 External links ## Signs and symptoms[edit] Ranula in a female A ranula usually presents as a translucent, blue, dome-shaped, fluctuant swelling in the tissues of the floor of the mouth. If the lesion is deeper, then there is a greater thickness of tissue separating from the oral cavity and the blue translucent appearance may not be a feature. A ranula can develop into a large lesion many centimeters in diameter, with resultant elevation of the tongue and possibly interfering with swallowing (dysphagia). The swelling is not fixed, may not show blanching, and is non-painful unless it becomes secondarily infected. The usual location is lateral to the midline, which may be used to help distinguish it from a midline dermoid cyst.[1] A cervical ranula presents as a swelling in the neck, with or without a swelling in the mouth. In common with other mucoceles, ranulae may rupture and then cause recurrent swelling. Ranulae may be asymptomatic, although they can fluctuate rapidly in size, shrinking and swelling, making them difficult to detect. ### Complications[edit] * Infection * Repeated trauma * Bursting and reformation * Dysphagia (in the case of a large ranula) ## Causes[edit] Minor trauma to the floor of the mouth is thought to damage the delicate ducts that drain saliva from the sublingual gland into the oral cavity.[2] The lesion is a mucous extravasation cyst (mucocele) of the floor of mouth, although a ranula is often larger than other mucoceles (mainly because the overlying mucosa is thicker).[3] They can grow so large that they fill the mouth. The most usual source of the mucin spillage is the sublingual salivary gland, but ranulae may also arise from the submandibular duct or the minor salivary glands in the floor of the mouth. A cervical ranula occurs when the spilled mucin dissects its way through the mylohyoid muscle,[1] which separates the sublingual space from the submandibular space, and creates a swelling in the neck. It may occur following rupture of a simple ranula.[4] Rarely, ranulae may extend backwards into the parapharyngeal space.[4] ## Mechanism[edit] The fluid within a ranula has the viscous, jellylike consistency of egg white. ## Diagnosis[edit] Ranula, micrograph. H&E stain. The histologic appearance is similar to mucoceles from other locations. The spilled mucin causes a granulation tissue to form, which usually contains foamy histiocytes.[1] Ultrasound and magnetic resonance imaging may be useful to image the lesion.[4] A small squamous cell carcinoma obstructing the Wharton duct may require clinical examination to be distinguished from a ranula.[5] ### Criteria[edit] * Mostly seen in young children and adolescents, both sexes are equally affected. Swelling in floor of mouth, which may be painful. Mostly unilateral, on one side of frenulum. * Shape is spherical * Size varies from 1 – 5 cm in diameter * Color is pale blue with characteristics semi transparent appearance. * Surface is smooth and mucous membrane is mobile over the swelling. * Tenderness is absent * Fluctuation test is positive * Transillumination test is positive * Cervical lymph nodes are not enlarged. * May or may not have prolongation in the neck. ### Classification[edit] A ranula is a type of mucocele, and therefore could be classified as a disorder of the salivary glands. Usually a ranula is confined to the floor of the mouth (termed a "simple ranula").[6] An unusual variant is the cervical ranula (also called a plunging or diving ranula), where the swelling is in the neck rather than the floor of the mouth.[1] The term ranula is also sometimes used to refer to other similar swellings of the floor of mouth such as true salivary duct cysts, dermoid cysts and cystic hygromas.[1] The Latin word rana means "frog" (ranula = "little frog"). ## Treatment[edit] Treatment of ranulae usually involves removal of the sublingual gland. Surgery may not be required if the ranula is small and asymptomatic.[2] Marsupialization may sometimes be used, where the intra-oral lesion is opened to the oral cavity with the aim of allowing the sublingual gland to re-establish connection with the oral cavity. ## Epidemiology[edit] The lesion is usually present in children.[2] Ranulae are the most common pathologic lesion associated with the sublingual glands.[3] ## Other animals[edit] * Ranula in a dog * excision of both mandibular and major sublingual glands in a dog ## References[edit] * Kahn, Michael A. Basic Oral and Maxillofacial Pathology. Volume 1. 2001. 1. ^ a b c d e Bouquot, Brad W. Neville, Douglas D. Damm, Carl M. Allen, Jerry E. (2002). Oral & maxillofacial pathology (2. ed.). Philadelphia: W.B. Saunders. pp. 391–392. ISBN 978-0721690032. 2. ^ a b c Newlands, edited by Cyrus Kerawala, Carrie (2010). Oral and maxillofacial surgery. Oxford: Oxford University Press. p. 199. ISBN 9780199204830.CS1 maint: extra text: authors list (link) 3. ^ a b Hupp JR, Ellis E, Tucker MR (2008). Contemporary oral and maxillofacial surgery (5th ed.). St. Louis, Mo.: Mosby Elsevier. pp. 410–411. ISBN 9780323049030. 4. ^ a b c La'Porte, S. J.; Juttla, J. K.; Lingam, R. K. (14 September 2011). "Imaging the Floor of the Mouth and the Sublingual Space". Radiographics. 31 (5): 1215–1230. doi:10.1148/rg.315105062. PMID 21918039. 5. ^ Boulos MI, Cheng A (2006-02-01). "Case 1: What is that in your mouth?". Paediatrics & Child Health. 11 (2): 107–8. PMC 2435329. PMID 19030265. 6. ^ Shaw, JHF. "Salivary Gland Surgery". unsupplied. Retrieved 8 February 2013. ## External links[edit] Classification D * ICD-10: K11.6 * ICD-9-CM: 527.6 * MeSH: D011900 * DiseasesDB: 31432 External resources * MedlinePlus: 001639 * eMedicine: derm/648 Wikimedia Commons has media related to Ranula. * DermAtlas 259163774 * v * t * e Oral and maxillofacial pathology Lips * Cheilitis * Actinic * Angular * Plasma cell * Cleft lip * Congenital lip pit * Eclabium * Herpes labialis * Macrocheilia * Microcheilia * Nasolabial cyst * Sun poisoning * Trumpeter's wart Tongue * Ankyloglossia * Black hairy tongue * Caviar tongue * Crenated tongue * Cunnilingus tongue * Fissured tongue * Foliate papillitis * Glossitis * Geographic tongue * Median rhomboid glossitis * Transient lingual papillitis * Glossoptosis * Hypoglossia * Lingual thyroid * Macroglossia * Microglossia * Rhabdomyoma Palate * Bednar's aphthae * Cleft palate * High-arched palate * Palatal cysts of the newborn * Inflammatory papillary hyperplasia * Stomatitis nicotina * Torus palatinus 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Pulp polyp * Pulpitis * Regional odontodysplasia * Resorption * Shovel-shaped incisors * Supernumerary root * Taurodontism * Trauma * Avulsion * Cracked tooth syndrome * Vertical root fracture * Occlusal * Tooth loss * Edentulism * Tooth wear * Abrasion * Abfraction * Acid erosion * Attrition Periodontium (gingiva, periodontal ligament, cementum, alveolus) – Gums and tooth-supporting structures * Cementicle * Cementoblastoma * Gigantiform * Cementoma * Eruption cyst * Epulis * Pyogenic granuloma * Congenital epulis * Gingival enlargement * Gingival cyst of the adult * Gingival cyst of the newborn * Gingivitis * Desquamative * Granulomatous * Plasma cell * Hereditary gingival fibromatosis * Hypercementosis * Hypocementosis * Linear gingival erythema * Necrotizing periodontal diseases * Acute necrotizing ulcerative gingivitis * Pericoronitis * Peri-implantitis * Periodontal abscess * Periodontal trauma * Periodontitis * Aggressive * As a manifestation of systemic disease * Chronic * 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Crossbite * Open bite * Overbite * Overeruption * Overjet * Prognathia * Retrognathia * Scissor bite * Maxillary hypoplasia * Temporomandibular joint dysfunction Salivary glands * Benign lymphoepithelial lesion * Ectopic salivary gland tissue * Frey's syndrome * HIV salivary gland disease * Necrotizing sialometaplasia * Mucocele * Ranula * Pneumoparotitis * Salivary duct stricture * Salivary gland aplasia * Salivary gland atresia * Salivary gland diverticulum * Salivary gland fistula * Salivary gland hyperplasia * Salivary gland hypoplasia * Salivary gland neoplasms * Benign: Basal cell adenoma * Canalicular adenoma * Ductal papilloma * Monomorphic adenoma * Myoepithelioma * Oncocytoma * Papillary cystadenoma lymphomatosum * Pleomorphic adenoma * Sebaceous adenoma * Malignant: Acinic cell carcinoma * Adenocarcinoma * Adenoid cystic carcinoma * Carcinoma ex pleomorphic adenoma * Lymphoma * Mucoepidermoid carcinoma * Sclerosing polycystic adenosis * Sialadenitis * Parotitis * Chronic sclerosing sialadenitis * Sialectasis * Sialocele * Sialodochitis * Sialosis * Sialolithiasis * Sjögren's syndrome Orofacial soft tissues – Soft tissues around the mouth * Actinomycosis * Angioedema * Basal cell carcinoma * Cutaneous sinus of dental origin * Cystic hygroma * Gnathophyma * Ludwig's angina * Macrostomia * Melkersson–Rosenthal syndrome * Microstomia * Noma * Oral Crohn's disease * Orofacial granulomatosis * Perioral dermatitis * Pyostomatitis vegetans Other * Eagle syndrome * Hemifacial hypertrophy * Facial hemiatrophy * Oral manifestations of systemic disease *[v]: View this template *[t]: Discuss this template *[e]: Edit this template *[c.]: circa *[AA]: Adrenergic agonist *[AD]: Acetaldehyde dehydrogenase

Ranula

c2242813

wikipedia

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

{"mesh": ["D011900"], "umls": ["C0026686", "C2242813"], "wikidata": ["Q1756640"]}