abstract
stringlengths 101
4.14k
| label
class label 2
classes |
|---|---|
The increasing indications for allogeneic stem-cell transplant in patients with hematologic malignancies and non-malignant diseases combined with improved clinical outcomes have contributed to increase the number of long-term survivors. However, survivors are at increased risk of developing a unique set of complications and late effects, besides graft-versus-host disease and disease relapse. In this setting, the management capacity of a single health-care provider can easily be overwhelmed. Thus, to provide appropriate survivorship care, a multidisciplinary approach for the long-term follow-up is essential. This review aims at summarizing the most relevant information that a health-care provider should know to establish a follow-up care plan, in the light of individual exposures and risk factors, that includes all organ systems and considers the psychological burden of these patients. | 01 = IsEpi
|
Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors. | 01 = IsEpi
|
Here, we describe the first case of familial hemiplegic migraine type 1 (FHM1) resulting from a T666M mutation in the CACNA1A gene of a Chinese individual. A 54-year-old female patient demonstrated extensive clinical manifestations, including transient paropsia, hemianesthesia, logaphasia, hemiplegia, migraine, fever, impaired consciousness, and progressive cerebellar ataxia. At admission, neurological examination showed a fever of 38.6°C, coma, bilateral pupillary constriction, left-sided deviation of both eyes, meningeal irritation, and bilateral positive Chaddock's sign. Brain magnetic resonance imaging (MRI) displayed only cerebellar atrophy. The pressure and white blood cells of the cerebrospinal fluid (CSF) were elevated. Her nine relatives also had similar clinical spectra. To further clarify the diagnosis, we conducted a genetic analysis on the family. The results of genetic testing showed that all seven living affected members carried the T666M mutation in the CACNA1A gene. This case report indicates that the diagnosis of FHM should be taken into account when a patient manifests migraine accompanied with hemiplegia, acute encephalopathy, and abnormal CSF. In addition, genetic testing is indispensable for the identification of some atypical attacks of hemiplegic migraine. | 01 = IsEpi
|
Food-dependent exercise-induced anaphylaxis (FDEIA) is a life-threatening but relatively rare disorder which occurs mainly in older children and young adults and manifests with symptoms of anaphylaxis upon exercise following ingestion of certain kinds of food. We herewith report 3 cases of soybean-induced FDEIA. We also highlight 2 types of soybean-induced FDEIA, one caused by storage protein components Gly m 5 and Gly m 6 and the other caused by pollen-related allergen components. | 01 = IsEpi
|
Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performed DYSF gene analyses of 200 cases suspected of having dysferlinopathy (Cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families, including 80 previously diagnosed and 129 newly diagnosed cases (Cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%), including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb-girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp, and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies. | 01 = IsEpi
|
Population-based plasmacytoma incidence and survival data are sparse. We analyzed incidence rates (IRs), IR ratios (IRRs), and 5-year relative survival for plasmacytoma overall and by site -- bone (P-bone) and extramedullary (P-extramedullary) -- in the Surveillance, Epidemiology and End Results (SEER) Program (1992-2004). For comparison, we included cases of multiple myeloma (MM) diagnosed over the same time period in SEER. Incidence of MM (n = 23,544; IR 5.35/100,000 person-years) was 16-times higher than plasmacytoma overall (n = 1543; IR = 0.34), and incidence of P-bone was 40% higher than P-extramedullary (P < 0.0001). The male-to-female IRRs for P-bone, P-extramedullary, and MM were 2.0, 2.6, and 1.5, respectively. For plasmacytoma and MM, IRs were highest in Blacks, intermediate in Whites, and lowest in Asian/Pacific Islanders. Compared with Whites, the Black IR was approximately 30% higher for P-extramedullary and P-bone and 120% higher for MM. IRs for all neoplasms increased exponentially with advancing age, less prominently at older ages for plasmacytoma than MM. Distinct age, gender, and race incidence patterns of plasma cell disorders suggest underlying differences in clinical detection, susceptibility, disease biology and/or aetiological heterogeneity. Five-year relative survival for P-bone, P-extramedullary, and MM varied significantly by age (<60/60+ years), supporting age-related differences in disease burden at presentation, disease biology, and/or treatment approaches. | 10 = IsNotEpi
|
CASE:We present an 18-year-old man with poor alignment of the lower limbs, marked by congenital dislocation of the left patella, with gait impairment, and an associated 20° flexion contracture. Surgical treatment was performed with a single complex procedure with the release of the lateral retinaculum, capsule, and iliotibial tract, followed by a subtraction trochleoplasty, tibial tubercle transfer, elongation of the quadriceps tendon, and anatomical reconstruction of the medial patellofemoral ligament. At the 5-year follow-up, the patient had a significant improvement in gait pattern, with the patella centered on the new trochlear groove without any signs of patellar instability. CONCLUSIONS:The approach of congenital dislocation of the patella is controversial, and although numerous procedures have been described in children, the approach in adults should be individually tailored. In this case, trochlear deepening and preserving the trochlear cartilage proved to be an effective option for treating a congenital dislocation. | 01 = IsEpi
|
Purpose: The objective of this study was to compare the symptoms of cluttering among school-age children who do and do not clutter in the contexts of monologue, conversation and expository discourse.Method: A matched pairs design was used to compare cluttering symptoms according to the Lowest Common Denominator (LCD) definition of cluttering, a definition representing the core speech and fluency characteristics of cluttering agreed upon among experts. Cluttering symptoms (over-coarticulated words, normal disfluencies, abnormal pauses) in eight school-aged males with cluttering were compared to eight controls matched by sex and grade level in school. Symptoms were compared in the speech contexts of conversation, monologue and expository discourse.Result: Regardless of the speaking context, significantly more over-coarticulated words were found in children with cluttering (CWC) as compared to controls. Significantly more normal disfluencies were produced by CWC during monologue only.Conclusion: Study findings confirm increased over-coarticulation and normal disfluencies in specific speaking contexts in CWC when compared to controls. These findings provide the premise for clinical implications for cluttering assessment and diagnosis. Findings also provide the basis for further investigation of the validity of the LCD's symptom of abnormal pausing for accurate diagnosis of people who clutter. | 01 = IsEpi
|
BACKGROUND:Conservative treatment or debridement is generally sufficient for Freiberg's disease grades I and II but operative intervention for the late stages of the disease process (III-V) is more challenging. Debridement alone is not sufficient and various forms of arthroplasty have been put forward. We have evaluated the outcomes of patients treated with an interpositional arthroplasty technique using a pedicle graft of periosteum and fat made into a "Rollmop" spacer for severe Freiberg's disease. No results have previously been reported for this technique. METHODS:Twenty-five consecutive cases (23 patients) were performed from February 2009 to September 2016 (20 females, 5 males). Mean age at surgery was 52.6 years (range 19-70.5 years) with 92% affecting the second metatarsal. Twenty-three were primary cases and 2 were revision cases. Five cases were stage III, 12 were stage IV, and 8 were stage V. All patients underwent interpositional arthroplasty using a periosteum and fat pedicle graft from the affected metatarsal shaft as described by Myerson. Patients were evaluated using Manchester-Oxford Foot Questionnaire (MOXFQ) and American Orthopaedic Foot & Ankle Society Questionnaire (AOFAS). Mean follow-up was 3.5 years (0.6-7.6 years). Paired 2-tailed Student t tests were used to assess clinical significance. RESULTS:Surgery allowed 8 patients to return to normal footwear, 10 patients returned to fashion footwear/heels, and 5 returned to sports. Nineteen cases (17 patients) were assessed with patient-reported outcome measures and all showed a clinically and statistically significant improvement in their scores. Mean pre- and postoperative VAS pain scores were 6.2 (range 4-9) and 1.8 (range 0-6) ( P < .05). Mean perioperative AOFAS scores were 45.6 (range 15-73) and 82.7 (range 57-100) ( P < .05). Mean perioperative MOXFQ scores were 60.0 (range 23-89) and 18.1 (range 0-80) ( P < .05). CONCLUSION:This novel interpositional arthroplasty technique using a "rollmop" of periosteum and fat for severe Freiberg's disease produced significant improvements in pain, functional outcome, and patient satisfaction without donor site morbidity. Furthermore, it allowed patients to return to desired footwear and sporting activities. The functional outcome and joint range of motion was superior after a K-wire was no longer placed across the joint, and we believe it is essential to avoid this to permit early range-of-motion exercises. LEVEL OF EVIDENCE:Level IV, retrospective case series. | 01 = IsEpi
|
Normal sex development depends on the precise spatio-temporal sequence and coordination of mutually antagonistic activating and repressing factors. These factors regulate the commitment of the unipotential gonad into the binary pathways governing normal sex development. Typically, the presence of the SRY gene on the Y chromosome triggers the cascade of molecular events that lead to male sex development. Disorders of sex development comprise a heterogeneous group of congenital conditions associated with atypical development of internal and external genitalia. These disorders are generally attributed to deviations from the typical progression of sex development. Disorders of sex development can be classified into several categories including chromosomal, gonadal, and anatomic abnormalities. Genetic tools such as microarray analyses and next-generation sequencing techniques have identified novel genetic variants among patients with disorders of sexual development. Most importantly, patient management needs to be individualized, especially for decisions related to sex of rearing, surgical interventions, hormone treatment, and potential for fertility preservation. | 01 = IsEpi
|
The transcription factor Hypermethylated in Cancer 1 (HIC1) is associated with both tumorigenesis and the complex human developmental disorder Miller-Dieker Syndrome. While many studies have characterized HIC1 as a tumor suppressor, HIC1 function in development is less understood. Loss-of-function mouse alleles show embryonic lethality accompanied with developmental defects, including craniofacial abnormalities that are reminiscent of human Miller-Dieker Syndrome patients. However, the tissue origin of the defects has not been reported. In this study, we use the power of the Xenopus laevis model system to explore Hic1 function in early development. We show that hic1 mRNA is expressed throughout early Xenopus development and has a spatial distribution within the neural plate border and in migrating neural crest cells in branchial arches. Targeted manipulation of hic1 levels in the dorsal ectoderm that gives rise to neural and neural crest tissues reveals that both overexpression and knockdown of hic1 result in craniofacial defects with malformations of the craniofacial cartilages. Neural crest specification is not affected by altered hic1 levels, but migration of the cranial neural crest is impaired both in vivo and in tissue explants. Mechanistically, we find that Hic1 regulates cadherin expression profiles and canonical Wnt signaling. Taken together, these results identify Hic1 as a novel regulator of the canonical Wnt pathway during neural crest migration. | 01 = IsEpi
|
BACKGROUND:A highly reduced expression of Rh antigens in the erythrocyte membrane is the main feature of Rhmod , an extremely rare phenotype. Mutations within RHAG gene, which encodes RhAG glycoprotein and modulates Rh antigen expression and Rh complex formation, are the molecular events responsible for the Rhmod phenotype. Here we report a clinical, serologic, and molecular study of an Argentinean proband with Rh-deficiency syndrome. MATERIALS AND METHODS:Rh antigens, RhAG and CD47 glycoproteins were studied by serologic methods in the proband, her parents and sister. Osmotic fragility and viscoelastic parameters were also examined. RHD zygosity was analyzed by RFLP-PCR. RHD, RHCE, and RHAG genes were studied by Sanger sequencing. RESULTS:No Rh antigens were detected in the proband by standard techniques. However, adsorption-elution and anti-RhAG tests showed that the proposita was Rhmod . Reduced expression of CD47, enhanced osmotic fragility, and surface viscosity alterations giving rise to spherocytes were observed in the patient. Sequencing analysis showed that a c.920C>T mutation in RHAG Exon 6 was present in a homozygous state in the proband and in a heterozygous state in the rest of the family. This novel missense mutation caused the p.Ser307Phe amino acid substitution in Transmembrane Segment 10 of the RhAG glycoprotein. CONCLUSION:This comprehensive study determined the causes of the proband's anemia allowing the diagnosis of Rh-deficiency syndrome. | 01 = IsEpi
|
Achalasia is a rare esophageal motility disorder, incurable but amenable to palliative treatments to relieve dysphagia. Given the rarity of the disease, there is a paucity of data from population-based studies on incidence and outcome of the two treatments most commonly used in clinical practice, i.e., endoscopic pneumatic dilation (PD) and surgical myotomy (SM).A retrospective longitudinal study was conducted on the Veneto region, in north-eastern Italy. All patients with achalasia as their primary diagnosis between 2001 and 2005 were identified and their demographics and treatment details obtained.The overall incidence of achalasia was 1.59 cases/100,000/year. Achalasia patients were mainly seen at University Hospitals. Fifty-five percent of the patients received treatment, 23.3% SM and 31.8% PD. The cumulative risk of any subsequent intervention for achalasia was 20% in treated patients (29.7% in patients treated primarily with PD and 4% in patients treated with SM first).The epidemiology of achalasia in the Veneto Region is in line with the situation reported elsewhere and did not change between 2001 and 2005. Achalasia patients are mostly seen at University Hospitals. We observed a greater risk of subsequent intervention for patients previously treated with PD compared with SM. | 10 = IsNotEpi
|
Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis. | 01 = IsEpi
|
BACKGROUND: Premature aging syndromes recapitulate many aspects of natural aging and provide an insight into this phenomenon at a molecular and cellular level. The progeria syndromes appear to cause rapid aging through disruption of normal nuclear structure. Recently, a coding mutation (c.34G > A [p.A12T]) in the Barrier to Autointegration Factor 1 (BANF1) gene was identified as the genetic basis of Néstor-Guillermo Progeria syndrome (NGPS). This mutation was described to cause instability in the BANF1 protein, causing a disruption of the nuclear envelope structure. RESULTS: Here we demonstrate that the BANF1 A12T protein is indeed correctly folded, stable and that the observed phenotype, is likely due to the disruption of the DNA binding surface of the A12T mutant. We demonstrate, using biochemical assays, that the BANF1 A12T protein is impaired in its ability to bind DNA while its interaction with nuclear envelope proteins is unperturbed. Consistent with this, we demonstrate that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope. CONCLUSIONS: Our study clarifies the role of the A12T mutation in NGPS patients, which will be of importance for understanding the development of the disease. | 01 = IsEpi
|
Culture negative endocarditis (CNE) is a common concern in patients with fever, heart murmur, cardiac vegetation, and negative blood cultures. The diagnosis of CNE is not based only on negative blood cultures and a cardiac vegetation. The clinical definition of CNE is based on negative blood cultures plus the findings of culture positive infective endocarditis (IE), e.g., fever, cardiac vegetation, splenomegaly, peripheral manifestations. Because embolic splenic infarcts may occur with culture positive IE, some may assume that splenic infarcts are a sign of CNE. Previously, CNE was due to fastidious and non-culturable organisms. With current diagnostic methods, fastidious organisms grow in 2-3 days. Therefore, fastidious IE are a subset of culture positive IE, but do not represent true CNE. We describe a case of an elderly female who presented with a fever of unknown origin (FUO) and multiple splenic infarcts thought by some to represent CNE. An extensive workup for CNE pathogens was negative. The final cause of her splenic infarcts was a diffuse large B-cell lymphoma (DLBCL). Review of the literature, as well as this case, confirms that splenic infarcts are not a feature of CNE. In patients with fever, splenic infarcts, and negative blood cultures, physicians should search for an alternate explanation rather than CNE, e.g., malignancy and hypercoaguable state (lupus anticoagulant). | 01 = IsEpi
|
Irreversible sequels of some genetic diseases can be prevented by neonatal screening. The aim of this paper was to verify the prevalence of diseases diagnosed by the National Program of Neonatal Screening (PNTN) in Maringá, Paraná, Brazil, between 2001 and 2006. This cross-sectional descriptive study included 20,529 newborn infants screened by that program. Out of those, 859 were re-examined, and 21 had the disease confirmed. Considering all screened newborn infants and the number of diagnostics per disease, the following disease prevalence was determine: phenylketonuria--1:20,529; congenital hypothyrodism--1:2,281; hemoglobinopahies--1:3,421; cystic fibrosis--1:10,264; and biotinidase deficiency--1:6,843. Understanding disease status and prevalence of newborns in a population allows the establishment and the improvement of public policies aimed at the children. | 10 = IsNotEpi
|
OBJECTIVE:Respiratory compromise in congenital muscular dystrophy (CMD) occurs, in part, from chest wall contractures. Passive stretch with hyperinsufflation therapy could reduce related costo-vertebral joint contractures. We sought to examine the impact of hyperinsufflation use on lung function and quality of life in children with CMD. STUDY DESIGN:We conducted a randomized controlled trial on hyperinsufflation therapy in children with CMD at two centers. An individualized hyperinsufflation regimen of 15 minutes twice daily using a cough assist device over a 12 months period was prescribed. We measured lung function, quality of life, and adherence. To demonstrate reproducibility, pulmonary function was measured twice on the same day. A mixed-effects regression model adjusting for confounders was used to assess the effects of hyperinsufflation. RESULTS:We enrolled 34 participants in the study; 31 completed the trial (n = 17 treatment group and n = 14 controls). Participants in the treatment group demonstrated a relative gain in lung volume measured at 4 and 8 months, but not at 12 months. The control group required increases in the maximum insufflation pressures to achieve maximum lung volumes while the treatment group did not. Adherence was best early in the study, peaking at the first visit and decreasing at subsequent visits. Caregiver-reported quality of life was higher in the treatment group. CONCLUSION:Hyperinsufflation therapy is effective in increasing and sustaining lung volume over time. Adherence, however, was inconsistent and difficult to maintain. Further research should determine if improved adherence leads to sustained benefits of hyperinsufflation. | 01 = IsEpi
|
Resident neural stem and progenitor cells, collectively termed neural precursor cells (NPCs), reside in a well-defined neurogenic niche in the subventricular zone (SVZ) and contribute to ongoing postnatal neurogenesis. It is well established that the NPC niche can alter the behavior of NPCs. NPC activation is a promising therapeutic strategy for brain repair. The drug metformin has been shown to activate neural stem cells, promote differentiation, and lead to functional motor recovery in a neonatal stroke model. We demonstrate that metformin-induced NPC expansion and functional recovery is sex hormone dependent. Metformin increases the size of the NPC pool in adult females, but not males, and promotes cognitive recovery in a model of brain injury in females, but not males. Our data demonstrate that metformin has age- and sex-dependent effects on NPCs that correlate with functional recovery, which has important implications for neural repair. | 01 = IsEpi
|
Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is an autosomal recessive ciliary chondrodysplasia characterized by a recognizable craniofacial gestalt, skeletal abnormalities, and ectodermal features. To date, four genes have been shown to underlie the syndrome, namely, IFT122 (WDR10), WDR35 (IFT121), IFT43 (C14orf179), and WDR19 (IFT144). Clinical characterization of a larger cohort of patients with CED has been undertaken previously. Nevertheless, there are too few molecularly confirmed patients reported in the literature to determine precise genotype-phenotype correlations. To date, biallelic IFT122 mutations have been described in only five families. We therefore studied three unrelated Argentinian patients with typical features of CED using a 4813 next-generation sequencing (NGS) gene panel, which we call the "Mendeliome." The three patients had different, novel, compound heterozygous mutations in IFT122. Consequently, we compared these three patients to those previously described with IFT122 mutations. Thus, our report serves to add 6 novel mutations to the IFT122 mutation spectrum and to contribute to the IFT122-related clinical characterization. | 01 = IsEpi
|
Erosive pustular dermatosis of the scalp is a rare chronic inflammatory disorder defined. It usually affects elderly people and is characterized by extensive pustular lesions, erosions, and crusts located on the scalp. The pathogenesis of this disease is not completely understood, but a known predisposing factor is skin trauma. Autoimmune disorders including rheumatoid arthritis, autoimmune hepatitis, Hashimoto thyroiditis, and Takayasu aortitis are associated diseases reported. The clinical examination reveals erythema, erosions, crusts, follicular pustules, and in advanced stages, scarring alopecia. A scalp biopsy is recommended but not specific, founding epidermal atrophy, focal erosions, and a mixed inflammatory infiltrate consisting of neutrophils, lymphocytes, and plasma cells. Bacterial cultures, fungal and viral stains are not necessary and are usually negative. . Topical high-potency corticosteroids, retinoids, calcipotriol, dapsone, and topical tacrolimus are reported treatments, while photodynamic therapy has been effective in some patients, but has induced the disease in others. All the findings are suggestive but not specific, so it is an excluding diagnosis. The combination of predisposing factors is very important for a correct diagnosis, such as elderly age, sun-damaged skin, presence of androgenetic alopecia, together with clinical manifestations, non-specific histology and laboratory investigations negative for other disease. In our opinion, this scalp disease is a challenge for the dermatologist. We review all the literature to better define the possible solutions in case of suspected erosive pustular dermatosis of the scalp. | 01 = IsEpi
|
OBJECTIVES:The aim was to comparatively assess the clinical and imaging features in patients with SAPHO syndrome. METHODS:The clinical data, laboratory results, imaging data of forty-six SAPHO patients were reviewed and the SAPHO patients were divided into spinal involvement group and non-spinal involvement group. Fifty patients with ankylosing spondylitis were recruited as control group. The clinical and radiological features of them were analyzed and compared. RESULTS:Thirty-four of 46 (73.9%) of all the SAPHO patients had spinal involvement. The lesions exhibited as abnormal hyper-intensity signal in vertebral bodies, vertebral body erosion or collapse, bone marrow edema, endplate inflammation, spondyldiscitis, paravertebral ossification, and facet joint involvement. Compared with patients in non-spinal involvement group, the age at disease onset was older (P = 0.033), the disease duration was longer (P = 0.048), and CRP level was elevated (P = 0.047) in patients in spinal involvement group. Compared with patients with ankylosing spondylitis, SAPHO patients were more likely to have cervical vertebra involvement (P = 0.024), endplate inflammation (P = 0.019), and spondyldiscitis (P = 0.001), but less multiple vertebral body and facet joint involvement (P = 0.002). Patients regularly received DMARDS or biologics treatment had symptoms relieved and lesions turned into chronic stage or better than before. CONCLUSIONS:A total of 73.9% of the SAPHO patients had spinal involvement and the involvement could affect any part of the spine. Cervical vertebral involvement, endplate inflammation, and sponlypodiscitis were more common in SAPHO than in patients with ankylosing spondylitis. In SAPHO patients with spinal involvement, the disease duration was longer and the inflammatory reaction was more intensive. DMARDs and biologics may help to prevent the disease progress. KEY POINTS:• To the best of our knowledge, this paper is the first one to comparatively study the clinical and radiological features of SAPHO syndrome, especially the characteristics of spinal involvement. | 01 = IsEpi
|
This study was designed to describe the spectrum of epilepsy phenotypes in Koolen-de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1.We were invited to attend a large gathering of individuals with KdVS and their families. While there, we recruited individuals with KdVS and seizures, and performed thorough phenotyping. Additional subjects were included who approached us after the family support group brought attention to our research via social media. Inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least one seizure.Thirty-one individuals were studied, aged 2-35 years. Median age at seizure onset was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset. Focal impaired awareness seizures were the most frequent seizure type occurring in 20 of 31, usually with prominent autonomic features. Twenty-one patients had prolonged seizures and, at times, refractory status epilepticus. Electroencephalography (EEG) showed focal/multifocal epileptiform discharges in 20 of 26. MRI studies of 13 patients were reviewed, and all had structural anomalies. Corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles were the most common, although periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also observed. One patient underwent epilepsy surgery for a lesion that proved to be an angiocentric glioma.The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features. Multifocal epileptiform discharges are the typical EEG pattern. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Epilepsy surgery should be undertaken with care given the widespread neuroanatomic abnormalities; however, tumors are a rare, yet important, occurrence. | 01 = IsEpi
|
BACKGROUND:The mitochondrial aminoacyl-tRNA synthetase proteins (mt-aaRSs) are a group of nuclear-encoded enzymes that facilitate conjugation of each of the 20 amino acids to its cognate tRNA molecule. Mitochondrial diseases are a large, clinically heterogeneous group of disorders with diverse etiologies, ages of onset, and involved organ systems. Diseases related to mt-aaRS mutations are associated with specific syndromes that affect the central nervous system and produce highly characteristic MRI patterns, prototypically the DARS2, EARS, and AARS2 leukodystrophies, which are caused by mutations in mitochondrial aspartyl-tRNA synthetase, mitochondria glutamate tRNA synthetase, and mitochondrial alanyl-tRNA synthetase, respectively. BODY: The disease patterns emerging for these leukodystrophies are distinct in terms of the age of onset, nature of disease progression, and predominance of involved white matter tracts. In DARS2 and EARS2 disorders, earlier disease onset is typically correlated with more significant brain abnormalities, rapid neurological decline, and greater disability. In AARS2 leukodystrophy cases reported thus far, there is nearly invariable progression to severe disability and atrophy of involved brain regions, often within a decade. Although most mutations are compound heterozygous inherited in an autosomal recessive fashion, homozygous variants are found in each disorder and demonstrate high phenotypic variability. Affected siblings manifest disease on a wide spectrum. CONCLUSION:The syndromic nature and selective vulnerability of white matter tracts in these disorders suggests there may be a shared mechanism of mitochondrial dysfunction to target for study. There is evidence that the clinical variability and white matter tract specificity of each mt-aaRS leukodystrophy depend on both canonical and non-canonical effects of the mutations on the process of mitochondrial translation. Furthermore, different sensitivities to the mt-aaRS mutations have been observed based on cell type. Most mutations result in at least partial retention of mt-aaRS enzyme function with varied effects on the mitochondrial respiratory chain complexes. In EARS2 and AARS2 cells, this appears to result in cumulative impairment of respiration. Mt-aaRS mutations may also affect alternative biochemical pathways such as the integrated stress response, a homeostatic program in eukaryotic cells that typically confers cytoprotection, but can lead to cell death when abnormally activated in response to pathologic states. Systematic review of this group of disorders and further exploration of disease mechanisms in disease models and neural cells are warranted. | 01 = IsEpi
|
PURPOSE:To review epidemiological and clinical aspects of systemic lupus erythematosus (SLE) in Martinique, French West Indies. METHODS:Cases of SLE were identified by attending physicians. Patients who presented with at least four of the criteria defined by the American College of Rheumatology were included. Determination of incidence and prevalence included the new cases arising during the 1990-1999 period and 1999 population census results. Probability of survival was based on the use of the Kaplan-Meier estimator. RESULTS:Two hundred and eighty-six patients were studied, including 265 females (92.7%). The average annual incidence was 4.7 cases per 100,000 inhabitants (95% confidence interval [CI]: 2.5-6.9). The prevalence for 1999 was 64.2 cases per 100,000 inhabitants (CI: 56.2-72.2). The mean age at onset was 30 years. Eleven percent of all patients had at least one parent with SLE. Renal disease was present in 139 patients (48.6%), and neurological disorders were diagnosed in 70 patients (24.5%). Patients tested positive for the following antibodies: anti-Sm (37.1%), anti-RNP (58.7%), anti-SSA (47.2%). Mean survival time was: 96.4% (CI: 94.1-98.7) at 5 years, 91.8% (CI: 87.9-95.7) at 10 years. Survival was significantly reduced in patients with end-stage renal disease (n = 40, chi 2 = 6.96, P < 0.01). CONCLUSION:The high incidence of SLE in Martinique and the immunological characteristics of patients were found to be similar to those described in other populations of African descent. The frequency of renal disease and survival rates were identical to those reported in Caucasians. | 10 = IsNotEpi
|
OBJECTIVE:While patients with primary progressive aphasia (PPA) typically present with predominant language impairment, behavioural symptoms, such as apathy, are often under-recognised. We aimed to systematically characterise apathy across the three recognised subtypes of PPA, plus atypical right-lateralised presentations of semantic dementia, and to evaluate the impact of apathy on carer burden and psychological wellbeing. METHODS:Baseline assessments from 114 PPA patients were included: 31 left semantic dementia (left SD) 16 right semantic dementia (right SD), 30 progressive nonfluent aphasia (PNFA) and 37 logopenic progressive aphasia (LPA). Clinician (Neuropsychiatric Inventory; NPI) and carer rated (Cambridge Behavioural Inventory; CBI, Frontal Systems Behaviour Scale; FrSBe) measures were used to quantify symptoms of apathy, and carer burden and psychological wellbeing were determined using the Zarit Burden Interview and Depression, Anxiety and Stress Scale. RESULTS:On the NPI, symptoms of apathy were present in 39% left SD, 56% right SD, 33% PNFA and 43% LPA patients. Multiple regression analysis revealed that 17.9% of the variance in carer burden was uniquely explained by scores on carer rated measures of apathy (CBI, FrSBe), even after accounting for diagnosis, disease duration, and cognitive and language impairment. CONCLUSIONS:Apathy is much more common than current diagnostic criteria for PPA would suggest, though the severity of apathy is similar across patient groups. Increased awareness and routine assessments of apathy symptoms are needed, together with targeted pharmacological and behavioural interventions. Moreover, as apathy substantially contributes to carer burden in PPA, psychoeducation addressing behavioural symptoms may be beneficial. | 01 = IsEpi
|
Peeling skin syndrome is a rare genodermatosis characterized by variably pruritic superficial generalized peeling of the skin with several genes involved until now little is known about the association between FLG2 and peeling skin syndrome. We describe multiple family members from a consanguineous Saudi family with peeling skin syndrome. Next Generation Sequencing identifies a cosegregating novel variant in FLG2 c.632C>G (p.Ser211*) as a likely etiology in this family. Here, we reported on the clinical manifestation of homozygous loss of function variant in FLG2 as a disease-causing gene for peeling skin syndrome and expand the dermatology findings. | 01 = IsEpi
|
Familial amyloidotic polyneuropathy (FAP-type I) was first described in Portugal by Andrade in 1952, a time when 54 among 64 patients (belonging to 25 families) originated from Póvoa do Varzim or its surrounding districts. Since then, a total of 1,233 patients, belonging to 489 pedigrees (so far unrelated), have been diagnosed at Centro de Estudos de Paramiloidose, Porto, Portugal. Although age-of-onset showed a wide range (17 to 78 years), 87% of these 1,233 patients developed symptoms before 40 years of age (mean 33.5, SD 9.4 years). Among all patients, 432 belong to 140 families originating from the area of Póvoa do Varzim/Vila do Conde, 330 of whom lived in that area at the time of diagnosis; age-of-onset was, on average, lower than in the overall group of patients (mean 31.1, SD 6.7 years), and no patient had onset after 57 years (versus 3.3% in the global sample). As in previous studies, women were found to have a later onset (33.7) than men (29.0) years. In 1991, the crude prevalence rate was 90.3 x 10(-5) (one in every 1,108 inhabitants), and the frequency of gene carriers was estimated to be 186 x 10(-5) (one in every 538); about 48.4% of these carriers had manifested symptoms by 1991. Female patients had a significantly higher number of children (mean 3.7, SD 2.6) than male patients (mean 2.7, SD 2.1) and the length of their reproductive period (mean 8.4, SD 5.8 yr) was also greater than for men (mean 5.6, SD 4.4 yr). Altogether, the 122 patients who ever reproduced contributed 457 children to the next generation, a mean fertility of 3.7. Further studies using a control groups may answer the question of whether this is the result of a specific high fertility of these patients or just their belonging to a population in natural expansion. | 10 = IsNotEpi
|
Deficiency of Itch, an E3 ubiquitin ligase, usually induced severe systemic and progressive autoimmune disease. The Itch function is well studied in T cells but not in B cells. We hypothesize that B-cell-specific Itch deficiency promoted antigen-induced B-cell activation and antibody-expressing plasma cell (PC) production. We found that unlike Itch KO, Itch cKO (CD19cre Itchf/f ) mice did not demonstrated a significant increase in the sizes of spleens and LNs, antibody level, and base mutation of antibody gene. However, in line with the fact that Itch expression decreased in GC B cells, PCs, and plasmablast (PB)-like SP 2/0 cells, Itch deficiency promoted B-cell activation and antibody production induced by antigens including lipopolysaccharide (LPS) and sheep red blood cells (SRBCs). Mechanistically, we found that Itch deficiency promotes antigen-induced cytokine production because Itch controls the proteins (e.g., eIF3a, eIF3c, eIF3h) with translation initiation factor activity. Altogether, our data suggest that Itch deficiency promotes antigen-driven B-cell response. This may provide hints for Itch-targeted treatment of patients with autoimmune disease. | 01 = IsEpi
|
BACKGROUND:Bartter syndrome subtypes are a group of rare renal tubular diseases characterized by impaired salt reabsorption in the tubule, specifically the thick ascending limb of Henle's loop. Clinically, they are characterized by the association of hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II. Bartter syndrome type II is caused by mutations in the renal outer medullary potassium channel (ROMK) gene (KCNJ1), can present in the newborn period and typically requires lifelong therapy. CASE PRESENTATION:We describe a case of a prematurely born female infant presenting with antenatal polyhydramnios, and postnatal dehydration and hyponatremia. After 7 weeks of sodium supplementation, the patient demonstrated complete resolution of her hyponatremia and developed only transient metabolic alkalosis at 2 months of age but continues to be polyuric and exhibits hypercalciuria, without development of nephrocalcinosis. She was found to have two pathogenic variants in the KCNJ1 gene: a frameshift deletion, p.Glu334Glyfs*35 and a missense variant, p. Pro110Leu. While many features of classic ROMK mutations have resolved, the child does have Bartter syndrome type II and needs prolonged pediatric nephrology follow-up. CONCLUSION:Transient neonatal hyponatremia warrants a multi-system workup and genetic variants of KCNJ1 should be considered. | 01 = IsEpi
|
Alport syndrome (AS) is a genetic disorder involving mutations in the genes encoding collagen IV α3, α4 or α5 chains, resulting in the impairment of glomerular basement membrane. Podocytes are responsible for production and correct assembly of collagen IV isoforms; however, data on the phenotypic characteristics of human AS podocytes and their functional alterations are currently limited. The evident loss of viable podocytes into the urine of patients with active glomerular disease enables their isolation in a non-invasive way. We here isolated, immortalized and subcloned podocytes from the urine of three different AS patients for molecular and functional characterization. AS podocytes expressed a typical podocyte signature and showed a collagen IV profile reflecting each patient's mutation. Furthermore, RNA-sequencing analysis revealed 348 genes differentially expressed in AS podocytes compared with control podocytes. Gene Ontology analysis underlined the enrichment in genes involved in cell motility, adhesion, survival, and angiogenesis. In parallel, AS podocytes displayed reduced motility. Finally, a functional permeability assay, using a podocyte-glomerular endothelial cell co-culture system, was established and AS podocyte co-cultures showed a significantly higher permeability of albumin compared to control podocyte co-cultures, in both static and dynamic conditions under continuous perfusion. In conclusion, our data provide a molecular characterization of immortalized AS podocytes, highlighting alterations in several biological processes related to extracellular matrix remodelling. Moreover, we have established an in vitro model to reproduce the altered podocyte permeability observed in patients with AS. This article is protected by copyright. All rights reserved. | 01 = IsEpi
|
Cystic fibrosis is the most common lethal genetic disease in white populations. The outlook for patients with the disease has improved steadily over many years, largely as a result of earlier diagnosis, more aggressive therapy, and provision of care in specialised centres. Researchers now have a more complete understanding of the molecular-biological defect that underlies cystic fibrosis, which is leading to new approaches to treatment. One of these treatments, hypertonic saline, is already in use, whereas others are in advanced stages of development. We review clinical care for cystic fibrosis and discuss recent advances in the understanding of its pathogenesis, implementation of screening of neonates, and development of therapies aimed at treating the basic defect. | 10 = IsNotEpi
|
In 1977 Hunter et al. J Med Genet 1977: 14 (6): 430-437, reported a family with six affected members, connected over three generations through unaffected individuals. Subsequently, several other patients purported to have the condition were reported. The condition became known as the Hunter-McAlpine syndrome, and there was debate as to whether or not it was identical to the Ruvalcaba syndrome or a type of tricho-rhino-phalangeal syndrome. In this article we confirm that the original family and a patient reported by Ades et al. Clin Dysmorphol 1993: 2 (2): 123-130 have cryptic translocations resulting in duplication of 5q35-qter. Similarities are noted between our patients and others in the literature with duplication of this chromosome segment. | 01 = IsEpi
|
Acquired generalized lipodystrophy (AGL) is a rare condition characterized by an altered distribution of adipose tissue and predisposition to develop hepatic steatosis and fibrosis, diabetes, and hypertriglyceridemia. Diagnosis of AGL is based on the observation of generalized fat loss, autoimmunity and lack of family history of lipodystrophy. The pathogenic mechanism of fat destruction remains unknown but evidences suggest an autoimmune origin. Anti-adipocyte antibodies have been previously reported in patients with AGL, although their involvement in the pathogenesis has been poorly studied and the autoantibody target/s remain/s to be identified. Using a combination of immunochemical and cellular studies, we investigated the presence of anti-adipocyte autoantibodies in patients with AGL, acquired partial lipodystrophy, localized lipoatrophy due to intradermic insulin injections or systemic lupus erythematosus. Moreover, the impact of anti-adipocyte autoantibodies from AGL patients was assessed in cultured mouse preadipocytes. Following this approach, we identified anti-perilipin 1 IgG autoantibodies in the serum of patients with autoimmune variety-AGL, but in no other lipodystrophies tested. These autoantibodies altered the ability of perilipin 1 to regulate lipolysis in cultured preadipocytes causing abnormal, significantly elevated basal lipolysis. Our data provide strong support for the conclusion that perilipin 1 autoantibodies are a cause of generalized lipodystrophy in these patients. | 01 = IsEpi
|
Primary cold agglutinin disease (CAD) is characterized by a very indolent bone marrow clonal B-cell lymphoproliferative disorder that initiates an autoimmune hemolytic anemia. The clonal B cells produce a monoclonal autoantibody termed cold agglutinin, most often of the immunoglobulin (Ig) Mκ class. After binding to its antigen, the IgM initiates a complement classical pathway-driven erythrocyte destruction, predominantly mediated by opsonization with complement protein C3b and extravascular hemolysis in the liver. We review the molecular biology, histopathology, clinical features, and diagnostic procedures in CAD. Some patients are only slightly anemic and do not require treatment, but moderate or severe anemia frequently occurs, and the disease burden has been underestimated. CAD should not be treated with corticosteroids. Several B-cell-directed treatment options are available, and complement-directed approaches are being rapidly developed. Current and possible future therapies are reviewed. | 01 = IsEpi
|
OBJECTIVE:The early diagnosis of beta-propeller protein-associated neurodegeneration (BPAN) before distinct brain magnetic resonance imaging (MRI) findings of iron deposition occur remains challenging. This study examined whether children with BPAN have characteristic high-amplitude (>50 μV) fast activity (HAFA) on electroencephalography (EEG). METHODS:We conducted a retrospective analysis of EEG performed during childhood in five patients with BPAN. We also examined 143 EEGs from 59 patients with different etiologies, including epilepsy (n = 33), acute encephalopathy (n = 6), neurodevelopmental disorders (n = 5), non-epileptic events (n = 4), and others (n = 11). Trained electroencephalographers reviewed all of the EEGs. When excessive fast activity was observed, the amplitude, frequency, and locality were assessed. RESULTS:All five patients with BPAN underwent initial EEGs at 12-21 months old, and diffuse continuous HAFA (range 20-50 Hz) was observed on both awake and sleep EEGs. In the awake records, there was no clear posterior dominant rhythm in 4 of the 5 patients. Although 28% of the 143 EEGs had continuous excessive fast activity, mainly in the sleep records, only two (1.4%) exhibited HAFA when asleep, and their awake EEGs had clear posterior dominant rhythm. CONCLUSIONS:The EEGs of children with BPAN showed diffuse HAFA continuously when both awake and asleep, which is uncommon in children with other etiologies. SIGNIFICANCE:This study provides an important clue for the early diagnosis of BPAN. | 01 = IsEpi
|
We report a family of Indian origin presenting with Tarsal-carpal coalition syndrome (TCC), which is a rare genetic disorder of skeletal abnormalities, inherited in autosomal dominant manner. In this family, three individuals (mother and two children) were found to be similarly affected with slight intrafamilial individual variability in the phenotype. Sanger sequencing revealed a novel heterozygous missense mutation in NOG gene (NM_005450.4:c.611G>A) in all the affected individuals of the family. Until now only six mutations have been reported in different families affected with TCC syndrome worldwide. This report further delineates the phenotypic spectrum of this rare disorder with the addition of a new variant to the mutation spectrum. | 01 = IsEpi
|
BACKGROUND:Pulmonary hypertension (PH) remains one of the rarest and deadliest diseases. Pulmonary Capillary Hemangiomatosis (PCH) is one of the sub-classes of PH. It was identified using histological and molecular tools and is characterized by the proliferation of capillaries into the alveolar septae. Mutations in the gene encoding the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) have recently been linked to this particular subgroup of PH. METHODS:In our effort to unveil the genetic basis of idiopathic and familial cases of PH in Lebanon, we have used whole exome sequencing to document known and/or novel mutations in genes that could explain the underlying phenotype. RESULTS:We showed bi-allelic mutations in EIF2AK4 in two non-consanguineous families: a novel non-sense mutation c.1672C > T (p.Q558*) and a previously documented deletion c.560_564drlAAGAA (p.K187Rfs9*). Our histological analysis coupled with the CT-scan results showed that the two patients with the p.Q558* mutation have PH. In contrast, only one of the individuals harboring the p.K187Rfs9* variant has a documented PCH while his older brother remains asymtomatic. Differential analysis of the variants in the genes of the neighboring network of EIF2AK4 between the two siblings identified a couple of interesting missense mutations that could account for this discrepancy. CONCLUSION:These findings represent a novel documentation of the involvement of EIF2AK4 in the different aspects of pulmonary hypertension. The absence of a molecular mechanism that relates the abrogated function of the protein to the phenotype is still a major hurdle in our understanding of the disease. | 01 = IsEpi
|
BACKGROUND Granulocytic sarcoma, or 'chloroma,' due to extramedullary acute myeloid leukemia (AML) or due to acute myelomonocytic leukemia (AML M5), is rare and is associated with a poor prognosis. This report is of a case of granulocytic sarcoma of the gallbladder and describes the approach to diagnosis and treatment. CASE REPORT A 74-year-old Hispanic woman from Ecuador presented to the emergency department with a five-day history of fever, jaundice, and right upper quadrant abdominal pain. The right upper quadrant ultrasound showed a thickened gallbladder wall with cholelithiasis, a positive sonographic Murphy sign, and marked dilatation of the common bile duct, which was up to 17 mm in diameter. Endoscopic retrograde cholangiopancreatography (ERCP) showed purulence and a stone in the common bile duct, which was removed. She underwent laparoscopic cholecystectomy which identified gangrenous cholecystitis. Despite cholecystectomy and treatment with broad-spectrum antibiotics, she remained febrile with a leukocytosis of up to 80,000 cells/µL. Histopathology of the gallbladder showed infiltrating myeloblasts within the mucosa, submucosa, and muscularis consistent with a granulocytic sarcoma associated with gangrenous cholecystitis due to cholelithiasis. Immunohistochemistry, using a panel of antibodies to CD33, CD68, HLA-DR, and lysozyme, supported the diagnosis of granulocytic sarcoma or extramedullary acute myelomonocytic leukemia (AML M5). CONCLUSIONS A rare case of an extramedullary hematologic malignancy, granulocytic sarcoma of the gallbladder is presented, which highlights the importance of timely diagnosis and treatment, due to the high mortality rate associated with granulocytic sarcoma, or extramedullary AML. | 01 = IsEpi
|
PURPOSE OF REVIEW:New daily persistent headache (NDPH) is a rare primary headache disorder, which often has a refractory clinical course. This narrative review seeks to highlight what is known about the development of NDPH, to outline a diagnostic approach to a patient with new daily headache, and to explore management considerations and potential future therapies for patients diagnosed with NDPH. RECENT FINDINGS:Interval work at the level of case series and cohort studies has identified novel triggering factors (e.g., Valsalva), subgroups with unique temporal profiles (e.g., thunderclap onset), psychophysical profiles (e.g., increased pain catastrophizing), and potential treatment options. The approach to the diagnosis and treatment of NDPH remains individualized, driven by clinical features and challenging in most cases. Earlier identification of patients (e.g., prediction of patients with status migrainosus destined to develop NDPH) may allow for more effective treatment. | 01 = IsEpi
|
Acromesomelic dysplasia, type Maroteaux (AMDM) is a congenital bone dysplasia characterized by disproportionate, acromesomelic shortening of the limbs and mild spondylar dysplasia. AMDM is caused by biallelic loss-of-function mutations in NPR2 encoding natriuretic peptide receptor-B. We report on a 25-yr-old Japanese woman with AMDM. Her height was 119.0 cm (-7.4 SD) and weight 35 kg (-2.3 SD). She had acromesomelic shortening of limbs and severe brachydactyly. Radiological examination showed that her metacarpals and phalanges were short and wide, and her vertebral bodies were mildly flattened. Molecular analysis revealed a novel homozygous NPR2 mutation (c.1163G>A, p.Arg388Gln). We performed in vitro functional studies using HA-tagged wild-type (WT) and Arg388Gln vectors (HA-WT-NPRB and HA-R388Q-NPRB). Cells expressing HA-R388Q-NPRB showed negligible cGMP responses to C-type natriuretic peptide (CNP) stimulation, indicating that the mutation led to severe loss-of-function. By immunofluorescence experiments under permeabilized conditions, HA-WT-NPRB was expressed on plasma membrane, while HA-R388Q-NPRB co-localized with an Endoplasmic Reticulum marker. Cells co-expressing R388Q and the WT exhibited lower responses under CNP treatment than cells co-expressing the WT and empty vectors. Thus, it was thought that R388Q caused a dominant-negative effect with a defect in cellular trafficking to the plasma membrane. | 01 = IsEpi
|
First reported in 1956, hereditary fructose intolerance (HFI) illustrates vividly how interactions between genes and nutrients can influence taste preferences; the disease also reflects the ascendancy of sucrose and fructose as energy sources and as the world's principal sweeteners. However, HFI is not the only genetic ill to have emerged from our obsession with sugar: the slave trade, which had such a key part in the development of the sugar industry, also included major genetic consequences in its haunting legacy. | 10 = IsNotEpi
|
Immunotherapy with chimeric antigen receptor T (CAR-T cells) has been recently approved for patients with relapsed/refractory B-lymphoproliferative neoplasms. Along with great efficacy in patients with poor prognosis, CAR-T cells have been also linked with novel toxicities in a significant portion of patients. Cytokine release syndrome (CRS) and neurotoxicity present with unique clinical phenotypes that have not been previously observed. Nevertheless, they share similar characteristics with endothelial injury syndromes developing post hematopoietic cell transplantation (HCT). Evolution in complement therapeutics has attracted renewed interest in these life-threatening syndromes, primarily concerning transplant-associated thrombotic microangiopathy (TA-TMA). The immune system emerges as a key player not only mediating cytokine responses but potentially contributing to endothelial injury in CAR-T cell toxicity. The interplay between complement, endothelial dysfunction, hypercoagulability, and inflammation seems to be a common denominator in these syndromes. As the indications for CAR-T cells and patient populations expand, there in an unmet clinical need of better understanding of the pathophysiology of CAR-T cell toxicity. Therefore, this review aims to provide state-of-the-art knowledge on cellular therapies in clinical practice (indications and toxicities), endothelial injury syndromes and immunity, as well as potential therapeutic targets. | 01 = IsEpi
|
BACKGROUND:Transient receptor potential cation channel subfamily V member 4 (TRPV4) is an ion channel permeable to Ca2+ that is sensitive to physical, hormonal, and chemical stimuli. This protein is expressed in many cell types, including osteoclasts, chondrocytes, and sensory neurons. As such, pathogenic variants of this gene are associated with skeletal dysplasias and neuromuscular disorders. Pathogenesis of these phenotypes is not yet completely understood, but it is known that genotype-phenotype correlations for TRPV4 pathogenic variants often are not present. METHODS:Newly characterized, suspected pathogenic variant in TRPV4 was analyzed using protein informatics and personalized protein-level molecular studies, genomic exome analysis, and clinical study. RESULTS:This statement is demonstrated in the family of our proband, a 47-year-old female having the novel c.2401A>G (p.K801E) variant of TRPV4. We discuss the common symptoms between the proband, her father, and her daughter, and compare her phenotype to known TRPV4-associated skeletal dysplasias. CONCLUSIONS:Protein informatics and molecular modeling are used to confirm the pathogenicity of the unique TRPV4 variant found in this family. Multiple data were combined in a comprehensive manner to give complete overall perspective on the patient disease and prognosis. | 01 = IsEpi
|
Extrinsic allergic alveolitis is an occupational condition intensively studied and published about, unlike cutaneous leukocytoclastic angiitis. The coexistence of these two diseases is even more rare in the same patient with exposure to occupational pollutants of animal origin. We present the case of a 44-year-old man, a pigeon breeder admitted to hospital with a pruritic purpuric eruption and lower limb paresthesia, dyspnea on exertion, polymyalgia rheumatica, mixed polyarthralgias. Based on the clinical, paraclinical and laboratory investigations (electroneuromyography, plethysmography, computed tomography scan, musculocutaneous biopsy, current laboratory tests and immunoassays), the main diagnoses of extrinsic allergic alveolitis and leukocytoclastic vasculitis were determined. The patient underwent treatment with corticosteroids with a favorable outcome, but which becomes aggravated by the occurrence of necrotic skin lesions at the cessation of corticosteroid therapy on the patient's own initiative. After the resumption of the corticosteroid therapy, the lesions and symptoms improve. To our knowledge, this case report is the first one that describes an association of two major conditions, extrinsic allergic alveolitis and cutaneous leukocytoclastic angiitis, in the same clinical context of an occupational exposure to specific pollutants. Long-term corticosteroid therapy has proved to be useful in preventing relapses and improving the patient's clinical status with the association of cutaneous leukocytoclastic angiitis and extrinsic allergic alveolitis. Considering our findings in this case report, we may suggest the inclusion of systemic vasculitis on the list of recognized professional diseases. | 01 = IsEpi
|
Recombination-activating genes ( RAG) 1 and RAG2 initiate the molecular processes that lead to lymphocyte receptor formation through VDJ recombination. Nonsense mutations in RAG1/ RAG2 cause the most profound immunodeficiency syndrome, severe combined immunodeficiency (SCID). Other severe and less-severe clinical phenotypes due to mutations in RAG genes are now recognized. The degree of residual protein function may permit some lymphocyte receptor formation, which confers a less-severe clinical phenotype. Many of the non-SCID phenotypes are associated with autoimmunity. New findings into the effect of mutations in RAG1/2 on the developing T- and B-lymphocyte receptor give insight into the development of autoimmunity. This article summarizes recent findings and places the genetic and molecular findings in a clinical context. | 01 = IsEpi
|
Coffin-Siris syndrome (CSS) is a rare congenital disorder with variable clinical phenotype consisting of developmental delay and characteristic facial features. It is caused by mutations in the chromatin remodeling switch/sucrose nonfermenting complex. Although SWI/SNF genes are widely implicated in tumorigenesis, only 8 cases of neoplasm have been reported in patients with CSS. We report a case of anaplastic astrocytoma (WHO grade III) in an 18-month-old child with CSS due to a de novo germline missense SMARCE1 mutation. Additional molecular features of the tumor are described as well. The role of missense SMARCE1 mutations in tumor predisposition in children with CSS should be further investigated to better inform genetic counselling. | 01 = IsEpi
|
Stüve-Wiedemann syndrome is a rare autosomal recessive disorder characterized by bowed long bones, joint restrictions, dysautonomia, and respiratory and feeding difficulties, leading to death in the neonatal period and infancy in several occasions. Since the first cases in 1971, much has been learned about this condition, including its molecular basis - mutations in the leukemia inhibitory factor receptor gene (LIFR) -, natural history and management possibilities. This review aims to highlight the clinical aspects, radiological features, molecular findings, and management strategies in Stüve-Wiedemann syndrome. | 01 = IsEpi
|
Few hematological complications have previously been reported in association with Cri du Chat syndrome (CdCS). A case of myelodysplastic syndromes (MDS) in a pediatric patient with CdCS is herein presented. A 17-year-old female with CdCS caused by ring chromosome 5 was admitted to the hospital for investigation of a 1-month history of anemia. Based on the morphological findings of bone marrow, the patient was diagnosed with refractory cytopenia with multilineage dysplasia. The risk group was classified as intermediate-1 in the International Prognostic Scoring System (IPSS), and low in the revised IPSS. Assessment by microarray comparative genomic hybridization (CGH) identified the breakpoints of ring chromosome 5 as 46,XX,r(5)(p14.3q35.3). This revealed that the 5q terminal deletion did not include the common deleted region of MDS with del(5q). Treatment with azacitidine was initiated to control disease progression and improve quality of life. At baseline, the patient had a mean transfusion requirement of 3 units/month, which decreased to 2 units/month after six cycles of azacitidine and to 1 unit/month after 10 cycles of azacitidine. Cytopenia observed in the presented case seemed irrelevant to ring chromosome 5 which is the causative cytogenetic abnormality of CdCS, and further analyses may be needed to clarify the pathogenesis. | 01 = IsEpi
|
Mutations in mitochondrial acylglycerol kinase (AGK) cause Sengers syndrome, which is characterized by cataracts, hypertrophic cardiomyopathy, and skeletal myopathy. AGK generates phosphatidic acid and lysophosphatidic acid, bioactive phospholipids involved in lipid signaling and the regulation of tumor progression. However, the molecular mechanisms of the mitochondrial pathology remain enigmatic. Determining its mitochondrial interactome, we have identified AGK as a constituent of the TIM22 complex in the mitochondrial inner membrane. AGK assembles with TIMM22 and TIMM29 and supports the import of a subset of multi-spanning membrane proteins. The function of AGK as a subunit of the TIM22 complex does not depend on its kinase activity. However, enzymatically active AGK is required to maintain mitochondrial cristae morphogenesis and the apoptotic resistance of cells. The dual function of AGK as lipid kinase and constituent of the TIM22 complex reveals that disturbances in both phospholipid metabolism and mitochondrial protein biogenesis contribute to the pathogenesis of Sengers syndrome. | 01 = IsEpi
|
3-Hydroxyisobutyryl-CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome-like phenotype, mitochondrial dysfunction, and increased C4-OH. We report the most severe case to date in a full-term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow-up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature. | 01 = IsEpi
|
Charcot-Marie-Tooth neuropathy type 1 (CMT1) is an inherited demyelinating neuropathy characterized by distal muscle weakness and atrophy. Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare form of CMT1 caused by mutations in the lipopolysaccharide-induced tumor necrosis factor (LITAF) or small integral membrane protein of the lysosome/late endosome (SIMPLE) gene. Phenotypically, CMT1C is characterized by sensory loss and slow conduction velocity, and is typically slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. A 42-year-old female presented with a 10-year history of slowly progressive bilateral calf pain and cramps. After multiple electromyography/nerve conduction studies (EMG/NCS) and genetic testing, the patient was revealed to have CMT1C with a heterozygous pathogenic variant, c.334G>A (p.Gly112Ser). However, the presentation of the patient's CMT1C phenotype was unusual compared to patients with similar diagnosis in a previous study, including a normal sensory exam with the exception of high arches and mildly reduced vibratory sense. Additionally, the patient's teenage son already started showing symptoms of CMT1C despite the fact that the onset of the disease typically occurs at an older age. This particular case further highlights the idea that the phenotype related to CMT1C may have a wide spectrum of disease severity. | 01 = IsEpi
|
Renpenning syndrome (OMIM: 309500) is a rare X-linked disorder that causes intellectual disability, microcephaly, short stature, a variety of eye anomalies, and characteristic craniofacial features. This condition results from pathogenic variation of PQBP1, a polyglutamine-binding protein involved in transcription and pre-mRNA splicing. Renpenning syndrome has only been reported in affected males. Carrier females do not usually have clinical features, and in reported families with Renpenning syndrome, most female carriers exhibit favorable skewing of X-chromosome inactivation. We describe a female with syndromic features typical of Renpenning syndrome. She was identified by exome sequencing to have a de novo heterozygous c.459_462delAGAG mutation in PQBP1 (Xp11.23), affecting the AG hexamer in exon 4, which is the most common causative mutation in this syndrome. Streaky hypopigmentation of the skin was observed, supporting a hypothesized presence of an actively expressed, PQBP1 mutation-bearing X-chromosome in some cells. X-inactivation studies on peripheral blood cells demonstrated complete skewing in both the proband and her mother with preferential inactivation of the maternal X chromosome in the child. We demonstrated expression of the PQBP1 mutant transcript in leukocytes of the affected girl. Therefore, it is highly likely that the PQBP1 mutation arose from the paternal X chromosome. | 01 = IsEpi
|
Fragile X syndrome (FXS) is the most common single gene cause of autism and intellectual disabilities. Humans with FXS exhibit increased anxiety, sensory hypersensitivity, seizures, repetitive behaviors, cognitive inflexibility, and social behavioral impairments. The main purpose of this review is to summarize developmental studies of FXS in humans and in the mouse model, the Fmr1 knockout mouse. The literature presents considerable evidence that a number of early developmental deficits can be identified and that these early deficits chart a course of altered developmental experience leading to symptoms well characterized in adolescents and adults. Nevertheless, a number of critical issues remain unclear or untested regarding the development of symptomology and underlying mechanisms. First, what is the role of FMRP, the protein product of Fmr1 gene, during different developmental ages? Does the absence of FMRP during early development lead to irreversible changes, or could reintroduction of FMRP or therapeutics aimed at FMRP-interacting proteins/pathways hold promise when provided in adults? These questions have implications for clinical trial designs in terms of optimal treatment windows, but few studies have systematically addressed these issues in preclinical and clinical work. Published studies also point to complex trajectories of symptom development, leading to the conclusion that single developmental time point studies are unlikely to disambiguate effects of genetic mutation from effects of altered developmental experience and compensatory plasticity. We conclude by suggesting a number of experiments needed to address these major gaps in the field. | 01 = IsEpi
|
We present the case of a male patient who presented progressive cerebellar ataxia since childhood who developed partial hypogonadotropic hypogonadism discovered when searching for a cause of low fecundity. The association of these two entities has been described in several rare syndromes: Homes ataxia, Boucher-Neuhauser syndrome and Richards-Rundle syndrome. The genetic background of these three syndromic associations defined solely on the basis of clinical manifestations remains to be elucidated, leading to uncertain diagnosis. The present case suggests the syndromic entity could be associated with autosomal recessive spinocerebellar ataxia with hypogonadotropic hypogonadism which includes several genotypic entities. | 01 = IsEpi
|
Maintaining mitochondrial health is emerging as a keystone in aging and associated diseases. The selective degradation of mitochondria by mitophagy is of particular importance in keeping a pristine mitochondrial pool. Indeed, inherited monogenic diseases with defects in mitophagy display complex multisystem pathologies but particularly progressive neurodegeneration. Fortunately, therapies are being developed that target mitophagy allowing new hope for treatments for previously incurable diseases. Herein, we describe mitophagy and associated diseases, coin the term mitophaging and describe new small molecule interventions that target different steps in the mitophagic pathway. Consequently, several age-associated diseases may be treated by targeting mitophagy. | 01 = IsEpi
|
The 16p11.2 duplication (BP4-BP5) is associated with Autism Spectrum Disorder (ASD), although significant heterogeneity exists. Quantitative ASD, behavioral and neuropsychological measures and DSM-IV diagnoses in child and adult carriers were compared with familial non-carrier controls, and to published results from deletion carriers. The 16p11.2 duplication phenotype ranges widely from asymptomatic presentation to significant disability. The most common diagnoses were intellectual disability, motor delays and Attention Deficit Hyperactivity Disorder in children, and anxiety in adults. ASD occurred in nearly 20 % of child cases, but a majority of carriers did not show the unique social features of ASD. The 16p11.2 duplication phenotype is characterized by wider variability than the reciprocal deletion, likely reflecting contributions from additional risk factors. | 01 = IsEpi
|
Preeclampsia (PE) is a disorder that affects 3-5% of normal pregnancies. It was believed for a long time that the kidney, similarly to all vessels in the whole system, only sustained endothelial damage. The current knowledge gives rise to a presumption that the main role in the development of proteinuria is played by damage to the podocytes and their slit diaphragm. The podocyte damage mechanism in preeclampsia is connected to free VEGF and nitric oxide (NO) deficiency, and an increased concentration of endothelin-1 and oxidative stress. From national cohort studies, we know that women who had preeclampsia in at least one pregnancy carried five times the risk of developing end-stage renal disease (ESRD) when compared to women with physiological pregnancies. The focal segmental glomerulosclerosis (FSGS) is the dominant histopathological lesion in women with a history of PE. The kidney's podocytes are not subject to replacement or proliferation. Podocyte depletion exceeding 20% resulted in FSGS, which is a reason for the later development of ESRD. In this review, we present the mechanism of kidney (especially podocytes) injury in preeclampsia. We try to explain how this damage affects further changes in the morphology and function of the kidneys after pregnancy. | 01 = IsEpi
|
Stress is under-recognised as a potential causative factor for reversible cerebral vasoconstriction syndrome (RCVS). Here we present a case of RCVS occurring during a time of extreme emotional duress. A 46-year-old female patient with medical history of bipolar disorder developed a severe headache during her father's funeral. The following day she was discovered to have bilateral hemiparesis, aphasia, encephalopathy and was brought emergently to the hospital. Neuroimaging revealed a 33 mL left fronto-parietal haematoma with subarachnoid blood near the vertex bilaterally. She underwent craniotomy, haematoma evacuation and external ventricular drain placement. The patient received two cerebral angiograms, the first showing multifocal cerebral vasoconstriction and the second showing resolution of these changes. She improved significantly over the course of her 3-week hospitalisation and eventually made a full recovery, including the ability to speak fluently in six languages with no significant deficits other than hypersomnia; she now requires 10 hours of sleep each night as compared with 7 hours prior to her brain injury. | 01 = IsEpi
|
Congenital lactic acidosis due to pyruvate dehydrogenase phosphatase (PDP) deficiency is very rare. PDP regulates pyruvate dehydrogenase complex (PDC) and defective PDP leads to PDC deficiency. We report a case with functional PDC deficiency with low activated (+dichloroacetate) and inactivated (+fluoride) PDC activities in lymphocytes and fibroblasts, normal activity of other mitochondrial enzymes in fibroblasts, and novel biallelic frameshift mutation in the PDP1 gene, c.575dupT (p.L192FfsX5), with absent PDP1 product in fibroblasts. Unexpectedly, the patient also had low branched-chain 2-ketoacid dehydrogenase (BCKDH) activity in fibroblasts with slight elevation of branched-chain amino acids in plasma and ketoacids in urine but with no pathogenic mutations in the enzymes of BCKDH, which could suggest shared regulatory function of PDC and BCKDH in fibroblasts, potentially in other tissues or cell types as well, but this remains to be determined. The clinical presentation of this patient overlaps that of other patients with primary-specific PDC deficiency, with neonatal/infantile and childhood lactic acidosis, normal lactate to pyruvate ratio, elevated plasma alanine, delayed psychomotor development, epileptic encephalopathy, feeding difficulties, and hypotonia. This patient exhibited marked improvement of overall development following initiation of ketogenic diet at 31 months of age. To the best of our knowledge, this is the fourth case of functional PDC deficiency with a defined mutation in PDP1. Synopsis:Pyruvate dehydrogenase phosphatase (PDP) regulates pyruvate dehydrogenase complex (PDC) and defective PDP due to PDP1 mutations leads to PDC deficiency and congenital lactic acidosis. | 01 = IsEpi
|
The aim of our study was to evaluate the prognostic factors and treatment options of a very rare and highly aggressive type of uterine neoplasms, the malignant mixed Müllerian tumor, known as carcinosarcoma.Between 2009 and 2017, 29 patients were treated with malignant mixed Müllerian tumor. At stage I, surgery and postoperative radiotherapy were performed. At stages II-IV, trimodal treatment (surgery, chemotherapy and radiotherapy) was administered.The average age of patients was 68.51 (49-90) years, mean body mass index was 30.22 (20.90-37.22). We have experienced recurrence of disease after complete resection in 6 cases (4 of 6 patients did not accept radiation therapy). Local recurrence has occurred after an average 15.52 (6-36) months, distant metastasis with an average 19.2 (8-32) months. Overall survival was 11.92 (1-75) months. Six patients are free of tumours at the moment.As overall survival has not increased in recent decades by using combined chemotherapy, there is no congruent consensus associated with the optimal treatment. The standard surgical treatment is total abdominal hysterectomy with bilateral oophorectomy, although due to high rates of recurrence and metastases, the necessity of lymphadenectomy and postoperative treatment is in the focus of recent studies. Though postoperative irradiation improves local control, the beneficial effect on overall survival is still not proven. Adjuvant chemotherapy decreases the rate of both pelvic and extrapelvic recurrence at the same time, although there is no recommendation for the optimal chemoterapeutic agent. Multimodal therapy should lead to better outcomes. Recently there are many ongoing studies with biologic and target therapies to improve efficiency, however, the relevant results will be disclosed in many years only, due to the small number of patients. Orv Hetil. 2018; 159(19): 741-7747. | 01 = IsEpi
|
The ridged skin of the palms and soles has several unique features: (i) presence of dermatoglyphics created by alternating ridges and grooves forming a unique pattern, (ii) presence of the highest density of eccrine sweat glands and absence of pilosebaceous units, and (iii) differential expression of keratins compared to the glabrous skin. These features explain the preferential localization of palmoplantar keratoderma (PPK) and several of its characteristic clinical features. PPK develops as a compensatory hyperproliferation of the epidermis and excessive production of stratum corneum in response to altered cornification of the palmoplantar skin due to mutations in the genes encoding several of the proteins involved in it. PPK can manifest as diffuse, focal, striate, or punctate forms per se or as a feature of several dermatological or systemic diseases. There is a wide genetic and phenotypic heterogeneity in hereditary PPK, due to which reaching an accurate diagnosis only on the basis of clinical features may be sometimes challenging for the clinicians in the absence of molecular studies. Nevertheless, recognizing the clinical patterns of keratoderma, extent of involvement, degree of mutilation, and associated appendageal and systemic involvement may help in delineating different forms. Molecular studies, despite high cost, are imperative for accurate classification, recognizing clinical patterns in resource poor settings is important for appropriate diagnosis, genetic counseling, and management. This review intends to develop a practical approach for clinical diagnosis of different types of hereditary PPK with reasonable accuracy. | 01 = IsEpi
|
Best's disease is an inherited macular dystrophy with autosomal dominant inheritance pattern, characterized by the presence of autofluorescent vitelliform deposition whose development is stereotyped from its manifestation to the fragmentation of the material and then to its resorption. Age at onset is between 7 and 12 years. Except in the presence of complications, patients are more often asymptomatic and the disease is discovered fortuitously. We report the case of 8 year-old only daughter with no particular past medical history. Ophthalmologic examination showed corrected visual acuity 7/10 in the left and right eyes, the examination of the anterior segment was normal, fundus examination showed macular yellowish-white stain (A, B). On fluorescein angiography, hyperfluorescence occurred early followed by a hypofluorescence. Macular imaging by optical coherence tomography (OCT) showed the presence of an empty optical space between the neuroretina and the pigment epithelium (C, D). Assessment was performed: electrooculogram was perturbed using Arden ratio of 146% in the right eye and 179% in the left eye. Electroretinogram, visual fields and color vision test were normal. Fundus examination of parents was normal. The diagnosis of previtelliform BEST's disease was made based on early hypofluorescence, OCT appearance and alteration of the electroretinogram. Differential diagnoses included: stargardt's disease, progressive dystrophy of the cones and X-linked retinoschisis. No treatment was proposed, only simple monitoring. | 01 = IsEpi
|
Pattern recognition, using a group of characteristic, or discriminating features, is a powerful tool in metabolic diagnostic. A classic example of this approach is used in biochemical analysis of urine organic acid analysis, where the reporting depends more on the correlation of pertinent positive and negative findings, rather than on the absolute values of specific markers. Similar uses of pattern recognition in the field of biochemical genetics include the interpretation of data obtained by metabolomics, like glycomics, where a recognizable pattern or the presence of a specific glycan sub-fraction can lead to the direct diagnosis of certain types of congenital disorders of glycosylation. Another indispensable tool is the use of clinical pattern recognition-or syndromology-relying on careful phenotyping. While genomics might uncover variants not essential in the final clinical expression of disease, and metabolomics could point to a mixture of primary but also secondary changes in biochemical pathways, phenomics describes the clinically relevant manifestations and the full expression of the disease. In the current review we apply phenomics to the field of congenital disorders of glycosylation, focusing on recognizable differentiating findings in glycosylation disorders, characteristic dysmorphic features and malformations in PMM2-CDG, and overlapping patterns among the currently known glycosylation disorders based on their pathophysiological basis. | 01 = IsEpi
|
A 33-year-old man admitted to our hospital for the evaluation of progressive muscular atrophy of his left lower leg. From his childhood, he had suffered from transient attacks of limb paralysis and myalgia lasting about 1 hour. At age 30, the muscle weakness and atrophy of his left lower leg emerged and progressed gradually. Muscle MR images showed atrophy and fat replacement in left lower leg, and muscle biopsy revealed tubular aggregates (TA). Genetic analysis showed heterozygous c.2111C>T/p.T704M missense mutation of SCN4A gene, which causes hyperkalemic periodic paralysis (HyperPP). Although HyperPP is rare, it is quite critical for clinicians to recognize that the patients of HyperPP often present progressive myopathy. We emphasize the importance of paying attention to progressive myopathy and discuss the pathological mechanism of myopathy through this case report. | 01 = IsEpi
|
Cerebral disorders are known to be associated with myoclonus, but spinal pathologies have received little attention as a causative factor in movement disorders. Propriospinal myoclonus (PSM) is a rare hyperkinetic movement disorder caused by activity of a spinal pattern generator localized in a few segments of the spinal cord, spreading to other intraspinal segments via propriospinal pathways. Majority of cases of PSM are reported as functional movement disorders. Structural lesions were found in only a small number of reported cases. We present this rare case report of a patient who developed PSM 2 years following spinal surgery, done 5 years ago for D6-D7 vertebral body collapse. To the best of our knowledge, only few cases of PSM have been reported after spinal surgery and none from India. | 01 = IsEpi
|
We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing. | 01 = IsEpi
|
Objective: Marchiafava-Bignami disease (MBD) is a rare complication associated with chronic heavy alcohol use, with case reports documenting a range of cognitive outcomes. Given the variability in MBD presentation and outcomes, milder cases may remain undiagnosed and few studies or case reports have presented a comprehensive neuropsychological profile of these patients. The objective of this case study was to describe the neuropsychological presentation and findings of a case of likely MBD.Method: The patient was a 46-year-old, African American female with a complex history of malnutrition and alcohol abuse presenting for outpatient neuropsychological evaluation. She was administered a comprehensive battery of neuropsychological tests as part of routine clinical care.Results: Neuropsychological data demonstrated severe deficits in executive functions, complex visuoconstruction, and motor dexterity, as well as an amnestic verbal and visual memory pattern.Conclusions: Overall, data and the patient's initial presentation of acute behavioral change were consistent with some reports of cognitive and behavioral sequela of MBD. Additionally, the patient's history of chronic poor nutritional intake with exacerbation from chronic heavy alcohol use, and imaging findings of severe cerebral/corpus callosum white matter loss and bilateral frontoparietal atrophy, were highly suggestive of MBD. | 01 = IsEpi
|
Given that psychiatric symptoms are common, not only during the course of the illness but also on presentation, in children and adolescents with anti-N-methyl-d-aspartate receptor encephalitis, it is important that practitioners possess an adequate understanding of the clinical features and potential treatment of this disease. We describe the clinical characteristics of 24 patients who presented to the California Encephalitis Project.Patients were referred by physicians, and standardized forms were used to gather demographic, clinical, and laboratory data.Twenty-four patients between ages two and 18 years were identified. Psychosis was a primary presenting symptom in two thirds of patients, and just over 20% of these were admitted to an inpatient psychiatric facility. Ultimately, all patients developed psychiatric symptoms during the course of the illness. There was a characteristic progression of symptoms that was consistent with that noted in other studies, with prominent psychiatric symptoms initially, which then progressed to seizures and autonomic instability in most patients. All of those examined developed movement abnormalities, which included primarily orofacial dyskinesias and choreiform movements.Anti-N-methyl-d-aspartate receptor encephalitis, unlike other paraneoplastic or autoimmune encephalitides, affects those 18 years and under an estimated 40% of the time based on prior studies. Recognizing the signs and symptoms of this condition is essential to making a diagnosis and initiating timely treatment. Child psychiatrists have an important role in this disorder. | 01 = IsEpi
|
Purpose:To identify different preintervention prognostic factors between renal pelvic cancer (RPc) and ureteral cancer (Uc) and to develop different preintervention risk stratifications for each cancer type. Materials and Methods:A total of 1,768 patients with organ-confined upper urinary tract urothelial carcinoma (1,067 patients with RPc and 701 with Uc) who presented between 2004 and 2015 were selected from the Surveillance, Epidemiology, and End Results database. Clinicopathologic characteristics were compared between RPc and Uc. Univariable and multivariable Cox regression models were used to examine the prognostic ability of the clinicopathologic characteristics with respect to oncology outcomes. Results:Age greater than 75 years was significantly associated with cancer-specific survival (CSS) in RPc patients but not in Uc patients. Tumor size had a significant influence on CSS in Uc patients but not in RPc patients; in contrast, age had an influence in RPc but not in Uc. Unlike CSS, age was significantly associated with overall survival (OS) in both RPc and Uc. Tumor size had an effect on OS in Uc patients but not in RPc patients. Conclusions:The preintervention prognostic factors differed between RPc and Uc. Thus, we should develop separate preintervention risk stratification standards for RPc and Uc. Using these specific preintervention risk stratifications, we may be able to select the most appropriate surgical options for patients in the clinic. | 01 = IsEpi
|
Mosquito-borne flaviviruses are emerging pathogens of an increasing global public health concern because of their rapid increase in geographical range and the impact of climate change. Japanese encephalitis virus (JEV) and West Nile virus (WNV) are of concern because of the risk of reemergence and introduction by migratory birds. In Singapore, human WNV infection has never been reported and human JEV infection is rare. Four sentinel vector surveillance sites were established in Singapore to understand the potential risk posed by these viruses. Surveillance was carried out from August 2011 to December 2012 at Pulau Ubin, from March 2011 to March 2013 at an Avian Sanctuary (AS), from December 2010 from October 2012 at Murai Farmway, and from December 2010 to December 2013 at a nature reserve. The present study revealed active JEV transmission in Singapore through the detection of JEV genotype II in Culex tritaeniorhynchus collected from an Avian Sanctuary. Culex flavivirus (CxFV), similar to the Quang Binh virus isolated from Cx. tritaeniorhynchus in Vietnam and CxFV-LSFlaviV-A20-09 virus isolated in China, was also detected in Culex spp. (vishnui subgroup). No WNV was detected. This study demonstrates the important role that surveillance plays in public health and strongly suggests the circulation of JEV among wildlife in Singapore, despite the absence of reported human cases. A One Health approach involving surveillance, the collaboration between public health and wildlife managers, and control of mosquito populations remains the key measures in risk mitigation of JEV transmission in the enzootic cycle between birds and mosquitoes. | 01 = IsEpi
|
BACKGROUND:Congenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. CASE PRESENTATION:We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. CONCLUSIONS:Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples. | 01 = IsEpi
|
Cytochrome c oxidase (COX) deficiency is known to be associated with Leigh syndrome (LS), however there are limited studies on genetic screening of mitochondrial (mt) DNA encoding COX genes as well as the functional validation of identified variants. In our previous studies, we cared for total 165 LS patients and analyzed the nucleotide variations across entire mt genome. We observed a high level of genetic heterogeneity in these patients. We identified various reported and novel variation across entire genome including COX genes. In our present study we have further studied and functionally validated the selected novel nucleotide variant of COX I and COX II gene using different in-silico tools and trans mitochondrial cybrid based assays. As a result of our study, G6036A (G45S) variant of COX I gene, reduced the COX activity in both spectrophotometric as well as In-gel BN-PAGE assays. FACS analysis also revealed this variant to affect the mitochondrial membrane potential in the respective cybrids. Interestingly most of our in-silico studies indicated that this variant might affect the secondary structure and confirmation of COX I protein. Thus we report the first missense mutation in the COX I gene of LS patients and justify its pathogenic role in these patients by different assays. Variant A7746G (N54K) in COX II gene was also predicted to affect the secondary structure as well as stability of COX II protein. Though, the effect of this variant was not significant, however it will be interesting to investigate its significance by other assays in future. | 01 = IsEpi
|
The objectives of this paper were to study the reported haemophilia A prevalence (per 100 000 males) on a country-by-country basis and address the following: Does the reported prevalence of haemophilia A vary by national economies? We collected prevalence data for 106 countries from the World Federation of Hemophilia (WFH) annual global surveys and the literature. We found that the reported haemophilia A prevalence varied considerably among countries, even among the wealthiest of countries. The prevalence (per 100 000 males) for high income countries was 12.8 +/- 6.0 (mean +/- SD) whereas it was 6.6 +/- 4.8 for the rest of the world. Within a country, there was a strong trend of increasing prevalence over time--the prevalence for Canada ranged from 10.2 in 1989 to 14.2 in 2008 (R = 0.94 and P < 0.001) and for the United Kingdom it ranged from 9.3 in 1974 to 21.6 in 2006 (R = 0.94 and P < 0.001). Prevalence data reported from the WFH compared well with prevalence data from the literature. Patient registries generally provided the highest quality of prevalence data. The lack of accurate country-specific prevalence data has constrained planning efforts for the treatment and care of people with haemophilia A. With improved information, healthcare agencies can assess budgetary needs to develop better diagnostic and treatment facilities for affected patients and families and work to ensure adequate supplies of factor VIII concentrates for treatment. In addition, this information can help manufacturers plan the production of concentrates and prevent future shortages. | 10 = IsNotEpi
|
The infantile-onset axonal neuropathies and neuronopathies are an uncommon and heterogeneous group of conditions causing weakness, wasting, and developmental delay in early childhood. Many are associated with central nervous system or other systemic manifestations and cause early mortality. We review the axonal Charcot-Marie-Tooth subtypes with onset in infancy, spinal muscular atrophy, and related syndromes of early infancy, giant axonal neuropathy, infantile neuroaxonal dystrophy, hereditary motor and sensory neuropathy with agenesis of the corpus callosum, early-onset neuropathies associated with mitochondrial disorders, and other less well-delineated clinical entities. Useful clinical and neuropathologic features in the diagnostic work-up of these conditions are also presented. | 10 = IsNotEpi
|
Pemphigus is a group of autoimmune intraepidermal blistering diseases caused by immunoglobulins directed against keratinocyte cell surface components. In this case report, we identify a non-classical paraneoplastic pemphigus (PNP) foliaceous related to an undifferentiated uterine sarcoma. The patient is a 54-year-old Chinese female with a past medical history of arthritis who presented with worsening fatigue in November 2017 and an itchy, blistering, erythematous annular plaque that first appeared on her chest in February 2018. Given high suspicion for primary immunobullous disease despite negative immunofluorescence and lack of subepidermal split on initial biopsy, a repeat biopsy was performed from the right thigh showing positive intraepidermal "net-like" staining for C3 and IgG, but was negative for IgA, IgM, and fibrinogen. IgG antibodies against desmoglein 1 were elevated at 280u (reference range <18), but none resulted against desmoglein 3, consistent with pemphigus foliaceus. This patient's PNP was resistant to treatment with azathioprine, dapsone, mupirocin cream, or betamethasone ointment, but responded to prednisone and rituximab per lymphoma protocol at 375 mg/m2 weekly for one month in December 2018. In February 2019, the patient had 2-3 episodes of postmenopausal vaginal bleeding and subsequent hysteroscopy with dilation and curettage revealed an undifferentiated uterine sarcoma. The patient underwent an exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic lymph node sampling. After surgical staging, she noted significant improvement in her baseline skin lesions and has had no new lesions since surgery. Repeat desmoglein antibodies showed anti-Dsg1 antibodies of 32u (reference range <18) and anti-Dsg3 antibodies of 1u (reference range <19), as compared to the anti-Dsg1 antibodies of 280u in June 2018. She has since completed 4 cycles of adjuvant gemcitabine and docetaxel for her stage IIB undifferentiated uterine sarcoma with no recurrence of the pemphigus lesions. | 01 = IsEpi
|
Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes. | 01 = IsEpi
|
Bifid nose, an indicator of Tessier No.0, is a rare congenital malformation. Because of its rarity, few cases were reported and the optimal surgical procedure and the best time for surgery have not been widely acknowledged. In this brief report, a 9-year-old girl with mild bifid nose and unilateral mini-microform cleft lip, and its surgical management, is presented. We focused our attention on modifying the shape of the nose through open rhinoplasty without excising the surplus skin on the nasal dorsum and achieved good results. | 01 = IsEpi
|
Otodental syndrome is a rare autosomal-dominant disease characterized by globodontia, associated with sensorineural, high-frequency hearing loss. Here, we describe the clinical, pathological, and genetic evaluations of a 9-year-old girl with otodental syndrome and multiple complex odontoma.The patient presented with a draining sinus tract in her left cheek, globodontia, and hearing loss. The odontomas which caused the cutaneous sinus tracts were extracted because of the odontogenic infection. The extracted odontoma and primary tooth was studied by micro-CT and further observed histopathologically. The micro-CT findings revealed that the primary tooth had three crowns with two separated pulp chambers, and their root canals were partially fused. The histological findings showed abnormal morphologies of odontoblasts and dentin, hyperplasia of enamel, and malformation of odontogenic epithelium. Furthermore, DNA sequencing and analyze of deafness associated gene GJB2, GJB3, and PDS had not revealed any SNP or mutation; but exon 3 of the causative gene FGF3 could not be amplified, which may be associated with the microdeletion at chromosome 11q13.3. Three month after surgery, the patient was found to be asymptomatic and even the evidence of the extra-oral sinus had disappeared.The dental abnormality of otodental syndrome included congenital missing teeth, globodontia, and multiple complex odontoma. Globodontia exhibited characteristic features of fusion teeth. In addition, gene FGF3 haploinsufficiency was likely to be the cause of otodental syndrome. The report provides some new information in the field of otodental syndrome, which would make dentists more familiar with this disease. | 01 = IsEpi
|
Werner syndrome (WS), also known as adult progeria, is extremely rare, with about 1300 known cases in the world, with over 1000 of these in Japan. It occurs due to loss of function mutations in the WRN gene located on chromosome 8p12. WS is characterized by premature aging and increased risk of neoplasms, with meningiomas being the commonest intracranial tumor. We report the case of a 39-year-old male patient, who presented with occasional numbness in right arm for three weeks. The patient had developed signs and symptoms of premature aging which started in his adolescence. MRI brain done was suggestive of left frontal convexity extra-axial lesion, suggestive of meningioma. Genetic analysis performed has identified an autosomal recessive, apparently homozygous c.3383+3A>G mutation, a mutation not previously reported. As per the existing literature, this is the index case of meningioma in Werner syndrome from India. A new mutation has been identified. | 01 = IsEpi
|
The majority of human chromosome ends remain incompletely assembled due to their highly repetitive structure. In this study, we use BioNano data to anchor and extend chromosome ends from two European trios as well as two unrelated Asian genomes. At least 11 BioNano assembled chromosome ends are structurally divergent from the reference genome, including both missing sequence and extensions. These extensions are heritable and in some cases divergent between Asian and European samples. Six out of nine predicted extension sequences from NA12878 can be confirmed and filled by nanopore data. We identify two multi-kilobase sequence families both enriched more than 100-fold in extension sequence (p-values < 1e-5) whose origins can be traced to interstitial sequence on ancestral primate chromosome 7. Extensive sub-telomeric duplication of these families has occurred in the human lineage subsequent to divergence from chimpanzees. | 01 = IsEpi
|
Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome consists of Mullerian aplasia with or without other anomalies, most commonly renal and skeletal. The genetic etiology of MRKH syndrome is unknown for most patients, but supportive evidence exists for heterozygous mutations in WNT4, LHX1, and HNF1B. Chromosomal microarray analyses have demonstrated chromosomal regions with copy number variants in multiple patients - deletions in17q12 and 16p11.2, and either deletions or duplications in 22q11.2. Genomic analyses of expression and methylation have also suggested potential molecular pathways. Positional cloning in MRKH patients with chromosomal rearrangements and exome sequencing are likely to result in new genes. Although some single gene defects and copy number variant regions have been identified, the molecular basis for the vast majority of MRKH remains unknown. | 01 = IsEpi
|
The occurrence of cutaneous angiolipomas and intra-abdominal retroperitoneal chemodectomas in two brothers is described. Both died from malignant dissemination of the chemodectomas. It is possible but speculative that two other brothers suffered from the same syndrome. | 01 = IsEpi
|
This review aims to present and compare different surgical techniques of root translocation of the great arteries except the Ross procedure. The historical aspects, technical considerations, and results are briefly elucidated. | 01 = IsEpi
|
Menetrier disease is a rare disease characterised by hyperplasia of the gastric epithelium and large gastric folds. We present a case of a 58-year-old woman who was referred with iron deficiency anaemia, with a family history of a sibling who had undergone gastrectomy for presumed gastric malignancy. Endoscopy showed prominent gastric mucosal folds and biopsies showed hyperplastic gastric mucosa, with prominent foveolar hyperplasia suggestive of Menetrier disease. Further information about her brother's diagnosis was sought, and it was found that his pathology after gastrectomy showed diffuse glandular hyperplasia also in keeping with Menetrier disease. Adult familial Menetrier disease has so far been a rarity in the literature-review elicits five previous cases of this presentation in siblings. | 01 = IsEpi
|
OBJECTIVES:This study was performed with the aim of investigating the temporal patterns and determinants associated with mortality from asbestosis among 21 cohorts of Asbestos-Cement (AC) workers who were heavily exposed to asbestos fibres. METHODS:Mortality for asbestosis was analysed for a cohort of 13 076 Italian AC workers (18.1% women). Individual cumulative asbestos exposure index was calculated by factory and period of work weighting by the different composition of asbestos used (crocidolite, amosite, and chrysotile). Two different approaches to analysis, based on Standardized Mortality Ratios (SMRs) and Age-Period-Cohort (APC) models were applied. RESULTS:Among the considered AC facilities, asbestos exposure was extremely high until the end of the 1970s and, due to the long latency, a peak of asbestosis mortality was observed after the 1990s. Mortality for asbestosis reached extremely high SMR values [SMR: males 508, 95% confidence interval (CI): 446-563; females 1027, 95% CI: 771-1336]. SMR increased steeply with the increasing values of cumulative asbestos exposure and with Time Since the First Exposure. APC analysis reported a clear age effect with a mortality peak at 75-80 years; the mortality for asbestosis increased in the last three quintiles of the cumulative exposure; calendar period did not have a significant temporal component while the cohort effect disappeared if we included in the model the cumulative exposure to asbestos. CONCLUSIONS:Among heaviest exposed workers, mortality risk for asbestosis began to increase before 50 years of age. Mortality for asbestosis was mainly determined by cumulative exposure to asbestos. | 01 = IsEpi
|
This study investigated if the protective effect of taurine against high fat diet-induced hepatic steatosis involves modulating the hepatic activity of 5' AMP-activated protein kinase (AMPK) and levels/activity of the sterol regulatory element-binding proteins-1/2 (SREBP1/2). Rats were divided into 4 groups (n=12/groups) as 1) STD: fed standard diet (3.85 kcal/g), 2) STD + taurine (500 mg/kg), 3) HFD: fed HFD (4.73 kcal/g, and 4) HFD + taurine. All treatments were conducted for 12 weeks. Independent of food intake or modulating glucose or insulin levels, taurine administration to STD and HFD-fed rats significantly lowered weekly weight gain and the accumulation of the retroperitoneal, visceral and subcutaneous fats. In both groups, taurine also reduced serum and hepatic levels of triglycerides and cholesterol and reduced hepatic mRNA and protein levels of fatty acid synthase (FAS), acetyl CoA carboxylase-1 (ACC-1), HMGCOA-reductase and HMGCOA synthetase. In control rats only, taurine reduced hepatic levels of mature forms of SREBP-1/2. In HFD-fed rats, taurine reduced SREBP-1/2 precursor and mature forms in the livers of HFD-fed rats. Besides, taurine significantly increased levels of glutathione (GSH), the activity of superoxide dismutase (SOD), and the activity of AMPK and its downstream β-oxidation genes including peroxisome proliferator-activated receptor-α (PPAR-α) and carnitine palmitoyltransferase (CPT-1) in the livers of both the control and HFD-fed rats. In conclusion, taurine protects against HFD-induced hepatic steatosis stimulating antioxidant levels, and concomitant stimulating hepatic β-oxidation and suppressing lipid synthesis, mediated by activation of AMPK and suppression of SREBP-1. | 01 = IsEpi
|
BACKGROUND:Retinitis punctata albescens is a form of retinitis pigmentosa characterized by white fleck-like deposits in the fundus, in most cases caused by pathogenic variants in RLBP1 gene. The purpose of this work is to report the phenotypic and genotypic data of a patient with retinitis punctata albescens carrying a deletion in the RLBP1 gene. RESULTS:An 8-year-old Caucasian female has been complaining of nyctalopia for the last 2 years. No other ocular symptoms were present. No relevant past medical or familiar history was described. At clinical examination, the patient's best-corrected visual acuity was 20/20 in both eyes. Anterior segment evaluation and intraocular pressure were normal in both eyes. At fundoscopy, multiple punctate whitish-yellow fleck-like lesions were observed in the proximity of temporal superior and inferior vascular arcades. Scotopic electroretinogram demonstrated severely reduced rod response, without improvement or recovery of rod system function after prolonged dark adaptation. Blood DNA samples of this patient and from her parents were screened for causal variants in RLBP1, RDH5, and PRPH2. CONCLUSION:A probable pathogenic frameshift variant was identified in homozygosity in the RLBP1 gene with an autosomal recessive transmission as another cause of retinitis punctata albescens. This DNA variant will aid ongoing functional studies and add to our understanding of the molecular pathology about RLBP1-associated retinopathies. | 01 = IsEpi
|
The Peter the Great Museum of Anthropology and Ethnography (Kunstkamera) in Saint Petersburg is the oldest museum in Russia. It keeps the remains of the anatomical collection of the world-famous 17th century Dutch anatomist Frederik Ruysch. This unique collection was bought and shipped in 1717 by Czar Peter the Great, and presently still comprises more than 900 specimens, a modest number of which concerns specimens with congenital anomalies. We searched for teratological clues in the existing collection and in all his descriptions and correspondence regarding specimens and cases he encountered during his career as doctor anatomiae and chief instructor of the surgeons and midwives in Amsterdam. A total of 63 teratological specimens and case descriptions were identified in this legacy, including some exceedingly rare anomalies. As it turns out, Ruysch was the first to describe several of the conditions we encountered, including intracranial teratoma, enchondromatosis, and Majewski syndrome. Although his comments pose an interesting view on how congenital anomalies were scientifically perceived in early 18th century Europe, Ruysch mostly refrained from explaining the causes of the conditions he encountered. Instead, he dedicated himself to careful descriptions of his specimens. Almost 300 years after his demise, Ruysch's legacy still impresses and inspires both scientists and lay men. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc. | 01 = IsEpi
|
This consensus-based guideline was developed by all relevant German pediatric medical societies. Ultrasound is the standard imaging modality for pre- and postnatal kidney cysts and should also exclude extrarenal manifestations in the abdomen and internal genital organs. MRI has selected indications. Suspicion of a cystic kidney disease should prompt consultation of a pediatric nephrologist. Prenatal management must be tailored to very different degrees of disease severity. After renal oligohydramnios, we recommend delivery in a perinatal center. Neonates should not be denied renal replacement therapy solely because of their age. Children with unilateral multicystic dysplastic kidney do not require routine further imaging or nephrectomy, but long-term nephrology follow-up (as do children with uni- or bilateral kidney hypo-/dysplasia with cysts). ARPKD (autosomal recessive polycystic kidney disease), nephronophthisis, Bardet-Biedl syndrome and HNF1B mutations cause relevant extrarenal disease and genetic testing is advisable. Children with tuberous sclerosis complex, tumor predisposition (e. g. von Hippel Lindau syndrome) or high risk of acquired kidney cysts should have regular ultrasounds. Even asymptomatic children of parents with ADPKD (autosomal dominant PKD) should be monitored for hypertension and proteinuria. Presymptomatic diagnostic ultrasound or genetic examination for ADPKD in minors should only be done after thorough counselling. Simple cysts are very rare in children and ADPKD in a parent should be excluded. Complex renal cysts require further investigation. | 01 = IsEpi
|
We report a unique case of a digital tourniquet in a patient with ichthyosis vulgaris. We have identified no previous case reports documenting the occurrence of a digital tourniquet in patients caused by this condition. Ichthyosis vulgaris is a skin condition which causes increased scaling of the skin and in this case, resulted in the formation of a tourniquet-like circumferential constriction to one of the patient's digits. | 01 = IsEpi
|
BACKGROUND:The aim of our study is to study the association between eye lesions in Hereditary Hemorrhagic Telangiectasia (HHT) and other signs of the disease, as well as to characterize its genetics. METHODS:A cross-sectional study was conducted of a cohort of 206 patients studied in the HHT Unit of Hospital de Sierrallana, a reference centre for Spanish patients with HHT. Odds ratios for several symptoms or characteristics of HHT and ocular lesions were estimated using logistic regression adjusting for age and sex. RESULTS:The ocular involvement was associated with being a carrier of a mutation for the ENG gene, that is, suffering from a type 1 HHT involvement (OR = 2.09; 95% CI [1.17-3.72]). p = 0.012). In contrast, patients with ocular lesions have less frequently mutated ACVRL1/ALK1 gene (OR = 0.52; 95% CI [0.30-3.88], p = 0.022). CONCLUSIONS:In conclusion, half of the patients with HHT in our study have ocular involvement. These eye lesions are associated with mutations in the ENG gene and ACVRL1/ALK1 gene. Thus, the ENG gene increases the risk of ocular lesions, while being a carrier of the mutated ACVRL1/ALK1 gene decreases said risk. | 01 = IsEpi
|
OBJECTIVE:We present molecular cytogenetic characterization of prenatally detected inverted duplication and deletion of 10p [inv dup del(10p)]. CASE REPORT:A 39-year-old, primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a derivative chromosome 10 with additional material at the end of the short arm of one chromosome 10. Simultaneous array comparative genomic hybridization (aCGH) analysis revealed the result of arr 10p15.3 (136,361-451,013) × 1, 10p15.3p12.1 (536,704-25,396,900) × 3 [GRCh37 (hg19)] with a 0.31-Mb deletion of 10p15.3 encompassing ZMYND11 and DIP2C, and a 24.86-Mb duplication of 10p15.3p12.1. The pregnancy was subsequently terminated, and a female fetus was delivered with facial dysmorphism. Postnatal aCGH analysis showed that the umbilical cord had the same result as that of amniotic fluid, whereas the placenta had only the deletion of 10p15.3. Fluorescence in situ hybridization (FISH) analysis of the cord blood confirmed inverted duplication and deletion of 10p. The cord blood had a karyotype of 46,XX,der(10) del(10) (p15.3)dup(10) (p15.3p12.1)dn. Polymorphic DNA marker analysis confirmed a maternal origin of the chromosome 10 aberration. CONCLUSION:Prenatal diagnosis of inv dup del(10p) with haploinsufficiency of ZMYND11 should include a genetic counseling of mental retardation and chromosome 10p15.3 microdeletion syndrome. aCGH, FISH and polymorphic DNA marker analysis are useful for perinatal investigation of inv dup del(10p). | 01 = IsEpi
|
Amino acid transporters play very important roles in nutrient uptake, neurotransmitter recycling, protein synthesis, gene expression, cell redox balance, cell signaling, and regulation of cell volume. With regard to transporters that are closely connected to metabolism, amino acid transporter-associated diseases are linked to metabolic disorders, particularly when they involve different organs, cell types, or cell compartments. To date, 65 different human solute carrier (SLC) families and more than 400 transporter genes have been identified, including 11 that are known to include amino acid transporters. This review intends to summarize and update all the conditions in which a strong association has been found between an amino acid transporter and an inherited metabolic disorder. Many of these inherited disorders have been identified in recent years. In this work, the physiological functions of amino acid transporters will be described by the inherited diseases that arise from transporter impairment. The pathogenesis, clinical phenotype, laboratory findings, diagnosis, genetics, and treatment of these disorders are also briefly described. Appropriate clinical and diagnostic characterization of the underlying molecular defect may give patients the opportunity to avail themselves of appropriate therapeutic options in the future. | 01 = IsEpi
|
BACKGROUND:Adrenal hypoplasia is a rare congenital disorder, which can be classified into a non-syndromic form, without extra-adrenal features, and a syndromic form, with such features. Despite biochemical and molecular genetic evaluation, etiologic diagnosis cannot be performed in many patients with adrenal hypoplasia. CASE PRESENTATION:The patient in this case was a boy born at 31 weeks of gestation with a weight of 882 g (< 3rd percentile) to non-consanguineous parents. Genital examination showed micropenis and bilateral cryptorchidism. On the third day of life, he manifested hypotension with high urine output, hyponatremia, hyperkalemia, hypernatriuria, high plasma adrenocorticotropic hormone level, and high plasma renin activity, suggesting acute adrenal insufficiency. The serum 17α-hydroxyprogesterone level was normal. Adrenal insufficiency improved following administration of hydrocortisone and 9α-fludrocortisone, but the patient died of recurrent infection at 4 months of age. He was suspected as IMAGE (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies) syndrome. However, no mutation in CDKN1C was identified. Targeted exome sequencing using the TruSight One Sequencing Panel (Illumina) identified a heterozygous mutation of c.2944C > T (p.R982C) in exon 3 in SAMD9. CONCLUSION:This report describes the first Korean case of MIRAGE syndrome. The patient presented with severe primary adrenal insufficiency, intrauterine growth retardation, and recurrent infection. SAMD9 mutation should be considered in patients who present with adrenal hypoplasia and extra-adrenal phenotypes. | 01 = IsEpi
|
Laugier-Hunziker syndrome is a rare benign idiopathic condition characterized by acquired macular pigmentation of the lips and buccal mucosa, often accompanied by melanonychia. Although the etiopathogenesis is not fully known, tyrosine is thought to be responsible for the pathogenesis of enzyme hyperactivity in melanin biosynthesis. We present the case of a 66-year-old woman diagnosed with Laugier-Hunziker syndrome and rheumatoid arthritis. | 01 = IsEpi
|
Background: Granulomatous interstitial nephritis (GIN) is uncommon in native kidneys, and descriptions in allografts are few. We report clinical and pathologic findings in 22 allograft recipients with GIN identified in renal allograft biopsies and nephrectomies. Methods: Renal allografts with GIN were retrieved from the pathology files of two academic medical centers. Available clinical and pathologic data were compiled retrospectively for a 23-year period. Results: GIN was present in 23 specimens from 22 patients (15 males and 7 females) with allograft dysfunction [serum creatinine averaged 3.3 mg/dL (range 1.4-7.8)], at a mean age of 48 years (range 22-77). GIN was identified in 0.3% of biopsies at a mean of 552 days post transplantation (range 10-5898). GIN was due to viral (5), bacterial (5) and fungal (2) infections in 12 (54.5%), and drug exposure was the likely cause in 5 cases (22.7%). One had recurrent granulomatosis with polyangiitis. In 4 cases, no firm etiology of GIN was established. Of 18 patients with follow up data, 33.3% had a complete response to therapy, 44.5% had a partial response and 22.2% developed graft loss due to fungal and E. coli infections. All responders had graft survival for more than 1 year after diagnosis of GIN. Conclusions: Allograft GIN is associated with a spectrum of etiologic agents and was identified in 0.3% of biopsies. Graft failure occurred in 22% of this series, due to fungal and bacterial GIN; however, most had complete or partial dysfunction reversal and long-term graft survival after appropriate therapy. | 01 = IsEpi
|
Congenital dysfibrinogenemia is characterized with undetectable or low fibrinogen level by Clauss assay complicated by bleeding and/or thrombosis. These may lead to a diagnostic problem to some clinicians unfamiliar with this disease. We reported a case of congenital dysfibrinogenemia manifested as hemorrhage, repeated thrombosis, low fibrinogen levels through Clauss assay and but normal levels of fibrinogen through PT-derived tests. In conclusion, to patients with thrombosis complicated by decreased fibrinogen level, clinicians and laboratory physicians should be alert to the possibility of congenital dysfibrinogenemia. | 01 = IsEpi
|
OBJECTIVE:To detect disease-causing mutations in a patient with hereditary elliptocytosis. METHODS:Sodium dodecyl sulfate polyacrylamide gel electropheresis (SDS-PAGE) was used to identify the type of erythrocyte membrane protein defect. Potential mutations of the exons and adjacent introns of relevant genes were analyzed by Sanger sequencing. RESULTS:SDS-PAGE has failed to detect any difference between the patient and healthy controls. However, Sanger sequencing has detected three mutations in the SPTA1 gene in the patient, which included c.5077A>C (p.Lys1693Gln) missense mutation in exon 36, c.5572C>G (p.Leu1858Val) missense mutation in exon 40, and a IVS45nt-12C>T in intron 45. The father and grandmother of the patient were both heterozygous for c.5077A>C mutation, while her mother was heterozygous for c.5572C>G and IVS45nt-12C>T mutations. CONCLUSION:The hereditary elliptocytosis in the patient may be attributed to the synergistic action of c.5077A>C, c.5572C>G and IVS45nt-12C>T mutations of the SPTA1 gene. | 01 = IsEpi
|
XMEN (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia) is a complex primary immunological deficiency caused by mutations in MAGT1, a putative magnesium transporter. In this issue of the JCI, Ravell et al. greatly expand the clinical picture. The authors investigated patients' mutations and symptoms and reported distinguishing immunophenotypes. They also showed that MAGT1 is required for N-glycosylation of key T cell and NK cell receptors that can account for some of the clinical features. Notably, transfection of the affected lymphocytes with MAGT1 mRNA restored both N-glycosylation and receptor function. Now we can add XMEN to the ever-growing family of congenital disorders of glycosylation (CDG). | 01 = IsEpi
|