Phenotypic Variability in Majeed Syndrome.
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ABSTRACT:
SUBMITTER: Rao AP
PROVIDER: S-EPMC4898189 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Publications
Phenotypic Variability in Majeed Syndrome.
Rao Anand Prahalad AP Gopalakrishna Dharmanand Balebail DB Bing Xinyu X Ferguson Polly J PJ
The Journal of rheumatology 20160601 6
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Project description:Background and objectiveMajeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2. Long-term outcome is poor. This is the first report detailing the treatment of Majeed syndrome with biological agents and demonstrates clinical improvement with IL-1blockade.MethodsWe describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed syndrome.ResultsBoth boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bone disease and anaemia were refractory to treatment with corticosteroids. Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor α (TNF-α), however a trial of the TNF inhibitor etanercept resulted in no improvement. IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1β antibody (canakinumab) resulted in dramatic clinical and laboratory improvement.ConclusionsThe differential response to treatment with TNF-α or IL-1 blocking agents sheds light into disease pathogenesis; it supports the hypothesis that Majeed syndrome is an IL-1β dependent autoinflammatory disorder, and further underscores the importance of IL-1 in sterile bone inflammation.
| S-EPMC3660147 | biostudies-literature
Project description:BackgroundSjögren-Larsson syndrome (SLS) is an early childhood-onset disorder with ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy caused by the deficiency of fatty aldehyde dehydrogenase due to mutations in the ALDH3A2 gene (the gene that encodes microsomal fatty aldehyde dehydrogenase). Cerebral proton magnetic resonance spectroscopy in those with SLS demonstrates an abnormal white matter peak at 1.3 ppm, consistent with long-chain fatty alcohol accumulation.ObjectiveTo define the clinical course and proton magnetic resonance spectroscopic findings of SLS in adults.Design and settingCase series in a tertiary care center.PatientsSix siblings of a consanguineous Arab family with early childhood-onset SLS who carry the 682C-->T mutation in the ALDH3A2 gene were reinvestigated in adulthood.ResultsThe 6 affected siblings ranged in age from 16 to 36 years. All exhibited the typical clinical and imaging manifestations of SLS, but their severity markedly varied. Neurological involvement was apparently nonprogressive, and its severity showed no correlation with age. Cerebral proton magnetic resonance spectroscopy showed a lipid peak at 1.3 ppm, with decreasing intensity in the older siblings.ConclusionThese observations document significant clinical variability and the nonprogressive neurological course of SLS in adult siblings with the same ALDH3A2 genotype, and demonstrate possible correlation of proton magnetic resonance spectroscopic changes with age, suggesting unknown pathogenic mechanisms to compensate for the responsible biochemical defect in this disease.
| S-EPMC3086176 | biostudies-literature
Project description:Background22q11.2 deletion syndrome (22q11.2DS) is a common microdeletion syndrome, which occurs in approximately 1:4000 births. Familial autosomal dominant recurrence of the syndrome is detected in about 8-28% of the cases. Aim of this study is to evaluate the intergenerational and intrafamilial phenotypic variability in a cohort of familial cases carrying a 22q11.2 deletion.MethodsThirty-two 22q11.2DS subjects among 26 families were enrolled.ResultsSecond generation subjects showed a significantly higher number of features than their transmitting parents (212 vs 129, P = 0.0015). Congenital heart defect, calcium-phosphorus metabolism abnormalities, developmental and speech delay were more represented in the second generation (P < 0.05). Ocular disorders were more frequent in the parent group. No significant difference was observed for the other clinical variables. Intrafamilial phenotypic heterogeneity was identified in the pedigrees. In 23/32 families, a higher number of features were found in individuals from the second generation and a more severe phenotype was observed in almost all of them, indicating the worsening of the phenotype over generations. Both genetic and epigenetic mechanisms may be involved in the phenotypic variability.ConclusionsSecond generation subjects showed a more complex phenotype in comparison to those from the first generation. Both ascertainment bias related to patient selection or to the low rate of reproductive fitness of adults with a more severe phenotype, and several not well defined molecular mechanism, could explain intergenerational and intrafamilial phenotypic variability in this syndrome.
| S-EPMC3893549 | biostudies-literature
Project description:BACKGROUND Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive genetic condition that was first described in 1983. Since its original description, approximately 50 cases have been reported with various clinical signs and symptoms. Characteristics include progressive neurologic deterioration with extrapyramidal involvement and polyendocrinopathy most notable for hypogonadism starting in early adolescence. Clinical presentation is variable, and a subset of patients may have additional features, such as premature aging, alopecia, distinctive facial features, cognitive impairment, or deafness. CASE REPORT We illustrate the phenotypic variability of 5 patients with WSS due to the previously reported homozygous single nucleotide deletion c.436delC in the DCAF17 gene, identified in 2008. Despite identical genetic alteration, our 5 patients had various clinical features among them and compared with previously reported cases with the same pathogenic mutation. CONCLUSIONS The phenotypic variability of WSS due to c.436delC founder mutation may have a wider range than previously recognized.
| S-EPMC5881453 | biostudies-other
Project description:Majeed syndrome (MS) is a rare, autosomal recessive, autoinflammatory disease characterized by recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and inflammatory dermatome. In this article, we report the cases of two siblings with MS. Genetic studies of both siblings were obtained and revealed mutations in LPIN2 gene by means of a homozygous single-base pair change in the donor splice site of exon 17 (c.2327+1G>C). Both patients underwent different modalities of treatment for MS which involved immune-suppressive and biologic therapies. We observed a significant clinical response to biologic anti-interleukin-1 (IL-1) therapy in our patients. This impressive clinical response indicates the pivotal role of IL-1 in MS pathogenesis. There are limited data on the use of anti-IL-1 therapy in treating MS due to the rarity of the condition. Anti-IL-1 therapy should be considered as a promising treatment for this disease.
| S-EPMC6768791 | biostudies-literature
Project description:OBJECTIVE:To describe the phenotypic features of an ethnically homogenous group of patients with Fanconi-Bickel syndrome harboring the p.R310X mutation. METHODS:The study group consisted of eight patients from a single Bedouin family with clinically and molecularly diagnosed Fanconi-Bickel syndrome who had been followed at the same tertiary medical center for 8 years or more. All were homozygous for the p.R310X mutation. The medical files were reviewed for presenting signs and symptoms, laboratory and imaging findings, treatment regimens, and disease severity over time. RESULTS:Seven patients were diagnosed at our center before age 1 year, and one transferred from another center at age 16 years. Most patients presented with failure to thrive and/or hepatomegaly. All had short stature and doll-like facies. Most had biochemical abnormalities. Evaluation of the long-term findings revealed a wide spectrum of disease severity according to the following parameters: growth patterns, maximal electrolyte replacement therapy, skeletal and renal complications, frequency of follow-up visits, and hospitalizations for disease exacerbations. There was no apparent association of the clinical picture at presentation and later disease severity. CONCLUSION:Fanconi-Bickel syndrome has a broad phenotypic variability in patients harboring the same homozygous p.R301X mutation. This finding might be explained by genetic elements such as modifier genes and epigenetic factors, as well as the effects of still-undetermined environmental and nutritional factors.
| S-EPMC4270862 | biostudies-literature
Project description:BackgroundInterstitial deletions of 4q21 (MIM 613509) have already been reported in more than a dozen patients with deletions ranging from 2 to 15.1 Mb delineating a common phenotype including marked growth restriction, hypotonia, severe developmental delay with absent or delayed speech and distinctive facial features. A minimal critical region of 1.37 Mb accounting for the common features with 5 known genes (PRKG2, RASGEF1B, HNRNPD, HNRPDL, and ENOPH1) has been described so far.ResultsHere we report on a 5 year-old Hungarian girl presenting with severe developmental delay, good receptive language but absent spoken speech, short stature, dystrophy, hypotonia, distinctive facies including broad forehead, frontal bossing, downward slanting palpebral fissures, hypertelorism, hypoplastic ear-lobes, anteverted nostrils, short philtrum, small mouth, higharched palate, short, small hands and feet, distally narrowing fingers and clinodactyly. Cerebral MRI showed ventricular dilation and an increase in periventricular signal intensity. After extensive metabolic tests and exclusion of subtelomeric deletions array CGH analysis was performed using the Agilent Human Genome G3 SurePrint 8x60K Microarray (Agilent Technologies, USA), which detected a 4,85 Mb de novo interstitial deletion of 4q21.21-4q21.23. The clinical symptoms only partly overlap with reported 4q21 microdeletion cases. Among multiple annotated genes our patient is also haploinsufficient for the following genes: RASGEF1B being a strong candidate for the neurodevelopmental features and PRKG2 for severe growth delay.ConclusionThe first Hungarian case of 4q21 deletion adds to the phenotypic spectrum of this novel microdeletion syndrome and underlines the importance of array CGH to uncover the heterogeneous causes of intellectual disability.
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Project description:This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome's variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000-7000 men and 1 in 4000-6000 women worldwide. FXS is associated with the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene's promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of FMR1 mutations and FXS's variable expressivity by regulating the pathophysiological mechanisms related to the syndrome's behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.
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Project description:Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.
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Project description:Chromosome 17q12 microdeletion syndrome is a contiguous gene deletion syndrome caused by an 1-2 Mb loss, characterized by multicystic dysplastic kidneys or other urinary system anomalies starting in utero, including autism or maturity-onset diabetes of the young in its postnatal phenotype. Here, we report on three cases (two prenatal and one postnatal) with distinct and novel clinical presentations as compared with a large number of reviewed patients, thus emphasizing the phenotypic variability of this syndrome and the consequent difficulties in genetic counselling. Prenatal hyperechogenic multicystic kidneys, as well as other urinary tract anomalies, should be considered a marker, therefore indicating the necessity of comprehensive genetic testing, and autism should also be acknowledged as a possible clinical presentation, postnatally.
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