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A novel mutation in VPS33B gene causing a milder ARC syndrome phenotype with prolonged survival.

ABSTRACT: Introduction:ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is an uncommon multisystem disorder that entails a very poor prognosis. It is caused by mutations in either VPS33B or VIPAS39 gene, both playing a key role in intracellular trafficking. We report two siblings born to first cousin parents with a novel mutation in VPS33B who have both shown prolonged survival. Cases Presentation:The index patient presented with bilateral hip dysplasia and arthrogryposis, failure to thrive, undernourishment, developmental delay, and low gamma-glutamyl transferase cholestasis. She at age 2?years underwent external biliary diversion with improvement in pruritus but liver disease continued to progress. She developed stomal bleeding at 7?years of age and liver biopsy displayed cirrhosis. Her 3-year-old sibling showed a similar trajectory as well as he had ichthyotic skin with excoriations. Their renal involvement was mild and stable. Genetic analysis in both patients revealed a novel homozygous mutation in NM_018668.4 (VPS33B):c.1157A?>?C (p.His386Pro). Conclusions:ARC syndrome is a severe disorder with few patients reported to survive beyond 12?months of age. This report discloses a novel mutation in the VPS33B gene and describes a phenotype with prolonged survival, mild renal involvement, and progressive liver disease.

SUBMITTER: Del Brio Castillo R

PROVIDER: S-EPMC6498830 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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A novel mutation in <i>VPS33B</i> gene causing a milder ARC syndrome phenotype with prolonged survival.

Del Brío Castillo Rodrigo R Squires James E JE McKiernan Patrick J PJ

JIMD reports 20190322 1

<h4>Introduction</h4>ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is an uncommon multisystem disorder that entails a very poor prognosis. It is caused by mutations in either <i>VPS33B</i> or <i>VIPAS39</i> gene, both playing a key role in intracellular trafficking. We report two siblings born to first cousin parents with a novel mutation in <i>VPS33B</i> who have both shown prolonged survival.<h4>Cases presentation</h4>The index patient presented with bilateral hip dysplasia ...[more]

PMID: 31240160

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Project description:Purpose:The aims of this study were to examine novel mutations in PITX2 and FOXC1 in Chinese patients with anterior segment dysgenesis (ASD) and to compare the clinical presentations of these mutations with previously reported associated phenotypes. Methods:Twenty-six unrelated patients with different forms of ASD were enrolled from our paediatric and genetic eye clinic. The ocular manifestations of both eyes of each patient were recorded. Genomic DNA was prepared from venous leukocytes. All coding exons of PITX2 and FOXC1 were amplified by polymerase chain reaction (PCR) from genomic DNA and subjected to direct DNA sequencing. Analysis of mutations in control subjects was performed by heteroduplex single-strand conformation polymorphism (SSCP) analysis. Results:Sequence analysis of the PITX2 gene revealed four mutations, including c.475_476delCT (P.L159VfsX39), c.64C?>?T (P.Q22X), c.296delG (P.R99PfsX56), and c.206G?>?A (P.R69H). The first three mutations were found to be novel. The c.475_476delCT (P.L159VfsX39) mutation, located at the 3' end of the PITX2-coding region, was identified in a Chinese Axenfeld-Rieger syndrome (ARS) patient who presented with an unusual severe phenotype of bilateral aniridia. The clinical characteristics, including the severity and manifestations of the patient's phenotype, were compared with reported PITX2-associated aniridia phenotypes of ARS in the literature. Conclusions:These results expand the mutation spectrum of the PITX2 gene in patients with ARS. The PITX2 gene may be responsible for a significant portion of ARS with additional systemic defects in the Chinese population. This is the first reported case of a mutation at the 3' end of the PITX2-coding region extending the phenotypic consequences to bilateral aniridia. The traits of ARS could display tremendous variability in severity and manifestations due to the dominant-negative effect of PITX2. Our results further emphasize the importance of careful clinical and genetic analysis in determining mutation-disease associations and may lead to a better understanding of the role of PITX2 in ocular development.

Project description:Objective: Salivary gland ultrasound (SGUS) is emerging as a valid tool in the management of primary Sjögren's syndrome (pSS). This study aimed to investigate whether pSS patients with normal-appearing or pathological SGUS findings showed different clinical, laboratory, and pathologic pSS-related features, and to compare the results by using two different SGUS scores. Methods: Consecutive pSS patients, according to the ACR-EULAR classification criteria, were evaluated. Salivary glands were scored using the early 1992 score by De Vita et al. and the latest 2019 OMERACT score, both being semiquantitative 0-3 scoring systems focused on ultrasonographic parenchymal inhomogeneity (grades 0 and 1, normal-appearing; grades 2 and 3, pathological). The patients were then divided into two groups: "SGUS normal-appearing" if all the salivary glands had normal-appearing parenchyma (grade 0 or 1), or "SGUS pathological" if the grade was 2 or 3 in at least one salivary gland. The associations between SGUS and pSS-related clinical, laboratory, and pathological features were then investigated in the two groups. Results: One hundred pSS patients were evaluated, the mean age (±SD) was 60.9 ± 12.0 years, and mean disease duration was 11.7 ± 7.2 years. Twenty-nine out of 100 (29%) patients were in the "SGUS normal-appearing" group and 71/100 (71%) were in the "SGUS pathological" group. A normal-appearing SGUS was significantly associated with the absence of anti-La/SSB antibodies (p < 0.001) and normal unstimulated salivary flow rate (p = 0.02) by both univariate and multivariate analyses. By univariate analysis, a normal-appearing SGUS was significantly associated also with the absence of rheumatoid factor (p = 0.002) and of serum monoclonal component (p = 0.003), ESSDAI < 5 (p = 0.03), and with a negative lip biopsy (p = 0.029). No associations were found with other items, including anti-Ro/SSA (p = 0.145), Schirmer's test (p = 0.793), ESSPRI (p = 0.47), and demographic data. No differences in these results were observed by using the two SGUS scoring systems. Conclusion: The SGUS allowed the identification of different phenotypes of pSS, and different SGUS scores focused on salivary gland inhomogeneity may be effective to this end.

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A novel mutation in VPS33B gene causing a milder ARC syndrome phenotype with prolonged survival.

Publications

A novel mutation in <i>VPS33B</i> gene causing a milder ARC syndrome phenotype with prolonged survival.

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