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

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.