Arthrogryposis-renal dysfunction-cholestasis syndrome

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare, severe multisystem disorder that typically presents at birth or in early infancy. It is also known as ARC syndrome. The condition is characterized by three cardinal features: arthrogryposis multiplex congenita (multiple joint contractures causing limited movement), renal tubular dysfunction (particularly renal tubular acidosis and nephrogenic diabetes insipidus), and neonatal cholestasis (impaired bile flow from the liver, leading to jaundice and liver dysfunction). ARC syndrome is caused by mutations in the VPS33B gene or the VIPAS39 (VIPAR) gene, both of which encode proteins involved in intracellular vesicle trafficking and protein sorting, processes critical for normal cell function in multiple organ systems. Beyond the three defining features, affected individuals may also present with ichthyosis (dry, scaly skin), failure to thrive, platelet dysfunction with abnormal bleeding, recurrent infections due to immune deficiency, sensorineural hearing loss, and central nervous system abnormalities including corpus callosum agenesis. The renal dysfunction often manifests as Fanconi syndrome with aminoaciduria, glycosuria, and phosphaturia. Liver biopsy typically shows a characteristic finding of lipofuscin granule accumulation in hepatocytes and a paucity of interlobular bile ducts. The prognosis for ARC syndrome is unfortunately very poor, with most affected children dying within the first year of life due to recurrent infections, severe dehydration, metabolic acidosis, or liver failure. There is currently no curative treatment, and management is supportive, focusing on nutritional support, correction of metabolic derangements, management of cholestasis, and treatment of infections. Liver transplantation has been attempted in some cases but outcomes remain limited due to the multisystem nature of the disease.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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