A Novel VPS33B Mutation Causing a Mild Phenotype of ARC Syndrome.

JPGN Volume 69, N CASE A 14-month-old boy with a history of moderate sensorineural hearing loss, language delay, and gross motor delay presents with several months of severe pruritus. His family tried over the counter ointments, oral diphenhydramine, and topical hydrocortisone without relief. He lost 1 pound over the preceding month (weight percentile less than the first percentile). He had no complaints of vomiting, abdominal pain, diarrhea, constipation, fatigue, or fever and no history of fractures, bleeding, jaundice, or xanthomas. Family history was unremarkable without liver disease, hearing loss, bleeding disorders, or consanguinity, and the family is of Hispanic ancestry. He had no known allergies or surgical history. Physical examination was notable for a weight of 7.7 kg (less than first percentile), head circumference 44.5 cm (second percentile), length 68.9 cm (less than first percentile). There was no jaundice, scaly skin, hepatosplenomegaly, hypotonia, or severe flexion contractures. To evaluate his symptoms, his primary care physician sent laboratory studies that showed: alanine aminotransferase (ALT)— 170 (normal: 0–29 IU/L); aspartate aminotransferase (AST)—152 (normal: 0–75 IU/L); alkaline phosphatase—879 (normal: 130 – 317 IU/L); total bilirubin—0.7 (normal: 0–1.2 mg/dL); gammaglutamyl transferase (GGT)—12 (normal: 0–65 IU/L). Further work-up focused on cholestatic processes that would require intervention and included a right upper quadrant ultrasound, alpha-1antitrypsin phenotype, and thyroid testing, all of which were normal. Total serum bile acids showed: ursodeoxycholic acid— 0.30 (normal: <1.9 mmol/L); cholic acids—26 (normal: <2.2 mmol/L); chenodeoxycholic acid—11 (normal: <5.8 mmol/ L); deoxycholic acid—<0.1 (normal: <3.3 mmol/L); total bile acids—37 (normal: <9.2 mmol/L). A cholestasis genetic panel was sent because of the abnormal bile acid testing. This identified a maternally inherited novel pathogenic nonsense mutation c.1246C>T (p.R416X) and a paternally inherited previously reported splice site mutation c.1225þ 5G>C in VPS33B, consistent with a diagnosis of arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. Variants of uncertain significance were also identified in ATP8B1, LIPA, and CFTR. A single likely pathogenic mutation was also identified in the CFTR gene (c.[220C>T; 3808G>A]).