Discussion:
Arthrogryposis renal dysfunction cholestasis (ARC) syndrome is a rare multisystem disorder involving liver, kidney, musculoskeletal, skin, and central nervous systems with early mortality and poor prognosis seen with severe forms. ARC is characterized by autosomal recessive mutations in the VPS33B (vacuolar protein sorting 33 homolog B) and VIPAR (VPS33B-interacting protein, apical basolateral polarity regulator) genes which are involved in the intracellular protein sorting and vesicular trafficking pathways.1 These are expressed in several organs and mutations lead to disruption of cell polarization that is crucial to cellular development and function.
There are various described phenotypes associated with ARC syndrome with the three core features being arthrogryposis, renal dysfunction, and cholestasis. Different genetic mutations are associated with different phenotypic variations. The prognosis of ARC syndrome is poor especially in cases with severe mutations. Most patients usually die within the first year of life after developing acidosis, recurrent infection, or internal bleeding. 2,3
Our patients’ genetic testing identified pathogenic variants in VPS33B (c.1225+5G>C) and (c.1609del p. Asp538Metfs*17), with the latter not described in the literature or reported in a large population database previously. The phenotype of our patients is unique in that on presentation there was no ichthyosis or sepsis like illness that is typically life limiting before one year of age. Table 2 illustrates the differentiating factors of a classic ARC patient as compared to our patients (Image 1) with a milder phenotype. Hepatitis and hepatomegaly with giant cell transformation, biliary plugs, and portal fibrosis can be seen to varying degrees in this disorder in part due to disruption in trafficking of bile components. While severe cholestasis is one of the core findings in ARC syndrome, proband 1 only had mild elevation in total and direct bilirubin that resolved overtime. Proband 2 also followed a similar course which may be explained by milder phenotype associated with this unique mutation. 1,2,4 Both patients continue to have intermittently elevated serum bile acids and pruritus that is currently treated with selective inhibitor of the ileal bile acid transporter (odevixibat). These features along with fasting hypoglycemia and rickets are clinical features less described in literature in the setting of a novel mutation (c.1609del, p. Asp538Metfs*17).
This current case series adds to the spectrum of ARC-associated variants. Increased awareness and early genetic testing for ARC are suggested in cases with failure to thrive, renal tubular dysfunction, and rickets even when the degree of cholestasis is mild.