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.