A Novel Mutation of VPS33B Gene Associated with Incomplete Arthrogryposis-Renal Dysfunction-Cholestasis Phenotype

Abstract

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is an autosomal recessive disorder caused by mutations of the VPS33B encoding the vacuolar protein sorting 33B (VPS33B), which is involved in the intracellular protein sorting and vesicular trafficking. We report a rare case of ARC syndrome without arthrogryposis caused by a novel mutation of VPS33B. A female patient of Greek origin presented on the 14th day of life with renal tubular acidosis, Fanconi syndrome, nephrogenic diabetes insipidus, and cholestasis with normal gamma-glutamyl transpeptidase, without arthrogryposis and dysmorphic features. She was born to apparently healthy, nonconsanguineous parents. Additional features included dry and scaling skin, generalized hypotonia, hypoplastic corpus callosum, neurodevelopmental delay, failure to thrive, short stature, recurrent febrile episodes with and without infections, and gastrointestinal bleeding. DNA testing revealed that the patient was homozygous for the novel c.1098_1099delTG (p.Glu367Alafs∗17) mutation of exon 14 of VPS33B gene (NM_018668) on chromosome 15q26.1, leading to a nonsense frameshift variant of VPS33B with premature termination of translation. Her parents were heterozygous for the same VPS33B mutation. The prognosis was predictably poor in the context of the intractable polyuria necessitating long-term parenteral fluid administration via indwelling central catheter leading to catheter-related sepsis, to which she eventually succumbed at the age of 7 months. This is the first published VPS33B mutation in an ARC patient of Greek origin. The current case adds to the spectrum of ARC-associated VPS33B mutations and provides evidence supporting the existence of incomplete ARC phenotype. Increased awareness and early genetic testing for ARC are suggested in cases with isolated cholestasis and/or renal tubular dysfunction, even in the absence of arthrogryposis.

Mild Phenotype of Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome 1 Caused by a Novel VPS33B Variant

“…Currently, they have 17, 10, and 11 years old, respectively, and to our knowledge, patient 1 is one of the oldest patients described with ARCS to date. Other similar patients with milder phenotypes have been reported indicating the possibility of incomplete ARCS phenotype (Bull et al, 2006;Smith et al, 2012;Agawu et al, 2019;Del Brio Castillo et al, 2019;Qiu et al, 2019;Agakidou et al, 2020).…”

“…Interestingly, three patients with the same missense p.(Gly131Glu) variant were described as having the phenotype of Keratoderma-ichthyosis-deafness (ARKID) syndrome, a rare multisystem disorder also caused by biallelic mutations in VPS33B (Gruber et al, 2017;Seidl-Philipp et al, 2020). It is important to note that at least six patients with incomplete phenotype have been reported with loss of functions variants, which shows that an incomplete phenotype is not always caused by missense variants-these patient's phenotypes were also summarized on the Supplementary Table S1 (Bull et al, 2006;Smith et al, 2012;Agawu et al, 2019;Agakidou et al, 2020;Duong et al, 2020b;a).…”

Arthrogryposis, renal dysfunction, cholestasis syndrome with a novel mutation in two siblings

“…While severe cholestasis is one of the core findings in ARC syndrome, patient 1 only had mild elevation in total and direct bilirubin that resolved overtime. Patient 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 the selective inhibitor of the ileal bile acid transporter (odevixibat).…”

“…Patient 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 the selective inhibitor of the ileal bile acid transporter (odevixibat). These features along with fasting hypoglycemia and rickets are clinical features less described in the literature in the setting of a novel mutation (c.1609del, p. Asp538Metfs*17).…”

Arthrogryposis, Renal dysfunction, Cholestasis (ARC) Syndrome with A Novel Mutation in two siblings

“…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).…”