ARKID syndromeQ80.-

ARKID-stands for: Autosomal recessive keratoderma ichthyosis deafness syndrome. ARKID is a rare multisystem disorder caused by biallelic mutations in the VPS33B gene; < 5 patients have been described to date.

As yet unknown.

Biallelic mutations were detected in VPS33B, which encodes the eponymous protein VPS33B, a protein of the Sec1/Munc18 family that interacts with the proteins Rab11a and Rab25 and is involved in the transport of the collagen-modifying enzyme LH3. Compared to VPS33B -wild type-, in one patient the mutant VPS33B p.Gly131Glu showed reduced co-immunoprecipitation and colocalization with Rab11a and Rab25 and was unable to restore LH3 transport.

In confirmation of the cell-based experiments, deficient LH3-specific collagen-lysine modifications are found in urine and skin fibroblasts of the patients.

Severe palmoplantar keratoderma associated with ichthyosis and sensorineural deafness. Also described are: mental retardation, unilateral hip dislocation, microcephaly and short stature. One patient also suffered from copper hepatopathy and exocrine pancreatic insufficiency (Alter S et al. 2018)

Patients show a disturbed epidermal structure, which has been attributed to an abnormal secretion of lamellocytes, which are essential for the formation of the epidermal barrier.

Clinic, genetic testing

ARKID syndrome is allelic to arthrogryposis renal dysfunction cholestasis syndrome (ARC) (MIM #208085), a severe disease with early lethality whose phenotypic features also include ichthyosis, hearing loss, severe failure to thrive, platelet dysfunction and osteopenia.

1. Alter S et al. (2018) Novel VPS33B mutation in a patient with autosomal recessive keratoderma-ichthyosis-deafness syndrome. Am J Med Genet A 176:2862-2866

2. Chai M et al. (2018) Identification of genes and signaling pathways associated with arthrogryposis-renal dysfunction-cholestasis syndrome using weighted correlation network analysis. Int J Mol Med 42:2238-2246.

3. Huang DG et al. (2017) Clinical features and VPS33B mutations in a family affected by arthrogryposis, renal dysfunction, and cholestasis syndrome. Zhongguo Dang Dai Er Ke Za Zhi 19:1077-1082.
   

4. Gruber R et al. (2017) Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification. J Invest Dermatol 137:845-854.
5. Bull LN et al. (2006) VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype. J Pediatr 148:269-271.