A number sign (#) is used with this entry because of evidence that autosomal recessive keratoderma-ichthyosis-deafness syndrome (KDIDAR) is caused by homozygous or compound heterozygous mutation in the VPS33B gene (608552) on chromosome 15q26.

Autosomal recessive keratoderma-ichthyosis-deafness syndrome (KDIDAR) is characterized by severe palmoplantar keratoderma, mild generalized ichthyosis, and progressive sensorineural deafness. Other variable features include contractures, mild bleeding diathesis, and psychomotor retardation (Gruber et al., 2017).

Gruber et al. (2017) reported 3 Austrian patients who had palmoplantar keratoderma (PPK) and mild generalized ichthyosis with sensorineural deafness, and mutation in the VPS33B gene. Patient 1 was a 13-year-old boy whose skin issues were noted at birth, and who also had progressive sensorineural hearing loss (SNHL) requiring hearing aids by age 9 years. His psychomotor development was normal. He had recurrent epistaxis in childhood, and 2 episodes of macrohematuria at 12 and 13 years of age, with minimal relative proteinuria. Patient 2 was a 43-year-old woman who was born with bilateral hip dislocation and presented with PPK and mild generalized ichthyosis in infancy. Bilateral SNHL requiring hearing aids was diagnosed at age 8 years. She attended a school for the mentally impaired, although no formal IQ testing was done, and in adulthood she was believed to have difficulties with social interactions rather than intellectual disability. She developed type 2 diabetes mellitus at age 32 years, and examination at age 43 showed marked PPK, generalized ichthyosis, contractures of different interdigital joints of all fingers, and acromicria. Patient 3 was a man born with clubfeet who also had ichthyosis and severe PPK resulting in autoamputation of the small toes by age 49 years. He wore hearing aids for SNHL that was diagnosed in adulthood. He did not finish school or job training, and displayed anxious and shy behavior; no IQ tests were performed. He developed dyspnea at age 52 and was later diagnosed with interstitial lung fibrosis, and died unexpectedly soon thereafter. Neither patient 2 nor 3 had evidence of cholestasis, edema, or a bleeding disorder.

Alter et al. (2018) described an 11-year-old German boy with KDIDAR and mutation in the VPS33B gene. He was small at birth and displayed unilateral hip dislocation as well as bilateral pes planovalgus. He had elevated transaminases with slightly elevated serum copper and normal ceruloplasmin, and liver biopsy showed moderate steatosis, discrete perilobular fibrosis, and copper pigment in hepatocytes with elevated copper concentration in hepatic tissues. There were no signs of liver dysfunction or cholestasis. Zinc treatment normalized transaminase levels and the copper concentration in the liver. Ichthyosis and PPK were noted at age 13 months, at which time mild exocrine pancreas insufficiency was also diagnosed. Moderate bilateral SNHL was diagnosed at age 4 years and treated with hearing aids. Psychomotor development was delayed, and he had microcephaly with hypoplastic corpus callosum on brain MRI. He exhibited slight ataxia and muscle weakness with calf hypotrophy. Dysmorphic features included bilateral sandal gap and short toes. He had recurrent epistaxis in early childhood, and platelet analysis showed hypogranulation in approximately 75% of platelets. The authors noted that exocrine pancreatic insufficiency and hepatic copper overload had not previously been reported in patients with mutation in VPS33B and might represent coincidental findings.

The transmission pattern of KDIDAR in the families reported by Gruber et al. (2017) was consistent with autosomal recessive inheritance.

Gruber et al. (2017) noted that Austrian patients 2 and 3 with KDIDAR were not known to be related but carried the same rare surname, and a distant relationship was discovered. Whole-genome linkage analysis revealed a 3-Mb region on chromosome 15q26, flanked by markers rs12914139 and rs493258, for which a lod score of 3.6 was obtained under the assumption of autosomal recessive inheritance.

By exome sequencing in an Austrian woman (P2) with KDIDAR, Gruber et al. (2017) identified homozygosity for a missense mutation in the VPS33B gene (G131E; 608552.0008). A distantly related Austrian man (P3) with KDIDAR was found to be heterozygous for the G131E substitution and a splice site mutation (608552.0009); compound heterozygosity could not be confirmed due to lack of parental DNA for analysis. Sanger sequencing confirmed the variants and segregation with disease in the family of P2. Neither variant was found in 300 blood donors from western Austria or in public variant databases. Sequencing of the VPS33B gene in an Austrian boy (P1) with KDIDAR revealed homozygosity for the G131E substitution, for which his unaffected parents were heterozygous. Haplotype analysis indicated that the G131E variant was derived from a common Austrian founder.

In an 11-year-old German boy with KDIDAR and abnormal copper metabolism, who was negative for mutation in the ATP7A (300011), ATP7B (606882), and AP1S1 (603531) genes, Alter et al. (2018) performed whole-genome sequencing and identified compound heterozygosity for the G131E substitution in the VPS33B gene, and a 1-bp deletion (608552.0010). Sanger sequencing of the unaffected parents confirmed the G131E mutation in the father and the 1-bp deletion in the mother's family. The 1-bp deletion was not found in public variant databases. The authors suggested that the more severe clinical phenotype observed in this patient might be explained by the combination of the G131E mutation with complete functional loss of the second allele.