Ichthyosis, Leukocyte Vacuoles, Alopecia, And Sclerosing Cholangitis

A number sign (#) is used with this entry because of evidence that ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) is caused by homozygous mutation in the CLDN1 gene (603718) on chromosome 3q28.

Clinical Features

Baala et al. (2002) described a novel autosomal recessive ichthyosis syndrome characterized by scalp hypotrichosis, scarring alopecia, sclerosing cholangitis, and leukocyte vacuolization in 4 affected individuals from 2 small inbred Moroccan kindreds. This syndrome shares some similarities with Dorfman-Chanarin syndrome (275630) but is distinct in that there is lack of muscular or ocular involvement, hepatomegaly is related to cholestasis and sclerosing cholangitis and not fatty infiltration, and small leukocytes and keratinocyte vacuoles are negative for lipid staining. Ultrastructural analysis of a skin biopsy from an affected individual showed split anchoring plaques of desmosomes in the granular layer.

Feldmeyer et al. (2006) reported a Swiss girl with ILVASC. She was born with generalized erythroderma, massive lamellar desquamation with absent hair, eyelashes, and eyebrows, and marked icterus with hyperbilirubinemia and increased biliary acids. Other features included dysplastic enamel and koilonychia. Liver biopsy showed panlobular cholestasis and acute hepatitis.

Mapping

Baala et al. (2002) mapped ILVASC to a 21.2-cM interval of chromosome 3q27-q28 and reduced the genetic interval to a 16.2-cM region by homozygosity mapping. Two-point linkage analysis gave a maximum lod score at D3S1601 (Zmax of 2.61 at theta = 0). The maximum pairwise lod score was 3.25 assuming maximum informativity, a unique mutant allele at the disease locus, and a recombination fraction of 0 between the disease locus and the marker. Comparison of mutant chromosomes in the 2 families suggested a common ancestral mutant haplotype, and linkage disequilibrium reduced the genetic interval encompassing the disease gene to less than 9.5 cM.

Molecular Genetics

Hadj-Rabia et al. (2004) considered the gene encoding claudin-1 to be a strong candidate for ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis based on its mapping to the minimum linkage interval for the disorder and on the expression pattern of the mouse ortholog. In the 4 affected patients with ILVASC previously described by Baala et al. (2002), Hadj-Rabia et al. (2004) identified a 2-bp deletion in exon 1 of the CLDN1 gene (200delTT; 603718.0001), resulting in a premature stop codon and a total absence of claudin-1 protein in the liver and skin.

In a Swiss girl with ILVASC, Feldmeyer et al. (2006) identified a homozygous 1-bp deletion in the CLDN1 gene (603718.0002). The parents, who were heterozygous for the mutation, originated from 2 small nearby villages.