Dyschromatosis Universalis Hereditaria 3

A number sign (#) is used with this entry because of evidence that dyschromatosis universalis hereditaria-3 (DUH3) is caused by heterozygous mutation in the ABCB6 gene (605452) on chromosome 2q35.

Description

Dyschromatosis universalis hereditaria (DUH) is a rare autosomal dominant genodermatosis characterized by irregularly shaped asymptomatic hyper- and hypopigmented macules that appear in infancy or early childhood and occur in a generalized distribution over the trunk, limbs, and sometimes the face. Involvement of the palms or soles is unusual. Abnormalities of hair and nails have been reported, and DUH may be associated with abnormalities of dermal connective tissue, nerve tissue, or other systemic complications (summary by Zhang et al., 2013).

For a discussion of genetic heterogeneity of DUH, see DUH1 (127500).

Clinical Features

Zhang et al. (2013) studied a large Chinese family with dyschromatosis universalis hereditaria in which 13 members over 5 generations were affected. The proband was a 9-year-old boy who had normal skin at birth. Hyperpigmented and hypopigmented macules appeared initially on his trunk at age 2 years, then gradually extended to involve his face, neck, and limbs. He had no pruritus or pain. Examination of the skin showed motley hyper- and hypopigmented macules over nearly the entire body. The lesions occurred in a symmetric pattern and were most prominent on the face, neck, trunk, and dorsa of hands and feet. His palms and soles, oral mucosa, hair, nails, and teeth were normal. Histopathologic examination of a skin lesion biopsy showed a pigmented basal layer of the epidermis, pigmentary incontinence in the papillary dermis, and some melanophages and lymphocytes in the upper dermis. None of the affected family members had skin cancer or ocular defects.

Cui et al. (2013) studied a large Han Chinese family in which 24 individuals over 5 generations exhibited typical features of DUH without other systemic disease; in particular, none had skin cancer or ocular coloboma. The proband was a 33-year-old woman who had hypo- and hyperpigmented 3- to 7-mm macules scattered over her entire body, sparing the palms, soles, and mucous membranes. Hair, teeth, and nails were normal. The proband stated that the macules appeared within 2 months after birth, and became darker when exposed to sun. Skin biopsy of hypo- and hyperpigmented lesions revealed a normal number of melanocytes in the basal layer in both samples; however, whereas the content and distribution of mature melanosomes in hyperpigmented patient skin were similar to control skin, the content in hypopigmented skin was less than control, and many immature melanosomes were observed. Cui et al. (2013) suggested that DUH may represent a disorder of melanosome maturation rather than of melanocyte number.

Mapping

By linkage and haplotype analysis in a 5-generation Chinese family segregating autosomal dominant dyschromatosis universalis hereditaria in which mapping to the 2 known DUH loci had been excluded, Zhang et al. (2013) found linkage to the 2q33.1-q36.1 region, between D2S325 and D2S126. Multipoint analysis yielded a maximum lod score of 3.49 at D2S2382.

By parametric multipoint linkage analysis in a large 5-generation Han Chinese family segregating autosomal dominant DUH, Cui et al. (2013) detected 2 regions of linkage: an approximately 17-Mbp interval at chromosome 2q35-q37.2 with a lod score of 4.68, and an approximately 0.3-Mbp interval at 6p22 with a lod score of 4.59. No annotated gene was identified in the 6p22 region.

Molecular Genetics

By whole-exome and Sanger sequencing in a 5-generation Chinese family segregating autosomal dominant dyschromatosis universalis hereditaria mapping to chromosome 2q33.1-q36.1, Zhang et al. (2013) identified a heterozygous missense mutation in the ABCB6 gene (L356P; 605452.0008) that segregated with disease in the family and was not found in 500 geographically matched controls. Screening of the ABCB6 gene in 6 sporadic DUH patients revealed heterozygosity for missense mutations (S170G, 605452.0009; G579E, 605452.0010) in 2 patients. Neither of the mutations in the sporadic patients was found in 400 controls or in the 1000 Genomes Project or UCSC Genome Browser databases.

By exome sequencing in 3 affected members and 1 unaffected member of a 5-generation Han Chinese family with DUH mapping to chromosome 2q35-q37.2, Cui et al. (2013) identified heterozygous mutations in 4 candidate genes. Sanger sequencing excluded 3 of the genes; the remaining missense mutation in the ABCB6 gene (Q555K; 605452.0011) was present in 21 affected family members but absent in 14 unaffected relatives. Analysis of ABCB6 in 3 sporadic Chinese DUH patients also revealed a 1-bp deletion (c.459delC, g.776delC) in 1 of them. Neither mutation was found in 455 ethnically matched controls or in the dbSNP database.