Dyschromatosis Universalis Hereditaria 1

A number sign (#) is used with this entry because of evidence that dyschromatosis universalis hereditaria-1 (DUH1) is caused by heterozygous mutation in the SASH1 gene (607955) on chromosome 6q24.

Homozygous mutation in the SASH1 gene results in cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma (CAPOK; 618373).

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).

The autosomal dominant SASH1-associated DUH1 phenotype is characterized by generalized lentigines accompanied by mottled hyper- and hypopigmentation (Zhang et al., 2017).

DUH is distinct from dyschromatosis symmetrica hereditaria (DSH; 127400), which also occurs particularly in Japanese and Korean individuals, but shows a characteristic mixture of hyper- and hypopigmented macules limited largely to the dorsal aspects of the hands and feet (Suenaga, 1952). Gao et al. (2005) noted that lesions associated with DUH appear within the first year of life predominantly on the trunk, whereas the age of onset of DSH is approximately 6 years and lesions appear predominantly on the extremities.

Genetic Heterogeneity of Dyschromatosis Universalis Hereditaria

Dyschromatosis universalis hereditaria-2 (DUH2; 612715) maps to chromosome 12q21-q23. DUH3 (615402) is caused by mutation in the ABCB6 gene (605452) on chromosome 2q35.

Clinical Features

Pacheco et al. (2002) studied a large 6-generation Hispanic family with multiple lentigines. Affected family members presented multiple small 1- to 5-millimeter hyperpigmented macules over the entire body, sparing the palmoplantar surfaces. Histopathologic analysis of biopsies of select lesions revealed increased numbers of melanocytes along the dermal-epidermal junction. Three family members had undefined learning disabilities, but the authors stated that there was no evidence of other features of LEOPARD syndrome (see 151100) in the observed affected family members.

Shellman et al. (2015) restudied the family described by Pacheco et al. (2002) and noted that the lentigines were most prominent in sun-exposed areas. In some patients, the lentigines covered the face, trunk, and extremities, whereas other affected individuals showed lesions primarily over the face and distal extremities. Analysis of patient skin biopsies showed an approximately 2-fold increase in the number of melanocytes per millimeter of skin in both hyperpigmented lesional skin and nonlesional skin; however, only lesional skin showed a dramatic increase in melanin. In addition, there were approximately 2-fold more proliferating cells in both lesional and nonlesional patient skin compared to control skin.

Xing et al. (2003) reported 2 large families from the Henan and Yunnan provinces of China segregating autosomal dominant cutaneous dyschromatosis: a 5-generation pedigree (family A) and a 3-generation pedigree (family B). The authors provided photographs showing a mixture of hypopigmented and hyperpigmented macules of various sizes on the trunks and arms of the affected individuals. One patient, shown in their Figure 2A, had a mixture of hypo- and hyperpigmented macules of various sizes on the entire trunk and on the arms, as well as on the neck and face. Biopsies of hypo- and hyperpigmented macules from the dorsa of the feet revealed basal melanosis and hypomelanosis, similar to previous reports in Japanese patients who also showed an increased number of melanocytes with high metabolic activity; however, none of the affected members in either Chinese family was found to have skin cancer. Although Xing et al. (2003) designated the disorder as DSH, Miyamura et al. (2003) suggested that these patients, who exhibited dyschromatosis over almost their entire bodies, in fact had DUH.

In a family with DUH reported by Nuber et al. (2004), the male proband presented with randomly distributed hyper- and hypopigmented skin lesions of variable shape and size with a mottled appearance. Light and electron microscopy showed normal numbers of active melanocytes, but different amounts of fully melanized melanosomes in hyper- and hypopigmented macules. The findings were interpreted as indicating that DUH is not a disorder of melanocyte number.

Zhang et al. (2016) studied 2 Chinese boys with multiple lentigines. Hypopigmented spots were intermixed with the lentigines, and there was mild dyschromatosis at the elbows and on the dorsa of the hands and feet. Histologic analysis of affected skin was consistent with features of typical lentigines.

Wang et al. (2017) reported a Chinese mother and son with multiple lentigines. The son had multiple 'freckles' on his forehead beginning at age 18 months; the lesions gradually increased and spread to his entire body by age 10 years. Neither patient had facial malformations, cardiac defects, or mental abnormalities.

Zhong et al. (2019) described the probands from 2 unrelated Chinese families with DUH. The proband from the first family was a 25-year-old woman born with normal skin pigmentation, who developed freckle-like macules at 3 years of age that appeared initially on her trunk, then extended to her face, neck, and limbs, with accentuation on sun-exposed areas. Hypopigmented patches were also noted on these areas, intermingled with hyperpigmentation. Her mother and deceased maternal grandfather exhibited similar lesions. The proband from the second family was a 42-year-old man with a similar clinical history but with earlier onset of skin lesions, at 7 months of age. The dyschromatosis progressed with age and involved nearly his entire body by age 7 years, with sparing of the palmoplantar and mucosal areas. There were 12 similarly affected members over 4 generations in the second family.

Inheritance

In a family with DUH reported by Suenaga (1952), a consanguineous marriage occurred in each of 4 successive generations, suggesting autosomal recessive inheritance.

Nuber et al. (2004) described a familial case of DUH compatible with autosomal dominant inheritance; in 2 instances there was father-to-son transmission.

Mapping

In 2 Chinese families from the Henan and Yunnan provinces with DUH, Xing et al. (2003) found evidence of linkage to chromosome 6q24.2-q25.2, with a maximum multipoint lod score of 10.64. Haplotype analysis placed the locus within an interval of 10.2 Mb. The 2 families showed no haplotype identity within the defined region, suggesting that these 2 families were different in origin.

In a large Hispanic family with nonsyndromic multiple lentigines, previously studied by Pacheco et al. (2002), Pacheco et al. (2004) performed pairwise linkage analysis and obtained a maximum lod score of 4.129 at marker D6S1654 on chromosome 6q, in the 10-cM region between markers D6S308 and D6S411.

Exclusion Studies

In a large 7-generation Hispanic family with multiple lentigines, Pacheco et al. (2002) excluded linkage to chromosomes 2, 10, 12, 17, and 19. In addition, lod scores for genetic markers flanking the PTEN (601728), NF1 (162200), STK11/LKB1 (602216), PRKAR1A (188830), and PTPN11 (176876) genes, as well as 'Carney locus 1' on chromosome 2p16 and 'Peutz-Jeghers locus 2' on chromosome 19p13.4, were less than 3.

Molecular Genetics

By screening 50 candidate genes within a 10-Mb DUH-associated region on chromosome 6q24.2-q25.2, Zhou et al. (2013, 2017) identified heterozygous missense mutations in the SASH1 gene (Y551D, 607955.0001; L515P, 607955.0002; and E509K, 607955.0003) in affected individuals from 3 nonconsanguineous families with dyschromatosis, including 2 Chinese families from the Henan and Yunnan provinces (families I and II) and 1 American family (family III). The mutations segregated fully with disease in each family, respectively, and were not found in 500 controls or in public variant databases.

In 17 affected members of a large Hispanic family with nonsyndromic multiple lentigines mapping to a 10-Mb interval on chromosome 6q24.2-q25.2, previously studied by Pacheco et al. (2002, 2004), Shellman et al. (2015) screened candidate genes and identified heterozygosity for a SASH1 missense mutation (S519N; 607955.0005) that segregated fully with disease and was not found in 150 ethnically matched controls or in public variant databases.

In 2 Chinese boys with multiple lentigines, Zhang et al. (2016) screened 4 candidate genes and identified heterozygous SASH1 mutations in both: a missense mutation (S513R; 607955.0006) in patient 1, and a frameshift mutation (607955.0007) in patient 2. The mutations segregated with disease in the respective families and were not found in 100 controls.

In a Chinese mother and son with multiple lentigines, Wang et al. (2017) identified heterozygosity for a SASH1 missense mutation (S507A; 607955.0008) that had arisen de novo in the mother. The authors stated that their findings further verified SASH1 as a causal gene of lentiginous phenotypes with or without dyschromatosis.

In 2 Chinese families with DUH, Zhong et al. (2019) screened 3 dyschromatosis-associated genes and identified heterozygous missense mutations in SASH1 in affected members of both families: Y551H (607955.0009) and M595T (607955.0010), respectively.