Huriez Syndrome

A number sign (#) is used with this entry because of evidence that Huriez syndrome (HRZ) is caused by heterozygous mutation in the SMARCAD1 gene (612761) on chromosome 4q22.

Mutation in the SMARCAD1 gene can also cause phenotypes with features overlapping those of Huriez syndrome, including Basan syndrome (BASAN; 129200) and isolated adermatoglyphia (ADERM; 136000).

Description

Huriez syndrome (HRZ) is characterized by the triad of congenital scleroatrophy of the distal extremities, palmoplantar keratoderma, and hypoplastic nail changes. The development of aggressive squamous cell carcinoma (SCC) in areas of affected skin is a distinctive feature of the syndrome, occurring in approximately 15% of patients. HRZ-associated SCC shows early onset, mostly in the third to fourth decades of life, and early metastasis formation (summary by Lee et al., 2000).

See also 610644 for description of a disorder resembling Huriez syndrome, involving palmoplantar hyperkeratosis and squamous cell carcinoma in association with SRY (480000)-negative female-to-male XX sex reversal, caused by mutation in the RSPO1 gene (609595).

Clinical Features

Huriez et al. (1968) described a 'new' genodermatosis in 44 members of 3 French kindreds. The characteristics were atrophic fibrosis of the skin of the limbs, hypoplasia of nails, and keratoderma of the palms and soles. Skin cancer and bowel cancer were frequent.

Lambert et al. (1977) studied 3 patients in a family reported by Huriez et al. (1968); the family lived in Lille, France. Fischer (1978) reported a fourth family, living in Bourges, France, at a considerable distance from Lille. Mother and 2 daughters were affected. MN blood groups were consistent with linkage. The deceased maternal grandfather was also affected. The triad of manifestations was scleroatrophic lesions predominantly of the hands, hypoplastic nail changes, and palmoplantar keratoderma. Changes were present at birth.

Delaporte et al. (1995) stated that since the initial description of the disease, 3 other families, and possibly a fourth, had been reported. They reassessed the clinical, pathologic, and genetic data in 114 members of one of the families originally described by Huriez et al. (1968), of whom 27 who were affected by the disorder were still alive. Squamous cell carcinomas (SCCs) had occurred in 3. One patient had 7 successive SCCs on different fingers, the first at the age of 35; he subsequently died from metastatic SCC at the age of 54.

Lucker et al. (1997) described a mother and son with this form of palmoplantar keratoderma characterized by scleroatrophy, sclerodactyly, and nail anomalies. In the affected skin of the mother, 3 squamous cell carcinomas developed at a young age. Retinoid treatment was started prophylactically. Malignant degeneration of affected skin is a distinctive feature of the syndrome. A high mortality rate for this type of skin cancer has also been reported.

Hamm et al. (1996) reported the first German family with Huriez syndrome, in which there were 13 affected members over 5 generations. They studied an affected mother and son and daughter. The maternal grandmother had died at age 37 years from a poorly differentiated metastatic squamous cell carcinoma that had developed on the skin of the right thenar eminence. Immunohistochemical and ultrastructural analysis of skin from the hypothenar eminence of the affected mother revealed an absence of Langerhans cells in involved skin. The authors suggested that this might account for the tendency of scleroatrophic skin to undergo malignant change.

Kavanagh et al. (1997) reported the first family from the U.K. with the scleroatrophic syndrome of Huriez. The proband was a 29-year-old nurse who, in addition to a worsening hand dermatitis, had hands small from birth with abnormal finger- and toenails that did not require cutting. There was notable absence of sweating on the extremities. A sister had died at the age of 22 years of metastatic squamous cell carcinoma that developed on scleroatrophic skin on the finger. An aunt also had an SCC excised at 45 years of age and later developed bowel carcinoma. The proband and other members of the family showed poikiloderma-like changes of the nose and telangiectases of the lips.

Lee et al. (2000) pointed out that aggressive squamous cell carcinoma of the affected skin is a distinctive feature of this syndrome, occurring in approximately 15% of affected individuals. SCC in Huriez syndrome has an early onset, mostly in the third to fourth decade, and early metastasis formation (Hamm et al., 1996). Development of SCC in Huriez syndrome bears striking similarity to Marjolin ulcer, which refers to malignancies arising in chronic ulcers of the skin, scar tissue, and burn scars (Fleming et al., 1990).

Mapping

Mennecier (1967) reported linkage of the disorder with the MN blood group (111300) locus in the segment 4q28-q31. However, Delaporte et al. (1995) challenged the linkage to MN; a maximum lod score of 1.68 was obtained at recombination fraction theta = 0.18. It appeared, in fact, that the authors' findings supported loose linkage. Kavanagh et al. (1997) were unable to confirm the linkage to 4q28-q31.

Lee et al. (2000) studied one of the families first described by Huriez et al. (1968) and a second family originating from the same region of northern France. They excluded linkage to the MN locus. Further studies with DNA markers indicated linkage to the 4q23 region. Lee et al. (2000) also excluded epidermal growth factor (EGF; 131530) as a candidate gene.

Molecular Genetics

In a large 5-generation French family with HRZ (family A), originally reported by Huriez et al. (1968), and another French family with HRZ (family B), both of which showed linkage to chromosome 4q23 (Lee et al., 2000), Gunther et al. (2018) performed whole-genome sequencing and identified heterozygous splice site mutations in the SMARCAD1 gene (612761.0003 and 612761.0006). Targeted Sanger sequencing of SMARCAD1 in a German family with HRZ, previously reported by Hamm et al. (1996), revealed an 18-bp deletion spanning the same splice site involved in the previous 2 mutations. The mutations segregated fully with disease in each family and were not found in 400 German controls or in public variant databases.