Clouston Syndrome

A number sign (#) is used with this entry because Clouston syndrome is caused by heterozygous mutation in the GJB6 gene (604418), which encodes connexin-30, on chromosome 13q12.

Description

The main features of Clouston syndrome are dystrophy of the nails that tend to be hypoplastic and deformed with increased susceptibility to paronychial infections, defects of the hair that range from brittleness and slow growth rate to total alopecia, and moderate to severe palmoplantar hyperkeratosis with reduced keratinocyte desquamation (summary by Kibar et al., 1996).

Clinical Features

Clouston (1929) described members of a large French Canadian family with a form of ectodermal dysplasia affecting predominantly the nails, hair, and skin. Sweating was normal. Fingernails and toenails were short, thick, and slow growing; in some cases the nails were absent. Hair was fine, dry, and brittle and in some cases absent; eyelashes and eyebrows were also affected. Patients had clubbing of fingers, palmar hyperkeratosis, and hyperpigmentation of the skin. Although 'as a whole' those affected had 'poor teeth,' dentition was 'mostly normal.' Several other reports described an extensive kindred of French extraction that migrated to Canada, Scotland, and northern United States (Clouston, 1939; Joachim, 1936; MacKay and Davidson, 1929; Wilkey and Stevenson, 1945). In a large French Canadian family living in rural New Hampshire and Vermont, Gagnon et al. (1989) found that all affected females had complete balding while the males had variable expression ranging from light blond hair with focal alopecia to total balding. All females wore wigs beginning in childhood. Presumably this kindred had genealogic connections to those studied by Clouston (1929, 1939) and others.

Rajagopalan and Tay (1977) described autosomal dominant hidrotic ectodermal dysplasia in 15 members in 5 generations of a Chinese family in Malaysia. All 15 had typical nail, hair, and skin lesions. Scalp alopecia was more extensive in females, whereas keratoderma of the palms and soles was more notable in males. Stevens et al. (1999) examined 14 affected members over 3 generations of the family originally described by Rajagopalan and Tay (1977). A diffuse warty palmoplantar keratoderma developed over the entire sole and the hypothenar eminence of the hands. The skin changes extended to involve the periungual regions of the nails. The nail changes were variable and ranged from discolored, thickened, and dystrophic nails to hypoplasia with a classic cone-shaped or triangular nail. The distal ends of the fingers were thickened and the digits appeared clubbed. Some developed a severe alopecia in infancy, whereas in others it occurred later. The eyebrows, eyelashes, and pubic and axillary hair were almost invariably involved and were either very sparse or lost completely. Sweating, teeth, breast development, and oral mucosa all appeared normal. The authors noted that multiple cutaneous squamous cell carcinomas of the palmar tissue and nail bed had been reported in the Canadian family (Campbell and Keokarn, 1966; Williams and Fraser, 1967; Mauro et al., 1972), but were not observed in the Chinese-Malay family.

Bixler and Patel (1990) described a large kindred of British ancestry. They emphasized the occurrence of palmoplantar hyperkeratosis and alopecia as well as severely dysplastic nails.

Hassed et al. (1996) described a family with a hair-nail dysplasia in 10 persons through 4 generations. Affected individuals had features consistent with Clouston syndrome, including variable sparsity of hair, thick, discolored, hyperconvex nails with onycholysis, and normal sweating. Unlike affected members of the families originally described by Clouston (1929), however, they lacked hyperkeratosis and dental caries. Hassed et al. (1996) noted that dental abnormalities had not been reported in other families with Clouston syndrome. They proposed that dental abnormalities, typical of other ectodermal dysplasias, are not a usual component of the Clouston syndrome.

Scriver et al. (1965) found that the hair from affected patients was thin with reduced tensile strength, disorganized fibrillar structure by light microscopy, reduced birefringence in polarized light, and increased amount of reactive SH groups. A full report was provided by Gold and Scriver (1971). Ultrastructural studies of hair showed disorganization of hair fibrils with loss of the cuticular cortex (Escobar et al., 1983). The changes were considered consistent with a molecular defect of keratin.

Inheritance

The transmission pattern of ectodermal dysplasia in the French Canadian family described by Clouston (1929) was consistent with autosomal dominant inheritance.

Mapping

By 2-point and multipoint linkage analysis of 9 microsatellite markers in 8 French Canadian families segregating Clouston hidrotic ectodermal dysplasia, Kibar et al. (1996) mapped the locus for this disorder to the pericentromeric region of chromosome 13q. Data from haplotype analysis showed that D13S143 is the telomeric flanking marker for the Clouston hidrotic ectodermal dysplasia gene region.

In a large Indian kindred from the Gujarat region, Radhakrishna et al. (1997) mapped the Clouston syndrome to 13q11-q12.1 through linkage with DNA markers. Multipoint linkage analysis yielded a lod score of 5.04 at theta = 0.00 with D13S1316; haplotype analysis indicated that the gene for Clouston syndrome in this kindred is located proximal to D13S292.

Taylor et al. (1998) found linkage to 13q11-q12.1 in 2 additional families of French Canadian descent, 1 of Scottish-Irish descent, and 1 French family. The 2 families of French Canadian descent shared haplotypes with those reported by Kibar et al. (1996), indicating a common founder. The French and Scottish-Irish families did not demonstrate the common haplotype, indicating that the mutations in these populations were probably of different origin. Lamartine et al. (2000) confirmed linkage of Clouston syndrome to chromosome 13q11-q12.1 in a large French family. The maximum lod score was 8.5 at theta = 0 for D13S1835. They localized the gene to a 4.5-Mb interval between D13S1832 and D13S1826. Haplotypes were analyzed and found to be different from those found in French Canadian families, suggesting these mutations may have had different origins.

In the family of Chinese-Malay descent with autosomal dominant hidrotic ectodermal dysplasia originally described by Rajagopalan and Tay (1977), Stevens et al. (1999) found linkage to 13q11-q12.1.

Exclusion Studies

Hayflick et al. (1996) excluded linkage between Clouston syndrome and the keratin gene clusters on chromosomes 12 (see 139350) and 17 (see 607606). They also excluded linkage to 4 other candidate regions containing the genes encoding keratin-associated proteins: the desmoglein (125670) genes on 18q12.1; proteins expressed in terminally differentiated epidermis on 1q21; and transglutaminase (190195) on 20q12. It also did not map to 17q23-qter where the tylosis/esophageal cancer syndrome maps separate from the keratin gene cluster.

Population Genetics

In a genetic analysis applied to a multiethnic group of 29 hidrotic ectodermal dysplasia families, Kibar et al. (2000) found no evidence of genetic heterogeneity in families of French, Spanish, African, or Malaysian origin. They showed evidence for a strong founder effect in families of French Canadian origin, thereby representing the first example of a founder disease in the southwest part of the province of Quebec.

Molecular Genetics

In patients with Clouston syndrome, Lamartine et al. (2000) demonstrated mutations in the gene encoding connexin-30 (GJB6; 604418). One mutation, G11R (604418.0002), was found in individuals from several areas of Europe and in 1 from Africa. Another missense mutation in the GJB6 gene (604418.0001) causes autosomal dominant nonsyndromic sensorineural deafness (DFNA3; 601544).

It is possible that cases of Clouston syndrome with deafness represent a contiguous gene syndrome resulting from deletion of the GJB6 gene and of the connexin-26 gene (121011), which is the site of mutations causing both autosomal dominant and autosomal recessive forms of deafness and is localized to 13q11-q12 (Kelsell et al., 1997).

Nomenclature

The acronym HED has been used in the literature to designate both hypohidrotic ectodermal dysplasia (see 305100, 224900, and 129490) and hidrotic ectodermal dysplasia. In OMIM, HED is used to designate hypohidrotic ectodermal dysplasia.