Hypotrichosis 1

A number sign (#) is used with this entry because generalized hypotrichosis-1 (HYPT1) is caused by heterozygous mutation in the APCDD1 gene (607479) on chromosome 18p11.

Description

Hereditary hypotrichosis simplex (HHS) is a rare form of nonsyndromic hereditary hypotrichosis without characteristic hair shaft anomalies. Affected individuals typically show normal hair at birth, but hair loss and thinning of the hair shaft start during early childhood and progress with age. HHS can be largely divided into 2 forms: the scalp-limited form (e.g., 146520) and the generalized form, in which all body hair is affected. HHS is characterized by progressive hair follicle miniaturization, which is a typical feature of androgenetic alopecia (see 109200). HHS can be inherited either as an autosomal dominant or autosomal recessive trait (e.g., HYPT8, 278150) (summary by Shimomura et al., 2010).

Genetic Heterogeneity of Nonsyndromic Hypotrichosis

See also HYPT2 (146520), caused by mutation in the CDSN gene (602593) on chromosome 6p21; HYPT3 (613981), caused by mutation in the KRT74 gene (608248) on chromosome 12q13; HYPT4 (146550), caused by mutation in upstream regulatory regions of the HR gene (602302) on chromosome 8p21; HYPT5 (612841), mapped to chromosome 1p21-q21; HYPT6 (607903), caused by mutation in the DSG4 gene (607892) on chromosome 18q12; HYPT7 (604379), caused by mutation in the LIPH gene (607365) on chromosome 3q27; HYPT8 (278150), caused by mutation in the LPAR6 gene (609239) on chromosome 13q14; HYPT9 (614237), mapped to chromosome 10q11.23-q22.3; HYPT10 (614238), mapped to chromosome 7p22.3-p21.3; HYPT11 (615059), caused by mutation in the SNRPE gene (128260) on chromosome 1q32; HYPT12 (615885), caused by mutation in the RPL21 gene (603636) on chromosome 13q12; HYPT13 (615896), caused by mutation in the KRT71 gene (608245) on chromosome 12q13; and HYPT14 (618275), caused by mutation in the LSS gene (600909) on chromosome 21q22.

Clinical Features

In contrast to the total and permanent absence of hair in congenital atrichia (203655), hair is present in hereditary hypotrichosis simplex but is diffusely thinned. Another form of isolated hypotrichosis, the Marie Unna type (146550), is distinguished from hypotrichosis simplex by the presence of a twisting hair dystrophy.

Baumer et al. (2000) described a nonconsanguineous Italian family with hypotrichosis simplex in an autosomal dominant pedigree pattern. Nine affected adults presented with sparse, thin, and short hair. Somewhat less sparse and longer hair was observed in 2 affected young children in the third generation. Reduced hair growth affected the scalp and body, although normal eyelashes, eyebrows, and male beards were observed. No associated abnormality was detected, and the overall psychomotor development of the affected individuals was normal. Phenotypic variation was observed.

Shimomura et al. (2010) identified 2 Pakistani families with typical clinical features of HHS. All affected individuals had normal scalp hair density at birth; hair loss gradually progressed beginning around age 2 to 5 years. Hair grew slowly and stopped growing after a few inches. Some affected individuals showed light-colored or hypopigmented hair shafts. In most cases body hair, axillary hair, and public hair were also sparse. Eyebrows, eyelashes, and beard hairs were not affected. Under light microscopy, the bulb portion of the plucked hair showed dystrophic features and was miniaturized. The hair shaft was thin and without any characteristic anomalies, and the distal ends appeared tapered. Affected individuals in both families showed normal teeth, nails, and sweating and did not show keratosis pilaris.

Mapping

After exclusion of linkage to loci previously described in other forms of atrichia or hypotrichosis, Baumer et al. (2000) performed a genomewide linkage analysis in an Italian family with autosomal dominant hypotrichosis simplex, which resulted in a positive 2-point lod score of 3.31 at theta = zero at 18p11.32-p11.23.

Shimomura et al. (2010) performed a linkage study in 2 Pakistani families after excluding the CDSN locus on chromosome 6 (602593). Linkage analysis using a dominant model yielded a maximum lod score of 4.6 on chromosome 18p11.22. They further narrowed the interval to a 1.8-Mb region containing 8 genes, 4 pseudogenes, and 3 predicted transcripts.

Molecular Genetics

In both Pakistani families used to map the disorder and in an Italian family described by Baumer et al. (2000), Shimomura et al. (2010) identified a T-to-G transition at nucleotide 26 of the APCDD1 gene resulting in a leu9-to-arg substitution at codon 9 (L9R; 607479.0001). This mutation segregated with the phenotype and was not identified in 200 unrelated controls. The L9R mutation is located in the signal peptide of APCDD1 and perturbs its translational processing from the endoplasmic reticulum to the plasma membrane. Shimomura et al. (2010) hypothesized that L9R-mutated APCDD1 functions in a dominant-negative manner to inhibit the stability and membrane localization of the wildtype protein.