Hypotrichosis 12

A number sign (#) is used with this entry because of evidence that hypotrichosis-12 (HYPT12) is caused by heterozygous mutation in the RPL21 gene (603636) on chromosome 13q12.

For a general phenotypic description and a discussion of genetic heterogeneity of nonsyndromic hypotrichosis, see HYPT1 (605389).

Clinical Features

Xu et al. (2010) reported a 4-generation Chinese family from Shandong province in which 14 of 30 members had hypotrichosis. The pedigree showed clear autosomal dominant inheritance with full penetrance. Men and women were equally affected. Onset of hair loss occurred between 3 and 6 months of age in all affected individuals, with progression to almost complete loss of scalp hair. The remaining hairs were thin, sparse, dry, and fragile; there was no hair regrowth or twisting hair dystrophy. Eyebrows, eyelashes, and body hair were also affected in some individuals. Nails, teeth, skin, and sweating were normal, and there was no dysmorphism or intellectual disability. Examination of affected hair by light and polarization microscopy showed no specific changes or abnormalities.

Zhou et al. (2011) studied a large 4-generation Chinese family from Inner Mongolia in which 17 of 52 members exhibited a generalized form of autosomal dominant hereditary hypotrichosis simplex. All affected individuals had normal scalp hair density at birth; hair loss began at approximately 2 to 6 months of age and gradually progressed. Ultimately, most affected family members had nearly complete loss of scalp hair. The remaining hairs could reach the length of normal hair, but grew slowly and were thin, sparse, dry, and fragile. No hair regrowth or twisted hair shafts were observed. Body hair, axillary and pubic hair, and eyebrows and eyelashes of the affected individuals were also sparse or absent. Beard hair, however, was not affected. All affected individuals had normal nails, teeth, and sweating. There was no family history of neurologic abnormalities or of increased malignancies. Under light microscopy, hair shafts were slightly thin, without any characteristic anomalies, and skin biopsy from affected scalp showed hair follicles that were significantly decreased in size and number.

Inheritance

The transmission pattern of hypotrichosis in the Chinese families reported by Xu et al. (2010) and Zhou et al. (2011) was autosomal dominant.

Mapping

In a 4-generation Chinese family from Shandong province with autosomal dominant hypotrichosis, in which linkage to 8 chromosomal regions associated with hair-growth disorders had been excluded, Xu et al. (2010) performed genomewide screening and obtained a 2-point lod score of 4.041 (theta = 0) for microsatellite marker D13S217. Fine mapping showed significant linkage at 13q12, with a 2-point lod score of at least 3.0 for 4 markers. Analysis of recombination events defined an approximately 9.57-cM (5.8-Mb) critical interval between markers D13S1243 and D13S1299 on chromosome 13q12.12-q13.3.

In a large 4-generation Chinese family from Inner Mongolia segregating autosomal dominant hypotrichosis simplex, Zhou et al. (2011) analyzed microsatellite markers and obtained 2-point lod scores greater than 3 at chromosome 13q12.12-q12.3. Recombination events narrowed the critical region to a 9.57-cM interval between D13S1243 and D13S1299, which the authors noted was the same region previously mapped by Xu et al. (2010) in an unrelated Chinese family with hypotrichosis.

Molecular Genetics

In a large 4-generation Chinese family from Inner Mongolia segregating autosomal dominant hypotrichosis simplex mapping to chromosome 13q12.12-q12.3, Zhou et al. (2011) performed exome-target enrichment and next-generation sequencing and identified a heterozygous missense mutation in the RPL21 gene (R32Q; 603636.0001) that segregated completely with disease in the family and that was not found in 200 ethnically matched controls. In 2 affected individuals from the Chinese family with hypotrichosis reported by Xu et al. (2010), Zhou et al. (2011) identified heterozygosity for the same R32Q mutation. Genotyping and haplotype analysis revealed no founder effect in the 2 families.

Exclusion Studies

In a 4-generation Chinese family from Shandong province with autosomal dominant hypotrichosis mapping to chromosome 13q12, Xu et al. (2010) analyzed 3 candidate genes, GJB6 (604418), GJA3 (121015), and TNFRSF19 (606122), but found no sequence variants associated with disease.