Woolly Hair, Autosomal Recessive 3

A number sign (#) is used with this entry because of evidence that autosomal recessive woolly hair-3 (ARWH3) is caused by homozygous mutation in the KRT25 gene (616646) on chromosome 17q21.

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive woolly hair, see 278150.

Clinical Features

Ansar et al. (2015) studied 2 unrelated Pakistani families segregating autosomal recessive woolly hair. In the first family (AP188), 4 individuals from 3 sibships were affected, including 2 brothers and 2 female cousins. Initially, all 4 had soft, short, and sparse hair on the scalp, but at around 4 years of age, they developed tightly curled hair. They had normal eyebrows, but eyelashes were sparse compared to other family members. In the second family (AP216), 3 sibs presented with tightly curled scalp hair. All affected individuals from both families had normal craniofacial features, teeth, nails, and sweating, and there was no evidence of palmoplantar keratoderma, heart disease, chronic diarrhea, immune deficiency, or intellectual disability.

Zernov et al. (2016) studied 2 sisters and an unrelated woman from the Chuvash population of the Vogal-Ural region of Russia who had isolated congenital woolly hair. Scalp hair length was approximately 5 to 15 cm and hair growth rate was slow, with affected individuals having a haircut every 3 to 4 years. Hair follicle density decreased from 210 per cm(2) in the occipital to 90 per cm(2) in the frontotemporal area (normal range, 175-300 follicles per cm(2)). There was uniform hair rigidity. Light microscopy showed thin hair with slight differences in diameter and irregular wavy contours of the hair shaft; abnormalities were observed in 70% of hair shafts, with rare hair shaft fractures, and trichorrhexis nodosa was present. Trichogram showed that 25 to 30% of hairs examined were in telogen phase (normal range, 10-20%), and 70 to 75% were anagen (normal range, 80-90%).

Mapping

In 2 unrelated Pakistani families segregating autosomal recessive woolly hair, Ansar et al. (2015) analyzed genome scan data by homozygosity mapping and multipoint parametric linkage analysis. In the first family, they identified a 16.7-Mb homozygous region on chromosome 17q21.1-q22, for which they obtained a maximum multipoint lod score of 4.14. In the second family, the maximum multipoint lod score of 1.33 was observed at multiple regions of homozygosity, including a 20.4-Mb region on 17q12-q22.

Molecular Genetics

In affected individuals from 2 unrelated Pakistani families segregating autosomal recessive woolly hair mapping to chromosome 17q21, Ansar et al. (2015) identified homozygosity for a missense mutation in the KRT25 gene (L317P; 616646.0001). The mutation segregated with disease in both families and was not found in 154 ethnically matched in-house exomes or in 462 Pakistani control chromosomes.

In 2 sisters and an unrelated woman with woolly hair from the Chuvash population of the Volga-Ural area of Russia, who were negative for the LIPH exon 4 deletion (607365.0001) previously implicated in patients from the Volga-Ural region with hypotrichosis-7 (HYPT7; 604379), Zernov et al. (2016) performed whole-exome sequencing and identified homozygosity for a missense mutation in the KRT25 gene (V238L; 616646.0002). The healthy parents were heterozygous for the mutation, which was found at an allele frequency of 0.015% in the isolated Chuvash and Mari populations of the region; haplotype analysis suggested a founder effect. No hair shaft abnormalities were observed in the heterozygous carriers.