Hypotrichosis 7

A number sign (#) is used with this entry because of evidence that hypotrichosis, or woolly hair with or without hypotrichosis, can be caused by homozygous or compound heterozygous mutation in the LIPH (607365) gene on chromosome 3q27.

For a discussion of genetic heterogeneity of localized hypotrichosis, see LAH1 (607903).

For a discussion of genetic heterogeneity of nonsyndromic hypotrichosis, see 605389.

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

Clinical Features

Rogaev et al. (1999) described a hereditary form of hypotrichosis that is common in the Mari population, a large aboriginal Finno-Ugric population in the Volga-Ural region of Russia. They found 21 families with 26 affected individuals during a medical genetic study of this population. In each family, the parents of the proband were normal, and both sexes were affected, consistent with autosomal recessive inheritance. The frequency of the mutated gene for hypotrichosis in the Mari population was estimated to be 1% or higher. The affected Mari individuals had congenital hypotrichosis of the scalp hairs; any hair present was wiry and twisted. Eyebrows and eyelashes were absent after the first year of life, and remained sparse in adults. Pubic and axillary hairs were practically absent, and body hairs were scarce and thin. Nails and teeth, as well as other epidermal structures, were normal, with one exception: 2 sisters from 1 family with a hair abnormality also had follicular hyperkeratosis. However, ichthyosis and follicular hyperkeratosis appeared to be common abnormalities in the Mari population, and were thought to be associated with hypotrichosis in these sisters by chance.

Aslam et al. (2004) described a consanguineous Pakistani family segregating autosomal recessive hypotrichosis. At birth, sparse hair was present on the scalp but did not regrow after ritual shaving, which was usually performed 1 week after birth. The affected individuals were nearly devoid of normal eyebrows, eyelashes, axillary hair, and body hair. Affected male individuals of the family had normal beard hair; however, hair was absent on their legs and arms. Teeth and nails were normal in all affected individuals.

Ali et al. (2007) reported a consanguineous Pakistani family in which 3 sibs had autosomal recessive hypotrichosis. Hair was present on the scalp at birth but regrew sparsely after ritual shaving. Affected individuals were nearly devoid of normal eyebrows, eyelashes, axillary hair, and body hair. Teeth, nails, sweating, and hearing were all normal. Heterozygous carriers had normal hair. Skin biopsy from an affected individual showed absence of normal hair follicle structures replaced by comedo-like remnant hair follicles.

Shimomura et al. (2009) studied 11 consanguineous Pakistani families with woolly hair and/or hypotrichosis in whom homozygosity for mutations in the LIPH gene were identified (see MOLECULAR GENETICS). The 11 families showed a wide variation in phenotype, ranging from woolly hair to sparse hair between families and even within a single family, although all affected individuals had slow hair growth that stopped at a few inches. The woolly hair of some individuals was light-colored compared to the dark brown/black hair typical in this population. Facial and body hair was normal in patients with woolly hair, whereas eyebrows, eyelashes, and body hair were sparse in the patients with hypotrichosis. Affected individuals from all 11 families had normal teeth, nails, and sweating, did not display palmoplantar hyperkeratosis, and had no family history of heart disease, cancers, or neurologic abnormalities. Shimomura et al. (2009) stated that the key observation uniting these variable phenotypes was that all affected individuals had woolly hair at birth and/or during early childhood, and some, but not all, progressed to show different degrees of hypotrichosis.

Shimomura et al. (2009) reported 3 Japanese probands with woolly hair and hypotrichosis who came from families of the Niigata prefecture in Japan. One proband, a 4-year-old boy, had tightly curled hair at birth that at 2 years of age became thinner and stopped growing at a few inches. Eyebrows and eyelashes were thin and sparse. Small pale follicular papules were diffusely distributed on the scalp. Skin biopsy of scalp showed an enlarged infundibulum with keratotic plugs and a miniaturized bulb portion without obvious structural anomalies. The other 2 probands, 3- and 4-year-old girls, respectively, had similar clinical features.

Khan et al. (2011) studied 17 Pakistani families with the hypotrichosis/woolly hair phenotype. At birth, patients had sparse hair. Affected members of 8 families had features of hypotrichosis, with sparse fragile hair on the scalp and sparse to absent eyebrows, eyelashes, and axillary, pubic, and body hair. In 6 families, affected members exhibited features of woolly hair on the scalp, with sparse to absent eyebrows, eyelashes, and body hair. In the remaining 3 families, some affected individuals had features of hypotrichosis and others had woolly scalp hair. All male members in all 17 families had normal beard and moustache hair.

Mapping

Aslam et al. (2004) performed haplotype analysis in affected members of a consanguineous Pakistani family with hereditary hypotrichosis and excluded linkage to 14 hair loss and ectodermal dysplasia loci. A genome scan using the DNA samples of 4 affected individuals yielded a maximum multipoint lod score of 6.0 for marker D3S3592. The region of homozygosity was flanked by markers D3S2314 and D3S1602, a 7.1-cM region on chromosome 3q26.33-q27.3, referred to by the authors as 'AH.'

Kazantseva et al. (2006) performed linkage analysis on 14 Mari families with hypotrichosis and showed potential linkage to chromosome 3q26-q27. Using novel simple tandem repeat markers (STRs) and combining the data with haplotype mapping from 36 Chuvash families with hypotrichosis, they narrowed the interval to a 350-kb region on chromosome 3q27 containing 4 genes.

In 2 large unrelated consanguineous Pakistani families with woolly hair/hypotrichosis, Petukhova et al. (2009) performed genomewide analysis that failed to identify significant regions of autozygosity or linkage; however, parametric analysis in 1 of the families showed evidence for linkage on chromosome 3q27. Haplotype analysis using microsatellite markers within the LIPH gene demonstrated that 2 haplotypes, designated A and B, were segregating with the phenotype in each of these families, and every affected individual was either homozygous for A or B, or compound heterozygous for A and B. Petukhova et al. (2009) cautioned against making the a priori assumption of identity by descent in consanguineous families, noting that their data illustrated that evidence for linkage in the absence of evidence for homozygosity points to the possibility of allelic heterogeneity.

Molecular Genetics

In 14 Mari families and 36 Chuvash families with hypotrichosis mapping to chromosome 3q26-q27, Kazantseva et al. (2006) sequenced the entire coding regions of all 4 genes within the critical interval for hypotrichosis and found no point mutations. However, they were unable to amplify exon 4 of the candidate gene LIPH (607365) in affected individuals, although it was detectable in their parents, suggesting that deletion of exon 4 was present in homozygosity in affected individuals and in heterozygosity in their parents. Kazantseva et al. (2006) determined that an approximately 985-bp deletion (607365.0001) eliminated exon 4 and flanking intronic sequences.

In 3 sibs, born of consanguineous Pakistani parents, with autosomal recessive hypotrichosis, Ali et al. (2007) identified a homozygous mutation in the LIPH gene (607365.0002).

In affected members of 2 unrelated consanguineous Pakistani families with autosomal recessive hypotrichosis, Jelani et al. (2008) identified a homozygous mutation in the LIPH gene (607365.0003). gene. Affected individuals were nearly devoid of normal eyebrows, eyelashes, axillary hair, and body hair. Adult males had normal beard hair but sparse scalp hair. There were no other clinical abnormalities.

Shimomura et al. (2009) studied 11 consanguineous Pakistani families with woolly hair and/or hypotrichosis that were negative for mutation in the P2RY5 gene (609239). Because 1 of the families showed linkage to chromosome 3q27 in the region of the LIPH gene, the authors performed direct sequencing of LIPH and identified 5 different homozygous mutations among the 11 families, (see, e.g., 607365.0003-607365.0005). Shimomura et al. (2009) noted that the 11 families with LIPH mutations in this study showed a wide variation in phenotype, even within a single family.

In 2 large, unrelated consanguineous Pakistani families with woolly hair/hypotrichosis showing linkage to the LIPH gene, in which microsatellite marker analysis demonstrated segregation of 2 distinct disease alleles within each family, Petukhova et al. (2009) identified 2 different LIPH mutations: a known 2-bp deletion (607365.0003) and a 90-bp duplication (607365.0006). Affected individuals were either homozygous for the deletion or the duplication, or compound heterozygous for both.

In probands from 3 Japanese families, who were born with tightly curled hair and developed hypotrichosis in the second year of life, Shimomura et al. (2009) identified homozygosity or compound heterozygosity for 2 missense mutations in the LIPH gene (607365.0007, 607365.0008). The authors stated that this was the first report of LIPH mutations in the Japanese population.

Khan et al. (2011) performed microsatellite genotyping in 17 Pakistani families with the hypotrichosis/woolly hair phenotype and found linkage to the LIPH gene in 9 families and to the LPAR6 gene (609239) in 8 families (see HYPT8; 278150). Sequence analysis of LIPH in the 9 linked families revealed 2 recurrent homozygous mutations (607365.0003, 607365.0005) in families with hypotrichosis, woolly hair with or without hypotrichosis, or a mixed phenotype. Khan et al. (2011) observed no difference in severity of hair loss in patients carrying different mutations in either LIPH or LPAR6, and there were no clear genotype/phenotype correlations.

Population Genetics

Kazantseva et al. (2006) tested 2,292 chromosomes in population samples collected irrespective of the hypotrichosis phenotype from Volga-Ural and other regions of Russia. Among the Chuvash people the mutant allele frequency was 0.033 and among the Mari it was 0.030. No mutant allele was found in other Finno-Ugric populations or Russian populations from distant geographic regions. Kazantseva et al. (2006) suggested that there may be more than 98,000 heterozygous mutant carriers and 1,500 homozygous affected individuals in populations of Mari and Chuvash descent.

Nomenclature

Wali et al. (2007) noted clinical similarities among 3 genetically distinct forms of hypotrichosis, with affected individuals having normal beard hair (in men) and sparse to absent eyebrows, eyelashes, and body hair; they suggested that the form mapped to chromosome 18 be designated LAH1 (HYPT6; 607903), the form mapped to chromosome 3q27 be designated LAH2, and the form mapped to 13q14-q21 be designated LAH3 (HYPT8; 278150).