Hypotrichosis 4

A number sign (#) is used with this entry because of evidence that Marie Unna hereditary hypotrichosis-1 (MUHH1) can be caused by heterozygous mutation in the 5-prime UTR of the HR gene (602302).

See also MUHH2 (612841), which maps to chromosome 1.

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

Clinical Features

Peachey and Wells (1971) reported 3 kindreds, each with several members with hereditary hypotrichosis of the type reported by Marie Unna (Unna, 1925). Affected persons were born with little or no eyebrows, eyelashes, or body hair. Characteristically coarse, wiry, twisted hair developed in early childhood and was followed by the development of alopecia. Ludwig (1953) and Borelli (1954) added other cases from the family reported by Unna (1925). The Marie Unna type of hypotrichosis is distinguished from hypotrichosis simplex (see 605389) by the presence of a twisting hair dystrophy, for which reason Solomon et al. (1971) suggested the designation hereditary trichodysplasia for the disorder. Also see 609250 for a similar disorder with onycholysis and cleft lip/palate.

Bentley-Phillips and Grace (1979) described hypotrichosis in 11 members of 4 generations. Loss of hair, involving the scalp, eyebrows, eyelashes, and body, manifested itself in the school years and progressed to almost complete alopecia. No associated abnormalities were found. There was no instance of male-to-male transmission, but the disorder was equally severe in males and females.

Argenziano et al. (1999) described Marie Unna hypotrichosis in a large Italian pedigree comprising 6 generations with 20 affected members. The hair defect was an isolated feature in these patients and the ultrastructural hair findings consisted of both torsion and longitudinal grooving of the hair shaft.

Mansur et al. (2010) studied a Turkish father and 3 children who had sparse eyebrows from birth associated with normal scalp hair density in childhood; the father reported that his scalp hair density had decreased over time. Scalp hair in all 4 was dark, stiff, rough, and straight, and eyelashes varied from normal to sparse. Body hair was sparse, except in the 15-year-old daughter, who had hirsutism, irregular menstrual cycles, and bilateral polycystic ovaries. Skin biopsy from the father's scalp demonstrated scattered, small, hamartomatous anagen follicles. Light microscopy of hair shafts did not show any gross pathology. Scanning electron microscopy of hairs demonstrated a degenerate structure with abnormalities in both cuticular pattern and hair structure. The sheath showed nodular proliferation and longitudinal grooving, and fractures of the sheath were prominent. Distal ends of the hair were flattened and deformed. Medical histories of the father's relatives revealed 10 additional affected family members, who had sparse eyebrows, eyelashes, and body hair, but relatively normal scalp hair. Supraorbital ridges were prominent, especially in older individuals.

Mapping

By a genomewide search in a large Dutch family with Maria Unna hereditary hypotrichosis (MUHH), van Steensel et al. (1999) detected linkage with marker D8S258 on 8p. Analysis of this family and a further British kindred with additional markers in the region gave a combined maximum 2-point lod score of 13.42 with D8S560. Informative recombinants placed the MUHH locus in a 2.4-cM interval between D8S258 and D8S298 on 8p22-p21.

Sreekumar et al. (2000) found linkage of MUHH in a large Caucasian family to a 6.6-cM segment of chromosome 8p21 between D8S258 and D8S1739. Their maximum lod score was 3.92 at D8S298 (theta = 0).

In studies of 3 multigeneration families of Belgian, British, and French descent, Lefevre et al. (2000) confirmed the linkage to 8p21 and narrowed the genetic interval to about 12 cM.

Mansur et al. (2010) performed linkage and haplotype analysis in a 4-generation Turkish pedigree with sparse eyebrows and body hair but relatively normal scalp hair and confirmed linkage to the MUHH locus at chromosome 8p21.

Molecular Genetics

In affected members of a large Han Chinese family with Marie Unna hypotrichosis mapping to chromosome 8p21, Wen et al. (2009) identified heterozygosity for an initiation codon mutation in an ORF (which they designated U2HR) in the 5-prime UTR of the HR gene (602302.0013). The mutation was not found in unaffected members of the family or in 617 unrelated Han Chinese controls. In affected members of 18 additional families with a confirmed clinical diagnosis of MUHH, including families previously reported by van Steensel et al. (1999), Sreekumar et al. (2000), Lefevre et al. (2000), Cichon et al. (2000), He et al. (2004), and Scheper et al. (2007), they identified 12 more heterozygous mutations in U2HR (see, e.g., 602302.0014-602302.0016). No obvious genotype/phenotype correlation was observed in the 19 families. Functional analysis showed that these classes of mutations, which included loss of initiation, delayed termination codon, nonsense, and missense, all resulted in increased translation of the main HR physiologic ORF; the authors concluded that fine tuning of HR protein levels is important in control of hair growth.

In affected individuals from a 4-generation Turkish pedigree with sparse eyebrows, eyelashes, and body hair, but relatively normal scalp hair, Mansur et al. (2010) identified the same heterozygous initiation codon mutation (602302.0013) that had been found in 3 families with Marie Unna hypotrichosis by Wen et al. (2009). Mansur et al. (2010) concluded that there may be considerable clinical variation in MUHH and that eyebrow loss is an important clue for accurate diagnosis.

Exclusion Studies

Because the MUHH locus mapped to the same region of chromosome 8 as the human homolog of the mouse 'hairless' gene (HR; 602302), which had been shown to carry recessive mutations responsible for congenital atrichia (209500), and because of the existence of a semidominant murine Hr allele, van Steensel et al. (1999) performed mutation analysis on the HR gene in an individual with MUHH. Full-length sequencing of HR cDNA showed no mutations. Similarly, screening of all exons of the HR gene amplified from genomic DNA of an affected individual revealed no mutations. Sreekumar et al. (2000) likewise found no mutations in the hairless gene in a Caucasian family with MUHH.

By mutation analysis, Lefevre et al. (2000) also excluded the hairless gene as well as 9 other genes expressed in skin that are located within the linkage region as candidates for the disorder.

Animal Model

Baek et al. (2009) described the phenotype and histologic morphology of an animal model of Marie Unna hereditary hypotrichosis, the 'hairpoor' mouse, in which they identified a mutation in the mouse Hr gene corresponding to that of MUHH patients in the human HR gene.