Alopecia Universalis Congenita

A number sign (#) is used with this entry because of evidence that alopecia universalis congenita (ALUNC) is caused by homozygous mutation in the human homolog of the mouse 'hairless' gene (HR; 602302) on chromosome 8p21.

Description

Alopecia universalis congenita is a severe autosomal recessive form of alopecia characterized by a complete absence of hair development affecting all scalp and body hair (Nothen et al., 1998).

This rare disorder is clearly distinct from alopecia areata (AA1; 104000), which has an autoimmune basis with probable genetic predisposition.

Clinical Features

Ahmad et al. (1993) studied an inbred Pakistani kindred in which 9 males and 4 females had alopecia universalis as an isolated abnormality. The affected individuals were distributed in 7 related sibships. Skin biopsy from the scalp showed hair follicles without hair. Ahmad et al. (1993) pointed to the families reported by Tillman (1952) as probably representing the same disorder with autosomal recessive inheritance. They also referenced a boy described by Feinstein et al. (1987) whose normal parents were related as first cousins.

Pinheiro and Freire-Maia (1985) described what they called 'recessive atrichia' in 2 brothers. It should be pointed out that monilethrix (158000) may be labeled alopecia universalis or alopecia congenita unless a few hairs are found and examined for the characteristic morphology by microscopy.

Cantu et al. (1980) observed 2 families, each with 2 affected children, 3 girls and a boy. Scalp, eyelashes, eyebrows, and body hair were affected but not completely absent.

Ahmad et al. (1998) studied a large Pakistani kindred with alopecia universalis segregating as a single mendelian abnormality without associated ectodermal defects and containing 4 affected males and 7 affected females. The affected individuals were in good general health, with no evidence for immune system dysfunction or unusual susceptibility to skin tumors. At birth, the hair usually appears normal on the scalp but never regrows after a ritual shaving, usually performed a week after birth. A skin biopsy from the scalp of an affected person revealed very few hair follicles, which were dilated and without hairs, and the absence of an inflammatory infiltrate. Affected individuals were born completely devoid of eyebrows and eyelashes and never developed axillary and pubic hair. The pedigree was strongly suggestive of autosomal recessive inheritance and the large number of consanguineous loops counted for all affected individuals being homozygous for the same abnormal allele.

Mapping

Nothen et al. (1998) performed linkage analysis on the Pakistani kindred of Ahmad et al. (1993) and found a maximum lod score of 7.90 at a recombination fraction of 0.0 with locus D8S258. Haplotype analysis of recombination events localized the disease locus to a 15-cM region between marker loci D8S261 and D8S1771. This permitted assignment of the gene, which they symbolized ALUNC, to 8p22-p21.

Using homozygosity mapping in a large consanguineous Pakistani kindred with alopecia universalis, Ahmad et al. (1998) established linkage of the phenotype to a 6-cM interval on chromosome 8p12; lod = 6.19. By radiation hybrid mapping, Ahmad et al. (1998) localized the human homolog of the mouse 'hairless' (hr) gene to this interval.

Molecular Genetics

Ahmad et al. (1998) identified a homozygous missense mutation in the HR gene (602302.0001) in affected members of a Pakistani kindred with alopecia universalis. Ahmad et al. (1998) reported that human 'hairless' encodes a putative single zinc finger transcription factor with restricted expression in the brain and skin.

Nomenclature

In describing a mutation in the HR gene causing hairlessness in a large inbred family of Irish Travellers (atrichia with papular lesions; 209500), Ahmad et al. (1998) proposed that the term 'congenital atrichia with papules' be used to describe the phenotype caused by mutations in the human hairless gene. Christiano (1998) suggested that papular lesions may be a variable part of the phenotype.

Sundberg et al. (1999) suggested that generalized atrichia is a more descriptive and useful name for the phenotype caused by mutations in the HR gene in mice, humans, and other mammals. They expressed hope that the unrelated and common autoimmune disease, the alopecia universalis variant of alopecia areata (see 104000), will have its genetic basis identified using another mouse model, the C3H/HeJ strain (Sundberg et al., 1994), thereby providing new insights into hair loss and autoimmunity.