Papillary lesions over most of the body and almost complete absence of hair are features. The patients are born with hair that falls out and is not replaced. Histologic studies show malformation of the hair follicles. Damste and ... Papillary lesions over most of the body and almost complete absence of hair are features. The patients are born with hair that falls out and is not replaced. Histologic studies show malformation of the hair follicles. Damste and Prakken (1954) described a kindred in which 3 sisters and 2 sons of their mother's first cousin were affected. Loewenthal and Prakken (1961) described another case, the daughter of third cousins. Cystic malformation of hair follicles was observed. Ahmad et al. (1998) suggested that the human counterpart of the mouse 'hairless' mutation should be called atrichia with papular lesions. They pictured the characteristic cystic papules on the elbows and knees of their patients. Sprecher et al. (2000) assessed the pattern of androgenetic alopecia in 31 healthy male second-degree relatives of patients affected with APL belonging to a large consanguineous kindred. No difference in age at onset or extent of androgenetic alopecia was observed between healthy homozygotes and heterozygous carriers of the mutation. Sprecher et al. (2000) concluded that the presence of a deleterious mutation in one allele of the 'hairless' gene does not affect the pattern of androgenetic hair loss. Ahmad et al. (1998), who referred to this condition as congenital atrichia, reported the identification of a missense mutation in the zinc finger domain of the hairless gene in a large inbred family of Irish Travellers. The gypsies known as Irish Travellers had existed as a distinct indigenous ethnic minority within Ireland for centuries. Hairs were typically absent from the scalp, with shedding of the natal hair shortly after birth, and patients were completely devoid of eyebrows, eyelashes, and axillary and pubic hair. A biopsy of the scalp skin from one of the affected individuals showed absence of hair follicles, with sparsely distributed sebaceous glands. There was no histologic evidence of an inflammatory process. All affected individuals had grouped cystic and papular lesions on the knees and elbows, which had the clinical and histopathologic appearance of milia. Affected individuals showed no growth or developmental delay, normal hearing, teeth, and nails, and no abnormalities of sweating. Heterozygous individuals had normal hair and were clinically indistinguishable from genotypically normal persons. Published estimates of the prevalence of APL remain surprisingly low considering pathogenetic mutations in HR have been found in distinct populations around the world. Zlotogorski et al. (2002) and Henn et al. (2002) asserted that APL is more common than previously thought and is often mistaken for the putative autoimmune form of alopecia universalis (see 104000). Zlotogorski et al. (2002) proposed revised clinical criteria for APL based on their personal observation of 9 Arab families and retrospective analysis of other families described in the literature. These features include family history with autosomal recessive inheritance and possible consanguinity; atrichia at birth or shedding of normal scalp hair several months after birth with failure to regrow; appearance of skin papules (most commonly on the face, under the midline of the eye, and on the extremities) within the first year of life; sparse eyebrows and eyelashes; lack of secondary axillary, pubic, or body hair; whitish hypopigmented streaks on the scalp; normal nails, teeth, and sweating; normal growth and development; and failure of any treatment modality to restore hair growth. Miller et al. (2001) reported a patient with vitamin D-resistant rickets type IIA (277440), a compound heterozygote for mutations in the VDR gene (601769.0013, 601769.0014), in which the phenotype of atrichia with papular lesions was identical to that seen in patients carrying mutations in the HR gene. The authors suggested that VDR and HR, which are both zinc finger proteins, may be in the same genetic pathway that controls postnatal cycling of the hair follicle.
Although Ahmad et al. (1998) detected a mutation in the HR gene (arg620 to gln) in a family of Irish Travellers with atrichia with papular lesions, Hillmer et al. (2001) concluded that, in fact, this mutation is not ... Although Ahmad et al. (1998) detected a mutation in the HR gene (arg620 to gln) in a family of Irish Travellers with atrichia with papular lesions, Hillmer et al. (2001) concluded that, in fact, this mutation is not a disease-causing mutation but a polymorphism without consequences for hair development. In Germany they found a gln620 allele frequency of 2.7%, which would predict that almost 60,000 individuals in Germany are affected with autosomal recessive papular atrichia; however, no German has been reported with this disorder. They identified an individual homozygous for gln620 who was unambiguously not affected with papular atrichia. He had, however, male-pattern loss of scalp hair beginning at the age of 18 to 20 years and by the age of 26 years had developed severe androgenetic alopecia (109200). The rest of the scalp hair, eyebrows, and beard hair, as well as pubic, axillary, and body hair, developed normally and remained completely normal. There were no signs of a papular rash. By RT-PCR, Sprecher et al. (1999) compared the coding sequence of the HR gene in fibroblast cell lines derived from a patient with APL and an unrelated individual. They identified a 1-bp deletion (3434delC; 602302.0006) in the HR gene that cosegregated with the disease phenotype in the large family reported by Sprecher et al. (1998). This deletion was predicted to cause a frameshift mutation in the highly conserved C-terminal part of the HR protein, a region putatively involved in the transcription factor activity of the HR gene product. These results indicated phenotypic heterogeneity in inherited atrichias caused by mutations in the HR gene, suggesting different roles for the regions mutated in APL and in other forms of congenital atrichia during hair development. Henn et al. (2002) reported a small German kindred in which 2 sibs were compound heterozygous for different HR mutations (602302.0010, 602302.0011). They were both born with normal hair that was lost within the first few months of life and did not grow back. Both had undergone several unsuccessful invasive treatments for autoimmune alopecia universalis before the diagnosis of APL was made and confirmed by DNA analysis. Paller et al. (2003) identified 3 small nonconsanguineous families having 1 offspring affected by early-onset hair loss that never regrew with an associated papular eruption and/or failed response to treatment for alopecia universalis. The clinical findings in all 3 families were consistent with APL. Paller et al. (2003) identified compound heterozygous mutations in the HR gene in all 3 affected individuals. Their 3 additional compound heterozygous patients from families without consanguinity further supported the hypothesis that isolated cases of APL may be more common than previously thought and suggested that infants with presumed autoimmune alopecia universalis in small nonconsanguineous families may warrant testing for HR gene mutations, particularly before embarking on therapeutic modalities that will fail in APL. In affected individuals from 5 unrelated consanguineous Pakistani families with generalized scalp and body alopecia, sparse eyebrows and lashes, and papules, Kim et al. (2007) identified homozygosity for 1 of 3 nonsense mutations in the HR gene. Microsatellite marker analysis showed that each of 2 sets of families carrying the same nonsense mutation had an identical homozygous haplotype, suggesting that the mutations did not arise independently but were propagated in the population. All affected individuals presented with the same clinical manifestations. Kim et al. (2007) noted that, in keeping with previous reports, they did not observe any genotype/phenotype correlations.