Hypotrichosis, Congenital, With Juvenile Macular Dystrophy

A number sign (#) is used with this entry because of evidence that congenital hypotrichosis with juvenile macular dystrophy (HJMD) is caused by homozygous mutation in the CDH3 gene (114021), encoding P-cadherin, on chromosome 16q22.

Clinical Features

The association of juvenile macular dystrophy and congenital hypotrichosis was first described by Wagner (1935) in 2 sisters. Yasakura et al. (1967) also reported affected sibs. In a sporadic case presented by Kroll (1981), the parents were natives of the same village in Westphalia, Germany. Souied et al. (1995) reported a brother and sister with this complex (without any other manifestations of ectodermal dysplasia). Macular dystrophy in these sibs became evident after age 18. The parents of these patients were born in the same Portuguese village, suggesting autosomal recessive inheritance of the syndrome. Absence of digital abnormalities and normal eyelashes and eyebrows distinguish this syndrome from the EEM syndrome (225280).

The families with HJMD studied by Sprecher et al. (2001) originated from a small region of Northern Israel and belonged to the Druze population, a religious minority of Muslim origin. The Druze had lived in mountainous areas of the Middle East as a closed society almost from their inception in Cairo, around 1017 A.D. Affected individuals were born with seemingly normal hair but developed alopecia of the scalp at around 3 months of age. During puberty, however, partial regrowth of short and sparse hair occurred. Scalp skin biopsies showed normal findings, with the exception of a reduced ratio of terminal versus vellus hair follicles. By light and scanning electron microscopic examinations, they found fusiform beading along the hair shaft, due to flattening of the shaft as well as pili torti. Between ages 3 and 21 years, affected individuals developed progressive macular degeneration with slight peripheral retinal dystrophy.

Leibu et al. (2006) evaluated retinal function in 16 patients with hypotrichosis with juvenile macular dystrophy. Fundus examination revealed pigmentary abnormalities with atrophic changes at the posterior pole extending beyond the macular region. Follow-up of visual acuity and ERG testing indicated a slowly progressive retinal disorder affecting cone-mediated as well as rod-mediated vision. The authors therefore suggested that hypotrichosis with cone-rod dystrophy would be a more appropriate name for the disorder.

Mapping

Using homozygosity mapping in 4 consanguineous families, Sprecher et al. (2001) mapped the gene defective in hypotrichosis associated with juvenile macular dystrophy to chromosome 16q22.1.

Molecular Genetics

In affected members of 4 Druze families with HJMD, Sprecher et al. (2001) identified a homozygous deletion in exon 8 of the CDH3 gene (114021.0001). These findings implicated for the first time a cadherin molecule in the pathogenesis of a human hair and retinal disorder.

In all 4 members with hypotrichosis with juvenile macular dystrophy from a consanguineous family, Indelman et al. (2002) identified an arg503-to-his mutation (R503H; 114021.0002) in the CDH3 gene.