MADAM, Hereditary hypotrichosis simplex (HHS; OMIM 146520⁄ 605389) is a rare heritable disorder that is an auto somal dominant form of nonsyndromic alopecia. 1 It can be divided into two forms, namely, the scalp-limited and the generalized forms. In the latter, all body hair is affected. 2 Patients usually present with normal hair at birth; hair loss starts at approximately 3–6 months of age and progresses with age. 3 The hair shaft characteristically shows no gross abnormality. Patients display normal skin, teeth and nails. Mutations in the corneodesmosin (CDSN) gene have been identified in several families with the scalp-limited form of HHS. 3–6 The generalized form of HHS is reportedly caused by mutations in two genes: APCDD1 (adenomatosis polyposis coli downregulated 1) encoding a Wnt inhibitor7 and RPL21, the gene encoding ribosomal protein L21. 2 To date, only one study has reported that HHS is caused by a mutation of the APCDD1 gene. 7 In the present work, we report a recurrent APCDD1 mutation responsible for the generalized form of HHS.

We studied a large Chinese family extending over five generations and comprising 55 individuals, which included 17 with the generalized form of HHS (Fig. 1). This pedigree clearly shows an autosomal dominant inheritance with full penetrance. The proband was a 3-year-old boy born at 39 weeks of gestation. His mother had a normal pregnancy. He had normal scalp hair density at birth. Hair loss began at approximately 4 months of age and gradually progressed with age (Fig. 2a, b). Eyebrows, eyelashes and body hair were sparse; the scalp of the patient was normal. All affected individuals in this family had similar manifestations. In most of the affected members of the family, complete loss of hair occurred at the age of 15–20 years (Fig. 2c, d). The hair shaft was also slightly thin, as observed by a light microscope, with no characteristic abnormality. Eyebrows, eyelashes, body hair, axillary and pubic hairs were sparse; however, beard hairs were normal. No abnormalities in the skin, nails, teeth and eyes were noted in any of the affected individuals. This study was approved by the Ethics Committee of the Shanghai Jiaotong University School of Medicine. After obtaining informed consent, genomic DNA was extracted from the peripheral blood lymphocytes of patients. We analysed three genes (CDSN, APCDD1 and RPL21) from this family by direct sequencing using primers and reaction conditions as previously described. 2, 7 We sequenced the APCDD1 gene using an ABI PRISMÒ 3730 automated sequencer (Applied Biosystems, Foster City, CA, USA). Sequence comparisons and analysis were performed using the Phred-Phrap-Consed Version 12.0 program(http://www. phrap. org/phredphrapconsed. html). Samples from 100 unrelated population-matched controls were sequenced for mutations to exclude the possibility of polymorphism in the APCDD1 gene. Mutation was identified by comparing with the reported cDNA reference sequence (GenBank accession number: 153000.4). The entire coding and flanking intronic sequences of the APCDD1 gene were screened for mutation among affected and unaffected individuals of the family. A recurrent mutation, p. Leu9Arg, was identified in affected individuals of the family (Fig. 2e, f). This change was not detected in 100 unrelated, healthy Chinese control individuals (200 alleles). Sequence analysis of two other genes, CDSN and RPL21, failed to detect sequence variants in either affected or unaffected individuals of the family.