B4.7 Congenital Alopecia and nail dystrophy with Severe T-Cell Immunodeficiency: A UNIQUE PHENOTYPE OR A MISDIAGNOSED ENTITY?

J. Frank^{1, 2}, C. Pignata³, L. Gaetaniello³, N. Pozzi³, A.A. Panteleyev⁴, and A.M. Christiano^{4, 5}.

¹Dept. of Dermatology and Allergy and ²Division of Molecular Dermatology, University Clinic of the RWTH, Aachen, Germany; ³Dept. of Pediatrics, “Federico II” University, Naples, Italy; Depts. of ⁴Dermatology and ⁵Genetics and Development, Columbia University, New York, NY, USA.

The murine nude phenotype results from mutations in the whn (winged-helix-nude) gene encoding a forkhead/winged helix transcription factor family member characterized by exclusive expression in the thymus and skin. Phenotypically, these animals show congenital absence of hair and severe immunodeficiency. Until recently, identification of the human counterpart of the nude mutation has remained elusive. In 1996, however, the simultaneous occurrence of severe functional T-cell immunodeficiency, congenital alopecia and nail dystrophy (OMIM 601705) in two female siblings of Italian ancestry was reported. One sibling survived due to a bone marrow transplantation which corrected her immunodeficiency, but not the hair phenotype. To investigate if this syndrome represents a candidate disorder for  mutations in the human whn gene, we performed haplotype analyses and found suggestive evidence for linkage to the whn locus on human chromosome 17 (Z_max=1.32). Mutation analysis revealed a homozygous nonsense mutation in affected individuals that was present in the heterozygous state in obligate carriers, and in many members of the extended family originating from the same village. Further, we localized the expression of human whn to specific tissues involved in the pathogenesis of the disorder. These findings demonstrate the involvement of a forkhead/ winged helix family member in the etiology of such diverse developmental defects as congenital absence of the hair and athymia in humans. Surprisingly, no other case of this fascinating disorder has been reported to date. Possible explanations might be that, due to its rareness, the disease is i) misdiagnosed, ii) not diagnosed at all, or iii) the patients already as infants die of recurrent infections before the full clinical manifestation of the syndrome can be appreciated.