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Submitted on December 21, 2005
Accepted on July 24, 2006
Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM-42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Departamento de Medicina Interna, Divisão de Endocrinologia, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Departamento de Clínica Médica, Disciplina de Endocrinologia e Metabologia da Faculdade de Ciências Médicas da Universidade de Campinas, São Paulo, Brasil
* To whom correspondence should be addressed. E-mail: trarbach{at}hotmail.com or anacl{at}usp.br.
Context. Kallmann syndrome is a clinically and genetically heterogeneous disorder. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively.
Objective. To investigate genetic defects in the KAL1 and FGFR1 genes in patients with congenital isolated hypogonadotropic hypogonadism (IHH).
Patients. Eighty patients (71 males and 9 females) with IHH were studied, of which 21 were familial. Forty-six of them had olfactory abnormalities.
Methods. The coding regions of both KAL1 and FGFR1 genes were amplified and automatically sequenced. The KAL1 mutations were investigated only in patients with olfactory abnormalities, whereas FGFR1 was studied in the entire group.
Results. Two novel KAL1 mutations, an intragenic deletion of exons 3-6 and a splicing mutation IVS7 + 1G>A, were identified in 2 of 46 patients with Kallmann syndrome. Eight novel heterozygous FGFR1 mutations (G48S, L245P, R250W, A343V, P366L, K618fsX654, P722S and V795I) were identified in 9 of 80 patients with IHH. Eight of them had olfactory abnormalities. Interestingly, the G48S mutation was identified in a normosmic IHH patient. Two unrelated females, who carried FGFR1 mutations, had anosmia and normal reproductive function.
Conclusion. We identified novel mutations in KAL1 and FGFR1 genes in IHH patients. FGFR1 mutations were identified in 17% of the patients with olfactory abnormalities and in 1 of 34 normosmic IHH patients. In addition, isolated anosmia was identified in two unrelated females as a partial phenotypic manifestation of FGFR1 defects.
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