Pereira-Caetano, IrisSilva, JúliaKay, TeresaMirante, AliceAragüés, José MariaMascarenhas, MárioGonçalves, João2016-02-162016-02-162015-06-06Eur J Hum Genet. 2015 Jun 6; 23 (Spp1): 92-931018-4813http://hdl.handle.net/10400.18/3331Introduction: Idiopathic hypogonadotropic hypogonadism (IHH) comprises delayed/absent puberty, infertility and low serum gonadotropins in the context of normal anterior pituitary anatomy and function. Is due to partial/complete absence of gonadotropin-releasing hormone release/action or gonadotropin secretion and its incidence is low (1/10.000-1/86.000) with a nearly 4:1 male-to-female ratio. Approximately two-thirds of individuals with IHH have anosmia or hyposmia (Kallmann syndrome-KS) and one-third have normosmic IHH (nIHH). Mutations in KAL1 gene cause X-linked KS, and in GnRHR gene autosomal recessive IHH (almost 2% of nIHH patients). Material and Methods: 45 patients with IHH (42 males, 3 females), with and without hyposmia/anosmia were studied. Mutation analysis of KAL1 and/or GnRHR was performed by SSCP/DHPLC-PCR or by PCR-direct DNA sequencing. Results: We found two KAL1 mutations: c.769C>T (p.Arg257*) in a 15-years-old anosmic male; and a novel one, an extensive deletion encompassing exons 4 to 14 confirmed by MLPA, in a 3-years-old boy (detected also in his mother) with micropenis and maternal family history of HH. Two nIHH male patients were compound heterozygous for GnRHR: c.[2T>C];[785G>A], p.[(M1T)];[(R262Q)] (39-years-old, prepubertal testicules, gynecomastia, P1-A0 pilosity) and c.[317A>G];[416G>A], p.[(Q106R);(R139H)] (35-years-old with a brother non-tested with similar phenotype). All four mutations are known to be disease-causative. Discussion: We were able to find the genetic defects in 4 patients. The low detection rate of mutations (8.8%) is related with the existence of several genes implicated in the IHH’ pathogenesis. The NGS analysis in patients with IHH may improve the molecular diagnosis as it allows the screening of different genes simultaneously.engDoenças GenéticasGNHRKAL-1Hypogonadismconference object