Genotype and phenotype characterization of the cohort of Italian patients with idiopathic central hypogonadism (ICH)

Marco Bonomi; Libri Domenico Vladimiro; Fabiana Guizzardi; Paolo Duminuco; Sinisi Antonio Agostino; Manuela Simoni; Mohamad Magnie; Csilla Krausz; Luca Persani; behalf of the Italian Societies for Endocrinology and Pediatric Endocrinology On

doi:10.1530/endoabs.32.P678

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Endocrine Abstracts (2013) 32 P678 | DOI: 10.1530/endoabs.32.P678

ECE2013 Poster Presentations Neuroendocrinology (42 abstracts)

Genotype and phenotype characterization of the cohort of Italian patients with idiopathic central hypogonadism (ICH)

Marco Bonomi ¹ , Domenico Vladimiro Libri ¹ , Fabiana Guizzardi ¹ , Paolo Duminuco ¹ , Antonio Agostino Sinisi ³ , Manuela Simoni ⁴ , Mohamad Magnie ⁵ , Csilla Krausz ⁶ , Luca Persani ^1, & On behalf of the Italian Societies for Endocrinology and Pediatric Endocrinology ¹

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¹Divisione di Medicina Generale ad indirizzo Endocrino-Metabolico and Laboratorio di Ricerche Endocrino-metaboliche, IRCCS Istituto Auxologico Italiano, Cusano Milanino, Milan, Italy; ²Dipartimento di Scienze Cliniche e di Comunità, Università degli studi di Milano, Milan, Italy; ³Dipartimento di Scienze Cardiotoraciche e Respiratorie, II Università di Napoli, Naples, Italy; ⁴Dipartimento di Biomedicina, Metabolismo e Scienze Neurali, Università di Modena e Reggio Emilia, Modena, Italy; ⁵Dipartimento di Scienze Pediatriche, IRCCS Giannina Gaslini, Università di Genova, Genova, Italy; ⁶Dipartimento di Fisiopatologia Clinica, Unità di Andrologia, Università di Firenze, Florence, Italy.

ICH is a rare disease characterized by a complex pathogenesis, but with a strong genetic component. ICH may be associated to several other morphogenetic or inborn defects, such as the osmic defects that identify the Kallmann syndrome (KS). The description of several pedigrees including relatives affected either with isolated osmic defects or KS or normoosmic ICH (nICH) justifies the emerging idea of ICH as a complex genetic disease characterized by variable expressivity and penetrance. In order to improve the management of ICH patients we decided to create an Italian network aiming to collect and characterize a large national patients series. Among the 363 total index cases, 151 had KS and 212 nICH. The number of familial cases in the two categories was similar (21.8% KS and 19.3% nICH), but the prevalence of associated malformations or cryptorchidism was higher in KS (20.5 or 29.8% vs 5.6 or 12.7% in nICH respectively). Genetic analysis allowed the identification of contributing genetic defects in about 32% of the patients, with a major involvement of KAL-1 (8.2%), FGFR1 (11.5%) and PROKR2 (8.7%) and a rare involvement of other candidate genes. Variants were detected on a single allele in 88% of the cases, whereas biallelic variations affecting either GnRHR or PROKR2 genes were found in 2.4% and digenic defects in the remaining 9.6%. These digenic defects were quite heterogeneous involving elements on different pathways and were distributed among KS and nICH patients. In conclusion, although accumulating evidences indicate the existence of common pathogenic mechanisms for KS and nICH, the combination of hypogonadism with associated malformations or cryptorchidism appears more frequent in KS. Systematic analyses of candidate genes indicate that the pathogenesis of both phenotypes is still largely unknown, but a multiple gene involvement may be seen in both cases.