ECE2013 Poster Presentations Neuroendocrinology (42 abstracts)
Digenic and oligogenic cases in a large cohort of idiopathic central hypogonadism (ICH) patients
Domenico Libri 1 , Marco Bonomi 1 , Fabiana Guizzardi 1 , Paolo Duminuco 1 , Ida Pincelli 3 , Giovanni Russo 4 , Andrea Garolla 5 , Csilla Krausz 6 , Mohamed Maghnie 7 , Giuseppa Padova 8 & Luca Persani 1,
1Istituto Auxologico Italiano, Cusano Milanino, Italy; 2Università statale degli studi di Milano, Milano, Italy; 3Dipartimento Endocrinologia di Monza, Monza, Italy; 4Dipartimento di pediatria – Ospedale san Raffaele, Milano, Italy; 5Dipartimento Ist. Micr. e Biotec. Mediche, Padova, Italy; 6Dipartimento di Fisiopatologia Clinica, Firenze, Italy; 7IRCCS Ospedale Gaslini, Genova, Italy; 8Azienda ospedaliera Garibaldi, Catania, Italy.
ICH is a rare and heterogeneous condition due to defects in the onthogenesis, migration and action of GnRH secreting neurons. Recent publications indicate that ICH, though characterized by a strong genetic component, is a disease of multifactorial origin. Indeed, digenic and oligogenic defects have been described as a possible pathogenic explanation for this disease. Among the cohort of 315 ICH patients we identified 3 KS and 7 nICH patients (7 males, 3 females) with a biallelic defect. These oligogenic defects were quite heterogeneous involving elements on different pathways. First familial case (brother and sister) present a compound heterozygosity on the same gene, the GnRHR, the second pedigree show a duplication in KAL1 and a variant in FGFR1, while the other 7 show biallelic variants on different genes: PROKR2 and GnRHR; PROKR2 and PROK2, FGFR1 and SEMA3A, GNRHR and FGF8, FGFR1 and PROKR2 in 3 cases. In this small group of patients, we observe a suggestive enrichment for complex phenotypes, such as mono or bilateral cryptorchidism, midline defects and synkinesia. One case, with PROKR2/PROK2 variants, showed a permanent reversal of the ICH after 6 years of testosterone replacement therapy. Putting together the genetic and phenotypic data we could observed a more severe phenotype in patients carrying a biallelic defect involving the FGFR1 gene. Five out of ten patients were presenting a genetic variation on PROKR2 or FGFR1 gene, thus suggesting that single heterozygous mutations in these genes might represent frequent causes of genetic susceptibility to ICH which would need another hit to become manifest. Finally, mutations on GnRHR gene appear interestingly associated with the less severe phenotypes.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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