Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism

Cangiano, Biagio; Duminuco, Paolo; Vezzoli, Valeria; Guizzardi, Fabiana; Chiodini, Iacopo; Corona, Giovanni; Maggi, Mario; Persani, Luca; Bonomi, Marco

doi:10.3390/jcm8010126

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Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism

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Marco Bonomi

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Department of Clinical Sciences and Community Health, University of Milan, 20100 Milan, Italy

IRCCS Istituto Auxologico Italiano, Division of Endocrine and Metabolic Diseases & Lab. of Endocrine and Metabolic Research, 20149 Milan, Italy

Endocrinology Unit, Medical Department, Azienda USL, Maggiore-Bellaria Hospital, 40133 Bologna, Italy

⁴

Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy

Author to whom correspondence should be addressed.

J. Clin. Med. 2019, 8(1), 126; https://doi.org/10.3390/jcm8010126

Received: 21 November 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 21 January 2019

(This article belongs to the Special Issue Testosterone and Men’s Health: From Evidence to Clinical Practice)

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Abstract

Multiple metabolic and inflammatory mechanisms are considered the determinants of acquired functional isolated hypogonadotropic hypogonadism (IHH) in males, whereas classic IHH is a rare congenital condition with a strong genetic background. Since we recently uncovered a frequent familiarity for classic IHH among patients with mild adult-onset hypogonadism (AO-IHH), here we performed a genetic characterization by next generation sequencing of 160 males with classic or “functional” forms. The prevalence of rare variants in 28 candidate genes was significantly higher than in controls in all IHH patients, independently of the age of IHH onset, degree of hypogonadism or presence of obesity. In fact, it did not differ among patients with classic or milder forms of IHH, however particular genes appear to be more specifically associated with one or the other category of IHH. ROC curves showed that Total Testosterone <6.05 nmol/L and an age of onset <41 years are sensitive cutoffs to identify patients with significantly higher chances of harboring rare IHH gene variants. In conclusion, rare IHH genes variants can frequently predispose to AO-IHH with acquired mild hormonal deficiencies. The identification of a genetic predisposition can improve the familial and individual management of AO-IHH and explain the heritability of congenital IHH. View Full-Text

Keywords: GnRH; Kallmann’s Syndrome; Late onset hypogonadism; obesity; IHH; testosterone cutoff; BMI; oligogenicity

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MDPI and ACS Style

Cangiano, B.; Duminuco, P.; Vezzoli, V.; Guizzardi, F.; Chiodini, I.; Corona, G.; Maggi, M.; Persani, L.; Bonomi, M. Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism. J. Clin. Med. 2019, 8, 126. https://doi.org/10.3390/jcm8010126

AMA Style

Cangiano B, Duminuco P, Vezzoli V, Guizzardi F, Chiodini I, Corona G, Maggi M, Persani L, Bonomi M. Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism. Journal of Clinical Medicine. 2019; 8(1):126. https://doi.org/10.3390/jcm8010126

Chicago/Turabian Style

Cangiano, Biagio, Paolo Duminuco, Valeria Vezzoli, Fabiana Guizzardi, Iacopo Chiodini, Giovanni Corona, Mario Maggi, Luca Persani, and Marco Bonomi. 2019. "Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism" Journal of Clinical Medicine 8, no. 1: 126. https://doi.org/10.3390/jcm8010126

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Evidence for a Common Genetic Origin of Classic and Milder Adult-Onset Forms of Isolated Hypogonadotropic Hypogonadism

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