Oligogenicity in the idiopathic central hypogonadism
M. Bonomi1,2, D. Libri1, A. Pincelli3, F. Guizzardi1, E. Maiolo4, M. Maghnie5, C. Krausz6, L. Persani1,2,7 & On behalf of the Italian Network for ICH8
Author affiliations
1Istituto Auxologico Italiano IRCCS, Cusano Milanino, Italy; 2Istituto Auxologico Italiano IRCCS, Milano, Italy; 3Ospedale San Gerardo dei Tintori, Monza, Italy; 4EO Ospedali Galliera, Genova, Italy; 5Università di Genova, Genova, Italy; 6Università di Firenze, Firenze, Italy; 7Università di Milano, Milano, Italy; 8Italy.
Introduction: ICH is a rare and heterogeneous condition due to defects of GnRH secretion or action. Recent data indicate that ICH, though characterized by a strong genetic component, is a disease of multifactorial origin. Indeed, digenic defects have been described as a possible pathogenic explanation for ICH.
Subjects: We present two familial cases with particular clinical and genetic profiles, out of a cohort of 300 ICH patients.
Results: Proband 1 is a male diagnosed with normosmic ICH when he was 18 and then treated with testosterone. After 6 years of therapy he showed a complete recovery of a spontaneous GnRH function. Genetic analyses showed a heterozygous new nonsense mutation of the PROKR2 gene (15fsX43) and a known heterozygous loss-of-function mutation of the GnRHR (Q106R) respectively inherited from the unaffected father and mother. His sister has wild-type sequences but his brother, despite a normal puberty and eugonadism, shows the same digenic genotype. Proband 2, a male diagnosed at 24 years with Kallmann syndrome (KS), was found to carry a new heterozygous missense substitution in the FGFR1 gene (L713P) and a disrupting duplication of the exons 4 to 14 of KAL1 gene. His father, younger brother and sister are unaffected with normal sequences. His mother and a elder brother were carriers of the KAL1 duplication but not of the FGFR1 variation. This brother had a normal puberty but is affected by daltonism and arched palate (two minor stigmata of KS), while the mother only by daltonism.
Conclusions: we describe two ICH families displaying a highly variable penetrance of the underlying multiple genetic defects. The first case shows that heterozygous digenic defects may not be sufficient to cause ICH, thus giving rise to the idea of a multifactorial origin of this heterogeneous condition.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.