ESPE Abstracts (2016) 86 P-P1-729

Clinical and Mutational Spectrum in Slovenian Patients with Hypogonadotropic Hypogonadism

Magdalena Avbelj Stefanijaa, Tamara Obrezac, Marija Pfeiferb, Jernej Kovacc, Tadej Battelinoa,d & Katarina Trebusak Podkrajsekc,d


aDepartment for Endocrinology, Diabetes and Metabolism Ljubljana, University Medical Centre, University Children’s Hospital, Ljubljana, Slovenia; bDepartment of Endocrinology, University Medical Centre, Ljubljana, Slovenia; cUnit for Special Laboratory Diagnostics Ljubljana, University Medical Centre, University Children’s Hospital, Ljubljana, Slovenia; dMedical Faculty, University of Ljubljana, Ljubljana, Slovenia


Background: Congenital hypogonadotropic hypogonadism (HH) is a rare but clinically and genetically heterogeneous disease characterized by an absent or incomplete puberty and infertility. The association of HH with hyposmia or anosmia is defined as Kallmann syndrome. Molecular genetic testing of HH is valuable, as it can prompt the treatment in adolescence.

Objective and hypotheses: To identify causative variants in genes associated with HH in a cohort of 13 Slovenian patients.

Population and Method: 13 subjects (12 males, 1 female) with congenital HH were included. Targeted next generation sequencing (NGS) of 24 genes known to be associated with HH was used to identify causative genetic variants that were subsequently confirmed by Sanger sequencing.

Results: Three males had normosmic HH, all other patients had Kallmann syndrome, two of those in association with characteristics of CHARGE syndrome. Of the subjects with normal CHD7 gene, four subjects had other associated disorders including colour blindness, schizophrenia, sensorineural hearing loss and hypocalciuric hypercalcemia caused by a CASR gene mutation. Nine mutations in six genes (PROK2, GNRHR, PROKR2, FGFR1, CHD7 and FGF8) were identified in 9 out of 14 patients (64%), each of them carrying a single heterozygous mutation in a single gene. Among them, three variants namely PROK2 c.171_172delTT (p.Ile57MetfsTer17), FGFR1 c.196T>C (p.Typ66Arg) and CHD7 c. 5050+1G>T have not yet been described. Of the remaining five patients two were part of the pedigrees with multiple affected members, which suggests an unidentified genetic cause.

Conclusion: NGS enables fast and reliable identification of causal mutations in several genes related to HH simultaneously. Presented subject group with HH was genetically very diverse and the results expand the spectrum of mutations implicated in HH. By examining known genes oligogenicity was not identified and variable penetrance demonstrated in some pedigrees remained unexplained.

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