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

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.

SUBMITTER: Cangiano B

PROVIDER: S-EPMC6352096 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Isolated hypogonadotropic hypogonadism (IHH) is a rare, clinically heterogeneous condition, caused by the deficient secretion or action of gonadotropin releasing hormone (GnRH). It can manifest with absent or incomplete sexual maturation, or as infertility at adult-age; in a half of cases, IHH is associated with hypo/anosmia (Kallmann syndrome). Although a growing number of genes are being related to this disease, genetic mutations are currently found only in 40% of IHH patients. Case description: Severe congenital hyposmia was diagnosed in a 25-year-old Caucasian man referred to the Ear-Nose-Throat department of our clinic. The patient had no cryptorchidism or micropenis and experienced a physiological puberty; past medical history and physical examination were unremarkable. Olfactory structures appeared hypoplasic, while hypothalamus, pituitary gland, and stalk were normal on MRI (neuroradiological imaging); testosterone levels, as well as pulsatile gonadotropin secretion and other pituitary hormones were unaffected at the time of first referral. At the age of 48, the patient returned to our clinic for sexual complaints, and the finding of low testosterone levels (6.8 and 5.8 nmol/L on two consecutive assessments) with inappropriately normal gonadotropin levels led to the diagnosis of hypogonadotropic hypogonadism. GnRH test was consistent with hypothalamic origin of the defect. Next generation sequencing was then performed revealing a rare heterozygous allelic variant in SPRY4 gene (c.158G>A, p.R53Q). The biological and clinical effects of this gene variant had never been reported before. A diagnosis of Kallmann syndrome was finally established, and the patient was started on testosterone replacement therapy. Conclusion: This case describes the clinical phenotype associated with a rare SPRY4 gene allelic variant, consisting in congenital severe smell defect and adult-onset IHH; in patients with apparently isolated congenital anosmia genetic analysis can be valuable to guide follow up, since IHH can manifest later in adulthood. Characterization of other modifying genes and acquired environmental factors is needed for a better understanding of the physiopathology and clinical manifestations of this disease.

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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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