Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ∼12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH

Testosterone, Sex Hormone-Binding Globulin and the Metabolic Syndrome in Men: An Individual Participant Data Meta-Analysis of Observational Studies

Peer reviewe

d-Chiro-Inositol improves testosterone levels in older hypogonadal men with low-normal testosterone: a pilot study

Background: Several recent journal articles report that d-chiro-inositol (DCI), primarily known as insulin second messenger, influences steroidogenesis. In particular, new evidence is arising on DCI ability to regulate aromatase expression and testosterone biosynthesis. In this regard, DCI administration could represent a good therapeutic opportunity in case of reduced levels of testosterone. Older men generally have lower testosterone concentrations than younger men, and recent randomized controlled trials have examined whether testosterone treatment might improve health outcomes in this age group. There is limited information about the safety of testosterone replacement therapy in these men, hence DCI could represent an interesting alternative for future trials. Therefore, this study aims to evaluate the effect of DCI treatment on testosterone levels in older male patient. Results: Ten older men with basal low testosterone levels were enrolled in this study. Patients took 600 mg of DCI, two-times per day, for 30 days. We evaluated hormonal and glycaemic parameters, weight, waist circumference, and Body-Mass Index at baseline (T0) and after 30 days (T1). Finally, all patients also filled in the standardized International Index of Erectile Function questionnaire and performed the Handgrip test at T0 and T1. Men receiving DCI showed increased androgen and reduced oestrogen concentrations, and improved glycaemic profiles. DCI was also associated with reduced weight, Body-Mass Index, waist circumference, and improved grip strength and self-reported sexual function. All these effects led to the improvement of sexual function and physical strength. Conclusions: In this pilot study, DCI treatment improved the levels of testosterone and androstenedione at the expense of oestrogens in elder men with low basal levels of these hormones without adverse effects. Trial registration: Clinicaltrials.gov: D-chiroinositol Administration in Hypogonadal Males, NCT04708249

Two male patients with ring Y: definition of an interval in Yq contributing to Turner syndrome

Turner syndrome is thought to result from the haploinsufficiency of genes on the sex chromosomes, but these genes have not been identified yet. We describe two males with deleted ring Y chromosomes, one (TS) with full Turner syndrome and one (DM) without. TS has short stature, skeletal anomalies, lymphogenic obstruction, cardiovascular abnormalities, and miscellaneous features including pigmented naevi, antimongoloid slanting of the palpebral fissures, and widely spaced nipples. In contrast, DM has short stature but no other specific Turner stigmata except high arched palate and a few pigmented naevi. Since little chromosomal mosaicism was detected, the different segments of the Y chromosome retained by these two males identify the location of one or more "anti-Turner" genes. Most of the Yp pseudoautosomal region and Yq were deleted from both patients during the formation of the ring chromosome, while the Y specific portion of Yp and the centromere were retained. The major difference detected was an interval of proximal Yq present in DM and deleted in TS. None of the previously identified genes, DFFRY, DBY, UTY, or TB4Y, lies entirely within this interval, although DFFRY was truncated by DM's breakpoint. These data suggest that one or more additional "anti-Turner" gene(s) remains to be identified in the region of Yq proximal to DFFRY.


Keywords: Turner syndrome; Y chromosome; deletion mapping; candidate gene