👤 Nelly Pitteloud

What is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency? This study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency. Congenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD). The study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing. Genetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated. Cleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). N/A. Non-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken. This study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency. This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B₂₀₁₂₇₅ to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests. Show less

Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) function. A subset of individuals with CHH also present with developmental anomalies, including midline defects such as cleft lip and/or palate (CLP). This study investigates the genetic overlap between CHH and CLP. A total of 336 individuals diagnosed with CHH were clinically assessed for associated phenotypes, including CLP. High-throughput sequencing was performed using a targeted gene panel encompassing known CHH- and CLP-related genes. Variants were analyzed and classified according to the American College of Medical Genetics and Genomics (ACMG) criteria for pathogenicity. CLP was present in 21 patients with CHH (6%). Pathogenic or likely pathogenic variants in genes associated with both CHH and CLP-such as FGFR1 and CHD7-were identified in eight individuals. Furthermore, 17% of the patients with CHH without CLP harbored deleterious variants in genes implicated in clefting, including DVL3, PLCB4, NIPBL, and EDNRA. Evidence of digenic inheritance involving both CHH- and CLP-related genes was observed in multiple cases. FGFR1 variants were the most frequently detected and were commonly associated with anosmia and additional developmental anomalies. These findings highlight a genetic and phenotypic continuum between CHH and CLP, underscoring the involvement of shared developmental pathways. The high prevalence of FGFR1 variants in patients with CHH and CLP supports its role as a pleiotropic gene. Understanding the overlapping genetic mechanisms may enhance diagnostic precision and inform personalized management strategies for affected individuals. Show less

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. Show less

The optimal strategy for inducing fertility in men with congenital hypogonadotropic hypogonadism (CHH) is equivocal. Albeit a biologically plausible approach, pretreatment with recombinant FSH (rFSH) before GnRH/human chorionic gonadotropin administration has not been sufficiently assessed. The objective of the study was to test this method. This was a randomized, open-label treatment protocol at an academic medical center. GnRH-deficient men (CHH) with prepubertal testes (<4 mL), no cryptorchidism, and no prior gonadotropin therapy were randomly assigned to either 24 months of pulsatile GnRH therapy alone (inducing endogenous LH and FSH release) or 4 months of rFSH pretreatment followed by 24 months of GnRH therapy. Patients underwent serial testicular biopsies, ultrasound assessments of testicular volume, serum hormone measurements, and seminal fluid analyses. rFSH treatment increased inhibin B levels into the normal range (from 29 ± 9 to 107 ± 41 pg/mL, P < .05) and doubled testicular volume (from 1.1 ± 0.2 to 2.2 ± 0.3 mL, P < .005). Histological analysis showed proliferation of both Sertoli cells (SCs) and spermatogonia, a decreased SC to germ cell ratio (from 0.74 to 0.35), and SC cytoskeletal rearrangements. With pulsatile GnRH, the groups had similar hormonal responses and exhibited significant testicular growth. All men receiving rFSH pretreatment developed sperm in their ejaculate (7 of 7 vs 4 of 6 in the GnRH-only group) and showed trends toward higher maximal sperm counts. rFSH pretreatment followed by GnRH is successful in inducing testicular growth and fertility in men with CHH with prepubertal testes. rFSH not only appears to maximize the SC population but also induces morphologic changes, suggesting broader developmental roles. Show less

Adult patients with idiopathic hypogonadotropic hypogonadism (IHH) typically present with absent puberty and therefore have prepubertal testes. IHH is recognized as one of the few curable causes of male infertility and is often effectively treated with either gonadotropins or pulsatile GnRH therapy. The objective of this study was to determine the structure of the testis prior to initiation of treatment. Eight adult IHH patients with prepubertal testes (<4 ml), with no previous gonadotropin therapy and with no history of cryptorchidism underwent open bilateral testicular biopsy prior to the initiation of hormonal treatment. The testes of all patients showed seminiferous cords separated by interstitium composed of blood vessels, connective tissue cells and collagen fibres but typical adult Leydig cells were absent. The cords contained only Sertoli cells and early type A spermatogonia. The spermatogonia mostly resided in the centre of the cords and were often large, typical of gonocytes. Sertoli cells appeared immature with ovoid nuclei devoid of infoldings and cytoplasm that lacked polarity. Tight junctional complexes commonly found connecting adult Sertoli cells were lacking. These results demonstrate that the immature testes from patients with the severe form of IHH possess early spermatogonia that could possibly reinitiate spermatogenesis with appropriate hormone stimulation. Therefore, the immature testis of this IHH subset resembles those of prepubertal boys and may provide important biologic and genetic insights into testicular development. Show less