Endocrine Abstracts

Congenital hypogonadotropic hypogonadism (CHH) is a rare condition characterized by impairment of pubertal development, that can be associated with hypo/anosmia (Kallmann Syndrome, KS) or normosmia (nCHH). A genetic basis can be identified in nearly 50% of cases, with increasingly common detection of oligogenicity. CHH has a strong male predominance (MtoF ratio 5–3:1), although sex ratio for CHH in families with autosomal inheritance has been proven to be close to equal. The rationale for this epidemiologic difference is not clearly understood. Our study aims to evaluate gender differences in clinical and genetic diagnosis of CHH. 313 CHH patients with absent pubertal development, consecutively referred to our Center from 01/2016, were enrolled in this study. Data collection included clinical assessment at diagnosis and genetic analysis performed by next generation sequencing (NGS), employing a panel of 27 candidate genes (ANOS1, FGFR1, PROK2, PROK-R2, KISS1, KISS1R, GnRH, GnRHR, FGF8, TACR3, TAC3, HS6ST1, CHD7, DUSP6, FEZF1, FGF17, FLTR3, IL17RD, SEMA3A, SEMA3E, SEMA7A, SOX2, SOX10, SPRY4, WDR11, HESX1, NELF). Among 313 patients 87 were female (F) and 226 male (M) (FtoM ratio 1:2.6). 43.8% had a diagnosis of KS and 56.2% of nCHH (no significant gender difference). Rare genetic variants were found in 54.3% of patients (F 55.2% vs. M 54%). Monoallelic rare variants were found in 37.1% (F 33.3% vs. M 38.5%), biallelic monogenic rare variants in 4.2% (F 5.7 vs M 3.5%) and oligogenicity in 13.1% (16.1% vs. 11.9%), with no significant difference between sex, even after exclusion of X-linked ANOS1. Prevalence of rare variants in each candidate gene resulted in line with literature, showing no significant gender differences, except for IL17RD (F 5, 7% vs. M 1, 3%, P 0.040). Age at diagnosis was 17.2 ± 2.9 for F and 16.8 ± 3.5 for M (P 0.065). Presence of clinical “red flags” (family history, hypo/anosmia, micropenis, cryptorchidism, midline defects, bimanual synkinesis, renal abnormality, deafness) was significant higher in male (F 64.4% vs. M 79.2%, P 0.008), but not related to age at diagnosis or presence of rare variants. Nevertheless, these rates become similar after excluding micropenis and cryptorchidism, as only male manifestations. Our data confirm the male predominance in CHH but they do not allow to identify substantial differences in genetic or clinical presentation between gender, suggesting that gender gap in CHH prevalence do not depend upon variability of the underlying pathogenic mechanisms, but rather to gender specific characteristics of GnRH function or differences in diagnostic capability.