MON-224 Congenital Hypogonadotropic Hypogonadism: Features and Genetics of 60 Females Patients

Context Congenital hypogonadotropic hypogonadism (CHH) in females is a rare reproductive disorder about five times less prevalent than in males. Its diagnosis is often difficult to make due to the genetic and phenotypic heterogeneities. Recent progress in DNA sequencing technology has produced a wealth of information regarding the genetic makeup of CHH. However, a genetic mutation is only found in 30% cases and genetic approach concerns mostly male patients. Materials and Methods This retrospective, single-center study included 60 female patients with CHH; they underwent a genetic analysis of 16 genes: (ANOS1, GNRH1, GNRHR, FGFR1, FGF8, TAC3, TACR3, PROK2, PROKR2, CHD7, WDR11, SEMA3A, HS6ST1, KISS1, KISS1R, SOX10) using the next generation sequencing. Each variant was classified known as damaging the protein function or not by the literature. The population was retrospectively divided into four groups based on genetic analysis. Patients with a complete genotype confirming CHH phenotype were named the « CG group »; with a partial genotype, « PG group », women with 2 different gene defects supposing digenic mutations were « DG group » and patients without mutation found were « NM group ». Results 48 variants were identified in 36 patients, 45 of them were known for damaging the protein function with 17 nonsense, frameshift or splice site mutations. The phenotype was fully explained by the genetic anomalies in 20 patients, it seems partial in 8, a digenic cause is supposed in 5 cases and polymorphism in 3 patients. The most frequently mutated gene was GNRHR in 18,75%, followed by FGFR1 and PROKR2 in 16,7%, SEMA3A 12,5%, PROK2 and TAC3 in 6,25%, SOX10, KISS1R, FGF8 and CHD7 in 4% and TAC3, GNRH1 and SOX2 in 2%. The age at the diagnosis was statistically earlier in « CG group », p= 0,018. Additional symptoms such as middle line defects, tooth agenesis and hearing loss were statistically more important in « CG group » (30%) and « PG group » (37,50%) than in « DG group » (0%) and « NM group » (7,41%) p=0,05. 61,7% patients underwent trials stopped their treatment. Reversal was identified in 8% (3 patients) by spontaneous menstrual cycling for at least 1 month. Conclusion Recent findings on the reversibility, phenotypic variability and oligogenicity of CHH have challenged the conventional beliefs and current dogma associated with congenital defect and explain the difficulty to predict genotype-phenotype correlations. CHH patients with a complete genotype seems generally to have a more severe disease with an early age at diagnosis and additional symptoms.