ESPE Abstracts (2018) 89 P-P1-246

Clinical Phenotypes and Mutation Spectrum of Patients with Isolated Gonadotropin-Releasing Hormone Deficiency in a Single Academic Center

Han-Wook Yooa, Go Hun Seoa, Arum Oha, Gu-Hwan Kimb & Jin-Ho Choia

aDepartment of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; bMedical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

Background: Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is caused by a deficiency in GnRH production, secretion or action. IGD is a highly heterogeneous disorder with wide phenotypic spectrum including Kallmann syndrome (KS) with anosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). More than 30 different causative genes have been identified in several studies. However, there are no data on the prevalence, clinical characteristics, and molecular spectrum in Korea. Therefore, this study was performed to investigate the phenotypic and genotypic spectrum in patients with IGD in Korea.

Methods: This study included 41 patients from 40 families diagnosed between January 1995 and December 2017. Clinical and endocrine characteristics were retrospectively analyzed including cryptorchidism, micropenis, anosmia, associated anomalies, family history, and laboratory findings. Mutation analysis was performed using targeted gene panel for known 69 IGD genes (n=33) or whole exome sequencing (n=8).

Results: KS was predominant in men (M:F=24:0) compared to patients with nIHH (M:F=10:7). The mean age at presentation was 14.5±5.0 years (range, 4.7–21.3 years) in KS including two prepubertal males with isolated anosmia and 17.5±2.2 years (range, 13.7–22.5 years) in nIHH (P=0.015). Two pre-pubertal males presented with anosmia and aplasia of the olfactory bulbs at 8.1 and 5.8 years, respectively. The other patients presented with delayed puberty or primary amenorrhea. Non-reproductive features were found in 9 patients with KS [hearing defect (n=4), renal anomaly (n=1), cleft lip/palate (n=1), heart defects (n=3)] and 5 patients with nIHH [hearing defect (n=2), renal anomaly (n=1), syndactyly (n=2)]. Among 40 families, rare sequence variants were identified 8 probands with KS and 7 probands with nIHH, respectively. FGFR1 (5/40, 12.5%) was the most common, followed by CHD7 (3/40, 7.5%), ANOS1 (2/40, 5%), TACR3 (1/40, 2.5%), GNRHR (1/40), SOX3 (1/40), and PROKR2 (1/40).

Conclusions: KS was predominant in males, and they presented earlier than those with nIHH. The prevalence of non-reproductive features were not different between patients with KS and nIHH. Two prepubertal males with anosmia should be followed up to initiate timely hormonal replacement therapy. Overall, genetic diagnosis was possible in 37.5% of probands with IGD with 13 pathogenic or likely pathogenic variants and two variants of uncertain significance.

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