ESPE Abstracts (2018) 89 P-P2-308

A Novel Inactivating Compound Heterozygous Mutation in KISS1R/GPR54: Cases of Three Siblings

Ozlem Nalbantoglu, Gulcin Arslan, Ozge Koprulu, Fılız Hazan, Semra Gursoy & Behzat Ozkan


Dr Behcet Uz Children, Izmir, Turkey


Introduction: Kisspeptin is a neuropeptide, encoded by the KISS1 gene, which acts upstream of gonadotropin-releasing hormone (GnRH) neurons and also has a critical role for maturation and function of the reproductive axis. Inactivating mutations of its receptor (KISS1R) cause normosmic isolated hypogonadotropic hypogonadism (IHH). In this report, we aim to present three siblings who have IHH due to novel compound heterozygous KISS1R mutation.

Case report: Index case applied to our outpatient clinic with delayed puberty when he was 14 years old. On newborn period, he had bilateral cryptorchidism and micropenis and bilateral orchiopexy was done. His parents were nonconsanguineous. On physical examination, his height was 165.3 cm (0.14 SDS), weight was 62 kg (0.94 SDS). Pubertal stage was Tanner stage 1, stretched penis size was 4 cm, bilateral testises were in skrotum and testis sizes were 3 ml. On laboratory; FSH: 0.9 mIU/ml, LH: 0.13 mIU/ml, total testosterone: 15 ng/dl, ACTH: 34 pg/ml, cortisole: 15 μg/dl, 17OH progesterone: 0.11 ng/ml, AMH: 51.2 ng/ml (normal range 2–30.7). Karyotype analysis revealed 46 XY. The results of GnRH test confirmed IHH. In molecular analysis of index case, c.969C>A (p.Y323X) and novel c.170T>C (p.L57P) compound heterozygous mutations were obtained in KISS1R gene. In molecular analysis of family, while mother had novel p.L57P mutation, father had p.Y323X heterozygous mutation which was known as an inactivating mutation caused IHH. The rest three siblings who were 5, 12 and 14 years old were evaluated. All of the three sisters had normal female genitalia and their karyotypes were 46 XX. Also the same mutation was obtained in two siblings who were 12 and 14 years old.

Conclusion: Recent studies demonstrated inactivating mutations in KISS1R gene cause normosmic isolated hypogonadotropic hypogonadism (IHH) in animal models and human. We identified a novel inactivating compound heterozygous mutation in KISS1R gene in three members of a Turkish nonconsanguineous family. We recommend that if IHH is obtained in a member of a family, we might investigate the whole family members although the family is nonconsanguineous.

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