Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
J Clin Endocrinol Metab. 2018 Apr 1;103(4):1273-1276. doi: 10.1210/jc.2017-02636.
Hypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism, but it is unknown whether biallelic variants can also be associated with related reproductive disorders.
A missense homozygous variant (c.890G>T p.R297L) in KISS1R was identified in a child who presented with microphallus and bilateral cryptorchidism. This variant has been reported to reduce, but not abolish, postreceptor signaling in vitro. Biochemical evaluation during the neonatal period revealed low testosterone levels. By 11 years and 8 months, the boy began demonstrating increases in testicular volume. By 17 years and 3 months, his testicular volume was 20 mL; his penile length was 7.3 cm; and he had adult levels of circulating gonadotropins and testosterone.
This case report associates biallelic loss-of-function mutations in KISS1R with normal timing of adolescent puberty. Because these coding sequence variants occurred in a patient with microphallus and cryptorchidism, they demonstrate different levels of dependence of the hypothalamic-pituitary-gonadal cascade on kisspeptin signaling at distinct times in the reproductive life span. The suppression of the hypothalamic-pituitary-gonadal cascade during early life but not adolescence suggests that the mini puberty of infancy depends more on kisspeptin-induced, gonadotropin-releasing hormone-induced luteinizing hormone secretion than does adolescent puberty.
下丘脑 kisspeptin 信号在启动和维持生殖功能方面起着关键作用。编码序列中双等位基因突变 KISS1R（GPR54）已在特发性低促性腺激素性性腺功能减退症患者中被发现，但尚不清楚双等位基因变异是否也与相关生殖障碍有关。
一名患有小阴茎和双侧隐睾症的儿童被发现存在 KISS1R 的纯合错义变异（c.890G>T p.R297L）。该变异已被报道可降低，但不会完全阻断体外受体后信号。新生儿期的生化评估显示睾酮水平较低。11 岁 8 个月时，男孩开始表现出睾丸体积增加。到 17 岁 3 个月时，他的睾丸体积为 20ml；阴茎长度为 7.3 厘米；并且循环促性腺激素和睾酮水平达到成人水平。
本病例报告将 KISS1R 的双等位基因失活突变与青春期正常时间联系起来。由于这些编码序列变异发生在小阴茎和隐睾症患者中，因此它们在生殖寿命的不同时间点展示了下丘脑-垂体-性腺轴对 kisspeptin 信号的不同程度的依赖性。在生命早期而非青春期抑制下丘脑-垂体-性腺轴提示婴儿期的假性青春启动更依赖于 kisspeptin 诱导的促性腺激素释放激素诱导的黄体生成素分泌，而不是青春期。
