Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Eur J Endocrinol. 2020 Oct;183(4):R107-R117. doi: 10.1530/EJE-20-0103.
Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader-Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.
青春期启动受遗传、环境、营养和表观遗传因素的复杂相互作用调节。用于确定正常青春期启动的标准，即特发性性早熟的定义，是基于发表的人群研究而不断演变的。家族性青春期启动和双胞胎研究支持遗传因素对青春期启动的重要影响。与许多与促性腺激素低下性性腺功能减退症相关的单基因病因相反，仅有四个关于中枢性性早熟（CPP）的单基因病因被描述。MKRN3（一种位于 15 号染色体上的 Prader-Willi 综合征基因座中的母源印迹基因）的功能丧失性突变是 CPP 最常见的已识别遗传原因。最近，在第二个母源印迹基因 Delta-like noncanonical Notch ligand 1 (DLK1) 中也发现了几个突变与 CPP 相关。这两个基因的多态性也与全基因组关联研究中的初潮年龄相关。编码 kisspeptin（KISS1）及其受体（KISS1R）的基因中的突变也与 CPP 相关，但仍然是罕见的单基因病因。CPP 对儿童的短期和长期健康都有影响，这突出表明了理解导致性早熟的机制的重要性。此外，鉴于印迹基因 MKRN3 和 DLK1 中的突变在青春期启动中的作用，应考虑其他印迹候选基因在青春期启动中的作用。
