Pioneering studies on monogenic central precocious puberty.

Ana Pinheiro Machado Canton,Carlos Eduardo Seraphim,Ana Claudia Latronico,Vinicius Nahime Brito

doi:10.20945/2359-3997000000164

Ana Pinheiro Machado Canton, Carlos Eduardo Seraphim + Show 2 more

Open Access

https://doi.org/10.20945/2359-3997000000164

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Journal: Archives of Endocrinology and Metabolism	Publication Date: Aug 14, 2019
Citations: 37	License type: cc-by

Abstract

Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44.

Highlights

Pubertal development results from the re-emergence of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion, which is coordinated by a partially clarified mechanism involving inhibitory, stimulatory, and permissive factors acting upstream of GnRH neurons (1)
Pubertal timing in humans is determined by complex interactions of different influences, such as metabolic, environmental, ethnic, and genetic factors (2)
It is estimated that 60-80% of the variation in pubertal timing is due to genetic factors (1)

Summary

INTRODUCTION

Pubertal development results from the re-emergence of pulsatile hypothalamic gonadotropin-releasing hormone (GnRH) secretion, which is coordinated by a partially clarified mechanism involving inhibitory, stimulatory, and permissive factors acting upstream of GnRH neurons (1). Genetic factors that regulate the HPG axis and modulate pubertal timing have been partially elucidated, primarily enabled by more sensitive and powerful molecular biology tools and epidemiological studies, such as large-scale genome-wide association studies, genomic microarray, whole exome sequencing, and, more recently, whole genome sequencing. This diagnostic advancement is revealing genetic causes of CPP involving novel players that modulates the HPG. Temple syndrome: maternal uniparental disomy, epimutation or paternal deletion at chromosome 14q32.2

Rare cases of distinct copy number variants

Activating mutations in genes KISS1 and KISS1R leading to sporadic CPP

Frameshift

Inactivating mutations in imprinted gene MKRN3 leading to familial CPP

B Promoter region

Findings

Inactivating mutations in imprinted gene DLK1 leading to familial CPP