Pioneering studies on monogenic central precocious puberty

Area of Science:

• Endocrinology
• Genetics
• Reproductive Medicine

Background:

• Pubertal timing is influenced by hormonal, metabolic, environmental, ethnic, and genetic factors.
• Central precocious puberty (CPP) involves premature activation of the hypothalamic-pituitary-gonadal axis before ages 8/9.
• Familial CPP occurs in multiple family members, suggesting genetic underpinnings.

Purpose of the Study:

• To investigate genetic causes of familial CPP.
• To identify novel genes involved in pubertal timing regulation.
• To explore the link between reproductive and metabolic health.

Main Methods:

• Genetic analysis of familial CPP cases.
• Identification and characterization of gene mutations.
• Clinical evaluation of patients with identified mutations.

Main Results:

• Activating mutations in KISS1R and KISS1 were found in the kisspeptin pathway.
• Loss-of-function mutations in imprinted genes MKRN3 and DLK1 are significant causes of familial CPP.
• MKRN3 mutations are the most frequent cause of familial CPP, with indistinguishable clinical features from idiopathic CPP.
• Adults with DLK1 mutations exhibit high rates of overweight/obesity, type 2 diabetes, and hyperlipidemia.

Conclusions:

• Genetic factors play a crucial role in familial CPP.
• MKRN3 and DLK1 mutations represent key genetic causes of familial CPP.
• DLK1 mutations highlight a novel connection between the reproductive axis and metabolic regulation.