Genetic central precocious puberty

Genetic central precocious puberty (CPP) is a condition in which the hypothalamic-pituitary-gonadal (HPG) axis is activated prematurely due to underlying genetic causes, leading to the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Unlike idiopathic or acquired forms of central precocious puberty, genetic CPP is caused by pathogenic variants in specific genes that regulate the timing of puberty onset. Known causative genes include MKRN3 (makorin ring finger protein 3), DLK1 (delta-like 1 homolog), and activating mutations in KISS1 and KISS1R (kisspeptin and its receptor). Loss-of-function mutations in MKRN3, an imprinted gene on chromosome 15, represent the most common known monogenic cause of familial central precocious puberty. Clinical features include early breast development (thelarche) in girls, testicular enlargement in boys, accelerated linear growth, advanced bone age, early pubic and axillary hair development, and potential psychosocial difficulties related to early maturation. If untreated, premature activation of the HPG axis can lead to early epiphyseal fusion and compromised adult height. The condition may also be associated with emotional and behavioral challenges due to the mismatch between physical and cognitive maturity. Treatment for genetic central precocious puberty follows the same approach as other forms of CPP and primarily involves gonadotropin-releasing hormone (GnRH) agonist therapy, which suppresses the HPG axis and halts pubertal progression. This treatment can preserve adult height potential and alleviate psychosocial concerns. Genetic testing is increasingly important for identifying the underlying cause, enabling appropriate genetic counseling for affected families, and distinguishing genetic CPP from other etiologies. Long-term outcomes with treatment are generally favorable.

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