Precocious puberty in boys: current insights into etiology, genetic advances, and environmental factors

Central precocious puberty (CPP) in males results from the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, clinically diagnosed by a testicular volume >4 mL before the age of 9 years. Over the past two decades, a clear secular trend toward earlier pubertal onset has been reported. Historically, CPP in boys was strongly associated with intracranial lesions, observed in 40-50% of cases.

Over the last decade, converging evidence has indicated a markedly lower prevalence of brain lesions in males with CPP, approximately 6-8%. Identified risk factors for intracranial lesions include neurological symptoms, pubertal onset before 8 years, and maternal age at menarche above 11 years. These data support a more selective, risk-based approach to neuroimaging and highlight the need to re-define a new consensus, recently published. Idiopathic CPP represents the majority of cases also in males, with increasing evidence supporting a strong genetic basis. Key mutations include gain-of-function variants in KISS1 and KISS1R, as well as loss-of-function mutations in MKRN3 and DLK1. Additional candidate genes-LIN28B, GABRA1, NPYR, TAC3, and TACR3-have been recently linked to pubertal regulation, although their precise mechanistic roles remain unclear. Beyond genetics, environmental exposures, particularly to endocrine-disrupting chemicals (EDCs), have been implicated in modulating pubertal timing.

CPP in boys results from a multifactorial interplay between genetic predisposition and environmental influences. This review summarizes recent evidence regarding the prevalence of brain lesions, emerging genetic discoveries, and the role of endocrine disruptors, to promote a more personalized and precise diagnostic algorithm.