ESPE Abstracts

Introduction: Precocious development of secondary sexual characteristics in both sexes indicates early reactivation of the hypothalamic-pituitary-gonadal axis, known as central precocious puberty (CPP). CPP should be considered in males under nine years old when testicular volume exceeds 4 milliliters. This condition is rare (1 male per 15 girls), and secondary causes must be promptly excluded due to the higher likelihood of intracranial pathology. Recent studies highlight the genetic causes of CPP, but to our knowledge, none focus solely on males.

Aim: To clarify the genetic background of a cohort of CPP Portuguese male patients with normal brain magnetic resonance imaging (MRI).

Methods: From a nationwide Portuguese cohort of 596 patients, we excluded 101 patients with secondary causes of CPP and 232 patients with no MRI records. In the remaining 263 idiopathic CPP patients, 24 (9.1%) were boys, but only 14 participated in the study. Clinical records were reviewed. Blood samples were collected and analyzed for MKRN3 gene or using Whole Exome Sequencing (WES): next-generation sequencing (Illumina) of genomic DNA, upon capture of target regions of whole exome using oligonucleotide probes. Variant classification and description were performed according to international recommendations.

Results: Testicular enlargement was reported at the median age of 8 years old (minimum 6 months old). At the first endocrine evaluation, the median testicular volume was 6mL and all had basal LH levels above 0.4 UI/L (mean 1.5UI/L) with elevated total testosterone (mean 9.4 ng/mL). None of the patients had dysmorphic features and two patients had a familiar history of precocious puberty. A boy had X-linked ichthyosis, but no link was found with CPP. All patients were treated with triptorelin (monthly or 3-month depot), with good clinical response and no adverse effects. A genetic cause for CPP was found in 3 patients. Two patients had familiar history, and both were heterozygotic for an MKRN3 gene mutation: c.482dup p.(Ala162Glyfs*15) and c.799G>A p(Asp267Asn), the latter one not yet described. In the other patient, a heterozygotic TP53 gene mutation was found: c.1010G>A p.(Arg337His), associated with a de novo variant of Li-Fraumeni Syndrome.

Conclusion: Despite the limited number of male CPP patients, genetic analysis identified a genetic cause in 21% of cases previously classified as idiopathic CPP. Integrating genetic testing into the clinical management of idiopathic CPP holds significant promise for improving diagnosis, treatment, and overall patient outcomes. It represents a step toward more personalized and precise medicine.