ESPE Abstracts

Background: The etiological investigation of central precocious puberty (CPP) has improved with more precise clinical approach, neuroimaging, and genetic studies. CPP can be caused by congenital or acquired conditions, with or without central nervous system (CNS) lesions. More recently, genetic and epigenetic disorders have been identified in children with CPP, previously classified as idiopathic.

Objective: To update the etiological diagnosis of a large cohort of children with CPP.

Methods: We evaluated retrospectively the distinct etiologies of 292 patients (264 girls) followed in a single university hospital from 2000 to 2022. Among them, 182 patients with CPP without CNS lesions were investigated with genetic/epigenetic studies. We performed Sanger DNA sequencing (n=155), target panel sequencing (n=64), exome sequencing (n=64), genome sequencing (n=5), specific DNA methylation analysis (n=111), and genomic microarray (n=30).

Results: Pathological CNS lesions were identified in 51of 292 (17.5%) patients with CPP (17 boys and 34 girls), indicating a prevalence of CNS lesions of 60.7% in boys and 12.9% in girls. These pathological CNS lesions were classified as congenital (n=34) or acquired (n=17). The most common congenital causes were hypothalamic hamartoma (n=20, 11 girls), myelomeningocele (n=4), and neurofibromatosis type 1 (n=2), while the most common acquired causes were hydrocephalus (n=8) and cerebral palsy (n=3). The remaining 241 (82.5%) CPP patients presented without CNS lesions, being classified as apparently idiopathic. In the subset of patients submitted to genetic/epigenetic investigation (n=182; 173 girls, 9 boys), the overall frequency of genetic/epigenetic causes was 12.1% (20 girls, 2 boys); and it was higher in boys (22.2%) than in girls (11.5%). The genetic/epigenetic defects were MKRN3 inactivating mutations (n=8, from 7 families), DLK1 inactivating mutations (n=6, from 2 families), KISS1R activating mutation (n=1), KISS1 activating mutation (n=1), MECP2 mutations (n=2), DDX3X mutation (n=1), and Temple syndrome (n=3). Univariate logistic regression analysis identified positive family history (OR 3.43; 95%CI 1.35-8.69; P=0.009) and associated neurodevelopmental abnormalities (OR 3.53; 95%CI 0.99-12.48; P=0.05) as possible clinical predictors of congenital CPP in patients without CNS lesions.

Conclusion: The prevalence of pathological CNS lesions was 17.5%, confirming previous data. Genetic or epigenetic defects were identified in 12.1% of patients with CPP without CNS lesions, and family history and neurodevelopmental abnormalities were predictors of these congenital causes. Our findings evidenced the growing role of congenital causes among children with CPP without CNS lesions.