OR15-04 Central Precocious Puberty without Central Nervous System Lesions: Is It Really Idiopathic?

Background: The etiological diagnosis of central precocious puberty (CPP) has been classically divided into causes with or without central nervous system (CNS) lesions. Among the cases without CNS lesions, most of them are classified as idiopathic. In clinical practice, about 90% of girls and 40% of boys with CPP are considered having the idiopathic form. In the last two decades, pioneering studies have revealed underlying genetic causes in patients with apparently idiopathic CPP. Objective: To describe the frequency of genetic causes identified in a large cohort of patients with CPP followed in a single research center and to evaluate its role in the distribution of the etiology of CPP. Patients and methods: A retrospective evaluation was performed analyzing the etiological diagnosis of 276 patients (246 girls, 30 boys) with CPP followed in a single university hospital outpatient clinic from 2006 to 2019. The great majority (230 patients) presented without CNS lesions, being classified as idiopathic CPP group. Among the idiopathic CPP group, 170 of them had DNA samples available and were included for genetic analysis. Patients included for genetic analysis were systematically investigated for genetic causes of CPP using standard methodologies of genetic-molecular analysis. Briefly, they were studied as follows: 120 by Sanger sequencing; 18 by target panel sequencing; 27 by whole-exome sequencing; 5 by whole-genome sequencing; 113 by specific DNA methylation analysis; and 38 by genomic microarray. Results: Among the 276 patients with CPP, 46 (16.7%) had pathological CNS lesions: 19 boys and 27 girls, indicating the prevalence of CPP with CNS lesions (organic) of 63.3% in boys and 11% in girls. The most common cause of organic CPP was hypothalamic hamartoma (20 cases). Meanwhile 230 patients (83.3%) encompassed the apparently idiopathic CPP group. Main characteristics of this idiopathic CPP group were: 219 girls and 11 boys; 158 sporadic (69%), 68 familial (29.5%) and 4 adopted (1.5%). In the subset of patients with DNA available (162 girls, 8 boys), the frequency of genetic causes was 11.8% (20 cases: 18 girls and 2 boys). Analyzing by sex, the frequency of genetic causes was higher in boys (25%) than in girls (11.1%). The identified genetic defects were the following: 9 cases with inactivating MKRN3 mutations (8 families), 6 cases with inactivating DLK1 mutations (2 families), 1 case with activating KISS1R mutation, 1 case with activating KISS1 mutation, 2 sporadic cases with maternal uniparental disomy of chromosome 14, and 1 sporadic case with epimutation at DLK1 locus. Conclusion: Pathogenic genetic defects were identified in 11.8% of patients with apparently idiopathic CPP involving four distinct genes. Altogether, these genetic findings indicate a context of changing in the distribution of the etiological diagnosis of CPP in both sexes, highlighting the genetic causes.