ESPE Abstracts (2018) 89 RFC9.1

Clinical and Genetic Features of Central Precocious Puberty Associated with Complex Phenotypes

Ana Cantona, Vinicius Britoa, Luciana Montenegroa, Carolina Ramosa, Delanie Macedoa, Danielle Bessaa, Marina Cunhaa, Alexander Jorgea,b, Berenice Mendoncaa & Ana Claudia Latronicoa

aUnidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clinicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil; bUnidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil

Background: Idiopathic central precocious puberty (CPP) is mostly described as an isolated entity. A few studies have shown its association with clinical syndromes and rare cases of chromosomal abnormalities.

Objective: To clinically characterize patients with CPP, pointing out prevalent associated conditions and phenotypes.

Patients and Methods: One hundred and forty-five patients with idiopathic CPP were retrospectively evaluated. All patients had clinical follow up at the outpatient Endocrinology Division from the Sao Paulo University hospital. Patients were assessed by at least three experienced pediatric endocrinologists. A comprehensive phenotypic characterization was performed, including metabolic and hormonal studies. All patients had normal brain magnetic resonance imaging and were excluded for pathogenic variants in CPP-genes (KISS1, KISS1R, MKRN3 and DLK1). Whole-exome sequencing and/or genomic microarrays were performed in a subset of the cases.

Results: Twenty-six patients (17%) (23 girls, 3 boys; 17 sporadic, 9 familial) were identified as presenting with CPP and at least two additional features and/or conditions, characterizing complex phenotypes. In this group of patients with complex phenotypes, mean age at puberty onset was 6.3 year (±1.9) for girls and 7.9 year (±0.1) for boys. At first visit, mean chronological age was 8.3 year (±2.6), mean height SDS was 0.4 (±1.1), mean target height was −0.7 (±0.9), mean BMI SDS 1.2 (±1.1), and mean bone age advancement was 1.8 year (±1.4). All patients had pubertal baseline LH level, pubertal GnRH-stimulated LH level, or both. There was a wide phenotypic spectrum. The most prevalent clinical features described were as follows: overweight or obesity at first visit (n=15), born small for gestational age (n=10), learning difficulties/intellectual disability/autistic spectrum (n=7), short stature (n=7), motor and/or speech delay (n=6), high palate (n=6), acanthosis nigricans (n=5), and hyperinsulinemia (n=5). Less prevalent manifestations were non-specific dysmorphic facial features, impaired fasting glucose/early onset type 2 diabetes and congenital anomalies. Two patients were previously molecularly diagnosed with rare syndromes with a high CPP prevalence: a boy with a maternal uniparental disomy of chromosome 14 (Temple syndrome) and a girl with a 7q11.23 microdeletion syndrome (Williams syndrome). Moreover, three girls with disproportional stature were diagnosed with deletions in SHOX gene region.

Conclusion: CPP might be associated with additional clinical features and conditions, characterizing complex phenotypes with distinct genetic abnormalities.