MON-250 Chromosomal Microarray Analysis in Patients with Central Precocious Puberty Associated with Dysmorphic Features or Congenital Malformations

Abstract

Introduction: Central precocious puberty (CPP), defined as the onset of pubertal signs before the age of 8 in girls and 9 in boys, results from the premature reactivation of the hypothalamic-pituitary-gonadal axis. CPP is familial in as many as 27.5% of the cases, which supports a genetic origin of this disorder. Currently, monogenic defects associated with CPP include inactivating mutations in MKRN3 and rare defects in KISS1, KISS1R and DLK1. In addition, CPP has been associated with complex genetic syndromes resulting from distinct chromosomal abnormalities as Silver-Russel Syndrome and Temple Syndrome. However in many patients its genetic basis remains unknown. Objective: To investigate pathogenic copy number variations (CNVs) in patients with idiopathic CPP associated with dysmorphic features or congenital malformations. Methods: A cohort of 45 patients with idiopathic CPP was initially evaluated for mutations in the coding region of MKRN3. Subsequently, 3 patients screened negative for MKRN3 mutations and with additional dysmorphisms or congenital malformations were selected for chromosome microarray analysis (CMA) using the Affymetrix CytoScan 750k according to manufacturer’s protocols. Results: In patient 1 (P1), a boy presenting CPP at the age of 8 associated with autism spectrum disorder and overweight, a pathogenic previously described heterozygous microdeletion at 16p11.2 (761 kbp), and a microduplication at 18p11.22 (363kbp), a variant of unknown significance (VOUS), were detected. His younger brother, who also has ASD and was recently diagnosed with CPP, also carried the same CNVs. Patient 2 (P2) was a monozygotic twin boy with a past history of hypospadia, an angular deformity of the femur, and pubertal onset at age of 6.5years. His monozygotic twin was equally affected and both developed polycythemia in the beginning of the second decade of life. CMA revealed a heterozygous duplication of 155kbp at 7p15.2, classified as VOUS. The third case (P3), a girl with idiopathic CPP associated with congenital heart disease, exhibited no significant chromosomal rearrangements, except for blocks of homozygosity due to parental consanguinity. Conclusion: Our results underscore the relevance of CMA in the investigation of patients with CPP associated with syndromic features. Parental consanguinity can also be identified by CMA and is associated with an increased risk of congenital anomalies, as was the case of P3. The 16p11.2 microdeletion has been previously associated with ASD, however CPP has not been previously reported in these patients. Further studies are needed to address possible associations between CPP and the CNVs and/or genes presented inside these variant regions identified in P1 and P2. Source of research support: CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico; FAPDF - Fundação de Apoio a Pesquisa do Distrito Federal.