MON-251 Clinical Features of a Large Cohort of Patients with Familial Central Precocious Puberty Caused by Loss-of-Function Mutations in MKRN3

Context: Loss-of-function mutations in Makorin RING-finger 3 (MKRN3), a maternal imprinted gene located on the long arm of chromosome 15, are the most prevalent cause of familial central precocious puberty (CPP). Objectives: To describe the clinical and hormonal features of 70 patients with CPP due to MKRN3 mutations and to establish the phenotype-genotype correlation. Setting and Participants: We studied 70 individuals from 31 families originating from different ethnic backgrounds. DNA sequencing analysis of MKRN3 coding region by Sanger method was performed and loss-of-function MKRN3 mutations were identified in all of them. Results: The genetic analysis of MKRN3 revealed 15 different mutations in 70 affected patients with CPP (27 boys; 43 girls) who were studied in two university centers from 2013 to 2018. We identified frameshift (61%), missense (26%) and nonsense mutations (13%). Frameshift mutations affecting codon 162 were the most frequent. Female patients developed thelarche at a mean age of 5.9 ± 1.2 years, adrenarche at 6.4 ± 0.9 years, had bone age advance of 2.3 ± 1.6 years, a height standard deviation score (SDS) of 1.6 ± 1.2, and a BMI-SDS in the overweight range (1.05 ± 0.7) in the initial diagnosis. Eight patients (11%) developed thelarche and adrenarche simultaneously. Male patients developed pubertal signs at a median age of 8.0 years (range 5.9-8.5 years) and had a bone age advance of 1.7 years (0-2.7). Girls who harbored frameshift mutations were more likely to have simultaneous thelarche and adrenarche and had a more advanced bone age (2.7 ± 1.6 vs 1.3 ± 1.1 years, p = 0.003), but were otherwise unremarkable. Notably, 74% of the male patients were diagnosed in adulthood, during familial segregation analysis, suggesting that male CPP was under-diagnosed. Basal laboratory evaluation showed LH levels of 1.8 ± 1.5 IU/L and FSH levels of 4.4 ± 2.4 IU/L (n=37). GnRH stimulation tests resulted in a LH peak of 25 ± 24 IU/L and a FSH peak of 13.2 ± 9.5 IU/L. Nineteen patients were treated with depot GnRH analogue for 3.3 ± 0.8 years, achieving a final height of -0.6 ± 1.1 SDS, within their target height of -1.1 ± 1.0 SDS. Among the 7 untreated adult patients, height SDS was -1.8 ± 1.1, noticeably lower than that of treated patients, although not statistically significant (p=0.06). Conclusions: Deleterious MKRN3 mutations represent a frequent genetic cause of non-syndromic familial CPP in both sexes. Clinical and hormonal features of CPP caused by these mutations are indistinguishable from idiopathic CPP.