ESPE Abstracts (2014) 82 FC5.2

Mutations in the Maternally Imprinted Gene MKRN3 are a Frequent Cause of Familial Central Precocious Puberty

Nancy Mekhaila, Ibrahima Bab,g, Dominique Simona,b, Anne Paulsena,b, Delphine Zenatya,b, Muriel Houangc, Monique Jesuran-Perelroizand, Gianpaolo de Filippoe, Maria Carolina Salernof, Jean-Claude Carela,b, Juliane Légera,b & Nicolas de Rouxb,g

aService d’Endocrinologie et Diabétologie Pédiatrique, Hopital Robert Debré, Paris, France; bINSERM U1141, Paris Diderot University, Paris, France; cService d’Endocrinologie Clinique, Hopital Trousseau, Paris, France; dEndocrinologie Pédiatrique, Toulouse, France; eService d’Endocrinologie Pédiatrique, Hopital Bicetre, Kremlin-Bicetre, France; fService d’Endocrinologie Pédiatrique, CHU Frederico II, Naples, Italy; gLaboratoire de Biochimie–Hormonologie, Hopital Robert Debré, Paris, France

Background: Recently, mutations in the maternally imprinted MKRN3 gene have been associated to familial idiopathic central precocious puberty (iPPC). The clinical phenotype and the frequency of these mutations are poorly described.

Objective and hypotheses: Delineate the frequency of MKRN3 mutations in iPPC and perform a genotype–phenotype correlation in MKRN3 mutated patients.

Method: 59 index cases with iPPC have been included in the study. The criteria to include patients were: passage to Tanner stage 2 before 8 years in girls and 9 years in boys, with or without pubarche in both sexes, advanced bone age with an accelerated growth spurt, increased basal and peak LH after GnRH test and a normal brain MRI. MKRNB3 has been sequenced by the Sanger method from DNA extracted from blood lymphocytes.

Results: 38 cases were familial and 21 cases were sporadic. four faux-sens mutations, one nucleotide insertion or two nucleotides deletion leading to a frame shift of the coding sequence were found in 11 familial cases. Faux-sens mutations were novel and they were considered as loss of function mutation by in-silico analysis. No mutation was found in sporadic cases or in cases with mother–daughter transmission. The familial analysis has confirmed the transmission of the mutated allele by the father. The analysis of the phenotype in mutated patients, revealed a pubertal onset between 3.5 and 7.5 years and an explosive LH and FSH response to GnRH stimulation. The evolution of the puberty and the response to GnRH treatment were similar in mutated and non mutated patients.

Conclusion: MKRN3 must be sequenced in familial iPPC with a possible transmission of the mutated allele by the father. All MKRN3 mutations are loss of function mutations. The phenotype indicates a possible pituitary defect in addition to the hypothalamic defect initially suspected.