• Nikolaos Settas, Catherine Dacou-Voutetakis, Maria Karantza, Christina Kanaka-Gantenbein, George P Chrousos, and Antonis Voutetakis.
• Division of Endocrinology, Metabolism, and Diabetes, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, GR-11527 Athens, Greece.
• J. Clin. Endocrinol. Metab. 2014 Apr 1;99(4):E647-51.

ContextCentral precocious puberty (CPP), defined as the development of secondary sex characteristics prior to age 8 years in girls and 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal axis. Mutations in the imprinted gene MKRN3 have been recently implicated in familial cases of CPP.ObjectiveThe objective of the study was to uncover the genetic cause of CPP in a family with two affected siblings.Design And ParticipantsThe entire coding region of the paternally expressed MKRN3 gene was sequenced in two siblings, a girl with CPP and her brother with early puberty, their parents, and their grandparents.ResultsA novel heterozygous missense variant in the MKRN3 gene (p.C340G) was detected in the two affected siblings, their unaffected father, and the paternal grandmother. As expected, the mutated allele followed an imprinted mode of inheritance within the affected family. In silico analysis predicts the mutation as possibly damaging in all five software packages used. Furthermore, structural alignment of the ab initio native and mutant MKRN3 models predicts that the p.C340G mutation leads to significant structural perturbations in the 3-dimensional structure of the C3HC4 really interesting new gene motif of the protein, further emphasizing the functional implications of the novel MKRN3 alteration.ConclusionsWe report a novel MKRN3 mutation (p.C340G) in a girl with CPP and her brother with early puberty. MKRN3 alterations should be suspected in all cases with familial CPP or early puberty, especially if male patients are also involved or the precocious puberty trend does not follow the usually observed mother-to-daughter inheritance.

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