ESPE Abstracts

Introduction: We report a series of three siblings, two girls and one boy, diagnosed with Central Precocious Puberty (CPP) respectively at the age of 5.66, 6.67 and 8.5 years, carrying a mutation in the gene encoding the makorin RING finger protein 3 (MKRN3), usually responsible for the development of familial CPP.

Methods: We diagnosed CPP in all the patients by performing a GnRH test. We also dosed basal levels of LH, FSH, 17-beta-estradiol (E2) and testosterone. To further support the diagnosis, we assessed the bone age with X-ray of the left hand. Moreover, we performed pelvic ultrasounds and brain MRIs in the female patients. Given the recurrence of CPP in 3 out of 3 siblings, we decided to perform, on patients and parents as well, a Next Generation Sequencing (NGS) panel studying the most frequently implied genes in the occurrence of CPP (KISS1, KISS1R and MKRN3).

Results: When referred to our centre, all three patients showed clinical signs of precocious puberty. GnRH test showed elevated GnRH-stimulated LH levels confirming the initial hypothesis of CPP. Basal levels of LH and FSH were not consistent with a pre-pubertal status. One of the two girls showed elevated E2 levels (16.1 pg/mL). Both the girls and the boy had advanced bone age (approximately one year more than the chronological age). Pelvic ultrasounds showed signs of pubertal activation (longitudinal uterine diameter was 37 mm for both girls). Brain MRIs for the study of the pituitary gland, performed on the two girls, did not show secondary causes of pubertal activation. This last exam was deemed unnecessary for the boy, considering the highly probable genetic aetiology. NGS panel revealed, in all three patients, a paternally inherited variant of MKRN3 gene (c.475_476insC; p.Ala162GlyfsTer15), which leads to the introduction of a premature stop codon, as already reported by previous literature. MKRN3 is a maternally imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). Therefore, even if the transmission is described as autosomal dominant, the father may be not affected as in our case.

Conclusions: MKRN3 mutations are the most frequent genetic cause of CPP, in particular in the familial settings. Thus, when there is a familial history of CPP – two affected siblings or a father and at least one child – genetic studies could precede the brain MRI. Furthermore, the maternally imprinted mode of inheritance of MKRN3 gene makes the diagnosis remarkably challenging.