Supplementary Material for: Phenotypic Variability of Males with Loss-of-function Mutations of MKRN3: A Case Report and Literature Review

Introduction Loss-of-function mutations in MKRN3, a maternally imprinted gene, represent the most common genetic defects associated with familial central precocious puberty (CPP) in both sexes. In recent years, the number of affected females with CPP due to MKRN3 mutations has been greater than affected males, despite the evidence of a dominant inheritance and apparent complete penetrance of this genetic condition.

Case presentation: We described a Brazilian family with several members with CPP due to a recurrent loss-of-function mutation of MKRN3 (p.Ala162Glyfs*15). The index case was a 6-year-old-girl who had thelarche, pubarche, growth acceleration and advanced Tanner staging (B3P3) and bone age (BA, 11 years), confirmed by pubertal basal LH concentrations. This mutation was also identified in her affected sister (menarche at 7 years), paternal aunt (menarche at 9 years), and a paternal cousin who had a history of treatment of CPP. Her apparently asymptomatic father carried the same mutation, but had no memory of his puberty period. The paternal origin of the mutated allele in this father was indicated by the evidence of CPP in his sister, supporting that he had undiagnosed precocious puberty. In fact, he attained borderline adult short stature, suggesting a probable loss of his genetic height potential. In addition, we performed a literature review on male carriers of MKRN3 mutations and compared with data obtained with female cases.

Conclusion: We demonstrated a marked male phenotypic variability associated with MKRN3 mutations and suggested a large proportion of underdiagnosed male cases in previous descriptions. Additionally, incomplete penetrance involving males with paternally inherited MKRN3 mutations cannot be ruled out to date.