Background: Loss-of-function mutations in the imprinted gene MKRN3 represent the most common known genetic defects associated with central precocious puberty (CPP). The penetrance of these mutations remains to be established. To date, all reported individuals with MKRN3 mutations were already in puberty or postpubertal and were identified retrospectively.
Objective and hypotheses: To report the first case of a prepubertal child with an MKRN3 mutation who was followed prospectively and developed CPP.
Method: We describe the complete clinical and laboratory features of a female patient carrying an MKRN3 mutation, detected in childhood, followed until the development of pubertal signs.
Results: The patient was screened at the age of 4 years because of positive family history her sister developed CPP at the age of 6 years and was found to harbor the MKRN3 p.Pro161Argfs*16 mutation, inherited from their asymptomatic father. During close follow-up, this young girl initially developed increased growth velocity at age 6 years (9 cm/year), followed by a slightly increased basal LH level (0.4 mIU/ml) and, ultimately, clinical thelarche, with rapid progression (Tanner stage 1 to 3) between the ages of 6.3 and 6.7 years, when the LH level became clearly pubertal (0.9 mIU/ml). In the context of a loss-of-function MKRN3 mutation and a positive family history, these features established the diagnosis of CPP and supported the initiation of treatment with GnRH analog, with complete regression of the thelarche after 6 months of therapy. The absence of significant bone age advancement, of pubic or axillary hair, or of behavioral or social problems at the diagnosis could be ascribed to the early diagnosis.
Conclusion: The identification of carriers of MKRN3 mutations may contribute to early diagnosis of CPP, facilitating treatment decisions and guiding genetic counseling and prompt intervention in familial cases. This case deepens the available information on the penetrance and clinical characteristics of MKRN3 mutations, and illustrates how genetic testing can be useful in the clinical setting.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology