ESPE Abstracts

Background: Melanocortin receptor 2 (MC2R) is expressed in the adrenal cortex and has a major role in the control of the hypothalamic-pituitary-adrenal axis. It is reported that the ACTH receptor MC4R has an impact on premature adrenarche. The melanocortin signaling system is reported to have leptin mediated effect on the regulation of GnRH neuron activity and has an important role in the onset of puberty and fertility.

Objective: To evaluate the early onset puberty of patients with primary adrenal insufficiency (PAI) due to MC2R gene mutation.

Patients and Method: Four patients with PAI from three unrelated families were included in the study. The age of PAI diagnosis was between 1 day-11 months, and all of the patients presented with hypoglycemia, hypoglycemic convulsion, and hyperpigmentation. Clinical diagnosis was also molecularly confirmed in all patients, with homozygous MC2Rvariant c.560delT (P.V187Afs*29). Clinical data regarding anthropometry, puberty, and laboratory were evaluated retrospectively. MKRN3, DLK1, KISS1, and KISS1R were screened by Sanger sequencing.

Results: The mean age at onset of puberty was 8.4 years (range; 7.4-9.5) in boys (Patient(P)1, P2, and P3), and it was 8.5 years (range; 7.4-9.5) in girls (P4, P5, and P6). Tumor markers were negative and there was no evidence of adrenal rest/tumor in testes/ovaries. GnRH analog treatment was administered due to rapidly progressive puberty in P2, P3, and P6. The final heights of P1 and P2 were below the target height with -2.6 SDS and -0.7 SDS respectively. Menarche of P4 and P5 occurred at the age of 11 and 11.3 years respectively. No pathogenic variants were detected by Sanger sequencing.

Conclusion: Molecular studies related to CPP did not explain underlying mechanism. ACTH receptor-MC2R gene mutation, onset, and regulation of puberty may be related. Thus, puberty should be closely followed in patients with MC2R mutation.