Clinical and Genetic Mechanisms in Patients with MC2R Deficiency Presenting with Early Puberty

Esin Karakilic Ozturan; Zehra Yavas Abali; Volkan Karaman; Sukran Poyrazoglu; Zehra Oya Uyguner; Feyza Darendeliler; Firdevs Bas

doi:10.1159/000542307

Clinical and Genetic Mechanisms in Patients with MC2R Deficiency Presenting with Early Puberty

Horm Res Paediatr. 2024 Nov 1:1-8. doi: 10.1159/000542307. Online ahead of print.

Authors

Esin Karakilic Ozturan¹, Zehra Yavas Abali^{1

2}, Volkan Karaman³, Sukran Poyrazoglu¹, Zehra Oya Uyguner², Feyza Darendeliler¹, Firdevs Bas¹

Affiliations

¹ Department of Pediatrics, Pediatric Endocrinology Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
² Department of Pediatric Endocrinology, Marmara University Pendik Research and Training Hospital, Istanbul, Turkey.
³ Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

PMID: 39496238
DOI: 10.1159/000542307

Abstract

Introduction: Melanocortin receptor 2 (MC2R) in the adrenal cortex controls the hypothalamic-pituitary-adrenal axis. The melanocortin system, influenced by leptin, regulates GnRH neurons, crucial for puberty onset and fertility. This study evaluates early puberty in primary adrenal insufficiency (PAI) patients due to MC2R gene alterations.

Methods: Seven patients with PAI (P1-P7) from five unrelated families, all presenting with early or precocious puberty, were included. MC2R deficiency diagnosis ranged from 1 day to 11 months. MKRN3, DLK1, KISS1, and KISS1R genes were analyzed using Sanger sequencing in four cases (P2, P4, P6, and P7). All clinical data were obtained retrospectively.

Results: Puberty onset mean age was 8.6 years (7.4-9.5) in boys (P1, P2, P3, P7) and 8.5 years (7.4-9.5) in girls (P4, P5, P6). Tumor markers were negative; no adrenal rest or tumors were found. GnRH analogs were used for rapid puberty in P2, P3, P6. Final height in P1 and P2 was below target (-2.6 SDS, -0.7 SDS). Menarche occurred at 11 and 11.3 years in P4 and P5. No pathogenic variants were found.

Conclusion: Genetic causes of early puberty were not identified. Elevated ACTH may stimulate kisspeptin neurons, triggering puberty. Close monitoring of these patients for pubertal development is recommended.

Keywords: DLK1; Familial glucocorticoid deficiency type 1; KISS; KISS1R; MKRN3; Melanocortin receptor 2; Puberty.