Objective:

To outline the longitudinal endocrine and metabolic characteristics and therapeutic response of two siblings with a pathogenic MC4R mutation experiencing rapidly advancing puberty, highlighting the mutation's significance.

Key Findings:

• Both siblings exhibited severe early-onset obesity and rapidly advancing puberty, indicating a critical need for intervention.
• The proband showed premature thelarche and a significant luteinizing hormone response to GnRH stimulation, underscoring the mutation's impact.
• GnRH agonist therapy effectively stabilized pubertal development in both siblings, demonstrating its therapeutic potential.
• Metabolic assessments revealed impaired glucose tolerance and insulin resistance, which improved with lifestyle modifications and metformin, highlighting the importance of comprehensive management.

Interpretation:

The findings highlight the need for early identification and management of rapidly advancing puberty in children with MC4R mutations, as well as the importance of monitoring for cardiometabolic complications, which may have long-term implications for clinical practice.

Limitations:

• The study is based on a small sample size of two siblings, limiting generalizability and diversity in findings.
• Long-term outcomes beyond the follow-up period are not assessed, which may affect the understanding of the mutation's impact.

Conclusion:

This case report emphasizes the clinical priorities in managing severe pediatric obesity and associated rapid puberty, advocating for tailored interventions and ongoing surveillance for metabolic issues in a broader context.