Early childhood height, weight, and BMI development in children with monogenic obesity: a European multicentre, retrospective, observational study.

Summary

In 147 children with genetically confirmed monogenic obesity, biallelic variants produced distinct early BMI trajectories: a steep rise in year one and a plateau thereafter (LEP/LEPR/MC4R), with accelerated linear growth only in biallelic MC4R. A BMI threshold around 24 kg/m2 at age two discriminated biallelic variants from controls.

Key Findings

• From 6 months onward, biallelic LEP/LEPR/MC4R/POMC variants had substantially higher BMI than monoallelic MC4R and control children.
• Biallelic LEP/LEPR/MC4R variants showed a steep first-year BMI rise followed by a plateau to age 5, whereas biallelic POMC did not plateau.
• Accelerated linear growth occurred only in biallelic MC4R starting at age 1 year.
• A BMI cut-off of approximately 24 kg/m2 at age 2 optimized discrimination of biallelic variants from controls.

Clinical Implications

In children with severe early-onset obesity, a BMI ≥24 kg/m2 at age two and specific growth patterns should prompt evaluation for biallelic leptin–melanocortin pathway variants and consideration of precision therapies.

Limitations

• Retrospective design with heterogeneous measurement schedules across centres.
• Potential referral bias toward more severe phenotypes; external validation needed.

Future Directions

Prospective validation of the BMI cut-off in diverse populations, integration with early endocrine biomarkers, and evaluation of impacts on timing and outcomes of genetic testing and targeted therapies.