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

Zorn S; CJ de Groot; Brandt-Heunemann S; J von Schnurbein; Abawi O; Bounds R; Ruck L; Guijo B; Martos-Moreno GA; Nicaise C; Courbage S; Klehr-artinelli M; Siebert R; Dubern B; Poitou C; Clement K; Argente J; Kuhnen P; Farooqi IS; Wabitsch M; van den Akker E

doi:10.1530/ey.22.13.1

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 13.1 | DOI: 10.1530/ey.22.13.1

ESPEYB25 13. Global Health for the Paediatric Endocrinologist Endocrinology (7 abstracts)

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

Zorn S , de Groot CJ , Brandt-Heunemann S , von Schnurbein J , Abawi O , Bounds R , Ruck L , Guijo B , Martos-Moreno GÁ , Nicaise C , Courbage S , Klehr-Martinelli M , Siebert R , Dubern B , Poitou C , Clément K , Argente J , Kühnen P , Farooqi IS , Wabitsch M & van den Akker E

Lancet Child Adolesc Health. 2025 May;9(5):297-305. PMID: 40246357 doi: 10.1016/S2352-4642(25)00065-3.Erratum in: Lancet Child Adolesc Health. 2025;9(6):e14. doi: 10.1016/S2352-4642(25)00128-2.

Brief Summary: This European multi-center study analyzed early childhood growth trajectories in 147 children with genetically confirmed monogenic obesity. Distinct genotype-specific patterns of BMI development were identified. The authors propose a BMI cutoff ≥24.0 kg/m² or ≥4.69 SDS at age 2 years as a clinical threshold to distinguish children with biallelic LEP, LEPR, and MC4R variants from those with common obesity or monoallelic variants.

Monogenic obesity is a rare cause of obesity involving single gene mutations in the leptin–melanocortin pathway, which is crucial for regulating appetite and energy expenditure. It typically presents with severe, early-onset obesity and hyperphagia. Early diagnosis is critical to enable targeted pharmacological interventions, such as MC4R agonists or leptin analogues. However, access to genetic testing remains uneven across countries, and distinguishing monogenic from common obesity is often challenging due to overlapping phenotypes. This study addresses a key gap by proposing data-driven BMI thresholds for early genetic screening, based on the largest pooled cohort of monogenic obesity cases to date.

The authors highlight the value of early growth trajectories in selecting candidates for genetic testing. The steep BMI rise during the first year of life, followed by a plateau in biallelic LEP, LEPR, and MC4R variants - distinct from the rapid (yet less steep) and persistent BMI increase in POMC cases - can guide early recognition. Accelerated linear growth in biallelic MC4R carriers offers an additional diagnostic clue. Monoallelic MC4R variant carriers show a gradual BMI rise, undistinguishable from common obesity.

The proposed BMI thresholds, especially when combined with features such as hyperphagia or rapid linear growth, provide a practical tool to guide early identification of individuals with suspected monogenic obesity and a foundation for future genetic screening guidelines. Further validation in diverse populations and integration of additional genes linked to monogenic obesity will be essential to refine diagnostic algorithms and promote equitable access to personalized therapies in pediatric obesity care.