ESPE Yearbook of Paediatric Endocrinology

Obesity (Silver Spring). 33(5), 986-995 (2025). https://doi.org/10.1002/oby.24263. https://pubmed.ncbi.nlm.nih.gov/40231439/

Brief Summary: This case-control study, including 63 children with MC4R deficiency (59=monoallelic, n=4 biallelic), found larger head circumference (HC) and taller height in MC4R carriers compared to the Dutch reference population and 63 age- and BMI-matched control children with multifactorial obesity. Macrocephaly was present in all children with biallelic variants (n=4) and 36% of those with monoallelic variants (n=23), compared to 25% in controls (n=16). Interestingly, there was no difference in HC or height in adult monoallelic MC4R carriers (n=13) compared to the Dutch reference population.

Identifying genetic variants in clinical practice is challenging due to the phenotypic heterogeneity between and within different forms of genetic obesity [1]. Although genetic testing has become standard in clinical practice and novel pharmacological therapies are available for certain forms of genetic obesity [2], widespread genetic testing remains limited by capacity. Therefore, specific phenotypic criteria are needed to identify individuals for genetic testing. The present study is crucial for clinical practice, as monoallelic MC4R variants are the most common form of genetic obesity, previously characterized by non-specific clinical features as severe childhood obesity, hyperphagia, and increased linear growth [3,4]. This study highlights that large HC is a specific clinical feature of MC4R carriers, associated with insulin resistance. However, the exact underlying mechanisms remain unclear and require further investigation. Furthermore, validation of these findings in larger or longitudinal paediatric and adult MC4R cohorts is necessary, along with investigating whether large HC is unique to MC4R variants or shared with other forms of monogenic obesity.

In summary, these findings suggest that regular HC measurements, particularly in children and adolescents, should be included in the screening of individuals with suspected monogenic obesity, as HC appears to be a key phenotypic characteristic of MC4R variant carriers.

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