Abstract
ObjectivesTo determine the prevalence of Melanocortin-4 Receptor (MC4R) mutations in a cohort of children and adolescents with overweight or obesity and to determine whether treatment responses differed between carriers and noncarriers.MethodsUsing target region capture sequencing, an MC4R mutation screen was performed in 1261 Danish children and adolescents enrolled at a tertiary multidisciplinary childhood obesity treatment center. Measurements of anthropometrics, blood pressure, fasting blood biochemistry including lipid and hormone levels, and dual-energy X-ray absorptiometry were performed at baseline and throughout treatment.ResultsOf 1209 children and adolescents that met all criteria to be included in the described analyses, 30 (2.5%) carried damaging or unresolved MC4R mutations. At baseline, mutation carriers exhibited higher concentrations of plasma thyroid-stimulating hormone (p = 0.003), and lower concentrations of plasma thyroxine (p = 0.010) compared to noncarriers. After a median of 1 year of treatment (range 0.5–4.0 years), body mass index (BMI) standard deviation score (SDS) was reduced in noncarriers but not in carriers, and this difference in treatment response was statistically significant (p = 0.005). Furthermore, HDL cholesterol was reduced in carriers, a response significantly different from that of noncarriers (p = 0.017).ConclusionAmong Danish children and adolescents with overweight or obesity entering a tertiary lifestyle intervention, 2.5% carried damaging or unresolved MC4R mutations. In contrast to noncarriers, carriers of damaging or unresolved MC4R mutations failed to reduce their BMI SDS during obesity treatment, indicating a need for personalized treatment based on the MC4R genotype.
Highlights
The Melanocortin-4 Receptor (MC4R) is expressed throughout the brain, especially in the hypothalamus, and the encodedHospital, Kolding, Denmark 8 BGI-Shenzhen, Shenzhen, China 9 Ferring Pharmaceuticals, Copenhagen, Denmark 10 The Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark protein regulates appetite and energy expenditure [1]
When comparing phenotypic changes after lifestyle intervention between groups A and B, we found a significant difference in body mass index (BMI) standard deviation score (SDS): groups A and Ba (group B) decreased their BMI SDS, while group A did not (p = 0.005)
In our cohort of children and adolescents with overweight or obesity, we identified 30 carriers of damaging or unresolved MC4R mutations (2.5%)
Summary
The Melanocortin-4 Receptor (MC4R) is expressed throughout the brain, especially in the hypothalamus, and the encodedHospital, Kolding, Denmark 8 BGI-Shenzhen, Shenzhen, China 9 Ferring Pharmaceuticals, Copenhagen, Denmark 10 The Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark protein regulates appetite and energy expenditure [1]. While the prevalence of carriers of MC4R mutations varies with ethnicity [5,6,7], up to 2% carry damaging mutations in MC4R among samples of non-consanguineous individuals with obesity of European descent, making MC4R deficiency the most common form of monogenic obesity [4]. Based on studies including children with damaging MC4R mutations, specific characteristics have been associated with MC4R deficiency, namely increased fat and lean mass, increased linear growth, increased bone mineral density, hyperphagia, and hyperinsulinemia [8, 9]. The above phenotype characteristics of carriers of damaging MC4R mutations remain controversial as other studies have failed to replicate them [11,12,13,14,15]
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