Endocrine Abstracts (2015) 39 OC6.3 | DOI: 10.1530/endoabs.39.OC6.3

Skeletal changes in pre-pubertal children with loss of function mutations in the melanocortin-4 receptor

Paul Dimitri1, Tinh-Hai Collet2, Julia Keogh2 & Sadaf Farooqi2


1The Mellanby Bone Centre, The University of Sheffield, Sheffield, South Yorkshire, UK; 2Wellcome Trust–MRC Institute of Metabolic Science, The University of Cambridge, Cambridge, UK.


Background: Obese children are at greater risk of fracture. However, previous evidence suggests that obese children with a mutation in the melanocortin-4 receptor (MC4R) have a high age-adjusted bone mass. MC4R deficiency is associated with increased linear growth, so bone mass may be over-estimated due to patients being taller. We therefore aimed to compare body size-adjusted bone mass of lean and obese pre-pubertal children with those who have a mutation in MC4R.

Methods: We retrospectively reviewed the DXA derived total body bone area (BA (cm2)), bone mineral content (BMC (g)), and bone mineral density (BMD (g/cm2)) in pre-pubertal Caucasian children (<12.0 years) with known loss of function variants in MC4R (n=49) from the Cambridge Genetics of Obesity Study (GOOS) cohort. Skeletal parameters were adjusted for height and weight and compared with those derived from Caucasian pre-pubertal obese (n=22) and lean (n=110) children.

Results: Mean age of the lean, obese and MC4R cohorts was 8.2±2.0, 8.3±1.8, and 7.4±2.5 respectively (P=0.06). Mean height SDS was lower in lean children compared with obese and MC4R cohorts (ANOVA, P<0.001). BMI SDS of MC4R patients was significantly greater than obese (mean difference=0.78 (0.22, 1.33), P=0.003) and lean (mean difference=3.83 (3.46, 4.21), P<0.001). Body-size adjusted total BMC and bone area were greater in MC4R (P=0.03 and P=0.004 respectively) and obese (P=0.003 and P<0.001) when compared to lean subjects. In contrast body-size adjusted total BMD and BMC corrected for bone area was not different between the cohorts.

Conclusions: Pre-pubertal children with loss of function mutations in the MC4R and obese children have a higher body-size adjusted BMC compared to lean children. This is due to a larger bone size. Despite this, bone density does not increase. Mutations in MC4R do not appear to alter the bone phenotype when compared to obese children despite an increase in body size.

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