👤 Mila S Welling

The objective of this study was to investigate head circumference (HC) in patients with melanocortin 4 receptor (MC4R) deficiency, the most common cause of monogenetic obesity. Patients with (likely) pathogenic MC4R variants were included. HC, height, and weight were measured, and BMI and standard deviation score (SDS) were calculated. HC SDS was compared to the Dutch reference population. Children were matched 1:1 to a control group with common obesity. Children with MC4R deficiency (n = 63, mean age, 10.32 years) had significantly larger HC (mean, +1.73 SDS) compared to the reference population (0 SDS; p < 0.001) and controls (+1.22 SDS; p = 0.009). In adults (n = 13), HC (median, + 0.86 SDS) did not differ from the reference population (0 SDS; p = 0.152). Macrocephaly (HC ≥ 2 SDS) was present in 43%, 25%, and 23% of pediatric patients with MC4R deficiency, controls, and adult patients, respectively. Children with MC4R deficiency were taller than controls (+1.00 SDS vs. +0.42 SDS; p = 0.016), with similar BMI (+3.99 SDS vs. +3.75 SDS; p = 0.157). HC SDS was associated with height SDS (R Macrocephaly is a common feature of patients with MC4R deficiency. We recommend measuring HC in patients suspected for genetic obesity, as it can be a clue for MC4R deficiency. Show less

The melanocortin-4 receptor (MC4R) plays an important role in body weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity. We have identified 17 MC4R variants in adult and pediatric patients with obesity. Here we aimed to functionally characterize these variants by analyzing 4 different aspects of MC4R signaling. In addition, we aimed to analyze the effect of setmelanotide, a potent MC4R agonist, on these MC4R variants. Cell surface expression and α-melanocyte stimulating hormone (α-MSH)- or setmelanotide-induced cAMP response, β-arrestin-2 recruitment, and ERK activation were measured in cells expressing either wild type or variant MC4R. We found a large heterogeneity in the function of these variants. We identified variants with a loss of response for all studied MC4R signaling, variants with no cAMP accumulation or ERK activation but normal β-arrestin-2 recruitment, and variants with normal cAMP accumulation and ERK activation but decreased β-arrestin-2 recruitment, indicating disrupted desensitization and signaling mechanisms. Setmelanotide displayed a greater potency and similar efficacy as α-MSH and induced significantly increased maximal cAMP responses of several variants compared to α-MSH. Despite the heterogeneity in functional response, there was no apparent difference in the obesity phenotype in our patients. We show that these obesity-associated MC4R variants affect MC4R signaling differently yet lead to a comparable clinical phenotype. Our results demonstrate the clinical importance of assessing the effect of MC4R variants on a range of molecular signaling mechanisms to determine their association with obesity, which may aid in improving personalized treatment. Show less

Leptin receptor (LEPR) deficiency is a rare genetic disorder that affects the body's ability to regulate appetite and weight. For patients and their families, the disorder seriously disrupts daily life; however, little is published about this impact. We here report the experiences of a 10.5-year-old girl with leptin receptor deficiency and her family. The diagnosis of this rare genetic obesity had a deep impact on the life of the child and her family. It led to a better understanding of the cause of the impaired appetite regulation and early-onset obesity with subsequently less judgement by others and improved cooperation of their social network and school on maintaining a healthy lifestyle for this girl. A strict eating regimen and lifestyle measures resulted in the first year after diagnosis in a significantly decreased body mass index (BMI), followed by BMI stabilization, still categorized as obesity class three. However, the troublesome challenge of how to manage the disruptive behaviour due to hyperphagia remained. Eventually, due to treatment with targeted pharmacotherapy, i.e., melanocortin-4 receptor agonists, her BMI continued to decrease due to resolving hyperphagia. The daily routine of the family and the atmosphere at home positively changed as they were no longer dominated by the food-focused behaviour of the child and the adherence to the strict eating regimen. This case report demonstrates the importance and impact of a rare genetic obesity disorder diagnosis in a family. Additionally, it highlights the value of genetic testing in patients with a high suspicion of a genetic obesity disorder as it can eventually lead to personalized treatment, such as guidance by specialized healthcare professionals and educated caregivers or targeted pharmacotherapy. Show less