A growing concern
Genetic variants in the melanocortin-4 receptor (MC4R) pathway can impair the regulation of hunger, food intake, satiety and energy expenditure.1,2
Melanocortin-4 receptor & obesity
Impaired MC4R signalling can lead to hyperphagia (pathological, insatiable hunger) and early-onset, severe obesity, regardless of environmental and lifestyle factors.3,4
Rare genetic variants within the MC4R pathway may result in impaired neuronal signalling, leading to rare genetic diseases such as pro-opiomelanocortin (POMC) deficiency obesity and leptin receptor (LEPR) deficiency obesity.4,5
Undiagnosed root cause
A root cause of early-onset, severe obesity is often underdiagnosed. Proactive identification of cardinal symptoms can help move children living with a rare MC4R pathway disease, onto their appropriate care path.4,6
Identifying a rare MC4R pathway disease
Once the cardinal symptoms of hyperphagia and early-onset, severe obesity have been identified, genetic screening can help to identify the presence of a rare MC4R pathway disease.7
When considering whether your patients should be evaluated for a rare MC4R pathway disease, think of the following cardinal symptoms:
Early-onset, severe obesity (early-onset is typically at age 2-5 years)4,9,10
A BMI curve well above reference percentiles may indicate an underlying rare MC4R pathway disease.
Speeding up referral
Proactive identification and appropriate testing of cardinal symptoms can help move children living with a rare MC4R pathway disease onto their appropriate care path.6
There are a few vital clinical investigations to undertake for the prompt identification of rare MC4R pathway diseases:6,11
Previous resistance to traditional obesity management strategies may be a valuable measure to assess.
While individual variants are uncommon, rare MC4R pathway diseases are likely not uncommon among people with early-onset, severe obesity. The age of obesity onset is a key factor in selecting patients with potential variants in obesity-associated genes.4,6
Access to appropriate tools mean genetic variants that cause rare MC4R pathway diseases can be diagnosed early. Clinical guidelines recommend genetic testing to inform diagnosis and appropriate interventions in patients with the cardinal symptoms of hyperphagia and early-onset, severe obesity.6
Diagnosis of a rare MC4R pathway disease and an understanding of the root cause of their issues can make a significant difference in an individual's life. Including: 6,10,12
Genetic screening, utilising the correct gene panels, now allows many more rare diseases to be identified – rare MC4R pathway diseases can be part of this.6
Genetic testing, along with evaluation of clinical presentation, may aid in the diagnosis of rare MC4R pathway diseases, which may: 11
If you would like to be notified when new resourced are available, or any additional educational information, please contact us.
- Yazdi F, et al. PeerJ. 2015;3:e856.
- Acosta A, et al. Gens Nutr. 2014;9:384.
- Haqq AM, et al. Lancet Diabetes Endocrinol. 2022;10(12):859–868.
- Huvenne H, et al. Obes Facts. 2016;9(3):158–173.
- da Fonseca ACP, et al. J diabetes Complications. 2017;31(10):1549–1561.
- Clément K, et al. Physiol Behav. 2020;227:112134.
- Styne DM, et al. J Clin Endocrinol Metab. 2017;102(3):709–757.
- Heymsfield SB, et al. Obesity (Silver Spring). 2014;22 (Suppl 1):S1–S17.
- Ellacott KLJ, Cone RD. Philos Trans R Soc Lond B Biol Sci. 2006;361(1471):1265–1274.
- Kohldorf K, et al. Int J Obes (Lond). 2018;42(9):1602–1609.
- August GP, et al. J Clin Endocrinol Metab. 2008;93(12):4576–4599.
- Kleinendorst L, et al. BMJ Case Rep. 2017:bcr2017221067.