A growing concern

Uncovering a root cause of the 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:

Hyperphagia (pathological, insatiable hunger)8

Heightened and prolonged hunger

Severe preoccupation with food

Longer time to reach satiety

Excessive food behaviours (night eating, stealing food, foraging for food in the garbage)

Shorter duration of satiety

Significant stress and inappropriate response if denied food

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

Taking a detailed clinical history is critical
Record family history, if available

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

Early diagnosis

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

Improving management of the individual’s health by informing management strategies for hyperphagia and obesity treatment and determining eligibility for pharmacotherapies or clinical trials
Reducing the social stigma of obesity and providing coping strategies for managing stigmatisation
Empowering the individual and carers to understand the root cause of their condition and make informed decisions about their care
Allowing for preventive or prophylactic screening of associated conditions

Genetic screening

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

Help facilitate specialised management of the patient’s health
Empower the patient and their carer(s) to make informed decisions about health care

Educational resources

View all resources
In this section, you can find information on educational resources and meetings produced by Rhythm. We will continue to update this page with additional resources about rare diseases of the MC4R pathway.

If you would like to be notified when new resourced are available, or any additional educational information, please contact us
Clinical Features
Rare MC4R pathway diseases
Pro-opiomelanocortin (POMC) and Leptin receptor (LEPR) deficiency


  1. 1. Yazdi FT, et al. PeerJ. 2015;3:e856.
  2. 2. Acosta A, et al. Genes Nutr. 2014;9:384.
  3. 3. Haqq AM, et al. Lancet Diabetes Endocrinol. 2022;10:859–868.
  4. 4. Huvenne H, et al. Obes Facts. 2016;9:158-73.
  5. 5. Fonseca ACP, et al. Obes Facts. 2016;9:158‒73.
  6. 6. Clément K, et al. Physiol Behav. 2020;227:113134.
  7. 7. Styne DM, et al. J Clin Endocrinol Metab. 2017;102:709–757.
  8. 8. Heymsfield SB, et al. J Clin Endocrinol Metab. 2017;102:709–757. 8. Heymsfield SB, et al. Obesity (Silver Spring). 2014;22:S1‒S17.
  9. 9. Ellacott KLJ and Cone RD. Philos Trans R Soc Lond B Biol Sci. 2006;361:1265–74.
  10. 10. Kohldorf K, et al. Int J Obes (Lond). 2018;42:1602–1609.
  11. 11. August GP, et al. J Clin Endocrinol Metab. 2008;93:4576–99.
  12. 12. Kleinendorst L, et al. BMJ Case Rep. 2017;2017:bcr2017221067.