Monogenic obesity is a very rare, genetically determined form of extreme obesity in early childhood that occurs more frequently in regions with a high proportion of consanguineous marriages. The prevalence is not yet known. Extreme obesity in children and adolescents is defined as a BMI > 99.5 of the age- and sex-specific percentiles, with slightly different trajectories in girls and boys. Within this group, monogenic obesity occurs in 1 to 5% of cases. It usually manifests itself between the first and fourth year of life and is characterized by extreme food-seeking behavior.
The feeling of hunger or satiety is controlled by the release of the hormones leptin and insulin, among others, from the adipocytes and beta cells of the pancreas into the bloodstream. Once across the blood/brain barrier, leptin (LEP) interacts with its receptor (LEPR) in the hypothalamus. This results in the activation of proopiomelanocortin (POMC)-producing neurons. The prohormone POMC is converted to alpha-MSH (alpha-melanocyte stimulating hormone) by PCSK1 (proprotein convertase subtilisin/kexin type 1). PCSK1 is a neuroendocrine convertase that processes large precursor proteins, like POMC, into mature bioactive molecules, in this case, alpha-MSH. In a further step, alpha-MSH activates the melanocortin-4 receptor (MC4R), which induces a feeling of satiety.
Causative variants in the five genes MC4R, LEP, LEPR, PCSK1, and POMC of the leptin-melanocortin pathway are affected, with heterozygous alterations in the MC4R gene (autosomal dominant inheritance) being the most common cause. Variants in the LEP, LEPR, PCSK1, and POMC genes follow an autosomal recessive mode of inheritance. Outside of this pathway, causative variants in six other genes have been described, sometimes in individual study cohorts (KSR2, MC3R, MRAP2, NTRK2, SH2B1, SIM1).
In addition to marked hyperphagia in infancy and early childhood (LEP, LEPR), other clinical abnormalities may include hypogonadotropic hypogonadism (LEP, LEPR), delayed pubertal progression (LEP), reddish hair (POMC), or diabetes insipidus with diarrhea-related malabsorption in the first years of life (PCSK1). Prior to a molecular genetic diagnosis, determination of leptin bioactivity should be performed to differentiate functional leptin deficiency from biologically inactive leptin (with normal leptin levels).
Two therapeutic approaches are currently available for the treatment of monogenic obesity. The recombinant analog of human leptin, the protein metreleptin, is used in patients with biologically inactive leptin or leptin deficiency and is administered subcutaneously. The melanocortin-4 receptor agonist setmelanotide is currently in clinical trials for obesity due to POMC deficiency, obesity due to causative variants in the LEP receptor, Prader-Willi syndrome, and others.
Although monogenic obesity is very rare, early detection of this disease serves the targeted secondary prevention of comorbidities, also possibly due in part to causal therapy.
References
Baldini et Phelan 2019, J Endocrinol 241:R1 / Schnurbein et al. 2018, Monatsschr Kinderheilkd 166:388 / Kohlsdorf et al. 2017, medgen 29:30 / Ramos-Molina et al. 2016, Prog Mol Biol Transl Sci 140:47 / Wabitsch et al. 2015, J Clin Endocrinol Metab 100:3227 / Challis B.G. et Millington G.W.M. 2013, GeneReviews® [Internet]
