Rare Genetic Obesities: From Diagnosis to Tailored Management In 2025 

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Author(s):

	Beatrice Dubern
	Pr Beatrice Dubern, MD, PhD is professor of pediatrics in the department of pediatric nutrition and gastroenterology at Trousseau hospital in Paris, France. In clinics, she is the head of the reference center for rare diseases PRADORT specialized for the management of children with severe early-onset obesity or syndromic obesity. She is involved in the development of innovative therapeutics as setmelanotide in monogenic obesities.
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1. Introduction 

Obesity results from an imbalance in energy homeostasis with interactions between individual genetic predisposition and environmental factors (including psychosocial conditions, dietary habits, physical inactivity, and many other factors) (1). Strong evidence supports the heritability of body weight, revealing varying degrees of genetic influence on obesity development with  a continuum between common forms of obesity (polygenic obesity) and rarer monogenic and syndromic forms (Figure 1). Polygenic obesity results from complex interactions between multiple genetic variants and behavioral and environmental factors (eating behavior, physical activity, psychosocial stress) and is linked with hundreds of genes and thousands of polymorphisms involved in obesity (2). Individually, they have a minor effect on weight gain, but their combination (in polygenic scores) can confer a high risk of developing obesity, especially in an environment conducive to energy storage. Some so-called “rare” genetic variants, however, have a major impact on hypothalamic dysfunction, leading to impaired perception of hunger and satiety signals and disturbances in energy metabolism (3). They are associated with the phenotype of the so-called genetic obesities that are considered as rare neuroendocrine disorders in which the contribution of genetics is predominant. These forms account for around 5% of cases of severe obesity, but this prevalence is probably underestimated because of the limited access to genetic diagnosis. Dysfunction of the hypothalamic centers implicated in energy regulation is responsible for these extreme  phenotypes including severe early onset obesity and eating disorders associated with various endocrine and/or central neuropsychological abnormalities (4-6).  

Figure 1: Continuum between common forms of obesity (polygenic obesity) and rarer monogenic and syndromic forms 

Pathophysiology of rare genetic obesities  

Located in the hypothalamic arcuate nucleus, the leptin-melanocortin pathway plays a pivotal role in these situations (Figure 2) through its crucial role in regulation of energy balance and weight control. Indeed, its disruption whatever the etiology, is responsible for dysregulation of basal metabolism and satiety signals leading to impaired perception of hunger and satiety signals and severe early obesity (4). In addition, its close interactions with other organs implicated in eating behavior and metabolism regulation, such as the brain’s reward systems, cortical regions and peripheral organs explain specific associated phenotypes such as foraging (6,7).  

Figure 2: Pivotal role of the leptin-melanocortin pathway located in the hypothalamic arcuate nucleus  

The leptin-melanocortin pathway involves several actors such as the adipocyte-derived leptin. This latter activates its specific leptin receptors expressed within the hypothalamus, leading to the local production of melanocyte-stimulating hormones (α-MSH) derived from POMC (pro- opiomelanocortin). As the specific ligand for the G-protein-coupled receptor MC4R (melanocortin 4 receptor) expressed in the paraventricular nucleus, the α-MSH induces its activation and decrease of food intake. The major genes involved in this pathway are leptin (LEP), leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone subtilisin/kexin 1 convertase (PCSK1), melanocortin receptor type 3 and 4 (MC3R and MC4R) (8), MC4R regulatory protein, melanocortin receptor accessory protein 2 (MRAP2) (9) and adenylate cyclase 3 (ADCY3) (10). Genetic variants in one or more of these genes result in altered function of the pathway and consequently severe hyperphagia and obesity occurring with additional phenotypes including endocrine deficiencies especially in case of bi-allelic variants (3,10,11). More recently, pathogenic variants of other genes involved in or regulating this pathway have also been associated with early and severe obesity. The following genes have been shown to be involved : steroid coreceptor activator-1 (SRC-1), semaphorin 3A-G (SEMA3A-G), plexinA1-4 (PLXNA1-4), neuropilin1-2 (NRP1-2), kinase suppressor of ras 2 (KSR2) (11–12), and steroid-receptor co-activator 1 (SRC-1) (13). In the hypothalamus these defects also severely alter signaling in response to peripherally derived hormones such as peptide YY and to efferent signals from the autonomic nervous system or pituitary hormone pathways (14,15).  Basal metabolic rate is decreased and several central endocrine abnormalities and metabolic abnormalities (such as hyperinsulinism) also contribute to excessive fat mass accumulation (4).  

Phenotypes of rare genetic obesities  

Genetic defects especially if bi-allelic variant in one of these genes, are associated to development of generally severe obesity most often during early childhood leading almost constantly to BMI >40kg/m² in adulthood. This extreme phenotype is notably observed in patients bearing bi-allelic variants in genes including LEP, LEPR, POMC, PCSK1, and MC4R. It is characterized by severe obesity starting during the first 3 years of life and accompanied by impaired hunger and satiety signals which are revealed by major hyperphagia and insatiable hunger (Figure 3). Eating disorders are regularly observed during the first months of life. Parents often describe a lack of satiety, intolerance to food restriction with conflict over limitations. Later on, patients may have obsessions with food interfering with other activities, and foraging strategies that may include stealing or night-time feeding (4). Along with severe obesity and uncontrolled eating, patients may also express endocrine defects induced by the mutated gene involved   (pubertal delay and/or hypogonadotropic hypogonadism in case of leptin or LEPR deficiency, central thyrotropic or somatotropic insufficiencies, late postprandial hypoglycemia with insipidus diabetes in the rare cases of PCSK1 deficiency for example) (3,6). In case of bi-allelic variants of MC4R, the history of obesity is close to that of the other forms previously described but without associated endocrine deficit (3,6). These monogenic obesities are now considered as a global neuroendocrine pathology due to the hypothalamic dysfunction that results from the expression of the genetic defect in the corresponding pathways. Subjects carrying heterozygous variants in most of these same genes show an intermediate phenotype compared to that expressed in the presence of bi-allelic variants. However, the severity of the phenotype may depend on environmental and/or other genetic factors with potential cumulative effects, as recently described (3,16). 

Similarities exist with other conditions named syndromic obesities. Indeed, in case of associated neurodevelopmental disorder (NDD) (intellectual disability of variable intensity and/or other adaptive developmental disorders) and/or malformation syndrome to obesity, these phenotypes are part of syndromic obesities. Prader-Willi (PWS), X-fragile and Bardet-Biedl (BBS) syndromes are mostly described (4,8). However, these conditions are also responsible for overlapping phenotypes with hypothalamic obesity (Figure 1). For example, some patients suffering from monogenic obesity present neurodevelopmental and/or psychiatric disorders close to those observed in so-called syndromic obesity and on the other hand, endocrine deficiencies such as corticotropic or gonadotropic deficiencies are observed in syndromic obesity such as PWS (8). In addition, abnormal leptin-melanocortin pathways are described in some syndromic obesities. In BBS, alteration of the LEPR transportation and of its localization at the ciliary membrane of POMC neurons is implicated in the development of hyperphagia and obesity (18). In PWS, proconvertase 1 (PC1) deficiency and alterations of the orexigenic Agouti-related protein (AgRP) hypothalamic neurons have been also described (19). In Smith Magenis syndrome linked to the 17p11.2 locus, encompassing the RAI1 gene, haploinsufficiency of RAI1 in murine models leads to a decrease expression of POMC and Brain Derived Neurotrophic Factor (BDNF), thus  also involving the leptin-melanocortin pathway (20). Finally, these phenotypic features (obesity, NDD, endocrine deficiencies,) are also shared with the lesional hypothalamic obesities (HO) developed after resection of lesion such as craniopharyngioma or anatomic lesion such as, for example, septo-optic dysplasia (4).  

Since early diagnosis of these genetic HOs is crucial in order to propose innovative therapeutics, we developed a web-tool entitled Obsgen (http://obsgen.nutriomics.org/) helping physicians for the management of these rare forms of obesity (4-6). Our tool provides guidance to explore specific potential genetic etiologies by helping clinicians to identify these patients by as early as possible, on the basis of a few questions exploring the history of obesity, characteristics of food behavior and associated phenotypes such as endocrine or ND disorders (Figure 3). 

Figure 3: Principle of guidance provided by the Obsgen web-tool (http://obsgen.nutriomics.org/) to explore specific potential genetic etiologies.  

Tailored management of rare genetic obesities 

Multidisciplinary management 

In these situations,  very early onset obesity before the age of 6 years or even 3 years of age in the most severe cases, is often associated with inexistent or earlier adiposity rebound (before  3 years of age) and unusual feeding behavior (severe hyperphagia, lack of control, food impulsivity) (21). These lifelong medical situations are highly complex and a major burden for caregivers (4), requiring specific multidisciplinary management as proposed in centers of expertise. In France, this support is proposed within the of the Reference Centers for Rare Diseases network that have existed for 20 years. 

Because of this complexity, comprehensive, specialized, and multidisciplinary approaches are crucial in order to manage genetic obesities. The patients’ condition can be improved by implementing as early as possible during early childhood, control of eating behavior associated with adapted physical activity and combination of other approaches that may include psychomotor skills therapy, speech therapy, hormone replacement therapy, etc. (4). The treatment has so far been based on environmental control starting as early as possible in order to avoid obesity progression and to support the acquisition of appropriate eating and exercise behavior. This approach becomes more efficient if it is managed by a multidisciplinary team of specialized health professionals (physicians, nutritionists, and psychologists).  

Drugs 

The better understanding of the molecular causes of rare genetic obesity and its associated phenotype allows to consider a therapeutic approach focused on hunger control.  

Metreleptin 

In patients with congenital leptin deficiency, daily subcutaneous metreleptin administration rapidly improves eating disorders, reduces food intake, leads to significant fat mass loss, and improves associated metabolic complications and central hypogonadism (22). Metreleptin is specifically indicated for patients with leptin deficiency or inactive leptin secretion due to a bi-allelic pathogenic variant in the LEP gene (23,24). However, it cannot be used in case of dysfunction of LEPR or of one of the other key-proteins of the leptin-melanocortin pathway. 

MC4R agonist (setmelanotide) 

Research on the leptin-melanocortin pathway has led recently to the development of MC4R agonists that could be indicated in these situations. MC4R is a G-protein-coupled receptor that plays a central role in regulating weight, appetite, and energy expenditure, making it an ideal therapeutic target. The novel molecule, named setmelanotide, is a selective MC4R agonist administered daily via subcutaneous injection. It was first  used in 2 patients with bi-allelic variants in POMC, leading  to a drastic reduction of body weight (-51.0 kg after 42 weeks and -20.5 kg after 12 weeks of treatment respectively in the 2 subjects) confirming that this MC4R agonist can restore melanocortin signal (25). These results were then confirmed in phase 3 trials in which the average weight loss was  -25.6% of pretreatment body weight in patients with POMC deficiency and -12.5% in LEPR-deficient patients (26). In parallel, rapid decrease of hunger score was observed with setmelanotide confirming the restoration of satiety signal. An adverse event, skin hyperpigmentation due to the activation of melanocortin 1 receptor (MC1R) by setmelanotide is reported in more than 70% of the treated patients (27). A special attention will be paid to the chronic stimulation of melanocytes even if its long-term administration seems to be safe (28). Transient digestive manifestations are also reported as well as local reactions of the skin to injection and temporary increased sexual arousal. The evolution of the first two patients with POMC deficiency treated by setmelanotide for 7 years confirmed the persistence of weight loss and the reduction of hunger without severe long term side effects except for hyperpigmentation (29). In addition, quality of life improvement trough treatment argues for an early diagnosis of these rare genetic obesities in order to implement it early in life and limit weight evolution (30). Since 2021, setmelanotide (IMCIVREEÓ) is approved for patients with POMC/PCSK1 or LEPR deficiency older than 6 years of age. Recently, its efficacy was reported in children younger than 6 years suffering of obesity secondary to POMC/PCSK1 or LEPR deficiency and is in favor an early use in life in order to prevent the evolution to extreme obesity later in life and to an altered quality of life mainly secondary to stigma (31,32).  

Because of their shared pathophysiology, setmelanotide has been also tested in patients with other syndromic obesities, such as BBS and Alström syndrome (18). Its major beneficial effects  were observed on quality of life of the patients and their families thereby encouraging practitioners to use it to support BBS patients and their families in managing weight control and reducing stigma (33,34). Patients with lesional HO with eligibility to a treatment with setmelanotide should be involved as well (35). Early access for patients with BBS or lesional HO is now granted by the French Haute Autorité de Santé since 2022. 

As setmelanotide can restore satiety signal in case of impaired leptin-melanocortin pathway, adults and children carrying pathogenic heterozygous variants are probably other potential candidates. Indeed, their phenotype that may be close to that described in case of bi-allelic variants including severe early-onset obesity and uncontrollable hyperphagia may be improved with setmelanotide (16). Trials are on-going to evaluate the impact in patients carrying heterozygous variants in one of 60 genes involved in the pathway (NCT04963231). But questions are still debated about the indication of this treatment in patients, such as those carrying heterozygous variants in MC4R. Setmelanotide was more efficient in vitro than the endogenous ligand in cells expressing various heterozygous pathogenic variants of MC4R. Moreover, it appeared that treatment with setmelanotide can induce variable response to weight loss in humans, depending on the type of MC4R pathogenic variant (36,37).  

Glucagon-Like-Peptide-1 analogs 

Glucagon-Like-Peptide-1 (GLP-1) analogs are also promising molecules to improve weight status and food behavior in monogenic obesities (38). Indeed, human GLP-1, an incretin secreted by entero-endocrine cells in response to food intake, enhance insulin secretion by the pancreatic ß-cell and improves insulin sensitivity. It reduces appetite through a reduction of gastric emptying and central effects on the satiety signalization. Among patients with monogenic obesity, a trial compared daily 3 mg liraglutide efficacy on 14 carriers of MC4R pathogenic variants against 28 non-mutated patients. An equivalent weight loss between the 2 groups of about 6% of body weight after 16 weeks of treatment was observed with similar improvement in body fat mass, waist circumference, and glucose tolerance (39). These data suggest a preserved efficacy of GLP-1 agonists for genetic obesity with decreased MC4R signaling. There is no available evidence about the action on the other types of monogenic obesity and case reports about GLP-1 agonists efficacy are expected (38). Further studies are now crucial given the substantial expected benefit for these patients early in life (40,41). 

Bariatric surgery 

Bariatric surgery has regularly been undertaken for syndromic and monogenic obesity due to their severity, and were the most effective treatment for patients with complicated severe obesity (42). At present, the most common surgical techniques used are sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). These interventions result in a sustainable weight reduction and remission of comorbidities in most of patients with common obesity (43,44). However, the outcomes of these interventions remain uncertain over the long term, since the evidence of its use in syndromic obesity is limited and results are heterogenous. 

Bariatric surgery should not be proposed to patients carrying bi-allelic variant in one gene of the leptin-melanocortin pathway in as much as drugs such as setmelanotide are currently developed. The largest case series available to date reports the long-term outcome of 8 patients with POMC, LEPR, or MC4R bi-allelic variants. It revealed an unsatisfactory outcome with rapid weight regain in all patients (median weight regain of 24.1kg after an initial median weight loss of -21.5 kg) (45).  

Regarding monogenic non-syndromic obesity related to heterozygous variant, the most documented situation is the long-term outcome of bariatric surgery confronted with retrospective genetic analyses. The most important among these studies to date assessed the impact of heterozygous variants in the leptin-melanocortin pathway on the long-term outcomes after RYGB in a retrospective case-control study with 50 heterozygous variants carriers in seven genes (LEPR, PCSK1, POMC, SH2B1, SRC1, MC4R, and SIM1) and 100 matched (sex, age, BMI, and time since surgery) controls free of mutation. The percentage of weight loss 15 years after surgery was -16.6 ± 10.7 % for variants carriers against -28.7 ± 12.9 % in matched controls. The weight regain after maximum weight loss was also greater in patients bearing heterozygous variants with 52.7 ± 29.7 kg compared to 29.8 ± 20.7 kg for non-carriers. This lower long-term efficiency of RYGB in heterozygous variants carriers secondary to increased weight regain is likely to be explained by persistent eating behaviour disorders linked to the hypothalamic dysfunction (46). These results were consistent with those of the retrospective genetic analysis in 131 adults with obesity who underwent SG surgery, showing that the 10 patients carrying heterozygous variants in the leptin-melanocortin pathway lost less weight in both short-term and long-term periods (47). Another study of 1014 patients who underwent bariatric surgery, including 30 patients carrying heterozygous variant in the leptin-melanocortin pathway (12 in POMC, 11 in MC4R, 5 in PCSK1), showed similar weight loss among mutation carriers and controls after a short follow-up of 2 years (48). A recent multicentric case-control study also compared outcomes of 35 patients with heterozygous likely pathogenic MC4R variants to 70 mutations-free controls matched on age, sex, BMI and surgical procedure. Five years after bariatric surgery, a trend towards greater weight regain after nadir was observed for MC4R variant carriers, and was higher after SG than after RYGB (49). All together these data plead for genetic analysis prior to perform bariatric surgery especially in case of severe obesity associated with abnormal eating behavior developed early in life. It suggests also to be cautious in discussing bariatric surgery in teenagers and to explain the potential risk of rapid weight regain in case of identified pathogenic heterozygous variant. To conclude, melanocortin pathway heterozygous variants, in the absence of major eating or neurodevelopmental/psychiatric disorders, are not an absolute contraindication to bariatric surgery. But with the emergence of new effective treatments, caution and multidisciplinary discussion to accurately evaluate the benefit-risk balance are warranted before opting for bariatric surgery. 

References 

1. Bouchard C. Genetics of Obesity: What We Have Learned Over Decades of Research. Obes Silver Spring Md. mai 2021;29(5):802‑20.
2. Khera AV, Chaffin M, Wade KH, Zahid S, Brancale J, Xia R, et al. Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood. Cell. 18 avr 2019;177(3):587-596.e9.
3. Jia RY, Lockhart S, Lam BYH, Zhao Y, Kentistou KA, Gardner EJ, et al. Effects of rare coding variants in severe early-onset obesity genes in the population-based UK Biobank study. J Clin Endocrinol Metab. 28 févr 2025;dgaf132.
4. Dubern B, Mosbah H, Pigeyre M, Clément K, Poitou C. Rare genetic causes of obesity: Diagnosis and management in clinical care. Ann Endocrinol. févr 2022;83(1):63‑72.
5. Butler MG. Single Gene and Syndromic Causes of Obesity: Illustrative Examples. Prog Mol Biol Transl Sci. 2016;140:1‑45.
6. Farooqi IS. Monogenic Obesity Syndromes Provide Insights Into the Hypothalamic Regulation of Appetite and Associated Behaviors. Biol Psychiatry. 15 mai 2022;91(10):856‑9.
7. Saeed S, Bonnefond A, Froguel P. Obesity: exploring its connection to brain function through genetic and genomic perspectives. Mol Psychiatry. févr 2025;30(2):651‑8.
8. Huvenne H, Dubern B, Clément K, Poitou C. Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016. Obes Facts. 2016;9(3):158‑73.
9. Baron M, Maillet J, Huyvaert M, Dechaume A, Boutry R, Loiselle H, et al. Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension. Nat Med. nov 2019;25(11):1733‑8.
10. Saeed S, Bonnefond A, Tamanini F, Mirza MU, Manzoor J, Janjua QM, et al. Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Nat Genet. févr 2018;50(2):175‑9.
11. van der Klaauw AA, Croizier S, Mendes de Oliveira E, Stadler LKJ, Park S, Kong Y, et al. Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance. Cell. 7 févr 2019;176(4):729-742.e18.
12. Pearce LR, Atanassova N, Banton MC, Bottomley B, van der Klaauw AA, Revelli JP, et al. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. Cell. 7 nov 2013;155(4):765‑77.
13. Cacciottolo TM, Henning E, Keogh JM, Bel Lassen P, Lawler K, Bounds R, et al. Obesity Due to Steroid Receptor Coactivator-1 Deficiency Is Associated With Endocrine and Metabolic Abnormalities. J Clin Endocrinol Metab. 17 mai 2022;107(6):e2532‑44.
14. Kim JH, Choi JH. Pathophysiology and clinical characteristics of hypothalamic obesity in children and adolescents. Ann Pediatr Endocrinol Metab. déc 2013;18(4):161‑7.
15. Vlaardingerbroek H, van den Akker ELT, Hokken-Koelega ACS. Appetite- and weight-inducing and -inhibiting neuroendocrine factors in Prader-Willi syndrome, Bardet-Biedl syndrome and craniopharyngioma versus anorexia nervosa. Endocr Connect. 19 mai 2021;10(5):R175‑88.
16. Courbage S, Poitou C, Le Beyec-Le Bihan J, Karsenty A, Lemale J, Pelloux V, et al. Implication of heterozygous variants in genes of the leptin-melanocortin pathway in severe obesity. J Clin Endocrinol Metab. 7 juin 2021;dgab404.
17. Mariman ECM, Vink RG, Roumans NJT, Bouwman FG, Stumpel CTRM, Aller EEJG, et al. The cilium: a cellular antenna with an influence on obesity risk. Br J Nutr. août 2016;116(4):576‑92.
18. Guo DF, Cui H, Zhang Q, Morgan DA, Thedens DR, Nishimura D, et al. The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane. PLoS Genet. févr 2016;12(2):e1005890.
19. Burnett LC, LeDuc CA, Sulsona CR, Paull D, Rausch R, Eddiry S, et al. Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome. J Clin Invest. 3 janv 2017;127(1):293‑305.
20. Falco M, Amabile S, Acquaviva F. RAI1 gene mutations: mechanisms of Smith-Magenis syndrome. Appl Clin Genet. 2017;10:85‑94.
21. Wabitsch M, Fehnel S, Mallya UG, Sluga-O’Callaghan M, Richardson D, Price M, et al. Understanding the Patient Experience of Hunger and Improved Quality of Life with Setmelanotide Treatment in POMC and LEPR Deficiencies. Adv Ther. avr 2022;39(4):1772‑83.
22. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 16 sept 1999;341(12):879‑84.
23. Funcke JB, Moepps B, Roos J, von Schnurbein J, Verstraete K, Fröhlich-Reiterer E, et al. Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity. N Engl J Med. 15 juin 2023;388(24):2253‑61.
24. Fischer-Posovszky P, Funcke JB, Wabitsch M. Biologically inactive leptin and early-onset extreme obesity. N Engl J Med. 26 mars 2015;372(13):1266‑7.
25. Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, et al. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. N Engl J Med. 21 juill 2016;375(3):240‑6.
26. Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. déc 2020;8(12):960‑70.
27. Sridharan K, Sivaramakrishnan G. Adverse event profile of setmelanotide in obesity: an integrated assessment and systematic review using disproportionality analysis, case reports and meta-analysis. Expert Opin Drug Saf. 12 févr 2025;1‑10.
28. Kanti V, Puder L, Jahnke I, Krabusch PM, Kottner J, Vogt A, et al. A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway. Skin Pharmacol Physiol. 31 mai 2021;1‑10.
29. Kühnen P, Clément K. Long-Term MC4R Agonist Treatment in POMC-Deficient Patients. N Engl J Med. 1 sept 2022;387(9):852‑4.
30. Kühnen P, Wabitsch M, von Schnurbein J, Chirila C, Mallya UG, Callahan P, et al. Quality of life outcomes in two phase 3 trials of setmelanotide in patients with obesity due to LEPR or POMC deficiency. Orphanet J Rare Dis. 5 févr 2022;17(1):38.
31. Argente J, Verge CF, Okorie U, Fennoy I, Kelsey MM, Cokkinias C, et al. Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial. Lancet Diabetes Endocrinol. janv 2025;13(1):29‑37.
32. Dubern B, Lourdelle A, Clément K. Beneficial Effects of Setmelanotide in a 5-Year-Old Boy With POMC Deficiency and on His Caregivers. JCEM Case Rep. mai 2023;1(3):luad041.
33. Haqq AM, Poitou C, Chung WK, Forsythe E, Conroy R, Dollfus H, et al. Impact of Setmelanotide on Metabolic Syndrome Risk in Patients With Bardet-Biedl Syndrome. J Clin Endocrinol Metab. 7 févr 2025;dgaf079.
34. Forsythe E, Haws RM, Argente J, Beales P, Martos-Moreno GÁ, Dollfus H, et al. Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results. Orphanet J Rare Dis. 16 janv 2023;18(1):12.
35. Roth CL, Scimia C, Shoemaker AH, Gottschalk M, Miller J, Yuan G, et al. Setmelanotide for the treatment of acquired hypothalamic obesity: a phase 2, open-label, multicentre trial. Lancet Diabetes Endocrinol. juin 2024;12(6):380‑9.
36. Kühnen P, Biebermann H, Wiegand S. Pharmacotherapy in Childhood Obesity. Horm Res Paediatr. 2022;95(2):177‑92.
37. Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. oct 2017;6(10):1321‑9.
38. Welling MS, van Rossum EFC, van den Akker ELT. Anti-obesity pharmacotherapy for patients with genetic obesity due to defects in the leptin-melanocortin pathway. Endocr Rev. 11 févr 2025;bnaf004.
39. Iepsen EW, Zhang J, Thomsen HS, Hansen EL, Hollensted M, Madsbad S, et al. Patients with Obesity Caused by Melanocortin-4 Receptor Mutations Can Be Treated with a Glucagon-like Peptide-1 Receptor Agonist. Cell Metab. 3 juill 2018;28(1):23-32.e3.
40. Roth CL, Perez FA, Whitlock KB, Elfers C, Yanovski JA, Shoemaker AH, et al. A phase 3 randomized clinical trial using a once-weekly glucagon-like peptide-1 receptor agonist in adolescents and young adults with hypothalamic obesity. Diabetes Obes Metab. févr 2021;23(2):363‑73.
41. Fox CK, Barrientos-Pérez M, Bomberg EM, Dcruz J, Gies I, Harder-Lauridsen NM, et al. Liraglutide for Children 6 to <12 Years of Age with Obesity – A Randomized Trial. N Engl J Med. 6 févr 2025;392(6):555‑65.
42. Vos N, Oussaada SM, Cooiman MI, Kleinendorst L, Ter Horst KW, Hazebroek EJ, et al. Bariatric Surgery for Monogenic Non-syndromic and Syndromic Obesity Disorders. Curr Diab Rep. 30 juill 2020;20(9):44.
43. Poirier P, Cornier MA, Mazzone T, Stiles S, Cummings S, Klein S, et al. Bariatric surgery and cardiovascular risk factors: a scientific statement from the American Heart Association. Circulation. 19 avr 2011;123(15):1683‑701.
44. Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial – a prospective controlled intervention study of bariatric surgery. J Intern Med. mars 2013;273(3):219‑34.
45. Poitou C, Puder L, Dubern B, Krabusch P, Genser L, Wiegand S, et al. Long-term outcomes of bariatric surgery in patients with bi-allelic mutations in the POMC, LEPR, and MC4R genes. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. août 2021;17(8):1449‑56.
46. Campos A, Cifuentes L, Hashem A, Busebee B, Hurtado-Andrade MD, Ricardo-Silgado ML, et al. Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Roux-en-Y Gastric Bypass Outcomes: a 15-Year Case-Control Study. Obes Surg. août 2022;32(8):2632‑40.
47. Li Y, Zhang H, Tu Y, Wang C, Di J, Yu H, et al. Monogenic Obesity Mutations Lead to Less Weight Loss After Bariatric Surgery: a 6-Year Follow-Up Study. Obes Surg. avr 2019;29(4):1169‑73.
48. Cooiman MI, Kleinendorst L, Aarts EO, Janssen IMC, van Amstel HKP, Blakemore AI, et al. Genetic Obesity and Bariatric Surgery Outcome in 1014 Patients with Morbid Obesity. Obes Surg. févr 2020;30(2):470‑7.
49. Cooiman MI, Alsters SIM, Duquesnoy M, Hazebroek EJ, Meijers-Heijboer HJ, Chahal H, et al. Long-Term Weight Outcome After Bariatric Surgery in Patients with Melanocortin-4 Receptor Gene Variants: a Case-Control Study of 105 Patients. Obes Surg. mars 2022;32(3):837‑44.