Monogenic and Syndromic Obesity: Defects of the Leptin–Melanocortin Pathway

Literature and regulatory information updated: 6 October 2026.

Nonsyndromic genetic obesity (Orphanet ORPHA:98267): congenital leptin deficiency (LEP), leptin receptor deficiency (LEPR), pro-opiomelanocortin deficiency (POMC), prohormone convertase 1/3 deficiency (PCSK1), melanocortin 4 receptor deficiency (MC4R) and SH2B1 deficiency; diagnostic framework for syndromic forms of hyperphagic obesity

0. Initial Reference Table

1. Introduction

Monogenic obesity comprises the small group of disorders in which a variant in a single gene is sufficient to cause severe early-onset obesity, almost invariably through disruption of the hypothalamic leptin–melanocortin pathway that regulates appetite and energy expenditure [1]. Orphanet defines nonsyndromic genetic obesity as a rare disorder characterised by severe early-onset obesity due to variants in genes involved in hypothalamic development and function or in the leptin–melanocortin pathway, with disturbed energy homeostasis and endocrine dysfunction; before 5 years of age, patients have a body mass index (BMI) more than three standard deviations above normal, accompanied by hyperphagia, insulin resistance, reduced basal metabolic rate or hypogonadism, depending on the gene involved [1]. These forms differ both from common polygenic obesity, in which many small-effect variants interact with the environment, and from obesity syndromes with developmental delay or dysmorphism, such as Prader–Willi syndrome and Bardet–Biedl syndrome, which the Oxford Desk Reference considers separately in clinical assessment [5, 22]. Obesity prompting referral to a genetics clinic is usually severe, with weight above the 99.6th centile or a marked discrepancy between height and weight; the diagnostic yield of investigations available when that edition of the book was published was approximately 10% [5].

The French National Diagnosis and Care Protocol (PNDS) for obesities of rare causes, published by the Haute Autorité de Santé (HAS) in 2021 and drafted by the PRADORT reference centre, distinguishes four categories: syndromic obesities (ORPHA:240371), in which excess weight is associated with a neurodevelopmental disorder or a malformation syndrome; non-syndromic monogenic obesities (ORPHA:98267), due to pathogenic variants in genes of the hypothalamic leptin–melanocortin pathway; lesional hypothalamic obesities, caused by a tumour (above all craniopharyngioma), by its treatment or by infiltrative disease of the suprasellar region; and the obesity of ROHHAD syndrome (ORPHA:293987), with no identified genetic cause [23]. The protocol treats these forms as a neuroendocrine continuum with a common mechanism, which underpins joint recommendations for diagnosis and care, and refers common polygenic obesity, with heritability estimated at 40–75% depending on the study, to the general HAS recommendations [23].

The history of these disorders began in mice. In 1994, Zhang, Friedman and colleagues positionally cloned the mouse obese (ob) gene and its human homologue, mutations in which cause profound obesity and diabetes, and proposed that the gene product served as a signal from adipose tissue controlling the size of fat stores [25]. The first human genetic evidence emerged in 1997, when Montague, Farooqi, O'Rahilly and colleagues described two children with severe obesity from a highly consanguineous family, with very low serum leptin despite increased fat mass and homozygosity for a single-guanine deletion at codon 133 of LEP [26]. That year, Jackson and colleagues demonstrated that a woman with extreme childhood obesity, hypogonadotrophic hypogonadism, hypocortisolism, elevated plasma proinsulin and POMC, and very low insulin was compound heterozygous for variants in PCSK1, the prohormone convertase 1 gene [27]. Reports published in 1998 described leptin receptor deficiency, by Clément and colleagues, in a family with early morbid obesity, absent pubertal development and reduced growth hormone (GH) and thyrotrophin (TSH) secretion [28]; POMC deficiency, by Krude and colleagues, in two children with severe obesity, adrenal insufficiency and red hair [29]; and the first MC4R frameshift variants associated with dominantly inherited obesity, by Yeo and colleagues and by Vaisse and colleagues [30, 31].

The following decade translated these descriptions into treatment. In 1999 and 2002, the Cambridge group showed that subcutaneous recombinant human leptin in children with congenital leptin deficiency produced sustained benefits in appetite, fat mass, hyperinsulinaemia, dyslipidaemia, thyroid function, puberty and T-lymphocyte immunity for up to four years [9, 32]. In 2003, MC4R sequencing in 500 probands with severe childhood obesity defined the clinical spectrum and codominant inheritance of melanocortin 4 receptor deficiency, the most frequent monogenic form [7]. In 2007, a study of 300 patients with hyperphagia and severe early-onset obesity established that 3% had pathogenic LEPR variants and that serum leptin is unsuitable as a marker of this deficiency [10]. In 2010 and 2012, Bochukova, Doche and colleagues associated 16p11.2 deletions encompassing SH2B1, and subsequently point loss-of-function variants in this gene, with hyperphagia, disproportionate insulin resistance and behavioural abnormalities [8, 21]. The next step was pharmacological: in 2016, Kühnen and colleagues treated two patients with POMC deficiency with setmelanotide, a melanocortin 4 receptor agonist, achieving sustained reductions in hunger and weight losses of 51.0 kg over 42 weeks and 20.5 kg over 12 weeks [33]. Subsequent phase 3 trials led to approval by the United States Food and Drug Administration (FDA) on 25 November 2020 and by the European Commission on 16 July 2021 [17, 34, 35].

This article covers six monogenic disorders of the leptin–melanocortin pathway, due to LEP, LEPR, MC4R and PCSK1 as well as POMC and SH2B1, as they share mechanisms, diagnostic approaches and treatments. Syndromic forms are addressed in the differential diagnosis and assessment algorithm; Prader–Willi syndrome, Bardet–Biedl syndrome and 16p11.2 microdeletion are covered with regard to the differential diagnosis and the shared regulatory framework for setmelanotide.

2. Molecular Genetics and Pathophysiology

2.1 The leptin–melanocortin pathway

Leptin, encoded by LEP, is secreted by white adipocytes in proportion to fat mass and acts in the arcuate nucleus of the hypothalamus through the leptin receptor, encoded by LEPR [3]. The receptor belongs to the gp130-related cytokine receptor family and signals via the JAK2 kinase and the transcription factor STAT3, stimulating POMC transcription in POMC neurons and repressing agouti-related protein (AgRP) and neuropeptide Y (NPY) in orexigenic neurons [3, 36]. POMC is a polypeptide precursor that the prohormone convertases cleave, in a tissue-specific manner, into corticotrophin (ACTH), alpha-, beta- and gamma-melanocyte-stimulating hormones (α-, β- and γ-MSH) and β-endorphin; the effects of these peptides are mediated by five melanocortin receptors (MC1R to MC5R), all coupled to G proteins [2]. Prohormone convertase 1/3 (PC1/3), the product of PCSK1, is a calcium-dependent endoprotease of the secretory granules of neuroendocrine tissues and the gut, which cleaves prohormones at pairs of basic residues and releases, among others, α-MSH, ACTH, insulin, glucagon, growth hormone-releasing hormone and dynorphin [3]. The melanocortin 4 receptor, encoded by an intronless gene, is the central node of the pathway: when activated by α- or β-MSH it couples to the Gs protein, raises cyclic adenosine monophosphate (cAMP) and generates the anorexigenic signal that ends the meal, whereas AgRP, its antagonist, blocks it and stimulates intake [3]. SH2B1 is an adaptor protein that modulates signalling by ligands acting through receptor tyrosine kinases or JAK-associated cytokine receptors, including leptin, insulin, GH and nerve growth factor [8]. The pathway diagram in the French PNDS adds MRAP2, an accessory protein that regulates MC4R, and the genes involved in the development of hypothalamic neuronal populations (SIM1, ADCY3, NTRK2 and BDNF), and stresses that the hypothalamic dysfunction common to these forms also lowers basal metabolic rate and may be accompanied by dysautonomia, disorders of thermoregulation and sleep, and pituitary deficiencies [23].

This architecture explains both the clinical similarities and the differences between defects in the various genes. The brain interprets loss of leptin or its receptor as starvation despite massive adiposity: appetite is uncontrolled, energy expenditure falls, gonadotrophin secretion fails to begin, the thyroid axis is suppressed, and CD4+ T-lymphocyte numbers and function decrease [3, 9]. Absence of all POMC-derived peptides adds adrenal insufficiency, due to failure of ACTH to activate MC2R, and hypopigmentation, due to failure of α-MSH to activate melanocyte MC1R, to the hyperphagia caused by absent hypothalamic MC4R activation [2]. PC1/3 deficiency affects all prohormone processing, explaining elevated proinsulin with low mature insulin, multiple endocrinopathies and malabsorptive diarrhoea caused by the inability of enteroendocrine cells to produce functional hormones [11, 27]. In MC4R deficiency, the receptor lies downstream of all other components; Lotta and colleagues functionally characterised 61 MC4R variants in approximately half a million UK Biobank participants and found that maximal β-arrestin recruitment, rather than canonical Gαs-mediated cAMP production, explained 88% of the variance in variant associations with BMI; most variants caused loss of function, but a subset caused gain of function, with lower BMI and lower odds of obesity, type 2 diabetes and coronary disease [20].

The position of the defect within the pathway determines the response to MC4R agonism. In POMC, PCSK1 or LEPR deficiency, the receptor is intact but lacks its ligand, so a synthetic agonist bypasses the defect [16, 33]. In MC4R deficiency, the drug target is the defective receptor itself; in cells, setmelanotide disproportionately rescued signalling by a subset of severely impaired mutant receptors, mice heterozygous for Mc4r responded less than wild-type mice, and receptor-null mice did not respond; in a 28-day phase 1b trial, human carriers lost weight, but less than patients with upstream defects [37]. In congenital leptin deficiency, replacement of the missing hormone corrects the defect at its origin [9].

2.2 Genes, variants and inheritance patterns

Historical variant nomenclature requires attention. The LEP founder variant was described in 1997 as a single-guanine deletion at codon 133 and in Pakistani series as “G133_VfsX14”; normalisation to the MANE transcript using VariantValidator yields NM_000230.3:c.398del, with predicted protein consequence p.(Gly133ValfsTer15), and ClinVar lists it as pathogenic c.398del (p.Gly133fs), so the difference in frameshift length reflects different counting conventions rather than different variants [4, 26, 38, 41]. The first POMC variants were published using historical genomic numbering (G7013T, C7133delta, C3804A in the 5′ untranslated region), which does not correspond to current c. numbering and has not been converted in this article [2, 29]. The correspondence between the authors' numbering of the POMC nonsense variants (c.231C>A and c.202C>T) and the MANE transcript was confirmed only for the predicted effect in VariantValidator, which yields premature termination codons consistent with the original description [4, 45, 46].

To rank the diagnostic work-up, the French PNDS classifies the genes and syndromes of rare obesity into three classes, combining the penetrance of the obesity or eating-behaviour phenotype with the strength of the pathophysiological evidence: class A, complete penetrance and a certain genetic basis; class B, intermediate penetrance and a less well-demonstrated basis; class C, situations in which obesity is multifactorial and secondary to intellectual disability, physical inactivity, a preference for energy-dense foods, psychotropic drugs or sleep disorders, which the protocol does not regard as rare causes of obesity [23]. The authors stress that the classification is not definitive, because many syndromes are very rare, have a poorly described eating phenotype or genes of little-known function, and they maintain an online table of 61 syndromes and genes [23]. The following table summarises the leptin–melanocortin pathway genes from annex 2 of the protocol; the class A and B syndromes are included in the differential diagnosis (section 6).

Source of the table: annex 2 of the PNDS [23]. The attribution of dominant inheritance to heterozygotes for LEP, LEPR, POMC and PCSK1 reflects a susceptibility effect with incomplete penetrance, distinct from the biallelic autosomal recessive picture described above, and the failure of the EMANATE trial in these heterozygotes (section 7.6) shows that membership of class B is not sufficient to indicate targeted therapy [18, 23].

2.3 Genotype–phenotype correlations

In POMC deficiency, a large number of biallelic variants produce the full phenotype, whereas some individuals with a single heterozygous variant at a critical processing site have severe early-onset obesity without adrenal insufficiency or hypopigmentation [2]. In a large Turkish family with a homozygous frameshift variant, 11 of 12 heterozygotes were overweight or obese, compared with 1 of 7 relatives without the variant, with a mean BMI standard deviation score of 1.7 ± 0.5 versus 0.4 ± 0.4 and statistical evidence of linkage of the “overweight” trait to the locus [6]. In MC4R deficiency, homozygotes are more severely affected than heterozygotes, variants with residual signalling capacity are associated with a less severe phenotype, and the signalling capacity of the mutant receptors correlates with energy intake [7]. In consanguineous Pakistani families, a sibling heterozygous for MC4R NM_005912.3:c.482T>C p.(Met161Thr) [4] had normal weight and hormones and the parents were only mildly overweight, which the authors interpreted as non-penetrance of obesity in heterozygotes for this variant [38]. In LEPR deficiency, a review of 57 cases with 38 distinct variants found no clustering of the degree of obesity or other manifestations by genotype; the variants were concentrated in the fibronectin III and cytokine receptor homology II domains, none in the cytoplasmic domain, and the authors allowed for residual activity of some variants [52]. In leptin deficiency, missense variants may cause milder obesity with hypogonadism without impairment of the T-lymphocyte response, and one variant can produce secreted, immunoreactive but biologically inactive leptin [3, 39].

3. Clinical Spectrum and Manifestations by System

3.1 Shared feature: hyperphagia and early-onset obesity

The feature common to all forms is hyperphagia, which an expert group convened in 2023 defined as pathological, insatiable hunger accompanied by abnormal food-seeking behaviours, and which it proposed as the central manifestation of a dysfunction of MC4R signalling shared by several diseases [53]. The Endocrine Society guideline describes the behaviours that should prompt genetic investigation: seeking or stealing food, waking at night to look for food and eating leftovers from others [19]. The chronology is equally characteristic. In a Dutch study of BMI trajectories from birth, the median age at onset of obesity was 1.2 years in the non-syndromic forms (0.4 years in biallelic LEPR deficiency, 0.6 years in biallelic MC4R deficiency and 1.7 years in heterozygous MC4R deficiency), 2.0 years in the syndromic forms and 3.8 years in children with obesity from the general population [54]. The French PNDS provides complementary chronological landmarks: children with biallelic deficiency of leptin or its receptor have a BMI above 27 kg/m² at 2 years and above 33 kg/m² at 5 years, with a BMI Z-score above +4, and all biallelic carriers of LEPR variants are obese before 6 years; in a French cohort with early-onset or severe obesity, heterozygotes for LEP, LEPR, POMC or PCSK1 variants had a mean age at onset of obesity of 1.5 ± 1.3 years when diagnosed in childhood and 5.4 ± 4.3 years when diagnosed in adulthood (74% of adults with obesity before 12 years), and in MC4R heterozygotes onset was described between 2 and 5 years, always depending on the functional impact of the variant [23]. Before setmelanotide, patients in the phase 3 trials with POMC, PCSK1 or LEPR deficiency were above the 95th weight percentile throughout childhood, with continuous weight gain and no lasting weight loss with diet, exercise or surgery [55].

The same protocol distinguishes hunger, satiation (reduction of hunger during the meal) and satiety (absence of hunger until the next meal) and describes, alongside hyperphagia due to lack of satiety, a continuum of eating-behaviour disorders shared with polygenic obesity, from simple compulsions to DSM-5 binge-eating disorder, whose severe forms combine loss of control, irrepressible craving and recurrent episodes; intolerance of restriction, food seeking and stealing, food obsessions that interfere with daily activities, night eating up to night-eating syndrome, and pica are also sought [23]. In the melanocortin pathway, the inability to reach satiation appears in the first months: the infant takes the bottle very quickly and cries with frustration when it is finished; in carriers of MC4R variants, greater intake has been observed in ad libitum meals, especially in the youngest, together with higher binge-eating scores [23]. The rapid onset of these disturbances at a precise age, particularly with endocrine signs or signs of intracranial hypertension, should prompt a search for acquired hypothalamic dysfunction [23].

3.2 Manifestations by gene

Congenital leptin deficiency (LEP). Children have normal birth weight; marked hyperphagia and accelerated weight gain begin after weaning and are accompanied by hypogonadism and hypothalamic hypothyroidism [5]. The deficiency is associated with reduced circulating CD4+ T-lymphocyte numbers and impaired T-lymphocyte proliferation and cytokine release, with frequent infections [9, 19]. The American Academy of Pediatrics (AAP) describes normal linear growth with reduced final height, rapidly developing obesity with hypothalamic dysfunction, and responsiveness to leptin treatment [22]. In untreated adults, BMI reached 59–60 kg/m² in two Colombian sisters aged 24 and 27 years, with intense hunger from childhood and hypogonadotrophic hypogonadism [40]. In a Pakistani cohort, hypercortisolism was more pronounced in carriers of LEP variants [56]. A report of a 39-year-old woman treated with metreleptin described reduced preoccupation with food, accompanied by improved mood, as the most striking initial subjective experience [57].

Leptin receptor deficiency (LEPR). Patients have hyperphagia, severe obesity, immune dysfunction and delayed puberty due to hypogonadotrophic hypogonadism, with a less severe presentation than leptin deficiency [10]. In the original family, homozygotes lacked pubertal development and had reduced GH and TSH secretion [28], and the Oxford Desk Reference includes LEPR among genetic causes of combined pituitary hormone deficiency with central hypothyroidism [58]. In a systematic review of 88 published patients, all had early-onset obesity, 96% had hyperphagia and 34% had at least one pituitary hormone deficiency [12]. The case described in section 10 illustrates motor delay secondary to excess weight and obstructive sleep apnoea in the second year of life [36].

POMC deficiency. In the first months of life, most children exhibit exponential weight gain, hyperphagia, cholestasis and adrenal insufficiency; by the end of the first year, weight is well above the 98th centile without increased height [2]. Adrenal insufficiency may present as adrenal crisis or neonatal cholestasis due to cortisol deficiency [5]. Red hair and Fitzpatrick type I skin, which always burns and never tans, are frequent but not universal: a child of Turkish origin, a North African patient, a Hispanic child and a North African boy have been reported without the typical pigmentary phenotype, with altered pheomelanin demonstrated by chemical hair analysis in some cases [2, 45, 46, 59]. Central hypothyroidism may occur, followed by GH deficiency and hypogonadotrophic hypogonadism in adolescence [2, 59]. Hypoglycaemia may be the initial presentation: the Hispanic child was diagnosed with ACTH deficiency at 9 months after hypoglycaemia, and the North African boy had hypoglycaemia in the first days of life [2, 45]. The AAP reports accelerated childhood growth [22].

PC1/3 deficiency (PCSK1). Presentation is neonatal, with enteropathy and diarrhoea requiring parenteral nutrition, hypoglycaemia and impaired processing of several prohormones, with hypothyroidism, hypogonadism, hypocortisolism and central diabetes insipidus; proinsulin is elevated relative to insulin [5]. In Martín and colleagues' series of 13 children, newborns had severe malabsorptive diarrhoea and growth failure, required prolonged parenteral nutrition and experienced high mortality; endocrinopathies developed in an age-dependent manner and included diabetes insipidus, GH deficiency, hypogonadism, adrenal insufficiency and hypothyroidism, and despite early growth abnormalities, moderate obesity with severe polyphagia usually developed [11].

MC4R deficiency. The presentation constitutes a distinct obesity syndrome: severe obesity with hyperphagia, increased lean mass, increased linear growth and severe hyperinsulinaemia [7]. Orphanet additionally describes increased bone mineral density, hyperphagia from the first year of life and preserved reproductive function [1], and the Endocrine Society reports low or normal blood pressure [19]. Tall stature in childhood distinguishes these children from most endocrine causes of obesity, which are accompanied by impaired growth [5, 19].

SH2B1 deficiency. Carriers of loss-of-function variants have hyperphagia, childhood-onset obesity, insulin resistance disproportionate to obesity severity and reduced adult final height, together with behavioural abnormalities absent in controls, including social withdrawal and aggression [8]. Mild speech and language delay is frequent and, according to the Endocrine Society, tends to resolve [5, 19]. Carriers of the distal 16p11.2 deletion encompassing SH2B1 had hyperphagia and severe, disproportionate insulin resistance; some larger deletions were associated with developmental delay and autistic traits [5, 21].

3.3 Manifestations by system

The French PNDS adds, from clinical experience and without frequency data, that adults with biallelic variants of the pathway may develop lipoedema of the lower limbs, distinguishable from lymphoedema because it spares the feet (negative Stemmer sign) and by pain on pinching the skin, and that it responds poorly to weight loss; it also adds that leptin deficiency and GH deficiency may contribute to faster progression of steatotic liver disease, which in these forms appears earlier and tends to be more severe than in common obesity [23].

3.4 Adults with genetic obesity

Most of the literature concerns children. A Dutch study of 79 adults with genetic obesity (32 with nonsyndromic monogenic forms and 47 with syndromic forms), compared with 186 adults with common obesity, found similar median BMI (41.2, 39.5 and 38.7 kg/m²), but median age at obesity onset was 3, 9 and 21 years, respectively; increased appetite was reported by 65.6%, 68.1% and 33.9%, and intellectual disability and autism spectrum disorder were concentrated in syndromic forms [60]. In a Pakistani cohort of 126 young adults with severe obesity, pathogenic LEP and LEPR variants were absent or rare, unlike findings in children from the same region; the authors related this to morbidity, mortality and social disadvantage among affected children [61].

4. Clinical Recognition and Warning Signs

Recognition rests on three questions: when obesity began, what the appetite is like, and which features accompany excess weight. The Oxford Desk Reference recommends a three-generation pedigree including parental and sibling height and weight, sibling birth weights and consanguinity; pregnancy and perinatal history; a detailed feeding history in the first year, seeking feeding difficulties and hypotonia suggestive of Prader–Willi syndrome; the age at onset of abnormal weight gain, which occurs in the first years of life in most genetic obesity syndromes; assessment of appetite, food-seeking and stealing, and satiety; developmental and behavioural profiles; and enquiry about visual impairment, night blindness and deafness [5]. The Endocrine Society additionally recommends recording the family's ethnic and geographical background and family history of severe obesity or bariatric surgery [19].

The French PNDS stresses that no single sign distinguishes a rare cause, because each may occur in common obesity; it is the combination of early onset, rapid onset, severity (BMI Z-score ≥ +3 SD or BMI above the IOTF 30 curve in children, BMI > 35 kg/m² in adults), resistance to conventional treatment and eating-behaviour disturbance with difficulty of voluntary control that points to one [23]. The protocol asks for the pedigree with the BMI of relatives, consanguinity and geographical origin: severe early-onset obesity over several generations suggests dominant transmission, and parents without obesity with affected siblings suggest recessive transmission or a de novo occurrence, but parental excess weight is common whatever the mode of transmission; the child health record should always be requested and, in adults, childhood photographs or the family's account replace the missing curve [23]. The BMI curve identifies the adiposity rebound, physiologically at around 6 years, whose absence or extreme earliness (before 3 years) favours a rare genetic obesity; a reduced growth velocity or one without concomitant acceleration should prompt a search for an endocrinopathy first, and acceleration suggests an MC4R variant; in adults, height is compared with target height, (father's height + mother's height)/2 + 6.5 cm in men or − 6.5 cm in women [23].

Physical examination should document height, weight and head circumference, fat distribution (truncal obesity is typical of Prader–Willi, Bardet–Biedl, Alström and Cohen syndromes), facial dysmorphism, hands and feet, genitalia (small in boys with Prader–Willi syndrome, Bardet–Biedl syndrome and some patients with leptin deficiency), acanthosis nigricans, blood pressure and murmurs, and an ophthalmological examination of visual fields, strabismus, myopia, photophobia and retinal pigmentation [5]. The American Academy of Pediatrics notes that more recently discovered genetic disorders do not necessarily display the classic findings of short stature, dysmorphism, developmental delay or intellectual disability, and that short stature is not a feature of leptin deficiency in childhood [22]. In adults, the Endocrine Society's paediatric criteria were met by only 56.3% of patients with monogenic obesity and 29.8% of patients with syndromic obesity, prompting the authors to propose adult-specific criteria [60].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Whom to test

Recommendation 2.1 of the Endocrine Society guideline, co-sponsored by the European Society of Endocrinology and the Pediatric Endocrine Society, suggests genetic testing in patients with extreme early-onset obesity (before 5 years) who have clinical features of genetic obesity syndromes, particularly extreme hyperphagia, and/or a family history of extreme obesity (weak recommendation, low-quality evidence); the guideline estimates that approximately 7% of patients with extreme paediatric obesity have rare chromosomal abnormalities or highly penetrant variants [19]. The 2025 expert group on hyperphagia recommends genetic testing for all patients with hyperphagia [53]. There are no formal diagnostic criteria for POMC deficiency, which is suspected in infants with severe hyperphagic obesity and congenital adrenal insufficiency due to ACTH deficiency [2].

The French PNDS defines obesity in children as a BMI above the IOTF 30 curve or a BMI Z-score ≥ +3 SD (the Z-score is more precise) and in adults as a BMI > 30 kg/m², with grade I between 30 and 34.9, grade II between 35 and 39.9 and grade III from 40 kg/m² [23]. Genetic investigation is guided by four criteria: age at onset and severity, presence or absence of a neurodevelopmental disorder, altered eating behaviour, and endocrine abnormalities or other syndromic signs [23]. When there is a neurodevelopmental disorder, above all intellectual disability, the protocol recommends referral to a genetics department linked to a reference or competence centre for intellectual disability (DéfiScience network) and following the decision trees of those protocols and of the French association of molecular genetics laboratories; in severe early-onset obesity without a neurodevelopmental disorder, it proposes a panel with the genes and syndromes of annex 2, whose indication can be discussed at a regional or national multidisciplinary team meeting with the reference centre and the laboratories [23]. To support this orientation, the reference centre developed the online tool Obsgen, which, on the basis of these clinical criteria, suggests the genetic investigations and the laboratories that perform them and allows cases to be submitted to the meeting [23].

5.2 Biochemical and endocrine investigations

5.3 Genetic tests and their limitations

The Oxford Desk Reference recommends genomic analysis (microarray, gene panel, exome or genome sequencing) according to availability, supplemented by 15q11-q13 methylation studies when there is a history of hypotonia with weak suck [5]. Targeted sequencing of 52 obesity-related genes in 1230 Dutch patients yielded a definitive diagnosis in 3.9% and a possible diagnosis requiring further analysis in 5.4%; most definitive diagnoses involved MC4R (18 of 48), and the yield was 7.3% (12 of 164) in the paediatric subgroup with severe early-onset obesity [63]. Chromosomal microarray is needed to detect 16p11.2 deletions, which short-read sequencing targeting exons may miss [5, 21].

Technical limitations should be stated in the report. For POMC, GeneReviews indicated that sequencing detects single-nucleotide variants and small intragenic insertions or deletions, but not exon-level or whole-gene deletions or duplications, and that such rearrangements had not been described as causes of POMC deficiency; variants in the 5′ untranslated region that abolish translation or transcription (for example, the variant at position −11 relative to the initiation codon, described in 2014) require inclusion of this region in the analysis [2, 64]. In LEPR, sharing of the promoter and first two exons with LEPROT requires care in transcript assignment [3]. In MC4R, complete loss-of-function, partial loss-of-function and gain-of-function variants coexist, so classification depends on functional data; the assays used by Farooqi and Lotta are research tools rather than available clinical tests [3, 7, 20]. The US setmelanotide label states that no FDA-approved test is available to detect variants in POMC, PCSK1 or LEPR [16]. An appropriate report identifies the gene, versioned transcript (for example NM_002303.6 for LEPR), HGVS nomenclature, zygosity, classification according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, and methodological limitations [4]. A VUS does not become pathogenic because of a treatment response; this distinction has practical implications because the US setmelanotide label permits variants of uncertain significance, whereas the European label requires genetically confirmed biallelic loss-of-function deficiency (section 7) [16, 17].

5.4 Assessment algorithm

The algorithm combines Endocrine Society recommendations, the Oxford Desk Reference steps and the Dutch age threshold; figure 1 of the Endocrine Society guideline, adapted from Farooqi and O'Rahilly, presents a similar flowchart including insulin and proinsulin measurement in patients with features of PCSK1 deficiency [1, 5, 19, 54].

6. Differential Diagnosis

The Endocrine Society and Oxford Desk Reference organise the differential into obesity with and without developmental delay or dysmorphism, while also considering endocrine and acquired causes [5, 19].

In the particular case of POMC deficiency, adrenal insufficiency has its own differential diagnosis. PC1/3 deficiency reproduces the obesity and adrenal insufficiency but adds other endocrinopathies and, in some patients, small-bowel dysfunction with severe diarrhoea [2]. Deficiencies of the melanocortin 2 receptor, the MC2R accessory protein (MRAP), the steroidogenic acute regulatory protein (STAR) and nicotinamide nucleotide transhydrogenase (NNT), X-linked Addison disease, autoimmune polyendocrine syndrome type 1, natural killer cell and glucocorticoid deficiency with DNA repair defect, and combined pituitary hormone deficiency should also be considered, and may coexist with non-syndromic obesity [2]. A common MC1R variant, frequent in European populations, is associated with red hair and may be co-inherited with another rare disease causing early-onset obesity, so isolated red hair does not confirm POMC deficiency; Beckwith–Wiedemann syndrome presents with high birth weight and neonatal hypoglycaemia, but not typically with postnatal hyperphagia [2]. The rows added to the table come from the class A and B syndromes of annex 2 of the French PNDS, which excludes from the category of rare cause the class C situations in which obesity is secondary to intellectual disability and context [23].

7. Treatments and Risk Management Strategies

7.1 General principles and nonpharmacological interventions

Treatment combines general management of paediatric obesity, replacement of deficient hormones and, where available, treatment targeting the pathway defect. The Endocrine Society guideline recommends intensive, age-appropriate, culturally sensitive, family-centred lifestyle modification (diet, physical activity and behaviour), prioritised screening for comorbidities, and screening for mental health problems in the child and family [19]. The 2023 AAP guideline recommends that children aged 6 years or older with overweight or obesity receive or be referred for intensive health behaviour and lifestyle treatment (grade B), an option that may extend to children aged 2 to 5 years (grade C); the most effective programmes provide 26 or more hours of face-to-face, family-centred, multicomponent treatment over 2 to 12 months [22]. In monogenic forms, however, hyperphagia has a biological basis: dietary and behavioural measures did not durably change the weight trajectory of patients with POMC, PCSK1 or LEPR deficiency before setmelanotide, and GeneReviews indicated, before its availability, that lifestyle measures were the only obesity treatment option in POMC deficiency [2, 55]. The Endocrine Society emphasises that a genetic diagnosis helps families and professionals manage the child's health, may reduce social stigma and informs treatment decisions, including bariatric surgery, because many such patients are resistant to weight loss through diet and exercise [19]. A report of a 10.5-year-old girl with LEPR deficiency described how diagnosis reduced others' judgement and improved cooperation from her school and social network, and how a strict dietary regimen reduced BMI in the first year, followed by stabilisation at class 3 obesity until targeted treatment began [68].

Recommendations for paediatric pharmacotherapy and surgery changed between the two guidelines. In 2017, the Endocrine Society suggested restricting weight-loss medication in children and adolescents to clinical trials and reserving bariatric surgery for physically mature adolescents in whom lifestyle measures had failed, at experienced centres [19]. In 2023, the AAP recommended offering pharmacotherapy to adolescents aged 12 years or older with obesity, as an adjunct to behavioural treatment (grade B), and referring adolescents aged 13 years or older with severe obesity, defined as BMI ≥ 120% of the 95th centile, for surgical assessment (grade C) [22]. The difference mainly reflects the dates of the guidelines and intervening drug approvals; neither guideline was designed for monogenic forms, which the AAP excluded from its evidence review [22].

The French PNDS places dietary intervention at the centre and asks that it begin at diagnosis, whether or not obesity is already established, led by a dietitian experienced in eating-behaviour disorders and in a climate of trust, because families may need years to identify and work through the obstacles to an acceptable food framework [23]. The aims are to control access to food, structure the rhythm and setting of meals to reduce anxiety, treat behavioural difficulties early and coordinate professionals with the places where the person lives; in children the goal is to stabilise weight while height increases, so that BMI falls [23]. Annex 7 of the protocol translates these principles by age: in infants, pauses during bottle-feeding, respect for feeding frequency, adjustment of volume to the rate of weight gain and control of quantities during dietary diversification; in school-age children, a written meal plan with set times and structure, their own plate and cup, no bread or food within reach, a locked kitchen and an individualised reception plan (PAI) at school; in adolescents and adults, a written, individualised and non-negotiable plan, following the food-security principle of “no doubt, no hope”, with identification of sources of access to food, explanation of the framework to shopkeepers and institutions, no pocket money and no unsupervised cookery classes, and never using food as punishment or reward [23]. Because these patients' resting energy expenditure is lower than expected for age, sex and body size, and GH and sex-steroid deficiencies reduce lean mass, caloric intake is adjusted to needs, measured if possible by indirect calorimetry [23]. The conviviality of meals is preserved by keeping a varied offer for siblings, and the protocol asks that, in the first consultations, biologically driven hyperphagia be distinguished from the family's difficulty in imposing an educational framework, which frequently coexist [23].

Adapted physical activity is part of treatment from childhood, to counter cardiorespiratory and muscular deconditioning and establish habits that persist into adult life; the protocol proposes assessing leisure, occupational, domestic and travel-related activity and sedentary time, and making a personalised prescription, exemplified in adults without a neurodevelopmental disorder by a 20-minute walk per day, two supervised weekly sessions of resistance and muscle-strengthening exercise, less than 2 hours of screen time per day and standing up at least once an hour [23]. In the physical medicine and rehabilitation assessment, any child with severe obesity and open growth plates who reports hip or knee pain on exertion or a limp should have anteroposterior and lateral radiographs of the pelvis and hips, for suspected slipped capital femoral epiphysis, and be referred urgently to orthopaedics; the alignment of the spine, knees and feet is examined in all patients, with low-dose whole-body radiography from 10 years when scoliosis is suspected [23]. Conventional technical aids, including wheelchairs, generally have a limit of 130 kg; above this weight bariatric equipment is needed, and from 170 kg specific equipment [23].

On the psychological level, the protocol recommends case-by-case neuropsychological assessment in forms without a neurodevelopmental disorder when there are school, emotional or social-interaction difficulties, and psychiatric assessment when there are anxious, depressive or behavioural signs [23]. Psychotropic drugs are considered only after psychoeducational strategies have failed or in an acute decompensation; for anxiety or depression selective serotonin reuptake inhibitors are preferred, benzodiazepines should be avoided because of the risk of respiratory depression, particularly with untreated sleep apnoea, and, when an antipsychotic is needed, the protocol prefers aripiprazole for its better metabolic profile, with metabolic and neurological monitoring; in all cases the molecule least harmful to weight is chosen, at the lowest effective dose, and polypharmacy is avoided [23].

7.2 Setmelanotide (Imcivree®)

Mechanism and formulation. Setmelanotide is an MC4 receptor agonist with approximately 20-fold lower activity at MC3 and MC1 receptors; it restores pathway activity when upstream defects cause inadequate MC4R activation, and activation of melanocyte MC1R explains ultraviolet-independent skin hyperpigmentation [16]. It is supplied as a 10 mg/mL solution for injection in a 1 mL multidose vial, refrigerated before opening, and contains benzyl alcohol as a preservative (10 mg/mL in the European SmPC) [16, 17]. It is administered subcutaneously once daily.

Current indications. In the United States, the label dated 1 April 2026 indicates setmelanotide to reduce excess body weight and maintain weight reduction long term in adults and children aged 4 years or older with acquired hypothalamic obesity, and aged 2 years or older with syndromic or monogenic obesity due to Bardet–Biedl syndrome or POMC, PCSK1 or LEPR deficiency confirmed by genetic testing with variants interpreted as pathogenic, likely pathogenic or of uncertain significance [16]. Limitations of use exclude obesity due to suspected POMC, PCSK1 or LEPR deficiency with variants classified as benign or likely benign, and other forms of obesity, including obesity associated with other genetic syndromes and general polygenic obesity [16]. In the European Union, the SmPC indicates it for treatment of obesity and control of hunger in adults and children aged 4 years or older with acquired hypothalamic obesity due to hypothalamic injury or dysfunction, and aged 2 years or older with genetically confirmed Bardet–Biedl syndrome or genetically confirmed biallelic loss-of-function POMC deficiency (including PCSK1) or biallelic LEPR deficiency; prescribing and supervision should be undertaken by physicians experienced in rare forms of obesity of genetic or hypothalamic origin [17]. Neither label includes MC4R deficiency or SH2B1 deficiency; neither includes leptin deficiency, which should not be confused with leptin receptor deficiency [3, 16, 17].

Table sources: US label, European SmPC, Drugs@FDA, EMA procedural documents and marketing authorisation holder reports [16, 17, 34, 35, 69, 70]. The most recent EMA procedural document records the hypothalamic obesity variation with 20 March 2026 in the decision column, preceding the opinion date communicated by the marketing authorisation holder; this inconsistency between sources does not change the current status, which is an authorised indication in the SmPC [17, 69, 70]. Authorisation does not guarantee reimbursement or availability in each Member State; the marketing authorisation holder indicated that national launches for hypothalamic obesity in Europe would begin from 2027 [71].

Efficacy in pivotal trials. The two open-label, single-arm phase 3 trials with identical designs (NCT02896192 for POMC/PCSK1 and NCT03287960 for LEPR) took place at ten hospitals in Canada, the United States, Belgium, France, Germany, the Netherlands and the United Kingdom and included patients aged 6 years or older; after 12 open-label weeks, those losing at least 5 kg (or 5% if weighing less than 100 kg) entered an 8-week blinded withdrawal sequence with 4 weeks of setmelanotide and 4 of placebo, followed by 32 open-label weeks [72]. The VENTURE trial (NCT04966741) extended assessment to children aged 2 to 5 years [73].

These results require careful interpretation. The trials had no parallel control group; the implicit comparison is with natural history documented retrospectively in the same patients [55]. Figures differ between the US label and European SmPC because the former uses the full analysis set and the latter reports weight change in the subset losing weight in the first 12 weeks and entering withdrawal, thereby selecting responders [16, 17]. The mean response in LEPR deficiency was smaller than in POMC deficiency in all analyses, which should be communicated to families [16, 72]. In VENTURE, gene-specific subgroups contain three to five patients, the confidence intervals for LEPR deficiency include zero, and BMI changes in a growing child are not comparable to adult weight changes [16, 73]. The effect depends on continuous administration: the European SmPC states that weight loss and hunger control are maintained while treatment continues without interruption, and that symptoms return if it is discontinued or adherence lapses [17].

Adverse effects and management. In the European SmPC, which pools all indications, the most frequent reactions were hyperpigmentation disorders (66%), injection-site reactions (45%), nausea (36%) and headache (19%); vomiting occurred in 17%, and spontaneous penile erections and increased erections in 14% and 13% of male patients, with no erection lasting more than 4 hours [17]. Hyperpigmentation usually develops 2 to 3 weeks after initiation, persists during treatment and resolves on discontinuation; nausea and vomiting were concentrated in the first month and were mild and transient [17]. Melanocytic naevi are very common and dysplastic naevi uncommon; publications describe a paediatric LEPR deficiency case with dysplastic naevi excised at 6 months of treatment, with temporary discontinuation, and a report of eruptive dysplastic melanocytic naevi [17, 74, 75]. The US label includes warnings about disturbed sexual arousal, depression and suicidal ideation, severe hypersensitivity reactions including anaphylaxis (contraindicated after a previous severe reaction), and, in hypothalamic obesity, acute adrenal insufficiency and sodium disturbances in central diabetes insipidus [16]. Management includes a full-body dermatological examination before initiation and periodically (annually according to the European SmPC), heart rate and blood pressure monitoring at every visit (at least every six months), monitoring for depression at every visit with consideration of discontinuation for suicidal ideation, instructions to seek emergency care for an erection lasting more than 4 hours, dose reduction for gastrointestinal intolerance and, in children, growth monitoring using appropriate charts; 2-year-old patients should be monitored for metabolic acidosis due to benzyl alcohol accumulation [16, 17]. Treated children experienced more vomiting, hyperpigmentation and new or darkened naevi than adults [16].

7.3 Congenital leptin deficiency: metreleptin and investigational alternatives

Metreleptin (Myalept® in the United States, Myalepta® in the European Union) is a recombinant human leptin analogue. The US label (initial approval 24 February 2014) indicates it only as an adjunct to diet as leptin replacement therapy to treat the complications of leptin deficiency in congenital or acquired generalised lipodystrophy, and expressly excludes patients with metabolic disease without concurrent evidence of generalised lipodystrophy [13, 76]. The European SmPC (authorisation under exceptional circumstances on 30 July 2018) indicates it in generalised lipodystrophy from 2 years of age and in familial or acquired partial lipodystrophy from 12 years of age when standard treatment has failed [14]. Use in congenital leptin deficiency without lipodystrophy is therefore off-label in both jurisdictions, despite being the treatment that corrects the defect [3, 13, 14]. Annex 8 of the 2021 French PNDS describes metreleptin, given subcutaneously once daily, as authorised in patients homozygous or compound heterozygous for LEP variants, a statement that does not correspond to the European SmPC consulted (section 7.8) [14, 23]. In 2017 the Endocrine Society reported that recombinant human leptin was available on a named-patient basis at selected centres and that the manifestations of the deficiency could be fully treated with subcutaneous injections [19].

Efficacy evidence comes from small series: Farooqi and colleagues' three patients had sustained benefit for up to four years [9]; the boy with bioinactive leptin NM_000230.3:c.298G>T p.(Asp100Tyr) rapidly normalised his eating behaviour and lost weight [39]; and the two Colombian sisters treated for 12 months reduced BMI from 59 to 38 and from 60 to 48 kg/m², with lipid normalisation, improved insulin sensitivity and reversal of hypogonadism, in a study without a control group or antibody measurement [40]. In that study, the authors used 2.5 mg subcutaneously once daily, preferably in the evening, titrated to 5 mg/day, adopting the adult dose from the lipodystrophy label; this off-label use is supported only by that report [40]. For reference, the lipodystrophy label specifies 0.06 mg/kg/day at body weight up to 40 kg, adjusted in 0.02 mg/kg increments to 0.13 mg/kg/day, and above 40 kg, 2.5 mg/day for males or 5 mg/day for females, adjusted in increments of 1.25 to 2.5 mg to 10 mg/day [13, 14]. The US label carries a boxed warning about anti-metreleptin antibodies with neutralising activity (antibodies detected in 84% of studied patients with generalised lipodystrophy; neutralising activity associated with events in 6%) and T-cell lymphoma in acquired generalised lipodystrophy, and access in the United States is through a restricted risk evaluation and mitigation strategy (REMS) programme; hypoglycaemia with insulin or secretagogues, progression of autoimmune disease and hypersensitivity are also described, with gradual dose reduction recommended when discontinuing in patients at risk of pancreatitis [13]. In patients without lipodystrophy treated in studies, neutralising antibodies were associated with excessive weight gain and glucose intolerance or diabetes, warranting testing when efficacy is lost or severe infections occur [13].

Mibavademab (REGN4461), a leptin receptor agonist antibody, is being evaluated in an open-label, single-arm phase 3 trial (NCT07220772; European registration 2024-518674-14-00), which began recruitment on 9 February 2026 for approximately four patients with biallelic loss-of-function LEP variants and class ≥ 2 obesity, excluding patients treated with metreleptin; the primary endpoint is percentage BMI change at 24 weeks, with primary completion expected in June 2027 [15]. No results have been published.

7.4 Hormone replacement and gene-specific care

In POMC deficiency, neonatal adrenal insufficiency is treated conventionally with hydrocortisone under paediatric endocrinology care; mild central hypothyroidism is treated with levothyroxine, which should be initiated only after adrenal function has been assessed and treated; adolescent GH deficiency is treated with daily subcutaneous GH and hypogonadotrophic hypogonadism with sex steroids [2]. Fair skin requires sun protection counselling (avoiding exposure between 10:00 and 14:00, protective clothing and high-factor sunscreen) and discussion of the theoretical risk of skin cancer, although no associated malignant lesions have been described [2]. PC1/3 deficiency requires multidisciplinary management, with enteral or parenteral nutritional support for neonatal diarrhoea and lifelong endocrine surveillance with replacement of deficient hormones (levothyroxine, hydrocortisone, GH, sex steroids and desmopressin as indicated) [3, 11]. In LEP and LEPR deficiencies with hypogonadotrophic hypogonadism, treatment comprises pubertal induction and maintenance replacement; fertility can sometimes be induced with exogenous gonadotrophins or pulsatile GnRH [77]. In leptin deficiency, leptin itself facilitates age-appropriate puberty through age-dependent effects on gonadotrophin secretion [9].

The French PNDS systematises the assessment and replacement of pituitary deficiencies, which it frequently associates with the recessive forms of the pathway (gonadotrophic, thyrotrophic, corticotrophic, somatotrophic and diabetes insipidus) [23]. In thyrotrophic deficiency (low or normal TSH with low free T4), levothyroxine aims for a free T4 in the upper half of the reference range, whereas in peripheral hypothyroidism the target is normalisation of TSH; in corticotrophic deficiency (low 08:00 cortisol with normal or low ACTH, confirmed if necessary by a tetracosactide stimulation test), hydrocortisone should avoid overdosing and is accompanied by therapeutic education and an adrenal insufficiency card; diabetes insipidus is suspected with urine output above 30–40 mL/kg/day with hypotonic urine (osmolality below 250–300 mOsm/kg) and is treated with desmopressin, with education about the signs of hyponatraemia [23]. Gonadotrophic deficiency is assessed during minipuberty and in delayed puberty (micropenis or cryptorchidism at birth, testosterone, LH, FSH and inhibin B in boys; oestradiol, LH, FSH and anti-Müllerian hormone in girls) and is treated with pubertal induction and replacement with testosterone or with oestrogens followed by progestogens, with gonadotrophins when fertility is desired and prostate-specific antigen measurement from 50 years in men on replacement; multiple pituitary deficiencies require hypothalamic–pituitary MRI and, in the absence of a lesion, should prompt consideration of ROHHAD syndrome [23].

In situations of acute stress (infection, vomiting, diarrhoea), the protocol calls for an increase in oral hydrocortisone and, in case of any doubt, intravenous administration and hospital admission [23]. The PNDS does not give doses; by extrapolation from the Endocrine Society guideline for primary adrenal insufficiency, applied here to secondary insufficiency due to ACTH deficiency in POMC and PC1/3 deficiencies, replacement in children starts at about 8 mg/m²/day of hydrocortisone in three or four doses, adjusted for growth and without exceeding physiological needs, because doses above this value may already reduce growth velocity; during febrile illness the oral dose is doubled (fever > 38 °C) or tripled (> 39 °C) until recovery, usually 2 to 3 days; in case of vomiting or suspected adrenal crisis, immediate parenteral hydrocortisone is given at 50 mg/m² in children, up to a maximum of 100 mg, the adolescent and adult dose (for emergency intramuscular injection, 25 mg in infants, 50 mg in school-age children and 100 mg in adolescents), followed by 50–100 mg/m²/24 h in children and 200 mg/24 h in adults, by continuous infusion or every 6 hours, with fluid replacement [78].

In the emergency department, the protocol notes that these patients may have no fever despite severe infection, owing to hypothalamic dysregulation of thermoregulation, and may express pain poorly, so that a recent change in behaviour may be the only sign of a complication [23]. In the central diabetes insipidus of PC1/3 deficiency, dysnatraemia should be considered in the presence of altered alertness, nausea or vomiting, with immediate sodium measurement [23]. With acute or worsening dyspnoea the patient should not be laid flat; B-type natriuretic peptide (BNP) and NT-proBNP are interpreted knowing that values are inversely proportional to BMI, pulmonary embolism and acute respiratory failure on obesity hypoventilation syndrome (with blood gases looking for PaCO₂ > 45 mmHg) are considered, and benzodiazepines and other respiratory depressants are avoided [23]. During prolonged hospital admission, severe obesity may be accompanied by malnutrition, with albumin difficult to interpret owing to chronic inflammation, which requires prevention of refeeding syndrome; when there is an eating-behaviour disturbance, access to all food sources on the ward is controlled, with staff informed [23].

7.5 MC4R and SH2B1 deficiency: options without an approved targeted treatment

No drug is approved specifically for MC4R deficiency, and setmelanotide is excluded by the label's limitation of use [3, 16]. The 28-day phase 1b trial showed weight loss in carriers of MC4R variants, smaller than with upstream defects, and the authors considered demonstration of clinically meaningful benefit in a selected subset necessary [37]. Bariatric surgery has the largest evidence base. The Endocrine Society noted that adolescents and adults with heterozygous MC4R variants lose weight after Roux-en-Y gastric bypass [19]. In a Dutch bariatric cohort of 1014 patients, 3% had genetic obesity due to heterozygous pathogenic variants in MC4R, POMC, PCSK1, SIM1 or PTEN; weight loss after bypass did not differ from that in patients without a molecular diagnosis, but carriers of MC4R variants undergoing sleeve gastrectomy lost significantly less weight over two years [79]. In a series of six patients with MC4R deficiency followed for up to 10 years, surgery outperformed liraglutide for weight and glycaemic control; at 6 months, weight loss did not differ from wild-type controls (20.8% versus 23.0%; p = 0.65), but long-term outcomes were heterogeneous and depended on variant type [80]. In a series of four adults (two with 16p11.2 deletion and two with heterozygous pathogenic MC4R variants) treated with liraglutide 3.0 mg/day plus intensive lifestyle intervention, all lost at least 5% of body weight and three at least 10%, with follow-up ranging from 43 weeks to 12 years [81]. These data derive from very small series and do not support genotype-specific recommendations; liraglutide is used in these settings under its general obesity indication [22, 81].

The French PNDS reviewed bariatric surgery in the forms of the pathway. In a 2021 Franco-German study of eight patients with biallelic variants (two POMC, five LEPR and one MC4R; median age 19 years; mean BMI 51.9 kg/m²) who underwent gastric banding, sleeve gastrectomy or Roux-en-Y bypass, sometimes several procedures, initial weight loss was followed by weight regain in all; in heterozygotes the results were contradictory, with no difference at 2 years in the Dutch cohort and less weight loss after 6 years following sleeve gastrectomy in a Chinese cohort of 131 patients in which 8.4% (11) had a heterozygous variant [23]. In MC4R heterozygotes, weight loss after 1 year was similar to that of controls, but the variant was associated with more binge eating before surgery and with more reoperations and postoperative complications; in the Dutch cohort, 11 carriers operated on by bypass lost as much weight as non-carriers and 3 operated on by sleeve gastrectomy lost significantly less over 2 years, which the protocol interprets as an argument in favour of bypass [23, 79]. The protocol concludes that homozygous forms without psychiatric disorder, severe binge eating or intellectual disability are not an absolute contraindication, but that disappointing weight outcomes and the arrival of targeted treatments call for caution; in heterozygotes the data do not allow a rule, and the decision should be taken with a specialised centre, preferably at a national meeting of the reference centre, weighing MC4R agonists [23]. In rare obesities with a neurodevelopmental disorder, by contrast, surgery is not recommended, save in exceptional cases discussed at that meeting, because of disappointing medium- and long-term results and complications that are difficult to recognise [23].

As for drugs, the PNDS (July 2021) considered that there was no validated specific treatment and listed, in annex 8, metreleptin, GLP-1 analogues and setmelanotide [23]. For GLP-1 analogues it indicated liraglutide 3 mg/day (maximum dose) subcutaneously, available in France for common obesity since March 2021 and usable in rare obesities without reimbursement, and semaglutide 2.4 mg/week, then under a request for a cohort temporary authorisation for use for BMI > 40 kg/m² without diabetes; in associated type 2 diabetes it regarded them as the preferred option, because they reduce weight and, at maximum dose, may improve appetite control [23]. The PNDS date of March 2021 corresponds to marketing in France: liraglutide 3.0 mg (Saxenda®) has held a European marketing authorisation since 23 March 2015 [82], and its marketing in France was declared on 2 March 2021, at a free price and without reimbursement [83]. The current European SmPCs set out the titration. Liraglutide (Saxenda®) is started at 0.6 mg/day and increased by 0.6 mg per week to 3.0 mg/day, a dose that should not be exceeded, in adults with BMI ≥ 30 kg/m² (or ≥ 27 kg/m² with comorbidity), in adolescents from 12 years with obesity and weight > 60 kg and in children aged 6 to < 12 years with BMI ≥ 95th percentile and weight ≥ 45 kg; it is discontinued if, after 12 weeks at 3.0 mg or at the maximum tolerated dose, weight loss does not reach 5% of body weight in adults or 4% of BMI or its Z-score in children and adolescents [82]. Semaglutide (Wegovy®) is started at 0.25 mg/week and increased every 4 weeks (0.5, 1 and 1.7 mg) to 2.4 mg/week from week 17; in adults with BMI ≥ 30 kg/m² it may be increased to 7.2 mg/week after at least 4 weeks at 2.4 mg, and in adolescents from 12 years with obesity and weight > 60 kg it remains at 2.4 mg/week, with reassessment if BMI does not fall by at least 5% in 12 weeks [84]. The US labels indicate liraglutide from 12 years with weight > 60 kg, with a paediatric titration that may extend over 8 weeks up to the maximum dose of 3 mg/day, with reduction to 2.4 mg/day if 3 mg is not tolerated, and semaglutide from 12 years with paediatric maintenance at 2.4 mg/week, which is also the maximum dose at that age [85, 86]. None of these medicines has a specific indication in the monogenic forms, and they are used under the general obesity indications.

In SH2B1 deficiency, the SH2B1 substudy of the phase 3 EMANATE trial (section 7.6) showed no significant difference from placebo [18]. Management of 16p11.2 deletion carriers includes neurodevelopment.

7.6 Developments in the last 12 months and hierarchy of evidence

Interpretation of this table should respect the hierarchy of evidence: a sponsor press release reports preliminary results that may change on publication; a CHMP opinion is not an authorisation; an FDA or European Commission decision does not guarantee marketing, reimbursement or access in each country; and favourable post hoc EMANATE analyses do not replace the failed primary endpoint [18, 70]. A search yielding no results does not prove that other trials do not exist.

7.7 Comorbidities of severe obesity: screening and treatment according to the PNDS

In these forms, metabolic complications may be primary, linked to the defect itself and present from childhood, or secondary to obesity and later in onset. The French PNDS (French National Diagnosis and Care Protocol) recommends, in situations of moderate risk or of secondary abnormalities, annual screening from adolescence with fasting glucose, C-peptide, HbA1c and lipid profile, supplemented by an oral glucose tolerance test every 5 years, and reserves screening every 6 to 12 months from 4 years of age for high-risk situations (Alström syndrome and craniopharyngioma); acanthosis nigricans and abdominal fat distribution signal early metabolic risk [23]. In type 2 diabetes, metformin is first line, GLP-1 analogues are the preferred option because they reduce weight, DPP-4 and SGLT2 inhibitors are options in combination with metformin not yet studied in these forms, insulin is a last resort or for demonstrated insulinopenia, HbA1c is measured every 3 months and, where there is intellectual disability, the regimen should be simple and supervised, with caregiver education; complications are screened with annual fundoscopy and six-monthly microalbuminuria [23]. According to the US label, metformin is started at 500 mg twice daily with meals from 10 years of age, with weekly increases of 500 mg to a maximum of 2000 mg/day in two doses, and in adults at 500 mg twice daily or 850 mg once daily, to a maximum of 2550 mg/day; it is not used with an estimated glomerular filtration rate < 30 mL/min/1.73 m² and is not started between 30 and 45 [91]. In hypertriglyceridaemia, the protocol recommends a fibrate when fasting triglycerides exceed 5 mmol/L after 3 months of nutritional intervention, and fenofibrate immediately if they exceed 10 mmol/L or there is a history of acute pancreatitis, with three-monthly triglycerides, hepatic and muscle monitoring and dose adjustment with creatinine clearance < 60 mL/min; LDL cholesterol is not higher in these forms, but in adults at high vascular risk the target is < 2.0 mmol/L, with a statin as first line and six-monthly lipid profile [23]. The US label of fenofibrate (48 and 145 mg tablets) indicates, in severe hypertriglyceridaemia in adults, 48–145 mg once daily, up to a maximum of 145 mg/day, starting at 48 mg in mild to moderate renal impairment, avoidance in severe renal impairment and discontinuation if there is no response after 2 months at the maximum dose; safety and efficacy in children have not been established [92].

Steatotic liver disease appears earlier in these forms, sometimes before adulthood, and tends to be more severe owing to early and prolonged exposure to metabolic risk factors. The protocol asks for liver ultrasound in all patients, transaminases (looking for cytolysis between 1.5 and 5 times the upper limit, with ALT predominance), GGT and ferritin, exclusion of other causes of chronic liver disease and, in adults, estimation of fibrosis by simple blood scores (FIB-4 or NAFLD fibrosis score), which cannot be used in children, with referral to hepatology if they suggest fibrosis [23].

Severe obesity and hypothalamic dysfunction predispose to obstructive sleep apnoea, nocturnal hypoventilation, an early phase of obesity hypoventilation syndrome (daytime PaCO₂ ≥ 45 mmHg with BMI ≥ 30 kg/m², without another cause), hypersomnia and circadian rhythm disorders [23]. Apnoea is diagnosed by respiratory polygraphy or polysomnography, hypoventilation requires nocturnal transcutaneous capnography and blood gases, and treatment uses continuous positive airway pressure for apnoea and non-invasive ventilation for hypoventilation, with reassessment of sleep after 1 to 3 months of optimised ventilation; in children, or when behaviour prevents 48-hour hospital recording, at least home polygraphy and blood gases are proposed [23].

Obesity-related glomerulopathy results from hyperfiltration (glomerular filtration rate > 120 mL/min), activation of the renin–angiotensin system, chronic inflammation and raised leptin [23]. The protocol asks annually for creatinine with estimated filtration rate and albumin/creatinine or protein/creatinine ratio in a urine sample, notes that neither creatinine clearance nor the MDRD and CKD-EPI formulae are validated in severe obesity and suggests de-indexing the estimate by multiplying it by the calculated body surface area; it refers to nephrology with a filtration rate < 60 mL/min, decline > 5 mL/min/year, protein/creatinine > 100 mg/mmol or albumin/creatinine > 70 mg/mmol, proteinuria uncontrolled on the maximum tolerated dose of a renin–angiotensin system blocker (protein/creatinine > 50 or albumin/creatinine > 30 mg/mmol), uncontrolled hypertension, associated haematuria or morphological lesions; first-line treatment is an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker at progressive doses, with blood pressure targets < 130/80 mmHg and albumin/creatinine < 30 mg/mmol [23].

In the asymptomatic patient, the protocol recommends at least one electrocardiogram and one transthoracic echocardiogram, generally repeated every 3 to 5 years or earlier if there are symptoms, and reassessment of cardiovascular risk factors at each visit [23]. In the digestive tract, biallelic PC1/3 deficiency classically presents with severe neonatal diarrhoea requiring parenteral nutrition in the first years; in the other forms, gastro-oesophageal reflux, gallstones and acute pancreatitis, favoured by very high triglycerides, are more frequent, and symptoms should be sought at each visit because they may be atypical [23]. Skin examination looks for intertrigo, acanthosis nigricans, scratch excoriations, signs of venous and lymphatic insufficiency and lipoedema, and prevention of erysipelas relies on monitoring wounds and portals of entry on the feet [23].

7.8 Divergences between the French PNDS and other sources

8. Reproductive Options and Family Counselling

LEP, LEPR, POMC and PCSK1 deficiencies are autosomal recessive. Parents of an affected child are obligate heterozygotes; at conception, each sibling has a 25% probability of being affected, 50% of being a carrier and 25% of inheriting neither variant, and an unaffected sibling has a 2/3 probability of being a carrier; children of an affected individual are obligate heterozygotes, each parental sibling has a 50% carrier risk, and two of the four grandparents are expected to be carriers [2]. Carrier detection and prenatal diagnosis are possible only when familial variants have been identified and laboratory-confirmed in the proband [2, 5]. Consanguinity increases the likelihood of these forms: it underpinned the description of LEP and was present in 90 of the 300 probands in the LEPR study [10, 26].

Carrier status is not neutral for every gene. Heterozygotes for a POMC null allele do not develop adrenal insufficiency but are predisposed to obesity, which should be explained to parents and siblings [2, 6]. In MC4R deficiency, inheritance is codominant: an affected heterozygote has a 50% probability of transmitting the variant to each child, severity depends on residual receptor function, and consanguineous carrier couples may have homozygous children with more severe disease [5, 7]. SH2B1 variants are dominantly inherited; for distal 16p11.2 deletions, the Oxford Desk Reference estimates penetrance of 62.4% (95% CI 26.8–94.4) for the phenotype prompting microarray testing, with 7 of 21 (33.3%) deletions de novo among cases, and gives a recurrence risk of approximately 1% for de novo microdeletions (gonadal mosaicism) and approximately 50% when a parent is a carrier [51].

When POMC variants are known, prenatal diagnosis allows glucocorticoids to be initiated immediately after birth; if variants are unknown or prenatal testing has not been performed, every newborn at risk should be assessed for adrenal insufficiency and treated without delay [2]. Preimplantation genetic diagnosis is possible after familial variants have been identified, and the ideal time to discuss risk, carrier status and reproductive options is before pregnancy, offering counselling to affected, carrier or at-risk young adults and considering DNA storage from the proband [2]. Whether fertility is reduced in POMC deficiency is unknown [2]; in LEP, LEPR and PC1 deficiencies with hypogonadotrophic hypogonadism, pregnancy depends on assisted reproduction with induction of gametogenesis [77]. Reversal of hypogonadism with resumption of menstruation during metreleptin treatment has been described in two adult women [40]. A woman receiving setmelanotide who becomes pregnant should be managed according to the relevant jurisdiction's label (section 7.2), with monitoring of recommended gestational weight gain [16, 17].

The French PNDS points out that the question of genetic counselling arises whenever the genetic aetiology has been demonstrated, with assessment of the recurrence risk for the individual and for relatives by a geneticist or genetic counsellor working with the referring physician [23]. In France, a request for prenatal or preimplantation diagnosis, made after the counselling consultation, is examined at a meeting of a multidisciplinary prenatal diagnosis centre (CPDPN), and the law restricts these diagnoses to conditions “of particular severity without curative treatment at the time of diagnosis”, a criterion that each request must satisfy [23]. The aetiological diagnosis also has value for the family: it reduces the blaming of the individual and caregivers, common in a stigmatised disease, allows early parental guidance and supports the recognition of disability [23].

In women, the hypogonadotrophic hypogonadism of biallelic LEP and LEPR deficiencies results in absent or delayed puberty, low ovarian reserve (reduced anti-Müllerian hormone, antral follicle count and ovarian volume) and the need for stimulation with gonadotrophins or a GnRH pump, within a pregnancy project prepared by a multidisciplinary team with a geneticist, obstetrician, nutritionist and reproductive medicine specialist; in France, most medically assisted reproduction centres restrict access to BMI < 35 kg/m² [23]. Contraception is not contraindicated by a BMI ≥ 30 kg/m², but obesity triples the risk of venous thromboembolism, and obese women on combined oestrogen–progestogen contraception have a risk about 24 times higher than that of lean women without contraception, so the choice is individualised between continuous or cyclical combined contraception and progestogen-only contraception [23]. The protocol records one pregnancy described in a woman homozygous for a LEPR variant and the absence of published data on the management of these pregnancies; it recommends, by extension from severe obesity, a preconception consultation (folic acid, vaccines, serologies, screening for diabetes, hypertension, sleep apnoea, thromboembolic risk and liver disease, adjustment of chronic treatments and genetic counselling), early screening for gestational diabetes by fasting glucose and, if negative, a 75 g glucose test between 24 and 28 weeks of gestation, monthly weighing with a weight-gain target set by preconception BMI, an early anaesthetic consultation, thromboembolic prevention, delivery in a level 2 or higher maternity unit and breastfeeding, which it recommends in mothers with excess weight [23].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency by disorder

Frequencies should be attributed to the entity to which they refer and not transferred between groups. For the group of non-syndromic genetic obesity, Orphanet records unknown prevalence and incidence; for leptin, POMC, PC1/3 and SH2B1 deficiencies it records a prevalence class below 1 per million, with 30, 7, 16 and 13 validated cases or families, respectively [1]. For MC4R deficiency, Orphanet gives 1–5 per 10,000 based on an expert estimate in France, and a not yet validated European estimate in the same class [1]. In 2013 GeneReviews reported fewer than 50 published patients with POMC deficiency and no known increased prevalence in ethnic groups or regions [2]. In France, the 2020 Obepi study estimated obesity in 17% of adults, with 2% grade III obesity, and the PNDS estimates that the forms of the melanocortin pathway account for about 5% of early-onset and severe obesities, a figure it considers probably underestimated and higher in populations with high consanguinity [23].

Published case counts underestimate the true frequency. Using allele frequencies from 77,165 Europeans in gnomAD, Kleinendorst and colleagues predicted 998 patients with LEPR deficiency in Europe, or 1.34 per million (95% CI 0.95–1.72), compared with 21 published European patients among the 88 described worldwide, attributing the discrepancy to insufficient access to genetic testing and underrecognition [12]. For the United States, the setmelanotide marketing authorisation holder estimates approximately 600 to 2500 patients with biallelic POMC, PCSK1 or LEPR deficiency, with similar European prevalence; this is the sponsor's commercial estimate rather than a peer-reviewed epidemiological study [35].

9.2 Diagnostic yield in selected cohorts

The following proportions are yields in selected populations rather than population prevalence estimates. In the United Kingdom, MC4R variants were found in 5.8% of 500 probands with severe childhood obesity and pathogenic LEPR variants in 3% of 300 patients with hyperphagia and severe early-onset obesity, a cohort enriched with 90 probands from consanguineous families [7, 10]. The Oxford Desk Reference reports MC4R variants in 1–7% of patients with BMI > 40 and severe obesity before 10 years and loss-of-function LEPR variants in 2–3% of children with severe obesity; the Endocrine Society and AAP give 2–5% for MC4R in extreme paediatric obesity [5, 19, 22]. In the Netherlands, a 52-gene panel yielded a definitive diagnosis in 3.9% of 1230 patients and 7.3% of children with severe early-onset obesity, and 3% of 1014 bariatric surgery candidates had genetic obesity [63, 79]. In the UK Biobank, with approximately half a million participants, 61 MC4R variants with diverse functional effects, including protective variants, were identified [20].

9.3 Consanguineous populations and founder effects

A 2018 review summarised that only 2–5% of severe obesity cases in nonconsanguineous populations had a demonstrated monogenic cause, whereas in some highly consanguineous populations the proportion reached 30% [93]. In Pakistan, among 62 children of consanguineous parents with weight above the 97th centile, 16.1% had LEP variants, with nine probands carrying the same frameshift variant at codon 133, whose subethnic specificity suggested a founder effect, and 3.2% had homozygous MC4R variants [38]. In a second cohort of 73 Pakistani children with BMI above +3 standard deviations, homozygous loss-of-function variants in LEP, LEPR and MC4R explained 30% of cases [56]. In young adults from the same region, LEP and LEPR variants were absent or rare [61]. In Latin America, leptin deficiency was described in two Colombian sisters of consanguineous ancestry with p.(Cys117Phe), still classified as a variant of uncertain significance in ClinVar, and POMC deficiency in Hispanic and North African children without the typical pigmentary phenotype [40, 43, 45, 46, 59].

9.4 Phenotypic diversity and evidence gaps

The pigmentary phenotype of POMC deficiency is less apparent outside populations of European ancestry; the AAP describes it “in non-Hispanic white individuals”, and GeneReviews notes that a common red-hair-associated MC1R variant, frequent in European populations, may be co-inherited with another cause of obesity [2, 22]. Age-at-onset thresholds derived from Dutch cohorts may differ between ethnic groups [54]. No data from Portugal or Brazil on these disorders were found in the consulted sources; this does not establish that such data do not exist.

9.5 Special populations, networks and resources

Special populations include children younger than 2 years (no approved setmelanotide indication), young children exposed to benzyl alcohol, pregnant and breastfeeding women, patients with severe renal impairment and adults diagnosed late, for whom paediatric testing criteria have low sensitivity [16, 17, 60]. In Europe, the relevant reference network is Endo-ERN (European Reference Network on Rare Endocrine Conditions), whose thematic group MTG5 covers growth and genetic obesity syndromes [24]. The Oxford Desk Reference lists Cambridge's Genetics of Obesity Study (GOOS) as an information source and patient organisations for Prader–Willi syndrome (United Kingdom and United States) and Bardet–Biedl syndrome (United Kingdom), and GeneReviews listed the National Adrenal Diseases Foundation for POMC deficiency [2, 5]. No patient organisation devoted exclusively to nonsyndromic monogenic forms was identified in the consulted sources.

In France, the organisation of care rests on the three levels of graduated care defined by the Obesity Plan; the third level is provided by 37 specialised obesity centres (CSO), with expertise in endocrinology, nutrition, psychology, dietetics and physical activity and with specialised surgery and anaesthesia [23]. The PRADORT rare disease reference centre (Prader-Willi syndrome and other rare obesities with eating-behaviour disturbance), part since 2014 of the DéfiScience health network (rare neurodevelopmental diseases) and extended in 2017 to the other rare obesities, is coordinated at Toulouse University Hospital, with constituent sites at the Pitié-Salpêtrière (Paris) and the Hendaye maritime hospital and 20 competence centres, each with a paediatric and an adult lead, often linked to the CSOs; it organises monthly national multidisciplinary team meetings and, since 2019, therapeutic education programmes for patients and caregivers [23]. The care pathway includes assessment, respite or break stays in specialised rehabilitation units (Hendaye for adults, OCSYHTAN in Ramonville-Saint-Agne for children) and, for children with massive obesity of the melanocortin pathway, day hospital care in rehabilitation units of the Fondation des Étudiants and of UGECAM in Montreuil; the rare-disability liaison teams (ERHR), the departmental houses for persons with disabilities (MDPH), the long-term illness scheme (ALD), the global support plan (PAG) in breakdown situations and patient associations complete the pathway, and teleconsultation facilitates remote follow-up [23].

10. Illustrative Clinical Case

In 2026, Ruiz Pons and colleagues described in Obesity Facts a Spanish boy with leptin receptor deficiency treated with setmelanotide from 2 years and 4 months [36]. He was born at 36 weeks and 2 days with weight (2450 g) and length (45 cm) appropriate for gestational age and, during the first year, developed progressive hyperphagia, excessive weight gain, constant food-seeking and motor developmental delay. At 6 months, when referred to a paediatric nutrition clinic, he weighed 12.2 kg and measured 66.5 cm (BMI 27.6 kg/m², BMI standard deviation score +5.42); Prader–Willi syndrome testing was negative, a dexamethasone suppression test excluded hypercortisolism, hepatic steatosis was present and immunological investigation was normal. Triglycerides were 328 mg/dL at 5 months and total cholesterol 220 mg/dL at 6 months. He was readmitted at 8 and 11 months for progressive weight gain (BMI score +5.97), and at 14 months genetic testing identified the homozygous pathogenic LEPR variant c.93G>A, p.(Trp31Ter), normalised to the MANE transcript as NM_002303.6:c.93G>A and classified as pathogenic in ClinVar [4, 36, 44]. Hyperphagia and food-related anxiety worsened, with irritability when food was withheld, and obstructive sleep apnoea developed, requiring nocturnal ventilation. Motor delay was marked: crawling was achieved only at 2 years and 8.5 months and the first unaided steps at 3 years and 6 months [36].

Setmelanotide was initiated at 2 years and 4 months, at a weight of 39.8 kg, at 0.5 mg/day subcutaneously, increased in 0.5 mg steps over 13 months to 2.5 mg/day in accordance with the European SmPC [17, 36]. Within the first 72 hours, his mother described reduced interest in food and food-related anxiety; after 3 months, almost all hyperphagia symptoms assessed by caregiver questionnaires had changed from three or more occurrences in the preceding 24 hours to “never”, with improved sleep, mood and family relationships for the child and parents. Peak BMI was 43.55 kg/m² (score +11.05) at 2 years and 4 months, falling to 36.6 kg/m² (score +8.52) at 4 years and 4 months, with score reduction beginning at 3 years and 9 months, LDL cholesterol of 72–73 mg/dL and triglycerides of 75–86 mg/dL during treatment. Figure 1 of the article, consulted for this description, shows weight, height, BMI and BMI score curves from birth, with treatment initiation and dose increase dates (Figure 1 in PMC13249433) [36]. A 7-day interruption due to supply failure, approximately 9 months after initiation, was followed by markedly increased food-related anxiety, reversed on reintroduction. Skin hyperpigmentation appeared at the first follow-up visit and stabilised; pustular psoriasis, considered unrelated, and intertrigo required dermatological treatment. Sleep apnoea resolved after adenoidectomy at 3 years and 2 months [36].

The case illustrates the typical chronology of LEPR deficiency (normal birth weight, hyperphagia and severe obesity in the first year, absence of intellectual impairment), the diagnostic pathway beginning with exclusion of Prader–Willi syndrome and endocrine causes, and the dependence of response on continuous administration [10, 17, 36]. BMI reduction was smaller than the VENTURE trial mean, which included patients with POMC deficiency, who usually respond more strongly [36, 73]. The authors disclose editorial support funded by the marketing authorisation holder and fees received by the first author; this is an isolated report without a control group, and its described management does not establish routine recommendations [36].

11. Prognosis and Long-Term Follow-Up

Prognosis depends on the gene, early diagnosis and access to targeted treatment. Without treatment, hyperphagic obesity persists from childhood into adulthood, as shown by weight trajectories before setmelanotide and adults with leptin deficiency with BMI of 59–60 kg/m² [40, 55]. POMC deficiency carries an immediate life-threatening risk, adrenal insufficiency, prevented by glucocorticoid replacement [2]. PC1/3 deficiency is associated with high neonatal mortality due to malabsorptive diarrhoea [11]. The rarity of LEP and LEPR variants in young Pakistani adults compared with children from the same region was attributed by the authors to these children's morbidity, mortality and social disadvantage [61]. With targeted treatment, response persists while treatment continues and is lost on discontinuation [16, 17]; long-term data beyond the first year come mainly from conference presentations and the long-term extension, whose final results were submitted to the EMA in 2025 [69, 71].

The Oxford Desk Reference recommends considering referral to paediatric endocrinology, and the Endocrine Society stresses that adolescents receiving behavioural, pharmacological or surgical treatment need coherent planning of the transition to adult care [5, 19]. The French PNDS adds that transition is a period of worsening weight, eating behaviour and complications, which should be prepared from 15–16 years of age, and that teleconsultation and dedicated consultations with extended time and the caregiver present facilitate the performance of investigations [23].

12. Summary and Final Considerations

Monogenic forms of obesity result from defects in the leptin–melanocortin pathway and present with hyperphagia and severe obesity in the first years of life, without developmental delay, with endocrine signatures that guide diagnosis: undetectable leptin in leptin deficiency, impaired pituitary axes in deficiency of its receptor, adrenal insufficiency and hypopigmentation in POMC deficiency, neonatal diarrhoea and raised proinsulin in PC1/3 deficiency, accelerated growth and hyperinsulinaemia in MC4R deficiency, and insulin resistance with behavioural changes in SH2B1 deficiency [5, 19]. Genetic testing is indicated in extreme obesity before 5 years of age with hyperphagia or a family history, and the report should state the transcript, HGVS nomenclature, zygosity and classification, with particular caution regarding VUS and MC4R variants [19, 20]. Setmelanotide has an approved indication in biallelic POMC, PCSK1 and LEPR deficiencies from 2 years of age in the United States and the European Union, with differences in required genotype and titration between the two labels; metreleptin corrects leptin deficiency but is used off-label; and there is no approved therapy for MC4R and SH2B1 deficiencies, following the failure of the EMANATE trial in heterozygotes [13, 16–18]. Hormone replacement, annual endocrine surveillance, genetic counselling of relatives (including screening of newborns at risk of POMC deficiency) and referral to Endo-ERN centres complete the approach [2, 24]. The 2021 French PNDS adds a common framework for rare obesities, with suspicion criteria before 3 and 6 years of age, classification of genes by penetrance, structured dietary intervention from diagnosis, caution regarding bariatric surgery, periodic screening for comorbidities and care organised around the PRADORT reference centre and the specialised obesity centres; it diverges from current sources on dated points, such as the regulatory status of metreleptin and setmelanotide [23].

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