· Early-onset severe obesity with hyperphagia is a key clinical indicator of monogenic obesity, particularly in consanguineous settings.

· Homozygous MC4R mutations are associated with severe insulin resistance and nonsyndromic obesity in children.

· Liraglutide-based therapy offers a promising targeted approach with significant weight and metabolic benefits.

The rates of childhood and adolescent obesity have been increasing worldwide in recent years. More than 90% of childhood obesity is polygenic in nature, whereas only approximately 3%–10% is attributed to syndromic and/or monogenic causes [1,2]. Despite the rising prevalence of obesity in India, monogenic obesity remains underdiagnosed [3]. In this paper, we describe 2 cases of monogenic obesity resulting from mutations in the melanocortin-4 receptor (MC4R) gene. These cases were characterized by varied clinical presentations, diagnostic evaluations, and management strategies.

A 5-year-old boy, born of second-degree consanguinity, with a birth weight of 2.8 kg, presented with hyperphagia and a rapid increase in weight since 6 months of age. On examination, generalized obesity, bilateral lipomastia (Fig. 1A), and grade 4 acanthosis nigricans, as per the Burke scale (Fig. 1B and C), were noted, with no syndromic stigmata. The child’s height was 123 cm, +2.27 standard deviation score, which was calculated using World Health Organization 2006 and Indian Academy of Pediatrics 2015 combined growth charts. His weight was 75 kg with a body mass index (BMI) of 49.6 kg/m² (>97th percentile; extended BMI z-score +4.35) as per the Centers for Disease Control and Prevention (CDC) extended BMI-for-age growth chart (2022; Supplementary Fig. 1A). Genital examination showed a bilateral testicular volume of 2 mL each. The bone age was 6–7 years at a chronological age of 5.5 years. Neurological, ophthalmological, and audiometric evaluations were normal. The thyroid profile and cortisol dynamics were normal. An abdominal ultrasonogram revealed grade 1 fatty liver.

Owing to the child’s presentation of severe obesity with hyperphagia, monogenic causes were suspected, and genetic analysis was planned. Next-generation exome sequencing revealed a homozygous pathogenic frameshift loss-of-function mutation in the MC4R gene (NM_005912.3:c.559del[p.Tyr187ThrfsTer31],chr18:g.5803 9026del[GRCh37]). The variant was classified as pathogenic according to American College of Medical Genetics and Genomics (ACMG) criteria (PVS1, PM2) (Fig. 2A and B). The child was initiated on a low-calorie, lowcarbohydrate diet and a structured physical activity regimen. He was started on metformin and the oncedaily injectable glucagon-like peptide-1 (GLP-1) analog liraglutide at presentation. Liraglutide was initiated at 0.6 mg daily and increased by 0.6 mg every 8 weeks to 1.8 mg by 6 months. At 6 months, his weight decreased by 6.4%, with corresponding improvement in the BMI z-score (Table 1).

Case 2 was a 12-year-old girl, born of third-degree consanguinity with a birth weight of 3 kg. She presented with progressive childhood-onset obesity and severe hyperphagia since 1 year of age. She also had a history of bilateral leg bowing (genu varum), generalized hyperpigmentation, and excessive snoring for the past 3 years. On examination, she had morbid obesity (BMI 45.89 kg/m²; >97th percentile), calculated using the CDC extended BMI-for-age growth chart (2022; Supplementary Fig. 1B), grade 4 acanthosis nigricans according to the Burke scale (Fig. 1E), and bilateral genu varum (Fig. 1F). Tanner staging revealed breast stage 3 (B3) and pubic hair stage 3 (P3), as well as the absence of axillary hair. Laboratory investigations were suggestive of euthyroid status and normal cortisol dynamics (low-dose dexamethasone suppression test: 1.2 μg/dL). Owing to the presence of genu varum, she was evaluated for rickets. Her serum calcium, phosphorus, alkaline phosphatase, 25-hydroxy vitamin D, and intact parathyroid hormone levels were within normal limits. A skeletal survey ruled out rickets. Her bone age was 11–12 years at a chronological age of 12 years. Abdominal ultrasonography showed grade 1 hepatic steatosis.

Molecular genetic testing using next-generation exome sequencing identified a homozygous intragenic deletion of ~1.23 kb in the MC4R gene on chromosome 18 (NM_005912.3:chr18:g.[60371353_60372584del],GRCh3 7/hg19). The deletion was first detected by clinical exome copy number variation (CNV) analysis and subsequently confirmed in the homozygous state by quantitative polymerase chain reaction (qPCR; ClinGen CNV=0.9). According to ACMG criteria, this variant was classified as likely pathogenic (Fig. 2A). No corresponding entry was identified in ClinVar or dbVar as of September 25, 2025.

A multidisciplinary approach was initiated for the subject, which included a low-carbohydrate diet and tailored physical activity, which accounted for her limited lower limb movements. An orthopedic opinion was sought for correction of the genu varum, with corrective osteotomy planned after achieving desirable weight reduction. Initially, she was treated with metformin and basal-bolus insulin owing to uncontrolled hyperglycemia (hemoglobin A1c [HbA1c]:10.1%). After 3 months, the HbA1c level improved to 6.4%, and the insulin was discontinued. She was subsequently managed with metformin and liraglutide (initiated at 0.6 mg daily and uptitrated weekly in 0.6-mg increments to a maintenance dose of 3.0 mg) for glycemic control and weight management. At 6 months, her weight had decreased by 5.8%, and HbA1c had further reduced to 5.9% (Table 1).

Written informed consent was obtained from the parents for publication of clinical details and images. Ethical approval for publication of this case report was granted by the Institutional Ethics Committee, Madurai Medical College and Government Rajaji Hospital (Reference Number: 55/P/IEC/2025).

The genetic causes of early-onset obesity can be syndromic (Prader-Willi syndrome [PWS], Bardet-Biedl syndrome [BBS], and Cohen syndrome) or nonsyndromic. The nonsyndromic causes may be monogenic, polygenic, or chromosomal in origin [1,2]. Nonsyndromic monogenic obesity results from mutations in genes that regulate appetite, energy balance, and satiety, primarily through the leptin-melanocortin pathway [1,2].

Energy balance in humans is regulated through a complex interplay between neuroendocrine pathways in the brain and peripheral metabolic signals [4]. Key orexigenic substances include neuropeptide Y (NPY), agouti-related peptide (AGRP), ghrelin, and melaninconcentrating hormone, while anorexigenic signals include proopiomelanocortin/alpha-melanocyte stimulating hormone (POMC/α-MSH), leptin, insulin, brainderived neurotrophic factor (BDNF), GLP-1, and GLP-1 receptor [4,5]. The leptin-melanocortin pathway forms the core of central energy homeostasis. Leptin activates POMC neurons and inhibits NPY/AGRP neurons, with α-MSH acting on MC4R in the paraventricular nucleus (PVN) to suppress appetite (Fig. 3). Mutations in any of these genes can disrupt this pathway, leading to earlyonset obesity and severe hyperphagia [5,6].

The melanocortin 4 receptor (MC4R gene) is the most common cause of non-syndromic obesity, accounting for 4%–6% of causes, followed by the leptin receptor (LEPR; 3%). The other rarer mutations include POMC, leptin (LEP), PCSK1, neurotrophic tyrosine kinase receptor type 2 (NTRK2), BDNF, and single-minded homolog 1 (SIM1), all of which contribute to less than 2% of monogenic causes [7]. A short case series by George et al. [7] from North India reported leptin receptor mutation as the most common form, while MC4R mutation was observed in a single case. In contrast, we report 2 cases of MC4R mutation from Southern India.

Clinical suspicion is paramount in diagnosing monogenic obesity, given the high prevalence of childhood and adolescent obesity in the general population and the high cost of genetic testing [8]. Genetic etiology should be considered in specific situations, such as early-onset progressive weight gain (before 5 years of age), severe hyperphagia, consanguinity, syndromic features, developmental delay, and poor response to conventional treatment [8]. Hyperphagia is common in both syndromic and monogenic obesity. In monogenic obesity, symptoms typically begin in early infancy, whereas in syndromic obesity, they usually occur between 2 and 4 years of age. This difference in age of onset helps in early clinical distinction. Monogenic obesity typically lacks the dysmorphic facies observed in syndromic obesity, such as PWS, BBS, and Alström syndrome (AS) [1,2,9]. In addition, multisystem involvement is more common in syndromic obesity and very rare in monogenic obesity [1,2,9] (Table 2).

In the present study, case 1 had accelerated stature, and case 2 had normal stature. In MC4R mutations, patients have normal or accelerated linear growth owing to hyperinsulinemia-mediated IGF-1 action, in contrast to the short stature commonly observed in syndromic obesity (PWS, AS, and Cohen syndrome) [1,2,9]. Delayed puberty and hypogonadism are more often associated with leptin and leptin receptor deficiency; however, they are uncommon in MC4R mutations. Neurodevelopmental abnormalities are also not typically reported, although patients may rarely exhibit attention-deficit/hyperactivity disorder or autism spectrum disorders [9,10].

Both cases in this study exhibited features of severe insulin resistance. Despite documented evidence of insulin resistance, such as presentation of acanthosis nigricans and elevated homeostatic model assessment of insulin resistance indices, metabolic complications, such as diabetes mellitus and dyslipidemia, are rarely reported in childhood. Nonetheless, they may occur in adults during long-term follow-up [10]. The patient in case 2 developed diabetes mellitus, an uncommon presentation in this age group compared to previous reports, highlighting the potential for metabolic complications in early-onset monogenic obesity. In this case, early initiation and a short course of basal-bolus insulin, along with metformin, resulted in a significant improvement in HbA1c from 10% to 6.4% over 3 months, indicating preserved beta-cell function. Later, the patient was switched to liraglutide and metformin.

Case 2 presented with bilateral genu varum in the absence of clinical or biochemical evidence of rickets, suggesting a mechanical cause for the condition. In severe early-onset obesity, increased pressure on growing bones (proximal tibial growth plate) can lead to progressive bowing of the legs, highlighting the importance of monitoring for orthopedic complications. Homozygous MC4R mutations cause complete loss of receptor function, resulting in severe early-onset obesity, intense hyperphagia, and marked insulin resistance.

Heterozygous mutations lead to milder obesity owing to partial MC4R function, with variability in onset and severity. Genotype-phenotype correlation shows codominant inheritance, with homozygotes more severely affected than heterozygotes. In South Asian populations, particularly among those with consanguinity, rare homozygous mutations, such as frameshift mutations and deletions, are being increasingly reported [7]. In both cases 1 and 2 of this study, parental segregation analysis could not be performed on account of logistical constraints. Nevertheless, the homozygous variants that were identified in a consanguineous background, together with the clinical phenotype and ACMG criteria, were sufficient to classify them as pathogenic.

In all cases of syndromic and monogenic obesity, a multifactorial approach is the cornerstone of effective management. The initial treatment approach involves decreasing caloric intake of food and encouraging structured physical activity. However, these lifestyle interventions are less effective in monogenic forms of obesity, as they do not modulate the central dysregulation of appetite control [11]. GLP-1 analogs, such as liraglutide, are U.S. Food and Drug Administration-approved for obesity in adolescents ≥12 years. Their use in younger children (as in case 1) is off-label, and close safety monitoring must be ensured [11]. The recent SCALE Kids trial by Fox et al. [12] provided the first high-quality evidence in children aged 6–12 years, demonstrating that liraglutide significantly reduced BMI with an acceptable safety profile in polygenic obesity. Liraglutide directly activates the GLP-1 receptor in the PVN of the hypothalamus, bypassing the MC4R pathway and causing significant anorexia. Besides weight loss, liraglutide also improves hyperglycemia, overall metabolic profile, and hepatic steatosis. Importantly, although randomized trials have focused on polygenic obesity, emerging case reports and small series suggest that GLP-1 analogs may also be effective in monogenic obesity [12,13]. Our case report adds to this growing body of evidence by highlighting the role of liraglutide in MC4R-related monogenic obesity.

In case 1, liraglutide was up-titrated slowly (0.6 mg every 8 weeks) to ensure tolerability in a younger child. Case 2 followed the standard weekly escalation. No adverse events or treatment-related complications were observed in either case during the follow-up period, and both patients achieved meaningful weight reduction (6.4% and 5.8% at 6 months, respectively). Long-term follow-up studies are needed to confirm the efficacy and safety of liraglutide in monogenic obesity. Currently, limited evidence exists regarding the use of other GLP-1 analogs—e.g., semaglutide, dulaglutide, or dual agonists, such as tirzepatide—in monogenic obesity [13,14].

The role of metformin in managing genetic forms of obesity remains understudied. Preclinical and clinical studies have shown that metformin exerts appetite-suppressing effects through central hypothalamic mechanisms (decreasing the expression of NPY and AGRP, and enhancing leptin receptor expression) [14]. Despite these insights, clinical trials evaluating the impact of metformin in monogenic obesity are lacking. Metformin can be used off-label in monogenic obesity to improve insulin sensitivity when evidence exists of insulin resistance and to alleviate hepatic steatosis [14]. Setmelanotide, a MC4R agonist, is approved for weight management in individuals with LEPR, POMC, PCSK1 mutations, and BBS, but not for individuals with MC4R mutations [2,15]. Any potential benefit in MC4R variants remains investigational and largely depends on the nature of the mutation [15]. Patients with partial loss-offunction MC4R mutations may respond owing to restoration of impaired receptor signaling, whereas those with complete loss-of-function mutations are unlikely to benefit [15]. Therefore, mutation analysis is essential before considering setmelanotide therapy. However, setmelanotide is not widely available in most countries, including India; broader access could be valuable for eligible patients. Hence, liraglutide may be a suitable option for individuals with MC4R mutations, regardless of mutation subtype.

Bariatric surgery has shown variable outcomes in monogenic obesity. Children with heterozygous MC4R mutations have shown a better response than those with homozygous mutations in the leptin-melanocortin pathway. Long-term outcomes in homozygous mutations have been unsatisfactory, with significant rebound weight gain [16]. Monogenic forms of obesity remain underreported in India, despite the very high prevalence of obesity. This case report highlights the importance of targeted genetic analysis in appropriate clinical contexts in the future to enhance the diagnosis and management of monogenic obesity in diverse populations.