Endocrine Abstracts

JOINT705

Background: Monogenic obesity is a rare, severe form of early-onset obesity driven by genetic mutations that disrupt energy homeostasis. Leptin receptor (LEPR) mutations impair satiety signaling, leading to hyperphagia, excessive weight gain, and metabolic complications. Early diagnosis and intervention are critical to mitigate risks such as type 2 diabetes, hypertension, and cardiovascular disease. We present a case of a 7-month-old female with monogenic obesity due to a homozygous LEPR mutation.

Case Presentation: A 7-month-old female presented with rapid weight gain since 40 days of life. The parents reported marked hyperphagia, with over 10 breastfeeding sessions daily, and frequent crying relieved by feeding. Developmental milestones were normal, with no history of hypoglycemia or hospitalizations. The child was full-term, born via normal vaginal delivery, weighing 2.75 kg, with third-degree consanguinity noted. At presentation, she weighed 16.5 kg (>97th percentile), had a BMI of 39 kg/m², and a weight-for-length >99.9th percentile (+7 SD). Physical examination revealed generalized obesity, almond-shaped eyes, without signs of acanthosis nigricans or Cushingoid features.

Investigations: Laboratory tests showed impaired glucose tolerance (HbA1c 6.4%), hypertriglyceridemia (TG 231 mg/dL), and dyslipidemia. Abdominal ultrasound revealed grade 1 fatty liver, and echocardiography showed concentric left ventricular hypertrophy. Genetic testing confirmed a homozygous pathogenic LEPR mutation. Serum leptin levels were within the normal range (3.66 ng/mL).

Management: A low-carbohydrate, low-fat diet was initiated with close monitoring. Despite dietary modifications, her weight increased to 25 kg by 18 months, highlighting the progressive nature of LEPR-related obesity and the need for pharmacologic interventions.

Discussion: LEPR mutations disrupt leptin signaling, causing severe early-onset obesity¹. This case underscores the importance of considering monogenic obesity in infants with rapid weight gain, particularly in consanguineous families². Early genetic testing enables accurate diagnosis and personalized management³. While dietary interventions have limited efficacy, emerging therapies targeting the leptin-melanocortin pathway, such as setmelanotide, offer promising outcomes.

Conclusion: This case highlights the diagnostic and therapeutic challenges of LEPR-related monogenic obesity. A multidisciplinary approach, including genetic testing, dietary management, and novel therapies, is vital to mitigate complications and improve long-term outcomes.

References: 1. Clément, K., et al. (1998). A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature, 392(6674), 398–401.

2. Wabitsch, M., et al. (2015). Biologically inactive leptin and early-onset extreme obesity. New England Journal of Medicine, 372(1), 48–54.

3. Farooqi, I. S., & O’Rahilly, S. (2005). Monogenic obesity in humans. Annual Review of Medicine, 56, 443–458.