Endocrine Abstracts

Childhood-onset obesity is a complex clinical entity, especially in patients with rare genetic mutations. We present the longitudinal case of a female patient with KSR2 mutation, a gene encoding Kinase Suppressor of Ras-2, which plays a critical role in cellular energy balance and AMPK signalling. Pathogenic KSR2 variants are associated with early-onset severe obesity, hyperphagia, and insulin resistance, with limited response to conventional therapies. This patient began gaining weight at the age of 3 years and remained >99 th centile for BMI despite structured dietary intervention and active lifestyle. Initial investigations, including thyroid, liver, and lipid profiles, were normal; OGTT revealed normal glucose and insulin dynamics but reduced sex hormone–binding globulin. At age 14, genetic analysis confirmed a KSR2 mutation. She was commenced on metformin (1 g twice a day), resulting in ~10 kg weight loss initially, but the effect plateaued within one year despite good adherence. She followed a vegan diet and developed no obesity-related complications such as diabetes, Obstructive sleep apnea, or joint disease. Psychosocial challenges emerged, with low mood, anxiety, and depression, later compounded by a diagnosis of Autism Spectrum Disorder; she was treated with sertraline. At age 18, she was assessed for a clinical trial of setmelanotide (MC4 R agonist); however, recruitment ceased due to limited efficacy. Multidisciplinary recommendations included GLP-1 receptor agonist therapy and possible bariatric surgery. She was referred to a Tier 3 Specialist Weight Management Service. Investigations showed ALT 34 U/l, TSH 3.1 mIU/l, normal eGFR, with an Edmonton Obesity Staging System score of 2. She was commenced semaglutide (Wegovy), titrated from 0.25 mg weekly to a dose of 2.4 mg weekly. Her weight trajectory demonstrates significant clinical impact: in May 2024, she weighed 104.5 kg (BMI 34.2), but at her most recent review, she had reduced to 78 kg. This substantial weight loss, however, has been accompanied by sagging and loose skin, leading her to seek brachioplasty and abdominoplasty, and she is currently awaiting review by the plastic surgery team. This case illustrates the need for long-term, multidisciplinary, and precision-based care in severe genetic obesity. It highlights the evolving role of GLP-1 receptor agonists in monongenic causes of obesity, and the potential place for surgical and reconstructive intervention. The psychosocial burden, especially in the context of neurodevelopmental disorders, underscores the importance of integrated psychological support alongside metabolic management in childhood cases of obesity.