Early-Onset Monogenic Obesity due to Leptin Receptor Deficiency: Fatal Outcome in Childhood in the Era of Precision...

Early-onset monogenic obesity due to leptin receptor (LEPR) deficiency is characterized by severe hyperphagia, rapid weight gain, and obesity-related comorbidities, including obstructive sleep apnea syndrome (OSAS). Setmelanotide, a melanocortin-4 receptor agonist, is an approved targeted treatment for patients with LEPR deficiency. However, access to this treatment remains limited in many countries.

A 20-month-old boy born to first-degree consanguineous parents was referred for severe obesity and hyperphagia. At presentation, his weight was 23.4 kg (+5.3 standard deviation score [SDS]), with a BMI of 34.0 kg/m2 (+7.6 SDS). There were no dysmorphic features, developmental delay, or clinical findings suggestive of syndromic obesity. Targeted LEPR sequencing identified a homozygous splice-site variant (c.1603+2T>C), previously detected in his similarly affected sibling. Both parents were heterozygous carriers. At 2.5 years, BMI reached 39.3 kg/m2 (+6.7 SDS), and polysomnography confirmed severe OSAS. Adenoidectomy was deferred due to anesthesia-related risks associated with severe obesity and lack of an adequately equipped center. Following FDA approval of setmelanotide for children ≥2 years of age, a 6-month court-approved authorization for compassionate use was obtained. However, the drug was not yet available when the patient died suddenly during sleep at 3 years and 9 months of age, with presumed OSAS-related respiratory failure.

This case highlights the fatal consequences of delayed access to precision therapy in rare monogenic forms of obesity, such as LEPR deficiency, despite early molecular diagnosis. It also provides insight into the natural history and long-term outcomes of affected patients.