MON-718 - Genetic Causes of Severe, Early Onset Obesity in A Clinically Referred Adult Case Series

Context:
Early-onset severe obesity is a clinical marker of potential monogenic or syndromic etiologies, yet genetic testing is often delayed until adulthood after failure of conventional medical and surgical therapies.

Objective:
To characterize the clinical severity, medical and surgical treatment exposure, and indications for genetic evaluation in adults with severe, early-onset obesity referred to a regional endocrine center.

Methods:
We conducted a retrospective case series of 30 adults with obesity beginning in childhood, adolescence, or young adulthood, or with body mass index (BMI) ≥40 kg/m², who were referred over a one-year period for endocrine evaluation after failure of standard medical and/or surgical weight-loss therapies. Following comprehensive clinical assessment, the treating endocrinologist determined that genetic testing was indicated based on early onset, extreme severity, and treatment resistance. Demographic data, anthropometric measures, prior bariatric procedures—including sleeve gastrectomy, Roux-en-Y gastric bypass, or both—and pharmacologic treatment histories were abstracted from electronic health records. At the time of endocrine referral, all individuals had persistent obesity, with no evidence of prior BMI normalization. Descriptive analyses were performed using a centralized, de-identified clinical research database.

Results:
Pathogenic or likely pathogenic genetic variants were identified in 26 patients (86.7%), whereas 4 patients (13.3%) had no clinically significant variants detected following clinician-directed genetic testing. The cohort demonstrated extreme obesity, with a mean BMI of 47.9 kg/m² (median 45); 25 patients (83.3%) had BMI >35 kg/m² and 17 (56.7%) had BMI ≥40 kg/m². Fourteen patients (46.7%) had previously undergone bariatric surgery, including sleeve gastrectomy alone in 8 patients (26.7%), Roux-en-Y gastric bypass alone in 4 patients (13.3%), and combined sleeve gastrectomy followed by Roux-en-Y gastric bypass in 2 patients (6.7%); however, all remained classified as having obesity at the time of genetic evaluation. Eighteen patients (60.0%) had prior exposure to GLP-1 receptor agonists or dual incretin-based therapies, including semaglutide, tirzepatide, liraglutide, and dulaglutide, with heterogeneous and frequently limited durability of response.

Conclusions:
Adults referred to a regional endocrine center for further evaluation represent a population with severe treatment-refractory obesity despite contemporary pharmacologic and surgical interventions. The high prevalence of identifiable genetic variants following clinician-directed testing supports earlier incorporation of genetic evaluation in patients with severe, early-onset obesity and reinforces a precision, pathway-based approach to individualized obesity management.

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