ESPE Abstracts

Introduction: Heterozygous variants of the melanocortin-4 receptor gene (MC4R) are the most common cause of monogenic obesity. Until recently, patients with monogenic obesity often underwent a frustrating diagnostic and therapeutic odyssey of years of ineffective lifestyle interventions before a causal diagnosis was made. Data from case reports suggest that individuals with obesity caused by heterozygous MC4R pathogenic variants can be effectively treated with a glucagon-like peptide-1 receptor agonist. We present a family with early-onset obesity, in which the genetic diagnosis of the last offspring led to the diagnosis of 3 other ancestors.

Patients: Four members of a family (index patient, mother, maternal grandmother, maternal great-grandmother) with severe, early-onset obesity were studied. Genetic testing revealed a heterozygous MC4R variant (c.913C>T; p. (Arg305Trp)), which causes functional impairment of the MC4R.

Results: The index patient (female, 8 years old) presented with severe, early-onset obesity, hyperphagia, tall stature and dyslipidemia. As a toddler, she showed a strong interest in food intake with a rapid increase in body mass index (BMI). A complete medical evaluation was performed at the age of 3 years, mainly to rule out the presence of a brain tumor. In the absence of a causal diagnosis, lifestyle modification was recommended, which did not result in BMI change. Teasing and bullying at school led to social isolation. At the age of 8 years, genetic testing revealed the presence of a heterozygous MC4R variant. Treatment with liraglutide 3.0 mg/d was initiated, resulting in gradual stabilization of BMI and improvement of dyslipidemia. Similarly, the mother of the index patient had severe, early-onset obesity. During childhood, she underwent several diagnostic and therapeutic procedures, with no lasting result. At the age of 38 years genetic testing revealed the same MC4R variant. Genetic testing of her maternal grandmother and great-grandmother, who had early-onset severe obesity, insulin resistance, dyslipidemia and hypertension, revealed the same MC4R variant. We observed severe psychological distress, including stigmatization, in each individual of the four generations.

Conclusion: The description of this family highlights the need for early genetic testing in children with severe, early-onset obesity to avoid frustrating and potentially harmful treatments and to allow early initiation of appropriate medications. With the genetic diagnostics available today for children with early-onset obesity, it is possible to diagnose other family members as well as ancestors in the case of dominantly inherited variants. This will lead to enormous relief for those affected even in adults and seniors.