ESPE Abstracts

Introduction: Early-onset severe obesity (before five years of age) without intellectual deficit, dysmorphisms, or malformations raises the hypothesis of monogenic obesity. The leptin receptor (Lepr) pathway is essential for food intake regulation, energy expenditure, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans.

Objective: To report the clinical and molecular investigation of 2 sisters with severe obesity starting in the first year of life

Case report: MEGS and AVGS, second and third daughters of 3 offspring, the older brother being of normal weight. Non-obese, consanguineous parents who are cousins of third-degree. The patients are 5 and 6 years old, with severe obesity that started during the exclusive breastfeeding phase, reaching a maximal Z-BMI of 8.86 and 7.82, respectively. The two sisters present: hyperphagia, increased abdominal circumference, acanthosis nigricans, arterial hypertension, dyslipidemia, increased insulin, and HOMA IR. MEGS evolved with varus deformity of the lower limbs leading to gait impairment. Whole-exome sequencing (WES) followed by target gene panel analysis was performed, which identified the homozygous variant NM_002303.5:c.1603+3A>G in the LEPR gene in both sisters.

Discussion: The variant found in the sisters was identified in a homozygous state in the LEPR gene in the splice region (strand+, exon 11). This gene is intolerant of loss of function (pLI: 0.99), and the severity of the variant was predicted to be harmful. It was not reported in the GnomAD and ExAC public databases. The deleterious nature of the mutation is consistent with the clinical conditions of hyperphagia, rapid weight gain, and extreme obesity observed in both sisters. Furthermore, in addition to dietary measures and physical activity stimulation, treatment with the new medication Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, may be efficient and will be carried out as soon as it is available in our country.

Conclusion: WES, followed by target gene panel analysis, efficiently identified a homozygous mutation in a consanguineous case of early-onset severe obesity. Although cases of monogenic obesity represent a small portion of patients with childhood obesity, it is essential to recognize its existence and consider the clinical and therapeutic implications associated with such genetic conditions. Early identification, genetic counseling, and clinical and therapeutic approach directed according to molecular diagnosis prove fundamental for a practical approach to patients and genetic counseling.