ESPE Abstracts

Introduction: The leptin-melanocortin pathway is a well-studied pivotal player of body weight regulation and energy homeostasis. Pathogenic mutations of the genes involved in this pathway may result in early-onset severe obesity (ESO).

Case Report: We hereby report the case of a 14-year-old girl who was referred to our pediatric outpatient clinic for the evaluation of ESO. Her parents were non-obese first cousins born in Morocco. At the time of consultation, the two brothers of the proband were healthy and had normal BMI, while the 8-year-old sister presented with ESO. The proband’s birth weight was 3000 grams (-1.1 SDS, WHO). After the first month of life, she progressively became hyperphagic and rapidly developed severe obesity, with her height SDS being always within the reference ranges for age. Despite dietary and lifestyle interventions, her BMI progressively raised from 36.4 Kg/m² (+7.98 SDS) at the age of 3 years to 60.86 Kg/m² (+4.63 SDS) when she was 16 years old. Over time she developed obesity-related complications: impaired glucose tolerance, liver steatosis and obstructive sleep apnea syndrome. Endocrine testing and genetic counseling ruled out hypothyroidism, hypercortisolism and Prader-Willi syndrome. The extreme severity and early onset of the clinical picture in both proband and her sister, the patchy distribution of obesity among the proband’s relatives and the absence of syndromic features prompted to perform a next generation sequencing (NGS). A novel homozygous c.1603+3A>T variant involving the leptin receptor (LEPR) gene was demonstrated in both the proband and her sister. Parents were found to be heterozygous carriers, while both brothers were variant-negative. The proband and her sister have been enrolled in a clinical trial treatment with a melanocortin-4 receptor (MC4R)-agonist, a promising weight loss drug for patients presenting with LEPR resistance.

Discussion: Monogenic obesity resulting from mutations in the LEPR gene has been described for the first time two decades ago. The inheritance pattern and the genotype-phenotype association support the hypothesis of a pathogenic role of the novel c.1603+3A>T variant hereby described.

Conclusions: In conclusion, hyperphagia, patchy familiar involvement and consanguineous parents should promptly rise the suspicion of monogenic obesity. Functional analysis may confirm the pathogenicity of c.1603+3A>T variant. The therapeutic effectiveness of a novel MC4R-agonist will be tested in the proband and her sister, as they have been enrolled in a clinical trial for the treatment of patients with ESO due to inactivating LEPR gene mutations.