Endocrine Abstracts

Context

Genetic obesity, including syndromic and non-syndromic forms, represent a minority of cases but gene dysregulations make their management particularly difficult. Among them, Beckwith–Wiedemann syndrome (BWS) is a multisystem human genomic imprinting disorder characterized by overgrowth, macroglossia, abdominal wall defects, hemi hyperplasia, enlarged abdominal organs, and an increased risk of embryonal tumours. The syndrome is caused by genetic and epigenetic changes on the chromosome 11p15 region, that include genes such as cyclin-dependent kinase inhibitor 1C (CDKN1C) or insulin like growth factor 2 (IGF-2), strong related to fetal and postnatal growth. Genetic and epigenetic alterations are frequently mosaic and lead to different clinical phenotypes, including early onset obesity, although BWS is often an underestimated cause of syndromic obesity. Thus, less is known about obesity treatment in this syndrome.

Case description

We describe the first case of liraglutide treatment in an 18-year-old boy patient affected by BWS (Imprinting Center 1 Gain of Methylation (GoM IC1) associated with IC1 microdeletion) complicated by macroglossia, cryptorchidism, nephroblastoma, organomegaly, microscopic lymphocytic colitis, pharmacologically treated arterial hypertension, obesity and obstructive sleep apnea syndrome. He presented a normal cognitive development. BMI at the time of first transition visit in the adult endocrinology department was 40.6 kg/m² without glucose metabolism impairment. Lifestyles interventions failed because of a poor compliance. During 20 months of 3.0 mg liraglutide treatment weight loss of 19 kg (–13.3%) and BMI reduction of 6.8 points were registered without side effect. Normal glycemic and metabolic pattern was recorded without hypoglycemic episodes. Better control of blood pressure values was documented hesitating in improvement of quality of life.

Conclusion

liraglutide was effective on obesity in 7 subjects with Prader Willy Syndrome and 14 with melanocortin-4 receptor mutations. The efficacy of liraglutide in BWS could be related to a cross talk among glucagon like peptide (GLP)-1 system, mechanisms related to CDKN1C and dopamine mesolimbic circuit. Moreover, the causative mutation of BWS could interest genes such as IGF-2, implicated in postnatal overgrowth, and expresses by adipose tissue together with GLP-1 receptors. Thus, considering that GLP-1 promotes preadipocyte differentiation, reduces the expression of adipogenic and lipogenic genes, and enhances the expression of lipolytic markers, these could be some mechanisms targeted by liraglutide in BWS. On the other hand, the risk of hypoglycemia, although low during liraglutide, should be taken into account considering the intrinsic predisposition in BWS patients. Clinical trials aiming a tailored medicine in genetic obesity are needed.