Abstract :
[en] Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHHAD[NET] is a rare pediatric disorder characterized by rapid-onset obesity and hypothalamic dysfunction. Despite its acronym suggesting a defined clinical entity, no formal diagnostic criteria have been validated, and recent findings support a broader ROHHAD spectrum, including adult-onset cases and presentations lacking rapid weight gain. Genetic, autoimmune, and paraneoplastic hypotheses have been explored without conclusive results. However, epigenetic mechanisms remain non investigated, despite observations such as discordant monozygotic twins, suggesting a role for epigenetic alterations. ROHHAD syndrome exemplify the complexity of rare forms of early-onset obesity, among which monogenic causes are few and often underdiagnosed, suggesting that other mechanisms, such as hypothalamic inflammation, environmental disturbances, and epigenetic alterations, may be relevant for these forms of early-onset obesity. The diagnostic yield for monogenic forms remains low as demonstrated by our study on real world evidence data in a cohort of 223 patients. Expanding genomic approaches may improve diagnostic yield and help delineate patients who could benefit from targeted therapies. This thesis aims to explore the genetic, epigenetic, and phenotypic continuum between ROHHAD and monogenic hypothalamic obesities, contributing to a better understanding of the ROHHAD condition and the early-onset obesities.
