ESPE Abstracts

Background: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation (ROHHAD) is a rare syndrome associated with high morbidity and mortality presenting with rapid onset of obesity in early childhood. An immune-inflammatory aetiology has been postulated; however, the immune profile is not well described.

Case report: We report the case of a five-year-old female who presented in respiratory arrest after 6-months of rapid weight gain with central hypoventilation, central diabetes insipidus, growth hormone deficiency and hyperprolactinaemia fulfilling criteria for a diagnosis of ROHHAD. With no proven treatment for ROHHAD, two courses of the monoclonal antibody rituximab (750 g/m²) were given four weeks apart to target any underlying immune dysregulation. A cytokine profile was analysed before and after treatment including measuring tumour necrosis factor (TNF), interleukin-6 (IL-6), interleukin-1b (IL-1b) and interleukin-1 (IL-10) levels in response to stimulation by lipopolysaccharide (LPS) and anti-cluster of differentiation 3 (anti-CD3) with interleukin-2 (IL-2). Each of these pro-inflammatory molecules (TNF, IL-6 and IL-1b) have been heavily implicated in the development of obesity-related metabolic dysfunction, with IL-10 being metabolically protective.

Results: Our cytokine profile demonstrated a highly inflammatory state (table 1), with significantly raised TNF, IL-6 and IL-1b levels and low IL-10 levels in response to stimulation by both LPS and anti-CD3/IL-2. A repeat profile six months after rituximab therapy demonstrated a reduction in TNF of nearly a third, near halving of IL-6, two third’s reduction in IL-1b and a threefold increase in IL-10 on LPS stimulation compared to pre-rituximab. On anti-CD3/IL-2 stimulation a small reduction in TNF, a reduction in IL-6 of a quarter and a greater than threefold increase in IL-10 was noted. Significant weight loss was observed (2.13 BMI-SDS reduction) in the 12 months following rituximab therapy.

Discussion: We describe a highly inflammatory immune profile in this patient with ROHHAD with elevated TNF, IL-6 and IL-1b, and low IL-10, suggestive of both myeloid and T-cell lineage involvement. This suggests an immune-inflammatory pathology driving metabolic dysfunction and potentially other aspects of the condition. We demonstrate significant improvements in the inflammatory phenotype following rituximab therapy with potential clinical benefit. Further characterisation of the immune profile and response to immunomodulation in ROHHAD warrants exploration.