Endocrine Abstracts

Background: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation (ROHHAD) is a rare syndrome associated with high morbidity. An immune-inflammatory aetiology has been postulated; however, the immune characteristics and effect of immunomodulation have not been well described.

Case report: We describe the immune profile and the effect of rituximab on the immunomodulation potentially causing a clinical effect of weight loss in a patient with ROHHAD. A five-year-old female presented in respiratory arrest, rapid weight gain, central hypoventilation, central diabetes insipidus, growth hormone deficiency and hyperprolactinaemia suggestive of 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 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) was analysed before and after treatment. These pro-inflammatory molecules (TNF, IL-6 and IL-1b) have been implicated in the development of obesity-related metabolic dysfunction, with IL-10 being metabolically protective.

Results: An inflammatory cytokine profile (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 was demonstrated pre-rituximab. A reduction in TNF of nearly a third, near halving of IL-6, two third’s reduction in IL-1b and a three-fold increase in IL-10 on LPS stimulation was found six months after rituximab therapy. Significant weight loss was observed (2.13 BMI–SDS reduction) in the 12-months following rituximab therapy.

Discussion: This patient with ROHHAD has an inflammatory immune profile with elevated TNF, IL-6 and IL-1b, and low IL-10, suggestive of both myeloid and T-cell lineage involvement. We demonstrate significant improvement in the inflammatory phenotype following rituximab with potential clinical benefit. Further similar studies on the immune profile in ROHHAD is warranted.Table 1 Cytokine profile pre- and post-treatment with rituximab (pg/mL)