Hemophagocytic Lymphohistiocytosis (HLH) in Noonan's Syndrome (NS) Successfully Treated with Anti-IL-1beta Therapy

HLH is a syndrome characterized by uncontrolled macrophage activation. NS is an autosomal dominant disorder involving RAS-MAPKinase pathway associated with multiple end-organ defects, short stature, and dysmorphic features. We present the first reported case of HLH in NS who improved with use of anti-IL-1beta therapy. Genetic Screening for Familial HLH; Bone-Marrow Biopsy; NK-cell cytotoxicity assay; Familial Mediterranean fever (FMF) genetic test. Five-year-old female with NS (KRAS c40g>a), gastroparesis with G-tube placement, mitral valve prolapse and chronic anemia presented with recurrent fevers. Multiple admissions yielded negative work-up for infectious etiology. Fevers associated with joint pain and increased abdominal discomfort. She met 5 of 8 criteria for HLH: Ferritin >20,000ng/ml; hepatosplenomegaly; fevers; decreased NK-cell activity, and hemophagocytosis on bone-marrow biopsy. Primary HLH genetic screening was negative. FMF evaluation was negative. Other period fever syndrome evaluations are pending. Systemic steroids led to some improved symptoms. She was initiated on IL-1beta receptor antagonist (anakinra), which led to resolution of fevers and reduction in joint symptoms. She transitioned to long-acting anti-IL-1beta monoclonal antibody (canakinumab), which maintained control of symptoms. While HLH has not been a reported feature of NS, RAS-MAPKinase pathway is a crucial component of cell signaling that controls transcription of inflammatory mediators. This case illustrates importance of considering autoinflammatory conditions in NS patients with recurrent fevers. Steroids and cytoreductive agents are currently standard of care for HLH. Efficacy of IL-1beta blockade in this case highlights importance of considering these agents as alternative or adjunctive treatment for HLH.