HLH is a hyperinflammatory condition that presents with fever, hepatosplenomegaly and characteristic laboratory findings. HLH can be familial (fHLH) or secondary (sHLH). Mutations in the perforin gene PRF1 have been identified as pathogenic for fHLH and they can also cause isolated CNS-HLH in the absence of systemic HLH. HLH can be triggered by malignancy, infections, or autoimmunity. Viruses are a common trigger and there have been cases of SARS-CoV-2 triggering HLH. 

Clinical course, evaluation, management. 

A 5-year-old boy presented to the emergency department with 3 weeks of headaches, right blurry vision, and emesis. He underwent an extensive evaluation and was diagnosed with ADEM that was thought to be triggered by SARS-CoV-2 after a positive nasal swab. Myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. Patient completed a 5-day course of IV pulse steroids and plasma exchange. In the subsequent months, he was admitted twice due to worsening neuroinflammation and after several courses of IV pulse steroids, PLEX, and IVIG, the CNS inflammation stabilized with rituximab and monthly IVIG.

A few months later, his younger brother presented to the emergency department with a similar syndrome. It was found that his parents were cousins, leading to concern for a genetic disorder. Genetic testing revealed a homozygous mutation for PRF1 in both siblings (variant c.4422G>A). 

This is the first presentation of CNS-isolated HLH triggered by SARS-CoV-2 in the pediatric population. Furthermore, thisis the first report of PRF1 mutation, the variant c.4422G>A, shown to be pathogenic. It highlights the relevance of genetics in pediatric neuroinflammatory disorders. It is possible that as our knowledge in neurogenetics develops, certain genes will be identified as predisposing factors to presentations such as ADEM.