REPORT OF THE CASE: 

The patient, previously healthy except for atopic dermatitis, presented at age 16.8 with encephalopathy, progressive obtundation, seizures and fever. CSF studies showed neutrophilic pleocytosis; PCR was positive for HHV-6. Acyclovir resulted in resolution of symptoms within 48 hours. She experienced four similar recurrences within the next 18 months. Each responded promptly to acyclovir, pulse methylprednisolone, or ganciclovir. Colchicine or valganciclovir prophylaxis did not prevent recurrences. An extensive search for immune deficiency, and  infectious, toxicological or rheumatological/immunological pathologies was unrevealing. 

Hair follicle analysis confirmed chromosomal integration in the patient and her mother. HHV-6-mRNA was not detected during the last recurrence, indicating no active replication of the virus. 

Patients’s whole genome sequencing identified three variants of uncertain significance (VUS) in the TREX1, NLRP3, SCN9A genes. NLRP3 is part of the inflammasome complex of the innate immune system. Mutations in this gene cause Cryopyrin-associated periodic syndromes (CAPS), a group of autoinflammatory diseases due to overproduction of interleukin-1 (IL-1). The patient’s variant  NLRP3 c.892C>G  (p.Leu298Val) has not been reported as causal for CAPS, and her clinical presentation has not been described in CAPS. Another variant, Q703K, has recently been connected to  CNS inflammation. The finding suggested an autoinflammatory mechanism, possibly related to abnormal production of IL-1. A therapeutic trial with an IL-1 inhibitor – anakinra – was  initiated.