Background: Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) is a life-threatening hyperinflammatory syndrome caused by the dysregulated activation of macrophages and cytotoxic T-cells. The syndrome can be seen in autoimmune diseases, infections, or malignancies. Genetic predispositions can be a risk factor that needs more exploration.

Case presentation: A 25-year-old female with autism, neurodevelopmental delay, and fragile X syndrome was admitted to an outside hospital with fever, rash, pharyngitis, and pleuro-pericardial effusion. Lab tests showed anemia, thrombocytopenia, elevated inflammatory markers (including ferritin >3,000), and positive P-ANCA, raising suspicion for vasculitis or adult-onset Still’s disease. Despite broad-spectrum antibiotics and high-dose steroids, she developed acute renal failure and transaminitis. Renal and liver biopsies indicated acute tubular necrosis and non-specific inflammation without evidence of vasculitis. Stabilized on 30 mg prednisone, she was transferred to our facility. She developed Pneumocystis jirovecii pneumonia requiring intubation and mechanical ventilation. As steroids were tapered, her condition deteriorated with recurrent fever, persistent bicytopenia, and hyperferritinemia, indicating possible HLH/MAS. Tests for infections, malignancy, and an autoinflammatory genetic panel were negative. Pulse dose steroids were started, followed by anakinra, which proved to be ineffective and led to worsening transaminitis. A trial of IVIG was given but caused anaphylactic reaction. Tocilizumab at 8 mg/kg/day for three consecutive days led to some improvement but caused profound neutropenia. Eventually, ruxolitinib was started at 5mg twice daily and increased to 15mg twice daily; her lab values and clinical status stabilized with treatment. Whole genome sequencing later identified a pathogenic TAOK1 (c.2497G>T p.E833*) mutation, revealing her predisposition to inflammation and hyperactivation.