Haemophagocytic Lymphohistiocytosis (HLH) Associated With a Heterozygous PRF1 Mutation Not Previously Described As Pathogenic

A 16 year old male presented with three weeks of fatigue, nausea, vomiting, anorexia, arthralgias, and pancytopaenia. He was febrile, with mouth ulcers, hepato splenomegaly, and palpable non tender supraclavicular and axillary lymphadenopathy. Neurological examination was normal. Remarkable abnormal tests: Hb 77 g/L, platelets 29 x10⁹/L, WCC 0.7 x10⁹/L (neutrophils 0.33), normal PT and APTT but hypofibrinogenaemia 0.8 g/L. Ferritin was elevated 56 061 ug/L (20– 150). Liver function tests showed a mixed pattern with elevated LDH (2137 U/L), mild hypertriglyceridaemia (4.6 mmol/L) and low haptoglobin (< 0.06 g/L), EBV IgM was equivocal with reactive IgG. Bone marrow showed evidence of haemophagocytosis (Fig 1). All HLH-2004 criteria were fulfilled except elevated sCD25 (unavailable). NK cell chromium release assay revealed severely suppressed NK cell function. In addition, perforin gene (PRF1) sequencing for mutation screening showed a missense mutation Ala437Val (1310 C>T) PRF1 heterozygous, a previously unclassified variant. There was no evidence of an underlying cause of HLH. Our patient received induction therapy with etoposide 150 mg/m2 and dexamethasone 10 mg/m2 with dosing and frequency as suggested by the HLH-94 protocol. Pancytopaenia recurred and an increase in ferritin concentration was interpreted as relapse of the condition. At that point, cyclosporine was added on in conjunction with maintenance etoposide and dexamethasone obtaining partial remission. He underwent allogeneic SCT successfully in another centre.