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

Case Presentation 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.Figure 1Bone marrow aspirate of this patient showing evidence of haemophagocytosis (H & E). A and B show large macrophages undergoing phagocytosis of different cellular elements of the bone marrow.Figure 1. Bone marrow aspirate of this patient showing evidence of haemophagocytosis (H & E). A and B show large macrophages undergoing phagocytosis of different cellular elements of the bone marrow. Discussion Several genes have been implicated in the genesis of primary HLH; all of them have in common impaired cytotoxic function by NK and T cells. It has been reported that mutations of the PRF1 gene comprise approximately 20 to 30% of the cases of primary HLH. This variant has been reported as a polymorphism and was not conclusive for the diagnosis of perforin deficiency as the cause of HLH in this case. In addition, the mutation was heterozygous. Although HLH is usually a recessive disorder, there are reports of potential disease associations in the heterozygous state. There is significant overlap between primary and secondary HLH and the role of some heterozygous mutations remain to be investigated. Disclosures: No relevant conflicts of interest to declare.