HLH is a systemic hyperinflammatory syndrome characterized by the inappropriate overactivation of T cells, NK cells, and macrophages, leading to infiltration and damage of multiple organs. Familial forms caused by genetic defects in granule-mediated cytotoxicity often present in infancy or early childhood and are fatal without treatment. Herein, we describe a previously healthy 13-year-old female with a delayed, indolent presentation of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) due to perforin deficiency.
The patient had no significant past medical history and presented with 1 week of high fevers, a petechial rash, and pancytopenia progressing to fluid-refractory shock requiring multiple vasopressors.
Her initial labs and exam demonstrated splenomegaly, pancytopenia (platelets 13,000, hemoglobin 8.0 g/dL, and ANC 770 cells/μL), triglycerides of 200 mg/dL, ferritin of 1,036 ng/ml, and sIL2R of 10,806 U/ml. Bone marrow biopsy revealed hemophagocytosis with hypocellular marrow (40%). Although these labs are consistent with HLH, they are nonspecific and could also be consistent with an infectious or oncologic etiology, which were highest on our differential.
She was initially treated with broad-spectrum antibiotics, platelet and pRBC transfusions, and a single stress dose of hydrocortisone while she underwent extensive infectious, oncologic, and metabolic workups. Her condition stabilized, and after a week of clinical stability without further treatment, she was prepped for discharge.
Unfortunately, her discharge was delayed by recrudescence of fever, pancytopenia, and hypotension. Further workup at this time revealed reduced NK activity and absent perforin staining (Figure 1). Whole-genome sequencing confirmed a diagnosis of perforin deficiency with compound heterozygous likely pathogenic variants in PRF1: a paternally inherited c.695G>A (p.Arg232His) variant and a maternally inherited c.1337A>C (p.Gln446Pro) (Figure 2). She was started on steroids and ruxolitinib for HLH-directed therapy and demonstrated rapid clinical improvement. She ultimately underwent a matched sibling donor hematopoietic stem cell transplant and remains in good clinical condition 6 months later with full donor chimerism and emerging immune reconstitution.
Perforin and granzyme flow cytometry of patient and healthy sibling.
Whole-genome sequencing results.
Though typically presenting in infancy, later presentations of familial HLH are possible and can include atypical features. Providers should retain a high index of suspicion.
