Vignette #2: Hemophagocytic Lymphohistiocytosis (HLH)
A 15-year-old healthy male born in Nepal presented with progressive abnormal gait, unilateral tinnitus, paresthesia and pain of the right lower extremity, and difficulty urinating. MRI demonstrated multifocal hemorrhagic lesions in the cerebral white matter, brainstem, and cerebellum with mild pontine swelling. After undergoing negative hematology and infectious workup, he started a course of high-dose steroids given concern for a demyelinating process.
While hospitalized, he experienced a sudden hemorrhagic right pontine stroke. Workup revealed significantly decreased NK cell function, which, along with unexplained fevers, prompted workup for central nervous system (CNS) HLH. Subsequent testing showed absent perforin, and a genetic HLH panel revealed both a heterozygous pathologic variant and a heterozygous VUS in the PRF1 gene. This exact heterozygous compound variant has been described in a case report of immunocompromised patients in India and is thought to be pathogenic based on in silico predictors7,8.
Familial testing revealed the same pathogenic variant in the father, who is a presumed HLH carrier due to negative clinical history. The patient was diagnosed with familial CNS HLH, given the presence of a pathogenic variant and the aforementioned VUS in conjunction with clinical and laboratory findings of HLH. This patient ultimately recovered with a haploidentical hematopoietic stem cell transplant.