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.