Two Cases of Late Pediatric Onset Hemophagocytic Lymphohistiocytosis with Initial Central Nervous System Involvement
Laurel Kelley1, Jennifer Shin2, Gregory Aaen1
1Pediatric Neurology, 2Genetics, Loma Linda University Children's Hospital
Background:
Hemophagocytic lymphohistiocytosis (HLH) is a rare, severe and fatal syndrome of overwhelming systemic immune activation that is increasingly reported with initial and isolated central nervous system (CNS) presentations. HLH can be acquired through immune changes, or inherited mutations usually within the PRF1 and UNC13D genes which encode proteins essential to cytotoxic granule mediated toxicity. Impaired cytotoxicity causes unrestricted lymphohistiocyte proliferation and cytokine production causing a hyperinflammatory syndrome. While HLH classically presents before 36 months of age, it is increasingly being identified with older onset and higher incidence of CNS symptoms. Patients with CNS restricted disease often do not meet criteria, delaying timely diagnosis and treatment. They are often misdiagnosed as demyelinating disease in the absence of specific diagnostic criteria for CNS presentations of HLH when lacking evidence of systemic involvement. We present two cases of late pediatric onset disease, one isolated to the CNS and the other with systemic progression, that highlight the importance of genetic testing for the early diagnosis of CNS HLH.
Results:
A 16-year-old originally diagnosed with CLIPPERS who presented with ataxia, weakness, headaches and dysarthria found to have lymphohistiocytes on brain biopsy and homozygous variants in the PRF1 gene. Conversely, a 19-year-old who presented with vision changes, headaches and paresthesias originally diagnosed with demyelinating disease that progressed to severe headaches, altered mentation and systemic hyperinflammation with hemophagocytosis on bone marrow biopsy and likely heterozygous variants in the UNC13D gene.
Conclusions:
The absence of diagnostic criteria for isolated CNS presentations of HLH increases the risk of misdiagnosis and delays in treatment. Despite different clinical courses, both patients underscore the variable disease presentations and the importance of maintaining a high index of suspicion in atypical demyelinating cases. Importantly, these reports highlight an uncommon phenotype of a rare genetic disease and the diagnostic importance of early genetic testing.