Daniel Zhou1, Mohamed Darwish3, James Ford2, Sachit Patel2, Sookyong Koh4, Geetanjali Rathore4, Rana Zabad1
1Department of Neurological Sciences, 2Department of Pediatrics, Division of Hematology/Oncology, University of Nebraska Medical Center, 3Department of Pediatrics, Children's Mercy Kansas City, 4Division of Neurology, Children's Hospital & Medical Center
Objective:
To present a rare diagnosis of familial hemophagocytic lymphohistiocytosis (FHL) in an adolescent patient with clinical and imaging findings supportive of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).
Background:
CLIPPERS is an exceedingly rare and often under-recognized diagnosis in the pediatric population. One-third of adult patients presenting with CLIPPERS were recently found to have hemophagocytic lymphohistiocytosis (HLH) gene mutations. FHL is the result of mutations within the FHL-associated gene family, resulting in a dysfunctional inflammatory response. The central nervous system-restricted form of FHL is a potentially curable novel syndrome with limited published data.
Design/Methods:
Case report.
Results:
A 17-year-old right-handed young man presented subacutely with headache, diplopia, dysarthria, and ataxia, suggestive of a pontocerebellar syndrome. Brain magnetic resonance imaging (MRI) revealed T2 hyperintensities associated with miliary enhancement throughout the cortical, subcortical, and infratentorial white matter bilaterally, with a predilection to the pons and cerebellar peduncles, a pattern highly suggestive of CLIPPERS. He dramatically improved clinically and radiologically with empirical intravenous methylprednisolone. Unfortunately, a rapid tapering of prednisone resulted in disease recurrence. Workup for HLH per the Histiocyte Society guidelines-2004 was unremarkable. Serum perforin/granzyme B assay revealed markedly reduced perforin and unchanged granzyme expression in the natural killer and CD8 cells. Genetic testing revealed two heterozygous mutations in the PRF1 (perforin) gene. He was confirmed to have FHL, initiated emapalumab therapy, and received a hematopoietic stem cell transplantation.
Conclusions:
Our case supports the reported relationship between CLIPPERS and HLH. CLIPPERS might be a syndrome rather than a separate disease entity. While FHL is more likely in infancy, pediatric CLIPPERS is rare and calls for further investigations to reach a final diagnosis. However, FHL was recently reported in adults thanks to the continuous advancements in genetic testing for HLH, helping clinicians expedite the diagnosis and management of patients with HLH.