Isolated Central Nervous System FHL3 in an Asian Pediatric Patient: A Case Report and Literature Review

Familial hemophagocytic lymphohistiocytosis (FHL) is a genetic inflammatory response syndrome involving many organs. Central nervous system (CNS)-isolated FHL is a rare, neuroinflammatory condition. Here, we report a case of CNS-isolated FHL3. Brain magnetic resonance imaging (MRI) showed CNS lesions mimicking chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids and multiple sclerosis. Whole-exome sequencing (WES) demonstrated likely pathogenic, parentally inherited homozygous variants of UNC13D (c.2588G>A, p.G863D). Neuropathological examination of a brain biopsy specimen revealed lymphocyte infiltration. Reduced levels of CD107a were also observed. CNS-isolated FHL was final diagnosis. The patient's clinical and radiological condition improved after allogeneic hematopoietic stem cell transplantation (HSCT). A study of five isolated CNS FHL3 cases (onset: 7-31 years; three females, one male, and one unknown) identified the hotspot variants c.2588G>A and c.2346_2349del. Possible triggers include the Epstein-Barr virus and herpes simplex virus. Common CNS symptoms included headache, seizures, diplopia, and ataxia (3/5 each). MRI revealed multifocal cerebral/brainstem/spinal cord lesions. Cerebrospinal fluid revealed nonspecific inflammation. Biopsies revealed T-cell predominant lymphocytic infiltration (3/3). Reduced CD107a expression was observed in four patients. Two developed systemic hemophagocytic lymphohistiocytosis (HLH). Steroids (5/5) and intravenous immunoglobulin (4/5) were the primary treatments and HSCT (4/4) achieved good outcomes. One died of HLH. To date, homozygous variants of UNC13D (c.2588G>A, p.G863D) have not been reported in CNS-isolated FHL. Symptoms and brain MRI of CNS-isolated FHL simulate some neuroinflammatory diseases; however, WES and functional analysis may be useful for distinguishing between them. HSCT might be an effective therapeutic strategy.