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

Zhanwei Zhang,1 Haolin Duan,1 Ciliu Zhang,1 Fang He,1 Fei Yin,1,2 Lifen Yang,1 Jing Peng1,2 1Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People’s Republic of China; 2Clinical Research Center for Children Neurodevelopmental Disabilities of Hunan Province, Changsha, Hunan Province, People’s Republic of ChinaCorrespondence: Lifen Yang, Email [email protected] Jing Peng, Email [email protected]: 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.Keywords: familial hemophagocytic lymphohistiocytosis, central nervous system, UNC13D, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, allogeneic hematopoietic stem cell transplantation