Spinal cord involvement in a child with familial hemophagocytic lymphohistiocytosis
An 11-year-old boy was referred for on-going splenomegaly subsequent to tonsillopharyngitis 5 months ago. He was the second child born to consanguineous parents and his brother died of Epstein–Barr virus (EBV)-associated HLH 2 years ago. Unfortunately, molecular analysis for HLH was unavailable for his brother.\nAt the first presentation, he was conscious, alert, and afebrile. Only the spleen was palpable 4 cm below the left costal margin. Neurological examination was completely normal. Complete blood count revealed hemoglobin: 10.6 g/dL, platelet: 105 × 109/L, and leukocyte count: 2.6 × 109/L with an absolute neutrophil count of 1.1 × 109/L. Serum liver adrenal function tests and electrolytes were normal. Serum ferritin level was 24.4 ng/mL. Serum fasting triglyceride and plasma fibrinogen levels were 113 mg/dL and 250 mg/dL respectively. Bone-marrow aspiration demonstrated increased histiocytes and hemophagocytosis. Polymerase chain reaction for EBV DNA revealed 12.909 copies/mL and parenteral acyclovir therapy was commenced immediately.\nA week later, he began to suffer from persistent headache unresponsive to analgesics and vomiting. Fundoscopic examination showed bilateral papilledema. Cranial magnetic resonance imaging (MRI) showed bilateral symmetric signal changes on the periventricular deep white matter and increased micronodular contrast uptake on the right cerebellar hemisphere on T2w images which were suggestive for HLH involvement of CNS. Cervical spinal cord was normal. CSF examination yielded increased pressure (140 cm H2O) with normal protein and glucose levels. Cytological evaluation showed prominent lymphomononuclear cells, pointing to pleocytosis. Preliminary diagnosis was thought as EBV-associated HLH and intravenous gamma globulin – together with dexamethasone and cyclosporine – was given. Intrathecal chemotherapy with methotrexate and prednisolone was performed once a week, for 4 weeks. At the end of the 3rd week, splenomegaly disappeared and EBV copies decreased to 212 copies/mL. He was discharged from the hospital, with normal CSF values.\nOn the 7th week of follow-up as an outpatient – while receiving cyclosporine A and dexamethasone – he presented with headache, vomiting, and somnolence again. He was confused but responded to verbal stimuli. Bilateral papilledema was noticed on fundoscopic evaluation. Mild quadriparesia was also noted and deep tendon reflexes were hypoactive. Cranial MRI demonstrated apparent progression of the previous cerebral and cerebellar lesions and involvement of brain stem and cervical spinal cord. The lesions were extended to the level of 6th thoracal segment [Figure –]. CSF and serum EBV copies were negative. Cytological evaluation of CSF revealed reappearance of lymphomononuclear cells with prominent hemophagocytosis. HLH criteria including ferritin, fibrinogen, and triglyceride were unremarkable.\nMolecular analysis for FHL yielded a mutation in UNC13D gene which is c.1240C > T leading to p.Arg414Cys substitution. Due to recurrent CNS HLH and UNC13D mutation, he was diagnosed as FHL. HLH-2004 protocol including etoposide was initiated with the consent of his family.[] The clinical and biochemical findings remitted at the 4th week of the protocol. The radiological findings completely disappeared after the end of HLH 2004 protocol. He underwent a successful bone-marrow transplantation from a HLA-mismatched donor (9/10). He is alive and healthy now.