Primary necrotizing lymphocytic central nervous system vasculitis due to perforin deficiency in a four‐year‐old girl

Abstract

We report the case of a 4-year-old girl who presented with headaches, ataxia, and visual disturbances. Cranial magnetic resonance imaging showed multiple supra-and infratentorial lesions with peripheral contrast enhancement and central necrosis. Brain biopsy revealed necrotizing lymphocytic vasculitis of undetermined etiology. Perforin expression was found to be significantly reduced in the patient's peripheral blood cells, and sequence analysis of the patient's perforin gene showed a compound heterozygous state with 1 nonsense mutation and 2 missense alterations in exon 2. Central nervous system (CNS) vasculitis was thus attributed to the perforin deficiency, and the patient was successfully treated by transplantation of stem cells from an HLA-identical brother. The findings described herein indicate that, even in the absence of classic non-neurologic symptoms of hemophagocytic lymphohistiocytosis, measurement of perforin expression should be one of the diagnostic tests used to identify the cause of unexplained CNS vasculitis, since this may have profound implications regarding therapy.

Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases

“…These atypical presentations have been reported in adolescents and even in adults as late as 62 years of age. 7,8,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] They may be associated with milder and often recurrent HLH episodes and prolonged survival in the absence of hematopoietic stem cell transplantation (HSCT), which is unusual in patients with the typical disease. "Atypical FHL" is usually associated with missense or splice-site mutations in the affected genes.…”

Recurrent subacute post-viral onset of ataxia associated with a PRF1 mutation

“…Even when the patient cohort is limited to those with perforin mutations, the MRI findings are also not consistent (Table 2), although cerebellar disease predominates. [24][25][26]36,43,44 In the absence of systemic findings of HLH, therefore, one is unable to make a clinical diagnosis of PRF1-related neurodegeneration, and molecular testing is required.…”

“…We hypothesize that PRF1-related neurodegeneration is an under-recognized condition, and suggest that when suspicion of immune-mediated neurodegeneration arises, this diagnosis should be considered because it is potentially curable with hematopoietic stem cell transplantation. 15,44 WEB RESOURCES http://research.nhgri.nih.gov/software/Var-MD/…”

Treatment of CNS Vasculitis in Children

“…Secondary CNS vasculitis is increasingly recognized in systemic diseases; it may be the primary symptom or complication of hemophagocytic lymphohistiocytosis (HLH), Kawasaki disease, inflammatory bowel disease, or systemic immunedysregulations [55,56]. HLH is a rare but potentially fatal disease of nonmalignant but overactive histiocytes and lymphocytes commonly triggered by an infection.…”

“…The clinical picture of HLH includes fever, hepatosplenomegaly, pancytopenia, hyperferritinemia, raised liver enzymes, and hypertriglyceridemia [57,58]. CNS vasculitis is well described in children with HLH [56,59] (Fig. 3).…”