A teenage boy with late onset hemophagocytic lymphohistiocytosis with predominant neurologic disease and perforin deficiency

Abstract

Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disorder of cytotoxic cell function that results in abnormal proliferation of benign lymphocytes and histiocytes in response to infectious stimuli. FHLH generally occurs in very young children, and typically presents with fever, cytopenias, coagulopathy, lymphadenopathy, and hepatosplenomegaly. Central nervous system involvement occurs frequently and may precede the development of systemic symptoms by months to years. We report a case of an 18-year-old male with a 2-year history of symptoms attributed to a demyelinating disorder, who succumbed to rapidly progressive hemophagocyte lymphohistiocytosis. Post-mortem, two distinct perforin mutations were identified. We discuss the central nervous system and genetic findings in this unusual presentation of familial hemophagocytic lymphohistiocytosis.

Gender-Associated Differences of Perforin Polymorphisms in the Susceptibility to Multiple Sclerosis

“…Perforin involvement in the lysis of virus-infected cells and downregulation of cellular immune activation provides an attractive link between PRF1 and MS etiopathogenesis. It should also be mentioned that perforin-deficient FHLH may be associated with CNS demyelination, and some patients with the disease may be misdiagnosed as MS (42). 2) In addition, as a novel finding, to our knowledge, we identified a subgroup of patients with PPMS, mainly males, carrying strongly associated risk haplotypes and characterized by not only lower perforin expression in peripheral blood cells, but also deficient expression in additional genes that code for proteins involved in cell killing by CD8 + T cell and NK cells using effector mechanisms similar to perforin.…”

Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH

“…In older children and adults, a broader spectrum of clinical phenotypes (eg, encephalitis, autoimmune lymphoproliferative disease, acute lymphoblastic leukemia, aplastic anemia, and systemic onset juvenile idiopathic arthritis) 11,14,15,[30][31][32][33][34][35] have been reported. In some of these reported cases, patients were cleared from infections before the overt diseases, and therefore a negative clinical history of HLH does not rule out this syndrome.…”

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

“…23 Although there is an association of variations in PRF1 with susceptibility to multiple sclerosis, 41 very few patients with HLH have had neurological symptoms as the sole presenting feature, and consistent with the expected ascertainment and reporting bias, 29,30,32,39 all developed the diagnostic features of FHL2-HLH, with the exception of one individual who was diagnosed by brain histopathology but without identification of a mutation. 25,26,29,[31][32][33]36,42 The sisters reported herein are therefore the first individuals reported with neurodegeneration, biallelic pathogenic PRF1 mutations and no diagnostic features suggestive of FHL-HLH (Table 2).…”

“…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.…”

“…Also, two bone marrow biopsies in the proband did not demonstrate increased hemophagocytosis found in 82% of FHL2 patients. 23 Neurodegeneration has been reported as a possible feature of FHL2 and sporadic HLH, [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] with a frequency of 37-69%. 23,29,39,40 A third of patients have neurological symptoms at diagnosis, 40 and 36% of those with PRF1 mutations have some CNS involvement.…”