UNCD Mutations in Children with Familial Hemophagocytic Lymphohistiocytosis and Systemic Inflammatory Response Syndrome

Abstract Background Familial hemophagocytic lymphohistiocytosis (HLH) results in clinical manifestations of an extreme inflammatory process; leading to an overlap with other diseases with a hyperinflammation process. Implementing HLH criteria without genetic analysis might lead to inadvertent planned therapy with immunosuppressive and unnecessary bone marrow transplantation. Objectives This study assessed the frequency and types of UNCD mutations among patients clinically diagnosed with Familial HLH or systemic inflammatory response syndrome and correlated between the genetic mutations and clinical picture. Methods This study included 40 patients who were clinically diagnosed as Familial HLH or systemic inflammatory response syndrome with median age 28 months. All patients fulfilled at least 5 out of 8 of HLH criteria. Complete blood count, liver enzymes, total and direct bilirubin, serum ferritin, serum fibrinogen, serum triglycerides, sCD25, bone marrow aspirate, MRI brain and CSF analysis were assessed as well as analysis of UNC13D gene were performed. Results The studied population included 24 (60%) males and 16 (40%) females with median age at initial presentation being 26 months. Eighteen (45%) patients had a positive family history. At presentation, 25 (62.5%) patients had systemic manifestations: 36 (90%) patients had fever, 35 (87.5%) patients had hepatosplenomegaly. Nine (22.5%) patients presented with neurological manifestations and six (15%) patients had both systemic and neurological manifestations. Genetic testing of the studied population showed: 10 (25%) patients had UNCD gene mutation, 15 (37.5%) patients were found to have other gene mutations for FHLH, 3 patients had mutations for other genetic conditions while 12 (40%) patients had no any genetic mutations. Among the 15 patients who showed gene mutations for other FHLH subtypes; 12 (40%) patients had Perforin gene mutations, 1 patient had STXBP2 gene mutation, 1 patient had Lyst gene mutation and 1 patient had RAB27A gene mutations. Data showed no significant difference in clinical presentation between patients with UNCD gene mutation and other patients (Pvalue: 0.08). Nearly one third of patients (n = 11, 30.6%) were misdiagnosed and treated as FHLH which was then excluded by genetic study. 8 (32%) patients were diagnosed solely by genetic study to have FHLH and were not suspected upon presentation to have FHLH with a mean interval to diagnosis of 203 days. Conclusions Genetic testing is mandatory for diagnosis of FHLH to determine the exact gene mutation and to differentiate from other conditions with hyperinflammatory process to rapidly implement bone marrow transplantation in patients with positive mutations as it is the only radical cure.