Primary Hemophagocytic Lymphohistiocytosis: A Severe Immune Dysregulatory Disease with Various Genotypic Features and Outcomes: A Cross-Sectional Study from a Tertiary Pediatric Center.
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OBJECTIVE: Inborn errors of immunity (IEIs) are caused by deficiencies or functional abnormalities in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and/or malignancies. Primary hemophagocytic lymphohistiocytosis (HLH) arises from genetic mutations affecting the function of cytotoxic T lymphocytes and natural killer cells, while secondary HLH is triggered by infections, malignancies, rheumatologic disorders, or immune deficiencies. Treatment consists of remission induction, control of triggers, maintenance of remission, rescue treatment, and hematopoietic stem cell transplantation (HSCT) as curative steps. The aim of this study is to evaluate the clinical and laboratory features, as well as the outcomes, of primary HLH patients who were diagnosed and treated in a multidisciplinary manner over the past 25 years. MATERIALS AND METHODS: The study included 30 patients with primary HLH/IEI who were diagnosed and treated in the departments of pediatric hematology, immunology, and oncology of the Ankara University Faculty of Medicine Children’s Hospital and Bone Marrow Transplantation Unit from 2000 to 2025. RESULTS: Of the 30 patients, 18 were boys and 12 were girls. The median age at the onset of the first symptom was 10 months (range: 0.5-204 months), while the median age at the time of admission to our center was 12.5 months (range: 1-204 months). Pedigree analysis showed that 21 patients were born to consanguineous parents. All patients had a fever lasting longer than 5 days, with a mean duration of 13.30±14.05 days (range: 5-60 days). Splenomegaly was detected in 29 patients (96.6%) and hepatomegaly in 25 (83%). Anemia was observed in 27 patients (90%), neutropenia in 23 (76.6%), and thrombocytopenia in 30 (100%). Genetic evaluation was performed for all patients and a causative gene was identified in 19 of 30 cases (63%). The most common genetic diagnosis was perforin deficiency (FHLH2), detected in 8 patients (26.6%), followed by UNC13D defect (FHLH3) in 4 patients (13,3%). HSCT was performed for 17 patients (56.6%), with 6 receiving transplants from matched related donors, 4 from matched sibling donors, 5 from matched unrelated donors, and 2 from mismatched related donors. Thirteen patients remain alive, with mean survival of 119.89 months. Seventeen patients (56.6%) died, primarily due to multiorgan dysfunction syndrome, acute respiratory distress syndrome, HLH reactivation, septic shock, or heart failure. HSCT patients had a significantly longer survival (mean: 165.6 months) compared to patients who did not undergo HSCT (45.36 months; p<0.01). Admission to the pediatric intensive care unit, organ failure, and neurological involvement were identified as adverse prognostic factors, all significantly associated with higher mortality (p<0.05). CONCLUSION: Given the increasing recognition of HLH as a possible manifestation of IEIs, comprehensive immunological and genetic evaluations should be pursued without delay in suspected cases. Our findings, in line with the results of national and international cohorts, confirm that HSCT remains the only curative option for familial HLH and should be performed as early as possible after achieving disease remission. Improving access to early diagnostics and HSCT could significantly enhance outcomes, particularly in genetically predisposed populations.