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      Familial Hemophagocytic Lymphohistiocytosis (FHLH) Perforin Deficiency: A Case Study and Literature Review


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          Hemophagocytic lymphohistocytosis (HLH) is a severe and fatal immunological disorder that is either primary (i.e., familial) or secondary (i.e., acquired). The primary type comprises autosomal recessive disorders with gene mutations related to natural killer cells and cytotoxic T-cells, whereas the secondary type is related to other pathological causes, such as Epstein-Barr virus, bacterial or fungal infection, autoimmune conditions or autoinflammatory diseases, metabolic disorders, and cancer. In this report, we discuss a 37-day-old male who was brought to the emergency room with fever, decreased activity, and hepatosplenomegaly, with a strong family history of unknown cause of death for three siblings who died at the ages of one to two months. A whole exome sequencing confirmed the clinical diagnosis of familial HLH due to mutation in the PRF1 gene. We note the special importance of genetic counselling and antenatal screening or early neonatal screening in families affected by HLH, as this case highlights the importance of early diagnosis and intervention of primary HLH.

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          Pediatric hemophagocytic lymphohistiocytosis

          Hemophagocytic lymphohistiocytosis (HLH) is a syndrome describing patients with severe systemic hyperinflammation. Characteristic features include unremitting fever, cytopenias, hepatosplenomegaly, and elevation of typical HLH biomarkers. Patients can develop hepatitis, coagulopathy, liver failure, central nervous system involvement, multiorgan failure, and other manifestations. The syndrome has a high mortality rate. More and more, it is recognized that while HLH can be appropriately used as a broad summary diagnosis, many pediatric patients actually suffer from an expanding spectrum of genetic diseases that can be complicated by the syndrome of HLH. Classic genetic diseases in which HLH is a typical and common manifestation include pathogenic changes in familial HLH genes (PRF1, UNC13D, STXBP2, and STX11), several granule/pigment abnormality genes (RAB27A, LYST, and AP3B1), X-linked lymphoproliferative disease genes (SH2D1A and XIAP), and others such as NLRC4, CDC42, and the Epstein-Barr virus susceptibility diseases. There are many other genetic diseases in which HLH is an infrequent complication of the disorder as opposed to a prominent manifestation of the disease caused directly by the genetic defect, including other primary immune deficiencies and inborn errors of metabolism. HLH can also occur in patients with underlying rheumatologic or autoinflammatory disorders and is usually designated macrophage activation syndrome in those settings. Additionally, HLH can develop in patients during infections or malignancies without a known (or as-yet-identified) genetic predisposition. This article will attempt to summarize current concepts in the pediatric HLH field as well as offer a practical diagnostic and treatment overview.
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            The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.

            Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/μL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc lymphohistiocytosis are insufficient to differentiate hemophagocytic inflammatory syndromes with different pathogeneses. This is important because of implications for therapy, in particular for protocols targeting T cells.
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              Primary and secondary hemophagocytic lymphohistiocytosis have different patterns of T‐cell activation, differentiation and repertoire

              Hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening inflammatory syndrome characterized by hyperactivation of lymphocytes and histiocytes. T cells play a key role in HLH pathogenesis, but their differentiation pattern is not well characterized in patients with active HLH. We compared T‐cell activation patterns between patients with familial HLH (1°HLH), 2°HLH without apparent infectious trigger (2°HLH) and 2°HLH induced by a viral infection (2°V‐HLH). Polyclonal CD8+ T cells are highly activated in 1°HLH and 2°V‐HLH, but less in 2°HLH as assessed by HLA‐DR expression and marker combination with CD45RA, CCR7, CD127, PD‐1 and CD57. Absence of increased HLA‐DR expression on T cells excluded active 1° HLH with high sensitivity and specificity. A high proportion of polyclonal CD127−CD4+ T cells expressing HLA‐DR, CD57, and perforin is a signature of infants with 1°HLH, much less prominent in virus‐associated 2°HLH. The similar pattern and extent of CD8+ T‐cell activation compared to 2° V‐HLH is compatible with a viral trigger of 1°HLH. However, in most 1°HLH patients no triggering infection was documented and the unique activation of cytotoxic CD4+ T cells indicates that the overall T‐cell response in 1°HLH is different. This may reflect different pathways of pathogenesis of these two HLH variants.

                Author and article information

                Cureus (Palo Alto (CA) )
                8 March 2024
                March 2024
                : 16
                : 3
                : e55770
                [1 ] Pediatric Hematology and Oncology, Armed Forces Hospital Southern Region, Khamis Mushait, SAU
                [2 ] Pediatrics, Armed Forces Hospital Southern Region, Khamis Mushait, SAU
                [3 ] Pathology, Armed Forces Hospital Southern Region, Khamis Mushait, SAU
                [4 ] Flowcytometry, Flow Cytometry Laboratory for Leukemia & Lymphoma Diagnosis, Khartoum, SDN
                [5 ] Pediatric Intensive Care Unit, Armed Forces Hospital Southern Region, Khamis Mushait, SAU
                [6 ] Pediatrics, Najran General Hospital, Najran, SAU
                Author notes
                Badriah G. Alasmari b-a-1985@ 123456hotmail.com
                Copyright © 2024, Alasmari et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 8 March 2024

                prf1,severe sepsis,perforin,familial disease,hemophagocytic lymphohistocytosis (hlh)


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