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      Familial Hemophagocytic Lymphohistiocytosis May Present during Adulthood: Clinical and Genetic Features of a Small Series


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          Familial Hemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with defective cytotoxic function. The age at onset is usually young and the natural course is rapidly fatal if untreated. A later onset of the disease has been sporadically reported even in adolescents and adults. We report the results of our retrospective data collection of all cases diagnosed with FHL at an age of 18 years or older and enrolled in the Italian Registry of HLH. All cases were diagnosed with FHL based on evidence of genetic defect in one FHL-related gene. A total of 11 patients were diagnosed with FHL. They were 9 males and 2 females, from 10 unrelated families; their age ranged between 18 and 43 years (median, 23 years). Family history was unremarkable in eight families at the time of the diagnosis. Their genetic diagnoses are: FHL2 (n = 6), FHL3 (n = 2), FHL5 (n = 1), XLP1 (n = 2). Clinical, molecular and functional data are described. These data confirm that FHL may present beyond the pediatric age and up to the fifth decade. FHL2 due to perforin defect is the most frequently reported subtype. Adult specialists should consider FHL in the differential diagnosis of patients with cytopenia and liver or central nervous system disorders, especially when a lymphoproliferative disease is suspected but eventually not confirmed. FHL may turn to be fatal within a short time course even in adults. This risk, together with the continuous improvement in the transplant technique, especially in the area of transplant from matched unrelated donor, resulting in reduced treatment related mortality, might suggest a wider use of SCT in this population. Current diagnostic approach allows prompt identification of patients by flow-cytometry screening, then confirmed by the genetic study, and treatment with chemo-immunotherapy followed by stem cell transplantation.

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          Most cited references18

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

          Familial hemophagocytic lymphohistiocytosis (HLH) is a rare primary immunodeficiency disorder characterized by defects in cell-mediated cytotoxicity that results in fever, hepatosplenomegaly, and cytopenias. Familial HLH is well recognized in children but rarely diagnosed in adults. We conducted a retrospective review of genetic and immunologic test results in patients who developed HLH in adulthood. Included in our study were 1531 patients with a clinical diagnosis of HLH; 175 patients were 18 years or older. Missense and splice-site sequence variants in PRF1, MUNC13-4, and STXBP2 were found in 25 (14%) of the adult patients. The A91V-PRF1 genotype was found in 12 of these patients (48%). The preponderance of hypomorphic mutations in familial HLH-causing genes correlates with the later-onset clinical symptoms and the more indolent course in adult patients. We conclude that late-onset familial HLH occurs more commonly than was suspected previously.
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            A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes.

            Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder of immune regulation caused by defects in lymphocyte cytotoxicity. Rapid differentiation of primary, genetic forms from secondary forms of hemophagocytic lymphohistiocytosis (HLH) is crucial for treatment decisions. We prospectively evaluated the performance of degranulation assays based on surface up-regulation of CD107a on natural killer (NK) cells and cytotoxic T lymphocytes in a cohort of 494 patients referred for evaluation for suspected HLH. Seventy-five of 77 patients (97%) with FHL3-5 and 11 of 13 patients (85%) with Griscelli syndrome type 2 or Chediak-Higashi syndrome had abnormal resting NK-cell degranulation. In contrast, NK-cell degranulation was normal in 14 of 16 patients (88%) with X-linked lymphoproliferative disease and in 8 of 14 patients (57%) with FHL2, who were identified by diminished intracellular SLAM-associated protein (SAP), X-linked inhibitor of apoptosis protein (XIAP), and perforin expression, respectively. Among 66 patients with a clinical diagnosis of secondary HLH, 13 of 59 (22%) had abnormal resting NK-cell degranulation, whereas 0 of 43 had abnormal degranulation using IL-2-activated NK cells. Active disease or immunosuppressive therapy did not impair the assay performance. Overall, resting NK-cell degranulation below 5% provided a 96% sensitivity for a genetic degranulation disorder and a specificity of 88%. Therefore, degranulation assays allow a rapid and reliable classification of patients, benefiting treatment decisions.
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              Familial haemophagocytic reticulosis.


                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                7 September 2012
                : 7
                : 9
                : e44649
                [1 ]Department Pediatric Hematology Oncology, Azienda Ospedaliero Universitaria A. Meyer Children Hospital, Firenze, Italy
                [2 ]Hematology Department and BMT Unit, San Maurizio Regional Hospital, Bolzano, South Tyrol, Italy
                [3 ]Divisione di Ematologia, Department of Medicina Specialistica, U.L.S.S. 9 -Ospedale "S. Maria di Ca' Foncello", Treviso, Italy
                [4 ]Department of Internal and Experimental Medicine, Second University of Naples, Naples, Italy
                [5 ]I.R.C.C.S. Burlo Garofolo, UO Pediatric Hemato-Oncology, Trieste, Italy
                [6 ]Infectious Diseases, Azienda Ospedaliero Universitaria S.Orsola-Malpighi, Bologna, Italy
                [7 ]Hematology Department, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy
                [8 ]IRCCS A.O.U. San Martino-IST, Genova, Italy
                [9 ]IRCCS Giannina Gaslini, Genova, Italy
                Instituto de Ciencia de Materiales de Madrid - Instituto de Biomedicina de Valencia, Spain
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ES VC MA. Performed the experiments: VC DP. Analyzed the data: ES VC LM MA. Wrote the paper: ES VC DP LM MA. Cared for the patients: ES AP FG FCS MR LA AB MA. Collected the clinical data: ES AP FG FCS MR LA AB MA. Approved the manuscript in its final version: ES AP FG FCS MR LA AB MA.

                Copyright @ 2012

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

                : 10 May 2012
                : 6 August 2012
                Page count
                Pages: 5
                This study was supported by the following: Antonio Pinzino - Associazione per la Ricerca sulle Sindromi Emofagocitiche (ARSE); Italian Ministry of Health, Progetti di ricerca finalizzata 2008, Bando Malattie Rare RF-TOS-2008-1219488; A.O.U. Meyer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Genetic Mutation
                Genetics of Disease
                Human Genetics
                Molecular Genetics
                Genetics of the Immune System
                Immune Cells
                Molecular Cell Biology
                Clinical Genetics
                Autosomal Recessive
                Genetic Counseling
                Genetic Testing
                Clinical Immunology
                Immune Cells
                NK cells
                T Cells



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