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2.
J Clin Oncol ; 37(31): 2857-2865, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513482

RESUMO

PURPOSE: Off-label use of vemurafenib (VMF) to treat BRAFV600E mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 (P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAFV600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAFV600E clone. CONCLUSION: VMF seemed safe and effective in children with refractory BRAFV600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

3.
Cancer ; 125(6): 963-971, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30521100

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.


Assuntos
Sistema Hematopoético/imunologia , Histiocitose de Células de Langerhans/complicações , Fígado/imunologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Baço/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Sistema Hematopoético/patologia , Histiocitose de Células de Langerhans/imunologia , Humanos , Lactente , Recém-Nascido , Fígado/patologia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Prognóstico , Estudos Retrospectivos , Baço/patologia , Adulto Jovem
4.
J Allergy Clin Immunol Pract ; 6(5): 1508-1517, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30201097

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Transplante de Medula Óssea , Etoposídeo/uso terapêutico , Histiócitos/imunologia , Linfócitos/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Consenso , Citotoxicidade Imunológica , Diretrizes para o Planejamento em Saúde , Humanos , Ativação Linfocitária , Linfo-Histiocitose Hemofagocítica/diagnóstico , Sociedades Médicas
5.
Biol Blood Marrow Transplant ; 24(6): 1223-1231, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29410181

RESUMO

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34+ cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft.


Assuntos
Linfo-Histiocitose Hemofagocítica/terapia , Adolescente , Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Histocompatibilidade , Humanos , Lactente , Itália , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/mortalidade , Masculino , Recidiva , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
6.
J Neuroimmunol ; 311: 10-13, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28863861

RESUMO

Neuromyelitis optica is an autoimmune demyelinating inflammatory disease characterized by optic neuritis and myelitis with anti-aquaporin 4 antibodies. Hemophagocytic lymphohistiocytosis is a severe systemic inflammatory syndrome that can present in a genetic primary form or secondarily to infective, neoplastic or autoimmune diseases. Our case discusses the first reported case of atypical late-onset hemophagocytic lymphohistiocytosis in a patient with neuromyelitis optica, with multiple triggering factors and carrying the common A91V hypomorphic perforin mutation, that blurs the distinction between primary and secondary forms.


Assuntos
Linfo-Histiocitose Hemofagocítica/genética , Mutação/genética , Neuromielite Óptica/genética , Perforina/genética , Corticosteroides/uso terapêutico , Alanina/genética , Antígenos CD/metabolismo , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/complicações , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/tratamento farmacológico , Medula Espinal/diagnóstico por imagem , Valina/genética
8.
J Allergy Clin Immunol ; 137(1): 188-196.e4, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26342526

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease affecting mostly children but also adults and characterized by hyperinflammatory features. A subset of patients, referred to as having familial hemophagocytic lymphohistiocytosis (FHL), have various underlying genetic abnormalities, the frequencies of which have not been systematically determined previously. OBJECTIVE: This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. METHODS: From our registry, we have analyzed a total of 500 unselected patients with HLH. RESULTS: Biallelic pathogenic mutations defining FHL were found in 171 (34%) patients; the proportion of FHL was much higher (64%) in patients given a diagnosis during the first year of life. Taken together, mutations of the genes PRF1 (FHL2) and UNC13D (FHL3) accounted for 70% of cases of FHL. Overall, a genetic diagnosis was possible in more than 90% of our patients with FHL. Perforin expression and the extent of degranulation have been more useful for diagnosing FHL than hemophagocytosis and the cytotoxicity assay. Of 281 (56%) patients classified as having "sporadic" HLH, 43 had monoallelic mutations in one of the FHL-defining genes. Given this gene dosage effect, FHL is not strictly recessive. CONCLUSION: We suggest that the clinical syndrome HLH generally results from the combined effects of an exogenous trigger and genetic predisposition. Within this combination, different weights of exogenous and genetic factors account for the wide disease spectrum that ranges from HLH secondary to severe infection to FHL.


Assuntos
Predisposição Genética para Doença , Linfo-Histiocitose Hemofagocítica/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Itália , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Perforina/genética , Sistema de Registros , Adulto Jovem
9.
PLoS One ; 10(7): e0131635, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26176859

RESUMO

BACKGROUND: Neurodegenerative Langerhans Cell Histiocytosis (ND-LCH) is a rare, unpredictable consequence that may devastate the quality of life of patients cured from LCH. We prospectively applied a multidisciplinary diagnostic work-up to early identify and follow-up patients with ND-LCH, with the ultimate goal of better determining the appropriate time for starting therapy. METHODS: We studied 27 children and young adults with either ND-LCH verified by structural magnetic resonance imaging (MRI) (group 1) or specific risk factors for (diabetes insipidus, craniofacial bone lesions), but no evidence of, neurodegenerative MRI changes (group 2). All patients underwent clinical, neurophysiological and MRI studies. RESULTS: Seventeen patients had MRI alterations typical for ND-LCH. Nine showed neurological impairment but only three were symptomatic; 11 had abnormal somatosensory evoked potentials (SEPs), and five had abnormal brainstem auditory evoked potentials (BAEPs). MR spectroscopy (MRS) showed reduced cerebellar NAA/Cr ratio in nine patients. SEPs showed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for predicting ND-LCH of 70.6% (95%CI, 44.0%-89.7%), 100% (69.2%-100%), 100% (73.5%-100%), and 66.7% (38.4%-88.2%), respectively. Repeated investigations in group 1 revealed increasingly abnormal EP parameters, or neurological examination, or both, in nine of fifteen patients while MRI remained unchanged in all but one patient. CONCLUSION: A targeted MRI study should be performed in all patients with risk factors for ND-LCH for early identification of demyelination. The combined use of SEPs and careful neurological evaluation may represent a valuable, low-cost, well-tolerated and easily available methodology to monitor patients from pre-symptomatic to symptomatic stages. We suggest a multidisciplinary protocol including clinical, MRS, and neurophysiological investigations to identify a population target for future therapeutic trials.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Adolescente , Adulto , Área Sob a Curva , Criança , Pré-Escolar , Diagnóstico Precoce , Eletroencefalografia , Potenciais Evocados Auditivos , Potenciais Somatossensoriais Evocados , Feminino , Seguimentos , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Curva ROC , Fatores de Risco , Sensibilidade e Especificidade , Adulto Jovem
10.
J Allergy Clin Immunol ; 135(6): 1638-41, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25592983
11.
J Allergy Clin Immunol ; 135(5): 1310-8.e1, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25312756

RESUMO

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and often fatal disorder characterized by defective cellular cytotoxicity and hyperinflammation, and the only cure known to date is hematopoietic stem cell transplantation. Mutations in RAB27A, LYST, and AP3B1 give rise to FHL associated with oculocutaneous albinism, and patients with FHL are usually only screened for mutations in these genes when albinism is observed. A number of patients with FHL and normal pigmentation remain without a genetic diagnosis. OBJECTIVE: We asked whether patients with FHL with immunodeficiency but with normal pigmentation might sometimes have mutations that affected cellular cytotoxicity without affecting pigmentation. METHODS: We carried out mutation analysis of RAB27A, LYST, and AP3B1 in patients with FHL with pigment dilution, as well as a cohort with no clinical evidence of pigment dilution but no mutations in the other known FHL-related genes (PRF1, STXBP2, and UNC13D). RESULTS: We identify patients with Griscelli syndrome type 2 with biallelic mutations in RAB27A in the absence of albinism. All 6 patients carried mutations at amino acids R141, Y159, or S163 of Rab27a that disrupt the interaction of Rab27a with Munc13-4, without impairing the interaction between melanophilin and Rab27a. CONCLUSION: These studies highlight the need for RAB27A sequencing in patients with FHL with normal pigmentation and identify a critical binding site for Munc13-4 on Rab27a, revealing the molecular basis of this interaction.


Assuntos
Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/metabolismo , Proteínas de Membrana/metabolismo , Mutação , Pigmentação da Pele/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Albinismo/genética , Estudos de Casos e Controles , Degranulação Celular , Linhagem Celular , Criança , Pré-Escolar , Estudos de Coortes , Citotoxicidade Imunológica , Análise Mutacional de DNA , Feminino , Expressão Gênica , Marcadores Genéticos , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Proteínas de Membrana/química , Modelos Moleculares , Perforina/genética , Fenótipo , Ligação Proteica , Conformação Proteica , Proteínas rab de Ligação ao GTP/química , Proteínas rab27 de Ligação ao GTP
12.
J Allergy Clin Immunol ; 134(6): 1381-1387.e7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24985396

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, heterogeneous, hyperinflammmatory disorder. Prompt identification of inherited forms resulting from mutation in genes involved in cellular cytotoxicity can be crucial. X-linked lymphoproliferative disease 1 (XLP1), due to mutations in SH2D1A (Xq25) encoding signaling lymphocyte activation molecule-associated protein (SAP), may present with HLH. Defective SAP induces paradoxical inhibitory function of the 2B4 coreceptor and impaired natural killer (NK) (and T) cell response against EBV-infected cells. OBJECTIVE: To characterize a cohort of patients with HLH and XLP1 for SAP expression and 2B4 function in lymphocytes, proposing a rapid diagnostic screening to direct mutation analysis. METHODS: We set up rapid assays for 2B4 function (degranulation or (51)Cr-release) to be combined with intracellular SAP expression in peripheral blood NK cells. We studied 12 patients with confirmed mutation in SH2D1A and some family members. RESULTS: The combined phenotypic/functional assays allowed efficient and complete diagnostic evaluation of all patients with XLP1, thus directing mutation analysis and treatment. Nine cases were SAP(-), 2 expressed SAP with mean relative fluorescence intensity values below the range of healthy controls (SAP(dull)), and 1, carrying the R55L mutation, was SAP(+). NK cells from all patients showed inhibitory 2B4 function and defective killing of B-EBV cells. Carriers with SH2D1A mutations abolishing SAP expression and low percentage of SAP(+) cells showed neutral 2B4 function at the polyclonal NK cell level. Three novel SH2D1A mutations have been identified. CONCLUSIONS: Study of SAP expression is specific but may have insufficient sensitivity for screening XLP1 as a single tool. Combination with 2B4 functional assay allows identification of all cases.


Assuntos
Antígenos CD/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Receptores Imunológicos/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Masculino , Mutação , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Família de Moléculas de Sinalização da Ativação Linfocitária , Adulto Jovem
13.
Front Immunol ; 5: 167, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24795715

RESUMO

The human immune system depends on the activity of cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and NKT cells in order to fight off a viral infection. Understanding the molecular mechanisms during this process and the role of individual proteins was greatly improved by the study of familial hemophagocytic lymphohistiocytosis (FHL). Since 1999, genetic sequencing is the gold standard to classify patients into different subgroups of FHL. The diagnosis, once based on a clinical constellation of abnormalities, is now strongly supported by the results of a functional flow-cytometry screening, which directs the genetic study. A few additional congenital immune deficiencies can also cause a resembling or even identical clinical picture to FHL. As in many other rare human disorders, the collection and analysis of a relatively large number of cases in registries is crucial to draw a complete picture of the disease. The conduction of prospective therapeutic trials allows investigators to increase the awareness of the disease and to speed up the diagnostic process, but also provides important functional and genetic confirmations. Children with confirmed diagnosis may undergo hematopoietic stem cell transplantation, which is the only cure known to date. Moreover, detailed characterization of these rare patients helped to understand the function of individual proteins within the exocytic machinery of CTL, NK, and NKT cells. Moreover, identification of these genotypes also provides valuable information on variant phenotypes, other than FHL, associated with biallelic and monoallelic mutations in the FHL-related genes. In this review, we describe how detailed characterization of patients with genetic hemophagocytic lymphohistiocytosis has resulted in improvement in knowledge regarding contribution of individual proteins to the functional machinery of cytotoxic T- and NK-cells. The review also details how identification of these genotypes has provided valuable information on variant phenotypes.

14.
J Pediatr Hematol Oncol ; 36(6): e359-65, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24309606

RESUMO

Anaplastic large cell lymphoma (ALCL) accounts for approximately 15% of all pediatric non-Hodgkin lymphomas. It has distinct clinical features, including frequent involvement of extranodal sites and rare localization to the central nervous system. As some presenting features of ALCL are in common with the hemophagocytic syndrome, we previously analyzed a small series of patients with ALCL for PRF1 mutations and found that 27% of them carried mutations. We now expanded our preliminary study by increasing the cohort of ALCL patients to a total of 84 consecutive cases, in whom we extended mutation analysis to the genes SH2D1A, PRF1 e UNC13D, all related to familial HLH. Furthermore, perforin expression in tumor cells was investigated on paraffin-embedded tissues by immunohistochemical analysis. Mutations were observed in 23/84 patients (27.4%). Twenty-one patients (25%) carried a total of 10 different mutations of PRF1; they were monoallelic in 20 patients, biallelic in 1. No mutations were found in the gene SH2D1A. Two additional patients had missense mutations of the UNC13D gene. These data show that monoallelic germline mutations of PRF1 are frequent in patients with childhood ALCL, suggesting that partially impaired cytotoxic machinery may represent a predisposing factor for ALCL. Involvement is less frequent for UNC13D and absent for SH2D1A.


Assuntos
Mutação em Linhagem Germinativa , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Mutação de Sentido Incorreto , Proteínas Citotóxicas Formadoras de Poros/genética , Adolescente , Adulto , Alelos , Animais , Células COS , Criança , Simulação por Computador , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Proteínas de Membrana/genética , Perforina , Adulto Jovem
15.
J Pediatr Hematol Oncol ; 36(2): e128-30, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23669735

RESUMO

Familial hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by immune hyperactivation and clinical signs of extreme inflammation. We describe a 7-year-old male who presented with fever resistant to antibiotic therapy, pancytopenia, splenomegaly, hypertriglyceridemia, and hyperferritinemia. Bone marrow aspirate showed hemophagocytosis. Epstein-Barr virus genome was positive in blood. Functional screening showed reduced capacity of cytotoxic degranulation. Mutation analysis of the FHL-related genes revealed compound heterozygous for UNC13D mutations: c. 753+1G>T, and the novel c.544C>T (p.P182S). Patients with a clinical presentation of HLH, even if older than typically seen, should be screened for familial HLH by mutation analysis.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Idade de Início , Criança , Análise Mutacional de DNA , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Masculino , Proteínas de Membrana/genética
16.
PLoS One ; 7(9): e44649, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22970278

RESUMO

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.


Assuntos
Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/patologia , Adolescente , Adulto , Idade de Início , Feminino , Humanos , Masculino
17.
Indian Pediatr ; 49(6): 488-90, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22796692

RESUMO

Familial Hemophagocytic Lymphohistiocytosis (FHL) is a rare autosomal recessive disorder. Diagnosis is established in presence of genetic mutation or positive family history in one of the siblings. Common genetic mutations associated with FHL are mutations in gene PRF1 (also known as FHL 2), UNC13D (FHL 3) and STX11 (FHL 4). Recently mutation in STXBP2 encoding syntaxin binding protein 2 (Munc 18 -2) has been found to be associated with FHL type 5. Here we describe the first reported Indian patient with homozygous mutation in STX BP2 gene (c1697 G > A resulting in amino acid change p.G566D) causing FHL 5.


Assuntos
Linfo-Histiocitose Hemofagocítica/genética , Proteínas Munc18/genética , Mutação , Feminino , Humanos , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linhagem
18.
Cell Mol Life Sci ; 69(1): 29-40, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21990010

RESUMO

Cytotoxic T lymphocytes, natural killer cells, and NKT cells are effector cells able to kill infected cells. In some inherited human disorders, a defect in selected proteins involved in the cellular cytotoxicity mechanism results in specific clinical syndromes, grouped under the name of familial hemophagocytic lymphohistiocytosis. Recent advances in genetic studies of these patients has allowed the identification of different genetic subsets. Additional genetic immune deficiencies may also induce a similar clinical picture. International cooperation and prospective trials resulted in refining the diagnostic and therapeutic approach to these rare diseases with improved outcome but also with improved knowledge of the mechanisms underlying granule-mediated cellular cytotoxicity in humans.


Assuntos
Citotoxicidade Imunológica/fisiologia , Células Matadoras Naturais/imunologia , Linfo-Histiocitose Hemofagocítica , Células T Matadoras Naturais/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Síndrome de Chediak-Higashi/genética , Síndrome de Chediak-Higashi/imunologia , Grânulos Citoplasmáticos/metabolismo , Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/imunologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Subpopulações de Linfócitos/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/terapia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Proteínas Munc18/genética , Proteínas Munc18/imunologia , Perforina , Piebaldismo/genética , Piebaldismo/imunologia , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/imunologia , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/imunologia
19.
Acta Paediatr ; 101(3): 313-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22017632

RESUMO

AIM: Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening disturbance of immunoregulation. HLH comprises primary and acquired forms with different disease severity. A large proportion of deaths occur early into treatment. We investigated association with early death for laboratory and clinical parameters before the start of and 2 weeks into therapy. METHODS: A total of 232 children from Scandinavia, Germany or Italy, fulfilling diagnostic criteria and/or with familial disease and/or HLH-causing mutations, receiving HLH treatment 1994-2008 were included. The relation between clinical findings and early pre-transplant death was examined using the Cox proportional hazards model, with a 4-month right-truncation of the outcome. Patients were censored at last follow-up or transplant. Statistically significant predictors were adjusted for sex, age and each other. RESULTS: The following features were significantly associated with adverse outcome: hyperbilirubinaemia (>50 µmol/L; adjusted hazard ratio (aHR) 3.2; 95% confidence interval 1.3-8.1, p = 0.011), hyperferritinaemia (>2000 µg/L; aHR 3.2; 1.2-8.6, p = 0.019), cerebrospinal fluid pleocytosis (>100 × 10(6) /L; aHR 5.1; 1.4-18.5, p = 0.012) at diagnosis, and thrombocytopenia (<40 × 10(9) /L; aHR 3.4; 1.1-10.7, p = 0.033), and hyperferritinaemia (>2000 µg/L; aHR 10.6; 1.2-96.4, p = 0.037) 2 weeks into therapy. Non-improvement of fever, anaemia and/or thrombocytopenia also had adverse impact. CONCLUSION: There seem to be easily available clinical predictors of early mortality in HLH patients, which may help guide treatment decisions.


Assuntos
Linfo-Histiocitose Hemofagocítica/mortalidade , Adolescente , Anti-Inflamatórios/uso terapêutico , Criança , Ciclosporina/uso terapêutico , Dexametasona/uso terapêutico , Quimioterapia Combinada , Etoposídeo/uso terapêutico , Feminino , Ferritinas/sangue , Febre/etiologia , Humanos , Hiperbilirrubinemia/etiologia , Imunossupressores/uso terapêutico , Leucocitose/líquido cefalorraquidiano , Leucocitose/etiologia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/metabolismo , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Trombocitopenia/etiologia
20.
J Med Genet ; 48(5): 343-52, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21248318

RESUMO

BACKGROUND: Mutations of UNC13D are causative for familial haemophagocytic lymphohistiocytosis type 3 (FHL3; OMIM 608898). OBJECTIVE: To carry out a genotype-phenotype study of patients with FHL3. METHODS: A consortium of three countries pooled data on presenting features and mutations from individual patients with biallelic UNC13D mutations in a common database. RESULTS: 84 patients with FHL3 (median age 4.1 months) were reported from Florence, Italy (n=54), Hamburg, Germany (n=18), Stockholm, Sweden (n=12). Their ethnic origin was Caucasian (n=57), Turkish (n=10), Asian (n=7), Hispanic (n=4), African (n=3) (not reported (n=3)). Thrombocytopenia was present in 94%, splenomegaly in 96%, fever in 89%. The central nervous system (CNS) was involved in 49/81 (60%) patients versus 36% in patients with FHL2 (p=0.001). A combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia was present in 71%. CD107a expression, NK activity and Munc 13-4 protein expression were absent or reduced in all but one of the evaluated patients. 54 different mutations were observed, including 15 new ones: 19 missense, 14 deletions or insertions, 12 nonsense, nine splice errors. None was specific for ethnic groups. Patients with two disruptive mutations were younger than patients with two missense mutations (p<0.001), but older than comparable patients with FHL2 (p=0.001). CONCLUSION: UNC13D mutations are scattered over the gene. Ethnic-specific mutations were not identified. CNS involvement is more common than in FHL2; in patients with FHL3 and disruptive mutations, age at diagnosis is significantly higher than in FHL2. The combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia appears to be the most easily and frequently recognised clinical pattern and their association with defective granule release assay may herald FHL3.


Assuntos
Estudos de Associação Genética , Linfo-Histiocitose Hemofagocítica , Adolescente , Idade de Início , Degranulação Celular/genética , Degranulação Celular/imunologia , Criança , Pré-Escolar , Citotoxicidade Imunológica/genética , Citotoxicidade Imunológica/imunologia , Feminino , Ordem dos Genes , Genótipo , Humanos , Lactente , Recém-Nascido , Células Matadoras Naturais/fisiologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Proteínas de Membrana/genética , Mutação/genética , Fenótipo
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