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1.
Artigo em Inglês | MEDLINE | ID: mdl-32049770

RESUMO

BACKGROUND: The frequency of neutropenia in pediatric primary immunodeficiency disorders (PIDDs) is unknown and potentially underappreciated. Our study aimed to determine the overall frequency and severity of neutropenia in children diagnosed with a PIDD entered in the United States Immunodeficiency Network (USIDNET) patient registry. PROCEDURE: Neutropenia data and demographic/clinical information from 1145 patients younger than 21 years of age was obtained from the USIDNET registry. RESULTS: Neutropenia is more common in PIDD patients entered within the USIDNET registry than previously appreciated. There was a >10% occurrence rate of neutropenia in all broad primary immunodeficiency categories as well as in nearly all individual PIDDs. Neutropenia frequency was greater in African American pediatric PIDD patients than in white or Asian patients. The degree of neutropenia did not associate with mortality in pediatric patients with a PIDD. CONCLUSION: Although our study did not assess the frequency of PIDD in patients presenting with neutropenia, the possibility of a primary immune disorder should be considered in patients with idiopathic neutropenia.

2.
J Clin Immunol ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919711

RESUMO

PURPOSE: Pulmonary manifestations are common in patients with primary immunodeficiency disorders (PIDs) but the prevalence, specific diseases, and their patterns are not well characterized. METHODS: We conducted a retrospective analysis of pulmonary diseases reported in the database of the United States Immunodeficiency Network (USIDNET), a program of the Immune Deficiency Foundation. PIDs were categorized into 10 groups and their demographics, pulmonary diagnoses and procedures, infections, prophylaxis regimens, and laboratory findings were analyzed. RESULTS: A total of 1937 patients with various PIDs (39.3% of total patients, 49.6% male, average age 37.9 years (SD = 22.4 years)) were noted to have a pulmonary disease comorbidity. Pulmonary diseases were categorized into broad categories: airway (86.8%), parenchymal (18.5%), pleural (4.6%), vascular (4.3%), and other (13.9%) disorders. Common variable immune deficiency (CVID) accounted for almost half of PIDs associated with airway, parenchymal, and other pulmonary disorders. Pulmonary procedures performed in 392 patients were mostly diagnostic (77.3%) or therapeutic (16.3%). These patients were receiving a wide variety of treatments, which included immunoglobulin replacement (82.1%), immunosuppressive (32.2%), anti-inflammatory (12.7%), biologic (9.3%), and cytokine (7.6%)-based therapies. Prophylactic therapy was being given with antibiotics (18.1%), antifungal (3.3%), and antiviral (2.2%) medications, and 7.1% of patients were on long-term oxygen therapy due to advanced lung disease. CONCLUSIONS: Pulmonary manifestations are common in individuals with PID, but long-term pulmonary outcomes are not well known in this group of patients. Further longitudinal follow-up will help to define long-term prognosis of respiratory comorbidities and optimal treatment modalities.

3.
Biol Blood Marrow Transplant ; 26(1): 94-106, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31493539

RESUMO

Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.

4.
J Clin Immunol ; 39(4): 448-458, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31111420

RESUMO

PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency for which allogeneic hematopoietic stem cell transplant (HSCT) offers potential cure. Direct comparison of HSCT to non-HSCT management in the North American population was performed to identify clinical factors associated with overall survival (OS) and transplant-related survival (TRS). METHODS: Retrospective review of CGD subjects enrolled in the United States Immunodeficiency Network. Survival was estimated by the Kaplan-Meier method and modeled by proportional hazards regression. RESULTS: We identified 507 patients (66% CYBB mutants) diagnosed in 1953-2016. Fifty underwent allogeneic HSCT. Median follow-up was 9.1 years after diagnosis (0-45.8 years). OS was negatively associated with CYBB mutation (HR = 6.25; p = 0.034) and not associated with HSCT (88% v. 85% ± HCT) (HR = 1.26; p = 0.65). Transplant at ≤ 14 years old was associated with improved TRS (93% v. 82% at T + 60 months) (HR = - 4.51; p = 0.035). Patients transplanted before 15 years old had fewer severe infections pre-HSCT (mean 0.95 v. 2.13; p = 0.047). No mortality was reported in patients receiving stem cells from matched siblings. Infection incidence declined post-HSCT in subjects with greater than or equal to four infections pre-HSCT (p = 0.0010). Compared to non-HSCT patients ≥ 15 years old, post-transplant survivors had higher mean performance score (93.2 v. 85.9; p = 0.0039) and lower frequency of disability (11% v. 52%; p = 0.014). CONCLUSION: Allogeneic HSCT was associated with reduced infection incidence and improved functional performance, but not with a change in overall survival. Transplant-related survival was elevated in patients undergoing HSCT before 15 years old. Consider HSCT prior to late adolescence in patients with severely diminished reactive oxygen intermediate synthesis, particularly if a matched sibling is available.

6.
J Pediatric Infect Dis Soc ; 7(suppl_1): S18-S24, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29746679

RESUMO

Chronic granulomatous disease (CGD), a primary immunodeficiency characterized by a deficient neutrophil oxidative burst and the inadequate killing of microbes, is well known to cause a significantly increased risk of invasive infection. However, infectious complications are not the sole manifestations of CGD; substantial additional morbidity is driven by noninfectious complications also. These complications can include, for example, a wide range of inflammatory diseases that affect the gastrointestinal tract, lung, skin, and genitourinary tract and overt autoimmune disease. These diseases can occur at any age and are especially problematic in adolescents and adults with CGD. Many of these noninfectious complications present a highly challenging therapeutic conundrum, wherein immunosuppression must be balanced against an already markedly increased risk of invasive fungal and bacterial infections. In this review, the myriad noninfectious complications of CGD are discussed, as are important gaps in our understanding of these processes, which warrant further investigation.


Assuntos
Granuloma/etiologia , Doença Granulomatosa Crônica/complicações , Doenças Inflamatórias Intestinais/etiologia , Pneumopatias/etiologia , Doenças Autoimunes/complicações , Diagnóstico Diferencial , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Pneumopatias/diagnóstico
7.
J Allergy Clin Immunol Pract ; 6(3): 996-1001, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28939137

RESUMO

BACKGROUND: Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare condition. OBJECTIVE: Data from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases. METHODS: A query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016. RESULTS: Data on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa (P Fisher's exact test = .029) or A. fumigatus (P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions (P χ2 = .01; odds ratio: 4.03 [1.2-12.97]), depression (P Fisher's exact test = .036), and lower Karnofsky index scores (P Mann-Whitney = .007). DISCUSSION: Data from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES.


Assuntos
Aspergillus fumigatus/fisiologia , Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade Alimentar/epidemiologia , Síndrome de Job/imunologia , Pseudomonas aeruginosa/fisiologia , Sistema de Registros , Infecções Respiratórias/epidemiologia , Pele/patologia , Staphylococcus aureus/fisiologia , Dente/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Eosinofilia , Feminino , Seguimentos , Humanos , Imunoglobulina E/sangue , Síndrome de Job/epidemiologia , Masculino , Anamnese , Pessoa de Meia-Idade , Quebeque/epidemiologia , Adulto Jovem
8.
J Allergy Clin Immunol ; 141(3): 1028-1035, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28606585

RESUMO

BACKGROUND: We evaluated the overall and site-specific incidence of cancer in subjects with primary immunodeficiency diseases (PIDD) enrolled in the United States Immune Deficiency Network (USIDNET) registry compared with age-adjusted cancer incidence in the Surveillance, Epidemiology and End Results Program (SEER) database. OBJECTIVE: We hypothesized that subjects with PIDD would have an increased incidence of cancer due to impaired immune function. METHODS: Overall and site-specific cancer incidence rates were evaluated in subjects with PIDD (n = 3658) enrolled in the USIDNET registry from 2003 to 2015 and compared with age-adjusted incidence rates in the SEER database. RESULTS: We observed a 1.42-fold excess relative risk of cancer in subjects with PIDD compared with the age-adjusted SEER population (P < .001). Men with PIDD had a 1.91-fold excess relative risk of cancer compared with the age-adjusted male population (P < .001), while women with PIDD had similar overall cancer rates compared with the age-adjusted female population. Of the 4 most common malignancies in men and women in SEER (lung, colon, breast, and prostate cancers), we found no significant increase in these diagnoses in subjects with PIDD. Significant increases in lymphoma in both men (10-fold increase, P < .001) and women (8.34-fold increase, P < .001) with PIDD were observed. CONCLUSIONS: Excess incidence of cancer occurred in subjects with PIDD. An excess of lymphoma in specific PIDD populations principally drove this increased incidence, while no increased risk of the most common solid tumor malignancies was observed. These data point to a restricted role of the immune system in protecting from specific cancers.


Assuntos
Síndromes de Imunodeficiência/epidemiologia , Neoplasias/epidemiologia , Programa de SEER , Adulto , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologia
9.
J Clin Invest ; 127(5): 1689-1699, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28346229

RESUMO

BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADA-deficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study. METHODS: Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution. RESULTS: With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. CONCLUSION: These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile. TRIAL REGISTRATION: ClinicalTrials.gov NCT00794508. FUNDING: Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia , Regulação Enzimológica da Expressão Gênica , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Transdução Genética , Adenosina Desaminase/biossíntese , Adenosina Desaminase/genética , Adolescente , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Agamaglobulinemia/terapia , Autoenxertos , Criança , Pré-Escolar , Feminino , Vetores Genéticos , Humanos , Lactente , Masculino , Retroviridae , Imunodeficiência Combinada Severa/enzimologia , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia
10.
J Clin Invest ; 126(10): 4030-4044, 2016 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-27643438

RESUMO

In addition to the infectious consequences of immunodeficiency, patients with Wiskott-Aldrich syndrome (WAS) often suffer from poorly understood exaggerated immune responses that result in autoimmunity and elevated levels of serum IgE. Here, we have shown that WAS patients and mice deficient in WAS protein (WASP) frequently develop IgE-mediated reactions to common food allergens. WASP-deficient animals displayed an adjuvant-free IgE-sensitization to chow antigens that was most pronounced for wheat and soy and occurred under specific pathogen-free as well as germ-free housing conditions. Conditional deletion of Was in FOXP3+ Tregs resulted in more severe Th2-type intestinal inflammation than that observed in mice with global WASP deficiency, indicating that allergic responses to food allergens are dependent upon loss of WASP expression in this immune compartment. While WASP-deficient Tregs efficiently contained Th1- and Th17-type effector differentiation in vivo, they failed to restrain Th2 effector responses that drive allergic intestinal inflammation. Loss of WASP was phenotypically associated with increased GATA3 expression in effector memory FOXP3+ Tregs, but not in naive-like FOXP3+ Tregs, an effect that occurred independently of increased IL-4 signaling. Our results reveal a Treg-specific role for WASP that is required for prevention of Th2 effector cell differentiation and allergic sensitization to dietary antigens.


Assuntos
Hipersensibilidade Alimentar/metabolismo , Fatores de Transcrição Forkhead/fisiologia , Linfócitos T Reguladores/metabolismo , Células Th2/imunologia , Proteína da Síndrome de Wiskott-Aldrich/genética , Animais , Diferenciação Celular/imunologia , Feminino , Hipersensibilidade Alimentar/imunologia , Humanos , Imunoglobulina E/fisiologia , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Mutação , Linfócitos T Reguladores/imunologia , Transcriptoma , Proteína da Síndrome de Wiskott-Aldrich/metabolismo
13.
N Engl J Med ; 370(25): 2408-17, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24896819

RESUMO

A 14-year-old boy with severe combined immunodeficiency presented three times to a medical facility over a period of 4 months with fever and headache that progressed to hydrocephalus and status epilepticus necessitating a medically induced coma. Diagnostic workup including brain biopsy was unrevealing. Unbiased next-generation sequencing of the cerebrospinal fluid identified 475 of 3,063,784 sequence reads (0.016%) corresponding to leptospira infection. Clinical assays for leptospirosis were negative. Targeted antimicrobial agents were administered, and the patient was discharged home 32 days later with a status close to his premorbid condition. Polymerase-chain-reaction (PCR) and serologic testing at the Centers for Disease Control and Prevention (CDC) subsequently confirmed evidence of Leptospira santarosai infection.


Assuntos
Encéfalo/patologia , Líquido Cefalorraquidiano/microbiologia , DNA Bacteriano/análise , Leptospira/genética , Leptospirose/diagnóstico , Meningoencefalite/diagnóstico , Análise de Sequência de DNA/métodos , Adenosina Desaminase/deficiência , Adolescente , Agamaglobulinemia/complicações , Biópsia , Febre/etiologia , Cefaleia/etiologia , Humanos , Leptospira/isolamento & purificação , Leptospirose/complicações , Leptospirose/microbiologia , Masculino , Meningoencefalite/complicações , Meningoencefalite/microbiologia , Imunodeficiência Combinada Severa/complicações
16.
Proc Natl Acad Sci U S A ; 110(20): 8164-9, 2013 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-23637345

RESUMO

The ability of T-cells to respond to foreign antigens and to appropriately regulate this response is crucial for maintaining immune homeostasis. Using combinatorial peptide libraries, we functionally measured broad T-cell reactivity and observed impaired reactivity in established models of T-cell receptor repertoire restriction and in previously unrecognized disease contexts. By concurrently analyzing T-regulatory and T-effector cells, we show strong functional correlation between these subsets in healthy individuals and, strikingly, that alterations of this balance are associated with T helper type 2 (Th2)-mediated disease in a lymphopenic setting. Finally, we demonstrate that peptide-based priming of polyclonal naive cells with relatively low concentrations skews toward Th2 differentiation. These findings provide unique insight into the pathophysiology and functional consequences of abnormal T-cell repertoires and into differentiation of human naive T-cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Regulação da Expressão Gênica , Biblioteca de Peptídeos , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Proliferação de Células , Separação Celular , Técnicas de Cocultura , Citometria de Fluxo , Genes MHC da Classe II , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Ativação Linfocitária , Modelos Estatísticos , Peptídeos/química , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Células Th2/citologia , Células Th2/imunologia
17.
Platelets ; 24(4): 288-96, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22812495

RESUMO

The thrombocytopenia of Wiskott-Aldrich syndrome (WAS) is thought to be due to both reduced platelet production and accelerated platelet consumption. We have previously demonstrated that platelets from WASP-deficient mice are consumed more rapidly in vivo than are WT platelets, and that opsonization accelerates their uptake by bone marrow- derived macrophages more than it does that of WT platelets. Here we asked whether platelets from WAS patients show similar features. We show that ex vivo phagocytosis by activated THP-1 cells of DIO-labeled platelets from a series of WAS or XLT patients is increased in comparison to that of normal control platelets. Using a numerical analysis method, we distinguish this effect from a concurrent effect on the amount of detectable fluorescent signal transferred to the macrophage per phagocytosed platelet. We show that the latter quantity is reduced by platelet WASP deficiency, as might be expected if the fluorescence transferred from these smaller platelets is more rapidly quenched. We are unable to detect a differential effect of opsonization with anti-CD61 antibody on the uptake of WASP(-) vs. WT platelets. However, the high probability of phagocytosis per adsorbed WASP(-) platelet could limit the sensitivity of the assay in this case. We also see no effect of sera from WAS patients on the uptake of normal control platelets, suggesting that in vivo opsonization is not the cause of increased uptake of WASP(-) platelets. Finally, we show little, if any, increase in the reticulated platelet fraction in WAS patients, suggesting that impaired production of reticulated platelets contributes to the thrombocytopenia. Our findings suggest that rapid in vivo platelet consumption contributes significantly to the thrombocytopenia of WAS. They also demonstrate the feasibility of routinely performing functional assays of phagocytosis of small numbers of platelets obtained at remote locations, a method which should be applicable to the study of other types of thrombocytopenia such as ITP.


Assuntos
Plaquetas/imunologia , Fagocitose/imunologia , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/imunologia , Plaquetas/metabolismo , Linhagem Celular , Humanos , Contagem de Plaquetas , Proteína da Síndrome de Wiskott-Aldrich/deficiência
18.
Blood ; 120(18): 3635-46, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22968453

RESUMO

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.


Assuntos
Agamaglobulinemia/terapia , Transplante de Medula Óssea/métodos , Terapia Genética/métodos , Vetores Genéticos , Transplante de Células-Tronco Hematopoéticas/métodos , Imunodeficiência Combinada Severa/terapia , Adenosina Desaminase/deficiência , Adolescente , Antígenos CD34/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Retroviridae/genética , Transdução Genética , Condicionamento Pré-Transplante , Adulto Jovem
19.
J Allergy Clin Immunol ; 129(3): 762-769.e1, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22153773

RESUMO

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare malignant skin tumor associated with a characteristic chromosomal translocation (t[17;22][q22;q13]) resulting in the COL1A1-platelet-derived growth factor ß(PDGFB) fusion gene. This malignancy is rarely diagnosed in childhood. OBJECTIVE: We observed an unexpected high incidence of this DFSP in children affected with adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) and set out to evaluate the association of these 2 clinical entities. METHODS: Twelve patients with ADA-SCID were evaluated with a complete dermatologic examination and skin biopsy when indicated. Conventional cytogenetic and molecular analyses (fluorescence in situ hybridization, RT-PCR, or both) were performed when possible. RESULTS: Eight patients were found to have DFSP. Six patients had multicentric involvement (4-15 lesions), primarily of the trunk and extremities. Most lesions presented as 2- to 15-mm, round atrophic plaques. Nodular lesions were present in 3 patients. In all cases CD34 expression was diffusely positive, and diagnosis was confirmed either by means of cytogenetic analysis, molecular testing, or both. The characteristic DFSP-associated translocation, t(17;22)(q22;q13), was identified in 6 patients; results of fluorescence in situ hybridization were positive for fusion of the COL1A1 and PDGFB loci in 7 patients; and RT-PCR showed the COL1A1-PDGFB fusion transcript in 6 patients. CONCLUSIONS: We describe a previously unrecognized association between ADA-SCID and DFSP with unique features, such as multicentricity and occurrence in early age. We hypothesize that the t(17;22)(q22;q13) translocation that results in dermal overexpression of PDGFB and favors the development of fibrotic tumors might arise because of the known DNA repair defect in patients with ADA-SCID. Although the natural course of DFSP in the setting of ADA-SCID is unknown, this observation should prompt regular screening for DFSP in patients with ADA-SCID.


Assuntos
Dermatofibrossarcoma/complicações , Proteínas de Fusão Oncogênica/genética , Imunodeficiência Combinada Severa/complicações , Neoplasias Cutâneas/complicações , Adenosina Desaminase/genética , Adolescente , Adulto , Antígenos CD34/metabolismo , Criança , Cromossomos Humanos Par 22/genética , Distúrbios no Reparo do DNA , Dermatofibrossarcoma/diagnóstico , Dermatofibrossarcoma/genética , Dermatofibrossarcoma/patologia , Detecção Precoce de Câncer , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Translocação Genética
20.
Blood ; 118(10): 2688-94, 2011 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-21725047

RESUMO

Genetic deficiency of adenosine deaminase (ADA) can cause profound lymphopenia and result in the clinical presentation of severe combined immune deficiency (SCID). However, because of the ubiquitous expression of ADA, ADA-deficient patients often present also with nonimmunologic clinical problems, affecting the skeletal, central nervous, endocrine, and gastrointestinal systems. We now report that myeloid dysplasia features and bone marrow hypocellularity are often found in patients with ADA-SCID. As a clinical correlate to this finding, we have observed vulnerability to antibiotic-induced myelotoxicity and prolonged neutropenia after nonmyeloablative chemotherapy. We have also noted that, in the absence of enzyme replacement therapy, absolute neutrophil counts of patients with ADA deficiency vary inversely with the accumulation of deoxynucleotides. These data have significant implications for the application of standard and investigational therapies to patients with ADA-SCID and support further studies to investigate the possibility that ADA deficiency is associated with a stem cell defect. These trials were registered at www.clinicaltrials.gov as #NCT00018018 and #NCT00006319.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/complicações , Medula Óssea/patologia , Síndromes Mielodisplásicas/etiologia , Imunodeficiência Combinada Severa/complicações , Adenosina Desaminase/genética , Adolescente , Adulto , Agamaglobulinemia/terapia , Transplante de Medula Óssea , Criança , Pré-Escolar , Feminino , Terapia Genética , Humanos , Lactente , Masculino , Síndromes Mielodisplásicas/terapia , Imunodeficiência Combinada Severa/terapia , Adulto Jovem
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