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Neutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic Granulomatous Disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the NADPH oxidase enzyme. These mutations lead to failure of ROS generation followed by recurrent bacterial and fungal infections, frequently associated with hyper-inflammatory manifestations. We report a multi-center cumulative experience in diagnosing and treating patients with CGD. From 1986 to 2021, 2,918 patients suffering from frequent infections were referred for neutrophil evaluation. Among them, 110 patients were diagnosed with CGD, 56 of Jewish ancestry, 48 of Arabic ancestry and 6 non-Jewish/non-Arabic. As opposed to other Western countries, the autosomal recessive (AR) CGD subtypes were predominant in Israel (71/110 patients). Thirty-nine patients had X-linked CGD, in most patients associated with severe infections (clinical severity score ≥3) and poor outcomes, presenting at a significantly earlier age than AR-CGD subtypes. The full spectrum of infections and hyper-inflammatory manifestations are described. Six patients had hypomorphic mutations with significantly milder phenotype, clinical severity score ≤2, and better outcomes. Hematopoietic stem cell transplantation was implemented in 39/110 patients (35.5%). Successful engraftment was achieved in 92%, with 82% long-term survival and 71% full clinical recovery. CGD is a complex disorder requiring a multi-professional team. Early identification of the genetic mutation is essential for prompt diagnosis, suitable management and prevention.
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BACKGROUND: Implementation of newborn screening (NBS) programs for severe combined immunodeficiency (SCID) have advanced the diagnosis and management of affected infants and undoubtedly improved their outcomes. Reporting long-term follow-up of such programs is of great importance. OBJECTIVE: We report a 5-year summary of the NBS program for SCID in Israel. METHODS: Immunologic and genetic assessments, clinical analyses, and outcome data from all infants who screened positive were evaluated and summarized. RESULTS: A total of 937,953 Guthrie cards were screened for SCID. A second Guthrie card was requested on 1,169 occasions (0.12%), which resulted in 142 referrals (0.015%) for further validation tests. Flow cytometry immune-phenotyping, T cell receptor excision circle measurement in peripheral blood, and expression of TCRVß repertoire for the validation of positive cases revealed a specificity and sensitivity of 93.7% and 75.9%, respectively, in detecting true cases of SCID. Altogether, 32 SCID and 110 non-SCID newborns were diagnosed, making the incidence of SCID in Israel as high as 1:29,000 births. The most common genetic defects in this group were associated with mutations in DNA cross-link repair protein 1C and IL-7 receptor α (IL-7Rα) genes. No infant with SCID was missed during the study time. Twenty-two SCID patients underwent hematopoietic stem cell transplantation, which resulted in a 91% survival rate. CONCLUSIONS: Newborn screening for SCID should ultimately be applied globally, specifically to areas with high rates of consanguineous marriages. Accumulating data from follow-up studies on NBS for SCID will improve diagnosis and treatment and enrich our understanding of immune development in health and disease.
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Inmunodeficiencia Combinada Grave , ADN , Humanos , Recién Nacido , Israel/epidemiología , Tamizaje Neonatal/métodos , Receptores de Antígenos de Linfocitos T/genética , Receptores de Interleucina-7 , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/epidemiología , Inmunodeficiencia Combinada Grave/genéticaRESUMEN
Immunizations have been saving the lives of millions of people since they were first used by Edward Jenner in 1796, and new vaccines are being developed all the time. Hopefully, a new vaccine for coronavirus disease 2019 (COVID-19) will be developed in the near future, and perhaps even one for human immunodeficiency virus. Although the effectiveness of vaccinations has been proven over the years and adverse effects to currently available vaccinations are extremely rare, many people continue to defer immunizations for themselves and their families. According to the World Health Organization (WHO), this phenomenon, known as "vaccine hesitancy," is a major public health problem globally. This review summarizes the unproven adverse effects of various vaccines and stresses the importance of enforcing vaccination policies to minimize vaccine hesitancy. Every effort should be made to improve existing vaccines and to produce new ones, according to carefully designed scientific preclinical and clinical trials. This is particularly important in today's era, in light of the global transparency regarding vaccination development, and the potential for future pandemics such as COVID-19.
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Vacunas contra la COVID-19/uso terapéutico , COVID-19 , Cumplimiento de la Medicación , Pandemias/prevención & control , SARS-CoV-2 , Vacunación , COVID-19/epidemiología , COVID-19/prevención & control , Humanos , Organización Mundial de la SaludRESUMEN
Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.
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Inmunidad/genética , Síndromes de Inmunodeficiencia/genética , Autoinmunidad/genética , Genotipo , Enfermedades Autoinflamatorias Hereditarias/genética , Humanos , Hipersensibilidad , FenotipoRESUMEN
The original version of this article unfortunately contained mistakes in reference numbers. The in-text citations and the references were mismatched. The original article has been corrected.
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We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.
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In the last few months the world has witnessed a global pandemic due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19). Obviously, this pandemic affected individuals differently, with a significant impact on populations considered to be at high-risk. One such population, was assumed to be patients with primary genetic defect involving components or pathways of the immune system. While human immunity against COVID-19 is not fully understood, it is, so far, well documented, that both adaptive and innate cells have a critical role in protection against SARS-CoV-2. Here, we aimed to summarize the clinical and laboratory data on primary immunodeficiency (PID) patients in Israel, who were tested positive for SARS-CoV-2, in order to estimate the impact of COVID-19 on such patients. Data was collected from mid-February to end-September. During this time Israel experienced two "waves" of COVID-19 diseases; the first, from mid-February to mid-May and the second from mid-June and still ongoing at the end of data collection. A total of 20 PID patients, aged 4 months to 60 years, were tested positive for SARS-CoV-2, all but one, were detected during the second wave. Fourteen of the patients were on routine monthly IVIG replacement therapy at the time of virus detection. None of the patients displayed severe illness and none required hospitalization; moreover, 7/20 patients were completely asymptomatic. Possible explanations for the minimal clinical impact of COVID-19 pandemic observed in our PID patients include high level of awareness, extra-precautions, and even self-isolation. It is also possible that only specific immune pathways (e.g. type I interferon signaling), may increase the risk for a more severe course of disease and these are not affected in many of the PID patients. In some cases, lack of an immune response actually may be a protective measure against the development of COVID-19 sequelae.
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COVID-19/complicaciones , COVID-19/epidemiología , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/epidemiología , SARS-CoV-2 , Adolescente , Adulto , Niño , Preescolar , Femenino , Evaluación del Impacto en la Salud , Humanos , Lactante , Israel/epidemiología , Masculino , Persona de Mediana Edad , Vigilancia en Salud Pública , Adulto JovenRESUMEN
Leucocyte adhesion deficiency (LAD) is a rare, innate autosomal recessive immunodeficiency with three subtypes. Twenty-nine patients with LADs were diagnosed and treated in Israeli Medical Centers and in the Palestinian Authority. We discuss the phenotypic, genotypic and biochemical features of LAD-I, LAD-II and LAD-III diagnosed during the neonatal period and early infancy in 18, 6 and 5 patients, respectively. Consanguinity was frequent. Common features were severe infections of variable aetiology, excessive leukocytosis and delayed umbilical cord detachment. In LAD-I, the integrin CD18 expression varied from negligible to normal. However, CD11a expression was negligible in all tested patients, suggesting both CD11a and CD18 should be used to assess this subtype. LAD-II patients showed distinctive facial features, physical malformations, short stature and developmental delay. These patients show defective expression of SLeX (CD15a) on cell surface glycoproteins and lack of H antigen on erythroid cell surfaces resulting in Bombay blood group (hh). LAD-III showed intact but inactive ß2 integrins associated with severe infections and significant bleeding disorders caused by defective platelet aggregation and thrombocytopenia. We report four patients with two new unpublished mutations: two LAD-I patients with c.1099delG in ITGB2 and two LAD-III patients with c.1069C>T in FERMT3. LAD-I patients harbouring the c.119_128 deletion in ITGB2 seemed to have better outcomes as compared to other LAD-I patients. Eight patients with LAD-I and -III underwent successful haematopoietic stem cell transplantation. Cumulative survival was 75%, 50% and 40% for LAD-I, LAD-II and LAD-III, with a median follow-up of 4 (0.08-19), 3.25 (1-32) and 6 (0.08-8) years, respectively. Prenatal diagnosis is recommended in families with LAD syndromes.
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Síndrome de Deficiencia de Adhesión del Leucocito/etiología , Antígeno Lewis X/metabolismo , Antígenos Bacterianos/metabolismo , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/fisiopatología , Antígenos CD11/metabolismo , Antígenos CD18/metabolismo , Adhesión Celular/fisiología , Quimiotaxis/fisiología , Consanguinidad , Células Eritroides/metabolismo , Femenino , Humanos , Lactante , Recién Nacido , Síndrome de Deficiencia de Adhesión del Leucocito/diagnóstico , Síndrome de Deficiencia de Adhesión del Leucocito/terapia , Leucocitosis/etiología , Masculino , Glicoproteínas de Membrana/metabolismo , Mutación/genética , Micosis/diagnóstico , Neutrófilos/fisiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished T helper 17 cell numbers, in absence of STAT3 mutations. We identified two distinct homozygous nonsense mutations in ZNF341, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.
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Inmunocompetencia/genética , Síndrome de Job/genética , Factor de Transcripción STAT3/genética , Células Th17/inmunología , Factores de Transcripción/genética , Adolescente , Adulto , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Núcleo Celular/metabolismo , Niño , Codón sin Sentido , Consanguinidad , Exones/genética , Femenino , Genes Recesivos/genética , Genes Recesivos/inmunología , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Lactante , Síndrome de Job/sangre , Síndrome de Job/inmunología , Masculino , Linaje , Regiones Promotoras Genéticas/genética , Factor de Transcripción STAT3/inmunología , Células Th17/metabolismo , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo , Adulto Joven , Dedos de Zinc/genéticaRESUMEN
PURPOSE: Chronic granulomatous disease (CGD) is an innate immune deficiency disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex that impair the synthesis of oxygen radicals, thus rendering patients susceptible to recurrent infections and excessive hyperinflammatory responses. The most common autosomal recessive form of CGD is p47phox deficiency, which is often clinically milder than the more common X-linked recessive form. Here, we report data on genetics, clinical and biochemical findings in 17 CGD patients of Kavkazi origin with the nonsense mutation c.579G>A in the NCF1 gene, leading to p47phox deficiency. METHODS: Diagnosis was based on detailed clinical evaluation, respiratory burst activity by cytochrome c reduction and dihydrorhodamine-1,2,3 (DHR) assay by flow cytometry, expression of p47phox by immunoblotting and molecular confirmation by DNA sequence analysis. RESULTS: Twelve male and five female patients with median age at onset of 2.5 years (range 1 day to 9 years) were included in the study. The present cohort displays an encouraging 88% overall long-term survival, with median follow-up of 17 years. Clinical manifestations varied from mild to severe expression of the disease. Correlation between genotype and phenotype is unpredictable, although the Kavkazi patients were more severely affected than other patients with p47phox deficiency. CONCLUSIONS: Kavkazi CGD patients harbor a common genetic mutation that is associated with a heterogeneous clinical phenotype. Early diagnosis and proper clinical management in an experienced phagocytic leukocyte center is imperative to ensure favorable patient outcome. New treatment strategies are ongoing, but results are not yet conclusive.
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Variación Biológica Poblacional , Enfermedad Granulomatosa Crónica/epidemiología , Enfermedad Granulomatosa Crónica/genética , Mutación , NADPH Oxidasas/genética , Fenotipo , Edad de Inicio , Biomarcadores , Niño , Preescolar , Femenino , Enfermedad Granulomatosa Crónica/diagnóstico , Enfermedad Granulomatosa Crónica/terapia , Humanos , Lactante , Recién Nacido , Israel/epidemiología , MasculinoRESUMEN
Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients' fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.
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Encefalopatías Metabólicas Innatas/genética , Tronco Encefálico/metabolismo , Tronco Encefálico/virología , ARN/química , ARN/metabolismo , Alelos , Secuencia de Aminoácidos , Animales , Encefalopatías Metabólicas Innatas/patología , Tronco Encefálico/patología , Encefalitis Viral/genética , Escherichia coli/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/virología , Herpesvirus Humano 1 , Humanos , Interferones/metabolismo , Intrones/genética , Masculino , Ratones , Proteínas Mutantes/metabolismo , Mutación/genética , Sistemas de Lectura Abierta/genética , Linaje , ARN Nucleotidiltransferasas/química , ARN Nucleotidiltransferasas/deficiencia , ARN Nucleotidiltransferasas/genética , Receptor Toll-Like 3/metabolismo , Replicación ViralRESUMEN
Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification of the inborn errors of immunity. This complete catalog serves as a reference for immunologists and researchers worldwide. However, it was unadapted for clinicians at the bedside. For those, the IUIS PID EC is now publishing a phenotypical classification since 2013, which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification.
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Alergia e Inmunología , Inmunidad/genética , Síndromes de Inmunodeficiencia/inmunología , Humanos , Síndromes de Inmunodeficiencia/genética , Cooperación Internacional , FenotipoRESUMEN
Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.
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Alergia e Inmunología , Inmunidad/genética , Síndromes de Inmunodeficiencia , Humanos , Informe de Investigación , Sociedades Científicas , Organización Mundial de la SaludRESUMEN
Severe combined immunodeficiency (SCID), the most severe form of T cell immunodeficiency, is detectable through quantification of T cell receptor excision circles (TRECs) in dried blood spots obtained at birth. Herein, we describe the results of the first year of the Israeli SCID newborn screening (NBS) program. This important, life-saving screening test is available at no cost for every newborn in Israel. Eight SCID patients were diagnosed through the NBS program in its first year, revealing an incidence of 1:22,500 births in the Israeli population. Consanguine marriages and Muslim ethnic origin were found to be a risk factor in affected newborns, and a founder effect was detected for both IL7Rα and DCLRE1C deficiency SCID. Lymphocyte subset analysis and TREC quantification in the peripheral blood appear to be sufficient for confirmation of typical and leaky SCID and ruling out false positive (FP) results. Detection of secondary targets (infants with non-SCID lymphopenia) did not significantly affect the management or outcomes of these infants in our cohort. In the general, non-immunodeficient population, TREC rises along with gestational age and birth weight, and is significantly higher in females and the firstborn of twin pairs. Low TREC correlates with both gestational age and birth weight in extremely premature newborns. Additionally, the rate of TREC increase per week consistently accelerates with gestational age. Together, these findings mandate a lower cutoff or a more lenient screening algorithm for extremely premature infants, in order to reduce the high rate of FPs within this group. A significant surge in TREC values was observed between 28 and 30 weeks of gestation, where median TREC copy numbers rise by 50% over 2 weeks. These findings suggest a maturational step in T cell development around week 29 gestation, and imply moderate to late preterms should be screened with the same cutoff as term infants. The SCID NBS program is still in its infancy, but is already bearing fruit in the early detection and improved outcomes of children with SCID in Israel and other countries.
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The importance of the ubiquitin system in health and disease has been widely recognized in recent decades, with better understanding of the various components of the system and their function. Ubiquitination, which is essential to almost all biological processes in eukaryotes, was also found to play an important role in innate and adaptive immune responses. Thus it is not surprising that mutations in genes coding for components of the ubiquitin system cause immune dysregulation. The first defect in the system was described 30 years ago and is due to mutations in the nuclear factor κB (NF-κB) essential modulator, a key regulator of the NF-κB pathway. With use of novel sequencing techniques, many additional mutations in different genes involved in ubiquitination and related to immune system function were identified. This can be clearly illustrated in mutations in the different activation pathways of NF-κB, which result in aberrations in production of various proinflammatory cytokines. The inherited diseases typically manifest with immunodeficiency, autoimmunity, or autoinflammation. In this perspective we provide a short description of the ubiquitin system, with specific emphasis given to its role in the immune system. The various immunodeficiency conditions identified thus far in association with defective ubiquitination are discussed in more detail.
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Síndromes de Inmunodeficiencia , Ubiquitina , Animales , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Mutación , Ubiquitina/genética , Ubiquitina/inmunología , Ubiquitinación/genética , Ubiquitinación/inmunologíaRESUMEN
Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first.
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Agammaglobulinemia/inmunología , Ataxia Telangiectasia/inmunología , Síndrome de Inmunodeficiencia con Hiper-IgM/inmunología , Inmunoglobulina G/inmunología , Adolescente , Adulto , Agammaglobulinemia/complicaciones , Ataxia Telangiectasia/complicaciones , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/mortalidad , Proteínas de la Ataxia Telangiectasia Mutada/genética , Causas de Muerte , Niño , Estudios de Cohortes , Femenino , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/complicaciones , Deficiencia de IgA/complicaciones , Deficiencia de IgA/inmunología , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/inmunología , Esperanza de Vida , Masculino , Persona de Mediana Edad , Mutación , Neoplasias/etiología , Neoplasias/genética , Oportunidad Relativa , Fenotipo , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Chronic granulomatous disease (CGD) is an innate immunodeficiency with a genetic defect of the nicotinamide adenosine dinucleotide phosphate, reduced, oxidase components. This leads to decreased reactive oxygen species (ROS) production, which renders patients susceptible to life-threatening infections. Over the course of 30 years, we diagnosed CGD in 84 patients from 61 families using functional, molecular, and genetic studies. The incidence of CGD in Israel is 1.05 per 100,000 live-births in the Jewish population and 1.49 in the Israeli Arab population. We diagnosed 52 patients (62%) with autosomal recessive inheritance (AR-CGD) and 32 (38%) with X-linked recessive inheritance (XLR-CGD). Consanguinity was detected in 64% of AR-CGD families (14% in Jews and 50% in Israeli Arabs). We found 36 different mutations (23 in XLR-CGD and 13 in AR-CGD patients), 15 of which were new. The clinical spectrum of CGD varied from mild to severe disease in both XLR and AR forms, although the AR subtype is generally milder. Further, residual ROS production correlated with milder clinical expression, better prognosis and improved overall survival. Patients with recurrent pyogenic infections developed fibrosis and hyperinflammatory states with granuloma formation. The management of CGD has progressed substantially in recent years, evolving from a fatal disease of early childhood to one of long-term survival. Our present cohort displays an encouraging 81% overall long term survival. Early hematopoietic stem cell transplantation is advisable before tissue damage is irreversible. Successful transplantation was performed in 18/21 patients. Therapeutic gene modification could become an alternative cure for CGD. Am. J. Hematol. 92:28-36, 2017. © 2016 Wiley Periodicals, Inc.