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1.
J Clin Immunol ; 39(4): 414-420, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31041574

RESUMO

BACKGROUND: One of the limiting factors for successful hematopoietic stem cell transplantation (HSCT) is graft versus host disease (GVHD). The EBMT/ESID guidelines for HSCT in severe combined immunodeficiency (SCID) recommend no GVHD prophylaxis for a matched sibling donor (MSD). OBJECTIVE: To determine the risk of GVHD in MSD HSCT for SCID patients compared to matched related donor (MRD). METHODS: This retrospective cohort study compares MSD with MRD and the outcome of GVHD in all SCID patients who underwent HSCT between 1993 and 2013. All statistical analyses were done using IBM SPSS statistics software. RESULTS: One hundred forty-five SCID patients underwent 152 HSCTs while 82 (54%) received GVHD prophylaxis. GVHD occurred in 48 patients (31.5%); 20/48 (42%) had GVHD prophylaxis compared to 28/48 (58%) that did not, P = 0.022. Acute GVHD occurred at a higher trend in MSD, 37/120 (30.8%), compared to MRD, 6/32 (18.8%), P = 0.17. We also analyzed the outcome according to the period of HSCT. The first period was 1993 to 2003, 48 HSCTs, 43 MSD, 5 MRD; all patients had GVHD prophylaxis, and there was no difference in GVHD. The second period was 2004 to 2013: of 104 HSCTs, 77 had MSD and 27 had MRD; GVHD prophylaxis was used in 22.1% of MSD and 63% of MRD, P = 0.000. GVHD was significantly higher in the MSD (40.2%) compared to MRD (18.5%) patients, P = 0.041. CONCLUSION: GVHD prophylaxis in MSD transplant should be considered in SCID patients.

2.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

3.
Front Immunol ; 9: 203, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29479355

RESUMO

Combined immunodeficiencies are a heterogeneous collection of primary immune disorders that exhibit defects in T cell development or function, along with impaired B cell activity even in light of normal B cell maturation. CARMIL2 (RLTPR) is a protein involved in cytoskeletal organization and cell migration, which also plays a role in CD28 co-signaling of T cells. Mutations in this protein have recently been reported to cause a novel primary immunodeficiency disorder with variable phenotypic presentations. Here, we describe seven patients from three unrelated, consanguineous multiplex families that presented with dermatitis, esophagitis, and recurrent skin and chest infections with evidence of combined immunodeficiency. Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations not previously reported (p.R50T and p.L846Sfs) in CARMIL2. Real-time PCR analysis revealed that the biallelic frameshift mutation is under negative selection, likely due to nonsense-mediated RNA decay and leading to loss of detectable protein upon immunoblotting. Protein loss was also observed for the missense mutation, and 3D modeling suggested a disturbance in structural stability due to an increase in the electrostatic energy for the affected amino acid and surrounding residues. Immunophenotyping revealed that patient Treg counts were significantly depressed, and that CD4+ T cells were heavily skewed towards the naïve status. CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation. This work broadens the allelic heterogeneity associated with CARMIL2 and highlights a deleterious missense alteration located outside the leucine-rich repeat of the protein, where all other missense mutations have been reported to date.


Assuntos
Dermatite/genética , Esofagite/imunologia , Síndromes de Imunodeficiência/genética , Proteínas dos Microfilamentos/imunologia , Infecções Respiratórias/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Dermatite/imunologia , Esofagite/genética , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Masculino , Proteínas dos Microfilamentos/genética , Mutação , Linhagem , Infecções Respiratórias/genética , Arábia Saudita , Sequenciamento Completo do Exoma
4.
Tunis Med ; 96(10-11): 672-677, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30746660

RESUMO

INTRODUCTION: Primary Immunodeficiency (PIDs) is a set of 330 rare hereditary diseases that increase susceptibility to infections, allergies, autoimmunity, and neoplasia. North American registries give higher prevalence than Maghreb ones, whereas consanguinity is high. The purpose of this study is to compare prevalence and coverage rate of Maghreb PID registries with estimates based on USA. METHODS: We searched the prevalence of PIDs in the Maghreb registers. Next, we estimated the expected values based on recent publications. Finally, we calculated the coverage rate of the Maghreb registries compared to the new estimates and we evaluated the impact of consanguinity. RESULTS: The total number is N1 = 2456 patients. The current Maghreb PID Prevalence is 2.56 / 100,000 inhabitants (population of 94,804,694 Million in 2017). Tunisia leads with a prevalence of 8.70 followed by Morocco 2.09, Libya 1.65 and Algeria 1.46/100.000 habitants. We did not find values for Mauritania. If we extrapolate the prevalence of the USA to the Maghreb population, the number of patients in the Maghreb would be N2 = 27,588 and the coverage rate (N1 / N2) would be 8.90%. This low coverage rate is however better than the World average (1.21%), that of Latin America 1.19% and Africa 0.36%. The Maghreb prevalence is close to that of the Arab world 2.04 / 100,000 (population of 391,449,544 in 2017). Using the incidence found in the USA, the number of patients would be 9765 new patients per year in the Maghreb and 40,319 in Arab countries. CONCLUSION: PID Maghreb patients number is very low compared to global estimates, whereas consanguinity is very high. Special attention should be given to PIDs by governments and research teams in this region.


Assuntos
Síndromes de Imunodeficiência/epidemiologia , África/epidemiologia , África do Norte/epidemiologia , Argélia/epidemiologia , Ásia/epidemiologia , Consanguinidade , Europa (Continente)/epidemiologia , Humanos , Síndromes de Imunodeficiência/genética , Incidência , Oriente Médio/epidemiologia , Marrocos/epidemiologia , Prevalência , Sistema de Registros/estatística & dados numéricos , Estatística como Assunto/normas , Tunísia/epidemiologia , Estados Unidos/epidemiologia
5.
J Clin Immunol ; 37(6): 575-581, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28741180

RESUMO

INTRODUCTION: Non-homologous end joining gene 1 (NHEJ1) defect is a rare form of primary immune deficiency. Very few cases have been described from around the world. PURPOSE: We are reporting the first family from the Arabian Gulf with three siblings presenting with combined immunodeficiency (CID), microcephaly, and growth retardation due to a novel NHEJ1 splice site mutation, in addition to a review of the previously published literature on this subject. METHODS: Patients' clinical, immunological, and laboratory features were examined. Samples were subjected to targeted next-generation sequencing (NGS). The pathogenic change in NHEJ1 was confirmed by Sanger sequencing, then further assessed at the RNA and protein levels. RESULTS: Patients were found to have a homozygous splice site mutation immediately downstream of exon 3 in NHEJ1 (c.390 + 1G > C). This led to two distinct mRNA products, one of which demonstrated skipping of the last 69 basepairs (bp) of exon 3 while the other showed complete skipping of the entire exon. Although both deletions were in-frame, immunoblotting did not reveal any NHEJ1 protein products in patient cells, indicating a null phenotype. CONCLUSION: Patients presenting with CID, microcephaly, and growth retardation should be screened for NHEJ1 gene mutations. We discuss our data in the context of one of our patients who is still alive at the age of 30 years, without transplantation, and who is the longest known survivor of this disease.


Assuntos
Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Síndromes de Imunodeficiência/genética , Microcefalia/genética , Mutação/genética , Isoformas de Proteínas/genética , Sítios de Splice de RNA/genética , Adolescente , Adulto , Processamento Alternativo , Criança , Família , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Irmãos
6.
Clin Immunol ; 178: 39-44, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27890707

RESUMO

BACKGROUND: Hyper-IgE syndrome (HIES) due to DOCK8 deficiency is an autosomal recessive (AR) primary combined immunodeficiency which results in significant morbidity and mortality at a young age. Different mutations in the DOCK8 gene can lead to variable severity of the disease. OBJECTIVE: We evaluated the genetic mutations in three related patients with severe clinical manifestations suggestive of AR HIES. We also explored whether treatment with stem cell transplantation could lead to complete disease resolution. METHOD: We examined the clinical manifestations and immunological workup of these patients. Their DNA was also screened for causative mutation. Post transplantation, clinical and immunological data for the transplanted patient was also collected. RESULTS: All patients had a severe course of the disease with rarely reported severe complications in HIES. One patient died with lymphoma while another died with progressive multifocal leukoencephalopathy (PML) due to a slow virus. All our patients had two novel mutations in the DOCK8 gene. One of these mutations was a novel pathogenic mutation and explains the severity of the disease (homozygous splice site mutation at position 5 after the end of exon 45), while the other mutation was mostly non-pathogenic. Hematopoietic stem cell transplantation (HSCT) was performed in the youngest patient with excellent engraftment and full reversibility of the clinical manifestations. CONCLUSION: We report 3 patients from a consanguineous family diagnosed with AR-HIES due to a novel pathogenic mutation in DOCK8 gene leading to fatal outcome in 2 patients and complete resolution of the clinical and immunological features in the third patient by HSCT.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome de Job/genética , Adolescente , Neoplasias das Glândulas Suprarrenais/etiologia , Neoplasias das Glândulas Suprarrenais/virologia , Criança , Pré-Escolar , Colangite Esclerosante/etiologia , Consanguinidade , Eczema/etiologia , Eosinofilia/etiologia , Infecções por Vírus Epstein-Barr/etiologia , Esofagite/etiologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Herpes Simples/etiologia , Humanos , Síndrome de Job/complicações , Síndrome de Job/imunologia , Síndrome de Job/terapia , Leiomioma/etiologia , Leiomioma/virologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/etiologia , Leucoencefalopatia Multifocal Progressiva/patologia , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/virologia , Imagem por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Neoplasias Nasofaríngeas/etiologia , Neoplasias Nasofaríngeas/virologia , Linhagem , Recidiva , Infecções Estafilocócicas/etiologia , Adulto Jovem
8.
J Allergy Clin Immunol ; 137(6): 1780-1787, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26915675

RESUMO

BACKGROUND: Molecular genetics techniques are an essential diagnostic tool for primary immunodeficiency diseases (PIDs). The use of next-generation sequencing (NGS) provides a comprehensive way of concurrently screening a large number of PID genes. However, its validity and cost-effectiveness require verification. OBJECTIVES: We sought to identify and overcome complications associated with the use of NGS in a comprehensive gene panel incorporating 162 PID genes. We aimed to ascertain the specificity, sensitivity, and clinical sensitivity of the gene panel and its utility as a diagnostic tool for PIDs. METHODS: A total of 162 PID genes were screened in 261 patients by using the Ion Torrent Proton NGS sequencing platform. Of the 261 patients, 122 had at least 1 known causal mutation at the onset of the study and were used to assess the specificity and sensitivity of the assay. The remaining samples were from unsolved cases that were biased toward more phenotypically and genotypically complicated cases. RESULTS: The assay was able to detect the mutation in 117 (96%) of 122 positive control subjects with known causal mutations. For the unsolved cases, our assay resulted in a molecular genetic diagnosis for 35 of 139 patients. Interestingly, most of these cases represented atypical clinical presentations of known PIDs. CONCLUSIONS: The targeted NGS PID gene panel is a sensitive and cost-effective diagnostic tool that can be used as a first-line molecular assay in patients with PIDs. The assay is an alternative choice to the complex and costly candidate gene approach, particularly for patients with atypical presentation of known PID genes.


Assuntos
Marcadores Genéticos , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Biologia Computacional , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Síndromes de Imunodeficiência/imunologia , Mutação , Polimorfismo de Nucleotídeo Único , Fluxo de Trabalho
9.
Nat Genet ; 48(1): 74-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26642240

RESUMO

Patients with a combined immunodeficiency characterized by normal numbers but impaired function of T and B cells had a homozygous p.Tyr20His substitution in transferrin receptor 1 (TfR1), encoded by TFRC. The substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. Tfrc(Y20H/Y20H) mice recapitulated the immunological defects of patients. Despite the critical role of TfR1 in erythrocyte development and function, patients had only mild anemia and only slightly increased TfR1 expression in erythroid precursors. We show that STEAP3, a metalloreductase expressed in erythroblasts, associates with TfR1 and partially rescues transferrin uptake in patient-derived fibroblasts, suggesting that STEAP3 may provide an accessory TfR1 endocytosis signal that spares patients from severe anemia. These findings demonstrate the importance of TfR1 in adaptive immunity.


Assuntos
Antígenos CD/genética , Antígenos CD/imunologia , Síndromes de Imunodeficiência/genética , Mutação de Sentido Incorreto , Receptores da Transferrina/genética , Receptores da Transferrina/imunologia , Imunidade Adaptativa/genética , Anemia/genética , Animais , Antígenos CD/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Endocitose , Feminino , Fibroblastos/fisiologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Linhagem , Receptores da Transferrina/metabolismo
10.
J Clin Immunol ; 35(7): 651-60, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26395454

RESUMO

PURPOSE: Primary immunodeficiencies (PID) are a group of heterogeneous diseases. Epidemiological studies from databases worldwide show geographical variation. In this study the objective is to determine the spectrum of PID in Saudi Arabia by analyzing the database in a referral tertiary hospital. METHODS: This is a prospective data collection by interviews and medical chart review for all PID patients followed at the King Faisal Specialist Hospital & Research Center (KFSH&RC) from May 2010 to April 2013. RESULTS: A total of 502 patients presented (53 % male and 47 % female). Combined immunodeficiencies were the most common (59.7 %), followed by predominantly antibody deficiencies (12.3 %), congenital defects of phagocyte (9.4 %), combined immunodeficiencies with associated or syndromic features (6.2 %), disease of immune dysregulation (6 %), complement deficiencies (5.8), and defects in innate immunity (0.6 %). The most common combined immunodeficiencies phenotype was T-B-SCID (17 %). The patients' ages ranged from less than 1 year old to 78 years, and 394 patients (78.2 %) are in the paediatrics age group (<14 years). The overall mean age of symptoms onset was 17 months and the overall mean delay in diagnosis was 21.6 months. Recurrent infections were the most common occurring clinical presentation (66 %), followed by family history (26 %). Consanguinity was found in 75 % of the patients. A total of 308 (61 %) patients had undergone stem cell transplantation (SCT). CONCLUSION: The study revealed that combined immunodeficiencies are not uncommon and are the most frequent occurring diagnosis in our patient population. This study is a prerequisite to establish a national registry of primary immunodeficiency in Saudi Arabia.


Assuntos
Linfócitos B/fisiologia , Síndromes de Imunodeficiência/epidemiologia , Linfócitos T/fisiologia , Centros de Atenção Terciária , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Lactente , /etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Arábia Saudita , Transplante de Células-Tronco , Adulto Jovem
11.
Pediatr Transplant ; 19(6): 634-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26073206

RESUMO

HIGMI is a disease with a high risk for morbidity and mortality. HSCT has been shown to be a curative option. This study retrospectively reviewed and analyzed data from five patients who received HSCT at King Faisal Specialist Hospital & Research Centre (KFSH&RC) in Riyadh, Saudi Arabia, between 2005 and 2013. Five patients with HIGMI syndrome underwent HSCT at a median age of 41 months (range, 9-72 months). The median time from diagnosis to transplantation was 30 months (range, 5-58 months). For all five patients, the donors were HLA-identical siblings. In three patients, the conditioning regimen was composed of BU and CY. Fludarabine and melphalan with either ATG or alemtuzumab was used in two patients. For GVHD prophylaxis, cyclosporine was used in two patients, and the combination of cyclosporine and MTX was used in three patients. The survival rate was 100%, with a median follow-up of 69 months (range, 13-100 months). All patients engrafted. Two patients developed acute GVHD. Four patients showed complete immune recovery with positive CD40L expression in activated T cells and discontinued IVIG replacement. HSCT in early stage from an HLA-matched sibling donor is potentially effective at curing the disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/terapia , Ligante de CD40/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Marcadores Genéticos , Doença Enxerto-Hospedeiro , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/diagnóstico , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/genética , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/mortalidade , Lactente , Masculino , Estudos Retrospectivos , Condicionamento Pré-Transplante , Resultado do Tratamento
12.
J Clin Immunol ; 33(8): 1325-35, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24122029

RESUMO

PURPOSE: Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare form of primary immunodeficiency with few reported cases. In this study, we further characterize the clinical, immunological, and molecular profiles of the disease in a cohort of 11 patients. METHODS: Molecular genetic analysis and a comprehensive clinical review of patients diagnosed with HIGM3 at our tertiary care center from 1994 to 2011 were undertaken. RESULTS: Eleven patients from seven families were enrolled. The patients had a median age of 9 years [ranging from 2 to 22 years old]. All 11 patients had recurrent chest infections at presentation. Pneumocystis jiroveci pneumonia was confirmed in three patients. Five patients had sclerosing cholangitis, and five patients had Cryptosporidium isolated from their stool. Six patients had nasal and sinus infections, and two of these patients had destructive nasal fungal infections. Eight patients had neutropenia. All of the patients had low IgG and normal or high IgM levels. IgA was undetectable in all but three patients. Two novel mutations were found: a splice site for intron 3 and a missense mutation located in the coding region of exon 3. Two patients underwent successful stem cell transplantation from a matched donor. Four patients are doing well on prophylaxis; two are very sick, one with protracted diarrhea and persistent Cryptosporidium and the other with neurological complications. Three patients died early in life as a result of severe sepsis. CONCLUSIONS: To our knowledge, this report provides the largest cohort of patients with this disease with a very long follow-up period. Our cohort showed variable disease severity


Assuntos
Antígenos CD40/deficiência , Síndrome de Imunodeficiência com Hiper-IgM/genética , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Adolescente , Antígenos CD40/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/microbiologia , Síndromes de Imunodeficiência/microbiologia , Lactente , Masculino , Mutação , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Infecções Respiratórias/microbiologia , Estudos Retrospectivos , Adulto Jovem
13.
J Clin Immunol ; 33(4): 871-5, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23371790

RESUMO

INTRODUCTION: Complement deficiencies are rare primary immunodeficiency disorders, the diagnosis of which is often underestimated. Only a small number of molecular studies have been carried out for the characterization of the underlying genetic defects in these cases. PURPOSE: Reporting the first family from the Arabian Gulf region with multiple members affected by meningococcemia and abscent serum complement 5 (C5). We tried to correlate clinical, biochemical and molecular genetics features of this family. METHODS: Determination of the serum level of all complement proteins including the terminal cascade (C5-9), followed by mutation analysis on DNA extracted from fresh blood samples of each alive family member. RESULTS: Molecular studies showed a homozygous nonsense mutation in exon 1, with the change of cytosine to thymine at position 55 (55C > T) leading to change of the glutamine amino acid at position 19 to a stop codon (Q19X), and serologically absence of C5 in the serum. A similar but compound heterozygous mutation has been reported in one African-American family. previously. CONCLUSION: Characterization of the underlying mutations in C5 deficient families is important, to understand this uncommon complement deficiency, and try to elucidate structure-function relationships in the C5 gene. This report also highlights the importance of complement screening in cases of sporadic meningococcal Infections, especially in communities with high prevalence of consanguineous marriages, which will ensure timely and adequate clinical interventions.


Assuntos
Complemento C5/deficiência , Síndromes de Imunodeficiência/genética , Infecções Meningocócicas/genética , Neisseria meningitidis/imunologia , Pré-Escolar , Complemento C5/genética , Consanguinidade , Análise Mutacional de DNA , Genótipo , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Masculino , Infecções Meningocócicas/diagnóstico , Infecções Meningocócicas/etiologia , Infecções Meningocócicas/imunologia , Linhagem , Arábia Saudita , Deleção de Sequência/genética , Relação Estrutura-Atividade
14.
J Clin Immunol ; 33(1): 55-67, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22968740

RESUMO

PURPOSE: Autosomal recessive hyper-IgE syndrome is a rare combined immunodeficiency characterized by susceptibility to viral infections, atopic eczema, high serum IgE and defective T cell activation. The genetic etiologies are diverse. Null mutations in DOCK8 and TYK2 are responsible for many cases. This study aims to provide a detailed clinical and immunological characterization of the disease and explore the underlying genetic defects among a large series of patients followed by a single center. The available data might improve our understanding of the disease pathogenesis and prognosis. METHODS: Clinical data of twenty-five patients diagnosed with AR-HIES were collected. Seventeen patients screened for STAT3, TYK2 and DOCK8 mutations. RESULTS: Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. The rate of hepatic disorders and systemic infections were high. Twelve patients died with a median age of 10 years. CMV infection was the only statistically significant predicting factor for poor prognosis (early death). Three novel DOCK8 mutations and two large deletions were found in thirteen patients. No mutations found in STAT3 or TYK2 genes. CONCLUSION: Autosomal recessive hyper-IgE syndrome is a combined immunodeficiency disease characterized by high morbidity and mortality rate. The different genetic background and environmental factors may explain the more severe phenotypes seen in our series. DOCK8 defect is the most common identified genetic cause. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.


Assuntos
Deleção de Genes , Fatores de Troca do Nucleotídeo Guanina/química , Fatores de Troca do Nucleotídeo Guanina/deficiência , Hospitais Especializados , Síndrome de Job/genética , Síndrome de Job/imunologia , Adolescente , Criança , Pré-Escolar , Códon sem Sentido/genética , Feminino , Genes Recessivos/imunologia , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Imunoglobulina E/efeitos adversos , Imunoglobulina E/sangue , Incidência , Síndrome de Job/epidemiologia , Masculino , Arábia Saudita/epidemiologia , Prevenção Secundária
15.
Blood ; 120(17): 3615-24; quiz 3626, 2012 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-22791287

RESUMO

Deficiency of the purine salvage enzyme adenosine deaminase leads to SCID (ADA-SCID). Hematopoietic cell transplantation (HCT) can lead to a permanent cure of SCID; however, little data are available on outcome of HCT for ADA-SCID in particular. In this multicenter retrospective study, we analyzed outcome of HCT in 106 patients with ADA-SCID who received a total of 119 transplants. HCT from matched sibling and family donors (MSDs, MFDs) had significantly better overall survival (86% and 81%) in comparison with HCT from matched unrelated (66%; P < .05) and haploidentical donors (43%; P < .001). Superior overall survival was also seen in patients who received unconditioned transplants in comparison with myeloablative procedures (81% vs 54%; P < .003), although in unconditioned haploidentical donor HCT, nonengraftment was a major problem. Long-term immune recovery showed that regardless of transplant type, overall T-cell numbers were similar, although a faster rate of T-cell recovery was observed after MSD/MFD HCT. Humoral immunity and donor B-cell engraftment was achieved in nearly all evaluable surviving patients and was seen even after unconditioned HCT. These data detail for the first time the outcomes of HCT for ADA-SCID and show that, if patients survive HCT, long-term cellular and humoral immune recovery is achieved.


Assuntos
Agamaglobulinemia/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa/tratamento farmacológico , Condicionamento Pré-Transplante , Adenosina Desaminase/deficiência , Adenosina Desaminase/imunologia , Agamaglobulinemia/imunologia , Agamaglobulinemia/mortalidade , Agamaglobulinemia/patologia , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Imunidade Celular , Imunidade Humoral , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Masculino , Agonistas Mieloablativos/uso terapêutico , Estudos Retrospectivos , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/mortalidade , Imunodeficiência Combinada Severa/patologia , Irmãos , Linfócitos T/imunologia , Resultado do Tratamento , Doadores não Relacionados
17.
Pediatr Infect Dis J ; 31(2): 204-6, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22138680

RESUMO

Disseminated cryptococcal infection is the second most common cause of death after tuberculosis in acquired immune deficiency syndrome patients. Surprisingly, it has been reported only in few patients with primary immunodeficiency diseases. Herein, we report the clinical presentation and outcome of a 23-month-old boy with novel JAK3 mutation severe combined immunodeficiency disease complicated by severe disseminated cryptococcal infection.


Assuntos
Criptococose/diagnóstico , Criptococose/patologia , Janus Quinase 3/deficiência , Imunodeficiência Combinada Severa/complicações , Transplante de Células-Tronco , Humanos , Lactente , Janus Quinase 3/genética , Masculino , Imunodeficiência Combinada Severa/genética , Resultado do Tratamento
18.
Biol Blood Marrow Transplant ; 17(8): 1245-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21220036

RESUMO

Leukocyte adhesion deficiency type 1 is a rare autosomal recessive immunodeficiency disorder. The severe phenotype is fatal unless hematopoietic stem cell transplantation (HSCT) is performed. A retrospective analysis was performed in 11 patients with leukocyte adhesion deficiency type 1 who underwent HSCT and monitoring over a period of 19 years at our institution. The median age at HSCT was 8.8 months. Stem cell sources were unmanipulated bone marrow from an HLA-matched related donor in 7 patients, unrelated umbilical cord blood in 3 patients, and a mismatched related donor in 1 patient. Three patients underwent a second HSCT. Conditioning was provided with a busulfan- and cyclophosphamide-based regimen, with anti-thymocyte immunoglobulin added for the cord blood transplant recipients. Graft-versus-host-disease prophylaxis consisted of cyclosporine A and methotrexate for related donor recipients (8 patients) and cyclosporine A and prednisone for cord blood transplant recipients (3 patients). The overall event-free survival rate was 91% with a median follow-up of 94 months (range, 15-223 months). Ten patients had immune reconstitution and demonstrated sustained engraftment that ranged from 11% to 100% for lymphoid lines and from 0% to 100% for myeloid lines. HSCT from a matched related donor or unrelated cord blood provided excellent outcome, and mixed chimerism appeared satisfactory to prevent recurrent infections.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Síndrome da Aderência Leucocítica Deficitária/cirurgia , Quimerismo , Ciclosporina/administração & dosagem , Feminino , Humanos , Imunossupressores/administração & dosagem , Lactente , Recém-Nascido , Síndrome da Aderência Leucocítica Deficitária/imunologia , Masculino , Estudos Retrospectivos , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento
19.
J Clin Immunol ; 31(2): 245-52, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21120685

RESUMO

BACKGROUND: Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is an extremely rare autosomal recessive disorder. In addition to the juxtacentromeric heterochromatic instability, the disease is characterized by variable reduction in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood as well as exhibit facial dysmorphism including hypertelorism, epicanthal folds, and low-set ears. SUBJECTS AND METHODS: A case series of five patients with ICF from a major immunodeficiency center in Saudi Arabia were included. Immunological and cytogenetic studies were performed for all the five patients. Molecular data was conducted on three patients. RESULTS: All patients had variable hypogammaglobulinemia and characteristic centromeric instability of chromosomes 1, 16, and sometimes 9. One of the patients had pseudomonas meningitis. Pauciarticular arthritis was noted in one patient, a previously not reported finding in ICF, though it has been reported among patients with humoral immune defect. In addition, we identified a novel homozygous c.2506 G>A (p.V836M) mutation in DNMT3B in one of the three patients tested. CONCLUSIONS: This report describes five patients with ICF Saudi Arabia for the first time. ICF should be suspected in children with facial dysmorphism who present with recurrent infections especially in highly inbred populations.


Assuntos
Centrômero/genética , Instabilidade Cromossômica , Imunodeficiência de Variável Comum , Face/anormalidades , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Instabilidade Cromossômica/genética , Instabilidade Cromossômica/imunologia , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Biologia Computacional , Consanguinidade , DNA (Citosina-5-)-Metiltransferases/química , DNA (Citosina-5-)-Metiltransferases/genética , Feminino , Humanos , Cariotipagem , Modelos Moleculares , Dados de Sequência Molecular , Mutação/genética , Estrutura Terciária de Proteína , Arábia Saudita , Alinhamento de Sequência , Síndrome , Adulto Jovem
20.
Pediatr Blood Cancer ; 56(2): 289-93, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21157896

RESUMO

BACKGROUND: Second stem cell transplantation (SCT) is usually associated with high morbidity and mortality and the data on its outcome in pediatric patients with non-malignant disorders are scarce. PATIENTS AND METHODS: We present 30 children with non-malignant conditions who underwent second SCT at our institution for graft failure after the first SCT; 20 had a non-malignant hematological disorder and 10 had an immune deficiency disorder. Median age at the second SCT was 6.1 years (range, 0.4-13 years) and median time from the first SCT to the second SCT was 6.2 months (range, 1.2-96 months). RESULTS: Twenty patients (70%) engrafted; severe acute GVHD developed in four patients (13%), and chronic GVHD developed in two patients of those at risk (10%). Thirteen deaths occurred and nine were considered treatment related. The 5-year overall (OS) and event free survival (EFS) for all patients were 53% and 47% respectively. The interval between the two transplants seemed to affect the outcome; patients who had the second SCT ≥ 6 months from the first SCT had better survival; the 5-year OS for the two groups (<6 months and ≥ 6 months) respectively were 30% and 74% (P = 0.004), and the 5-year EFS were 27% and 66% (P = 0.004). The underlying disease did not affect the outcome nor did the use of radiation in the conditioning regimen for the second SCT. CONCLUSIONS: Second SCT for graft failure should be considered for children with non-malignant hematological and immune deficiency disorders.


Assuntos
Doenças Hematológicas/cirurgia , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/cirurgia , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/cirurgia , Doenças Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Síndromes de Imunodeficiência/mortalidade , Lactente , Estimativa de Kaplan-Meier , Masculino , Reoperação , Transplante Homólogo , Falha de Tratamento
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