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1.
J Pediatr Endocrinol Metab ; 30(3): 365-369, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28222032

RESUMO

Autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) is a rare but devastating primary immunodeficiency disease caused by loss-of-function mutations in autoimmune regulator (AIRE) gene on chromosome 21q22.3. The clinical spectrum of the disease is characterized by a wide heterogeneity because of autoimmune reactions toward different endocrine and non-endocrine organs. Here, we report a 17-year-old Turkish girl diagnosed with APECED at 9 years in whom a novel homozygote mutation in AIRE gene p.R15H (c.44G>A) was found. In the clinical course of the patient, chronic liver disease due to autoimmune hepatitis has evolved resulting in hepatopulmonary syndrome (HPS) which has not been reported before in patients with APECED.


Assuntos
Biomarcadores/metabolismo , Cianose/etiologia , Síndrome Hepatopulmonar/complicações , Mutação/genética , Poliendocrinopatias Autoimunes/fisiopatologia , Fatores de Transcrição/genética , Adolescente , Cianose/patologia , Feminino , Síndrome Hepatopulmonar/genética , Homozigoto , Humanos , Prognóstico
2.
Proc Natl Acad Sci U S A ; 113(51): E8277-E8285, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27930337

RESUMO

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.


Assuntos
Infecções Bacterianas/imunologia , Candidíase/imunologia , Micoses/imunologia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Alelos , Candida , Membrana Celular , Criança , Pré-Escolar , Saúde da Família , Feminino , Fibroblastos/metabolismo , Genes Recessivos , Estudo de Associação Genômica Ampla , Células HEK293 , Homozigoto , Humanos , Imunofenotipagem , Lactente , Recém-Nascido , Interleucina-17/metabolismo , Masculino , Mutação , Fases de Leitura Aberta , Linhagem , Receptores de Interleucina-17/metabolismo , Pele/microbiologia , Linfócitos T/citologia
3.
Orphanet J Rare Dis ; 11(1): 110, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27484815

RESUMO

BACKGROUND: Patients with syndromic features frequently suffer from recurrent respiratory infections, but little is known about the spectrum of immunological abnormalities associated with their underlying chromosomal aberrations outside the well-known examples of Down and DiGeorge syndromes. Therefore, we performed this retrospective, observational survey study. METHODS: All members of the European Society for Immunodeficiencies (ESID) were invited to participate by reporting their patients with chromosomal aberration (excluding Down and DiGeorge syndromes) in combination with one or more identified immunological abnormalities potentially relating to primary immunodeficiency. An online questionnaire was used to collect the patient data. RESULTS: Forty-six patients were included from 16 centers (24 males, 22 females; median age 10.4 years [range 1.0-69.2 years]; 36 pediatric, 10 adult patients). A variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immune deficiency was reported. The most important clinical presentation prompting the immunological evaluation was 'recurrent ear-nose-throat (ENT) and airway infections'. Immunoglobulin isotype and/or IgG-subclass deficiencies were the most prevalent immunological abnormalities reported. CONCLUSIONS: Our survey yielded a wide variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immunodeficiency. Although respiratory tract infections can often also be ascribed to other causes (e.g. aspiration or structural abnormalities), we show that a significant proportion of patients also have an antibody deficiency requiring specific treatment (e.g. immunoglobulin replacement, antibiotic prophylaxis). Therefore, it is important to perform immunological investigations in patients with chromosomal aberrations and recurrent ENT or airway infections, to identify potential immunodeficiency that can be specifically treated.


Assuntos
Aberrações Cromossômicas , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Deficiência de IgG/diagnóstico , Deficiência de IgG/genética , Lactente , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inquéritos e Questionários , Adulto Jovem
4.
Pediatr Infect Dis J ; 35(4): 428-31, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26658378

RESUMO

Caspase-associated recruitment domain-9 (CARD9) deficiency is an autosomal-recessive primary immunodeficiency with genetic defects in Th17 immunity marked by susceptibility to recurrent and invasive Candida infections. We present a case of relapsing Candida albicans meningoencephalitis over 1-year period despite appropriate antifungal therapy. We detected a homozygous p.Q295X mutation in CARD9 as well as a defective interleukin-17 and interferon gamma synthesis in Enzyme-Linked ImmunoSpot tests. We achieved complete clinical remission, and improvement of interleukin-17 secretion with subcutaneous granulocyte colony-stimulating factor) treatment.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/deficiência , Candida albicans , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/etiologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Meningoencefalite/tratamento farmacológico , Meningoencefalite/etiologia , Adulto , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Antifúngicos/uso terapêutico , Homozigoto , Humanos , Interleucina-17/sangue , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Mutação , Recidiva , Resultado do Tratamento
5.
Pediatr Transplant ; 19(2): E47-50, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25514831

RESUMO

PNP deficiency is a rare combined immunodeficiency with autosomal recessive mode of inheritance. The immunodeficiency is progressive with normal immune functions at birth, but then, T-cell deficiency with variable B-cell functions usually presents by the age of two yr. The only curative treatment for PNP deficiency is hematopoietic stem cell transplantation. Here, we present a 13-yr-old girl with late-onset PNP deficiency. Despite many complications of infections, she was successfully transplanted with a reduced intensity-conditioning regimen from an HLA-identical unrelated donor.


Assuntos
Transplante de Células-Tronco de Sangue Periférico , Purina-Núcleosídeo Fosforilase/deficiência , Erros Inatos do Metabolismo da Purina-Pirimidina/terapia , Adolescente , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoglobulinas/química , Síndromes de Imunodeficiência/fisiopatologia , Mutação , Paraplegia/complicações , Receptores de Antígenos de Linfócitos T/metabolismo , Infecções Respiratórias/complicações , Condicionamento Pré-Transplante
6.
J Allergy Clin Immunol ; 134(1): 155-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24767876

RESUMO

BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency is a rare form of autosomal recessive combined primary immunodeficiency caused by a enzyme defect leading to the accumulation of inosine, 2'-deoxy-inosine (dIno), guanosine, and 2'-deoxy-guanosine (dGuo) in all cells, especially lymphocytes. Treatments are available and curative for PNP deficiency, but their efficacy depends on the early approach. PNP-combined immunodeficiency complies with the criteria for inclusion in a newborn screening program. OBJECTIVE: This study evaluate whether mass spectrometry can identify metabolite abnormalities in dried blood spots (DBSs) from affected patients, with the final goal of individuating the disease at birth during routine newborn screening. METHODS: DBS samples from 9 patients with genetically confirmed PNP-combined immunodeficiency, 10,000 DBS samples from healthy newborns, and 240 DBSs from healthy donors of different age ranges were examined. Inosine, dIno, guanosine, and dGuo were tested by using tandem mass spectrometry (TMS). T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) levels were evaluated by using quantitative RT-PCR only for the 2 patients (patients 8 and 9) whose neonatal DBSs were available. RESULTS: Mean levels of guanosine, inosine, dGuo, and dIno were 4.4, 133.3, 3.6, and 3.8 µmol/L, respectively, in affected patients. No indeterminate or false-positive results were found. In patient 8 TREC levels were borderline and KREC levels were abnormal; in patient 9 TRECs were undetectable, whereas KREC levels were normal. CONCLUSION: TMS is a valid method for diagnosis of PNP deficiency on DBSs of affected patients at a negligible cost. TMS identifies newborns with PNP deficiency, whereas TREC or KREC measurement alone can fail.


Assuntos
Síndromes de Imunodeficiência/diagnóstico , Mutação , Purina-Núcleosídeo Fosforilase/deficiência , Purina-Núcleosídeo Fosforilase/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico , Adolescente , Pré-Escolar , Reparo do DNA , Desoxiguanosina/análise , Desoxiguanosina/metabolismo , Teste em Amostras de Sangue Seco , Feminino , Guanosina/análise , Guanosina/metabolismo , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/patologia , Lactente , Recém-Nascido , Inosina/análogos & derivados , Inosina/análise , Inosina/metabolismo , Linfócitos/patologia , Masculino , Triagem Neonatal , Erros Inatos do Metabolismo da Purina-Pirimidina/genética , Erros Inatos do Metabolismo da Purina-Pirimidina/patologia , Espectrometria de Massas em Tandem
7.
Artigo em Inglês | MEDLINE | ID: mdl-23367498

RESUMO

OBJECTIVE: To evaluate the contribution of cytotoxic T-Iymphocyte antigen-4(CTLA-4)+49A/G polymorphism to the susceptibility to type-1 diabetes (T1D) in Turkish children. METHODS: A case-control study was designed to include 91 Turkish children with T1D and 99 healthy controls. CTLA-4 (+99A/G) gene polymorphism typing was done by PCR amplification followed by restriction fragment length polymorphism method. RESULTS: The genotype and allele frequencies of the CTLA-4 (+99A/G)polymorphism in patients with T1D were not different from those in the controls (p>0.05). The allele frequency of G was 36.2% in patients with T1D,and 31.8% in controls (p>0.05). Additionally, this polymorphism was not associated with the clinical and laboratory characteristics of the patients with T1D (p>0.05). CONCLUSIONS: Our case-control study suggests that the CTLA-4 (+99A/G) gene polymorphism is not associated with T1D in the Turkish population.


Assuntos
Antígeno CTLA-4/genética , Diabetes Mellitus Tipo 1/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Fragmento de Restrição , Turquia
8.
Nucl Med Commun ; 30(10): 802-6, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19654561

RESUMO

OBJECTIVE: Gastroesophageal reflux (GER), a common problem during childhood, leads to chronic troublesome symptoms including chronic respiratory symptoms. Therefore, timely diagnostic work-up for GER is essential in children when GER is suspected. In this study, we aimed to establish whether scintigraphic parameters have clinical importance in investigating the reflux in children. METHODS: A total of 72 children older than 7 years with chronic cough of unknown etiology were enrolled for this study. The scintigraphic procedure was performed by using technetium-99m tin colloid (37-74 MBq). Cough and GER scores were used for children who were positive for GER both before and after GER treatment. RESULTS: Of 72 children, 65 children with a mean age of 10.3+/-2.3 (7-19) years had GER on gastroesophageal scintigraphy. Median reflux episode number was 7 (1-14). There was a significantly positive correlation between reflux episode number and cough (r = 0.446, P<0.001) and GER score (r = 0.432, P<0.001). The significant decrease was observed in cough (from 3.5+/-1.9 to 1.6+/-1.3) and GER scores (from 4.1+/-2.5 to 1.3+/-1.1) with GER treatment (P<0.001 for each). CONCLUSION: Scintigraphy should be used for the detection of GER in children who present with chronic cough. Increasing episode number in gastroesophageal scintigraphy might be a predictor for reflux-related symptom severity.


Assuntos
Tosse/complicações , Tosse/diagnóstico , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/diagnóstico por imagem , Adolescente , Criança , Feminino , Humanos , Masculino , Cintilografia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
9.
Pediatr Pulmonol ; 44(1): 86-9, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19061231

RESUMO

Allergic bronchopulmonary aspergillosis usually occurs in children with underlying airway disease such as asthma and cystic fibrosis. While the colonization and infection of pre-existing tuberculosis lesions by aspergillus species is well known, occurrence of allergic bronchopulmonary aspergillosis following pulmonary tuberculosis in children has not been reported yet. Here, an 11-year-old girl who developed allergic bronchopulmonary aspergillosis following active pulmonary tuberculosis is reported and the mechanisms of causality are also speculated.


Assuntos
Aspergilose Broncopulmonar Alérgica/complicações , Aspergilose Broncopulmonar Alérgica/diagnóstico por imagem , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico por imagem , Criança , Feminino , Humanos , Radiografia
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