RESUMO
Mutations in IFNGR1, IFNGR2, IL12RB1, IL12B, STAT1 and NEMO result in a common clinical phenotype known as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Interleukin-12 receptor beta1 (IL-12Rbeta1) deficiency is the most common genetic etiology for MSMD. Known mutations affecting IL12RB1 are recessively inherited and are associated with null response to both IL-12 and IL-23. Mutation IL12RB1 1623_1624delinsTT was originally described in 5 families from European origin (2 from Germany; 1 from Cyprus, France and Belgium). Interestingly, this same mutation was found in an unexpectedly high prevalence among IL-12Rbeta1 deficient patients in Argentina: 5-out-of-6 individuals born to unrelated families carried this particular change. To determine whether mutation 1623_1624delinsTT represents a DNA mutational hotspot or a founder effect, 34 polymorphic markers internal or proximal to IL12RB1 were studied in the Argentinean and the Belgian patients. A common haplotype spanning 1.45-3.51Mb was shared by all chromosomes carrying mutation 1623_1624delinsTT, and was not detected on 100 control chromosomes. Applying a modified likelihood-based method the age of the most recent common ancestor carrying mutation 1623_1624delinsTT was estimated in 475 years (95% CI, 175-1275), which is the time when the Spaniards initiated the colonization of the Americas. Mutation 1623_1624delinsTT represents the first founder effect described on IL-12Rbeta1, the most frequently affected gene in MSMD, and affecting patients with European ancestors. The reason(s) behind the persistency of this mutation across multiple generations, its relative high prevalence, and any potential selective advantage are yet to be established.
Assuntos
Efeito Fundador , Predisposição Genética para Doença , Infecções por Mycobacterium/genética , Receptores de Interleucina-12/genética , Animais , Argentina , Vacina BCG/administração & dosagem , Vacina BCG/efeitos adversos , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Mutação , Mycobacterium bovis/isolamento & purificação , População Branca/genéticaRESUMO
Herein, we describe a combination of clinical, microbiologic, and histopathologic findings significantly associated with osteomyelitis in chronic granulomatous disease. When present, these features should raise the suspicion of underlying chronic granulomatous disease. In patients with these findings, anti-infective prophylactic measures aiming to cover highly prevalent microorganisms, as well as aggressive therapeutic measures, should be strongly encouraged.
Assuntos
Antibacterianos/uso terapêutico , Quimioprevenção , Doença Granulomatosa Crônica/complicações , Doença Granulomatosa Crônica/microbiologia , Osteomielite/microbiologia , Osteomielite/patologia , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Aspergilose/patologia , Aspergilose/fisiopatologia , Aspergillus/isolamento & purificação , Osso e Ossos/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença Granulomatosa Crônica/patologia , Doença Granulomatosa Crônica/fisiopatologia , Humanos , Lactente , Micoses/tratamento farmacológico , Micoses/microbiologia , Micoses/patologia , Micoses/fisiopatologia , Osteomielite/tratamento farmacológico , Osteomielite/fisiopatologia , Penicillium/isolamento & purificação , Infecções por Serratia/tratamento farmacológico , Infecções por Serratia/microbiologia , Infecções por Serratia/patologia , Infecções por Serratia/fisiopatologia , Serratia marcescens/isolamento & purificaçãoRESUMO
Chronic granulomatous disease (CGD) is a genetically heterogeneous disease characterized by recurrent life-threatening infections with bacteria and fungi as well as dysregulated inflammatory mechanisms. CGD is caused by defects in the NADPH oxidase, the enzyme complex responsible for generation of superoxide and other reactive oxygen species (ROS) in phagocytic cells. In this review we will focus our attention on those particular inflammatory manifestations associated with CGD, their frequencies and the underlying immunologic mechanisms favoring it occurrence.
Assuntos
Doença Granulomatosa Crônica/imunologia , NADPH Oxidases/genética , Autoimunidade/genética , Feminino , Perfilação da Expressão Gênica , Genes Ligados ao Cromossomo X , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/fisiopatologia , Humanos , Inflamação/genética , Inflamação/imunologia , Masculino , Mutação , NADPH Oxidases/imunologia , Fagócitos/imunologiaRESUMO
Inmunoglobulina G Endovenosa UNC is a 5% liquid Argentine intravenous immunoglobulin obtained from South American donors. This prospective trial was designed to evaluate if the product meets the minimal efficacy requirement of the US Food and Drug Administration of <1 serious infection/subject/year as well as its safety in pediatric patients with Primary Immunodeficiency Diseases. Thirty patients under the age of 18, with well-defined Primary Immunodeficiency Diseases received Inmunoglobulina G Endovenosa UNC (330-700 mg/kg every 3-4 weeks) for 6 months. Vital signs, laboratory abnormalities, adverse events and viral tests were assessed to evaluate safety. Two serious infections occurred (pneumonia and bacteriemia). The estimated infection rate was 0.114 serious infection/subject/year (95% CI, 0.003-0.2277). Minor adverse events occurred in 5.5% of infusions; fever and headache were the most common. Neither severe adverse events, nor abnormal laboratory values were observed. All viral assessments were negative. Inmunoglobulina G Endovenosa UNC meets the minimal efficacy requirement of the US Food and Drug Administration for pediatric Primary Immunodeficiency Diseases patients and showed efficacy and safety data comparable with other data published.
Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Adolescente , Argentina , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina G/sangue , Infecções/epidemiologia , Masculino , Resultado do TratamentoRESUMO
Infections due to Penicillium species other than P.marneffei are rare. We identified a boy with X-linked chronic granulomatous disease (X-CGD) with a pulmonary nodule and adjacent rib osteomyelitis caused by Penicillium piceum. The only sign of infection was an elevated sedimentation rate. P. piceum was isolated by fine needle aspirate and from excised infected tissues. Surgical removal and one year of voriconazole treatment were very well tolerated and led to complete recovery. Microbiological, microscopic and molecular studies support the fungal diagnosis. P. piceum should be considered as a relevant pathogen in immunocompromised patients.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doença Granulomatosa Crônica/complicações , Micoses/diagnóstico , Micoses/tratamento farmacológico , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Penicillium/isolamento & purificação , Antifúngicos/uso terapêutico , Biópsia por Agulha Fina , Sedimentação Sanguínea , Criança , DNA Fúngico/química , DNA Fúngico/genética , Humanos , Masculino , Microscopia , Dados de Sequência Molecular , Micoses/microbiologia , Pirimidinas/uso terapêutico , Radiografia Torácica , Análise de Sequência de DNA , Triazóis/uso terapêutico , VoriconazolRESUMO
Patients with mutations in the IFNgamma/IL-12 pathway show an exquisite susceptibility to mycobacterial diseases. An IL-12Rbeta1 deficient patient with impaired intestinal absorption suffered from a 13 year culture-positive Mycobacterium bovis-BCG infection with acquired multidrug resistance. A combined parenteral and enteral anti-mycobacterial treatment, including recombinant IFNgamma, helped to clear his infection.
Assuntos
Antituberculosos/uso terapêutico , Mycobacterium bovis/isolamento & purificação , Receptores de Interleucina-12/deficiência , Tuberculose/tratamento farmacológico , Tuberculose/genética , Adolescente , Antituberculosos/efeitos adversos , Predisposição Genética para Doença , Humanos , Masculino , Receptores de Interleucina-12/genética , Tuberculose/microbiologiaRESUMO
Patients with a dominant small deletion (818del4, hotspot) in the interferon-gamma receptor 1 (IFNGR1) gene (6q23-q24) and increased susceptibility to mycobacterial infections have been recently reported. We describe a female patient homozygous for a 4-bp deletion in exon 5 of IFNGR1 (561del4) who developed postvaccinal disseminated Bacille Calmette-Guerin infection. She was born to unrelated Argentinean parents, each of whom was heterozygous for this mutation. 561del4 has been previously described as a maternally inherited mutation in a compound heterozygous German patient. By single nucleotide polymorphism analysis of the areas surrounding the deletion, we showed the independent inheritance of 561del4 in three heterozygous carriers. Polypurine runs and "direct repeats," previously shown to be associated with areas of recurrent small deletions, were found in the flanking region of 561del4. The independent inheritance of three identical mutational events defines 561del4 as a new hotspot in the IFNGR1 gene.
Assuntos
Receptores de Interferon/genética , Deleção de Sequência , Vacina BCG/efeitos adversos , Cromossomos Humanos Par 6 , Éxons , Feminino , Homozigoto , Humanos , Lactente , Íntrons , Infecções por Mycobacterium/genética , Polimorfismo de Nucleotídeo Único , Vacinação/efeitos adversos , Receptor de Interferon gamaRESUMO
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease (8q21) from the family of the genetically determined chromosomal instability syndromes. The disorder is characterized by microcephaly, growth retardation, immunodeficiency, and high incidence of cancer. Several noninflammatory anomalies of the musculoskeletal system have been described in patients with this syndrome. We describe an Argentinian girl with all the clinical, immunological, and cytogenic characteristics described for NBS plus a juvenile rheumatoid arthritis-like syndrome. To our knowledge this is the first report of a patient with the NBS who presented with a symmetric chronic polyarthritis resembling JRA.
Assuntos
Artrite Juvenil/complicações , Transtornos Cromossômicos/complicações , Síndromes de Imunodeficiência/complicações , Adolescente , Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/genética , Artrografia , Transtornos Cromossômicos/genética , Coloração Cromossômica , Fácies , Feminino , Humanos , Ibuprofeno/uso terapêutico , Síndromes de Imunodeficiência/genética , Resultado do TratamentoRESUMO
La neumonía recurrente (NR) es un motivo deconsulta ocasional en pediatría ambulatoria. Es necesario diferenciar al niño sano con intercurrencias de quien tiene trastornos predisponentes. Con el objetivo de investigar causas de NR y valorar los métodos de estudio evaluamos 42 niñosen forma prospectiva desde octubre de 1997 hasta noviembre de 1998. Incluimos niños derivados por NR, sin otra patología crónica conocida. Se definió NR a 2 neumonías en el lapso de 1 año ó 3 episodios en cualquier período de tiempo. Confeccionamos una historia clínica para NR. Con las Rx. previas evaluamos la existencia de NR. El diagnóstico clínico (D1) surgió de la anamnesis y el examen físico. Se solicitó a todos PPD, Rx. de Tórax F y P, hemograma, proteinograma, dosaje de Ig A, E, G, M, a los mayores de 2 años subclases de Ig G, títulos de isohemaglutininas, Ac antitetánicos, poblaciones linfocitarias, grupo y factor y test del sudor. Como segunda línea de estudio orientada por la evaluación clínica se solicitó endoscopía, complemento, NTB, espirometría, seriada esófago-gastro-duodenal y TAC de tórax. Con ello se estableció el diagnóstico final (D2) y el elemento diagnóstico clave. La edad media fue de 58.35 meses (rango 10 á 167). Hubo 23 mujeres y 19 varones. El número medio de neumonías fue de 4.2 (rango 2 á 13). En8 casos las neumonías fueron de una misma localización. Hubo internaciones previas en 27 niños. La causa de las NR fue única en 33 casos: asma (n:17), normal con intercurrencias (n:4), aspiración de cuerpo extraño (n:2), microaspiración por RGE (n:2), FQP (n:2), déficit de Ig G2 (n:1), inmunodeficiencia común variable(n:1), inmunodeficiencia combinada (n:1), colaterales aortopulmonares (n:1), bronquiectasias (n:1), causa indeterminada (n:1) y en 4 casos la causa fue múltiple con asma asociada a: déficit de IG A (n:3) y déficit de Ig G2 (n:1). En 5 casos se descartaron las NR. En el 35 por ciento de los caso D1 no concordó con D2. No hubo un único método diagnóstico clave. Concluimos que se deben confirmar losdiagnósticos de NR, es necesario un plan de estudio sistemático que complementeel examen clínico y que el asma es la causa más frecuente de NR. (AU)