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1.
Pediatr Infect Dis J ; 38(12): 1230-1235, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31738339

RESUMO

BACKGROUND: Congenital cytomegalovirus infection (CMVc) affects 0.7%-6% of recent births. Among its clinical manifestations are low weight and length at birth. OBJECTIVE: Describe the growth patterns of children with CMVc in their early years. METHODS: Observational, multicenter study of patients with CMVc. Anthropometric data were collected during the first 2 years of life and compared with World Health Organization standards. RESULTS: Anthropometric characteristics of 383 children with CMVc were studied, of which 198 (51%) were symptomatic at birth. At birth, 9% were small for gestational age (SGA) in terms of their weight and length and 17% had microcephaly. At 24 ± 3 months, 10% had a weight and length ≤2 SD, and 13% a head circumference ≤2 SD. Of those who were SGA at birth, at 24 ± 3 months >20% remained at ≤2 SD of their weight and length. Conversely, 75% of children with low weight or length at 24 ± 3 had not been SGA at birth. 20% of infants with microcephaly at birth remained with microcephaly, and 10% of those without microcephaly developed it at 24 ± 3 months. The average growth rate in length and weight was normal. Patients who were symptomatic at birth, premature and with motor and neurocognitive impairment had a significantly higher risk of low weight and length at 24 ± 3 months. CONCLUSION: Around 10% of children with CMVc are at ≤2 SD in weight, length and head circumference at 24 ± 3 months. The lack of adequate growth is associated with symptoms at birth, prematurity and motor and neurocognitive impairment. Growth impairment could be incorporated into the symptomatic spectrum of CMVc.

2.
Proc Natl Acad Sci U S A ; 115(34): E8007-E8016, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30072435

RESUMO

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.


Assuntos
Éxons , Síndromes de Imunodeficiência/genética , Mutação , Penetrância , Biossíntese de Proteínas/genética , Processamento de RNA/genética , Receptores de Laminina/genética , Proteínas Ribossômicas/genética , Baço/anormalidades , Regiões 5' não Traduzidas , Feminino , Efeito Fundador , Heterozigoto , Humanos , Síndromes de Imunodeficiência/metabolismo , Masculino , Receptores de Laminina/biossíntese , Proteínas Ribossômicas/biossíntese , Baço/metabolismo
3.
Clin Infect Dis ; 64(10): 1335-1342, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-28158709

RESUMO

Background: DNA detection of human cytomegalovirus (hCMV) in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) is a marker of central nervous system (CNS) involvement in congenital hCMV infection (cCMV), but its prognostic value is unknown. Methods: A multicenter, retrospective study was performed using the Spanish Congenital Cytomegalovirus Infection Database (REDICCMV; http://www.cmvcongenito.es). Newborns with cCMV and a lumbar puncture performed were included and classified according to their hCMV-PCR in CSF result (positive/negative). Clinical characteristics, neuroimaging abnormalities, plasma viral load, and audiological and neurological outcomes of both groups were compared. Results: A total of 136 neonates were included in the study: 21 (15.4%) with positive CSF hCMV-PCR and 115 (84.6%) with negative results. Seventeen patients (81%) in the positive group were symptomatic at birth compared with 52.2% of infants in the negative group (odds ratio [OR], 3.86; 95% confidence interval [CI], 1.28-14.1; P = .01). Only 4 asymptomatic newborns (6.8%) had a positive CSF hCMV-PCR. There were no differences between groups regarding the rate of microcephaly, neuroimaging abnormalities, neurological sequelae at 6 months of age, or plasma viral load. Sensorineural hearing loss (SNHL) at birth was associated with a positive CSF hCMV-PCR result (OR, 3.49; 95% CI, 1.08-11.27; P = .04), although no association was found at 6 months of age. Conclusions: A positive hCMV-PCR result in CSF is associated with symptomatic cCMV and SNHL at birth. However, no differences in neuroimaging studies, plasma viral load, or outcomes at 6 months were found. These results suggest that hCMV-PCR in CSF may not be a useful prognostic marker in cCMV.


Assuntos
Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/isolamento & purificação , DNA Viral/líquido cefalorraquidiano , Infecções Assintomáticas , Citomegalovirus/genética , Infecções por Citomegalovirus/complicações , DNA Viral/sangue , DNA Viral/isolamento & purificação , Feminino , Doenças Fetais/virologia , Seguimentos , Perda Auditiva Neurossensorial/virologia , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/virologia , Neuroimagem , Reação em Cadeia da Polimerase/métodos , Estudos Retrospectivos , Saliva/virologia , Punção Espinal , Carga Viral
4.
J Allergy Clin Immunol ; 136(5): 1337-45, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26025129

RESUMO

BACKGROUND: Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). OBJECTIVE: We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. METHODS: Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. RESULTS: Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation resulting in p.E257K. Both mutations substantially alter the electrostatic potential of the PSTPIP1 dimer model in a region critical for protein-protein interaction. Patients with Hz/Hc have extremely high MRP8/14 concentrations (2045 ± 1300 µg/mL) compared with those with PAPA syndrome (116 ± 74 µg/mL) and have a distinct clinical phenotype. A specific cytokine profile is associated with Hz/Hc. Hz/Hc mutations altered protein binding of PSTPIP1, increasing interaction with pyrin through phosphorylation of PSTPIP1. CONCLUSION: Mutations resulting in charge reversal in the y-domain of PSTPIP1 (E→K) and increased interaction with pyrin cause a distinct autoinflammatory disorder defined by clinical and biochemical features not found in patients with PAPA syndrome, indicating a unique genotype-phenotype correlation for mutations in the PSTPIP1 gene. This is the first inborn autoinflammatory syndrome in which inflammation is driven by uncontrolled release of members of the alarmin family.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas do Citoesqueleto/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Erros Inatos do Metabolismo dos Metais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Alarminas/genética , Alarminas/metabolismo , Calgranulina A/genética , Calgranulina A/metabolismo , Criança , Citocinas/metabolismo , Proteínas do Citoesqueleto/genética , Feminino , Genótipo , Humanos , Complexo Antígeno L1 Leucocitário/genética , Masculino , Erros Inatos do Metabolismo dos Metais/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Fosforilação , Ligação Proteica/genética , Mapas de Interação de Proteínas/genética , Multimerização Proteica , Pirina , Adulto Jovem
5.
Clin Infect Dis ; 58(2): 204-13, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24186907

RESUMO

BACKGROUND: Interleukin 12Rß1 (IL-12Rß1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon γ production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12Rß1 deficiency. RESULTS: Most (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin. CONCLUSIONS: Patients who are deficient in IL-12Rß1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.


Assuntos
Candidíase/imunologia , Candidíase/patologia , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Recidiva
6.
Diagn Microbiol Infect Dis ; 74(4): 432-4, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23017258

RESUMO

Among 3967 Staphylococcus aureus recovered from a Gran Canaria hospital (2003-2010), 28 strains were Panton-Valentine leukocidin-positive community-associated methicillin-resistant Staphylococcus aureus and were included in this study. Most isolates (89.3%) caused skin and skin-structure infections. Isolates belonging to clonal complex (CC)8 (ST8 and ST931; USA300) prevailed (82.1%). Among these, 5 (21.7%) were resistant to at least 3 antimicrobial classes.


Assuntos
Infecções Comunitárias Adquiridas/epidemiologia , Farmacorresistência Bacteriana , Staphylococcus aureus Resistente à Meticilina/classificação , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/epidemiologia , Adolescente , Adulto , Idoso , Toxinas Bacterianas/genética , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/microbiologia , Exotoxinas/genética , Feminino , Humanos , Lactente , Leucocidinas/genética , Masculino , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Pessoa de Meia-Idade , Epidemiologia Molecular , Tipagem Molecular , Espanha/epidemiologia , Infecções Estafilocócicas/microbiologia , Adulto Jovem
7.
Hum Mol Genet ; 20(8): 1509-23, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21266457

RESUMO

We report a series of 14 patients from 11 kindreds with recessive partial (RP)-interferon (IFN)-γR1 deficiency. The I87T mutation was found in nine homozygous patients from Chile, Portugal and Poland, and the V63G mutation was found in five homozygous patients from the Canary Islands. Founder effects accounted for the recurrence of both mutations. The most recent common ancestors of the patients with the I87T and V63G mutations probably lived 1600 (875-2950) and 500 (200-1275) years ago, respectively. The two alleles confer phenotypes that are similar but differ in terms of IFN-γR1 levels and residual response to IFN-γ. The patients suffered from bacillus Calmette-Guérin-osis (n= 6), environmental mycobacteriosis (n= 6) or tuberculosis (n= 1). One patient did not suffer from mycobacterial infections but had disseminated salmonellosis, which was also present in two other patients. Age at onset of the first environmental mycobacterial disease differed widely between patients, with a mean value of 11.25 ± 9.13 years. Thirteen patients survived until the age of 14.82 ± 11.2 years, and one patient died at the age of 7 years, 9 days after the diagnosis of long-term Mycobacterium avium infection and the initiation of antimycobacterial treatment. Up to 10 patients are currently free of infection with no prophylaxis. The clinical heterogeneity of the 14 patients was not clearly related to either IFNGR1 genotype or the resulting cellular phenotype. RP-IFN-γR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases.


Assuntos
Predisposição Genética para Doença , Infecções por Mycobacterium/genética , Receptores de Interferon/deficiência , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Feminino , Efeito Fundador , Genes Recessivos , Haplótipos , Humanos , Interferon gama/metabolismo , Masculino , Dados de Sequência Molecular , Monócitos/metabolismo , Mutação de Sentido Incorreto , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia , Mycobacterium avium , Mycobacterium bovis , Osteomielite/genética , Osteomielite/microbiologia , Linhagem , Fenótipo , Fosforilação , Pneumonia Bacteriana/genética , Transporte Proteico , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Fator de Transcrição STAT1/metabolismo , Salmonella , Infecções por Salmonella/genética , Tuberculose/genética , Tuberculose/microbiologia , Tuberculose/mortalidade , Adulto Jovem
8.
Medicine (Baltimore) ; 89(6): 403-25, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21057262

RESUMO

Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/deficiência , Fator 88 de Diferenciação Mieloide/deficiência , Adolescente , Antibacterianos/uso terapêutico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/prevenção & controle , Criança , Pré-Escolar , Suscetibilidade a Doenças , Feminino , Humanos , Imunidade , Lactente , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , Mutação , Fator 88 de Diferenciação Mieloide/genética , Receptores de Interleucina-1/metabolismo , Receptores Toll-Like/metabolismo
9.
J Med Genet ; 47(9): 635-7, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20798129

RESUMO

Genetic defects in the IL-12-IL-23/IFN-gamma circuit confer Mendelian susceptibility to mycobacteria and salmonella. The IL-12/IFN-gamma axis is essential for anti-tumoral immunity in mice. Cancer susceptibility has not been recognised in these patients so far. We report three relatives with IL-12R beta 1 deficiency. At the age of 25 years old, one patient presented with oesophageal squamous cell carcinoma (OSCC). The patient had no previous risk factors for OSCC. He died at the age of 29 years. OSCC is exceedingly rare in individuals under 30 years and frequently relates to alcohol intake and smoking. Disorders of the IL-12-IL-23/IFN-gamma axis may predispose to cancer.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Receptores de Interleucina-12/deficiência , Adolescente , Adulto , Carcinoma de Células Escamosas/patologia , Criança , Neoplasias Esofágicas/patologia , Evolução Fatal , Feminino , Humanos , Masculino , Receptores de Interleucina-12/metabolismo , Adulto Jovem
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