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3.
BMC Med Genet ; 21(1): 131, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32552675

RESUMO

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare immunodeficiency disease for which recurrent severe infection is the major clinical symptom. BTK is the main causative gene, with X chromosome recessive inheritance. However, the mutations reported to date do not fully explain the disorder. METHODS: We detected the percentage of CD19+ B cells and serum immunoglobulin (IgG, IgA, and IgM) levels by flow cytometry and rate scatter immunoturbidimetry, and investigated the BTK mutation profile in 22 XLA patients using Sanger sequencing and real-time PCR . RESULTS: We evaluated the clinical symptoms of 22 XLA patients and investigated genetic mutations present, identifying six novel mutations in the BTK gene: 2 missense mutations (c.23G > T and c.112 T > C), 2 frameshift mutations (c.522_523insC and c.1060delA), 1 large deletion (deletion of exon 2 to 5), and 1 splice-site mutation (c.1631 + 2 T > C). Prenatal diagnoses were performed in six families (F10, F11, F15, F18, F20 and F21), with the following results: the male fetus in Family 10 (F10) did not carry the c.922_923delGA mutation; the male fetus in Family 15 (F15) did not carry the c.1631 + 1G > T splicing mutation; the female fetus in Family 20 (F20) did not carry the c.1931 T > C mutation; the female fetus in Family 21 (F21) did not carry the large deletion mutation. Hence, these four fetuses are not likely to develop XLA. Male fetuses with c.1060delA and c.1684C > T mutations were identified in Family 11 and Family 18, respectively. The pregnant woman in F18 chose to terminate the pregnancy, whereas the pregnant woman in F11 chose to continue the pregnancy. CONCLUSION: We confirmed the diagnosis of 22 XLA patients from 22 unrelated families and detected six new pathogenic mutations. Prenatal diagnosis was performed in six families. Early genetic diagnosis and routine lifelong immunoglobulin replacement therapy can prevent and treat infections in XLA children, saving their lives.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/enzimologia , Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação/genética , Diagnóstico Pré-Natal , Agamaglobulinemia/diagnóstico , Sequência de Bases , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Análise Mutacional de DNA , Família , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem
4.
Pediatr Allergy Immunol ; 31 Suppl 24: 11-12, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32017208

RESUMO

Primary B-cell immunodeficiency is the most frequent immune defect in infancy. Selective absence of serum and secretory immunoglobulin IgA is the most common, with rates ranging from 1/333 persons to 1/16 000, among different races. By contrast, it has been estimated that hypo/agammaglobulinemia occurs with a frequency of 1/50 000 persons. Patients with antibody deficiency are usually recognized because they have recurrent infections with encapsulated bacteria or a history of failure to respond adequately to antibiotic treatment. However, some individuals, mainly those affected by IgA deficiency (SIgAD) or transient hypogammaglobulinemia of infancy , may have few or no infections.


Assuntos
Agamaglobulinemia/diagnóstico , Linfócitos B/imunologia , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/diagnóstico , Deficiência de IgA/diagnóstico , Imunoglobulina A/genética , Infecções/diagnóstico , Agamaglobulinemia/genética , Ligante de CD40/genética , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/genética , Deficiência de IgA/genética , Lactente , Recém-Nascido , Infecções/genética , Ativação Linfocitária , Recidiva
6.
Scand J Immunol ; 91(1): e12811, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31378960

RESUMO

Hypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B-cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa-deleting-recombination-excision circles (KRECs) reliably identifies classical X-linked agammaglobulinaemia (XLA) patients with profound B-cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. One patient had an invasive pneumococcal infection at the age of 4 years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B-cell lymphopenia with residual B-cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of 8, 6 and 3 years, respectively. BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshold set for detection of patients with profound B-cell lymphopenia. Male patients with impaired polysaccharide responsiveness should be evaluated for B-cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/etiologia , Mutação , Fenótipo , Polissacarídeos/imunologia , Biomarcadores , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Seguimentos , Genótipo , Humanos , Imunofenotipagem , Recém-Nascido , Masculino , Triagem Neonatal , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/etiologia , Avaliação de Sintomas
7.
Curr Opin Hematol ; 27(1): 11-17, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31652152

RESUMO

PURPOSE OF REVIEW: WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis, or WHIMs) is a very rare autosomal dominant immunodeficiency disorder attributable to mutations in CXCR4. We reviewed clinical manifestations in 24 patients in 9 families to expand understanding of this syndrome. RECENT FINDINGS: Warts, cellulitis and respiratory infections are common in patients with WHIMs. Less commonly these patients have congenital heart disease, human papilloma virus-associated malignancies (cervical and vulvular) and lymphomas. Hearing loss because of recurrent otitis media is another important complication. Treatment with granulocyte colony-stimulating factor is controversial; this review indicates that it is effective to prevent and treat infections based upon long-term observations of patients enrolled in the Severe Chronic Neutropenia International Registry. Understanding the natural history and diversity of this syndrome are important for ongoing clinical trials of novel agents to treat WHIMs. SUMMARY: WHIM syndrome has diverse manifestations; some features occur consistently in almost all patients, for example, neutropenia, lymphocytopenia and mild hypogammaglobulinemia. However, the clinical consequences are quite variable across patient cohorts and within families. Each complication is important as a cause for morbidity and a source for patient and family concerns.


Assuntos
Agamaglobulinemia , Família , Mutação , Doenças da Imunodeficiência Primária , Receptores CXCR4/genética , Sistema de Registros , Verrugas , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Agamaglobulinemia/patologia , Agamaglobulinemia/terapia , Feminino , Humanos , Masculino , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/patologia , Doenças da Imunodeficiência Primária/terapia , Fatores de Risco , Verrugas/diagnóstico , Verrugas/genética , Verrugas/patologia , Verrugas/terapia
8.
BMC Neurol ; 19(1): 320, 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830942

RESUMO

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a rare inherited primary immunodeficiency disease characterized by the B cell developmental defect, caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK), which may cause serious recurrent infections. The diagnosis of XLA is sometimes challenging because a few number of patients have higher levels of serum immunoglobulins than expected. In this study, we reported an atypical case with recurrent meningitis, delayed diagnosis with XLA by genetic analysis at the second episode of meningitis at the age of 8 years. CASE REPORT: An 8-year-old Chinese boy presented with fever, dizziness and recurrent vomiting for 3 days. The cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) results were suggestive of bacterial meningoencephalitis, despite the negative gram staining and cultures of the CSF. The patient was treated with broad-spectrum antibiotics and responded well to the treatment. He had history of another episode of acute pneumococci meningitis 4 years before. The respective level of Immunoglobulin G (IgG), Immunoglobulin A (IgA) and Immunoglobulin M (IgM) was 4.85 g/L, 0.93 g/L and 0.1 g/L at 1st episode, whereas 1.9 g/L, 0.27 g/L and 0 g/L at second episode. The B lymphocytes were 0.21 and 0.06% of peripheral blood lymphocytes at first and second episode respectively. Sequencing of the BTK coding regions showed that the patient had a point mutation in the intron 14, hemizyous c.1349 + 5G > A, while his mother had a heterozygous mutation. It was a splice site mutation predicted to lead to exon skipping and cause a truncated BTK protein. CONCLUSION: Immunity function should be routinely checked in patients with severe intracranial bacterial infection. Absence of B cells even with normal level of serum immunoglobulin suggests the possibility of XLA, although this happens only in rare instances. Mutational analysis of BTK gene is crucial for accurate diagnosis to atypical patients with XLA.


Assuntos
Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Encefalite Infecciosa/genética , Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Criança , Análise Mutacional de DNA , Diagnóstico Tardio , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , Mutação
9.
J Med Case Rep ; 13(1): 338, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31744540

RESUMO

BACKGROUND: Myotonic dystrophy type 1 is an autosomal dominant disorder characterized by muscle weakness, myotonia, cataracts, and cardiac conduction defects; it is associated with expansions of cytosine-thymine-guanine repeats in the myotonic dystrophy protein kinase. Hypogammaglobulinemia is a lesser known association of myotonic dystrophy type 1 and the underlying pathogenesis of immunoglobulin G depletion remains unclear. CASE PRESENTATION: Here we report a kindred of two members (a 62-year-old white woman and a 30-year-old white man; mother and son) with myotonic dystrophy type 1-associated hypogammaglobulinemia associated with altered intravenous immunoglobulin elimination kinetics and reduced half-life. There was no history of systemic immunosuppression or renal or gastrointestinal protein loss in either patient, and no underlying case for a secondary immunodeficiency could be found. One patient required fortnightly intravenous immunoglobulin to maintain adequate trough immunoglobulin G levels. CONCLUSIONS: Ongoing study of myotonic dystrophy type 1-associated hypogammaglobulinemia using contemporary tools of genomic medicine may help to further delineate the pathogenesis of this entity.


Assuntos
Agamaglobulinemia/diagnóstico , Imunoglobulina G/sangue , Imunoglobulinas Intravenosas/uso terapêutico , Mães , Distrofia Miotônica/diagnóstico , Núcleo Familiar , Adulto , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Feminino , Predisposição Genética para Doença , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/imunologia , Distrofia Miotônica/terapia
11.
Braz J Med Biol Res ; 52(10): e8926, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618370

RESUMO

Humoral immunological defects are frequent and important causes of hypogammaglobulinemia, leading to recurrent infections, autoimmunity, allergies, and neoplasias. Usually, its onset occurs in childhood or during the second and third decades of life; however, the diagnosis is made, on average, 6 to 7 years afterwards. As a consequence, antibody defects can lead to sequelae. Here we describe the clinical-laboratory characteristics, treatment, and prognoses of patients with hypogammaglobulinemia. An observational, cross-sectional, and retrospective study of patients attending the recently established outpatient group of Clinical Immunology between 2013 and 2018 was carried out. Patients with IgG levels below 2 standard deviations from the mean values for the age and/or impaired antibody response were included. Eight patients (3 F and 5 M; median age=41 years (16-65), average symptom onset at 25 years (1-59), and time to diagnosis of 10 years were included. The main infections were: sinusitis in 7/8, pneumonia in 6/8, otitis in 2/8, tonsillitis and diarrhea in 2/8, and diarrhea in 2/8 patients. Hypothyroidism was identified in 4/8 (50%) patients. Rhinitis was found in 7/8 (87.5%) and asthma in 3/8 (37.5%) patients. The tomographic findings were consolidations, atelectasis, emphysema, ground glass opacity, budding tree, bronchial thickening, and bronchiectasis. Immunoglobulin reposition was used between 466 and 600 mg/kg monthly (514.3 mg·kg-1·dose-1). Prophylactic antibiotic therapy was included in 7/8 (87.5%) patients. Airway manifestations prevailed in patients with hypogammaglobulinemia. There is a need for educational work to reduce the time of diagnosis and initiation of treatment, avoiding sequelae.


Assuntos
Agamaglobulinemia/diagnóstico , Imunoglobulinas Intravenosas/administração & dosagem , Adolescente , Adulto , Agamaglobulinemia/tratamento farmacológico , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Adulto Jovem
12.
Pan Afr Med J ; 32: 161, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31303930

RESUMO

Serum protein electrophoresis (SPE) is a routine analysis in the daily practice of a medical biology laboratory. This study aimed to analyze the different electrophoretic profiles seen in our current practice. We conducted a cross-sectional study of 410 serum samples collected during the routine analyses in the Laboratory of Biochemistry at the University Hospital Mohammed VI in Oujda. Serum protein electrophoresis was performed using automated instrument CAPILLARYS 2 FLEX-PIERCING, SEBIA. 241 sera from women and 169 sera from men were collected. Patients were aged between 1-91 years, with an average age of 49 years; 19.5% of SPEs were normal, hypoalbuminemia was found in 34% of cases, chronic inflammatory syndrome in 19.5% of cases, nephrotic syndrome in 2% of cases, 5.8% of our patients had betagamma block, hypogammaglobulinemia was found in 8.5% of cases and 29 monoclonal peaks were noted, bisalbuminemia was found in 2 patients. Out of 410 collections: 92 immunofixations were performed, of whom 23 were positive (showing monoclonal gammopathy). This study highlights the variability in prescribing serum protein electrophoresis as well as the importance of clinical data for a better interpretation.


Assuntos
Eletroforese das Proteínas Sanguíneas/métodos , Hipoalbuminemia/diagnóstico , Inflamação/diagnóstico , Paraproteinemias/diagnóstico , Adolescente , Adulto , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos Transversais , Feminino , Hospitais Universitários , Humanos , Hipoalbuminemia/epidemiologia , Lactente , Inflamação/epidemiologia , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/epidemiologia , Paraproteinemias/epidemiologia , Adulto Jovem
13.
Rheumatol Int ; 39(10): 1829-1838, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31312887

RESUMO

Kawasaki disease (KD) has features that appear supporting an infectious cause with a secondary deranged inflammatory/autoimmune response. The association of KD in adults with human immunodeficiency virus infection and the presence of KD in patients with immunodeficiency disorders support the infectious theory. We present four KD patients associated with immunodeficiencies: one with X-linked agammaglobulinemia, one with HIV infection, and two with leukemia; one of these patients also had Down syndrome. We did a literature search to find out all reported cases of immunodeficiency with KD in children. In immunodeficiency disorders, the inability of the immune system to eradicate the pathogens coupled to an exaggerated inflammatory response, especially in chronic granulomatous disease, may lead to the development of KD. The study of patients with immunodeficiencies complicated with KD may shed light into the etiopathogenesis of the disease.


Assuntos
Agamaglobulinemia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Infecções por HIV/imunologia , Hospedeiro Imunocomprometido , Leucemia/imunologia , Síndrome de Linfonodos Mucocutâneos/imunologia , Corticosteroides/uso terapêutico , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Síndrome de Down/complicações , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Leucemia/complicações , Leucemia/diagnóstico , Leucemia/tratamento farmacológico , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Fatores de Risco , Resultado do Tratamento
14.
Immunol Lett ; 210: 55-62, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31059734

RESUMO

Common Variable Immunodeficiency (CVID) and agammaglobulinemia are two of the main types of symptomatic primary antibody deficiencies. The pathogenic origins of these two diseases are different; agammaglobulinemia is a group of inherited disorders that usually are caused by mutations in the gene encoding Bruton Tyrosine Kinase (BTK) protein while CVID is a heterogeneous disorder mainly without monogenic cause. However, both diseases share a characteristic of frequent bacterial infections, a decline in serum immunoglobulin levels, and abnormality in antibody responses. The demographics and immunologic parameters, clinical manifestation, and mortality statistics from 297 patients with CVID and agammaglobulinemia followed up over 2 decades in the Children's Medical Center of Iran. Age at onset of symptom in agammaglobulinemia was earlier than CVID but the course of disease in CVID patients was longer than agammaglobulinemia patients. Pulmonary infections were the most prevalent clinical manifestations in both groups of patients. Lymphadenopathy, hepatomegaly, and splenomegaly were significantly higher in CVID patients than agammaglobulinemia patients and there was a significant association between these complications and mortality in CVID patients. Among 297 patients, 128 patients (88 CVID and 40 agammaglobulinemia) deceased. The predominant causes of death in CVID patients were infections, chronic lung disease, and malignancy while in agammaglobulinemia patients were infections and respiratory failure. Infections, especially respiratory infections were the most common complication and cause of death in both CVID and agammaglobulinemia groups and recent treatment advances even Immunoglobulin replacement cannot completely control these complications. Thus prompt recognition and specific management of these complications are worthwhile.


Assuntos
Agamaglobulinemia/diagnóstico , Agamaglobulinemia/imunologia , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Adolescente , Adulto , Agamaglobulinemia/mortalidade , Biomarcadores , Criança , Imunodeficiência de Variável Comum/mortalidade , Comorbidade , Suscetibilidade a Doenças , Feminino , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Fenótipo , Prognóstico , Avaliação de Sintomas , Adulto Jovem
15.
Indian Pediatr ; 56(5): 423-425, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31102385

RESUMO

BACKGROUND: X-linked agammaglobulinemia, a primary immunodeficiency, can present with musculoskeletal manifestations. CASE CHARACTERISTICS: A 4-year-old boy, diagnosed as systemic juvenile idiopathic arthritis at the age of 3 years and treated with biological agents, presented with fever, dyspnea and chest pain. Blood culture and pericardial fluid culture revealed Achromobacter xylosoxidans. OUTCOME: Investigation revealed normal serum ferritin but low levels of serum immunoglobulins. Further immunological work-up revealed diagnosis of X-linked agammaglobulinemia. Child improved on antibiotic therapy; treatment with steroids and biological was discontinued. MESSAGE: Underlying immunodeficiency disease must be looked for in children suspected to have juvenile arthritis, more so if they develop unusual serious infection in response to immunomodulatory therapy.


Assuntos
Achromobacter denitrificans/isolamento & purificação , Agamaglobulinemia/diagnóstico , Artrite Juvenil/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Infecções por Bactérias Gram-Negativas/etiologia , Sepse/etiologia , Agamaglobulinemia/complicações , Pré-Escolar , Diagnóstico Diferencial , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Infecções por Bactérias Gram-Negativas/diagnóstico , Humanos , Masculino , Sepse/diagnóstico
16.
Int J Immunopathol Pharmacol ; 33: 2058738419843364, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30968707

RESUMO

Humoral immunodeficiency with accompanying infections is an indication for human immunoglobulin replacement therapy. Whether treatment will be lifelong or necessary only temporarily depends on the nature of deficiency: primary (persistent) or secondary (persistent or transient). It is not always easy to distinguish between primary and secondary immunodeficiency, especially in adults. The article presents a case of a 39-year-old patient with anamnesis and medical tests results that suggested primary humoral immunodeficiency. The deficiency was diagnosed for the first time at the age of 38, when the patient was pregnant. The patient was qualified for immunoglobulin G replacement therapy. Clinical improvement was achieved. After the end of pregnancy, systematic improvement in immunological parameters was observed, suggesting the resolution of immunodeficiency. A decision was made to discontinue immunoglobulin replacement. Due to the ability to respond to vaccine, confirmed during diagnosis, preventive vaccines were recommended. There was no recurrence of serious infections. The clinical course finally enabled a diagnosis of secondary immunodeficiency. The presented case shows the importance of an active approach to the diagnostic and therapeutic process, constant assessment of clinical course, monitoring of IgG concentrations, and the awareness that in the situation when we do not have a genetic confirmation of the disease, the diagnosis may change.


Assuntos
Agamaglobulinemia/tratamento farmacológico , Deficiência de IgG/tratamento farmacológico , Imunoglobulina G/administração & dosagem , Infecções/tratamento farmacológico , Adulto , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Esquema de Medicação , Feminino , Humanos , Deficiência de IgG/complicações , Deficiência de IgG/diagnóstico , Infecções/diagnóstico , Infecções/etiologia , Infusões Intravenosas/tendências , Recidiva
17.
Rheumatol Int ; 39(5): 911-919, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30783801

RESUMO

Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle-Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.


Assuntos
Testes Genéticos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Adolescente , Adulto , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Anemia Diseritropoética Congênita/diagnóstico , Anemia Diseritropoética Congênita/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Criança , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/diagnóstico , Síndromes Periódicas Associadas à Criopirina/genética , Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Feminino , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/genética , Pessoa de Meia-Idade , Proteínas de Transporte de Nucleosídeos/genética , Osteomielite/diagnóstico , Osteomielite/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Pirina/genética , Análise de Sequência de DNA , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Adulto Jovem
19.
Front Immunol ; 10: 33, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30800120

RESUMO

Antibody deficiency or hypogammaglobulinemia can have primary or secondary etiologies. Primary antibody deficiency (PAD) is the result of intrinsic genetic defects, whereas secondary antibody deficiency may arise as a consequence of underlying conditions or medication use. On a global level, malnutrition, HIV, and malaria are major causes of secondary immunodeficiency. In this review we consider secondary antibody deficiency, for which common causes include hematological malignancies, such as chronic lymphocytic leukemia or multiple myeloma, and their treatment, protein-losing states, and side effects of a number of immunosuppressive agents and procedures involved in solid organ transplantation. Secondary antibody deficiency is not only much more common than PAD, but is also being increasingly recognized with the wider and more prolonged use of a growing list of agents targeting B cells. SAD may thus present to a broad range of specialties and is associated with an increased risk of infection. Early diagnosis and intervention is key to avoiding morbidity and mortality. Optimizing treatment requires careful clinical and laboratory assessment and may involve close monitoring of risk parameters, vaccination, antibiotic strategies, and in some patients, immunoglobulin replacement therapy (IgRT). This review discusses the rapidly evolving list of underlying causes of secondary antibody deficiency, specifically focusing on therapies targeting B cells, alongside recent advances in screening, biomarkers of risk for the development of secondary antibody deficiency, diagnosis, monitoring, and management.


Assuntos
Agamaglobulinemia/diagnóstico , Agamaglobulinemia/etiologia , Agamaglobulinemia/terapia , Agamaglobulinemia/prevenção & controle , Gerenciamento Clínico , Suscetibilidade a Doenças , Medicina Baseada em Evidências , Humanos , Guias de Prática Clínica como Assunto
20.
Immunol Allergy Clin North Am ; 39(1): 95-111, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30466775

RESUMO

Immunoglobulin replacement therapy is the cornerstone of management for most primary immunodeficiency disease patients. The selection of a particular product, dose, and route of administration requires an understanding of the features of therapeutic immunoglobulin as well as patient-specific risk factors in order to maximize efficacy and tolerability and minimize risk. Individualizing therapy, taking into consideration the burdens of care, is necessary in order to optimize patient outcomes.


Assuntos
Agamaglobulinemia/terapia , Medicina de Precisão , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/etiologia , Animais , Tomada de Decisão Clínica , Efeitos Psicossociais da Doença , Gerenciamento Clínico , Vias de Administração de Medicamentos , Acesso aos Serviços de Saúde , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/farmacocinética , Imunoglobulinas Intravenosas/uso terapêutico , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Resultado do Tratamento
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