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1.
Artigo em Inglês | MEDLINE | ID: mdl-31238161

RESUMO

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.

3.
Pediatr Hematol Oncol ; : 1-5, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30346863

RESUMO

INTRODUCTION: Severe congenital neutropenia (SCN) includes a group of genetic disorders which cause to arrest of neutrophil maturation. SCN can be associated with heterogenous group of genetic defects in ELANE, GFI1, HAX1, G6PC3, JAGN1, VPS45 or activating mutations in the Wiskott-Aldrich syndrome (WAS) gene. AIM: Here we report a patient who has a HAX1 mutation presented with cyclic manner. CASE REPORT: A 6 year old female patients was admitted with recurrent apthous stomatitis. We followed the patient as cyclic neutropenia according to complete blood count results 2 times for 6 weeks. After persistant neutropenia developed during a severe varicella infection, we analysed HAX1 mutation, the result was interesting and incompatible with reported cyclic neutropenia patients. CONCLUSION: We suggest that HAX1 deficiency should be thought in patients who have normal neutrophil counts in the between of infections.

4.
J Clin Immunol ; 38(3): 273-277, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29564582

RESUMO

PURPOSE: Adenosine deaminase 2 (ADA2) have been reported to cause vasculitic diseases and immunodeficiency recently. Patients present with stroke episodes and rashes mimicking polyarteritis nodosa (PAN). We report a patient who has been followed up with severe neutropenia and found an unexpectedly revealed novel mutation in CECR1 affecting ADA2. METHODS: We reviewed medical records and clinical history of the patient. No mutations in other known neutropenia genes such as ELA, G6PC3, HAX1, AP3B1, LAMTOR2, VPS13B, VPS45, GFI1, JAGN1, or WAS could be detected. Sanger sequencing was used to confirm the genetic variants in the patient and relatives. RESULTS: Genetic analysis by exome sequencing revealed a novel mutation in the gene CECR1 (c.G962A; p.G321E) which segregated perfectly in the relatives. CONCLUSION: This is the first DADA2 patient presenting with severe neutropenia. We suggest that in patients with unexplained cytopenias combined with immunodeficiency, fevers of unknown origin and high inflammation markers, DADA2 should be considered.

5.
Blood ; 130(10): 1205-1208, 2017 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-28743717

RESUMO

Mutations in T-cell antigen receptor (TCR) subunit genes cause rare immunodeficiency diseases characterized by impaired expression of the TCR at the cell surface and selective T lymphopenia. Here, detailed analyses of spontaneously arising somatic mutations that recover CD247, and thus TCR expression, in a newly identified CD247-deficient patient are described. The recovery of CD247 expression in some patient T cells was associated with both reversion of the inactivating mutation and a variant with a compensating mutation that could reconstitute TCR expression, but not as efficiently as wild-type CD247. Multiple mutations were found in CD247 complementary DNAs (cDNAs) cloned from the patient as well as in cDNA and genomic DNA from other individuals, suggesting that genetic variation in this gene is frequent. Analyses of other genes mutated in primary immunodeficiency diseases (PIDs) where reversions have been described also revealed a higher rate of mutation than that observed for genes mutated in PIDs where revertants have not been identified or control genes. These data support the hypothesis that the occurrence of somatic mutations that may reconstitute genetic defects in PID is related to an increased propensity of those genes to mutate.


Assuntos
Complexo CD3/genética , Reparo do DNA/genética , Regulação da Expressão Gênica , Síndromes de Imunodeficiência/genética , Humanos , Leucócitos Mononucleares/metabolismo , Mutação/genética , Probabilidade
7.
Case Rep Pediatr ; 2016: 8712962, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27429821

RESUMO

Cardiac rhabdomyoma often shows spontaneous regression and usually requires only close follow-up. However, patients with symptomatic inoperable rhabdomyomas may be candidates for everolimus treatment. Our patient had multiple inoperable cardiac rhabdomyomas causing serious left ventricle outflow-tract obstruction that showed a dramatic reduction in the size after everolimus therapy, a mammalian target of rapamycin (mTOR) inhibitor. After discontinuation of therapy, an increase in the diameter of masses occurred and everolimus was restarted. After 6 months of treatment, rhabdomyomas decreased in size and therapy was stopped. In conclusion, everolimus could be a possible novel therapy for neonates with clinically significant rhabdomyomas.

8.
Biomed Res Int ; 2016: 6896279, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27298827

RESUMO

Background. Tuberculosis (TB) still remains a growing public health problem globally. TB in children is often diagnosed clinically. Methods. We conducted a retrospective chart review of children with TB from November 2004 through December 2010 to determine the appropriateness of using contact history and diagnostic testing. Results. A total of 250 children with TB were identified. One hundred and sixty-two children had only pulmonary disease while 39 had features of both extrapulmonary and pulmonary TB. Mean age was 7.8 years. Thirty-six patients had known contacts. The index case/cases were first-degree relatives in 75%. Sixteen patients who were symptomless were yielded by contact investigation of newly identified TB cases. Tuberculin skin test positivity was 53.3%. Acid-fast bacilli smear positivity was 13.1%, and culture positivity was 18.7%. Twenty-six patients had histopathology of nonrespiratory specimens (lymph nodes and other tissues) showing granulomatous inflammation and caseous necrosis consistent with TB. Conclusions. Presence of contact history directed us to search for TB in children with nonspecific symptoms even if physical examinations were normal. Some children who were close contacts to TB cases were identified to have TB before development of symptoms.


Assuntos
Busca de Comunicante/métodos , Hospitais Urbanos/estatística & dados numéricos , Vigilância da População/métodos , Centros de Cuidados de Saúde Secundários/estatística & dados numéricos , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Criança , Saúde da Criança/estatística & dados numéricos , Pré-Escolar , Feminino , Humanos , Masculino , Prevalência , Fatores de Risco , Turquia/epidemiologia
9.
Asian Pac J Allergy Immunol ; 34(1): 73-6, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26994629

RESUMO

BACKGROUND: Mutations in the HAX-1 gene cause an autosomal recessive form of severe congenital neutropenia (SCN), which particularly manifests with recurrent skin, lung and deep tissue infections from the first few months of life. OBJECTIVE: We retrospectively evaluated the clinical and laboratory findings of the patients diagnosed with SCN carrying HAX1 gene mutations. METHODS: A total of five patients with SCN, carrying a HAX1 gene mutation, were evaluated in terms of clinical and laboratory findings. Mutation analysis of the candidate genes (HAX1, ELANE and CSF3R) was performed. RESULTS: All of the patients lived in Turkey; four of them were of Kurdish origin and one was Turkish. Of the five patients, three were girls and two were boys, and the mean age of the patients was 8.8 years old (range 4-15 years). The mean age of diagnosis was 25.8 months (range 2 months-5 years). The infections diagnosed included recurrent gingivitis, stomatitis, and skin and soft tissue abscesses. Developmental retardation and epilepsy were present in only one patient, whereas speech retardation was present in two. All of our patients had a HAX1 mutation, and are still alive and none of them has shown malignant transformation yet. CONCLUSION: Complete blood count should be performed and absolute neutrophil count should be evaluated in patients with recurrent severe infections. In the event that neutropenia is detected, they should be investigated in terms of SCN and mutation analysis should be performed.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação , Neutropenia/congênito , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Adolescente , Criança , Pré-Escolar , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Masculino , Neutropenia/genética , Estudos Retrospectivos
10.
Turk J Pediatr ; 58(5): 545-549, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28621099

RESUMO

Pediatric sarcoidosis comprises a spectrum of childhood granulomatous inflammatory conditions. Pathological hallmark of the disease is granuloma formation that is seen in the affected tissues and almost any organ or system can be involved. There are two forms of pediatric sarcoidosis. One is seen in older children and the clinical picture is very similar to that of adult sarcoidosis and the other one is seen in early childhood. Sarcoidosis in early childhood can be divided as Blau syndrome (familial form) and early onset sarcoidosis (sporadic form). In both of the diseases there is a defect in the NOD2/CARD15 gene. The typical triad of early onset sarcoidosis is polyarthritis, dermatitis and uveitis. Interferon-γ receptor 1 deficiency is caused by defects in the IFNγR1 gene and non-tuberculosis mycobacterial pathogens are the leading causes of infections that start in early childhood. Herein we report a patient who presented with the symptoms of early onset sarcoidosis and also had partial interferon-γ receptor 1 deficiency that presented with BCG-osis. In addition to anti-mycobacterial treatment, methotrexate and prednisolone were used in therapy.


Assuntos
Artrite/genética , Receptores de Interferon/deficiência , Sarcoidose/genética , Sinovite/genética , Uveíte/genética , Artrite/complicações , Vacina BCG/efeitos adversos , Humanos , Lactente , Interferon gama , Masculino , Sarcoidose/complicações , Sinovite/complicações , Tomografia Computadorizada por Raios X , Uveíte/complicações
13.
Immunol Rev ; 264(1): 103-20, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25703555

RESUMO

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.


Assuntos
Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Hospedeiro Imunocomprometido , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/etiologia , Mycobacterium tuberculosis/imunologia , Tuberculose/etiologia , Fatores Etários , Criança , Genes Dominantes , Genes Recessivos , Humanos , Síndromes de Imunodeficiência/diagnóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
14.
Turk J Pediatr ; 57(5): 518-21, 2015 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27411422

RESUMO

Systemic onset juvenile idiopathic arthritis (SoJIA) is characterized by arthritis, fever and visceral organ involvement including hepatosplenomegaly, lympadenopathy and serositis. This is a case of SoJIA misdiagnosed as Kawasaki disease (KD) and developed machrophage activation syndrome (MAS) secondary to Ebstein-Barr virus (EBV) infection. It is presented to point out the conditions that may come along. First of all, SoJIA should be kept in mind while making the differential diagnosis of coronary arterial ectasias and dilatations usually seen in vasculitic diseases like KD. Second, as a very fatal complication MAS should always be considered while following a patient with the diagnosis of SoJIA. Infections like EBV may be the potential triggers for development of MAS especially in immunesupressed patients.


Assuntos
Artrite Juvenil/diagnóstico , Doença da Artéria Coronariana/complicações , Infecções por Vírus Epstein-Barr/complicações , Síndrome de Ativação Macrofágica/complicações , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Artrite Juvenil/complicações , Pré-Escolar , Vasos Coronários/patologia , Diagnóstico Diferencial , Erros de Diagnóstico , Dilatação Patológica , Humanos , Masculino
15.
Case Rep Pediatr ; 2014: 296479, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24800095

RESUMO

Familial Mediterranean Fever is an autosomal recessive disease. Major symptoms of disease are recurrent fever accompanied by serositis attacks. The disease is usually diagnosed before 20 years of age. Symptoms related to FMF are noted when children become more verbal, usually after 2 years of age. In this case report, the youngest patient with the diagnosis of FMF is presented. She was consulted to pediatric rheumatology for the high acute phase response and fever. It was learned that her mother had recurrent swelling of her ankle joints. Mutation analysis was performed and two homozygous mutations (M694V and R202Q) were identified. She was diagnosed as FMF at 3 months of age and colchicine was started. She responded to colchicine. Her uncontrolled acute phase response declined gradually. This case was reported to point out the importance of early remembrance of autoinflammatory diseases even at very early ages especially at endemic countries.

16.
Case Rep Pediatr ; 2014: 614238, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24511403

RESUMO

Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomologous end joining pathways of DNA repair mechanisms have been identified as responsible for radiosensitive SCID. Here, we present a 3-year-old girl patient with severe growth retardation, bird-like face, recurrent perianal abscess, pancytopenia, and polydactyly. Firstly, she was thought as Fanconi anemia and spontaneous DNA breaks were seen on chromosomal analysis. After that DEB test was found to be normal and Fanconi anemia was excluded. Because of that she had low IgG and IgA levels, normal IgM level, and absence of B cells in peripheral blood; she was considered as primary immunodeficiency, Nijmegen breakage syndrome. A mutation in NBS1 gene was not found; then Cernunnos/XLF deficiency was investigated due to clinical similarities with previously reported cases. Homozygous mutation in Cernunnos/XLF gene (NHEJ1) was identified. She is now on regular IVIG prophylaxis and has no new infection. Fully matched donor screening is in progress for bone marrow transplantation which is curative treatment of the disease. In conclusion, the patients with microcephaly, bird-like face, and severe growth retardation should be evaluated for hypogammaglobulinemia and primary immunodeficiency diseases.

17.
Int J Pediatr Otorhinolaryngol ; 77(10): 1655-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23958393

RESUMO

OBJECTIVE: It is well-known that number of drugs may interfere with wheal reactions in skin prick test. However, the effect of long-term use of montelukast, a cystenil leukotriene receptor antagonist, on skin prick test hasn't been full elucidated. The aim of present study was to demonstrate the effect of montelukast on skin prick tests (SPT). METHODS: This is a single-center, randomized, double-blinded, placebo-controlled study including two treatment periods with a wash-out interval. The subjects received montelukast (5 mg per day), fexofenadine HCl (60 mg per day) and placebo (lactose) with a double-blinded manner during 7- and 21-days treatment periods with a 14 days wash-out period. Dermatophagoides farinae (D. farinae) was used as the skin test material, while histamine as positive control and normal saline as negative control. Overall, 7 skin prick tests were performed at following time points: before treatment periods, on the last days of both treatment periods, 24 h after completion of treatment periods, and on the last day of 14-days interval. RESULTS: Sixty house dust mite (HDM) allergic children (23 girls and 37 boys) with allergic rhinitis and/or asthma completed the study. Mean age was 8.3 ± 2.0 years. In the fexofenadine group, a significant suppression was observed in post-treatment values when compared to baseline values in SPT with D. farinae (p = 0.019). In the montelukast group, no significant suppression was observed in SPT with D. farinae at all time points when compared to baseline. CONCLUSIONS: Our results showed that montelukast had no effect on measurements of SPT. Thus, we concluded that there is no need to discontinue the treatment in order to perform SPT in patients receiving montelukast, even in those on montelukast treatment for at least 21 days.


Assuntos
Acetatos/administração & dosagem , Asma/imunologia , Quinolinas/administração & dosagem , Rinite Alérgica Perene/imunologia , Terfenadina/análogos & derivados , Urticária/imunologia , Alérgenos , Animais , Asma/tratamento farmacológico , Distribuição de Qui-Quadrado , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pyroglyphidae/imunologia , Valores de Referência , Rinite Alérgica , Rinite Alérgica Perene/tratamento farmacológico , Sensibilidade e Especificidade , Testes Cutâneos/métodos , Estatísticas não Paramétricas , Terfenadina/administração & dosagem , Urticária/prevenção & controle
18.
Value Health Reg Issues ; 2(2): 226-230, 2013 Sep - Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29702869

RESUMO

OBJECTIVE: To evaluate the direct medical cost of hospital admissions for patients with varicella (i.e., chickenpox) to assess the cost burden of varicella from a health care perspective for ultimate use in health economics studies in Turkey. METHODS: Records of children hospitalized with varicella at the Bakirkoy Maternity and Children's Hospital between November of 2006 and June of 2011 were reviewed. Reasons for hospitalization, types of varicella-associated complications, and direct medical cost of hospitalization were noted. Patients with underlying risk factors were excluded. Data obtained from one hospital were used to estimate the national cost of the disease. RESULTS: During the 4.5-year study period, 234 patients were hospitalized with varicella. Of these cases, 48 (20%) children previously ill with underlying cancers or chronic diseases were excluded from the study. Ultimately, 186 previously healthy children (age range: 14 days to 159 months, median age: 14 months) were included. The main reasons for hospitalization were complications related to varicella (79%), the most frequent of which was skin and soft tissue infections, followed by neurological complications and pneumonia. The median cost of hospitalization per patient was US $283, 50% of which was attributed to medication costs. The annual cost for varicella hospitalizations in Turkey was estimated at US $396,200. CONCLUSIONS: A significant number of healthy children are hospitalized for varicella and associated complications. Descriptions of these complications and their related costs provide important data for cost-effectiveness studies for decisions about the inclusion of the varicella vaccine in a childhood vaccination program.

20.
PLoS One ; 6(4): e18524, 2011 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-21533230

RESUMO

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rß1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rß1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rß1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rß1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rß1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity.


Assuntos
Subunidade beta 1 de Receptor de Interleucina-12/genética , Tuberculose/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Lactente , Irã (Geográfico) , Masculino , Marrocos , Linhagem , Índice de Gravidade de Doença , Turquia
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