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1.
Artigo em Inglês | MEDLINE | ID: mdl-33634762

RESUMO

BACKGROUND: Dedicator of Cytokinesis 8 (DOCK8) deficiency, the most frequent cause of autosomal recessive hyper immunoglobulin (Ig)E syndrome, is a rare combined immunodeficiency. OBJECTIVE: In this study, we report seven patients with consanguineous parents with five novel variants within the DOCK8 gene. METHODS: For genetic analysis, we performed Whole Exome Sequencing (WES), or targeted sequencing by means of Next-generation sequencing (NGS) for some of the patients. For others, Sanger sequencing, Fluorescence-activated cell sorting (FACS), or polymerase chain reaction (PCR) was used. RESULTS: We report five novel variants within the DOCK8 gene: three deletions (deletion of exons 4-12, 24-30, and 22-27), one frameshift (LRG_196:g.189315dup;p.(Leu1052Profs*7)), and a splice region variant (LRG_196t1:c.741+5G>T). Patients presented with skin lesions, food allergy, candidiasis, otitis, recurrent respiratory infections, short stature, aortic aneurism, gynecomastia, and coarse facial features. Patients had leukocytosis, eosinophilia, lymphopenia, and monocytosis, elevated IgE, IgG, IgA , reduced IgM and IgA levels. Patients had a low percentage of CD3+ and CD4+ cells, and a high percentage of CD19+, CD27+CD19+, and recent thymic emigrants T cells. The percentage of natural killer cells was increased in one of the patients while it was decreased in another patient. One patient died due to disseminated intravascular coagulation after hematopoietic stem cell transplantation. CONCLUSION: We reported novel variants within the DOCK8 gene and highlighted risk of aneurysms in these patients, which have been rarely reported in these patients.

2.
Allergol Immunopathol (Madr) ; 49(2): 80-83, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33641298

RESUMO

INTRODUCTION AND OBJECTIVES: X-linked agammaglobulinemia (XLA), the first known primary immunodeficiency, is caused by rare mutations in Bruton's tyrosine kinase (BTK) gene. Mutations in the BTK gene lead to a failure in the development and maturation of B-cell linage. A decreased number of B-cells results in agammaglobulinemia and increased susceptibility to a variety of infections. Therefore, patients with XLA usually manifest with repetitive bacterial infections, such as upper respiratory tract infections, septic arthritis, osteomyelitis, and urinary tract infections, since their infancy. PATIENTS: We report a 17-year-old Iranian boy with XLA, referred to us with a history of severe and recurrent episodes of bacterial infections for a period of six years. RESULTS: Genetic analysis using the whole Exome sequencing revealed a hemizygous missense mutation in the BTK gene (c.428 A > T, p.His143Leu). CONCLUSION: To our knowledge, c.428 A > T has not been reported in the BTK gene.

3.
Acta Biomed ; 91(3): e2020044, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32921737

RESUMO

Coronavirus disease 2019 (COVID-19) pandemic is a global challenge. Several governments of the world have decided to take drastic actions in order to combat the spread of the disease, including the closing of air, maritime and land borders, as an extreme measure of isolation of each country/region. However, such measures had not prevented the disease from spreading globally; as COVID-19 has already spread in almost all countries. This virus's main victims are the healthcare personnel (HCP), who are physically and psychologically affected. The HCP serves as the first line of defense against this pandemic, what if we faced a significant loss in their number? And what if our HCP was going through a deep dark depression? The condition would be terrifying not only for now but also in the future. This raises the need for an intensified International collaboration, that mainly supports the HCP. We are throwing by challenging moments, and it is clear that social distancing, cooperation, hygiene awareness and abide by the recommendation and help of all governments, as well as obtaining the support of international organizations could be an excellent tool for preventing an increase in the number of cases, principally in countries and regions were COVID-19 is in the early stage of the epidemic. However, this is not the final solution for the current pandemic. An intensified global program, which mainly supports the HCP, then considers the other aspects of the COVID19 pandemic might bring this pandemic to a peaceful end.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Transmissão de Doença Infecciosa/prevenção & controle , Pessoal de Saúde/organização & administração , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Humanos
4.
Immunol Invest ; : 1-15, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32633164

RESUMO

We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK-), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.

5.
Sci Immunol ; 5(49)2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32646852

RESUMO

The WAVE regulatory complex (WRC) is crucial for assembly of the peripheral branched actin network constituting one of the main drivers of eukaryotic cell migration. Here, we uncover an essential role of the hematopoietic-specific WRC component HEM1 for immune cell development. Germline-encoded HEM1 deficiency underlies an inborn error of immunity with systemic autoimmunity, at cellular level marked by WRC destabilization, reduced filamentous actin, and failure to assemble lamellipodia. Hem1-/- mice display systemic autoimmunity, phenocopying the human disease. In the absence of Hem1, B cells become deprived of extracellular stimuli necessary to maintain the strength of B cell receptor signaling at a level permissive for survival of non-autoreactive B cells. This shifts the balance of B cell fate choices toward autoreactive B cells and thus autoimmunity.

6.
Blood ; 136(23): 2638-2655, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-32603431

RESUMO

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

10.
Sci Immunol ; 3(24)2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.


Assuntos
Regulação da Expressão Gênica/imunologia , Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Fatores de Transcrição/genética , Transcrição Genética/imunologia , Adolescente , Adulto , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Núcleo Celular/metabolismo , Consanguinidade , Citocinas/imunologia , Citocinas/metabolismo , Éxons/genética , Feminino , Genes Recessivos/genética , Genes Recessivos/imunologia , Homozigoto , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Síndrome de Job/sangue , Síndrome de Job/imunologia , Mutação com Perda de Função , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Linhagem , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem , Dedos de Zinco/genética
11.
Acta Med Iran ; 55(6): 354-359, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28843235

RESUMO

Inflammatory elements and genetics have major roles in febrile seizures (FS) pathogenesis. Seventy patients were enrolled and compared with 139 controls. The allele and genotype frequency of the IL-2 gene at -330 and +166 positions and the IFN-γ at +874 position were determined. A significant positive association with GG genotype at position -330 in the patient group was found (P=0.003). Further, a positive association was detected in simple and complex FS groups at the same position (P=0.03, P=0.004). IL-2 GT haplotype was significantly more common in the patients compared to controls (P=0.0008). Higher frequency of GT haplotype was detected in simple FS patients in comparison to controls (P=0.0003). Contrary, IL-2 TG haplotype frequency was lower in complex FS group (P=0.005). Overrepresentation of certain alleles, genotypes and haplotypes in IL-2 gene in FS patients could predispose individuals to this disease.


Assuntos
Predisposição Genética para Doença , Interferon gama/genética , Interleucina-2/genética , Convulsões Febris/genética , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único
12.
Acta Microbiol Immunol Hung ; 64(2): 191-201, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28597685

RESUMO

Heterozygous gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) have increasingly been identified as a genetic cause of autosomal-dominant (AD) chronic mucocutaneous candidiasis (CMC). In this article, we describe a 33-year-old man who experienced chronic refractory candidiasis, recurrent otitis media, and pneumonia resulting in bronchiectasis, severe oral and esophageal candidiases with strictures associated with hypothyroidism and immune hemolytic anemia. His son also suffered from persistent candidiasis, chronic diarrhea, poor weight gain, and pneumonia that resulted in his demise because of sepsis. The immunological workup showed that an inverse CD4/CD8 ratio and serum immunoglobulins were all within normal ranges. The laboratory data revealed failure in response to Candida lymphocyte transformation test. In addition, by Sanger sequencing method, we found a heterozygous mutation, Thr385Met (T385M), located in the DNA-binding domain of STAT1, which was previously shown to be GOF. These findings illustrate the broad and variable clinical phenotype of heterozygous STAT1 GOF mutations. However, more clinical information and phenotype-genotype studies are required to define the clinical phenotype caused by AD STAT1 GOF.


Assuntos
Candidíase Mucocutânea Crônica/genética , Mutação Puntual , Fator de Transcrição STAT1/genética , Adulto , Candida/genética , Candida/isolamento & purificação , Candida/fisiologia , Candidíase Mucocutânea Crônica/microbiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transdução de Sinais
14.
Clin Rheumatol ; 36(1): 77-81, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27646136

RESUMO

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. Genetics and inflammatory elements seem to act as major underlying factors in its pathogenesis. The aim of this study is to identify the associations between interleukin-6 (IL-6) gene polymorphisms and individuals' vulnerability to JIA in a group of Iranian pediatric patients. Fifty-four patients with JIA were enrolled in this investigation and compared with 139 healthy individuals. Using polymerase chain reaction with sequence-specific primers, cytokine genotyping was performed. The allele and genotype frequencies of two single nucleotide polymorphisms (SNPs) within the IL-6 gene at -174 and +565 positions were assessed. A significant positive association was observed for IL -6 -174 G allele in the patient group (p = 0.02). Furthermore, a positive association was observed in patients with JIA for the GG genotype at the same position (p < 0.01), thus revealing a predisposing effect in JIA patients. On the other hand, a significant negative association was found for IL-6 -174 CG genotype (p < 0.01) in the case group. No significant difference was discovered in both the allelic and genotypic frequencies of IL-6 +565 position between patients and controls. Additionally, haplotype analysis divulged over representation of IL-6 GG haplotype in patient group (p < 0.01) as well as IL-6 CG haplotype in healthy controls (p < 0.01). Certain allele, genotype, and haplotype in IL-6 gene were over expressed in patients with JIA, which probably could render individuals more susceptible to this disease.


Assuntos
Artrite Juvenil/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Alelos , Criança , Citocinas/metabolismo , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Irã (Geográfico) , Masculino
15.
Clin Rheumatol ; 36(4): 831-836, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27878683

RESUMO

Systemic lupus erythematosus (SLE) is a multi-factor autoimmune disorder with diverse clinical manifestations and unclear pathogenesis. Genetic components play important roles in the incidence and development of SLE. Among these, APRIL as a cytokine has roles in the stimulation and antibody production in B cells. APRIL was hypothesized to be associated with SLE. The aim of this study was to assess the involvement of the APRIL gene in SLE susceptibility in Iranian patients. A single-nucleotide polymorphism (SNP) for rs11552708 of APRIL gene was analyzed by real-time PCR in 60 SLE Iranian children and 64 healthy controls. DNA samples of patients and healthy controls were extracted from peripheral blood leukocytes by phenol-chloroform. Serum samples obtained from 45 children with SLE and 45 healthy controls were assayed by enzyme-linked immunosorbent assay (ELISA). The G/G genotype (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.22-2.07; P = 0.68) and G allele (OR 0.81, 95% CI 0.25-2.56; P = 0.89) frequencies of polymorphism at codon 67 (67G) do not differ significantly in the SLE patients compared with those in the healthy controls. The serum APRIL levels in the SLE patients (mean ± SD = 29.27 ng/ml ± 20.77, range from 0 to 55.33 ng/ml) were significantly higher than those in the healthy controls (P = 0.02). Our results demonstrated that rs11552708 of the APRIL gene is not associated with SLE susceptibility in Iranian children. Likewise, these findings suggest that APRIL antagonist could be a potential therapeutic target to control SLE in children.


Assuntos
Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Adolescente , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Irã (Geográfico) , Masculino , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
16.
Immunotherapy ; 8(10): 1193-204, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27605068

RESUMO

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Several approaches of active and passive immunotherapy for EOC have been studied. The aim of this systematic review was to assess the clinical efficacy of specific immunotherapy in patients with EOC. We found 4524 references in seven databases and we included ten controlled clinical trials with 2285 patients with EOC reporting five active immunotherapeutic agents and three passive immunotherapies. Meta-analysis of six studies showed that overall there was not any significant difference in overall survival and recurrence-free survival between patients undergoing specific immunotherapy and those in control group. Most of the studies we evaluated reported a positive outcome from treatment with specific immunotherapy, although this was not significant.


Assuntos
Imunoterapia , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias Ovarianas/terapia , Carcinoma Epitelial do Ovário , Ensaios Clínicos como Assunto , Feminino , Humanos , Neoplasias Epiteliais e Glandulares/imunologia , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Análise de Sobrevida , Resultado do Tratamento
17.
Clin Rheumatol ; 35(8): 1943-1948, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26951255

RESUMO

As cytokines, including interleukin-4 (IL-4), seem to have a pivotal role in the pathogenesis of juvenile idiopathic arthritis (JIA), this study is aimed at investigating of association of polymorphisms in IL-4 and IL-4 receptor α (IL-4RA) genes with susceptibility to JIA. A case-control study was conducted on 53 patients with JIA and 139 healthy unrelated controls. Single nucleotide polymorphisms of IL-4 gene at positions -1098, -590, and -33, as well as IL-4RA gene at position +1902 were genotyped using polymerase chain reaction with sequence-specific primers method and compared between patients and healthy individuals. At the allelic level, C allele at IL-4 -33 was found to be more frequent in patients compared to control (P value <0.01). At the genotypic level, CC genotype at IL-4 -590 (P value <0.01), together with CC and TT genotypes at IL-4 -33 (P value <0.01), were significantly higher in patients with JIA, while TC genotypes at IL-4 -590 and -33 positions were found to be lower in case group (P value <0.01). At the haplotypic level, IL-4 (positions -1098, -509, -33) TTC, GCC, and TTT haplotypes were significantly lower than controls (P value <0.01, P value = 0.03, and P value = 0.04, respectively). Although, TCC haplotype at the same positions was found to be higher in patients (P value <0.01). Polymorphic site of +1902 IL-4RA gene did not differ between cases and controls. Polymorphisms in promoter region of IL-4 but not IL-4RA genes confer susceptibility to JIA and may predispose individuals to adaptive immune responses.


Assuntos
Artrite Juvenil/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Irã (Geográfico) , Masculino
18.
Eur J Med Genet ; 59(4): 237-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26808426

RESUMO

ARC syndrome is a rare autosomal recessive disease, characterized by arthrogryposis, renal tubular dysfunction and cholestasis. Herein a 2.5 month old infant with dysmorphic features, including small anterior fontanel, low set ears, beaked nose and high arched palate is presented who was referred because of icterus. He also suffered from some additional anomalies, including unilateral choanal atresia, club foot, and bilateral developmental dislocation of hip, while further studies showed renal tubular acidosis and hearing impairment in addition to cholestasis. Genetic studies showed a homozygous mutation in the VIPAS39 gene. Making the definite diagnosis of the syndrome is important, while increased risk of mutation in other siblings highlights the importance of prenatal diagnosis.


Assuntos
Anormalidades Múltiplas/genética , Acidose Tubular Renal/genética , Artrogripose/genética , Colestase/genética , Insuficiência Renal/genética , Proteínas de Transporte Vesicular/genética , Anormalidades Múltiplas/patologia , Acidose Tubular Renal/patologia , Artrogripose/patologia , Pré-Escolar , Colestase/patologia , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/patologia , Humanos , Masculino , Mutação , Fenótipo , Diagnóstico Pré-Natal , Insuficiência Renal/patologia , Análise de Sequência de DNA , Irmãos
19.
J Child Neurol ; 31(6): 673-7, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26500244

RESUMO

Interleukin-1 (IL-1) plays a key role in inflammation, has an effect on a wide variety of cells, and often leads to tissue destruction. While the ratio between IL-1 and IL-1Ra could influence the development of different diseases of the central nervous system, its gene polymorphisms were investigated in a group of patients with febrile seizures. Ninety patients with febrile seizures were enrolled and compared with 140 controls. The allele and genotype frequency of single nucleotide polymorphisms within the IL-1α, ß, IL-1 R and IL-1Ra gene were determined. The frequency of the IL-1Ra/C allele at position Mspa-I 11100 was decreased significantly (P= .002) and the IL-1Ra/T frequency was significantly increased in patients (P= .002). In addition, the CT genotype frequency at the same position was significantly overrepresented in controls compared to patients (P= .001). Certain alleles and genotypes in the IL-1 gene were overrepresented in patients with febrile seizures, which possibly could predispose individuals to this disease.


Assuntos
Predisposição Genética para Doença/genética , Interleucina-1/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina-1/genética , Convulsões Febris/genética , Criança , Pré-Escolar , Intervalos de Confiança , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Razão de Chances
20.
J Neurol Sci ; 356(1-2): 153-6, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26119396

RESUMO

Febrile seizures (FS) is the most common seizure disorder during childhood. This study was performed in 78 patients with FS and 137 control subjects to assess polymorphisms of the TNF-α gene at positions -308 and -238, using the polymerase chain reaction and the sequence specific primers method. The highest positive allelic association that made the patients susceptible to FS was seen for TNF-α -238/G (p<0.0001). The GG genotype at TNF-α -238 was significantly higher in the patients with FS, compared to the controls (p=0.0001). Also, GA genotype at the same position was significantly lower in patients than in controls (P=0.0001). The GG haplotype had a significant positive association at TNF-α (308, 238) while GA haplotype showed a negative association (P<0.001). Our data support the idea that TNF-α single-nucleotide polymorphisms play a role in the pathogenesis of FS.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Convulsões Febris/genética , Fator de Necrose Tumoral alfa/genética , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Humanos , Lactente , Masculino
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