Artigos e Materiais de Revistas Científicas - FM/MPE

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A coleção de Artigos e Materiais de Revistas Científicas engloba artigos originais, artigos de revisão, artigos de atualização, artigos técnicos, relatos de experiências, resenhas, ensaios, editoriais, cartas ao editor, debates, notas científicas e técnicas, depoimentos, entrevistas e pontos de vista. Consideram-se como artigos científicos originais os trabalhos redigidos para divulgação de informações e resultados sobre determinada pesquisa científica, publicados em periódico científico após avaliação por outros pesquisadores.


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  • article 1 Citação(ões) na Scopus
    Germline mutations in cancer predisposition genes among pediatric patients with cancer and congenital anomalies
    (2024) DANGONI, Gustavo D.; TEIXEIRA, Anne Caroline B.; COSTA, Silvia S. da; SCLIAR, Marilia O.; CARVALHO, Laura M. L.; SILVA, Luciana N.; NOVAK, Estela M.; VINCE, Carolina S. C.; MASCHIETTO, Mariana C.; SUGAYAMA, Sofia M. M.; ODONE-FILHO, Vicente; KREPISCHI, Ana Cristina V.
    BackgroundChildhood cancer has a poorly known etiology, and investigating the underlying genetic background may provide novel insights. A recognized association exists between non-chromosomal birth defects and childhood cancer susceptibility.MethodsWe performed whole-exome sequencing and chromosomal microarray analysis in a cohort of childhood cancer (22 individuals, 50% with congenital anomalies) to unravel deleterious germline variants.ResultsA diagnostic yield of 14% was found, encompassing heterozygous variants in bona fide dominant Cancer Predisposition Genes (CPGs). Considering candidate and recessive CPGs harboring monoallelic variants, which were also deemed to play a role in the phenotype, the yield escalated to 45%. Most of the deleterious variants were mapped in genes not conventionally linked to the patient's tumor type. Relevant findings were detected in 55% of the syndromic individuals, mostly variants potentially underlying both phenotypes.ConclusionWe uncovered a remarkable prevalence of germline deleterious CPG variants, highlighting the significance of a comprehensive genetic analysis in pediatric cancer, especially when coupled with additional clinical signs. Moreover, our findings emphasized the potential for oligogenic inheritance, wherein multiple genes synergistically increase cancer risk. Lastly, our investigation unveiled potentially novel genotype-phenotype associations, such as SETD5 in neuroblastoma, KAT6A in gliomas, JAG1 in hepatoblastomas, and TNFRSF13B in Langerhans cell histiocytosis.ImpactNovel gene-phenotype associations and candidate genes for pediatric cancer were unraveled, such as in gliomas, in neuroblastoma, in hepatoblastomas, and in Langerhans cell histiocytosis.Our analysis revealed a high frequency of deleterious germline variants, particularly in cases accompanied by additional clinical signs, highlighting the importance of a comprehensive genetic evaluation in childhood cancer.Our findings also underscored the potential for oligogenic inheritance in pediatric cancer risk.Understanding the cancer etiology is crucial for genetic counseling, often influencing therapeutic decisions and offering valuable insights into molecular targets for the development of oncological therapies.
  • article
    Novel FERMT3 and PTPRQ Mutations Associated with Leukocyte Adhesion Deficiency-III and Sensorineural Hearing Loss
    (2023) CANDELARIA, Gabriela de Toledo Passos; ANTUNES, Alexandre de A.; PASTORINO, Antonio C.; DORNA, Mayra de B.; ZANARDO, Evelin A.; DIAS, Alexandre T.; SUGAYAMA, Sofia M. M.; ODONE-FILHO, Vicente; KULIKOWSKI, Leslie D.; GARANITO, Marlene P.
    Leukocyte adhesion deficiency-III (LAD-III) is a rare genetic disease caused by defective integrin activation in hematopoietic cells due to mutations in the FERMT3 gene. The PTPRQ gene encodes the protein tyrosine phosphatase receptor Q and is essential for the normal maturation and function of hair bundle in the cochlea. Homozygous PTPRQ mutations impair the stereocilia in hair cells which lead to nonsyndromic sensorineural hearing loss (SNHL) with vestibular dysfunction. Here, we report two novel pathogenic homozygous mutations found in two genes, FERMT3 and PTPRQ, in a Brazilian patient with LAD-III and SNHL, which may develop our understanding of the phenotypegenotype correlation and prognosis of patients with these rare diseases.
  • article 0 Citação(ões) na Scopus
    Variants in Candidate Genes for Phenotype Heterogeneity in Patients with the 22q11.2 Deletion Syndrome
    (2024) NUNES, Natalia; NUNES, Beatriz Carvalho; ZAMARIOLLI, Malu; SOARES, Diogo Cordeiro de Queiroz; SANTOS, Leonardo Caires dos; DANTAS, Anelisa Gollo; MELONI, Vera Ayres; BELANGERO, Sintia Iole; GIL-DA-SILVA-LOPES, Vera Lucia; KIM, Chong Ae; MELARAGNO, Maria Isabel
    22q11.2 deletion syndrome (22q11.2DS) is a microdeletion syndrome with a broad and heterogeneous phenotype, even though most of the deletions present similar sizes, involving similar to 3 Mb of DNA. In a relatively large population of a Brazilian 22q11.2DS cohort (60 patients), we investigated genetic variants that could act as genetic modifiers and contribute to the phenotypic heterogeneity, using a targeted NGS (Next Generation Sequencing) with a specific Ion AmpliSeq panel to sequence nine candidate genes (CRKL, MAPK1, HIRA, TANGO2, PI4KA, HDAC1, ZDHHC8, ZFPM2, and JAM3), mapped in and outside the 22q11.2 hemizygous deleted region. In silico prediction was performed, and the whole-genome sequencing annotation analysis package (WGSA) was used to predict the possible pathogenic effect of single nucleotide variants (SNVs). For the in silico prediction of the indels, we used the genomic variants filtered by a deep learning model in NGS (GARFIELD-NGS). We identified six variants, 4 SNVs and 2 indels, in MAPK1, JAM3, and ZFPM2 genes with possibly synergistic deleterious effects in the context of the 22q11.2 deletion. Our results provide the opportunity for the discovery of the co-occurrence of genetic variants with 22q11.2 deletions, which may influence the patients ' phenotype.
  • article 1 Citação(ões) na Scopus
    Novel compound heterozygous ABCA2 variants cause IDPOGSA, a variable phenotypic syndrome with intellectual disability
    (2024) INOUE, Yuta; TSUCHIDA, Naomi; KIM, Chong Ae; STEPHAN, Bruno de Oliveira; CASTRO, Matheus Augusto Araujo; HONJO, Rachel Sayuri; BERTOLA, Debora Romeo; UCHIYAMA, Yuri; HAMANAKA, Kohei; FUJITA, Atsushi; KOSHIMIZU, Eriko; MISAWA, Kazuharu; MIYATAKE, Satoko; MIZUGUCHI, Takeshi; MATSUMOTO, Naomichi
    The gene for ATP binding cassette subfamily A member 2 (ABCA2) is located at chromosome 9q34.3. Biallelic ABCA2 variants lead to intellectual developmental disorder with poor growth and with or without seizures or ataxia (IDPOGSA). In this study, we identified novel compound heterozygous ABCA2 variants (NM_001606.5:c.[5300-17C>A];[6379C>T]) by whole exome sequencing in a 28-year-old Korean female patient with intellectual disability. These variants included intronic and nonsense variants of paternal and maternal origin, respectively, and are absent from gnomAD. SpliceAI predicted that the intron variant creates a cryptic acceptor site. Reverse transcription-PCR using RNA extracted from a lymphoblastoid cell line of the patient confirmed two aberrant transcripts. Her clinical features are compatible with those of IDPOGSA.
  • article 0 Citação(ões) na Scopus
    Brazilian growth charts for Williams- Beuren Syndrome at ages 2 to 18 years
    (2024) STRAFACCI, Amanda de Sousa Lima; BERTAPELLI, Fabio; KIM, Chong Ae; RIVADENEIRA, Maria Jos; HONJO, Rachel Sayuri; KULIKOWSKI, Leslie Domenici; FERREIRA, Danilo Moretti; BATISTA, Leticia Cassimiro; LOPES, Vera ucia Gil da Silva; JR, Gil Guerra
    Objective: To develop growth charts for weight-for-age, height-for-age, and body mass index (BMI)-for-age for both genders aged 2 to 18 years for Brazilian patients with Williams-Beuren Syndrome (WBS). Methods: This is a multicenter, retrospective, and longitudinal study, data were collected from the medical records of boys and girls with a con fi rmed diagnosis of WBS in three large university centers in the state of Sao Paulo, Brazil. Growth charts strati fi ed by gender and age in years were developed using LMSchartmaker Pro software. The LMS (Lambda Mu Sigma) method was used to model the charts . The quality of the settings was checked by worm plots. Results: The fi rst Brazilian growth charts for weight-for-age, height-for-age, and BMI-for-age strati fi ed by gender were constructed for WBS patients aged 2 to 18 years. Conclusion: The growth charts developed in this study can help to guide family members and to improve the health care offered by health professionals. (c) 2023 Published by Elsevier Editora Ltda. on behalf of Sociedade Brasileira de Pediatria. This is an open access article under the CC BY -NC -ND license ( by-nc-nd/4.0/).
  • article 0 Citação(ões) na Scopus
    Neuropsychological Profile of 25 Brazilian Patients with 22q11.2 Deletion Syndrome: Effects of Clinical and Socioeconomic Variables
    (2024) PIMENTA, Larissa Salustiano Evangelista; MELLO, Claudia Berlim de; BENEDETTO, Luciana Mello Di; SOARES, Diogo Cordeiro de Queiroz; KULIKOWSKI, Leslie Domenici; DANTAS, Anelisa Gollo; MELARAGNO, Maria Isabel; KIM, Chong Ae
    The 22q11.2 deletion syndrome (22q11.2DS) is associated with a heterogeneous neurocognitive phenotype, which includes psychiatric disorders. However, few studies have investigated the influence of socioeconomic variables on intellectual variability. The aim of this study was to investigate the cognitive profile of 25 patients, aged 7 to 32 years, with a typical approximate to 3 Mb 22q11.2 deletion, considering intellectual, adaptive, and neuropsychological functioning. Univariate linear regression analysis explored the influence of socioeconomic variables on intellectual quotient (IQ) and global adaptive behavior. Associations with relevant clinical conditions such as seizures, recurrent infections, and heart diseases were also considered. Results showed IQ scores ranging from 42 to 104. Communication, executive functions, attention, and visuoconstructive skills were the most impaired in the sample. The study found effects of access to quality education, family socioeconomic status (SES), and caregiver education level on IQ. Conversely, age at diagnosis and language delay were associated with outcomes in adaptive behavior. This characterization may be useful for better understanding the influence of social-environmental factors on the development of patients with 22q11.2 deletion syndrome, as well as for intervention processes aimed at improving their quality of life.
  • article 0 Citação(ões) na Scopus
    Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil
    (2024) MIGLIAVACCA, Michele P.; SOBREIRA, Joselito; BERMEO, Diana; GOMES, Mireille; ALENCAR, Dayse; SUSSUCHI, Luciane; SOUZA, Camila Alves; SILVA, Juliana Santos; KROLL, Jose Eduardo; BURGER, Matheus; GUARISCHI-SOUSA, Rodrigo; VILLELA, Darine; YAMAMOTO, Guilherme L.; MILANEZI, Fernanda; HORIGOSHI, Nelson; CESAR, Regina Grigolli; CARVALHO, Werther Brunow de; HONJO, Rachel Sayuri; BERTOLA, Debora Romeo; KIM, Chong Ae; SOUZA, Lucian de; PROCIANOY, Renato S.; SILVERIA, Rita C.; ROSENBERG, Carla; GIUGLIANI, Roberto; CAMPANA, Gustavo Aguiar; SCAPULATEMPO-NETO, Cristovam; SOBREIRA, Nara
    In this pilot study, we aimed to evaluate the feasibility of whole genome sequencing (WGS) as a first-tier diagnostic test for infants hospitalized in neonatal intensive care units in the Brazilian healthcare system. The cohort presented here results from a joint collaboration between private and public hospitals in Brazil considering the initiative of a clinical laboratory to provide timely diagnosis for critically ill infants. We performed trio (proband and parents) WGS in 21 infants suspected of a genetic disease with an urgent need for diagnosis to guide medical care. Overall, the primary indication for genetic testing was dysmorphic syndromes (n = 14, 67%) followed by inborn errors of metabolism (n = 6, 29%) and skeletal dysplasias (n = 1, 5%). The diagnostic yield in our cohort was 57% (12/21) based on cases that received a definitive or likely definitive diagnostic result from WGS analysis. A total of 16 pathogenic/likely pathogenic variants and 10 variants of unknown significance were detected, and in most cases inherited from an unaffected parent. In addition, the reported variants were of different types, but mainly missense (58%) and associated with autosomal diseases (19/26); only three were associated with X-linked diseases, detected in hemizygosity in the proband an inherited from an unaffected mother. Notably, we identified 10 novel variants, absent from public genomic databases, in our cohort. Considering the entire diagnostic process, the average turnaround time from enrollment to medical report in our study was 53 days. Our findings demonstrate the remarkable utility of WGS as a diagnostic tool, elevating the potential of transformative impact since it outperforms conventional genetic tests. Here, we address the main challenges associated with implementing WGS in the medical care system in Brazil, as well as discuss the potential benefits and limitations of WGS as a diagnostic tool in the neonatal care setting.
  • article 1 Citação(ões) na Scopus
    Bronchopulmonary dysplasia: temporal trend from 2010 to 2019 in the Brazilian Network on Neonatal Research
    (2024) STOLZ, Camila; COSTA-NOBRE, Daniela Testoni; SANUDO, Adriana; FERREIRA, Daniela Marques de Lima Mota; JR, Jose Mariano Sales Alves; SANTOS, Julia Paula dos; MIYOSHI, Milton Harumi; SILVA, Nathalia Moura de Mello; MELO, Fernanda Pegoraro de Godoi; SILVA, Regina Vieira Cavalcanti da; BARCALA, Dafne; VALE, Marynea Silva; RUGOLO, Ligia Maria Suppo de Souza; DINIZ, Edna Maria Albuquerque; RIBEIRO, Manoel; MARBA, Sergio T. M.; CWAJG, Silvia; DUARTE, Jose Luiz Muniz Bandeira; FERRI, Walusa Assad Goncalves; PROCIANOY, Renato S.; ANCHIETA, Leni Marcia; LOPES, Jose Maria de Andrade; ALMEIDA, Maria Fernanda B. de; GUINSBURG, Ruth
    Objective To evaluate the temporal trend of bronchopulmonary dysplasia (BPD) in preterm infants who survived to at least 36 weeks' post-menstrual age (PMA) and BPD or death at 36 weeks' PMA, and to analyse variables associated with both outcomes.Design Retrospective cohort with data retrieved from an ongoing national registry.Setting 19 Brazilian university public hospitals.Patients Infants born between 2010 and 2019 with 23-31 weeks and birth weight 400-1499 g.Main outcome measures Temporal trend was evaluated by Prais-Winsten model and variables associated with BPD in survivors or BPD or death were analysed by logistic regression.Results Of the 11 128 included infants, BPD in survivors occurred in 22%, being constant over time (annual per cent change (APC): -0.80%; 95% CI: -2.59%; 1.03%) and BPD or death in 45%, decreasing over time (APC: -1.05%; 95% CI: -1.67%; -0.43%). Being male, small for gestational age, presenting with respiratory distress syndrome, air leaks, needing longer duration of mechanical ventilation, presenting with treated patent ductus arteriosus and late-onset sepsis were associated with an increase in the chance of BPD. For the outcome BPD or death, maternal bleeding, multiple gestation, 5-minute Apgar <7, late-onset sepsis, necrotising enterocolitis and intraventricular haemorrhage were added to the variables reported above as increasing the chance of the outcome.Conclusion The frequency of BPD in survivors was constant and BPD or death decreased by 1.05% at each study year. These results show some improvement in perinatal care in Brazilian units which resulted in a reduction of BPD or death, but further improvements are still needed to reduce BPD in survivors.
  • article 0 Citação(ões) na Scopus
    Advantages of whole-exome sequencing over immunomapping in 67 Brazilian patients with epidermolysis bullosa
    (2024) KELMANN, Samantha Vernaschi; STEPHAN, Bruno de Oliveira; BARBOSA, Silvia Maria de Macedo; POLASTRINI, Rita Tiziana Verardo; OLIVEIRA, Zilda Najjar Prado de; RIVITTI-MACHADO, Maria Cecilia; SPOLADOR, Gustavo Marquezani; HONJO, Rachel Sayuri; SAIDA, Ken; MATSUMOTO, Naomichi; KIM, Chong Ae
    Background: Epidermolysis bullosa (EB) is characterized by skin fragility and blistering. In Brazil, the diagnosis is usually obtained through immunomapping, which involves a skin biopsy. Most recently, whole exome sequencing (WES) has become an important tool for the diagnosis of the subtypes of EB, providing information on prognosis as well as allowing appropriate genetic counseling for the families. Objective: To compare the results of immunomapping and molecular analysis and to describe the characteristics of a Brazilian cohort of patients with EB. Methods: Patients were submitted to clinical evaluation and WES using peripheral blood samples. WES results were compared to those obtained from immunomapping testing from skin biopsies. Results: 67 patients from 60 families were classified: 47 patients with recessive dystrophic EB (DEB), 4 with dominant DEB, 15 with EB simplex (EBS), and 1 with junctional EB (JEB). Novel causative variants were: 10/60 (16%) in COL7A1 associated with recessive DEB and 3 other variants in dominant DEB; one homozygous variant in KRT5 and another homozygous variant in PLEC, both associated with EBS. Immunomapping was available for 59 of the 67 patients and the results were concordant with exome results in 37 (62%), discordant in 13 (22%), and inconclusive in 9 patients (15%). Study limitations: Even though EB is a rare disease, for statistical purposes, the number of patients evaluated by this cohort can still be considered limited; other than that, there was a significant difference between the proportion of types of EB (only one case with JEB, against more than 50 with DEB), which unfortunately represents a selection bias. Also, for a small subset of families, segregation (usually through Sanger sequencing) was not an option, usually due to deceased or unknown parent status (mostly the father). Conclusion: Although immunomapping has been useful in services where molecular studies are not available, this invasive method may provide a misdiagnosis or an inconclusive result in about 1/3 of the patients. This study shows that WES is an effective method for the diagnosis and genetic counseling of EB patients. (c) 2024 Sociedade Brasileira de Dermatologia.
  • article 0 Citação(ões) na Scopus
    Assessment of school readiness and the importance of executive functions for learning
    (2024) COELHO, Rachel Mocelin Dias; GRISI, Sandra Josefina Ferraz Ellero; BRENTANI, Alexandra Valeria Maria; FERRER, Ana Paula Scoleze
    Objective: Considering the importance of the beginning of the academic trajectory for children to reach their full development, this work aims to evaluate the school readiness of preschool -age children and identify which factors influence these results, in order to contribute to the proposition of strategies that allow improving the teaching -learning process and child development. Methods: This is a cross-sectional, descriptive and analytical study with 443 preschool children belonging to the West Region Cohort (ROC Cohort), from the public school system of the city of S & atilde;o Paulo. School readiness was assessed by the International Development and Early Learning Assessment (IDELA) tool. Nonparametric techniques were used for the correlation analysis between IDELA scores and sociodemographic and socioeconomic conditions: Spearman's parametric correlation, Mann -Whitney and Kruskal-Wallis tests. Results: The children's mean age was 69 months (standard deviation - SD=2.8; ranging from 55 to 72 months) and most of them came from families with low socioeconomic level. Most children showed adequate readiness in the overall score (65%) and in most domains, except for emergent literacy, in which most (56.9%) were classified as ""emergent"". The highest percentage of insufficiency was identified in executive functions (4.1%), which showed a correlation only with the caregiver's education. Conclusions: Children had adequate school readiness scores, except for emergent literacy, but the insufficiency in executive functions may compromise the future schooling of these children. Thus, pedagogical proposals should consider these aspects for learning and pediatricians need to reinforce the habit of reading and playing games to stimulate child development.
  • article 1 Citação(ões) na Scopus
    Mother-infant bonding and postpartum depression during the COVID-19 pandemic - a risk for nurturing care and child development
    (2024) DINIZ, Barbara Portela; GRISI, Sandra Josefina Ferraz Ellero; SOUZA, Danton Matheus de; FERRER, Ana Paula Scoleze
    Objective: The COVID-19 pandemic Increased the risk of impairing the mother -infant bonding. The objectives of this study were to evaluate the early bond established between mother and infant and postpartum depression (PPD) in pregnancies that occurred during the pandemic period, to identify the factors that may have influenced these outcomes and to verify if there was an association between bonding and probable PPD. Methods: This is a cross-sectional study of postpartum women from a public maternity hospital in the city of S & atilde;o Paulo conducted from February to June 2021, involving 127 mother -baby dyads. The initial data were collected in the immediate postpartum period and between 21-45 days after birth, using a semi -structured questionnaire on sociodemographic characteristics, gestational and birth conditions, and baby characteristics; the Edinburgh Postnatal Depression Scale (EPDS) and Postpartum Bonding Questionnaire (PBQ) were used to evaluate PPD and bonding, respectively. Results: The presence of probable PPD and unplanned pregnancies were associated with higher PBQ score and risk to impaired bonding (p = 0.001 and p = 0.004, respectively). EPDS showed a high prevalence of PPD (29.1%) and was not associated with any Studied variable. Probably, this high prevalence of probable PPD was due to the context of insecurity secondary to the pandemic. Conclusions: We observed an increase in the prevalence of probable PPD and unplanned pregnancies during the first 18 months of the pandemic, which were associated with worse scores in mother -infant bonding. The impaired bond can affect the future development of children born during this period.
  • article 4 Citação(ões) na Scopus
    The acute effects of community violence on young children's regulatory, behavioral, and developmental outcomes in a low-income urban sample in Brazil
    (2024) MCCOY, Dana C.; DORMAL, Marta; CUARTAS, Jorge; SANTOS, Angelica Carreira dos; FINK, Gunther; BRENTANI, Alexandra
    BackgroundExisting research on the impacts of adversity on young children's psychological well-being has largely focused on household-level risk factors using observational methods in high-income countries. This study leverages natural variation in the timing and location of community homicides to estimate their acute effects on the regulatory, behavioral, and developmental outcomes of Brazilian 3-year-olds. MethodsWe compared the outcomes of children who were assessed soon after a recent neighborhood homicide to those of children from the same residential neighborhoods who had not recently experienced community violence. Our sample included 3,241 3-year-olds (M-age = 41.05 months; 53% female; 45% caregiver education less than middle school; 26% receiving a public assistance program) from seven neighborhoods in Sao Paulo, Brazil. Child outcome measures included parent reports of effortful control and behavior problems as well as direct assessments of children's developmental (cognitive, language, and motor) skills. Community homicides were measured using police records. ResultsRecent exposure to community homicides was associated with lower effortful control, higher behavior problems, and lower overall developmental performance for children (d = .05-.20 standard deviations; p = ns - <.001). Effects were consistent across subgroups based on sociodemographic characteristics and environmental supports, but generally largest when community violence exposure was geographically proximal (within 600 m of home) and recent (within 2 weeks prior to assessment). ConclusionsResults highlight the pervasive effects that community violence can have on young children as well as the need to expand support to mitigate these effects and prevent inequities early in life.
  • article 0 Citação(ões) na Scopus
    22q11.2 Deletion Syndrome: Influence of Parental Origin on Clinical Heterogeneity
    (2024) WALLAU, Melissa Bittencourt de; XAVIER, Ana Carolina; MORENO, Carolina Araujo; KIM, Chong Ae; MENDES, Elaine Lustosa; RIBEIRO, Erlane Marques; OLIVEIRA, Amanda; FELIX, Temis Maria; FETT-CONTE, Agnes Cristina; BONADIA, Luciana Cardoso; CORREIA-COSTA, Gabriela Roldao; MONLLEO, Isabella Lopes; GIL-DA-SILVA-LOPES, Vera Lucia; VIEIRA, Tarsis Paiva
    22q11.2 deletion syndrome (22q11.2DS) shows significant clinical heterogeneity. This study aimed to explore the association between clinical heterogeneity in 22q11.2DS and the parental origin of the deletion. The parental origin of the deletion was determined for 61 individuals with 22q11.2DS by genotyping DNA microsatellite markers and single-nucleotide polymorphisms (SNPs). Among the 61 individuals, 29 (47.5%) had a maternal origin of the deletion, and 32 (52.5%) a paternal origin. Comparison of the frequency of the main clinical features between individuals with deletions of maternal or paternal origin showed no statistically significant difference. However, Truncus arteriosus, pulmonary atresia, seizures, and scoliosis were only found in patients with deletions of maternal origin. Also, a slight difference in the frequency of other clinical features between groups of maternal or paternal origin was noted, including congenital heart disease, endocrinological alterations, and genitourinary abnormalities, all of them more common in patients with deletions of maternal origin. Although parental origin of the deletion does not seem to contribute to the phenotypic variability of most clinical signs observed in 22q11.2DS, these findings suggest that patients with deletions of maternal origin could have a more severe phenotype. Further studies with larger samples focusing on these specific features could corroborate these findings.
  • article 0 Citação(ões) na Scopus
    Reduced expressions of apoptosis-related proteins TRAIL, Bcl-2, and TNFR1 in NK cells of juvenile-onset systemic lupus erythematosus patients: relations with disease activity, nephritis, and neuropsychiatric involvement
    (2024) LIPHAUS, Bernadete L.; SILVA, Simone C.; PALMEIRA, Patricia; SILVA, Clovis A.; GOLDENSTEIN-SCHAINBERG, Claudia; CARNEIRO-SAMPAIO, Magda
    Background Lupus pathogenesis is mainly ascribed to increased production and/or impaired clearance of dead cell debris. Although self-reactive T and B lymphocytes are critically linked to lupus development, neutrophils, monocytes, and natural killer (NK) cells have also been implicated. This study assessed apoptosis-related protein expressions in NK cells of patients with juvenile-onset systemic lupus erythematosus (jSLE) and relations to disease activity parameters, nephritis, and neuropsychiatric involvement.Methods Thirty-six patients with jSLE, 13 juvenile dermatomyositis (JDM) inflammatory controls, and nine healthy controls had Fas, FasL, TRAIL, TNFR1, Bcl-2, Bax, Bim, and caspase-3 expressions in NK cells (CD3-CD16+CD56+) simultaneously determined by flow cytometry. Disease activity parameters included Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, erythrocyte sedimentation rate, C-reactive protein level, anti-double strain DNA antibody level, complement fractions C3 and C4 levels.Results Patients with jSLE had a profile of significantly reduced expression of TRAIL, Bcl-2, and TNFR1 proteins in NK cells when compared to healthy controls. Similar profile was observed in patients with jSLE with active disease, positive anti-dsDNA, nephritis, and without neuropsychiatric involvement. Patients with jSLE with positive anti-dsDNA also had reduced expression of Bax in NK cells when compared healthy controls and to those with negative anti-dsDNA. Yet, patients with jSLE with negative anti-dsDNA had reduced mean fluorescence intensity (MFI) of Bim in NK cells compared to healthy controls. Patients with jSLE with nephritis also had reduced MFI of Fas in NK cells when compared to those without nephritis. In addition, in patients with jSLE, the proportion of FasL-expressing NK cells directly correlated with the SLEDAI-2K score (rs = 0.6, p = 0.002) and inversely correlated with the C3 levels (rs = -0.5, p = 0.007). Moreover, patients with jSLE had increased NK cell percentage and caspase-3 protein expression in NK cells when compared to JDM controls.Conclusion This study extends to NK cells an altered profile of TRAIL, Bcl-2, TNFR1, Fas, FasL, Bax, Bim, and caspase-3 proteins in patients with jSLE, particularly in those with active disease, positive anti-dsDNA, nephritis, and without neuropsychiatric involvement. This change in apoptosis-related protein expressions may contribute to the defective functions of NK cells and, consequently, to lupus development. The full clarification of the role of NK cells in jSLE pathogenesis may pave the way for new therapies like those of NK cell-based.
  • article 55 Citação(ões) na Scopus
    Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children
    (2023) LEE, Danyel; PEN, Jeremie Le; YATIM, Ahmad; DONG, Beihua; AQUINO, Yann; OGISHI, Masato; PESCARMONA, Remi; TALOUARN, Estelle; RINCHAI, Darawan; ZHANG, Peng; PERRET, Magali; RICE, Charles M.; SILVERMAN, Robert H.; ZHANG, Shen-Ying; CASANOVA, Jean-Laurent; LIU, Zhiyong; JORDAN, Iolanda; BOZDEMIR, Sefika Elmas; BAYHAN, Gulsum Iclal; BEAUFILS, Camille; BIZIEN, Lucy; BISIAUX, Aurelie; LEI, Weite; HASAN, Milena; CHEN, Jie; GAUGHAN, Christina; ASTHANA, Abhishek; LIBRI, Valentina; LUNA, Joseph M.; JAFFRE, Fabrice; HOFFMANN, H. Heinrich; MICHAILIDIS, Eleftherios; MOREEWS, Marion; SEELEUTHNER, Yoann; BILGUVAR, Kaya; MANE, Shrikant; FLORES, Carlos; ZHANG, Yu; ARIAS, Andres A.; BAILEY, Rasheed; SCHLUTER, Agatha; MILISAVLJEVIC, Baptiste; BIGIO, Benedetta; VOYER, Tom Le; MATERNA, Marie; GERVAIS, Adrian; MONCADA-VELEZ, Marcela; PALA, Francesca; LAZAROV, Tomi; LEVY, Romain; NEEHUS, Anna-Lena; ROSAIN, Jeremie; PEEL, Jessica; CHAN, Yi-Hao; MORIN, Marie-Paule; PINO-RAMIREZ, Rosa Maria; BELKAYA, Serkan; LORENZO, Lazaro; ANTON, Jordi; DELAFONTAINE, Selket; TOUBIANA, Julie; BAJOLLE, Fanny; FUMADO, Victoria; DEDIEGO, Marta L.; FIDOUH, Nadhira; ROZENBERG, Flore; PEREZ-TUR, Jordi; CHEN, Shuibing; EVANS, Todd; GEISSMANN, Frederic; LEBON, Pierre; WEISS, Susan R.; BONNET, Damien; DUVAL, Xavier; PAN-HAMMARSTROM, Qiang; PLANAS, Anna M.; MEYTS, Isabelle; HAERYNCK, Filomeen; PUJOL, Aurora; SANCHO-SHIMIZU, Vanessa; DALGARD, Clifford L.; BUSTAMANTE, Jacinta; PUEL, Anne; BOISSON-DUPUIS, Stephanie; BOISSON, Bertrand; MANIATIS, Tom; ZHANG, Qian; BASTARD, Paul; NOTARANGELO, Luigi; BEZIAT, Vivien; DIEGO, Rebeca Perez de; RODRIGUEZ-GALLEGO, Carlos; SU, Helen C.; LIFTON, Richard P.; JOUANGUY, Emmanuelle; COBAT, Aurelie; ALSINA, Laia; KELES, Sevgi; HADDAD, Elie; ABEL, Laurent; BELOT, Alexandre; QUINTANA-MURCI, Lluis
    Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.
  • article 1 Citação(ões) na Scopus
    Biallelic variants in DNA2 cause poikiloderma with congenital cataracts and severe growth failure reminiscent of Rothmund-Thomson syndrome
    (2023) LAZZARO FILHO, Ricardo Di; YAMAMOTO, Guilherme Lopes; SILVA, Tiago J.; ROCHA, Leticia A.; LINNENKAMP, Bianca D. W.; CASTRO, Matheus Augusto Araujo; BARTHOLDI, Deborah; SCHALLER, Andre; LEEB, Tosso; KELMANN, Samantha; UTAGAWA, Claudia Y.; STEINER, Carlos E.; STEINMETZ, Leandra; HONJO, Rachel Sayuri; KIM, Chong Ae; WANG, Lisa; ABOURJAILI-BILODEAU, Raphael; CAMPEAU, Philippe; WARMAN, Matthew; PASSOS-BUENO, Maria Rita; HOCH, Nicolas C.; BERTOLA, Debora Romeo
    Rothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I, with biallelic variants in ANAPC1 and juvenile cataracts, and type II, with biallelic variants in RECQL4, increased cancer risk and no cataracts. We report on six Brazilian probands and two siblings of Swiss/Portuguese ancestry presenting with severe short stature, widespread poikiloderma and congenital ocular anomalies. Genomic and functional analysis revealed compound heterozygosis for a deep intronic splicing variant in trans with loss of function variants in DNA2, with reduction of the protein levels and impaired DNA double-strand break repair. The intronic variant is shared by all patients, as well as the Portuguese father of the European siblings, indicating a probable founder effect. Biallelic variants in DNA2 were previously associated with microcephalic osteodysplastic primordial dwarfism. Although the individuals reported here present a similar growth pattern, the presence of poikiloderma and ocular anomalies is unique. Thus, we have broadened the phenotypical spectrum of DNA2 mutations, incorporating clinical characteristics of RTS. Although a clear genotype-phenotype correlation cannot be definitively established at this moment, we speculate that the residual activity of the splicing variant allele could be responsible for the distinct manifestations of DNA2-related syndromes.
  • article 2 Citação(ões) na Scopus
    Burden of Rare Copy Number Variants in Microcephaly: A Brazilian Cohort of 185 Microcephalic Patients and Review of the Literature
    (2024) TOLEZANO, Giovanna Cantini; BASTOS, Giovanna Civitate; COSTA, Silvia Souza da; FREIRE, Bruna Lucheze; HOMMA, Thais Kataoka; HONJO, Rachel Sayuri; YAMAMOTO, Guilherme Lopes; PASSOS-BUENO, Maria Rita; KOIFFMANN, Celia Priszkulnik; KIM, Chong Ae; VIANNA-MORGANTE, Angela Maria; JORGE, Alexander Augusto de Lima; BERTOLA, Debora Romeo; ROSENBERG, Carla; KREPISCHI, Ana Cristina Victorino
    Microcephaly presents heterogeneous genetic etiology linked to several neurodevelopmental disorders (NDD). Copy number variants (CNVs) are a causal mechanism of microcephaly whose investigation is a crucial step for unraveling its molecular basis. Our purpose was to investigate the burden of rare CNVs in microcephalic individuals and to review genes and CNV syndromes associated with microcephaly. We performed chromosomal microarray analysis (CMA) in 185 Brazilian patients with microcephaly and evaluated microcephalic patients carrying < 200 kb CNVs documented in the DECIPHER database. Additionally, we reviewed known genes and CNV syndromes causally linked to microcephaly through the PubMed, OMIM, DECIPHER, and ClinGen databases. Rare clinically relevant CNVs were detected in 39 out of the 185 Brazilian patients investigated by CMA (21%). In 31 among the 60 DECIPHER patients carrying < 200 kb CNVs, at least one known microcephaly gene was observed. Overall, four gene sets implicated in microcephaly were disclosed: known microcephaly genes; genes with supporting evidence of association with microcephaly; known macrocephaly genes; and novel candidates, including OTUD7A, BBC3, CNTN6, and NAA15. In the review, we compiled 957 known microcephaly genes and 58 genomic CNV loci, comprising 13 duplications and 50 deletions, which have already been associated with clinical findings including microcephaly. We reviewed genes and CNV syndromes previously associated with microcephaly, reinforced the high CMA diagnostic yield for this condition, pinpointed novel candidate loci linked to microcephaly deserving further evaluation, and provided a useful resource for future research on the field of neurodevelopment.
  • article 0 Citação(ões) na Scopus
    Childhood-onset systemic lupus erythematosus (cSLE) and malignancy: a nationwide multicentre series review
    (2024) BRUFATTO, Matheus Zanata; LANCAS, Sean Hideo Shirata; FERNANDES, Taciana de Albuquerque Pedrosa; SALLUM, Adriana Maluf Elias; CAMPOS, Lucia Maria Arruda; SAKAMOTO, Ana Paula; TERRERI, Maria Teresa; SZTAJNBOK, Flavio Roberto; BICA, Blanca Elena Rios Gomes; FERRIANI, Virginia Paes Leme; CARVALHO, Luciana Martins de; SILVA, Clovis Artur Almeida; SAAD-MAGALHAES, Claudia
    BackgroundIncreased malignancy frequency is well documented in adult-systemic lupus erythematosus (SLE), but with limited reports in childhood-onset SLE (cSLE) series. We explored the frequency of malignancy associated with cSLE, describing clinical and demographic characteristics, disease activity and cumulative damage, by the time of malignancy diagnosis.MethodA retrospective case-notes review, in a nationwide cohort from 27 Pediatric Rheumatology centres, with descriptive biopsy-proven malignancy, disease activity/damage accrual, and immunosuppressive treatment were compiled in each participating centre, using a standard protocol.ResultsOf the 1757 cSLE cases in the updated cohort, 12 (0.7%) developed malignancy with median time 10 years after cSLE diagnosis. There were 91% females, median age at cSLE diagnosis 12 years, median age at malignancy diagnosis 23 years. Of all diagnosed malignancies, 11 were single-site, and a single case with concomitant multiple sites; four had haematological (0.22%) and 8 solid malignancy (0.45%). Median (min-max) SLEDAI-2 K scores were 9 (0-38), median (min-max) SLICC/ACR-DI (SDI) score were 1 (1-5) Histopathology defined 1 Hodgkin's lymphoma, 2 non-Hodgkin's lymphoma, 1 acute lymphoblastic leukaemia; 4 gastrointestinal carcinoma, 1 squamous cell carcinoma of the tongue and 1 anal carcinoma; 1 had sigmoid adenocarcinoma and 1 stomach carcinoid; 3 had genital malignancy, being 1 vulvae, 1 cervix and 1 vulvae and cervix carcinomas; 1 had central nervous system oligodendroglioma; and 1 testicle germ cell teratoma.ConclusionEstimated malignancy frequency of 0.7% was reported during cSLE follow up in a multicentric series. Median disease activity and cumulative damage scores, by the time of malignancy diagnoses, were high; considering that reported in adult series.
  • article 0 Citação(ões) na Scopus
    Disease progression in Sanfilippo type B: Case series of Brazilian patients
    (2024) MONTENEGRO, Yorran Hardman Araujo; KUBASKI, Francyne; TRAPP, Franciele Barbosa; RIEGEL-GIUGLIANI, Mariluce; SOUZA, Carolina Fischinger Moura de; RIBEIRO, Erlane Marques; LOURENCO, Charles Marques; CARDOSO-DOS-SANTOS, Augusto Cesar; RIBEIRO, Marcia Goncalves; KIM, Chong Ae; CASTRO, Matheus Augusto Araujo; EMBIRUCU, Emilia Katiane; STEINER, Carlos Eduardo; VAIRO, Filippo Pinto e; BALDO, Guilherme; GIUGLIANI, Roberto; POSWAR, Fabiano de Oliveira
    Mucopolysaccharidosis type IIIB (MPS IIIB) is caused by deficiency of alpha-N-acetylglucosaminidase, leading to storage of heparan sulphate. The disease is characterized by intellectual disability and hyperactivity, among other neurological and somatic features. Here we studied retrospective data from a total of 19 MPS IIIB patients from Brazil, aiming to evaluate disease progression. Mean age at diagnosis was 7.2 years. Speech delay was one of the first symptoms to be identified, around 2-3 years of age. Behavioral alterations include hyperactivity and aggressiveness, starting around age four. By the end of the first decade, patients lost acquired abilities such as speech and ability to walk. Furthermore, as disease progresses, respiratory, cardiovascular and joint abnormalities were found in more than 50% of the patients, along with organomegaly. Most common cause of death was respiratory problems. The disease progression was characterized in multiple systems, and hopefully these data will help the design of appropriate clinical trials and clinical management guidelines.
  • article 0 Citação(ões) na Scopus
    Study of the peripheral and central auditory pathways in patients with mucopolysaccharidosis
    (2024) CHIMELO, Flavia Teixeira; SILVA, Liliane Aparecida Fagundes; NEVES-LOBO, Ivone Ferreira; KIM, Chong Ae; MATAS, Carla Gentile
    Objective: To investigate the peripheral and central auditory pathways in mucopolysaccharidosis (MPS) individuals. Method: The research sample comprised 15 individuals (one female and 14 males), aged 8 to 46 years. The following procedures were used: medical history survey, otoscopy, speech and puretone threshold audiometry, acoustic immittance measures, and central auditory pathway assessment with brainstem auditory evoked potentials (BAEP) and long-latency auditory evoked potentials (LLAEP). Results: The pure-tone audiometry identified hearing loss in 13 individuals, and more than 90 % of the hearing loss was sensorineural. The degree of hearing loss was between mild to moderately severe with descendent configuration. Type A tympanogram predominated, and acoustic reflexes were present according to the types and degrees of hearing loss. Among the individuals with abnormal BAEP, longer wave III and V absolute latencies were the main findings. In addition, the unilateral absence of wave I was observed in two cases. In the LLAEP, longer latencies were observed in 14 individuals, and the most impaired components were the P1 and P3 in children and adolescents and the P2, N2 and P3 in adult individuals. Conclusion: The peripheral auditory pathway assessment revealed a predominantly sensorineural hearing loss, affecting mainly high frequencies, and in the central pathway was observed abnormal brainstem and cortical auditory processing in individuals with MPS.