CMIN_SP_Artigos publicados em revistas indexadas na Pubmed/Medline
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- Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference CenterPublication . Barbosa-Gouveia, Sofia; Vázquez-Mosquera, María E.; González-Vioque, Emiliano; Álvarez, José V.; Chans, Roi; Laranjeira, Francisco; Martins, Esmeralda; Ferreira, Ana Cristina; Avila-Alvarez, Alejandro; Couce, María L.Next-generation sequencing (NGS) technologies have been proposed as a first-line test for the diagnosis of inborn errors of metabolism (IEM), a group of genetically heterogeneous disorders with overlapping or nonspecific phenotypes. Over a 3-year period, we prospectively analyzed 311 pediatric patients with a suspected IEM using four targeted gene panels. The rate of positive diagnosis was 61.86% for intermediary metabolism defects, 32.84% for complex molecular defects, 19% for hypoglycemic/hyperglycemic events, and 17% for mitochondrial diseases, and a conclusive molecular diagnosis was established in 2-4 weeks. Forty-one patients for whom negative results were obtained with the mitochondrial diseases panel underwent subsequent analyses using the NeuroSeq panel, which groups all genes from the individual panels together with genes associated with neurological disorders (1870 genes in total). This achieved a diagnostic rate of 32%. We next evaluated the utility of a tool, Phenomizer, for differential diagnosis, and established a correlation between phenotype and molecular findings in 39.3% of patients. Finally, we evaluated the mutational architecture of the genes analyzed by determining z-scores, loss-of-function observed/expected upper bound fraction (LOEUF), and haploinsufficiency (HI) scores. In summary, targeted gene panels for specific groups of IEMs enabled rapid and effective diagnosis, which is critical for the therapeutic management of IEM patients.
- Can the Synergic Contribution of Multigenic Variants Explain the Clinical and Cellular Phenotypes of a Neurodevelopmental Disorder?Publication . Maia, N; Nabais Sá, Maria João; Oliveira, Cláudia; Santos, Flávia; Soares, Celia A; Prior, Catarina; Tkachenko, Nataliya; Santos, Rosário; de Brouwer, Arjan P. M.; Jacome, Ariana; Porto, Beatriz; Jorge, PaulaWe describe an infant female with a syndromic neurodevelopmental clinical phenotype and increased chromosome instability as cellular phenotype. Genotype characterization revealed heterozygous variants in genes directly or indirectly linked to DNA repair: a de novo X-linked HDAC8 pathogenic variant, a paternally inherited FANCG pathogenic variant and a maternally inherited BRCA2 variant of uncertain significance. The full spectrum of the phenotype cannot be explained by any of the heterozygous variants on their own; thus, a synergic contribution is proposed. Complementation studies showed that the FANCG gene from the Fanconi Anaemia/BRCA (FA/BRCA) DNA repair pathway was impaired, indicating that the variant in FANCG contributes to the cellular phenotype. The patient's chromosome instability represents the first report where heterozygous variant(s) in the FA/BRCA pathway are implicated in the cellular phenotype. We propose that a multigenic contribution of heterozygous variants in HDAC8 and the FA/BRCA pathway might have a role in the phenotype of this neurodevelopmental disorder. The importance of these findings may have repercussion in the clinical management of other cases with a similar synergic contribution of heterozygous variants, allowing the establishment of new genotype-phenotype correlations and motivating the biochemical study of the underlying mechanisms.
- Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNsPublication . Bastard, Paul; Vazquez, Sara E.; Liu, Jamin; Laurie, Matthew T.; Wang, Chung Yu; Gervais, Adrian; Le Voyer, Tom; Bizien, Lucy; Zamecnik, Colin; Philippot, Quentin; Rosain, Jérémie; Catherinot, Emilie; Willmore, Andrew; Mitchell, Anthea M.; Bair, Rebecca; Garçon, Pierre; Kenney, Heather; Fekkar, Arnaud; Salagianni, Maria; Poulakou, Garyphallia; Siouti, Eleni; Sahanic, Sabina; Tancevski, Ivan; Weiss, Günter; Nagl, Laurenz; Manry, Jérémy; Duvlis, Sotirija; Arroyo-Sánchez, Daniel; Paz Artal, Estela; Rubio, Luis; Perani, Cristiano; Bezzi, Michela; Sottini, Alessandra; Quaresima, Virginia; Roussel, Lucie; Vinh, Donald C.; Reyes, Luis Felipe; Garzaro, Margaux; Hatipoglu, Nevin; Boutboul, David; Tandjaoui-Lambiotte, Yacine; Borghesi, Alessandro; Aliberti, Anna; Cassaniti, Irene; Venet, Fabienne; Monneret, Guillaume; Halwani, Rabih; Sharif-Askari, Narjes Saheb; Danielson, Jeffrey; Burrel, Sonia; Morbieu, Caroline; Stepanovskyy, Yurii; Bondarenko, Anastasia; Volokha, Alla; Boyarchuk, Oksana; Gagro, Alenka; Neuville, Mathilde; Neven, Bénédicte; Keles, Sevgi; Hernu, Romain; Bal, Antonin; Novelli, Antonio; Novelli, Giuseppe; Saker, Kahina; Ailioaie, Oana; Antolí, Arnau; Jeziorski, Eric; Rocamora-Blanch, Gemma; Teixeira, Carla; Delaunay, Clarisse; Lhuillier, Marine; Le Turnier, Paul; Zhang, Yu; Mahevas, Matthieu; Pan-Hammarström, Qiang; Abolhassani, Hassan; Bompoil, Thierry; Dorgham, Karim; Gorochov, Guy; Laouenan, Cédric; Rodríguez-Gallego, Carlos; Ng, Lisa F. P.; Renia, Laurent; Pujol, Aurora; Belot, Alexandre; Raffi, François; Allende, Luis M.; Martinez-Picado, Javier; Ozcelik, Tayfun; Imberti, Luisa; Notarangelo, Luigi D.; Troya, Jesus; Solanich, Xavier; Zhang, Shen-Ying; Puel, Anne; Wilson, Michael R.; Trouillet-Assant, Sophie; Abel, Laurent; Jouanguy, Emmanuelle; Ye, Chun Jimmie; Cobat, Aurélie; Thompson, Leslie M.; Andreakos, Evangelos; Zhang, Qian; Anderson, Mark S.; Casanova, Jean-Laurent; DeRisi, Joseph L.Life-threatening "breakthrough" cases of critical COVID-19 are attributed to poor or waning antibody (Ab) response to SARS-CoV-2 vaccines in individuals already at risk. Preexisting auto-Abs neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; their contribution to hypoxemic breakthrough cases in vaccinated people is unknown. We studied a cohort of 48 individuals (aged 20 to 86 years) who received two doses of a messenger RNA (mRNA) vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Ab levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal Ab response to the vaccine. Among them, 10 (24%) had auto-Abs neutralizing type I IFNs (aged 43 to 86 years). Eight of these 10 patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, whereas two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized type I IFNs at 10 ng/ml and three at 100 pg/ml only. Seven patients neutralized SARS-CoV-2 D614G and Delta efficiently, whereas one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only type I IFNs at 100 pg/ml neutralized both D614G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating Abs capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a notable proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.
- Domiciliary High-Flow Nasal Therapy in Primary Ciliary DyskinesiaPublication . Gomes, Rita; Queirós, Joana; Borges, Joana; Cardoso, Ana Lúcia; Barbosa, TelmaWe report the case of an adolescent with severe primary ciliary dyskinesia (PCD) phenotype associated with a rare genotype. His clinical condition deteriorated, with daily cough and breathlessness, hypoxemia, and lung function decline. Despite being started on home noninvasive ventilation (NIV), the symptoms progressed to dyspnea at rest and thoracic pain. High-flow nasal cannula (HFNC) was started during the daytime as an adjuvant to NIV, and he was started on regular oral opioids for pain and dyspnea control. There was a clear improvement in comfort and dyspnea and breathing work relief. Additionally, better exercise tolerance was also noted. He is currently on the lung transplant waiting list. We aim to emphasize the benefits of HFNC as an add-on therapy for the management of chronic breathlessness since our patient experienced an improvement in breathing and exercise tolerance. However, there is a paucity of studies regarding domiciliary HFNC, particularly in pediatric age. Therefore, further studies are needed to achieve optimal and personalized care. Close monitoring and frequent reassessment in a specialized center are key to adequate management.
- Pediatric Thyroidectomy: Experience From a Portuguese HospitalPublication . Vieira, Paula; Barbosa Sequeira, Joana; Santos Monteiro, Sílvia; De Carvalho Vaz, Ana; da Silva Cardoso, Juliana; Ribeiro, Luís; Mendes, Catarina; Freitas, Joana; Ribeiro de Castro, João; Borges, Teresa; Oliveira, Maria JoãoBackground and objective Pediatric thyroid disease requiring surgery is rare. Thyroid nodules are a frequent indication for surgery and are mostly benign. However, up to 25% of cases can be malignant. In this study, we aimed to describe our center's experience with regard to pediatric thyroid surgery. Methods This was a retrospective transverse study involving pediatric patients who underwent thyroid surgery at a tertiary hospital between January 2010 and December 2021. Results A total of 14 patients underwent 15 surgeries. The main reason for referral to pediatric endocrinology was thyroid nodules (n=10). Thirteen fine needle aspirations (FNAs) were performed, with follicular tumor (n=6) being the most common finding. The median age of patients at surgery was 15.9 years [interquartile range (IQR): 14.0-16.8]. The most common surgical indications were the presence of a follicular tumor on FNA (n=5) and thyroid nodule size causing symptoms (n=5). There was one case of prophylactic thyroidectomy due to the identification of a multiple endocrine neoplasia type 2A (MEN2A) mutation. The most frequently described histopathology results were follicular adenoma (n=6) and colloid nodular goiter (n=6). Three postoperative complications were observed in three different patients: bilateral lesion of the recurrent laryngeal nerve, cervical hematoma, and transient hypoparathyroidism with hypocalcemia. Conclusion In our study, the most frequent surgical indication was a follicular tumor. A good correlation was found between FNA cytology and final histopathology results, which is in accordance with previous studies. This reinforces the importance of FNA in diagnosis and surgical planning. The rate of complications in our study is comparable to that in larger single-center series in the literature.
- Food Allergy in Preschoolers: Parents’ Perception and Self-Reported PrevalencePublication . Da Silva Cardoso, Juliana; Ashworth, Joanna; Pinto, Diana; Teixeira, Fernanda; Araújo, Ana RitaBackground: Food allergy is a potentially fatal condition (in the case of anaphylaxis, for example) and is characterized by an increasing prevalence. The main purpose of this study is to identify preschool children with parent-reported food allergies and characterize this population and type of allergy. Methods: This is a cross-sectional study, based on questionnaires to parents/legal guardians. All children who attend daycare or preschool in an area of the city of Porto, Portugal, were included. Results: A total of 740 questionnaires were distributed to nine schools, and responses were obtained from 363 (49.1%). Self-reported food reaction and/or allergy was related in 11.2% of children. The median age of the first reaction was 12 months and the most registered foods were milk, dry seed, and peanut. Cutaneous (48.7%) and gastrointestinal (35.9%) symptoms were the main manifestations. History of parents' and siblings' food allergies had statistically significant associations with food reactions and/or allergies of the child, with OR 3.05 (p=0.04, 95% CI 1.01-8.81) and OR 8.69 (p<0.01, 95% CI 2.11-35.79), respectively. Besides that, children's atopic dermatitis also had a statistically significant association with self-reported food reactions and/or allergies, with OR 2.30 (p<0.05, 95% CI 1.01-5.21). Conclusion: Food reactions and/or allergies were reported in 11.2% of children. The history of parents' and siblings' food allergies and children's atopic dermatitis had statistically significant associations with food reactions and/or allergies, which shows that it may be an important factor to consider.
- Clinical Role of Codon 87 of the CYFIP2 Gene in Early Infantile Epileptic Encephalopathy: A Clinical Case DescriptionPublication . Da Silva Cardoso, Juliana; Gomes, Rita; Abreu, Maria; Parente Freixo, João; Falcão Reis, Cáudia; Garrido, CristinaThe diagnosis of early infantile epileptic encephalopathy (EIEE) remains challenging, and next-generation sequencing (NGS) techniques have played a key role in identifying genetic causes. Recent studies have shown an association between mutations in the CYFIP2 gene and EIEE, with 20 deleterious variants reported so far and a de novo mutational hotspot at codon 87. A male infant presented with seizures since the age of four months as well as significant developmental delay and microcephaly. The seizures were of different types, frequent and refractory to treatment, including different anticonvulsant drugs. Metabolic studies showed no significant changes. The initial electroencephalogram revealed bilateral paroxysmal activity with hemispherical diffusion. Brain MRI showed no pathological changes. Analysis of a whole exome sequencing (WES) based multigene panel for epilepsy disclosed a heterozygous CYFIP2 gene variant [c.258_266del; p.(Trp86_Ser88del)] established as de novo. We describe the case of an infant with EIEE due to a de novo heterozygous in-frame deletion of three amino acids in CYFIP2: c.258_266del; p.(Trp86_Ser88del). This in-frame deletion eliminates codon 87, a mutational hotspot associated with a particularly severe EIEE phenotype. All previous reports had missense variants with a presumably gain-of-function mechanism. The clinical picture of our patient is very similar to the ones with deleterious variants affecting codon 87 reported in the literature. Our case report is the first to describe a disease-causing in-frame deletion in CYFIP2 and reiterates a consistent genotype-phenotype correlation.
- Enhancing Public Health Communication Regarding Vaccine Trials: Design and Development of the Pan-European VACCELERATE ToolkitPublication . Argyropoulos, Christos D; Leckler, Janina; Salmanton-García, Jon; Constantinou, Marinos; Alexandrou, Alexandra; Themistocleous, Sophia; Noula, Evgenia; Shiamakkides, George; Nearchou, Andria; Stewart, Fiona A; Albus, Kerstin; Koniordou, Markela; Kopsidas, Ioannis; Spivak, Orly; Hellemans, Margot; Hendrickx, Greet; Davis, Ruth Joanna; Azzini, Anna Maria; Simon, Paula Valle; Carcas-Sansuan, Antonio Javier; Askling, Helena Hervius; Vene, Sirkka; Prellezo, Jana Baranda; Álvarez-Barco, Elena; Macken, Alan J; Di Marzo, Romina; Luís, Catarina; Olesen, Ole F; Frias Iniesta, Jesus A; Barta, Imre; Tóth, Krisztina; Akova, Murat; Bonten, Marc M J; Cohen-Kandli, Miriam; Cox, Rebecca Jane; Součková, Lenka; Husa, Petr; Jancoriene, Ligita; Launay, Odile; Lundgren, Jens; Mallon, Patrick; Armeftis, Charis; Marques, Laura; Naucler, Pontus; Ochando, Jordi; Tacconelli, Evelina; van Damme, Pierre; Zaoutis, Theoklis; Hofstraat, Sanne; Bruijning-Verhagen, Patricia; Zeitlinger, Markus; Cornely, Oliver A; Pana, Zoi DorotheaBackground: The pan-European VACCELERATE network aims to implement the first transnational harmonized and sustainable vaccine trial Volunteer Registry, being a single entry point for potential volunteers of large-scale vaccine trials across Europe. This work exhibits a set of harmonized vaccine trial-related educational and promotional tools for the general public, designed and disseminated by the pan-European VACCELERATE network. Objective: This study primarily aimed to design and develop a standard toolkit to increase positive attitudes and access to trustworthy information for better access and increased recruitment to vaccine trials for the public. More specifically, the produced tools are focused on inclusiveness and equity, and are targeting different population groups, including underserved ones, as potential volunteers for the VACCELERATE Volunteer Registry (older individuals, migrants, children, and adolescents). The promotional and educational material is aligned with the main objectives of the Volunteer Registry to increase public literacy and awareness regarding vaccine-related clinical research or trials and trial participation, including informed consent and legal issues, side effects, and frequently asked questions regarding vaccine trial design. Methods: Tools were developed per the aims and principles of the VACCELERATE project, focusing on trial inclusiveness and equity, and are adjusted to local country-wise requirements to improve public health communication. The produced tools are selected based on the cognitive theory, inclusiveness, and equity of differently aged and underrepresented groups, and standardized material from several official trustworthy sources (eg, COVID-19 Vaccines Global Access; the European Centre for Disease Prevention and Control; the European Patients' Academy on Therapeutic Innovation; Gavi, the Vaccine Alliance; and the World Health Organization). A team of multidisciplinary specialists (infectious diseases, vaccine research, medicine, and education) edited and reviewed the subtitles and scripts of the educational videos, extended brochures, interactive cards, and puzzles. Graphic designers selected the color palette, audio settings, and dubbing for the video story-tales and implemented QR codes. Results: This study presents the first set of harmonized promotional and educational materials and tools (ie, educational cards, educational and promotional videos, extended brochures, flyers, posters, and puzzles) for vaccine clinical research (eg, COVID-19 vaccines). These tools inform the public about possible benefits and disadvantages of trial participation and build confidence among participants about the safety and efficacy of COVID-19 vaccines and the health care system. This material has been translated into several languages and is intended to be freely and easily accessible to facilitate dissemination among VACCELERATE network participant countries and the European and global scientific, industrial, and public community. Conclusions: The produced material could help fill knowledge gaps of health care personnel, providing the appropriate future patient education for vaccine trials, and tackling vaccine hesitancy and parents' concerns for potential participation of children in vaccine trials.
- Association between attention-deficit/hyperactivity symptoms and sleep in preschoolersPublication . Gomes, Rita; Sousa, Bebiana; Gonzaga, Diana; Prior, Catarina; Rios, Marta; Vaz Matos, InêsIntroduction: Sleep problems are frequent in children with attention-deficit/hyperactivity disorder (ADHD). Some authors have tried to characterize paediatric sleep habits in Portugal, but none has focused on preschool-age children nor attempted to establish their association with ADHD. We aimed to assess the prevalence of ADHD symptoms in preschool-age children and to study their association with sleep habits. Material and methods: We conducted a cross-sectional study. We distributed questionnaires to a random sample of caregivers of children enrolled in early childhood education centres in Porto. We collected data on sociodemographic characteristics, television watching and outdoor activities. We assessed ADHD symptoms and sleep habits with the Portuguese versions of the Conners' Parents Rating Scale, Revised and the Children's Sleep Habits Questionnaire (CSHQ-PT), respectively. Results: The study included 381 preschoolers (50.90% male). We found high scores for ADHD symptoms in 13.10%, with a higher prevalence in girls (14.40% vs. 11.85%; P = 0.276). In the CSHQ-PT, 45.70% of participants had a mean total score greater than 48, which is the cut-off point applied in the screening of sleep disturbances in the Portuguese population. There was a significant association between high scores for ADHD symptoms and a lower maternal education level (P < 0.001), a shorter sleep duration (P = 0.049), and higher scores on parasomnias (P = 0.019) and sleep disordered breathing (P = 0.002) in CSHQ-PT subscales. Conclusions: ADHD and sleep disorders are common in preschoolers, in Porto, and this study suggests some clinical correlations between them. Since these interactions are complex and far from being elucidated, further studies are paramount to provide guidance for prevention and managing strategies in younger children at risk for ADHD.
- Estimating the Glomerular Filtration Rate in Pediatric Patients With Neurogenic Bladder: A Comparison Between Creatinine- and Cystatin C-EquationsPublication . Menezes, Catarina; Costa, Teresa; Brás, Catarina; Sousa, Patrícia; Mendes, Ana; Amorim, Rosa; Faria, Maria Do Sameiro; Mota, ConceiçãoBackground and objective Patients with neurogenic bladder (NB) are at a higher risk of developing chronic kidney disease (CKD). Due to their lower muscle mass, the estimated glomerular filtration rate (eGFR) based on creatinine (Cr) may be overestimated and delay the diagnosis of renal failure. This study compared eGFR calculated with different equations based on Cr and/or cystatin C (CysC) in children with NB, and the differences between patients with lower muscle mass (underdeveloped lower limbs) and those with independent gait (less muscle depletion). Methods We calculated the eGFR in pediatric patients with NB and CKD stages 1 and 2 by using the following equations: Chronic Kidney Disease in Children equation for serum creatinine (CKiD-Cr), CKiD-CysC, CKiD combined-Cr/CysC, Zappitelli-CysC, and Zappitelli combined-Cr/CysC. Results We evaluated a total of 47 patients, 74.5% with CKD stage 1, with a median age of 14.1 years. Of these participants, 59.6% had lipo/myelomeningocele. The CKiD-Cr and CysC-based equations led to significantly lower calculated eGFR (p<0.05), specifically CKiD-CysC (p<0.001), Zappitelli-CysC (p<0.001), CKiD-Cr/CysC (p<0.001), and Zappitelli combined-Cr/CysC (p<0.05). When CKiD-CysC was used, 68% of the patients moved to a more advanced CKD stage. In patients without independent gait, with lower muscle mass (55.3%), the median eGFR calculated using the CKiD-Cr and CKiD combined-Cr/CysC equations was significantly higher (p<0.05). However, there were no differences between the two groups when using the other CysC-based equations. Conclusion In patients with NB and poor muscle mass, the CKiD-Cr equation may overestimate renal function. CysC-based equations seem more reliable in these patients, especially in those with greater muscular atrophy.