CMIN_DIA_SP_Artigos publicados em revistas indexadas na Pubmed/Medline
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- Acute Fulminant Cerebral Edema in a Child With Suspected MeningoencephalitisPublication . Monteiro, Sara; Teixeira, Beatriz; Fraga, Carolina; Dias, Andreia; Cardoso, Ana Lúcia; Meireles, Daniel; Sarmento, Alzira; Ferreira, Paula Regina; Silva, João; Garrido, Cristina; Gonçalves, SaraAcute fulminant cerebral edema (AFCE) is a recently identified encephalitis type associated with significant morbimortality. Described as rare, limited data exists on its early detection and treatment. This paper describes a case of AFCE that progressed to unresponsive intracranial hypertension. A previously healthy four-year-old boy presented with fever, myalgias, and neurological symptoms. Diagnostic assessments showed cerebrospinal fluid abnormalities, and despite medical interventions, his condition deteriorated rapidly and developed severe cerebral edema and herniation within 24 hours. A decompressive craniectomy was attempted to decrease intracranial pressure, without success. This case emphasizes the urgency of early AFCE recognition and effective management strategies given its severe prognosis, aiming to improve understanding and spur further research
- Ambiguous Genitalia: An Unexpected Diagnosis in a NewbornPublication . Losa, Ana; Da Silva Cardoso, Juliana; Leite, Sara; Barros, Ana Cristina; Guedes, Ana; Rodrigues, Cidade; Borges, Teresa; Oliva-Teles, Natália; Soares, Ana Rita; Mota, CéuAlterations in gonad formation or function can lead to congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. These conditions are referred to as disorders of sex development (DSD) and have a heterogeneous etiology. The assessment of these children by a multidisciplinary team is crucial for an accurate diagnosis and should be initiated promptly due to the potentially life-threatening nature of congenital adrenal hyperplasia, a common cause of DSD. We present a neonate born at 39 weeks with a weak cry, slight hypotonia, poor suction reflex, peculiar facies, and ambiguous genitalia. From the study carried out, the abdominopelvic ultrasound revealed a nodular structure compatible with the left gonad. Aneuploidy screening confirmed the presence of the Y chromosome. Additionally, normal endocrinological studies and the karyotype showed a genotype compatible with cri-du-chat syndrome with partial trisomy of chromosome 3. Children with cri-du-chat syndrome characteristically exhibit a cat-like cry and distinctive facial features, along with developmental delay and intellectual disability. Duplication of 3p is a rare genetic disorder, usually associated with other chromosomal anomalies and congenital malformations, namely, of the genitals
- Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare VariantsPublication . Encarnação, Marisa; Coutinho, Maria Francisca; Silva, Lisbeth; Ribeiro, Diogo; Ouesleti, Souad; Campos, Teresa; Santos, Helena; Martins, Esmeralda; Cardoso, Maria Teresa; Vilarinho, Laura; Alves, SandraLysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders with variable degrees of severity and a broad phenotypic spectrum, which may overlap with a number of other conditions. While individually rare, as a group LSDs affect a significant number of patients, placing an important burden on affected individuals and their families but also on national health care systems worldwide. Here, we present our results on the use of an in-house customized next-generation sequencing (NGS) panel of genes related to lysosome function as a first-line molecular test for the diagnosis of LSDs. Ultimately, our goal is to provide a fast and effective tool to screen for virtually all LSDs in a single run, thus contributing to decrease the diagnostic odyssey, accelerating the time to diagnosis. Our study enrolled a group of 23 patients with variable degrees of clinical and/or biochemical suspicion of LSD. Briefly, NGS analysis data workflow, followed by segregation analysis allowed the characterization of approximately 41% of the analyzed patients and the identification of 10 different pathogenic variants, underlying nine LSDs. Importantly, four of those variants were novel, and, when applicable, their effect over protein structure was evaluated through in silico analysis. One of the novel pathogenic variants was identified in the GM2A gene, which is associated with an ultra-rare (or misdiagnosed) LSD, the AB variant of GM2 Gangliosidosis. Overall, this case series highlights not only the major advantages of NGS-based diagnostic approaches but also, to some extent, its limitations ultimately promoting a reflection on the role of targeted panels as a primary tool for the prompt characterization of LSD patients.
- 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.
- 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.
- Cerebral vasculitis in Henoch‐Schönlein purpuraPublication . GONÇALVES, C.; FERREIRA, G.; MOTA, C.; VILARINHO, A.An Pediatr (Barc). 2004 Feb;60(2):188-9. [Cerebral vasculitis in Henoch-Schönlein purpura]. [Article in Spanish] Gonçalves C, Ferreira G, Mota C, Vilarinho A. PMID: 14757029 [PubMed - indexed for MEDLINE]
- Clinical and Genetic Analysis of Children with Kartagener SyndromePublication . Pereira, R.; Barbosa, T.; Gales, L.; Oliveira, E.; Santos, R.; Oliveira, J.; Sousa, M.Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia causing ineffective mucus clearance and organ laterality defects. In this study, two unrelated Portuguese children with strong PCD suspicion underwent extensive clinical and genetic assessments by whole-exome sequencing (WES), as well as ultrastructural analysis of cilia by transmission electron microscopy (TEM) to identify their genetic etiology. These analyses confirmed the diagnostic of Kartagener syndrome (KS) (PCD with situs inversus). Patient-1 showed a predominance of the absence of the inner dynein arms with two disease-causing variants in the CCDC40 gene. Patient-2 showed the absence of both dynein arms and WES disclosed two novel high impact variants in the DNAH5 gene and two missense variants in the DNAH7 gene, all possibly deleterious. Moreover, in Patient-2, functional data revealed a reduction of gene expression and protein mislocalization in both genes' products. Our work calls the researcher's attention to the complexity of the PCD and to the possibility of gene interactions modelling the PCD phenotype. Further, it is demonstrated that even for well-known PCD genes, novel pathogenic variants could have importance for a PCD/KS diagnosis, reinforcing the difficulty of providing genetic counselling and prenatal diagnosis to families.
- 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.
- Comparison of Kristjansson Respiratory Score and Wang Respiratory Score in infants with bronchiolitis in a hospital emergency departmentPublication . Pinto, Frederico Ramos; Correia-Costa, Liane; Azevedo, InêsObjective: Several respiratory scores have been created to evaluate bronchiolitis' severity level, but it is still not clear which is the best score. The aim of this study is to compare the Wang Respiratory Score (WRS) and the Kristjansson Respiratory Score (KRS) in the setting of an emergency room. Methods: We performed a prospective observational study with 60 infants with bronchiolitis admitted to a paediatric emergency department. For both scores, we assessed inter-rater reliability between two different health professionals (physician and physiotherapist), internal consistency, and correlation with SpO2 testing the intraclass-correlation coefficient (ICC), weighted kappa, Cronbach α coefficient and Spearman tests, respectively. Results: The inter-rater reliability was higher in KRS (ICC 0.79) and the Cronbach α and weighted kappa had similar values in KRS versus WRS. The correlation between the KRS/WRS and SpO2 was poor/moderate upon admission and discharge for the first observer and the second observer. Conclusions: While the internal consistency was similar in both scores, inter-rater reliability of KRS was higher than WRS, which allows us to conclude that it would have more consistent results when used to assess bronchiolitis' level of severity by health personnel in a busy hospital emergency room.
- Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B MutationsPublication . Aldrian, Denise; Vogel, Georg F.; Frey, Teresa K.; Ayyıldız Civan, Hasret; Aksu, Aysel Ünlüsoy; Avitzur, Yaron; Ramos Boluda, Esther; Çakır, Murat; Demir, Arzu Meltem; Deppisch, Caroline; Duba, Hans-Christoph; Düker, Gesche; Gerner, Patrick; Hertecant, Jozef; Hornová, Jarmila; Kathemann, Simone; Koeglmeier, Jutta; Koutroumpa, Arsinoi; Lanzersdorfer, Roland; Lev-Tzion, Raffi; Lima, Rosa; Mansour, Sahar; Meissl, Manfred; Melek, Jan; Miqdady, Mohamad; Montoya, Jorge Hernan; Posovszky, Carsten; Rachman, Yelena; Siahanidou, Tania; Tabbers, Merit; Uhlig, Holm H.; Ünal, Sevim; Wirth, Stefan; Ruemmele, Frank M.; Hess, Michael W.; Huber, Lukas A.; Müller, Thomas; Sturm, Ekkehard; Janecke, Andreas R.Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.