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- 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.
- 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.
- 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.
- Extracorporeal Membrane Oxygenation: The First 10 Years Experience of a Portuguese Pediatric Intensive Care UnitPublication . Meireles, Daniel; Abecasis, Francisco; Boto, Leonor; Camilo, Cristina; Abecasis, Miguel; Neves, José Pedro; Soares, Zélia Cristo; Vieira, MarisaIntroduction: In Portugal, extracorporeal membrane oxygenation (ECMO) is used in pediatric patients since 2010. The aim of this study was to describe the clinical characteristics of patients, indications, complications and mortality associated with the use of ECMO during the first 10-years of experience in the Pediatric Intensive Care Unit located in Centro Hospitalar Universitário Lisboa Norte. Material and methods: Retrospective observational cohort study of all patients supported with ECMO in a Pediatric Intensive Care Unit, from the 1st of May 2010 up to 31st December 2019. Results: Sixty-five patients were included: 37 neonatal (≤ 28 days of age) and 28 pediatric patients (> 28 days). In neonatal cases, congenital diaphragmatic hernia was the main reason for ECMO (40% of neonatal patients and 23% of total). Among pediatric patients, respiratory distress was the leading indication for ECMO (47% of total). The median length of ECMO support was 12 days. Clinical complications were more frequent than mechanical complications (65% vs 35%). Among clinical complications, access site bleeding was the most prevalent with 38% of cases. The overall patient survival was 68% at the time of discharge (65% for neonatal and 71% for pediatric cases), while the overall survival rate in Extracorporeal Life Support Organization registry was 61%. The number of ECMO runs has been increasing since 2011, even though in a non-linear way (three cases in 2010 to 11 cases in 2019). Discussion: In the first 10 years we received patients from all over the country. Despite continuous technological developments, circuitrelated complications have a significant impact. The overall survival rate in the Pediatric Intensive Care Unit was not inferior to the one reported by the Extracorporeal Life Support Organization. Conclusion: The overall survival of our Pediatric Intensive Care Unit is not inferior to one reported by other international centers. Our experience showed the efficacy of the ECMO technique in a Portuguese centre.
- TYROSINEMIA TYPE III: A CASE REPORT OF SIBLINGS AND LITERATURE REVIEWPublication . Barroso, Fábio; Correia, Joana; Bandeira, Anabela; Carmona, Carla; Vilarinho, Laura; MF, Almeida; Rocha, Júlio César; Martins, EsmeraldaObjective: Tyrosinemia type III (HT III) is the rarest form of tyrosinemia, and the full clinical spectrum of this disorder is still unknown. The neurological involvement varies, including intellectual impairment and attention deficit disorder with hyperactivity (ADHD). We report the case of two siblings diagnosed with HT III at different ages. Case description: The index case was diagnosed by newborn screening for endocrine and metabolic disorders, starting a low-protein diet immediately, with a consistent decrease in tyrosine levels. By the age of three, the child displayed a hyperactive behavior, starting treatment for ADHD two years later. At seven years of age, he shows a slight improvement in terms of behavior and attention span and has a cognitive performance slightly lower than his peers, despite maintaining acceptable tyrosine levels. His sister, who had a history of ADHD since age five, was diagnosed with HT III after family screening at the age of eight. Despite initiating a dietetic treatment, her behavior did not improve, and she has a mild intellectual impairment. Comments: This is the first case report describing siblings with HT III who underwent nutritional treatment with a low-protein diet in different phases of life, with a better neurological and behavioral evaluation in the patient who started treatment earlier.
- 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.
- Portuguese Consensus on Diagnosis, Treatment, and Management of Anemia in Pediatric Inflammatory Bowel DiseasePublication . Lopes, Ana Isabel; Azevedo, Sara; Cabral, José; Ferreira, Maria Gomes; Sande-Lemos, Piedade; Ferreira, Ricardo; Trindade, Eunice; Lima, Rosa; Antunes, HenedinaAnemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), both in pediatric and in adult patients. Iron deficiency is the main cause of anemia in patients with IBD. Anemia is a clinically relevant comorbidity, with impact on patients' quality of life and it should be timely diagnosed and adequately treated. Currently, an active treatment approach is the recommended strategy, with evidence showing efficacy and safety of intravenous iron formulations. However, evidence in pediatric age remains scarce and no clinical recommendations exist for the diagnosis and treatment of this particular age group. The present document represents the first national consensus on the management of anemia in pediatric IBD and is therefore particularly relevant. The authors anticipate that the proposed recommendations will be useful in daily clinical practice for diagnosing and managing iron deficiency and iron-deficiency anemia in the pediatric population with IBD.
- Hyperinsulinaemic Hypoglycaemia and Polycystic Kidney Disease – A Rare Case Concerning PMM2 Gene PleiotropyPublication . Borges, Teresa; Fortuna, Ana; Faria, Maria Do Sameiro; Oliveira, Maria João; Freitas, Joana; Santos Silva, Ermelinda; Quelhas, D; Figueiredo, Catarina Matos; Soares, Ana RitaCo-occurrence of hyperinsulinaemic hypoglycaemia and polycystic kidney disease (HIPKD) has been recently described. It is caused by a non-coding variant in the promoter region for phosphomannomutase 2 (PMM2), c.-167G>T, both in homozygous or compound heterozygous variants with deleterious coding. Although PMM2 has been associated with congenital disorder of glycosylation, patients do not present with this phenotype and have normal carbohydrate-deficient transferring testing. The authors present a rare case where specific PMM2 study was performed as a result of clinical suspicions. The patient was a 6-year-old female followed at our clinic due to congenital hyperinsulinism since she was 1 month old. She also presented with bilateral polycystic kidneys, detected in prenatal set, and simple hepatic cysts, for which she was treated with diazoxide and captopril. Initial metabolic and genetic studies were normal. PMM2 gene sequence study revealed the promotor variant c.-167G>T in compound heterozygosity with the previously described pathogenic variant c.422G>A (p.Arg141His), confirming the diagnosis of HIPKD. This is a notable case as it highlights the importance of keeping this diagnostic hypothesis in mind and serves as a reminder to perform proper clinical and genetic investigation. A correct, and early, diagnosis will avoid unnecessary additional investigations and will allow appropriate genetic counselling for this autosomal recessive disorder.
- Maternal Eating Behavior and Problematic Eating Behaviors of Children Undergoing Weight Loss Treatment: A Cluster AnalysisPublication . Ramalho, Sofia; Félix, Sílvia; Goldschmidt, Andrea B.; Silva, Diana; Costa, Cristiana; Mansilha, Helena Ferreira; Conceição, Eva M.Background: Research on the interplay between mothers' and children's eating behaviors is needed to better inform sensitive and tailored interventions for treatment-seeking children with overweight/obesity. The present study aimed to identify mothers' eating behavior phenotypes, investigating their associations with problematic eating behaviors of children undergoing weight loss treatment in two central hospitals. Methods: This is a cross-sectional study evaluating 136 mother-child dyads (Mothers: age 39.58 ± 5.40 years; Children: n = 75 female; age 10.13 ± 1.37 years). Mothers' eating behavior (restraint, emotional, and uncontrolled eating) and depression/anxiety, and children's problematic eating attitudes/behaviors were assessed. A cluster analysis (K-means) was performed using mothers' eating behavior dimensions. Multivariate Analysis of Covariance investigated differences between clusters on mothers' and children's sociodemographic, anthropometric, psychological, and eating-related variables. Results: Three clusters emerged: The Disordered Eating group (n = 39) of mothers with the highest scores on emotional eating and uncontrolled eating dimensions, the Restraint Eating group (n = 48), including mothers scoring high in cognitive restraint, and the Low Disordered Eating (n = 49) group where mothers scored low in all eating behavior dimensions. Children of mothers in the Disordered Eating cluster had significantly higher emotional overeating relative to children of mothers in the other two clusters. Conclusions: Distinctive eating behavior profiles of mothers, instead of the presence of single eating behaviors, seem to be associated with specific problematic eating behaviors of children undergoing weight loss treatment. Prospective studies are essential to determine whether these profiles can predict differential weight change trajectories in pediatric obesity treatment.
- Enterococcus faecalis-associated lung abscess in a male adolescent- a case reportPublication . Mendes, Ana Raquel; Costa, António; Ferreira, Helena; Ferreira, CristinaBackground: Enterococci are rarely considered pulmonary pathogens; they are usually regarded as colonizers of the airway. The authors present the case of a previously healthy male adolescent, with complaints of fatigue and chest pain, who was diagnosed with Enterococcus faecalis-associated acute primary lung abscess. Case presentation: A previously healthy 17-year old boy was admitted to the pediatric ward due to a one-week history of fatigue, inspiratory left side chest pain, dry cough and nasal obstruction. On admission at the emergency department, he was afebrile, with no signs of respiratory distress, but with diminished breath sounds on the left side. A chest x-ray showed a round opacity on the posterior basal segment of the left lower lobe; he was discharged with oral amoxicillin 1000 mg three times a day with the diagnosis of community-acquired pneumonia. Due to the worsening of the productive cough with purulent stinking sputum he was re-evaluated after 4 days. Laboratory studies showed a leukocyte count of 15200/uL and a c-reactive protein of 172 mg/l. The chest computed tomography scan was suggestive of a consolidation of the left lower lobe base and a central abscess. An intravenous course of ceftriaxone and clindamycin was initiated, with a favourable clinical evolution. The bronchofibroscopy performed on day four after his admission revealed the presence of a tracheal bronchus and numerous purulent secretions. Culture examination of bronchoalveolar lavage fluid samples was positive (> 10^5) for Enterococcus faecalis. No complications were registered during his stay in the pediatric ward. He was discharged after a 14-day course of intravenous ceftriaxone and clindamycin, with the recommendation to complete a four-week course of oral amoxicillin/clavulanic acid. On his reevaluation 4 weeks after his discharge, he was asymptomatic. Conclusion: This case report highlights the importance of considering Enterococcus faecalis as an etiologic agent in cases of non-resolving or complicated cases of pneumonia, such as lung abscesses, even in young patients with no comorbidities or risk factors.