André Anjos da Silva

The phenotypic spectrum of congenital Zika syndrome

In October 2015, Zika virus (ZIKV) outbreak the Brazilian Ministry of Health (MoH). In response, the Brazilian Society of Medical Genetics established a task force (SBGM‐ZETF) to study the phenotype of infants born with microcephaly due to ZIKV congenital infection and delineate the phenotypic spectrum of this newly recognized teratogen. This study was based on the clinical evaluation and neuroimaging of 83 infants born during the period from July, 2015 to March, 2016 and registered by the SBGM‐ZETF. All 83 infants had significant findings on neuroimaging consistent with ZIKV congenital infection and 12 had confirmed ZIKV IgM in CSF. A recognizable phenotype of microcephaly, anomalies of the shape of skull and redundancy of the scalp consistent with the Fetal Brain Disruption Sequence (FBDS) was present in 70% of infants, but was most often subtle. In addition, features consistent with fetal immobility, ranging from dimples (30.1%), distal hand/finger contractures (20.5%), and feet malpositions (15.7%), to generalized arthrogryposis (9.6%), were present in these infants. Some cases had milder microcephaly or even a normal head circumference (HC), and other less distinctive findings. The detailed observation of the dysmorphic and neurologic features in these infants provides insight into the mechanisms and timings of the brain disruption and the sequence of developmental anomalies that may occur after prenatal infection by the ZIKV.

Efficacy and safety of intravenous laronidase for mucopolysaccharidosis type I: A systematic review and meta-analysis

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease caused by deficient activity of alpha-L-iduronidase. Intravenous (IV) enzyme replacement therapy (ERT) with laronidase is currently used for treating patients with MPS I. Objective To evaluate the efficacy and safety of IV laronidase for MPS I. Methods A systematic literature review was performed by searching the ClinicalTrials.gov, MEDLINE/PubMed, EMBASE, LILACS, and Cochrane Library databases, limited to clinical trials published until December 31, 2016. The first inclusion criterion was being a randomized controlled trial (RCT). If < five RCTs were identified, open-label and nonrandomized trials, controlled or uncontrolled (quasi-experimental), including ≥ five patients, and evaluating relevant outcomes defined a priori, would also be included. For meta-analysis, primary inferences were based on random-effects models. Assessment of article quality was performed in accordance with the GRADE criteria. The Cochrane Risk of Bias tool was used to examine the risk of bias for RCTs. Results The selection phase retrieved 632 articles. During the first phase of selection, 158 had the abstract or full text read for assessment of eligibility, of which nine (two RCTs) were included for qualitative synthesis. Four papers were included in the meta-analysis, which was performed for the following outcomes: occurrence of treatment-emergent or infusion-related adverse events (65%; 95%CI 53, 76), mild in most cases; development of IgG antibodies to laronidase (88%; 95%CI 67, 100); apnea-hypopnea index (not significant—NS), urinary glycosaminoglycans (GAGs) [mean change -65.5 μg/mg creatinine (95%CI -68.8, -62.3)], liver size [mean change -31.03% (95%CI -36.1, -25.9)], left ventricular mass index (LVMI) [mean change -1.8 (95%CI -2.32, -0.25)], and distance covered in the 6-minute walk test (NS). Among the outcomes not included in meta-analysis, we found evidence for benefit of laronidase only on shoulder flexion. Conclusions Our findings suggest that IV laronidase effectively reduces urinary GAGs excretion, hepatomegaly and LVMI, and can improve shoulder flexion in MPS I patients. Laronidase appears to be safe in the studied population.

Prevalência das malformações congênitas identificadas em fetos com trissomia dos cromossomos 13, 18 e 21

PURPOSE To describe the prevalence of malformations found in fetuses with trisomy of chromosomes 13, 18 and 21 by identifying the most frequent within each condition. METHODS A retrospective cross-sectional study with the analysis of trisomy cases of chromosomes 13, 18 and 21 diagnosed through fetal karyotype obtained by amniocentesis/cordocentesis, between October 1994 and May 2014, at a Teaching Hospital in Brazil Southern Region. Malformations identified through morphological ultrasonography were described and, subsequently, confirmed in newborn examinations and/or fetal autopsy. The results were analyzed using Fishers test and analysis of variance (ANOVA), with a 5% level of significance (p=0.05). RESULTS Sixty-nine cases of trisomy were diagnosed among 840 exams; nine were excluded due to outcome outside Hospital de Clínicas de Porto Alegre or incomplete records, remaining 60 cases (nine cases of chromosome 13 trisomy, 26 of chromosome 18, and 25 of chromosome 21). In all three groups, heart disease occurred in most cases; the ventricular septal defect was more prevalent and occurred in 66.7% of the trisomy 13 group. Gastrointestinal abnormalities were more prevalent in the trisomy 18 group, especially omphalocele (38.5%; p<0.01). Genitourinary anomalies were more significantly frequent in the trisomy 13 group (pyelectasis, 55.6% - p<0.01; ambiguous genitalia, 33.3% - p=0.01). Central nervous system defects were identified in all cases of trisomy 13. Facial cracks were significantly more prevalent among fetuses with trisomy 13 (66.7%; p<0.01). Hand and feet malformations significantly differed among the trisomy groups. Hand defects occurred in 50% of trisomy 18 cases, and in 44.4% of all trisomy 13 cases (p<0.01); congenital clubfoot was more common in the trisomy 18 group, being detected in 46.2% of fetuses (p<0.01). The abnormalities were found in 50.9, 27.3 and 21.7% of trisomy 18, 13 and 21 cases respectively. CONCLUSION Many fetal malformations identified at ultrasound are suggestive of trisomy and represent an important tool for etiologic diagnosis and prenatal and pre-conception genetic counseling.OBJETIVO: Descrever a prevalencia das malformacoes encontradas nos fetos com trissomia dos cromossomos 13, 18 e 21, identificando as mais frequentes em cada condicao. METODOS: Estudo transversal retrospectivo, com analise dos casos de trissomias dos cromossomos 13, 18 e 21 que foram diagnosticados pelo cariotipo fetal obtido por amniocentese/cordocentese, entre outubro de 1994 e maio de 2014, em um Hospital de Ensino da regiao Sul do Brasil. Foram descritas as malformacoes identificadas no exame ultrassonografico morfologico e, posteriormente, confirmadas em exames do recem-nascido e/ou por necropsia fetal. Os resultados foram analisados por meio do teste de Fisher e da analise de variância (ANOVA). O nivel de significância empregado foi 5% (p=0,05). RESULTADOS: Em 840 exames realizados, foram diagnosticados 69 casos de trissomias; nove deles foram excluidos por desfecho ocorrido fora do Hospital de Clinicas de Porto Alegre ou prontuario incompleto, restando 60 casos (nove de trissomia do cromossomo 13, 26 do cromossomo 18 e 25 do cromossomo 21). As cardiopatias ocorreram, na maioria dos casos, nos tres grupos; a comunicacao interventricular foi mais prevalente, em 66,7% do grupo da trissomia 13. As anomalias gastrintestinais aconteceram mais no grupo da trissomia 18, principalmente a onfalocele (38,5%; p<0,01). As anomalias geniturinarias foram significativamente mais frequentes no grupo da trissomia 13 (pielectasia com 55,6% - p<0,01; genitalia ambigua com 33,3% - p=0,01). Defeitos do sistema nervoso central foram identificados em todos os casos de trissomia 13. Fendas faciais foram mais prevalentes dentre os fetos com trissomia 13 (66,7%; p<0,01). Malformacoes nas maos e nos pes tiveram diferencas estatisticas entre os grupos de trissomia. Os defeitos nas maos ocorreram em 50% dos casos de trissomia 18 e em 44,4% dos casos de 13 (p<0,01); pe torto congenito foi mais comum no grupo da trissomia 18, descrito em 46,2% dos fetos (p<0,01). As malformacoes foram identificadas em 50,9; 27,3 e 21,7% dos casos de trissomias 18, 13 e 21, respectivamente. CONCLUSAO: Muitas malformacoes identificadas na ultrassonografia sao sugestivas de trissomias e mostram-se ferramentas importantes para o diagnostico etiologico e aconselhamento genetico pre-natal e pre-concepcional.

Zika virus infection and congenital anomalies in the Americas: opportunities for regional action

The Zika virus (ZIKV) was identified in 1947 in the Zika forest in Uganda, but recently it has emerged as a public health threat. The first evidence of human infection occurred in 1952, but only in April 2007 was the first outbreak in humans recognized. In the Americas, a ZIKV outbreak began in Brazil in 2015, and from the second half of 2015 onward, a substantial number of newborns with severe microcephaly began to be reported to health authorities. In February 2016, the World Health Organization (WHO) declared that the clusters of microcephaly cases in areas affected by ZIKV constituted a Public Health Emergency of International Concern. Seldom has there been such a resultingly vast production of scientific literature in record time. In this report we discuss the impact of ZIKV infection during pregnancy, the diagnosis and surveillance of microcephaly, the recognition of a clinical phenotype of ZIKV congenital infection, and opportunities for public health action. We consider this to be a unique opportunity for countries in the Region of the Americas to develop, strengthen, and improve surveillance systems for congenital anomalies and teratogen information services. Creating health needs assessment tools for low- and middle-income countries may help them to develop effective policies to ensure primary, secondary, and tertiary prevention measures for congenital anomalies. Such initiatives will be useful for ZIKV congenital syndrome control and also for having a much wider impact on a significant proportion of preventable and manageable congenital conditions.