RESUMO
Cutis marmorata telangiectatica congenita is a rare congenital vascular malformation characterised by cutaneous vascular abnormalities, typically diagnosed at birth or in the early postnatal period. Although typically benign, this disease is associated with other systemic abnormalities, including rare ocular alterations, such as congenital glaucoma, cataracts and retinopathy.This manuscript describes a female infant, who presented with generalised livedo reticularis, a band of alopecia and cutaneous atrophy in the temporal region above the coronal suture. The patient was diagnosed with cutis marmorata telangiectatica congenita by a paediatrician, and an ophthalmological evaluation was requested. A funduscopy examination in both eyes showed temporal and superior retina with avascular areas with new vessels, venous dilations and shunts, and no retinal detachments. Given these findings, we performed retinal photocoagulation laser treatment with excellent results.This case report highlights the importance of early ophthalmological evaluation of children with this disease to prevent secondary complications, such as vitreous haemorrhage and tractional retinal detachment.
Assuntos
Livedo Reticular , Dermatopatias Vasculares , Telangiectasia , Humanos , Feminino , Telangiectasia/congênito , Telangiectasia/complicações , Telangiectasia/diagnóstico , Dermatopatias Vasculares/diagnóstico , Dermatopatias Vasculares/complicações , Lactente , Fotocoagulação a Laser/métodos , Vasos Retinianos/anormalidades , Vasos Retinianos/diagnóstico por imagem , Retina/anormalidades , Retina/diagnóstico por imagemRESUMO
Venous malformations (VMs) are a type of vascular malformation formed by abnormally developed venous channels, with variations in size, pathway and thickness and are therefore a condition which can predispose to thrombosis. We present the case of a VM associated with phlebothrombosis/phlebolith, located on the lingual dorsum of a 20-year-old female patient. Clinical examination revealed a nodule of approximately 5 mm in diameter involving the anterior third of lingual dorsum, with a firm, compressible and non-pulsatile consistency. Histopathologically, the lesion revealed a VM with evidence of phlebothrombosis and phlebolith development. Although VMs manifest infrequently in this age group, they should be considered in the differential diagnosis of other lesions with similar characteristics in young people.
Assuntos
Doenças da Língua , Malformações Vasculares , Trombose Venosa , Adolescente , Adulto , Feminino , Humanos , Língua/patologia , Malformações Vasculares/complicações , Malformações Vasculares/diagnóstico , Veias/patologia , Adulto JovemRESUMO
OBJECTIVE: To delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to primary symptoms, the contribution of small copy number variations, and the impact of molecular diagnosis on clinical management. STUDY DESIGN: This was a prospective study of 17 tertiary care centers in Japan, conducted between April 2019 and March 2021. Critically ill neonates and infants less than 6 months of age were recruited in neonatal intensive care units and in outpatient clinics. The patients underwent medical exome, whole exome, or whole genome sequencing as the first tier of testing. Patients with negative results after medical exome or whole exome sequencing subsequently underwent whole genome sequencing. The impact of molecular diagnosis on clinical management was evaluated through contacting primary care physicians. RESULTS: Of the 85 patients, 41 (48%) had positive results. Based on the primary symptoms, patients with metabolic phenotypes had the highest diagnostic yield (67%, 4/6 patients), followed by renal (60%, 3/5 patients), and neurologic phenotypes (58%, 14/24 patients). Among them, 4 patients had pathogenic small copy number variations identified using whole genome sequencing. In the 41 patients with a molecular diagnosis, 20 (49%) had changes in clinical management. CONCLUSIONS: Genome analysis for critically ill neonates and infants had a high diagnostic yield for metabolic, renal, and neurologic phenotypes. Small copy number variations detected using whole genome sequencing contributed to the overall molecular diagnosis in 5% of all the patients. The resulting molecular diagnoses had a significant impact on clinical management.
Assuntos
Estado Terminal , Variações do Número de Cópias de DNA , Testes Genéticos/métodos , Humanos , Fenótipo , Estudos Prospectivos , Sequenciamento do Exoma/métodosRESUMO
Congenital disorders of glycosylation type I (CDG-I) are inherited human diseases caused by deficiencies in lipid-linked oligosaccharide (LLO) synthesis or the glycan transfer to proteins during N-glycosylation. We constructed a platform of 16 Schizosaccharomyces pombe strains that synthesize all possible theoretical combinations of LLOs containing three to zero glucose (Glc) residues and nine to five mannose (Man) residues. The occurrence of unexpected LLOs suggested the requirement of specific Man residues for glucosyltransferase activities. We then quantified protein hypoglycosylation in each strain and found that in S. pombe the presence of Glc in the LLO is more relevant to the transfer efficiency than the number of Man residues. Surprisingly, a decrease in the number of Man residues in glycans somehow improved the glycan transfer. The most severe hypoglycosylation was produced in cells that synthesized LLOs completely lacking Glc and having a high number of Man residues. This deficiency could be reverted by expressing a single-subunit oligosaccharyltransferase with a broad range of substrate specificity. Our work shows the usefulness of this new S. pombe set of mutants as a platform to model the molecular bases of human CDG-I diseases. This article has an associated First Person interview with the first authors of the paper.
Assuntos
Defeitos Congênitos da Glicosilação , Schizosaccharomyces , Defeitos Congênitos da Glicosilação/genética , Glicosilação , Humanos , Manose/metabolismo , Oligossacarídeos/metabolismo , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismoRESUMO
Resumen Los desórdenes congénitos de la glicosilación son un grupo de desórdenes genéticos de herencia, generalmente autosómica y recesiva. Descriptos por primera vez por Jaeken en 1980, comprenden defectos en la N- y O-glicosilación de proteínas y de lípidos. Los pacientes con defectos de N-glicosilación muestran un amplio espectro de manifestaciones clínicas, con alto compromiso neurológico. Por esta razón, se hace necesaria la implementación de una metodología que ayude en el diagnóstico. El Laboratorio de Pesquisa Neonatal incorporó el isoelectroenfoque de transferrina como método de screening y, posteriormente, secuenciación del gen PMM2 como método confirmatorio para las muestras con screening alterado. Se presentan, en este trabajo, la experiencia y los resultados obtenidos entre noviembre de 2017 y diciembre de 2018, los que permitieron establecer un algoritmo de trabajo que impactó positivamente en el diagnóstico de estos pacientes.
Abstract Congenital disorders of glycosylation are a group of genetic, autosomal and recessive diseases, first reported by Jaeken in 1980. These include defects in N- and O-glycosilation of proteins and lipids. Most N-glycosylation defects are multi-organ diseases with neurological involvement. Therefore, the implementation of a screening methodology is necessary to contribute in the diagnosis. Newborn Screening Laboratory included the transferrin isoelectrofocusing as a screening method and, subsequently, PMM2 gene sequencing as a confirmatory method for samples with altered screening. The present study shows the experience and results obtained between November 2017 and December 2018, which made it possible to establish an algorithm that positively impacted in the diagnosis of these patients.
Resumo Os defeitos congênitos da glicosilação (CDG) são um grupo de doenças genéticas, autossômicas e recessivas.Descritos pela primeira vez por Jaeken em 1980, eles incluem na N- e O- glicosilação de proteínas e lipídios.Pacientes com defeitos da N-glicosilação mostram um amplo espectro de manifestações clínicas, com alto comprometimento neurológico. Por esse motivo, a implementação de uma metodologia necessária para contribuirno diagnóstico. O Laboratório de Pesquisa Neonatal incorporou isoeletro-enfoque da transferrina (IEF)como método de screening e posterior sequenciamento do gene PMM2 como método confirmatório para asamostras que apresentaram triagem alterada. Neste trabalho, são apresentadas as experiências e resultadosobtidos entre novembro de 2017 e dezembro de 2018, que permitiram estabelecer um algoritmo de trabalhoque teve um impacto positivo no diagnóstico desses pacientes.
Assuntos
Anormalidades Congênitas , GlicosilaçãoRESUMO
Congenital disorders of glycosylation (CDG) are a heterogeneous group of genetic defects in glycoprotein and glycolipid glycan synthesis and attachment. A CDG subgroup are defects in the conserved oligomeric Golgi complex encoded by eight genes, COG1-COG8. Pathogenic variants in all genes except the COG3 gene have been reported. COG1-CDG has been reported in five patients. We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing. Exome sequencing identified a homozygous COG1 variant (NM_018714.3: c.2665dup: p.[Arg889Profs*12]), which has been reported previously in one patient. We review the reported patients.
Assuntos
Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/fisiopatologia , Proteínas Adaptadoras de Transporte Vesicular/genética , Defeitos Congênitos da Glicosilação/patologia , Mutação da Fase de Leitura , Glicosilação , Humanos , Recém-Nascido , Masculino , Sequenciamento do ExomaRESUMO
Human ALG2 encodes an α 1,3mannosyltransferase that catalyzes the first steps in the synthesis of N-glycans in the endoplasmic reticulum. Variants in ALG2cause a congenital disorder of glycosylation (CDG) known as ALG2-CDG. Up to date, nine ALG2-CDG patients have been reported worldwide. ALG2-CDG is a rare autosomal recessive inherited disorder characterized by neurological involvement, convulsive syndrome of unknown origin, axial hypotonia, and mental and motor regression. In this study, we used MALDI-TOF MS to define both total serum protein and transferrin (Tf) N-glycan phenotypes in three ALG2-CDG patients carrying a c.752G > T, p.Arg251Leu ALG2 missense variant in homozygous state, as determined by exome sequencing. Comparing it to control samples, we have observed Tf under-occupancy of glycosylation site(s) typical of a defective N-glycan assembly and the occurrence of oligomannose and hybrid type N-glycans. Moreover, we have observed a slight oligomannose accumulation in total serum glyco-profiles. The increased heterogeneity of serum N-glycome in the studied patients suggests a marginal disarrangement of the glycan processing in ALG2-CDG. Previous studies reported on slightly increased concentrations of abnormal serum N-glycans in CDG-I due to defects in the mannosylation steps of dolichol-linked oligosaccharide biosynthesis. This preliminary work aims at considering serum N-glycan accumulation of high mannosylated glycoforms, such as oligomannose and hybrid type N-glycans, as potential diagnostic signals for ALG2-CDG patients.
Assuntos
Defeitos Congênitos da Glicosilação/etiologia , Manosiltransferases/genética , Polissacarídeos/sangue , Argentina , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/genética , Feminino , Glicosilação , Homozigoto , Humanos , Focalização Isoelétrica , Masculino , Fenótipo , Polissacarídeos/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Transferrina/metabolismo , Sequenciamento do ExomaRESUMO
Herlyn-Werner-Wunderlich syndrome (HWWS), defined by the triad of uterus didelphys, obstructed hemivagina and ipsilateral renal agenesis, is a rare Mullerian duct malformation, usually diagnosed after menarche, when symptoms related to haematocolpos arise. We report a case of a 14-year-old patient who presented to the emergency department complaining of proctalgia and pelvic pain treated in our medical centre. Ultrasound and abdomino-pelvic MRI imaging studies confirmed the diagnosis. Treatment was surgical incision of the vaginal septum. At the follow-up visit, after the initial procedure, excess vaginal tissue was excised using a hysteroscopic approach during diagnostic vaginoscopy. Vaginoscopy-assisted treatment of the patient proved to be a safe and effective minimally invasive treatment modality that resulted in symptomatic relief and fertility preservation. In conclusion, although premenarche is asymptomatic in the vast majority of cases, HWWS would be optimally diagnosed in childhood to avoid acute late complications, although it is usually first diagnosed after menarche as a result of haematocolpos. Gynaecologists should consider the syndrome in the presence of pelvic mass, renal agenesis, menstrual changes and cyclic pelvic pain.
Assuntos
Nefropatias , Anormalidades Urogenitais , Adolescente , Feminino , Humanos , Rim/diagnóstico por imagem , Ductos Paramesonéfricos , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/diagnóstico por imagem , Útero/diagnóstico por imagem , Útero/cirurgia , Vagina/diagnóstico por imagem , Vagina/cirurgiaRESUMO
OBJECTIVE: To describe the clinical, biochemical, and genetic features of both new and previously reported patients with congenital disorders of glycosylation (CDGs) diagnosed in Portugal over the last 20 years. STUDY DESIGN: The cohort includes patients with an unexplained multisystem or single organ involvement, with or without psychomotor disability. Serum sialotransferrin isoforms and, whenever necessary, apolipoprotein CIII isoforms and glycan structures were analyzed. Additional studies included measurement of phosphomannomutase (PMM) activity and analysis of lipid-linked oligosaccharides in fibroblasts. Sanger sequencing and massive parallel sequencing were used to identify causal variants or the affected gene, respectively. RESULTS: Sixty-three individuals were diagnosed covering 14 distinct CDGs; 43 patients diagnosed postnatally revealed a type 1, 14 a type 2, and 2 a normal pattern on serum transferrin isoelectrofocusing. The latter patients were identified by whole exome sequencing. Nine of them presented also a hypoglycosylation pattern on apolipoprotein CIII isoelectrofocusing, pointing to an associated O-glycosylation defect. Most of the patients (62%) are PMM2-CDG and the remaining carry pathogenic variants in ALG1, ATP6AP1, ATP6AP2, ATP6V0A2, CCDC115, COG1, COG4, DPAGT1, MAN1B1, SLC35A2, SRD5A3, RFT1, or PGM1. CONCLUSIONS: Portuguese patients with CDGs are presented in this report, some of them showing unique clinical phenotypes. Among the 14 genes mutated in Portuguese individuals, 8 are shared with a previously reported Spanish cohort. However, regarding the mutational spectrum of PMM2-CDG, the most frequent CDG, a striking similarity between the 2 populations was found, as only 1 mutated allele found in the Portuguese group has not been reported in Spain.
Assuntos
Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Portugal , Fatores de Tempo , Adulto JovemRESUMO
Signal sequence receptor protein 4 (SSR4) is a subunit of the translocon-associated protein complex, which participates in the translocation of proteins across the endoplasmic reticulum membrane, enhancing the efficiency of N-linked glycosylation. Pathogenic variants in SSR4 cause a congenital disorder of glycosylation: SSR4-congenital disorders of glycosylation (CDG). We describe three SSR4-CDG boys and review the previously reported. All subjects presented with hypotonia, failure to thrive, developmental delay, and dysmorphic traits and showed a type 1 serum sialotransferrin profile, facilitating the diagnosis. Genetic confirmation of this X-linked CDG revealed one de novo hemizygous deletion, one maternally inherited deletion, and one de novo nonsense mutation of SSR4. The present subjects highlight the similarities with a connective tissue disorder (redundant skin, joint laxity, blue sclerae, and vascular tortuosity). The connective tissue problems are relevant, and require preventive rehabilitation measures. As an X-linked disorder, genetic counseling is essential.
Assuntos
Proteínas de Ligação ao Cálcio , Defeitos Congênitos da Glicosilação , Glicoproteínas de Membrana , Receptores Citoplasmáticos e Nucleares , Receptores de Peptídeos , Proteínas de Ligação ao Cálcio/genética , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/patologia , Tecido Conjuntivo/patologia , Glicosilação , Humanos , Masculino , Glicoproteínas de Membrana/genética , Fenótipo , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Peptídeos/genéticaRESUMO
Abstract The newborn screening program in Ecuador has been operating since 2011 under the responsibility of the Ministry of Health. This program is centralized and diagnoses four diseases: congenital hypothyroidism, phenylketonuria, galactosemia, and congenital adrenal hyperplasia. This study aimed to assess the geographical distribution of newborn screening cases in Ecuador. Spatial analysis techniques were applied using the records of the National Newborn Screening Program with a congenital disease confirmed from January 2012 to December 2019. Morbidity rates per 100,000 were calculated by newborn screening disease detected and the province of birth, posteriorly, the map of its distribution was graphed and assessed using the QGIS 3.12 software. In total, 393 cases born confirmed between 2012 and 2019 were registered. The distribution of every disease tends to be different in all provinces in Ecuador; the spatial variation was significant and relative rates showed a higher incidence in some eastern provinces. In conclusion, we found a different distribution and rates of newborn screening disorders in Ecuador. The high incidence of congenital hypothyroidism, phenylketonuria, galactosemia, and congenital adrenal hyperplasia in some areas should be investigated, due could be related to ethnic, genetic, and cultural aspects of the population.
RESUMO
Abstract Objectives: To characterize cases of suspected congenital disorders of glycosylation (CDG) investigated in a laboratory in southern Brazil using the transferrin isoelectric focusing TfIEF test from 2008 to 2017. Method: Observational, cross-sectional, retrospective study. The laboratory records of 1,546 individuals (median age = 36 months, 25-75 IQR = 10-108; males = 810) submitted to the TfIEF test during the period were reviewed. Results: Fifty-one individuals (3%) had an altered TfIEF pattern (5 ± 2.8 cases/year; median age = 24 months, 25-75 IQR = 11-57 months; males = 27, 53%). For 14 of them, data on diagnosis conclusion were available (classic galactosemia = 4; hereditary fructose intolerance = 4; peroxisomal diseases = 2; PMM2-CDG = 2; MPDU1-CDG = 1; SLC35A2-CDG = 1).Comparing the cases with the normal and altered TfIEF patterns, there was a higher prevalence of altered cases in the age group from 11 months to 3 years. There was an increase in the likelihood of change in TfIEF, especially in the presence of inverted nipples or liver disease. Conclusions: The data suggest that the investigation of a case with suspected CDG is a complex problem, being aggravated by the existence of other IEMs (inborn errors of metabolism) associated with altered TfIEF pattern and lack of access to confirmatory tests. The presence of inverted nipples and liver disease, especially in individuals aged 11 months to 3 years, should suggest the need for TfIEF investigation.
Resumo Objetivos: Caracterizar os casos com suspeita de CDG investigados em laboratório do sul do Brasil pelo exame de IEFTF de 2008 a 2017. Metodologia: Estudo observacional, transversal, retrospectivo. Foram revisadas as fichas laboratoriais de 1.546 indivíduos (mediana de idade = 36 meses, IQ 25-75 = 10-108; sexo masculino = 810) que fizeram o exame de IEFTF no período. Resultados: Cinquenta e um indivíduos (3%) apresentaram padrão alterado na IEFTF (5 ± 2,8 casos/ano; mediana de idade = 24 meses, IQ 25-75 = 11-57 meses; sexo masculino = 27, 53%). Para 14 deles, estavam disponíveis dados sobre a conclusão do diagnóstico (galactosemia clássica = 4; intolerância hereditária à frutose = 4; doenças peroxissomais = 2; PMM2-CDG = 2; MPDU1-CDG = 1; SLC35A2-CDG = 1). Comparando os casos com padrão normal e alterado na IEFTF, houve maior prevalência de casos alterados na faixa etária de 11 meses a 3 anos. Verificou-se um aumento na probabilidade de alteração na IEFTF principalmente na presença de mamilos invertidos ou de hepatopatia. Conclusões: Os nossos dados sugerem que a investigação de um caso com suspeita de CDG é complexa, é agravada pela existência de outros EIM associados a padrão alterado na IEFTF e pela falta de acesso a exames confirmatórios. A presença principalmente de mamilos invertidos e de hepatopatia em indivíduos na faixa etária de 11 meses a 3 anos deve sugerir a necessidade de investigação por IEFTF.
Assuntos
Humanos , Lactente , Transferrina/análise , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/epidemiologia , Focalização Isoelétrica , Brasil , Estudos Transversais , Estudos RetrospectivosRESUMO
Ebstein anomaly is a congenital heart defect with a low prevalence and high mortality in the early stages of life. In medical literature, there is no reported association between Ebstein anomaly and cri du chat syndrome. Here, we report the case of a full-term newborn with a low weight for his age and who had a prenatal diagnosis of Ebstein anomaly and a postnatal diagnosis of cri du chat syndrome and 20q duplication detected on array CGH. The patient required medical treatment with inotropic support, high-frequency ventilation and nitric oxide, with an adequate response. Surgical intervention was not needed.
Assuntos
Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 20 , Síndrome de Cri-du-Chat , Anomalia de Ebstein , Manuseio das Vias Aéreas/métodos , Cardiotônicos/uso terapêutico , Cromossomos Humanos Par 20/genética , Síndrome de Cri-du-Chat/complicações , Síndrome de Cri-du-Chat/diagnóstico , Síndrome de Cri-du-Chat/genética , Diagnóstico Diferencial , Anomalia de Ebstein/complicações , Anomalia de Ebstein/genética , Anomalia de Ebstein/fisiopatologia , Anomalia de Ebstein/terapia , Testes Genéticos/métodos , Humanos , Recém-Nascido , Masculino , Triagem Neonatal/métodos , Óxido Nítrico/uso terapêutico , Administração dos Cuidados ao Paciente , Diagnóstico Pré-Natal/métodos , Doenças RarasRESUMO
Resumen: En el contexto de Asociación VACTERL, el diagnóstico prenatal de atresia esofágica concomitante con atresia duodenal es poco común. En el presente artículo se realiza el reporte de un caso con la descripción de los hallazgos ecográficos encontrados a partir semana doce de gestación, con la aparición del signo de doble burbuja intraabdominal compatible con atresia duodenal y una arteria umbilical única; y hacia la semana 31 el hallazgo de imagen anecóica y dilatación esofágica del tercio distal con comunicación con la cámara gástrica en corte longitudinal, representando una atresia esofágica, asociada además a polihidramnios. Desde el momento del nacimiento por examen físico y estudios complementarios, se evidenció además ano imperforado con fístula recto vestibular, arcos costales derechos fusionados y hemivértebras. Por los anteriores hallazgos clínicos y radiológicos, se considera que se trata de una asociación VACTERL; sin embargo, sin alteraciones cardiacas, que es una de las características más frecuentemente encontradas. Se realiza una revisión del estado del arte con respecto a la asociación VACTERL y el diagnóstico prenatal de la atresia esofágica y duodenal.
Abstract: In the context of the VACTERL Association, prenatal diagnosis of concomitant esophageal atresia with duodenal atresia is rare. In this article, a case report is described with the description of the ultrasound findings found from week twelve of gestation, with the appearance of the intra-abdominal double bubble sign compatible with duodenal atresia and a single umbilical artery; and towards week 31 the finding of anechoic image and esophageal dilation of the distal-third with communication with the gastric chamber in longitudinal section, representing esophageal atresia, also associated with polyhydramnios. Physical examination and complementary studies from birth showed an imperforate anus with a rectovestibular fistula, and hemivertebrae. Based on the above clinical and radiological findings, it is considered to be a VACTERL association; however, without cardiac abnormalities, which is one of the most frequently found characteristics. A review of the state of the art is carried out with regard to the VACTERL association and the prenatal diagnosis of esophageal and duodenal atresia.
Resumo: No contexto da Associação VACTERL, o diagnóstico pré-natal de atrésia do esôfago concomitante com atrésia de duodeno é pouco comum. Neste artigo, é realizado relato de um caso com a descrição dos achados ecográficos encontrados a partir da 12a semana de gestação, com o surgimento do sinal de dupla bolha intra-abdominal compatível com a atrésia duodenal e uma artéria umbilical única; na 3ia semana, o achado de imagem anecoica e dilatação esofágica do rádio distai com comunicação com a câmara gástrica em corte longitudinal, o que representa atrésia esofágica, associada, ainda, a polidrâmnio. Desde o momento do nascimento por exame físico e estudos complementares, é evidenciado ânus imperfurado com fístula retal vestibular, arcos costais direitos fusionados e hemivértebras. A partir dos achados clínicos e radiológicos, é considerado que se trata de uma associação VACTERL; contudo, sem alterações cardíacas, que é uma das características mais frequentemente encontradas. É realizada uma revisão do estado da arte a respeito da associação VACTERL e o diagnóstico pré-natal da atrésia esofágica e duodenal.
Assuntos
Humanos , Gravidez , Recém-Nascido , Anormalidades Congênitas , Anus Imperfurado , Diagnóstico Pré-Natal , Atresia EsofágicaRESUMO
OBJECTIVES: To characterize cases of suspected congenital disorders of glycosylation (CDG) investigated in a laboratory in southern Brazil using the transferrin isoelectric focusing TfIEF test from 2008 to 2017. METHOD: Observational, cross-sectional, retrospective study. The laboratory records of 1,546 individuals (median age=36 months, 25-75 IQR=10-108; males=810) submitted to the TfIEF test during the period were reviewed. RESULTS: Fifty-one individuals (3%) had an altered TfIEF pattern (5±2.8 cases/year; median age=24 months, 25-75 IQR=11-57 months; males=27, 53%). For 14 of them, data on diagnosis conclusion were available (classic galactosemia=4; hereditary fructose intolerance=4; peroxisomal diseases=2; PMM2-CDG=2; MPDU1-CDG=1; SLC35A2-CDG=1).Comparing the cases with the normal and altered TfIEF patterns, there was a higher prevalence of altered cases in the age group from 11 months to 3 years. There was an increase in the likelihood of change in TfIEF, especially in the presence of inverted nipples or liver disease. CONCLUSIONS: The data suggest that the investigation of a case with suspected CDG is a complex problem, being aggravated by the existence of other IEMs (inborn errors of metabolism) associated with altered TfIEF pattern and lack of access to confirmatory tests. The presence of inverted nipples and liver disease, especially in individuals aged 11 months to 3 years, should suggest the need for TfIEF investigation.
Assuntos
Defeitos Congênitos da Glicosilação , Focalização Isoelétrica , Transferrina , Brasil , Defeitos Congênitos da Glicosilação/diagnóstico , Defeitos Congênitos da Glicosilação/epidemiologia , Estudos Transversais , Humanos , Lactente , Estudos Retrospectivos , Transferrina/análiseRESUMO
ABSTRACT Objective: analyze the pattern of spatial distribution of the prevalence rate of births with congenital disorders and its relationship with social, economic, health care and environmental indicators in Paraná, Brazil, from 2008 to 2015. Method: ecological study with variables extracted from secondary banks, related to the births of children of mothers residing in Paraná, in two quadrennial (2008-2011 and 2012-2015). The analysis of the rates was performed with univariate spatial (Moran) and multivariate approach (Ordinary Least Squares and Geographically Weighted Regression). Results: the occurrence of congenital disorders presented a significant association (p<0.05) with: registration in primary care of pregnant women over 20 years of age; urbanization degree; consumption of pesticides; and balance of female formal employment. Conclusion/Final considerations: social, health care and environmental variables showed a non-stationary spatial pattern in the analyzed period and influenced positively and negatively the rates.
RESUMEN Objetivo: Evaluar el patrón de distribución espacial de la tasa de prevalencia de los nacimientos con anomalías congénitas y su relación con los indicadores sociales, económicos, medioambientales, de atención a la salud en el estado de Paraná, Brasil, de 2008 a 2015. Método: Estudio ecológico con variables de bancos secundarios, relativas a los nacimientos de hijos de madres residentes en el estado de Paraná, en dos cuatrienios (2008-2011 y 2012-2015). Se hizo el análisis de las tasas desde el análisis espacial univariada (Moran) y multivariante (Ordinary Least Squares y Geographically Weighted Regression). Resultados: La presencia de anomalías congénitas presentó una asociación significativa (p <0,05) con: el registro en la atención primaria de gestantes mayores de 20 años de edad; el grado de urbanización; el consumo de agrotóxicos; y el saldo de empleo formal femenino. Conclusión: Las variables sociales, medioambientales y de atención a la salud demostraron haber un patrón espacial no estacionario en el período analizado, además influenciaron positiva y negativamente las tasas.
RESUMO Objetivo: Analisar o padrão de distribuição espacial da taxa de prevalência dos nascimentos com anomalias congênitas e sua relação com indicadores sociais, econômicos, de atenção à saúde e ambientais no estado do Paraná, Brasil, de 2008 a 2015. Método: Estudo ecológico com variáveis extraídas de bancos secundários, relativas aos nascimentos de filhos de mães residentes no estado do Paraná, em dois quadriênios (2008-2011 e 2012-2015). A análise das taxas foi realizada com abordagem espacial univariada (Moran) e multivariada (Ordinary Least Squares e Geographically Weighted Regression). Resultados: A ocorrência de anomalias congênitas apresentou associação significativa (p<0,05) com: cadastramento na atenção primária de gestantes maiores de 20 anos; grau de urbanização; consumo de agrotóxicos; e saldo de emprego formal feminino. Conclusão: As variáveis sociais, de atenção à saúde e ambientais demonstraram padrão espacial não estacionário no período analisado e influenciaram positiva e negativamente as taxas.
Assuntos
Adulto , Feminino , Humanos , Gravidez , Mapeamento Geográfico , Praguicidas/efeitos adversos , Fatores Socioeconômicos , Urbanização/tendências , Anormalidades Congênitas/epidemiologia , Brasil/epidemiologia , Resultado da Gravidez/epidemiologia , Estudos Retrospectivos , EcossistemaRESUMO
A 3-year-old mixed-breed female cat was diagnosed with a ventricular septal defect of the heart through an echocardiogram. After a 9-month treatment, progressive and diffuse hard thickening of all limbs was observed, which on radiographic examinations, revealed a marked thickening of the long bones. The necropsy findings were limited to the appendicular skeleton and thoracic vertebrae, in addition to a severe cardiac interventricular septal defect and lung edema. The histological evaluation revealed severe replacement of the cortical bone by spongy bone in all bone fragments examined. This is the first report of hypertrophic osteopathy occurring in association with a cardiac malformation in a cat.
Assuntos
Doenças do Gato/patologia , Comunicação Interventricular/veterinária , Hiperostose/veterinária , Animais , Doenças do Gato/diagnóstico , Gatos , Ecocardiografia/veterinária , Feminino , Comunicação Interventricular/diagnóstico por imagem , Hiperostose/diagnóstico , Hiperostose/patologiaRESUMO
BACKGROUND: Type II Congenital Disorders of Glycosylation (CDG-II) are a group of diseases with challenging diagnostics characterized by defects in the processing of glycans in the Golgi apparatus. Mass Spectrometry (MS) has been a valuable tool in the definition of CDG-II subtypes. While some CDG-II subtypes are associated with specific N-glycan structures, others only produce changes in relative levels, reinforcing the demand for quantification methods. METHODS: Plasma samples from control individuals were pooled, derivatized with deuterated iodomethane (I-CD3), and used as internal standards for controls and patients whose glycans were derivatized with iodomethane (I-CH3), followed by MALDI MS, LC-MS and -MS/MS analyses. RESULTS: Total N-glycans from fifteen CDG-II patients were evaluated, and 4 cases with molecular diagnosis were considered in detail: 2ATP6V0A2-CDG siblings, and 2 MAN1B1-CDG patients, one of them carrying a previously undescribed p.Gly536Val mutation. CONCLUSIONS: Our methodology offers a feasible alternative to the current methods for CDG-II diagnosis by MS, which quantify glycan structures as fractions of the total summed signal across a mass spectrum, a strategy that lowers the variability of minor components. Moreover, given its sensitivity for less concentrated yet biologically relevant structures, it might assist the uncovering of novel diagnostic glycans in other CDG-II subtypes.
Assuntos
Análise Química do Sangue/métodos , Defeitos Congênitos da Glicosilação/sangue , Polissacarídeos/sangue , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Adolescente , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/genética , Feminino , Genótipo , Humanos , Lactente , Masculino , MutaçãoRESUMO
Glucosidase I (GI) removes the outermost glucose from protein-linked Glc3Man9GlcNAc2 (G3M9) in the endoplasmic reticulum (ER). Individuals with congenital disorders of glycosylation MOGS-CDG bear mutations in the GI-encoding gene (gls1). Although GI absence has been reported to produce lethality in Schizosaccharomyces pombe yeasts, here we obtained two viable Δgls1 mutants, one with a very sick but not lethal phenotype (Δgls1-S) and the other with a healthier one (Δgls1-H). The sick strain displayed only G3M9 as an ER protein-linked oligosaccharide, whereas the healthier strain had both G3M9 and Man9GlcNAc2 The lipid-linked oligosaccharide patterns of the two strains revealed that the most abundantly formed glycans were G3M9 in Δgls1-S and Glc2Man9GlcNAc2 in Δgls1-H, suggesting reduced Alg10p glucosyltransferase activity in the Δgls1-H strain. A mutation in the alg10+ gene was indeed observed in this strain. Our results indicated that abrogated G3M9 deglucosylation was responsible for the severe defects observed in Δgls1-S cells. Further studies disclosed that the defects could not be ascribed to disruption of glycoprotein entrance into calnexin-folding cycles, inhibition of the oligosaccharyltransferase by transfer reaction products, or reduced proteasomal degradation of misfolded glycoproteins. Lack of triglucosylated glycoprotein deglucosylation neither significantly prevented glycan elongation in the Golgi nor modified the overall cell wall monosaccharide composition. Nevertheless, it resulted in a distorted cell wall and in the absence of underlying ER membranes. Furthermore, Golgi expression of human endomannosidase partially restored normal growth in Δgls1-S cells. We propose that accumulation of G3M9-bearing glycoproteins is toxic and at least partially responsible for defects observed in MOGS-CDG.
Assuntos
Defeitos Congênitos da Glicosilação , Deleção de Genes , Modelos Biológicos , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , alfa-Glucosidases , Defeitos Congênitos da Glicosilação/enzimologia , Defeitos Congênitos da Glicosilação/genética , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/genética , Glucosiltransferases/genética , Glucosiltransferases/metabolismo , Glicosilação , Humanos , Oligossacarídeos/genética , Oligossacarídeos/metabolismo , Schizosaccharomyces/enzimologia , Schizosaccharomyces/genética , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismo , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismoRESUMO
BACKGROUND: Supernumerary Marker Chromosomes consist in structurally abnormal chromosomes, considered as an extra chromosome in which around 70% occur as a de novo event and about 30% of the cases are mosaic. Tetrasomy 9p is a rare chromosomal abnormality described as the presence of a supernumerary isochromosome 9p. Clinical features of tetrasomy 9p include a variety of physical and developmental abnormalities. CASE PRESENTATION: Herein, we reported a postnatal case of a newborn who died in early infancy with multiple congenital malformations due to a mosaic de novo tetrasomy 9p detected by Chromosomal Microarray Analysis. Conventional cytogenetics analysis of the proband was 47,XY,+mar[45]/46,XY[5]. The parental karyotypes presented no visible numerical or structural alterations. Microarray Analysis of the proband revealed that the marker chromosome corresponded to a mosaic de novo gain at 9p24.3q21.11. CONCLUSIONS: Chromosomal Microarray Analysis was helpful to identify the origin of the supernumerary marker chromosome and it was a powerful tool to carry out genetic diagnostic, guiding the medical diagnosis. Furthermore, the CMA allowed observing at the first time in Central Brazil the tetrasomy 9p and partial tetrasomy 9q in mosaic, encompassing a large duplicated region with several morbid genes, in an infant with multiple congenital malformations.