Asunto(s)
Encéfalo/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/virología , Infección por el Virus Zika/congénito , Infección por el Virus Zika/complicaciones , Encéfalo/patología , Femenino , Humanos , Lactante , Malformaciones del Desarrollo Cortical/patologíaRESUMEN
In 2015, there was an increase in the incidence of congenital microcephaly in newborns in Brazil. Months later, the causal relationship between Zika virus and these findings was discovered. In Argentina, during the first outbreak there were 5 cases of congenital Zika syndrome reported. In 2017, there was a new outbreak which involved Salta province. We describe 2 patients with autochthonous congenital Zika syndrome: one of the babies with severe congenital microcephaly with lissencephaly, calcifications and ventriculomegaly; and another baby with postnatal microcephaly with asymmetric polymicrogyria, calcifications and delayed myelination. The real impact of this disease is still uncertain, so it is necessary an adequate multidisciplinary monitoring of patients exposed to Zika virus to better understand the infection and its natural history.
En 2015, se observó un incremento en la incidencia de microcefalia congénita en recién nacidos en Brasil. Meses más tarde, se descubrió la relación causal entre el virus del Zika y estos hallazgos. Durante el primer brote en la Argentina, se reportaron 5 casos de síndrome de Zika congénito. En 2017, hubo un nuevo brote que involucró la provincia de Salta. En este trabajo, se presentan 2 casos clínicos con síndrome de Zika congénito autóctonos: una paciente con microcefalia congénita grave con lisencefalia, calcificaciones corticosubcorticales y ventriculomegalia y otra paciente con microcefalia posnatal con polimicrogiria asimétrica y calcificaciones subcorticales y retraso en la mielinización. El real impacto de esta enfermedad aún es incierto; es necesario un adecuado seguimiento multidisciplinario de los pacientes expuestos al virus del Zika para comprender mejor la infección y su historia natural.
Asunto(s)
Lisencefalia/virología , Malformaciones del Desarrollo Cortical/virología , Microcefalia/virología , Infección por el Virus Zika/fisiopatología , Argentina , Femenino , Humanos , Hidrocefalia/virología , Recién Nacido , Infección por el Virus Zika/congénitoRESUMEN
OBJECTIVE: The etiology of focal cortical dysplasia type IIb (FCDIIb) remains enigmatic in patients suffering from drug-resistant epilepsy, and an aberrant activation of the mammalian target of rapamycin complex 1 signaling pathway (mTORC1) was detected in this developmental brain malformation. Recently, the human papillomavirus (HPV) oncoprotein E6 has been identified as a potent activator of mTORC1, and HPV16 E6 has been described to persist in balloon cells obtained from surgical FCDIIb specimens. Although this observation was replicated by an independent second report, it contradicts current knowledge of HPV biology. HPV infects the squamous or mucocutaneous epithelium; hematogenic spread into other tissues has not been observed. In addition, brain carcinogenesis has never been reported in FCDIIb patients. Herein, we have tried to confirm 2 previous reports of HPV16 E6 infection using an independent series of 14 surgical specimens with histopathologically confirmed FCDIIb. METHODS: Snap-frozen FCDIIb specimens were tested for HPV DNA using the primer set for amplification of the complete E6 reading frame of HPV16 and 3 other sets of primers (2 consensus primer sets detecting multiple HPV genotypes, and another primer set specifically used for HPV16). Furthermore, formalin-fixed and paraffin-embedded histopathological preparations were immunohistochemically analyzed using previously described antibodies directed against the HPV E6 oncoprotein. RESULTS: All 14 FCDIIb specimens were negative for HPV DNA with all 4 primer sets. Antibodies directed against the HPV E6 epitope showed weak labeling of cytoplasm in balloon cells, as previously described in FCDIIb, but also in other cell populations. INTERPRETATION: Our data did not confirm previously reported evidence for HPV16 detection in FCDIIb.
Asunto(s)
Proteínas de Unión al ADN/aislamiento & purificación , Malformaciones del Desarrollo Cortical/diagnóstico , Malformaciones del Desarrollo Cortical/virología , Proteínas Oncogénicas Virales/aislamiento & purificación , Infecciones por Papillomavirus/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Malformaciones del Desarrollo Cortical/cirugía , Diana Mecanicista del Complejo 1 de la Rapamicina , Complejos Multiproteicos/aislamiento & purificación , Infecciones por Papillomavirus/epidemiología , Serina-Treonina Quinasas TOR/aislamiento & purificación , Adulto JovenRESUMEN
We report the prenatal magnetic resonance imaging (MRI) appearance of polymicrogyria with pathologic correlation in a fetus with congenital parvovirus B19 infection. Prenatal ultrasound revealed non-immune hydrops, but detected no fetal brain abnormalities. A subsequent fetal MRI scan performed at 23 weeks' gestation demonstrated bilateral polymicrogyria, which was confirmed at autopsy. To our knowledge, prenatal diagnosis of polymicrogyria in association with congenital parvovirus B19 infection has not been previously described. This case provides further evidence for brain abnormalities resulting from congenital parvovirus B19 infection, and suggests that fetal neuroimaging with MRI would be of value in suspected cases of congenital parvovirus infection.
Asunto(s)
Eritema Infeccioso/diagnóstico , Hidropesía Fetal/diagnóstico , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical/diagnóstico , Complicaciones Infecciosas del Embarazo/diagnóstico , Ultrasonografía Prenatal , Aborto Inducido , Adulto , Diagnóstico Diferencial , Eritema Infeccioso/diagnóstico por imagen , Eritema Infeccioso/virología , Femenino , Humanos , Hidropesía Fetal/diagnóstico por imagen , Hidropesía Fetal/virología , Malformaciones del Desarrollo Cortical/diagnóstico por imagen , Malformaciones del Desarrollo Cortical/virología , Parvovirus B19 Humano , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico por imagen , Complicaciones Infecciosas del Embarazo/virologíaRESUMEN
OBJECTIVE: Focal cortical dysplasia type IIB (FCDIIB) is a sporadic developmental malformation of the cerebral cortex highly associated with pediatric epilepsy. Balloon cells (BCs) in FCDIIB exhibit constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Recently, the high-risk human papillomavirus type 16 oncoprotein E6 was identified as a potent activator of mTORC1 signaling. Here, we test the hypothesis that HPV16 E6 is present in human FCDIIB specimens. METHODS: HPV16 E6 protein expression was assayed by immunohistochemistry in FCDIIB specimens (n = 50) and control brain specimens (n = 36). HPV16 E6 DNA was assayed by polymerase chain reaction (PCR) and in situ hybridization; HPV16 E6 mRNA was assayed by reverse transcriptase PCR. HPV16 E6 was transfected into fetal mouse brains by in utero electroporation to test the effects of E6 on cortical development. RESULTS: HPV16 E6 protein was robustly expressed in all FCDIIB specimens in BCs, but not in regions without BCs or in control tissue specimens including normal brain, lymphoblasts, and fibroblasts, cortical tubers, and U87 glioma cells. E6 expression in FCDIIB colocalized with phosphoactivated S6 protein, a known mTORC1 substrate. HPV16 E6 DNA and mRNA were detected in representative specimens of FCDIIB but not control cortex, and were confirmed by sequencing. Transfection of E6 into fetal mouse brains caused a focal cortical malformation in association with enhanced mTORC1 signaling. INTERPRETATION: Our results indicate a new association between HPV16 E6 and FCDIIB and demonstrate for the first time HPV16 E6 in the human brain. We propose a novel etiology for FCDIIB based on HPV16 E6 expression during fetal brain development.
Asunto(s)
Encefalopatías/patología , Encéfalo/metabolismo , Malformaciones del Desarrollo Cortical/patología , Proteínas Oncogénicas Virales/metabolismo , Adolescente , Adulto , Anciano , Animales , Encéfalo/virología , Encefalopatías/etiología , Encefalopatías/virología , Línea Celular Tumoral , Niño , Preescolar , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Electroporación , Embrión de Mamíferos , Células Madre Embrionarias/metabolismo , Células Madre Embrionarias/virología , Epilepsia , Femenino , Regulación Viral de la Expresión Génica/fisiología , Infecciones por VIH/complicaciones , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Humanos , Lactante , Masculino , Malformaciones del Desarrollo Cortical/etiología , Malformaciones del Desarrollo Cortical/virología , Malformaciones del Desarrollo Cortical de Grupo I , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Complejos Multiproteicos/metabolismo , Proteínas Oncogénicas Virales/genética , ARN Mensajero/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias del Cuello Uterino/patología , Adulto JovenRESUMEN
Congenital cytomegalovirus (CMV) infection is the most common vertically transmitted disease with the rate of the infection ranging from 0.2 to 2.4% in newborn infants. Congenital CMV infection causes multiorgan affection, but the most severe and permanent sequelae are those affecting central nervous system such as mental retardation, cerebral palsy, sensorineural hearing loss, chorioretinitis and seizures as a result of direct interference of the virus with neurogenesis. The time of acquiring infection is strongly connected to the level of child's disability. Infection in early pregnancy results in severe neurological sequelae, while later infection has less prominent signs. Radiological findings show connection between onset of infection and brain imaging, from lissencephaly, pachygyria, polymicrogyria, schizencephaly, calcification, cerebellar hypoplasia and/or hypoplasia/agenesis of corpus callosum as a result of an early infection, to white matter abnormalities including disturbed myelination as a result of a late infection. We present nine patients with proven congenital CMV infection and malformations of cortical development and their computed tomography/magnetic resonance (CT/MRI) findings along with clinical assessments. According to CT/MRI results we assume that two of our children with lissencephaly had an early onset of infection. The other seven with less severe cortical dysplasia in form of pachy/polymicrogyria were probably infected later Cerebellar hypoplasia and/or calcifications in our patients also confirm an early onset of infection. Developmental outcome in all of our children was poor: moderate to severe psychomotor retardation has been diagnosed in all children; five of them have developed cerebral palsy (four have bilateral spastic and one dyskinetic) and one is estimated to have minor motor dysfunction. Seven out of nine developed epilepsy, chorioretinitis was found in three of them and sensorineural deafness in two of them. All of our children, except one, were presented by symptomatic infection, yet only four of them were recognized at birth. Therefore, congenital CMV infection should be considered as one of the reasons for childhood disability more often.
Asunto(s)
Infecciones por Citomegalovirus/congénito , Malformaciones del Desarrollo Cortical/virología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
We report a rare case of polymicrogyria diagnosed at 27 weeks' gestation on ultrasound examination and associated with cytomegalovirus (CMV) infection. The ultrasound finding suggesting this diagnosis was the direct visibility of the overfolded cortical ribbon. The cerebral surface was clearly visible because of a markedly enlarged pericerebral space associated with micrencephaly secondary to CMV infection. Bilateral opercular dysplasia was also present. Very few sonographic markers of infectious fetopathy were observed other than periventricular cysts located behind both ventricular horns. Magnetic resonance imaging (MRI) of the fetal brain confirmed the ultrasound findings and also showed the presence of marked micrencephaly, whereas cephalic measurements acquired on ultrasound examination (biparietal diameter and head circumference) were within the normal range. This case emphasizes the complementary roles of sonography and MRI in the prenatal diagnosis of cerebral abnormalities. Moreover, it illustrates the fact that polymicrogyria is easier to diagnose on ultrasound examination during the second trimester, before the development of secondary sulci.