RESUMEN
OBJECTIVE: To survey the incidence of intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) by gestational age and to report the impact on mortality and neurodevelopmental outcome in very preterm/very low birthweight infants. STUDY DESIGN: This was a population-based cohort study of 1927 very preterm/very low birthweight infants born in 2014-2016 and admitted to Flemish neonatal intensive care units. Infants underwent standard follow-up assessment until 2 years corrected age with the Bayley Scales of Infant and Toddler Development and neurological assessments. RESULTS: No brain lesion was present in 31% of infants born at <26 weeks of gestation and 75.8% in infants born at 29-32 weeks of gestation. The prevalence of low-grade IVH/PVL (grades I and II) was 16.8% and 12.7%, respectively. Low-grade IVH/PVL was not related significantly to an increased likelihood of mortality, motor delay, or cognitive delay, except for PVL grade II, which was associated with a 4-fold increase in developing cerebral palsy (OR, 4.1; 95% CI, 1.2-14.6). High-grade lesions (III-IV) were present in 22.0% of the infants born at <26 weeks of gestational and 3.1% at 29-32 weeks of gestation, and the odds of death were ≥14.0 (IVH: OR, 14.0; 95% CI, 9.0-21.9; PVL: OR, 14.1; 95% CI, 6.6-29.9). PVL grades III-IV showed an increased odds of 17.2 for motor delay and 12.3 for cerebral palsy, but were not found to be associated significantly with cognitive delay (OR, 2.9; 95% CI, 0.5-17.5; P = .24). CONCLUSIONS: Both the prevalence and severity of IVH/PVL decreased significantly with advancing gestational age. More than 75% of all infants with low grades of IVH/PVL showed normal motor and cognitive outcome at 2 years corrected age. High-grade PVL/IVH has become less common and is associated with adverse outcomes.
Asunto(s)
Parálisis Cerebral , Enfermedades del Prematuro , Leucomalacia Periventricular , Recién Nacido , Lactante , Humanos , Niño , Leucomalacia Periventricular/epidemiología , Recien Nacido Extremadamente Prematuro , Parálisis Cerebral/etiología , Estudios de Cohortes , Estudios Prospectivos , Recién Nacido de muy Bajo Peso , Hemorragia Cerebral/epidemiología , Hemorragia Cerebral/complicaciones , Enfermedades del Prematuro/epidemiologíaRESUMEN
The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier-Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Microcefalia , Trastornos del Neurodesarrollo , Humanos , Cisteína/genética , Trastornos del Neurodesarrollo/genética , Proteínas de Ciclo Celular/genética , ADN Helicasas/genética , Microcefalia/genética , Fenotipo , Zinc , Discapacidad Intelectual/genética , Componente 6 del Complejo de Mantenimiento de Minicromosoma/genéticaRESUMEN
Whether or not cranial ultrasound (crUS) and cerebral magnetic resonance imaging (MRI) have both a place in the assessment of children with congenital cytomegalovirus infection (cCMV) remains a topic of discussion between research groups. Literature suggests that MRI is indicated only in children with abnormal crUS.In Flanders, Belgium, combined crUS and MRI was performed on 639 children with cCMV, referred for diagnostic assessment. Cranial US was classified as abnormal in the presence of striatal vasculopathy, calcifications, cysts, cystic germinolysis, and/or ventriculomegaly. MRI findings were classified as abnormal in the presence of gyration disorders, cerebellar abnormalities, ventriculomegaly, cysts, or pathologic white matter lesions.One in five children (93/480) with normal crUS showed abnormal findings on MRI. Of them, 85 (91.4%) were classified as symptomatic. In 37 of those 93 children (39.8%), classification as severely symptomatic was made based on MRI lesions alone. MRI and crUS proved to be complementary in the assessment of CNS involvement in children with cCMV. Long-term studies are needed to evaluate the importance of this finding with respect to outcome and benefit of therapy in this particular subgroup of patients with cCMV infection.Conclusion: Our findings support an enhanced role of MRI in the diagnosis of CNS involvement in children with cCMV infection. The ideal assessment should include both imaging techniques, as the strengths of each test compensate for the other's weaknesses. What is Known: ⢠Congenital CMV infection involves the central nervous system with direct injury to and possible disruption of brain development. ⢠Experts suggest that MRI is indicated only in children with abnormal crUS. What is New: ⢠In almost 20% of our children with a normal cranial ultrasound, abnormalities were detected on MRI. ⢠Our results suggest that performing both MRI and cranial US is important to obtain a complete assessment of central nervous system involvement in children with cCMV.
Asunto(s)
Infecciones por Citomegalovirus , Enfermedades del Sistema Nervioso , Niño , Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/diagnóstico por imagen , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , UltrasonografíaRESUMEN
BACKGROUND: With constant changes in neonatal care practices, recent information is valuable for healthcare providers and for parental counselling. The aim of the study was to describe the neurodevelopmental outcome in a cohort of very preterm (VPT)/very-low-birthweight (VLBW) infants at 2 years corrected age (CA). MATERIAL AND METHODS: This is a population-based cohort study of all infants born with a GA <31 weeks and/or BW < 1500 g between 2014 and 2016 admitted to the Flemish (Belgium) neonatal intensive care units. Infants had routine clinical follow-up around 2 years CA. The diagnosis of cerebral palsy (CP), visual and hearing impairments were recorded. Motor, cognitive and language outcomes were assessed using the Bayley-III. Neurodevelopmental impairment (NDI) was classified as mild (<1 standard deviation [SD]) or moderate-severe (<2SD) based on the defined categories of motor, cognitive, hearing, and vision impairments. RESULTS: Of the 1941 admissions, 92% survived to discharge and follow-up data were available for 1089 infants (61.1%). Overall, 19.3%, 18.9% and 41.8% of infants had a motor, cognitive and language delay, respectively. CP was diagnosed in 4.3% of the infants. Mild and moderate-to-severe NDI was observed in 25.2% and 10.9% of the infants, respectively. The number of infants with a normal outcome increased from nearly 40% in the category of GA<26 weeks to 70% for infants in the category of 30â31 weeks GA. CONCLUSION: At 2 years CA, 64% were free from NDI and 90% were free from moderate-to-severe NDI. However, a lower GA and BW are associated with higher rates of adverse neurodevelopmental outcomes at 2 years CA.
Asunto(s)
Parálisis Cerebral/epidemiología , Discapacidades del Desarrollo/epidemiología , Recien Nacido Extremadamente Prematuro , Recién Nacido de muy Bajo Peso , Bélgica , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Nacimiento Prematuro/fisiopatologíaRESUMEN
To evaluate the potential of dried blood spots (DBS) as a congenital cytomegalovirus (cCMV) testing specimen, the laboratory diagnostic accuracy of polymerase chain reaction (PCR) on DBS was compared to viral urine cultures from neonates suspected for cCMV. Two different extraction methods (EasyMAG, bioMérieux versus Qiagen) and 2 real-time PCR protocols (in-house versus Argene) were compared. We were able to collect both DBS and urine samples in 6 Belgian neonatal units from 276 neonates suspected for cCMV registered in CMVREG (an online neonatal registry system). Forty-eight neonates (17.4%) were positive by viral culture in urine. Laboratory diagnostic accuracy parameters of DBS-PCR were both extraction method and PCR protocol dependent. Not all DBS-CMV-PCR methods successfully detected urine-culture-positive neonates born after first-trimester seroconversions. Interestingly, however, all urine-culture-positive neonates having clinical signs of cCMV did consistently score positive.
Asunto(s)
Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/diagnóstico , Citomegalovirus/aislamiento & purificación , Pruebas con Sangre Seca , Reacción en Cadena en Tiempo Real de la Polimerasa , Orina/virología , Bélgica , Citomegalovirus/genética , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/orina , ADN Viral/genética , Humanos , Recién Nacido , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Sensibilidad y Especificidad , Carga ViralRESUMEN
OBJECTIVE: With the identification of mutations in the conserved telomere maintenance component 1 (CTC1) gene as the cause of Coats plus (CP) disease, it has become evident that leukoencephalopathy with calcifications and cysts (LCC) is a distinct genetic entity. PATIENTS AND METHODS: A total of 15 patients with LCC were identified from our database of patients with intracranial calcification. The clinical and radiological features are described. RESULTS: The median age (range) at presentation was 10 months (range, 2 days-54 years). Of the 15 patients, 9 presented with epileptic seizures, 5 with motor abnormalities, and 1 with developmental delay. Motor abnormalities developed in 14 patients and cognitive problems in 13 patients. Dense calcification occurred in the basal ganglia, thalami, dentate nucleus, brain stem, deep gyri, deep white matter, and in a pericystic distribution. Diffuse leukoencephalopathy was present in all patients, and it was usually symmetrical involving periventricular, deep, and sometimes subcortical, regions. Cysts developed in the basal ganglia, thalamus, deep white matter, cerebellum, or brain stem. In unaffected areas, normal myelination was present. No patient demonstrated cerebral atrophy. CONCLUSION: LCC shares the neuroradiological features of CP. However, LCC is a purely neurological disorder distinguished genetically by the absence of mutations in CTC1. The molecular cause(s) of LCC has (have) not yet been determined.
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Encefalopatías/diagnóstico , Calcinosis/diagnóstico , Quistes/diagnóstico , Leucoencefalopatías/diagnóstico , Enfermedades del Sistema Nervioso/diagnóstico , Adolescente , Adulto , Encefalopatías/complicaciones , Calcinosis/complicaciones , Niño , Preescolar , Quistes/complicaciones , Humanos , Lactante , Recién Nacido , Leucoencefalopatías/complicaciones , Imagen por Resonancia Magnética , Persona de Mediana Edad , Tomógrafos Computarizados por Rayos X , Adulto JovenRESUMEN
Hypotonia-cystinuria syndrome (HCS) is an autosomal recessive disorder caused by combined deletions of SLC3A1 and PREPL. Clinical features include cystinuria, neonatal hypotonia with spontaneous improvement, poor feeding in neonates, hyperphagia in childhood, growth hormone deficiency, and variable cognitive problems. Only 14 families with 6 different deletions have been reported. Patients are often initially misdiagnosed, while correct diagnosis enables therapeutic interventions. We report two novel deletions, further characterizing the clinical and molecular genetics spectrum of HCS.
Asunto(s)
Sistemas de Transporte de Aminoácidos Básicos/genética , Sistemas de Transporte de Aminoácidos Neutros/genética , Anomalías Craneofaciales/genética , Cistinuria/genética , Discapacidad Intelectual/genética , Enfermedades Mitocondriales/genética , Hipotonía Muscular/genética , Serina Endopeptidasas/genética , Sistemas de Transporte de Aminoácidos Básicos/deficiencia , Sistemas de Transporte de Aminoácidos Neutros/deficiencia , Secuencia de Bases , Niño , Deleción Cromosómica , Cromosomas Humanos Par 21/genética , Anomalías Craneofaciales/patología , Cistinuria/patología , Femenino , Heterogeneidad Genética , Homocigoto , Humanos , Lactante , Discapacidad Intelectual/patología , Masculino , Enfermedades Mitocondriales/patología , Datos de Secuencia Molecular , Hipotonía Muscular/patología , Prolil Oligopeptidasas , Eliminación de Secuencia , Serina Endopeptidasas/deficiencia , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To assess health and neurodevelopmental outcome at 3 years of age in neonatal intensive care unit (NICU)-surviving children who were born at 26 or fewer weeks of gestation in a geographically defined region of Belgium from 1999 through 2000. METHODS: The study included a clinical examination and a standardized neurologic and developmental assessment. Disabilities were defined by international criteria. In 97% (92 of 95) of the children, accurate information on the presence of overall disability could be collected. RESULTS: Thirty-six percent (95% confidence interval [CI] 25-47%) of the formally assessed children (28 of 77) had deficient neuromotor development, with 5% of them showing severe sensory-communicative impairment. Mean (+/-standard deviation) scores on the Mental Developmental Index and Psychomotor Developmental Index were 81.2 (18.8) and 73.2 (17.8), respectively. Seventy percent (95% CI 60-80%) had a mental (Mental Developmental Index) or psychomotor (Psychomotor Developmental Index) impairment or both, assessed to be more than 1 standard deviation below the population mean. Mental and psychomotor outcome did not differ significantly when compared according to either gestational age, gender, or multiple birth (all P>.05). When either minor central dysfunction or cerebral palsy was not taken into account, normal mental development was recorded in 62% of the subjects. The cumulative of poor outcome (ie, disability- or prematurity-related death) among the 95 infants discharged alive was estimated to be 58% (95% CI 48-68%), representing 25 (26%) mildly-to-moderately disabled and 28 (29%) severely disabled toddlers, including two infants whose postdischarge deaths were directly related to prematurity. CONCLUSION: The average developmental outcome is poor in children born as extremely preterm infants. Finding early predictors of adverse outcome is a major challenge.