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OBJECTIVES: To estimate the association between fetal congenital heart defects (CHDs) and measures of brain size throughout pregnancy, from the end of the first trimester to birth. STUDY DESIGN: The cohort consisted of all fetuses scanned in Western Denmark in 2012 and 2013. Anthropometric measures in fetuses with isolated CHDs diagnosed within 12 months after birth were compared with those in the fetuses without CHDs. Z-scores standardized to gestational age were calculated for first trimester biparietal diameter, second trimester head circumference, fetal weight, birthweight, head circumference, and placental weight. RESULTS: We obtained data from 63 349 pregnancies and identified 295 fetuses with isolated CHDs (major n = 145; minor n = 150). The first trimester mean biparietal diameter Z-scores were not different between those with and those without CHDs. The head circumference mean Z-score difference was -0.13 (95% CI, -0.24 to -0.01; P = .03) in the second trimester and -0.22 (95% CI, -0.35 to -0.09; P < .001) at birth. Fetuses with univentricular physiology or tetralogy of Fallot showed the most pronounced compromise in cerebral size. CONCLUSIONS: Our results suggest that the brain alterations inducing an increased risk of impaired neurodevelopment in children with CHDs begin during pregnancy. Although fetuses with univentricular physiology or tetralogy of Fallot exhibited the most pronounced compromise in cerebral size, we recommend neurodevelopmental follow-up for all children with CHDs.
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Cefalometria , Cardiopatias Congênitas/epidemiologia , Ultrassonografia Pré-Natal , Peso ao Nascer , Estudos de Casos e Controles , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Peso Fetal , Humanos , Recém-Nascido , Placenta/anatomia & histologia , Gravidez , Análise de RegressãoRESUMO
Infant respiratory distress syndrome (IRDS) may be complicated by intracerebral hemorrhage, a known trigger of epilepsy. However, few data exist on long term epilepsy risk following IRDS. We therefore examined the association between IRDS in preterm infants and childhood epilepsy. We conducted a population-based cohort study using individual-level data linkage among nationwide registries. All infants born at 32-36 weeks of gestation in 1978-2009 were identified in the Medical Birth Registry. We identified children with IRDS and those with epilepsy using the Danish National Patient Registry. We computed the cumulative incidence of epilepsy with follow-up from birth until epilepsy, emigration, death, age 15, or December 31, 2014. We used Cox's regression analysis to compute hazard ratios comparing children with and without IRDS, adjusting for sex, birth year, gestational age, multiplicity, major malformations, and maternal age. We identified 95,026 infants, of whom 6426 (6.8%) had IRDS. The cumulative incidence of epilepsy was 3.4% by age 15 in children with IRDS and 2.1% in children without IRDS. The adjusted hazard ratio of epilepsy among children with IRDS compared to those without was 1.4 (95% CI 1.2-1.6). When we restricted the IRDS cohort to children with no simultaneous morbidities that had clinical symptoms overlapping with IRDS, the overall adjusted HR was 1.1 (95% CI 0.9-1.4). In children born preterm at 32-36 weeks' gestation, IRDS was associated with increased risk of childhood epilepsy.
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Epilepsia/epidemiologia , Recém-Nascido Prematuro , Síndrome do Desconforto Respiratório do Recém-Nascido/epidemiologia , Criança , Estudos de Coortes , Dinamarca/epidemiologia , Epilepsia/complicações , Feminino , Idade Gestacional , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Idade Materna , Transtornos do Neurodesenvolvimento/epidemiologia , Fatores de RiscoRESUMO
Deletion of chromosome 22q11.2 is considered one of the most frequent genetic causes of cardiovascular malformations. It is frequently associated with conotruncal malformations, but may also be present among patients with nonconotruncal malformations. The aim of the present study was to establish the prevalence of the 22q11.2 deletion in an unselected population-based cohort of children with various cardiovascular malformations. The study population was defined as children born in 2000-2008 who were registered in the Danish National Patient Registry with a diagnosis of cardiovascular malformation from one of the two national departments of pediatric cardiology. Sensitive multiplex ligation-dependent probe amplification was performed on dried blood spot samples from each individual's neonatal screening test. Of 2,952 children with cardiovascular malformations, 2,478 were eligible for genetic testing. A total of 46 individuals (1.9% [1.4-2.5%]) carried the deletion, with the highest prevalence among individuals registered with interrupted aortic arch (22% [11-40]). The most frequent diagnoses among individuals carrying the deletion were tetralogy of Fallot (n = 15) and ventricular septal defect (n = 15). One in four cases had not been diagnosed in the usual clinical setting. The prevalence of 22q11.2 deletions in an unselected population-based cohort of children with cardiac malformations was 1.9% [1.4-2.5%]. Genetic testing of every individual registered with a conotruncal malformation would have achieved a diagnostic sensitivity of 70% in the present cohort. Prospective studies outlining testing recommendations in children with ventricular septal defect are warranted.
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Anormalidades Cardiovasculares/genética , Deleção Cromossômica , Cromossomos Humanos Par 22 , Vigilância da População , Criança , Dinamarca , HumanosRESUMO
The prevalence of the 22q11.2 duplication is unknown in children with cardiovascular malformations (CVMs). As most individuals with the duplication are detected in the search for other conditions, especially the 22q11.2 deletion, CVMs associated with the duplication are subject to referral bias. We circumvented this bias by investigating the prevalence of the 22q11.2 duplication in a population-based cohort of children with CVMs. The study population was defined as children born in 2000-2008, who were registered in the Danish National Patient Registry with a diagnosis of CVM from one of the two national university departments of pediatric cardiology. Sensitive multiplex ligation-dependent probe amplification was performed on dried blood spot samples from each individual's neonatal screening test. The study population consisted of 2,952 children with CVMs, 2,424 of whom were eligible for genetic testing; 13 individuals (0.5% [0.3-0.9%]) carried the duplication. Nine individuals (69%) had not previously been tested for a copy number variation on chromosome 22q11.2 in the clinical setting for children with CVMs. We conclude that 22q11.2 duplication is rare in children with CVMs, and is primarily found in malformations that are also associated with the 22q11.2 deletion.
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Duplicação Cromossômica , Cromossomos Humanos Par 22 , Vigilância da População , Criança , Estudos de Coortes , Dinamarca , Ligação Genética , Humanos , Recém-NascidoRESUMO
OBJECTIVE: To explore paediatricians' attitudes to and treatment practice for children with functional seizures (FS). METHODS: In a nationwide survey, all 64 Danish neuro-paediatricians and social paediatricians were invited to complete a structured questionnaire encompassing FS-related issues that included beliefs and attitudes about aetiology and diagnostic assessment, current strategies for management, experienced need for clinical guidelines and better treatment options. RESULTS: A total of 61 paediatricians (95%) participated in the study. Nearly half (46%) had seen more than 30 children with FS during their career. Most (65%) believed in a primarily psychogenic aetiology. More than half (57%) stated that they could make the diagnosis by solely observing a seizure, and 18% indicated the children faked their symptoms. The paediatricians' responses to these issues did not significantly vary according to their level of clinical experience. Furthermore, the majority (78%) expressed a need for clinical guidelines, and only 13% rated existing treatment options as sufficient. Collaborative care between different specialties or management in a child and adolescent mental health services (CAMHS) setting was seen as the best model for treatment. However, only 23% reported often referring these children to CAMHS after making the diagnosis. CONCLUSION: The findings suggest that introduction of clinical guidelines in this area is highly needed. Such guidelines could promote more formal training of paediatricians in understanding and assessing FS and increased collaboration between paediatrics and CAMHS regarding care for children with this challenging and potentially costly and disabling disorder.
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Conhecimentos, Atitudes e Prática em Saúde , Pediatras , Convulsões/diagnóstico , Convulsões/terapia , Adolescente , Criança , Feminino , Humanos , Masculino , Inquéritos e QuestionáriosRESUMO
Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000 newborn boys making it the most frequent sex chromosome aneuploidy in the general population. The molecular basis for the phenotypic traits and morbidity in KS are not clarified. We performed genome-wide DNA methylation profiling of leucocytes from peripheral blood samples from 67 KS patients, 67 male controls and 33 female controls, in addition to genome-wide RNA-sequencing profiling in a subset of 9 KS patients, 9 control males and 13 female controls. Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. A subset of genes show significant correlation between methylation values and expression values. Gene set enrichment analysis of differentially methylated positions yielded terms associated with well-known comorbidities seen in KS. In addition, differentially expressed genes revealed enrichment for genes involved in the immune system, wnt-signaling pathway and neuron development. Based on our data we point towards new candidate genes, which may be implicated in the phenotype and further point towards non-coding genes, which may be involved in X chromosome inactivation in KS.
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Metilação de DNA/genética , Síndrome de Klinefelter/genética , Inativação do Cromossomo X/genética , Adulto , Cromossomos Humanos X/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Recém-Nascido , Síndrome de Klinefelter/patologia , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Transcriptoma/genéticaRESUMO
INTRODUCTION: The determinants of cognitive deficits among individuals with Klinefelter syndrome (KS) are not well understood. This study was conducted to assess the impact of general intelligence, personality, and social engagement on cognitive performance among patients with KS and a group of controls matched for age and years of education. METHODS: Sixty-nine patients with KS and 69 controls were assessed in terms of IQ, NEO personality inventory, the Autism Spectrum Quotient (AQ) scale, and measures of cognitive performance reflecting working memory and executive function. RESULTS: Patients with KS performed more poorly on memory and executive-function tasks. Patients with KS also exhibited greater neuroticism and less extraversion, openness, and conscientiousness than controls. Memory deficits among patients with KS were associated with lower intelligence, while diminished executive functioning was mediated by both lower intelligence and less social engagement. CONCLUSION: Our results suggest that among patients with KS, memory deficits are principally a function of lower general intelligence, while executive-function deficits are associated with both lower intelligence and poorer social skills. This suggests a potential influence of social engagement on executive cognitive functioning (and/or vice-versa) among individuals with KS, and perhaps those with other genetic disorders. Future longitudinal research would be important to further clarify this and other issues discussed in this research.
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Disfunção Cognitiva/fisiopatologia , Função Executiva/fisiologia , Inteligência/fisiologia , Síndrome de Klinefelter/fisiopatologia , Memória de Curto Prazo/fisiologia , Personalidade/fisiologia , Habilidades Sociais , Adolescente , Adulto , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Humanos , Inteligência/genética , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/genética , Masculino , Pessoa de Meia-Idade , Personalidade/genética , Adulto JovemRESUMO
BACKGROUND: Moebius Sequence (MS) is a rare disorder defined by bilateral congenital paralysis of the abducens and facial nerves in combination with various odontological, craniofacial, ophthalmological and orthopaedic conditions. The aetiology is still unknown; but both genetic (de novo mutations) and vascular events in utero are reported. The purpose of present study was through a multidisciplinary clinical approach to examine children diagnosed with Moebius-like symptoms. Ten children underwent odontological, ophthalmological, obstetric, paediatric, orthopaedic, genetic, radiological and photographical evaluation. Five patients maintained the diagnosis of MS according to the diagnostic criteria. RESULTS: All five patients had bilateral facial and abducens paralysis confirmed by ophthalmological examination. Three of five had normal brain MR imaging. Two had missing facial nerves and one had missing abducens nerves. The Strengths and Difficulties Questionnaire (SDQ) showed normal scores in three of five patients. Interestingly, two of five children were born to mothers with uterine abnormalities (unicornuate/bicornuate uterus). In the odontological examination three of five showed enamel hypomineralisation. All five had abnormal orofacial motor function and maxillary prognathism. Two patients had adactyly, syndactyly and brachydactyly. None of the five patients had Poland anomaly, hip dislocation or dysplasia but all had a mild degree of scoliosis. We observed congenital club-feet, calcaneovalgus deformities, macrodactyly of one or more toes or curly toes. Pedobarography showed plantar pressures within normal ranges. CONCLUSIONS: Adherence to standard diagnostic criteria is central in the diagnosis of MS. An accurate diagnosis is the basis for correct discussion of other relevant concomitant symptoms of MS, genetic testing and evaluation of prognosis. The multidisciplinary approach and adherence to diagnostic criteria taken in present study increases the knowledge on the relationship between genotype, phenotype and symptomatology of MS.
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Síndrome de Möbius/diagnóstico , Síndrome de Möbius/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Síndrome de Möbius/genética , Adulto JovemRESUMO
UNLABELLED: Cerebral palsy (CP) is often accompanied by psychopathology and learning disability. AIMS: (1) to evaluate the prevalence of psychopathology as estimated by the Child Behavior Checklist (CBCL) parental questionnaire in 8- to 15-year-old Danish children with CP and to analyze its association with cognitive ability and families' social characteristics; (2) to examine to what extent children with CP had been evaluated by a child psychiatrist and/or psychologist. METHOD: The parents of 462 children with CP answered a questionnaire about their child's treatment and the family's characteristics and 446 the CBCL. The cutoff for psychopathology was the Total CBCL score or DSM-oriented scores above the 93rd percentile in an age- and gender-stratified population. RESULTS: The psychopathology screening was positive in 46.2% (CI 41.6-50.8%) against 15.1% in general population. Cognitive disability was associated with an increased prevalence of psychopathology (odds ratio (OR) 2.6, CI 1.4-4.6, for Developmental Quotient of cognitive function (DQ) 50-85 and OR 3.0, CI 1.3-7.0, for DQ<50). Children with CP and a single parent showed increased odds for a positive CBCL screening compared to children living with two parents (OR 2.1, 95% CI 1.1-4.0). Children with DQ 50-85 more often had a psychological evaluation. A positive CBCL screening was strongly associated with a psychiatric assessment (21% vs. 7%, p<0.01). CONCLUSION: The high prevalence of emotional and behavioral problems indicates that screening for psychopathology should be a part of multidisciplinary follow-up of CP. The CBCL can be used as a screening instrument in children with CP without severe motor and cognitive disability.
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Paralisia Cerebral/epidemiologia , Lista de Checagem , Transtornos Cognitivos/epidemiologia , Transtornos Mentais/epidemiologia , Pais , Adolescente , Paralisia Cerebral/psicologia , Criança , Transtornos Cognitivos/psicologia , Estudos de Coortes , Estudos Transversais , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Programas de Rastreamento , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologia , Razão de Chances , Prevalência , Inquéritos e QuestionáriosRESUMO
In the exploratory study reported here, we tested the efficacy of an intervention designed to train teenagers with Möbius syndrome (MS) to increase the use of alternative communication strategies (e.g., gestures) to compensate for their lack of facial expressivity. Specifically, we expected the intervention to increase the level of rapport experienced in social interactions by our participants. In addition, we aimed to identify the mechanisms responsible for any such increase in rapport. In the study, five teenagers with MS interacted with three naïve participants without MS before the intervention, and with three different naïve participants without MS after the intervention. Rapport was assessed by self-report and by behavioral coders who rated videos of the interactions. Individual non-verbal behavior was assessed via behavioral coders, whereas verbal behavior was automatically extracted from the sound files. Alignment was assessed using cross recurrence quantification analysis and mixed-effects models. The results showed that observer-coded rapport was greater after the intervention, whereas self-reported rapport did not change significantly. Observer-coded gesture and expressivity increased in participants with and without MS, whereas overall linguistic alignment decreased. Fidgeting and repetitiveness of verbal behavior also decreased in both groups. In sum, the intervention may impact non-verbal and verbal behavior in participants with and without MS, increasing rapport as well as overall gesturing, while decreasing alignment.
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CONTEXT: Klinefelter syndrome, 47, XXY (KS), is underdiagnosed partly due to few clinical signs complicating identification of affected individuals. Certain phenotypic traits are common in KS. However, not all aspects of the KS phenotype are well described. OBJECTIVE: To describe anthropometry and body composition in KS and relate findings to biochemistry and X-chromosome related genetic markers. DESIGN, SETTING AND PARTICIPANTS: Seventy three KS males referred to our clinic and 73 age-matched controls underwent comprehensive measurements of anthropometry and body composition in a cross-sectional, case-controlled study. Furthermore, genetic analysis for parental origin of the supernumerary X-chromosome, skewed X-chromosome inactivation and androgen receptor (AR) CAG repeat length was done. MAIN OUTCOME MEASURE: Anthropometry and body composition in KS and the effect of genotype hereon. RESULTS: KS males were taller (absolute difference: 5.1 cm, P < .001) with longer legs (5.7 cm, P < .001) compared with controls. Furthermore, 2D:4D was increased in KS males (relative effect size: Cohen's d = 0.40), reflecting reduced fetal testosterone exposure. Also, bi-iliac width (0.41), waist (0.52), and hip circumference (0.47) (P < .02 for all), as well as total fat mass (0.74), abdominal fat mass (0.67), and total body fat percentage (0.84) was increased in KS males (P < .001 for all), while bitesticular volume was reduced (4.6). AR CAG repeat length was comparable in KS and controls, and among KS CAG correlated to arm length (P = .04), arm span (P = .01), and leg length (P = .04). Effects of parental origin of the supernumerary X-chromosome and skewed X-chromosome inactivation were negligible. CONCLUSIONS: Anthropometry and body composition in KS is specific and dysmorphic and affected by AR CAG repeat length and decreased exposure to testosterone already during fetal life.
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Pesos e Medidas Corporais , Hipogonadismo/complicações , Síndrome de Klinefelter , Efeitos Tardios da Exposição Pré-Natal , Testosterona/uso terapêutico , Expansão das Repetições de Trinucleotídeos , Adolescente , Adulto , Antropometria , Composição Corporal/genética , Estudos de Casos e Controles , Causalidade , Feminino , Humanos , Síndrome de Klinefelter/tratamento farmacológico , Síndrome de Klinefelter/epidemiologia , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/metabolismo , Masculino , Pessoa de Meia-Idade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Adulto JovemRESUMO
Brain imaging in Klinefelter syndrome (47, XXY) (KS), a genetic disorder characterized by the presence of an extra X chromosome, may contribute to understanding the relationship between gene expression, brain structure, and subsequent cognitive disabilities and psychiatric disorders. We conducted the largest to date voxel-based morphometry study of 65 KS subjects and 65 controls matched for age and education and correlated these data to neuropsychological test scores. The KS patients had significantly smaller total brain volume (TBV), total gray matter volume (GMV) and total white matter volume (WMV) compared to controls, whereas no volumetric difference in cerebral spinal fluid (CSF) was found. There were no differences in TBV, GMV, WMV or CSF between testosterone treated KS (T-KS) and untreated KS (U-KS) patients. Compared to controls, KS patients had significantly decreased GMV bilaterally in insula, putamen, caudate, hippocampus, amygdala, temporal pole and frontal inferior orbita. Additionally, the right parahippocampal region and cerebellar volumes were reduced in KS patients. KS patients had significantly larger volumes in right postcentral gyrus, precuneus and parietal regions. Multivariate classification analysis discriminated KS patients from controls with 96.9% (p < 0.001) accuracy. Regression analyses, however, revealed no significant association between GMV differences and cognitive and psychological factors within the KS patients and controls or the groups combined. These results show that although gene dosage effect of having and extra X-chromosome may lead to large scale alterations of brain morphometry and extended cognitive disabilities no simple correspondence links these measures.
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Encéfalo/patologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Síndrome de Klinefelter/complicações , Síndrome de Klinefelter/patologia , Testes Neuropsicológicos , Adolescente , Adulto , Estudos de Casos e Controles , Dinamarca , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise de Componente Principal , Escalas de Graduação Psiquiátrica , Adulto JovemAssuntos
Doença do Armazenamento de Ácido Siálico/diagnóstico , Adulto , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Diagnóstico Diferencial , Humanos , Imageamento por Ressonância Magnética , Doença do Armazenamento de Ácido Siálico/genética , Doença do Armazenamento de Ácido Siálico/psicologiaAssuntos
Doença do Armazenamento de Ácido Siálico , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Dinamarca , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Doença do Armazenamento de Ácido Siálico/diagnóstico , Doença do Armazenamento de Ácido Siálico/genética , Doença do Armazenamento de Ácido Siálico/patologia , Tomografia Computadorizada por Raios XRESUMO
INTRODUCTION: Primary cerebral vasculitis in children is a newly recognized, rare inflammatory condition affecting the vessels of the brain. It is characterized by newly acquired neurological deficit(s) with angiographic or histological evidence of central nervous system (CNS) vasculitis, in the absence of other known diseases with these findings. MATERIAL AND METHODS: We performed a retrospective review of children below 15 years submitted with CNS vasculitis to the department between 1999 and 2008. RESULTS: Six (two boys, four girls) of ten children with clinical and vascular imaging findings detected by magnetic resonance were diagnosed with primary CNS vasculitis. Age at onset was three to 12 years. Acutely acquired hemiparesis was seen in five children, two had facial palsy. Among other symptoms were headache, ataxia, dysarthria, loss of consciousness and seizures. Only modest changes in blood and spinal fluid values were seen. On magnetic resonance angiography, varying segmental stenoses were found. All had supratentorial lesions, and in two patients infratentorial lesions were also detected by MRI. Monthly treatment with high-dose intravenous corticosteroids for six months was successful in most of the patients. In two patients with progressive CNS vasculitis, the treatment was supplemented by intravenous cyclophosphamide and azathioprin, respectively. CONCLUSION: Primary CNS vasculitis is an acutely acquired inflammatory disease with severe neurological deficits and sequelae which may have a fatal outcome. Despite this the prognosis is acceptable since event-free survival can be achieved in almost 70% if early immunosuppressive therapy is initiated.