Evaluation of prenatal diagnosis of congenital heart disease in a regional controlled case study.

AIMS: This study evaluated the evolution of the prenatal diagnosis of congenital heart disease (CHD) between 2003 and 2008 and its repercussion for the CHD prevalence rate at birth in a well-defined population (Canton of Vaud, Switzerland). METHODS AND RESULTS: All 572 cases of CHD reported in the Eurocat Registry of Vaud-Switzerland between 1.5.2003 and 31.12.2008 were analysed and compared with the cases in our clinical database. CHD cases were divided into five different groups according to heart disease severity. The prenatal detection rates increased significantly between 2003 and 2008, with a mean detection rate of 25.2%. There was a significantly higher rate of prenatal diagnosis in the first four groups of CHD severity, with the highest detection rate (87.5%) found in the group with the most severe CHD (group 1). In this group, 85.7% of cases resulted in a termination of pregnancy, and there was a consequent 75% reduction in the prevalence of severe major cardiac malformation at birth. Detection rates were 66% in group 2, 68.6% in group 3, and the lowest in groups 4 and 5, with rates of 25.9% and 12.9%, respectively. CONCLUSION: This study shows that the prenatal detection rate for CHD increased in a well-defined population over the study period. Prenatal diagnosis thus has had a major impact on patients with the most severe types of CHD and has resulted in a significant reduction in severe CHD at birth.

Insuffisance surrénalienne et hypercalcémie: association fortuite [Adrenal insufficiency and hypercalcemia--an unusual presentation]

A 49 y.o. man was admitted for investigation of an intense fatigue associated with nausea, vomiting, weight loss and headache. Examination and work-up reveals a moderate hypercalcaemia and a panhypopituitarism attributed to a craniopharyngioma. Extensive work-up has excluded the most frequent causes of hypercalcaemia and we finally attributed this anomaly to the adrenal failure. In this article, we discuss the diagnostic approach, the etiology and physiopathology of this hypercalcemia and his association with endocrinological anomalies such as adrenal failure.

Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study.

INTRODUCTION: Published prevalence rates of congenital diaphragmatic hernia (CDH) vary. This study aims to describe the epidemiology of CDH using data from high-quality, population-based registers belonging to the European Surveillance of Congenital Anomalies (EUROCAT). METHODS: Cases of CDH delivered between 1980 and 2009 notified to 31 EUROCAT registers formed the population-based case series. Prevalence over time was estimated using multilevel Poisson regression, and heterogeneity between registers was evaluated from the random component of the intercept. RESULTS: There were 3373 CDH cases reported among 12 155 491 registered births. Of 3131 singleton cases, 353 (10.4%) were associated with a chromosomal anomaly, genetic syndrome or microdeletion, 784 (28.2%) were associated with other major structural anomalies. The male to female ratio of CDH cases overall was 1:0.69. Total prevalence was 2.3 (95% CI 2.2 to 2.4) per 10 000 births and 1.6 (95% CI 1.6 to 1.7) for isolated CDH cases. There was a small but significant increase (relative risk (per year)=1.01, 95% credible interval 1.00-1.01; p=0.030) in the prevalence of total CDH over time but there was no significant increase for isolated cases (ie, CDH cases that did not occur with any other congenital anomaly). There was significant variation in total and isolated CDH prevalence between registers. The proportion of cases that survived to 1 week was 69.3% (1392 cases) for total CDH cases and 72.7% (1107) for isolated cases. CONCLUSIONS: This large population-based study found an increase in total CDH prevalence over time. CDH prevalence also varied significantly according to geographical location. No significant association was found with maternal age.

Rupture d'une hyperplasie nodulaire focale. A propos de deux cas [Rupture of hepatic focal nodular hyperplasia. About two cases]

The diagnostics of focal nodular hyperplasia is reached through the use of imaging. When the diagnostic is certain, surgical abstention is the rule. Nevertheless, we were confronted with two cases of a rare complication; that of intraperitoneal rupture. In this situation, we suggest to first do an arteriography to control the bleeding, then to perform surgery when the patient has reached hemodynamic stability. Spontaneous rupture as a complication of benign nodular hyperplasia remains a rare event and only five cases were reported in litterature.

The role of epilepsy in early language development in a child with a congenital lesion in the right hemisphere

Early epilepsy is known to worsen the developmental prognosis of young children with a congenital focal brain lesion, but its direct role is often very difficult to delineate from the other variables. This requires prolonged periods of follow-up with simultaneous serial electrophysiological and developmental assessments which are rarely obtained. We studied a male infant with a right prenatal infarct in the territory of the right middle cerebral artery resulting in a left spastic hemiparesis, and an epileptic disorder (infantile spasms with transient right hemihypsarrhythmia and focal seizures) from the age of 7 months until the age of 4 years. Pregnancy and delivery were normal. A dissociated delay of early language acquisition affecting mainly comprehension without any autistic features was documented. This delay was much more severe than usually expected in children with early focal lesions, and its evolution, with catch-up to normal, was correlated with the active phase of the epilepsy. We postulate that the epilepsy specifically amplified a pattern of delayed language emergence, mainly affecting lexical comprehension, reported in children with early right hemisphere damage.

Comparative assessement of intimal hyperplasia development after 14 days in two different experimental settings : tissue culture versus ex vivo continuous perfusion of human saphenous vein

Résumé de l'article : L'hyperplasie intimale est un processus de remodelage vasculaire ubiquitaire après une lésion, pouvant menacer la perméabilité de tout type de reconstruction vasculaire. Les mécanismes physiopathologiques impliqués dans le développement de l'hyperplasie intimale ne sont que partiellement élucidés. Il est par conséquent nécessaire d'effectuer des recherches complémentaires afin d'en améliorer la compréhension et ainsi permettre l'élaboration de nouvelles stratégies thérapeutiques médicamenteuses. La culture de veines en milieu statique permet le développement de l'hyperplasie intimale. Ce modèle maintient la viabilité tissulaire, comme décrit précédemment dans d'autres études, mais empêche l'analyse des paramètres hémodynamiques. La mise au point d'un modèle de perfusion in vitro permettant la perfusion de segments vasculaires représente une approche expérimentale intégrant les différents facteurs hémodynamiques. Le système de perfusion (Ex Vivo Vein Support System) que nous avons élaboré conserve l'intégrité pariétale ainsi que les propriétés vasomotrices des veines pour une durée de 14 jours. Cette étude démontre que les deux modèles permettent le développement de l'hyperplasie intimale. Toutefois, les propriétés vasomotrices ainsi que l'influence des paramètres hémodynamiques ne peuvent être analysées que par l'utilisation du système de perfusion. Ce dernier a permis de perfuser des vaisseaux humains sans contamination bactérienne tout en maintenant l'intégrité cellulaire. Ce modèle de perfusion se rapproche plus des conditions hémodynamiques rencontrées in vivo que le modèle statique. Abstract : Background. Intimal hyperplasia (IH) is a vascular remodeling process which often leads to failure of arterial bypass or hemodialysis access. Experimental and clinical work have provided insight in IH development; however, further studies under precise con-trolled conditions are required to improve therapeutic strategies to inhibit IH development. Ex vivo perfusion of human vessel segments under standardized hemodynamic conditions may provide an adequate experimental approach for this purpose. Therefore, chronically perfused venous segments were studied and compared to traditional static culture procedures with regard to functional and histomorphologic characteristics as well as gene expression. Materials and methods. Static vein culture allowing high tissue viability was performed as previously described. Ex vivo vein support system (EVVSS) was performed using a vein support system consisting of an incubator with a perfusion chamber and a pump. EVVSS allows vessel perfusion under continuous flow while maintaining controlled hemodynamic conditions. Each human saphenous vein was divided in two parts, one cultured in a Pyrex dish and the other part perfused in EVVSS for 14 days. Testing of vasomotion, histomorphometry, expression of CD 31, Factor VIII, MIB 1, α-actin, and PAI-1 were determined before and after 14 days of either experimental conditions. Results, Human venous segments cultured under traditional or perfused conditions exhibited similar IH after 14 days as shown by histomorphometry. Smooth-muscle cell ( SMC) was preserved after chronic perfusion. Although integrity of both endothelial and smooth-muscle cells appears to be maintained in both culture conditions as confirmed by CD31, factor VIII and α-actin expression, a few smooth-muscle cells in the media stained positive for factor VIII. Cell-proliferation marker MIB-1 was also detected in the two settings and PAI-1 mRNA expression and activity increased significantly after 14 days of culture and perfusion. Conclusion. This study demonstrates the feasibility to chronically perfuse human vessels under sterile conditions with preservation of cellular integrity and vascular contractility. To gain insights into the mechanisms leading to IH, it will now be possible to study vascular remodeling not only under static conditions but also in hemodynamic environment mimicking as closely as possible the flow conditions encountered in reconstructive vascular surgery.

Para-arterial sparing phenotype in Leber congenital amaurosis associated with homozygous p.R108X SPATA-7 mutation

Purpose: To describe the genotype/phenotype correlation associated with homozygous p.R108X mutation in the SPATA7 gene. Methods: A consanguineous nuclear family of Ethiopian origin was ascertained for genotypic and phenotypic characterization, including fundus photography, fundus autofluorescence (FAF), and full-field ERG. Molecular diagnosis was performed using a microarray. Results: Two of the 5 family members were affected with LCA. A homozygous c.322C>T (p.R108X) mutation in exon 5 of SPATA-7 was identified in both of them. The patients were 4 and 11 years old, respectively. Fundus examination revealed an unremarkable macular area, but optic nerve pallor, attenuated vascular calibre and deep retinal nummular deposits with para-arterial sparing predominant in the midperiphery. FAF showed multiples areas of hyperautofluorescence, corresponding to the deep retinal deposits. ERG was not recordable in the young patient, and showed severe rods/cones dysfunction in the older one. Conclusions: The literature describing genotype/phenotype correlation of SPATA-7 mutations in Leber congenital amaurosis (LCA) is still limited. We report the occurrence of para-arterial sparing in two sibs with SPATA7-linked LCA which may represent a clinical marker of this condition.

A new locus for congenital cataract, microcornea, microphthalmia, and atypical iris coloboma maps to chromosome 2.

OBJECTIVE: To report a novel phenotype of autosomal dominant atypical congenital cataract associated with variable expression of microcornea, microphthalmia, and iris coloboma linked to chromosome 2. Molecular analysis of this phenotype may improve our understanding of anterior segment development. DESIGN: Observational case study, genome linkage analysis, and gene mutation screening. PARTICIPANTS: Three families, 1 Egyptian and 2 Belgians, with a total of 31 affected were studied. METHODS: Twenty-one affected subjects and 9 first-degree relatives underwent complete ophthalmic examination. In the Egyptian family, exclusion of PAX6, CRYAA, and MAF genes was demonstrated by haplotype analysis using microsatellite markers on chromosomes 11, 16, and 21. Genome-wide linkage analysis was then performed using 385 microsatellite markers on this family. In the 2 Belgian families, the PAX6 gene was screened for mutations by direct sequencing of all exons. MAIN OUTCOME MEASURES: Phenotype description, genome-wide linkage of the phenotype, linkage to the PAX6, CRYAA, and MAF genes, and mutation detection in the PAX6 gene. RESULTS: Affected members of the 3 families had bilateral congenital cataracts inherited in an autosomal dominant pattern. A novel form of hexagonal nuclear cataract with cortical riders was expressed. Among affected subjects with available data, 95% had microcornea, 39% had microphthalmia, and 38% had iris coloboma. Seventy-five percent of the colobomata were atypical, showing a nasal superior location in 56%. A positive lod score of 4.86 was obtained at theta = 0 for D2S2309 on chromosome 2, a 4.9-Mb common haplotype flanked by D2S2309 and D2S2358 was obtained in the Egyptian family, and linkage to the PAX6, CRYAA, or MAF gene was excluded. In the 2 Belgian families, sequencing of the junctions and all coding exons of PAX6 did not reveal any molecular change. CONCLUSIONS: We describe a novel phenotype that includes the combination of a novel form of congenital hexagonal cataract, with variably expressed microcornea, microphthalmia, and atypical iris coloboma, not caused by PAX6 and mapping to chromosome 2. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Paper 5: Surveillance of multiple congenital anomalies: implementation of a computer algorithm in European registers for classification of cases.

BACKGROUND: Surveillance of multiple congenital anomalies is considered to be more sensitive for the detection of new teratogens than surveillance of all or isolated congenital anomalies. Current literature proposes the manual review of all cases for classification into isolated or multiple congenital anomalies. METHODS: Multiple anomalies were defined as two or more major congenital anomalies, excluding sequences and syndromes. A computer algorithm for classification of major congenital anomaly cases in the EUROCAT database according to International Classification of Diseases (ICD)v10 codes was programmed, further developed, and implemented for 1 year's data (2004) from 25 registries. The group of cases classified with potential multiple congenital anomalies were manually reviewed by three geneticists to reach a final agreement of classification as "multiple congenital anomaly" cases. RESULTS: A total of 17,733 cases with major congenital anomalies were reported giving an overall prevalence of major congenital anomalies at 2.17%. The computer algorithm classified 10.5% of all cases as "potentially multiple congenital anomalies". After manual review of these cases, 7% were agreed to have true multiple congenital anomalies. Furthermore, the algorithm classified 15% of all cases as having chromosomal anomalies, 2% as monogenic syndromes, and 76% as isolated congenital anomalies. The proportion of multiple anomalies varies by congenital anomaly subgroup with up to 35% of cases with bilateral renal agenesis. CONCLUSIONS: The implementation of the EUROCAT computer algorithm is a feasible, efficient, and transparent way to improve classification of congenital anomalies for surveillance and research.

Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis

Deficiency of carbohydrate sulfotransferase 3 (CHST3; also known as chondroitin-6-sulfotransferase) has been reported in a single kindred so far and in association with a phenotype of severe chondrodysplasia with progressive spinal involvement. We report eight CHST3 mutations in six unrelated individuals who presented at birth with congenital joint dislocations. These patients had been given a diagnosis of either Larsen syndrome (three individuals) or humero-spinal dysostosis (three individuals), and their clinical features included congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfoot, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming functional impairment of CHST3 and distinguishing them from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells. These observations provide a molecular basis for recessive Larsen syndrome and indicate that recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani type form a phenotypic spectrum.

Lack of MRI neurohypophyseal bright signal in a child with congenital nephrogenic diabetes insipidus

Congenital nephrogenic diabetes insipidus (CNDI) is a rare disease characterized by the inability of the kidney to respond to arginine vasopressin (AVP). The absence of the neurohypophyseal 'bright signal' on T1 sequence magnetic resonance imaging (MRI) is considered as an argument in favour of the diagnosis of central diabetes insipidus (CDI). This observation is challenged as we hereby present a case of a child diagnosed with CNDI and who did not present MRI pituitary bright signal. A 6-month-old male presented with failure to thrive, polyuria and polydypsia. Family history revealed that the mother, 35 years of age, had been presenting polydypsia and polyuria, and she was investigated at the age of 6 years with no concluding diagnosis. The patient's physical exam showed a weight of 5215 g (−3 DS) and clinical signs of dehydration. The patient's plasma sodium level was 155 mmol/L, osmolality 305 mOsm/kg and urine osmolality 150 mOsm/kg. Brain MRI showed in T1 sequences the absence of the posterior pituitary bright signal suggesting the diagnosis of CDI (Figure 1). The child was treated with synthetic AVP analogue 1-desamino-8-d-arginine vasopressin (DDAVP) without improvement, which led to the consideration of CNDI. The diagnosis was confirmed by an elevated serum level of AVP of 214 pmol/L (reference value ≤4.34 pmol/L) and by genetic analysis demonstrating and T106C mutation in the V2R (X-linked CNDI). The child was treated with thiazide diuretic and increased fluids with restricted sodium intake. This resulted in catch-up growth and improved neurological development. A follow-up MRI was performed 6 months after the start of therapy with the same technique. At that time, the child's weight had improved to 9310 g (−1.5 DS) corresponding to a gain of 22 g per day, and he did not present any clinical signs of dehydration and had a normal plasma level of sodium (140 mmol/L). MRI showed that the bright signal was still absent.

Prenatal diagnosis of a fetal abdominal eventration: a rare congenital abdominal wall defect.

We report a case of abdominal eventration associated with cystic fibrosis, diagnosed by mid-trimester ultrasonography. The defect concerned the abdominal muscles and their aponevrotic sheath, but respected the skin. There was no associated malformation. The outcome was favorable after surgery, and the infant is well at the age of 6 months.

Pédiatrie. 3. Traitement du membre supérieur dans les hémiparésies congénitales: progrès et perspectives [Pediatrics. Upper limb treatment in congenital hemiparesis: progress and perspectives].

Congenital hemiparesis is one of the most frequent pediatric motor disorders. Upper limb rehabilitation of the hemiparetic child has considerably evolved during the last decade by the use of focal chemical denervation (intramuscular botulinum toxin) and the introduction of novel rehabilitation techniques such as constraint induced movement therapy or robotic reeducation.

Bax-induced apoptosis in Leber's congenital amaurosis: a dual role in rod and cone degeneration.

Pathogenesis in the Rpe65(-/-) mouse model of Leber's congenital amaurosis (LCA) is characterized by a slow and progressive degeneration of the rod photoreceptors. On the opposite, cones degenerate rapidly at early ages. Retinal degeneration in Rpe65(-/-) mice, showing a null mutation in the gene encoding the retinal pigment epithelium 65-kDa protein (Rpe65), was previously reported to depend on continuous activation of a residual transduction cascade by unliganded opsin. However, the mechanisms of apoptotic signals triggered by abnormal phototransduction remain elusive. We previously reported that activation of a Bcl-2-dependent pathway was associated with apoptosis of rod photoreceptors in Rpe65(-/-) mice during the course of the disease. In this study we first assessed whether activation of Bcl-2-mediated apoptotic pathway was dependent on constitutive activation of the visual cascade through opsin apoprotein. We then challenged the direct role of pro-apoptotic Bax protein in triggering apoptosis of rod and cone photoreceptors.Quantitative PCR analysis showed that increased expression of pro-apoptotic Bax and decreased level of anti-apoptotic Bcl-2 were restored in Rpe65(-/-)/Gnat1(-/-) mice lacking the Gnat1 gene encoding rod transducin. Moreover, photoreceptor apoptosis was prevented as assessed by TUNEL assay. These data indicate that abnormal activity of opsin apoprotein induces retinal cell apoptosis through the Bcl-2-mediated pathway. Following immunohistological and real-time PCR analyses, we further observed that decreased expression of rod genes in Rpe65-deficient mice was rescued in Rpe65(-/-)/Bax(-/-) mice. Histological and TUNEL studies confirmed that rod cell demise and apoptosis in diseased Rpe65(-/-) mice were dependent on Bax-induced pathway. Surprisingly, early loss of cones was not prevented in Rpe65(-/-)/Bax(-/-) mice, indicating that pro-apoptotic Bax was not involved in the pathogenesis of cone cell death in Rpe65-deficient mice.This is the first report, to our knowledge, that a single genetic mutation can trigger two independent apoptotic pathways in rod and cone photoreceptors in Rpe65-dependent LCA disease. These results highlight the necessity to investigate and understand the specific death signaling pathways committed in rods and cones to develop effective therapeutic approaches to treat RP diseases.

Seasonality of congenital anomalies in Europe.

BACKGROUND: This study describes seasonality of congenital anomalies in Europe to provide a baseline against which to assess the impact of specific time varying exposures such as the H1N1 pandemic influenza, and to provide a comprehensive and recent picture of seasonality and its possible relation to etiologic factors. METHODS: Data on births conceived in 2000 to 2008 were extracted from 20 European Surveillance for Congenital Anomalies population-based congenital anomaly registries in 14 European countries. We performed Poisson regression analysis encompassing sine and cosine terms to investigate seasonality of 65,764 nonchromosomal and 12,682 chromosomal congenital anomalies covering 3.3 million births. Analysis was performed by estimated month of conception. Analyses were performed for 86 congenital anomaly subgroups, including a combined subgroup of congenital anomalies previously associated with influenza. RESULTS: We detected statistically significant seasonality in prevalence of anomalies previously associated with influenza, but the conception peak was in June (2.4% excess). We also detected seasonality in congenital cataract (April conceptions, 27%), hip dislocation and/or dysplasia (April, 12%), congenital hydronephrosis (July, 12%), urinary defects (July, 5%), and situs inversus (December, 36%), but not for nonchromosomal anomalies combined, chromosomal anomalies combined, or other anomalies analyzed. CONCLUSION: We have confirmed previously described seasonality for congenital cataract and hip dislocation and/or dysplasia, and found seasonality for congenital hydronephrosis and situs inversus which have not previously been studied. We did not find evidence of seasonality for several anomalies which had previously been found to be seasonal. Influenza does not appear to be an important factor in the seasonality of congenital anomalies.