EUROCAT website data on prenatal detection rates of congenital anomalies.

The EUROCAT website www.eurocat-network.eu publishes prenatal detection rates for major congenital anomalies using data from European population-based congenital anomaly registers, covering 28% of the EU population as well as non-EU countries. Data are updated annually. This information can be useful for comparative purposes to clinicians and public health service managers involved in the antenatal care of pregnant women as well as those interested in perinatal epidemiology.

Anti-60kDa heat shock protein antibodies in fetal serum : a biomarker for unexplained small for gestational age fetuses

Rapport de synthèseObjectifsLe retard de croissance intrautérin (RCIU) est un problème affectant 10% des grossesses et est associé à une morbidité périnatale importante. Dans environ 80% des cas, une étiologie ou un facteur de risque majeur peuvent être identifiés. Mais près de 20% des cas sont considérés comme inexpliqués. La heat shock protéine 60kDa (HSP60) est une protéine fortement immunogène dont la synthèse est considérablement augmentée lors de conditions non- physiologiques. Les HSP60 humaines et bactériennes partagent un haut degré d'homologie de séquence ce qui peut engendrer une maladie auto-immune à la suite d'une infection bactérienne. Nous avons supposé que les RCIU inexpliqués pourraient être la conséquence d'une sensibilisation à l'HSP60 humaine.MéthodesLes RCIU inexpliqués ont été identifiés par mesure échographique avec un doppler normal, sans anomalies décelables chez la mère ou le foetus. Les sera foetaux ont été obtenus par cordocentèse, effectuée lors d'analyse du caryotype en cas de RCIU inexpliqué (groupe d'étude) ou pour le dépistage d'une incompatibilité Rhésus (groupe témoin). Ils ont été testés pour l'antigène HSP60 et les IgG et IgM anti-HSP60 par ELISA ainsi que pour d'autres paramètres immunitaires et hématologiques.RésultatsLes paramètres maternels sont similaires entre les 12 cas du groupe d'étude et les 23 cas du groupe contrôle. L'âge gestationnel moyen lors de la cordocentèse est de 29 semaines. Les IgM anti-HSP60 sont détectés dans 12 cas d'étude (100%) mais dans aucun cas contrôle (p <0,00017), les IgG anti-HSP60 dans 7 cas d'étude (58%) et un seul dans le groupe contrôle (p <0,001). Trois des quatre cas avec les taux d'IgM les plus élevés sont décédés. Il n'y a pas de différences entre les deux groupes quant aux taux d'antigène HSP60 ou d'autres marqueurs immunologiques ou hématologiques.ConclusionLes foetus avec un RCIU inexpliqué expriment un taux élevé d'anticorps IgM et IgG contre l'HSP60 humaine et le taux d'IgM est un facteur prédictif de la mortalité foetale. La détection de ces anticorps indique qu'une perturbation placentaire et une réaction auto-immune foetale liée à l'HSP60 sont associées à ce retard de développement chez le foetus.

Fetal MRI as complement to US in the diagnosis and characterization of anomalies of the genito-urinary tract.

The purpose of this study is to compare the accuracy of prenatal ultrasound (US) and prenatal magnetic resonance imaging (MRI) in the diagnosis and characterization of congenital abnormalities of the genito-urinary tract and to determine if the additional information obtained by MRI may influence the management of the fetus. We retrospectively evaluate 15 cases of congenital genito-urinary tract anomalies detected by prenatal US and with echographic inconclusive diagnosis. We compare the MRI findings with the US findings and the final diagnosis, obtained from neonatal outcomes, imaging studies and pathology records. Fetal US diagnosis was correct in 9 cases (60%) and MRI in 13 cases (86.7%). Prenatal MRI revealed additional information to US in 9 cases (60%), which modified the initial US diagnosis in 5 cases (33.3%) and changed the therapeutic approach in 5 fetuses (33.3%). Fetal MRI was better than US in cases of oligoamnios and in fetuses with genito-urinary pathology concerning the pelvic and perineum region. We believe that MRI should be considered as a complementary diagnostic method in cases of echographic suspicion of congenital pathology of the genito-urinary tract and inconclusive prenatal US.

RAX and anophthalmia in humans: Evidence of brain anomalies.

PURPOSE: To report the clinical and genetic study of two families of Egyptian origin with clinical anophthalmia. To further determine the role of the retina and anterior neural fold homeobox gene (RAX) in anophthalmia and associated cerebral malformations. METHODS: Three patients with clinical anophthalmia and first-degree relatives from two consanguineous families of Egyptian origin underwent full ophthalmologic, general and neurologic examination, and blood tests. Cerebral magnetic resonance imaging (MRI) was performed in the index cases of both families. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of RAX was performed after PCR amplification. RESULTS: Clinical bilateral anophthalmia was observed in all three patients. General and neurologic examinations were normal; obesity and delay in psychomotor development were observed in the isolated case. Orbital MRI showed a hypoplastic orbit with present but rudimentary extraocular muscles and normal lacrimal glands. Cerebral MRI showed agenesis of the optic nerves, optic tracts, and optic chiasma. In the index case of family A, the absence of the frontal and sphenoidal sinuses was also noted. In the index case of family B, only the sphenoidal sinus was absent, and there was significant cortical atrophy. The three patients carried a novel homozygous c.543+3A>G mutation (IVS2+3A>G) in RAX. Parents were healthy heterozygous carriers. No mutations were detected in orthodenticle homeobox 2 (OTX2), ventral anterior homeobox 1 (VAX1), or sex determining region Y-box 2 (SOX2). CONCLUSIONS: This is the first report of a homozygous splicing RAX mutation associated with autosomal recessive bilateral anophthalmia. To our knowledge, only two isolated cases of anophthalmia, three null and one missense case affecting nuclear localization or the DNA-binding homeodomain, have been found to be caused by compound heterozygote RAX mutations. A novel missense RAX mutation was identified in three patients with bilateral anophthalmia and a distinct systemic and neurologic phenotype. The mutation potentially affects splicing of the last exon and is thought to result in a protein that has an aberrant homeodomain and no paired-tail domain. Functional consequences of this change still need to be characterized.

Atrioventricular septal defects among infants in Europe: a population-based study of prevalence, associated anomalies, and survival.

OBJECTIVE: To describe the epidemiology of chromosomal and non-chromosomal cases of atrioventricular septal defects in Europe. METHODS: Data were obtained from EUROCAT, a European network of population-based registries collecting data on congenital anomalies. Data from 13 registries for the period 2000-2008 were included. RESULTS: There was a total of 993 cases of atrioventricular septal defects, with a total prevalence of 5.3 per 10,000 births (95% confidence interval 4.1 to 6.5). Of the total cases, 250 were isolated cardiac lesions, 583 were chromosomal cases, 79 had multiple anomalies, 58 had heterotaxia sequence, and 23 had a monogenic syndrome. The total prevalence of chromosomal cases was 3.1 per 10,000 (95% confidence interval 1.9 to 4.3), with a large variation between registers. Of the 993 cases, 639 cases were live births, 45 were stillbirths, and 309 were terminations of pregnancy owing to foetal anomaly. Among the groups, additional associated cardiac anomalies were most frequent in heterotaxia cases (38%) and least frequent in chromosomal cases (8%). Coarctation of the aorta was the most common associated cardiac defect. The 1-week survival rate for live births was 94%. CONCLUSION: Of all cases, three-quarters were associated with other anomalies, both chromosomal and non-chromosomal. For infants with atrioventricular septal defects and no chromosomal anomalies, cardiac defects were often more complex compared with infants with atrioventricular septal defects and a chromosomal anomaly. Clinical outcomes for atrioventricular septal defects varied between regions. The proportion of termination of pregnancy for foetal anomaly was higher for cases with multiple anomalies, chromosomal anomalies, and heterotaxia sequence.

Paper 4: EUROCAT statistical monitoring: identification and investigation of ten year trends of congenital anomalies in Europe.

BACKGROUND: As part of EUROCAT's surveillance of congenital anomalies in Europe, a statistical monitoring system has been developed to detect recent clusters or long-term (10 year) time trends. The purpose of this article is to describe the system for the identification and investigation of 10-year time trends, conceived as a "screening" tool ultimately leading to the identification of trends which may be due to changing teratogenic factors.METHODS: The EUROCAT database consists of all cases of congenital anomalies including livebirths, fetal deaths from 20 weeks gestational age, and terminations of pregnancy for fetal anomaly. Monitoring of 10-year trends is performed for each registry for each of 96 non-independent EUROCAT congenital anomaly subgroups, while Pan-Europe analysis combines data from all registries. The monitoring results are reviewed, prioritized according to a prioritization strategy, and communicated to registries for investigation. Twenty-one registries covering over 4 million births, from 1999 to 2008, were included in monitoring in 2010.CONCLUSIONS: Significant increasing trends were detected for abdominal wall anomalies, gastroschisis, hypospadias, Trisomy 18 and renal dysplasia in the Pan-Europe analysis while 68 increasing trends were identified in individual registries. A decreasing trend was detected in over one-third of anomaly subgroups in the Pan-Europe analysis, and 16.9% of individual registry tests. Registry preliminary investigations indicated that many trends are due to changes in data quality, ascertainment, screening, or diagnostic methods. Some trends are inevitably chance phenomena related to multiple testing, while others seem to represent real and continuing change needing further investigation and response by regional/national public health authorities.

Registration of congenital anomalies in Switzerland by EUROCAT.

Since 1988 the epidemiological surveillance of congenital anomalies (malformations, chromosomal aberrations, metabolic diseases, hereditary diseases, neurosensorial defects, etc.) is carried out by the Swiss registry of EUROCAT (European Registry of Congenital Anomalies and Twins). Several Swiss cantons collaborate through their own local registry, transmitting data to the central registry in Lausanne. We present the main objectives and methods of registration and give the global prevalence rates for the main malformations for 1996 and the period 1993-1996.

Descriptive epidemiology of isolated anal anomalies: a survey of 4.6 million births in Europe.

The prevalence of anal anomalies among 4,618,840 births recorded in 33 EUROCAT registries between 1980 and 1994 was 4.05 per 10,000 births. Of the 1,846 recorded cases, 672 (36.4%) were isolated anal anomalies while 1,174 (63.6%) occurred together with other anomalies. Only isolated anal anomalies were analyzed in this study: 75.5% were atresias, 10.1% of which were above and 89.9% were below the level of the levator ani muscle. Fistula occurred in 53% of supralevator and 37% of infralevator atresia. Other anal anomalies were ectopic anus (3.4%), congenital anal fistula (14.7%), and persistent cloaca (0.9%). There was a predominance of males in anal atresia without fistula (male to female (M:F) ratio was 6.7 for supralevator and 2.3 for infralevator atresia), but no significant sex difference in atresias with fistula. There was a predominance of females in ectopic anus and congenital anal fistula (M:F = 0.11 and 0.36 respectively). High frequencies of fetal deaths were recorded in supralevator atresia without fistula (8.3%) and in persistent cloaca (11.1%). Mean gestational length and mean birth weights were reduced for persistent cloaca but were within normal limits for other isolated anal anomalies. Odds ratios (ORs) for mothers above 35 years were increased for supralevator atresia without fistula, supralevator atresia with fistula, and congenital anal fistula. ORs for mothers below 30 years were slightly increased for supralevator atresia without fistula and decreased for persistent cloaca. There were marked differences in prevalence and distribution of anal anomalies among the EUROCAT registries. The results indicated that there are epidemiological differences among the various types of anal anomalies which might reflect different embryological origins.

Spectrum of congenital anomalies in pregnancies with pregestational diabetes.

BACKGROUND: Maternal pregestational diabetes is a well-known risk factor for congenital anomalies. This study analyses the spectrum of congenital anomalies associated with maternal diabetes using data from a large European database for the population-based surveillance of congenital anomalies. METHODS: Data from 18 population-based EUROCAT registries of congenital anomalies in 1990-2005. All malformed cases occurring to mothers with pregestational diabetes (diabetes cases) were compared to all malformed cases in the same registry areas to mothers without diabetes (non-diabetes cases). RESULTS: There were 669 diabetes cases and 92,976 non diabetes cases. Odds ratios in diabetes pregnancies relative to non-diabetes pregnancies comparing each EUROCAT subgroup to all other non-chromosomal anomalies combined showed significantly increased odds ratios for neural tube defects (anencephaly and encephalocele, but not spina bifida) and several subgroups of congenital heart defects. Other subgroups with significantly increased odds ratios were anotia, omphalocele and bilateral renal agenesis. Frequency of hip dislocation was significantly lower among diabetes (odds ratio 0.15, 95% CI 0.05-0.39) than non-diabetes cases. Multiple congenital anomalies were present in 13.6 % of diabetes cases and 6.1 % of non-diabetes cases. The odds ratio for caudal regression sequence was very high (26.40,95% CI 8.98-77.64), but only 17% of all caudal regression cases resulted from a pregnancy with pregestational diabetes. CONCLUSIONS: The increased risk of congenital anomalies in pregnancies with pregestational diabetes is related to specific non-chromosomal congenital anomalies and multiple congenital anomalies and not a general increased risk.

BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies.

RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.