Evaluation of prenatal diagnosis of associated congenital heart diseases by fetal ultrasonographic examination in Europe.

Ultrasound scans in the mid trimester of pregnancy are now a routine part of antenatal care in most European countries. With the assistance of Registries of Congenital Anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of congenital heart defects (CHD) by routine ultrasonographic examination of the fetus. All congenital malformations suspected prenatally and all congenital malformations, including chromosome anomalies, confirmed at birth were identified from the Congenital Malformation Registers, including 20 registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK and Ukrainia. These registries follow the same methodology. The study period was 1996-1998, 709 030 births were covered, and 8126 cases with congenital malformations were registered. If more than one cardiac malformation was present the case was coded as complex cardiac malformation. CHD were subdivided into 'isolated' when only a cardiac malformation was present and 'associated' when at least one other major extra cardiac malformation was present. The associated CHD were subdivided into chromosomal, syndromic non-chromosomal and multiple. The study comprised 761 associated CHD including 282 cases with multiple malformations, 375 cases with chromosomal anomalies and 104 cases with non-chromosomal syndromes. The proportion of prenatal diagnosis of associated CHD varied in relation to the ultrasound screening policies from 17.9% in countries without routine screening (The Netherlands and Denmark) to 46.0% in countries with only one routine fetal scan and 55.6% in countries with two or three routine fetal scans. The prenatal detection rate of chromosomal anomalies was 40.3% (151/375 cases). This rate for recognized syndromes and multiply malformed with CHD was 51.9% (54/104 cases) and 48.6% (137/282 cases), respectively; 150/229 Down syndrome (65.8%) were livebirths. Concerning the syndromic cases, the detection rate of deletion 22q11, situs anomalies and VATER association was 44.4%, 64.7% and 46.6%, respectively. In conclusion, the present study shows large regional variations in the prenatal detection rate of CHD with the highest rates in European regions with three screening scans. Prenatal diagnosis of CHD is significantly higher if associated malformations are present. Cardiac defects affecting the size of the ventricles have the highest detection rate. Mean gestational age at discovery was 20-24 weeks for the majority of associated cardiac defects.

Associated anomalies in multi-malformed infants with cleft lip and palate: An epidemiologic study of nearly 6 million births in 23 EUROCAT registries.

We studied 5,449 cases of cleft lip (CL) with or without cleft palate (CL/P) identified between 1980 and 2000 from the EUROCAT network of 23 registers (nearly 6 million births) in 14 European countries. We investigated specific types of defects associated with clefts. Among CL/P cases (prevalence = 9.1 per 10,000), 1,996 (36.6%) affected only the lip (CL) and 3,453 (63.4%) involved CL and palate (CLP). A total of 3,860 CL/P cases (70.8%) occurred as isolated anomalies and 1,589 (29.2%) were associated with other defects such as multiple congenital anomalies of unknown origin (970), chromosomal (455) and recognized syndromes (164). Associated malformations were more frequent in infants who had CLP (34.0%) than in infants with CL only (20.8%). Among multi-malformed infants, 2 unrelated anomalies were found in 351 cases, 3 in 242 cases, and 4 or more in 377 cases. Among 5,449 CL/P cases, 4,719 were live births (LB) (86.6%), 203 stillbirths (SB) (3.7%), while 508 (9.3%) were terminations of pregnancy (ToP). CL/P occurred significantly more frequently in males (M/F = 1.70), especially among total isolated cases (M/F = 1.87) and CLP isolated cases (M/F = 1.92). The study confirmed that musculoskeletal, cardiovascular, and central nervous system defects are frequently associated with CL/P. An association with reduction anomalies of the brain was found. This association suggests that clinicians should seek to identify structural brain anomalies in these patients with CL/P as the potential functional consequences may be important for rehabilitation and clinical management.

Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.

PTPN11 mutation manifesting as LEOPARD syndrome associated with hypertrophic plexi and neuropathic pain.

BACKGROUND: LEOPARD syndrome (LS) belongs to the family of neuro-cardio-facio-cutaneous syndromes, which include Neurofibromatosis-1 (NF1), Noonan syndrome, Costello Syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair and Legius syndrome. These conditions are caused by mutations in genes encoding proteins involved in the RAS-MAPK cellular pathway. Clinical heterogeneity and phenotype overlaps across those different syndromes is already recognized. CASE PRESENTATION: We hereby report a heterozygous de novo mutation in the PTPN11 gene (c.1403C > T) manifesting with a clinical picture of LS during childhood, and later development of neuropathic pain with hypertrophic plexi, which are typically observed in NF1 but have not been reported in LS. CONCLUSION: LS caused by PTPN11 mutations may be associated with hypertrophic roots and plexi. Consequently, clinicians should be aware of the possible development of neuropathic pain and consider specific diagnostic work-up and management.

Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers.

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.

[Place of volunteers in home care setting for taking care of individuals with Alzheimer's disease related dementia: Qualitative survey in a specialized unit] Place du bénévolat en EHPAD dans la prise en charge des personnes atteintes de la maladie d'Alzheimer ou démences apparentées : enquête qualitative dans une unité protégée.

Objectifs En EHPAD, selon les recommandations de la Haute Autorité de santé (HAS), la prise en charge non médicamenteuse des troubles psychocomportementaux associés à la maladie d'Alzheimer ou aux syndromes apparentés, implique une réorganisation, une formation spécifique du personnel et du temps. Se pose ici la question du rôle des bénévoles dans cette prise en charge. Matériels et méthodes Enquête descriptive à partir de questionnaires distribués aux différents intervenants (bénévoles, professionnels de santé et aidants familiaux) d'une unité protégée de l'EHPAD de la clinique du Diaconat (Colmar, France) et spécifiquement élaborés pour évaluer leur vécu de l'expérience de bénévolat dans la prise en charge des résidents souffrant d'une maladie d'Alzheimer ou d'un syndrome apparenté. Résultats Sur les 101 questionnaires qui ont été remplis, 85,7 % des aidants, 60 % des bénévoles et 42,1 % des professionnels constataient des bénéfices pour eux-mêmes. Les professionnels et les aidants avaient confiance dans l'intervention des bénévoles. Cependant, les bénévoles semblaient manquer de compétence pour le soutien des aidants et dans les techniques de communication avec les résidents. Les points essentiels pour permettre un fonctionnement harmonieux entre les différents intervenants étaient de bien définir préalablement le rôle de bénévoles et d'en informer les autres intervenants, de former les bénévoles à ce rôle et de favoriser la communication entre les bénévoles et les professionnels. Conclusion Cette enquête montre que les bénévoles ont une place aux côtés des équipes soignantes pour participer à la prise en charge non médicamenteuse des personnes atteintes de maladie d'Alzheimer ou syndromes apparentés. Ils ont une position singulière et jouent un rôle complémentaire de celui des soignants et des aidants. Objectives According to the recommendation of the French High Authority of Health (HAS), the non-pharmaceutical management of psycho-behavioural disorders associated with Alzheimer's disease or related disorders in a nursing home, involves reorganization an specific training for staff members and time. This raises the question of the role of volunteering in this approach. Materials and methods A descriptive survey using questionnaires distributed to various stakeholders (volunteers, healthcare professionals and caregivers) of a protected unit of the nursing home of the Diaconat clinic (Colmar, France) and specifically designed to assess their experience of the volunteering in supporting residents suffering from Alzheimer's diseases or related disorders. Results Of the 101 questionnaires that were filled in, 85.7% of caregivers, 60% of volunteers and 42.1% of professionals recorded benefits for themselves. Professionals and informal carers had confidence in the intervention of volunteers. However, volunteers seemed to lack skills to support informal caregivers and specific knowledge about the technique of communicating with residents. The key points to favor harmonious collaborations between the different stakeholders were: to properly define the role of volunteers and to inform other stakeholders about this role previously, and to specifically educate themselves in this task and to promote communication between volunteers and all other professionals. Conclusion This study shows that volunteers have a place alongside medical teams to participate in the non-pharmaceutical treatment for people with Alzheimer's disease or related syndromes. They have a unique position and play a complementary role to that of carers and informal caregivers.

Copy number variations and cognitive phenotypes in unselected populations

IMPORTANCE: The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. OBJECTIVE: To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency ≤0.05%; size ≥250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTS: The population biobank of Estonia contains 52,000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURES: Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTS: Of the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, ≤0.05%; ≥250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (≥250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (≥1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom. CONCLUSIONS AND RELEVANCE: Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment. Replication of these findings in additional population groups is warranted given the potential implications of this observation for genomics research, clinical care, and public health.

Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis.

OBJECTIVES: Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis. METHODS AND RESULTS: Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p<1×10(-5)). CONCLUSIONS: Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-β-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.

Analysis of the genetic basis of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.

PFAPA syndrome is the most common autoinflammatory syndrome in children from Western countries. In spite of its strong familial clustering, its genetic basis and inheritance pattern are still unknown. We performed a comprehensive genetic study on 68 individuals from 14 families. Linkage analysis suggested a susceptibility locus on chromosome 8, but direct molecular sequencing did not support this initial statistical finding. Exome sequencing revealed the absence of any gene that was mutated in all patients. Exhaustive screening of genes involved in other autoinflammatory syndromes or encoding components of the human inflammasome showed no DNA variants that could be linked to PFAPA molecular pathology. Among these, the previously-reported missense mutation V198M in the NLRP3 gene was clearly shown not to co-segregate with PFAPA. Our results on this relatively large cohort indicate that PFAPA syndrome is unlikely to be a monogenic condition. Moreover, none of the several genes known to be involved in inflammation or in autoinflammatory disorders seem to be relevant, alone, to its etiology, suggesting that PFAPA results from oligogenic or complex inheritance of variants in multiple disease genes and/or non-genetic factors.

Mild guanidinoacetate increase under partial guanidinoacetate methyltransferase deficiency strongly affects brain cell development.

Among cerebral creatine deficiency syndromes, guanidinoacetate methyltransferase (GAMT) deficiency can present the most severe symptoms, and is characterized by neurocognitive dysfunction due to creatine deficiency and accumulation of guanidinoacetate in the brain. So far, every patient was found with negligible GAMT activity. However, GAMT deficiency is thought under-diagnosed, in particular due to unforeseen mutations allowing sufficient residual activity avoiding creatine deficiency, but enough guanidinoacetate accumulation to be toxic. With poorly known GAA-specific neuropathological mechanisms, we developed an RNAi-induced partial GAMT deficiency in organotypic rat brain cell cultures. As expected, the 85% decrease of GAMT protein was insufficient to cause creatine deficiency, but generated guanidinoacetate accumulation causing axonal hypersprouting and decrease in natural apoptosis, followed by induction of non-apoptotic cell death. Specific guanidinoacetate-induced effects were completely prevented by creatine co-treatment. We show that guanidinoacetate accumulation without creatine deficiency is sufficient to affect CNS development, and suggest that additional partial GAMT deficiencies, which may not show the classical brain creatine deficiency, may be discovered through guanidinoacetate measurement.

Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2.

The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Yet, our knowledge of the molecular mechanisms underlying lymphatic vessel development is still limited. Here, we show that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of lymphatic vessel development. Endothelial-specific Cdk5 knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc2 as a key substrate of Cdk5 in the lymphatic vasculature, mechanistically linking Cdk5 to lymphatic development and valve morphogenesis. Collectively, our findings show that Cdk5-Foxc2 interaction represents a critical regulator of lymphatic vessel development and the transcriptional network underlying lymphatic vascular remodeling.

Cardiogene: an innovative multidisciplinary consultation for genetic arrhythmias

Introduction: Over the past decade clinically relevant progress has been made regarding the genetic origin of sudden cardiac death due to arrhythmic syndromes such as congenital long QT syndrome (LQTS), Brugada syndrome (BrS), catecholinergic polymorphic ventricular tachycardia (CPVT) and short QT (SQTS). An increased number of patients are diagnosed and their offspring sent for screening. In order to optimize care of these families we have set up a multidisciplinary consultation, "Cardiogene", consisting of a pediatric and an adult cardiologist and a clinical geneticist. All families are seen at a common consult in order to take the family history, genetic background and to explain the disease to patients and their families. Appropriate cardiac investigations and genetic testing are then performed and the families seen again in a multidisciplinary fashion for the results. We have reviewed all our cases over the past 5 years. Methods: retrospective review of all cases seen at Cardiogene Clinic for suspicion of arrhythmic syndromes since 2007. Results: 23 families were seen at the Cardiogene Clinic with a total of 41 children. The suspected arrhythmic syndrome was LQTS in 14 families (26 children), BrS in 7 families (14 children), SQTS in1 family (2 children) and CPVT in 1 family (3 children). Of the 41 children 17 were genetically positive for an arrhythmic syndrome: 14 were for LQTS, 3 for BrS. 24 children were genetically negative however 4 of those were phenotypically positive: 2 LQTS, 1 BrS and 1 CPVT. In 3 families the diagnosis was initially made in a child and then found in the parent. In 2 families the diagnosis was made after a sudden death of one of their children, 1 LQTS (3 week old child), 1 BrS (20 year old). Discussion: Genetic testing is an essential part of diagnosis and permits an improved targeting of patients needing follow-up and treatment. In our series, a mutation has been found in most families with LQTS. In all other genetic arrhythmias, the yield of genetic testing is less but nevertheless helpful for medical care of these pts. Conclusion: A multidisciplinary approach to genetic arrhythmias permits a better and more efficient screening and therapy in affected families. It helps families to better understand their disease and improves follow-up in the affected individuals.

Outcome of patients admitted with acute coronary syndrome on palliative treatment: insights from the nationwide AMIS Plus Registry 1997-2014.

OBJECTIVE: Compliance with guidelines is increasingly used to benchmark the quality of hospital care, however, very little is known on patients admitted with acute coronary syndromes (ACS) and treated palliatively. This study aimed to evaluate the baseline characteristics and outcomes of these patients. DESIGN: Prospective cohort study. SETTING: Eighty-two Swiss hospitals enrolled patients from 1997 to 2014. PARTICIPANTS: All patients with ACS enrolled in the AMIS Plus registry (n=45,091) were analysed according to three treatment groups: palliative treatment, defined as use of aspirin and analgesics only and no reperfusion; conservative treatment, defined as any treatment including antithrombotics or anticoagulants, heparins, P2Y12 inhibitors, GPIIb/IIIa but no pharmacological or mechanical reperfusion; and reperfusion treatment (thrombolysis and/or percutaneous coronary intervention during initial hospitalisation). The primary outcome measure was in-hospital mortality and the secondary measure was 1-year mortality. RESULTS: Of the patients, 1485 (3.3%) were palliatively treated, 11,119 (24.7%) were conservatively treated and 32,487 (72.0%) underwent reperfusion therapy. In 1997, 6% of all patients were treated palliatively and this continuously decreased to 2% in 2013. Baseline characteristics of palliative patients differed in comparison with conservatively treated and reperfusion patients in age, gender and comorbidities (all p<0.001). These patients had more in-hospital complications such as postadmission onset of cardiogenic shock (15.6% vs 5.2%; p<0.001), stroke (1.8% vs 0.8%; p=0.001) and a higher in-hospital mortality (25.8% vs 5.6%; p<0.001).The subgroup of patients followed 1 year after discharge (n=8316) had a higher rate of reinfarction (9.2% vs 3.4%; p=0.003) and mortality (14.0% vs 3.5%; p<0.001). CONCLUSIONS: Patients with ACS treated palliatively were older, sicker, with more heart failure at admission and very high in-hospital mortality. While refraining from more active therapy may often constitute the most humane and appropriate approach, we think it is important to also evaluate these patients and include them in registries and outcome evaluations. CLINICAL TRIAL NUMBER: ClinicalTrials.gov Identifier: NCT01 305 785.