Provincial and territorial congenital anomalies surveillance: a summary of surveillance programs across Canada. / Surveillance provinciale et territoriale des anomalies congénitales : résumé des programmes de surveillance au Canada.

The Canadian Congenital Anomalies Surveillance Network was established in 2002 to address gaps in the national surveillance of congenital anomalies (CAs) and support the sustainability of high-quality, population-based, CA surveillance systems within provinces and territories. This paper highlights the methodologies of each local CA surveillance system, noting similarities and variabilities between each system, to contribute to enhanced national CA surveillance efforts.

The Canadian Congenital Anomalies Surveillance Network was established in 2002 under the umbrella of the Canadian Perinatal Surveillance System to support highquality, population-based congenital anomalies surveillance systems in Canada. Each local congenital anomalies surveillance system covers diverse populations and geography, operates under different structures and has varying program maturity. Engagement of every jurisdiction is essential for sustaining local and national CA surveillance. Provincial and territorial CA surveillance systems are uniquely positioned to support public health priorities.

Le Réseau canadien de surveillance des anomalies congénitales a été créé en 2002, dans le cadre du Système canadien de surveillance périnatale, afin de soutenir des systèmes de surveillance des anomalies congénitales de haute qualité et fondés sur la population à l'échelle du Canada. Les systèmes locaux de surveillance des anomalies congénitales couvrent des populations et des zones géographiques diverses, fonctionnent selon des structures différentes et ont une maturité variable. La participation de chaque administration est essentielle pour soutenir la surveillance locale et nationale des anomalies congénitales. Les systèmes provinciaux et territoriaux de surveillance des anomalies congénitales sont particulièrement bien placés pour soutenir les priorités en matière de santé publique.

Éléments de données communs pour l'arthrogrypose multiple congénitale: Un cadre international.

OBJECTIF: Afin de faciliter les études multisites et la recherche clinique d'envergure internationale, cette étude a pour but d'identifier des éléments de données communs (EDCs) normalisés et fondés sur un consensus pour l'arthrogrypose multiple congénitale (AMC). MÉTHODE: Une étude à méthodes mixtes comprenant plusieurs groupes de discussion et trois séries d'enquêtes Delphi modifiées pour parvenir à un consensus ont été menées. RÉSULTATS: Dans l'ensemble, 45 experts cliniques ainsi qu'adultes ayant une expérience vécue (dont 12 membres d'un consortium d'AMC) ont participé à cette étude à travers 11 pays en Amérique du Nord, Europe et Australie. Les EDCs comprennent 321 éléments de données et 19 mesures standardisées dans divers domaines, du développement du fœtus à l'âge adulte. Les éléments de données relatifs aux traits phénotypiques de l'AMC ont été cartographiés conformément à l'ontologie du phénotype humain (HPO). Une structure de gouvernance universelle, des protocoles de fonctionnement et des plans de développement durable ont été identifiés comme les principaux facilitateurs considérant que la capacité limitée de partage des données et la nécessité d'une infrastructure informatique fédérée étaient les principaux obstacles. INTERPRÉTATION: Une collecte de données systématiques sur l'AMC à l'aide d'EDCs permettra d'étudier sur les voies étiologiques, décrire le profil épidémiologique, et établir des corrélations génotype­phénotype de manière standardisée. Les EDCs proposés faciliteront les collaborations internationales multidisciplinaires en améliorant à grande échelle les études multicentriques, les possibilités de partage des données, ainsi que le transfert et la diffusion des connaissances.

Elementos de datos comunes para la artrogriposis múltiple congénita: Un marco internacional.

OBJETIVO: Para facilitar los estudios multicéntricos y la investigación clínica internacional, este estudio pretende identificar de forma consensuada los elementos de datos estandarizados para la artrogriposis múltiple congénita (AMC). MÉTODO: Estudio de métodos mixtos de grupos de discusión y tres rondas de encuestas Delphi modificadas para llegar a un consenso utilizando dos escalas de clasificación por niveles. RESULTADOS: En total, 45 expertos clínicos y adultos con experiencia vivida (incluidos 12 miembros de un consorcio de AMC) participaron en este estudio procedentes de 11 países: Norteamérica, Europa y Australia. Los CDEs incluyen 321 elementos de datos y 19 medidas estandarizadas en varios dominios desde el desarrollo fetal hasta la edad adulta. Los elementos de datos relativos a los rasgos fenotípicos del CDEs se mapearon de acuerdo con la Ontología de Fenotipos Humanos. Se identificaron como principales facilitadores la estructura de gobernanza universal, protocolos operados de forma local y los planes de sostenibilidad, mientras que los principales obstáculos observados son la capacidad limitada para compartir datos y la necesidad de una infraestructura informática federada. INTERPRETACIÓN: La recopilación de datos sistemáticos sobre la AMC mediante CDEs permitirá investigar las vías etiológicas, describir el perfil epidemiológico y establecer correlaciones genotipo­fenotipo de forma estandarizada. Los CDEs propuestos facilitarán las colaboraciones multidisciplinares internacionales mejorando los estudios a gran escala y las oportunidades para compartir datos, translación de conocimiento y difusión.

Prenatal findings in 11 cases with craniofacial microsomia using the Alberta Congenital Anomalies Surveillance System, 1997-2019.

Craniofacial microsomia (CFM) primarily includes specific head and neck anomalies that co-occur more frequently than expected. The anomalies are usually asymmetric and affect craniofacial features; however, there are frequently additional anomalies of variable severity. Published prenatal findings for CFM are limited. This study contributes 11 cases with CFM and their anomalies identified prenatally. Cases born between January 1, 1997 and December 31, 2019 with CFM were abstracted from the Alberta Congenital Anomalies Surveillance System, which is a population-based program ascertaining congenital anomalies for livebirths, stillbirths, and termination of pregnancies for fetal anomalies. There were 11 cases ascertained with prenatal findings including facial anomalies: one each with left cleft lip, right microtia, and bilateral microphthalmia. Two cases had vertebral anomalies. In addition, anomalies of the kidneys, brain, heart, and radial ray were identified. Six (55%) had a single umbilical artery, five (45%) were small for gestational age, and three (27%) were from a twin pregnancy that were discordant for anomalies. Four (36%) overlapped another proposed recurrent constellations of embryonic malformation condition. This study describes prenatal findings for 11 cases with CFM. Comparable to prior published cases, there were recurring anomalies on prenatal imaging, including anomalies of the brain, eye, heart, kidneys, and radial ray, which may aid in the prenatal diagnosis of CFM.

Common data elements for arthrogryposis multiplex congenita: An international framework.

AIM: To facilitate multisite studies and international clinical research, this study aimed to identify consensus-based, standardized common data elements (CDEs) for arthrogryposis multiplex congenita (AMC). METHOD: A mixed-methods study comprising of several focus group discussions and three rounds of modified Delphi surveys to achieve consensus using two tiered-rating scales were conducted. RESULTS: Overall, 45 clinical experts and adults with lived experience (including 12 members of an AMC consortium) participated in this study from 11 countries in North America, Europe, and Australia. The CDEs include 321 data elements and 19 standardized measures across various domains from fetal development to adulthood. Data elements pertaining to AMC phenotypic traits were mapped according to the Human Phenotype Ontology. A universal governance structure, local operating protocols, and sustainability plans were identified as the main facilitators, whereas limited capacity for data sharing and the need for a federated informatics infrastructure were the main barriers. INTERPRETATION: Collection of systematic data on AMC using CDEs will allow investigations on etiological pathways, describe epidemiological profile, and establish genotype-phenotype correlations in a standardized manner. The proposed CDEs will facilitate international multidisciplinary collaborations by improving large-scale studies and opportunities for data sharing, knowledge translation, and dissemination.

Publicly funded healthcare costs associated with orofacial clefts for children born in Alberta, Canada between 2002 and 2018.

BACKGROUND: Orofacial clefts (OFCs) include cleft palate (CP), cleft lip (CL), and cleft lip with cleft palate (CLP) and require multidisciplinary healthcare services. Alberta, Canada has a publicly funded, universal access healthcare system. This study determined publicly funded healthcare costs for children with an OFC and compared these costs to children without congenital anomalies. METHODS: This retrospective population-based cohort analysis used the Alberta Congenital Anomalies Surveillance System to identify children born between 2002 and 2018 with an isolated OFC. They were matched 1:1 to a reference cohort based on sex and year of birth. The study population included 1614 children, from birth to 17 years of age linked to administrative databases to estimate annual inpatient and outpatient costs. Average annual all-cause costs were compared using two-sample independent t tests. RESULTS: The mean total cleft-related costs per patient were highest for children with CLP ($74,138 CAD, standard deviation (SD) $43,447 CAD), followed by CP ($53,062 CAD, SD $74,366 CAD), and CL ($35,288 CAD, SD $49,720 CAD). The mean total all-cause costs per child were statistically significantly higher (p < .001) in children with an OFC ($56,305 CAD, SD $57,744 CAD) compared to children without a congenital anomaly ($18,600 CAD, SD $61,300 CAD). CONCLUSIONS: Despite public health strategies to mitigate risk factors, the trend for OFCs has remained stable in Alberta, Canada for over 20 years. The costs reported are useful to other jurisdictions for comparison, and to families, healthcare professionals, service planners, and policy makers.

Craniofacial Microsomia, Associated Congenital Anomalies, and Risk Factors in 63 Cases from the Alberta Congenital Anomalies Surveillance System.

OBJECTIVE: To report associated congenital anomalies with unexplained craniofacial microsomia (CFM) and the phenotypic overlap with other recurrent constellations of embryonic malformations (RCEM), and to assess prenatal and perinatal risk factors. STUDY DESIGN: This is a retrospective cross-sectional study. Cases with CFM, delivered between January 1, 1997, and December 31, 2019, were abstracted from the population-based Alberta Congenital Anomalies Surveillance System. Livebirths, stillbirths, and early fetal losses were reviewed to include all types of pregnancy outcomes along the spectrum of this condition. Prenatal and perinatal risk factors were compared with the Alberta birth population to assess differences between the 2 groups. RESULTS: There were 63 cases with CFM, yielding a frequency of 1 per 16 949. There was a high rate of cases (65%) with anomalies outside the craniofacial and vertebral regions. Congenital heart defects were the most common (33.3%). A single umbilical artery was found in 12.7% of cases. The twin/triplet rate of 12.7% was significantly higher than the Alberta rate of 3.3% (P < .0001). There was an overlap with a second RCEM condition in 9.5% of cases. CONCLUSIONS: Although CFM is primarily a craniofacial condition, the majority of cases have congenital anomalies affecting other systems requiring additional assessments, including an echocardiogram, renal ultrasound examination, and a complete vertebral radiograph. The high rate of an associated single umbilical artery raises the possibility of a related etiological mechanism. Our findings support the proposed concept of RCEM conditions.

The Alberta Congenital Anomalies Surveillance System: a 40-year review with prevalence and trends for selected congenital anomalies, 1997-2019. / Le système de surveillance des anomalies congénitales de l'Alberta : compte rendu des données sur 40 ans avec prévalence et tendances de certaines anomalies congénitales entre 1997 et 2019.

INTRODUCTION: Current published long-term provincial or territorial congenital anomaly data are lacking for Canada. We report on prevalence (per 1000 total births) and trends in 1997-2019, in Alberta, Canada, for selected congenital anomalies. Associated risk factors are also discussed. METHODS: We used data from the Alberta Congenital Anomalies Surveillance System (ACASS) to calculate the prevalence and perform chi-square linear trend analyses. RESULTS: From 1997 to 2019, the overall prevalence of neural tube defects was stable, at 0.74 per 1000 total births. The same was true for spina bifida (0.38), orofacial clefts (1.99), more severe CHDs (transposition of the great arteries, 0.38; tetralogy of Fallot, 0.33; and hypoplastic left heart syndrome, 0.32); and gastroschisis (0.38). Anencephaly, cleft palate and anorectal malformation significantly decreased with a prevalence of 0.23, 0.75 and 0.54 per 1000 total births, respectively. Significantly increasing trends were reported for anotia/microtia (0.24), limb reduction anomalies (0.73), omphalocele (0.36) and Down syndrome (2.21) and for hypospadias and undescended testes (4.68 and 5.29, respectively, per 1000 male births). CONCLUSION: Congenital anomalies are an important public health concern with significant social and societal costs. Surveillance data gathered by ACASS for over 40 years can be used for planning and policy decisions and the evaluation of prevention strategies. Contributing genetic and environmental factors are discussed as is the need for continued surveillance and research.

Validation of case definition algorithms for the ascertainment of congenital anomalies.

BACKGROUND: Congenital anomalies (CA) are one of the leading causes of infant mortality and long-term disability. Many jurisdictions rely on health administrative data to monitor these conditions. Case definition algorithms can be used to monitor CA; however, validation of these algorithms is needed to understand the strengths and limitations of the data. This study aimed to validate case definition algorithms used in a CA surveillance system in British Columbia (BC), Canada. METHODS: A cohort of births between March 2000 and April 2002 in BC was linked to the Health Status Registry (HSR) and the BC Congenital Anomalies Surveillance System (BCCASS) to identify cases and non-cases of specific anomalies within each surveillance system. Measures of algorithm performance were calculated for each CA using the HSR as the reference standard. Agreement between both databases was calculated using kappa coefficient. The modified Standards for Reporting Diagnostic Accuracy guidelines were used to enhance the quality of the study. RESULTS: Measures of algorithm performance varied by condition. Positive predictive value (PPV) ranged between approximately 73%-100%. Sensitivity was lower than PPV for most conditions. Internal congenital anomalies or conditions not easily identifiable at birth had the lowest sensitivity. Specificity and negative predictive value exceeded 99% for all algorithms. CONCLUSION: Case definition algorithms may be used to monitor CA at the population level. Accuracy of algorithms is higher for conditions that are easily identified at birth. Jurisdictions with similar administrative data may benefit from using validated case definitions for CA surveillance as this facilitates cross-jurisdictional comparison.

Epidemiology, aetiology, interventions and genomics in children with arthrogryposis multiplex congenita: protocol for a multisite registry.

INTRODUCTION: Arthrogryposis multiplex congenita (AMC) is an umbrella term including hundreds of conditions with the common clinical manifestation of multiple congenital contractures. AMC affects 1 in 3000 live births and is caused by lack of movement in utero. To understand the long-term needs of individuals diagnosed with a rare condition, it is essential to know the prevalence, aetiology and functional outcomes in a large sample. The development and implementation of a multicentre registry is critical to gather this data. This registry aims to improve health through genetic and outcomes research, and ultimately identify new therapeutic targets and diagnostics for treating children with AMC. METHODS AND ANALYSIS: Participants for the AMC registry will be recruited from seven orthopaedic hospitals in North America. Enrollment occurs in two phases; Part 1 focuses on epidemiology, aetiology and interventions. For this part, retrospective and cross-sectional data will be collected using a combination of patient-reported outcomes and clinical measures. Part 2 focuses on core subset of the study team, including a geneticist and bioinformatician, identifying causative genes and linking the phenotype to genotype via whole genome sequencing to identify genetic variants and correlating these findings with pedigree, photographs and clinical information. Descriptive analyses on the sample of 400 participants and logistic regression models to evaluate relationships between outcomes will be conducted. ETHICS AND DISSEMINATION: Ethical approval has been granted from corresponding governing bodies in North America. Dissemination of findings will occur via traditional platforms (conferences, manuscripts) for the scientific community. Other modalities will be employed to ensure that all stakeholders, including youth, families and patient support groups, may be provided with findings derived from the registry. Ensuring the findings are circulated to a maximum amount of interested parties will ensure that the registry can continue to serve as a platform for hypothesis-driven research and further advancement for AMC.

Phenotype and pathology of the dilated cardiomyopathy with ataxia syndrome in children.

The dilated cardiomyopathy with ataxia syndrome (DCMA) is an autosomal recessive mitochondrial disease caused by mutations in the DnaJ heat shock protein family (Hsp40) member C19 (DNAJC19) gene. DCMA or 3-methylglutaconic aciduria type V is globally rare, but the largest number of patients in the world is found in the Hutterite population of southern Alberta in Canada. We provide an update on phenotypic findings, natural history, pathological findings, and our clinical experience. We analyzed all available records for 43 patients diagnosed with DCMA between 2005 and 2015 at the Alberta Children's Hospital. All patients studied were Hutterite and homozygous for the causative DNAJC19 variant (c.130-1G>C, IVS3-1G>C) and had elevated levels of 3-methyglutaconic acid. We calculated a birth prevalence of 1.54 cases per 1000 total births in the Hutterite community. Children were small for gestational age at birth and frequently required supplemental nutrition (63%) or surgical placement of a gastrostomy tube (35%). Early mortality in this cohort was high (40%) at a median age of 13 months (range 4-294 months). Congenital anomalies were common as was dilated cardiomyopathy (50%), QT interval prolongation (83%), and developmental delay (95%). Tissue pathology was analyzed in a limited number of patients and demonstrated subendocardial fibrosis in the heart, macrovesicular steatosis and fibrosis in the liver, and structural abnormalities in mitochondria. This report provides clinical details for a cohort of children with DCMA and the first presentation of tissue pathology for this disorder. Despite sharing common genetic etiology and environment, the disease is highly heterogeneous for reasons that are not understood. DCMA is a clinically heterogeneous systemic mitochondrial disease with significant morbidity and mortality that is common in the Hutterite population of southern Alberta.

A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita.

Arthrogryposis multiplex congenita (AMC) describes a group of conditions characterized by the presence of non-progressive congenital contractures in multiple body areas. Scoliosis, defined as a coronal plane spine curvature of ≥10 degrees as measured radiographically, has been reported to occur in approximately 20% of children with AMC. To identify genes that are associated with both scoliosis as a clinical outcome and AMC, we first queried the DECIPHER database for copy number variations (CNVs). Upon query, we identified only two patients with both AMC and scoliosis (AMC-SC). The first patient contained CNVs in three genes (FBN2, MGF10, and PITX1), while the second case had a CNV in ZC4H2. Looking into small variants, using a combination of Human Phenotype Ontogeny and literature searching, 908 genes linked with scoliosis and 444 genes linked with AMC were identified. From these lists, 227 genes were associated with AMC-SC. Ingenuity Pathway Analysis (IPA) was performed on the final gene list to gain insight into the functional interactions of genes and various categories. To summarize, this group of genes encompasses a diverse group of cellular functions including transcription regulation, transmembrane receptor, growth factor, and ion channels. These results provide a focal point for further research using genomics and animal models to facilitate the identification of prognostic factors and therapeutic targets for AMC.

Prevalence rates study of selected isolated non-Mendelian congenital anomalies in the Hutterite population of Alberta, 1980-2016.

A study of the prevalence rates for selected isolated non-Mendelian congenital anomalies in the Hutterite Brethren of Alberta, Canada was undertaken to further examine longitudinal data in this isolated community that was last reported in 1985 (Lowry et al., 1985), although there are numerous publications on recessive disorders (Boycott et al., 2008; Triggs-Raine et al., 2016). Cases were ascertained from the Alberta Congenital Anomaly Surveillance System for the years 1997-2016. Since our initial results showed some surprising findings in the Hutterite Brethren, such as zero cases of spina bifida, cleft lip and palate, gastroschisis, and omphalocele, and a significant excess of cases with hypospadias, we extended the study to prior years (1980-1996) for selected anomalies. For the extended study period (1980-2016), there was a significant increased prevalence of hypospadias, tetralogy of Fallot and tricuspid atresia in the Hutterite population, and although not statistically significant, zero cases of cleft lip with cleft palate, gastroschisis and omphalocele were confirmed. Further research is needed to determine the precise effects of rural environmental exposures, lifestyle factors, and genetic associations for selected multifactorial congenital anomalies.

International multidisciplinary collaboration toward an annotated definition of arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles, but the terminology used has been inconsistent in clinical and research communities. A definition of AMC was recently developed using a modified Delphi consensus method involving 25 experts in the field of AMC from 8 countries. Participants included health care professionals, researchers, and individuals with AMC. An annotation of the definition provides more in-depth explanations of the different sentences of the AMC definition and is useful to complement the proposed definition. The aim of this study was to provide an annotation of the proposed consensus-based AMC definition. For the annotation process, 17 experts in AMC representing 10 disciplines across 7 countries participated. A paragraph was developed for each sentence of the definition using an iterative process involving multiple authors with varied and complementary expertise, ensuring all points of view were taken into consideration. The annotated definition provides an overview of the different topics related to AMC and is intended for all stakeholders, including youth and adults with AMC, their families, and clinicians and researchers, with the hopes of unifying the understanding of AMC in the international community.

Research platform for children with arthrogryposis multiplex congenita: Findings from the pilot registry.

A pediatric registry for arthrogryposis multiplex congenita (AMC) proposes to advance research by providing the platform to inform the distribution, etiology, and natural history of AMC. The registry was piloted on 40 families of children (mean = 8.25 years, 48% males) presenting with AMC across two hospitals in North America. Data on the child's demographic and newborn variables, mothers' and fathers' demographic variables, lifestyle habits, and medical history were collected using a telephone interview with the primary caregiver and review of medical charts. Mean gestational age was 38 weeks, 97% of children presented with lower extremity deformities, and 74% of neonatal interventions targeted the lower extremity. Newborns spent an average of 14 days in the hospital (range 2-56 days) mostly for diagnostic workup and feeding difficulties. Half (49%) of the sample had internal organ involvement. Genetic testing was done on 48% of the children, including chromosome studies, single gene, whole-exome/genome sequencing, and/or microarray studies. Genetic findings were inconclusive in most. Two-thirds of mothers (67%) reported inconsistently feeling fetal movements. This pilot study contributed to the refinement of participant selection, identification of data source, expansion of data sets, and areas for future exploration prior to the implementation of a multisite AMC pediatric registry.

Disease coding systems for arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita (AMC) encompasses many different conditions, involves many different genes and thus can be very complex. Using historical disease coding systems to document syndrome diagnoses and anomalies associated with AMC is often challenging. However, disease coding systems are necessary to provide opportunities for a standard language to be maintained and pertinent data to be identified in the pediatric AMC registry, congenital anomalies surveillance systems, and routine or administrative health information systems. The ICD-10, Orphanet, Online Mendelian Inheritance in Man, and the Human Phenotype Ontology coding and classification systems are described to establish a comprehensive coding strategy. This strategy will provide a necessary tool to contribute to a better understanding of AMC and ultimately improve the health of individuals with AMC.

Prevalence rates of spina bifida in Alberta, Canada: 2001-2015. Can we achieve more prevention?

BACKGROUND: Despite a substantial prevention of neural tube defects with mandatory folic acid (FA) fortification, a significant number of cases still exist in Alberta, Canada, particularly spina bifida (SB). The purpose of this study was to review cases with SB to provide a possible explanation as to why SB is still prevalent in Alberta. METHODS: Cases with SB born between 2001 and 2015, ascertained by the Alberta Congenital Anomalies Surveillance System, were reviewed. Cases were classified as lipomeningomyelocele, syndrome/recognized condition, chromosome, associated multiple congenital anomalies, and isolated. The notice of birth forms were reviewed to determine FA supplement use before and/or during pregnancy. Socioeconomic status (SES) was also examined. RESULTS: The majority of cases were isolated (58%). The total prevalence of SB for 2001-2015 was 0.37/1,000 births, with isolated SB being 0.21/1,000 births. Urinary and congenital heart defects were the most frequently identified associated anomalies. FA supplementation could not be determined for 69% of our cases because of a lack of completeness of the notice of birth forms. There was no significant difference regarding SES between mothers of cases and all mothers in Alberta. CONCLUSIONS: It is important to examine cases with isolated SB to determine why mandatory FA fortification has not completely prevented SB and to identify which cases are not folate-responsive. A more concerted effort of public health education and promotion with the identification of women with suboptimal folate status and a better understanding of the role of other micronutrients is necessary.