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.

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.

Axenfeld-Rieger syndrome: more than meets the eye.

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition. METHODS: Genetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses. RESULTS: 128 individuals with causative variants in PITX2 or FOXC1, including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1-related ARS. Systemic anomalies were seen in all individuals with PITX2-related ARS and the majority of those with FOXC1-related ARS. PITX2-related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1-related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1-related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS. CONCLUSION: Since clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.

Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

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.

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.

Views on the Oberg-Manske-Tonkin Classification System for Congenital Anomalies of the Hand and Upper Limb.

A new classification system was proposed by Tonkin et al as a replacement for the Swanson/International Federation of Societies for Surgery of the Hand system. We have reviewed their aims and have pointed out a number of problems that will make it difficult to be universally accepted.

De novo exon 1 missense mutations of SKI and Shprintzen-Goldberg syndrome: two new cases and a clinical review.

Shprintzen-Goldberg syndrome (OMIM #182212) is a connective tissue disorder characterized by craniosynostosis, distinctive craniofacial features, skeletal abnormalities, marfanoid body habitus, aortic dilatation, and intellectual disability. Mutations in exon 1 of SKI have recently been identified as being responsible for approximately 90% of reported individuals diagnosed clinically with Shprintzen-Goldberg syndrome. SKI is a known regulator of TGFß signaling. Therefore, like Marfan syndrome and Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome is likely caused by deregulated TGFß signals, explaining the considerable phenotypic overlap between these three disorders. We describe two additional patients with exon 1 SKI mutations and review the clinical features and literature of Shprintzen-Goldberg syndrome.

Congenital heart defects and major structural noncardiac anomalies in Alberta, Canada, 1995-2002.

BACKGROUND: Although the majority of congenital heart defects (CHDs) occur in isolation, a significant number occur with noncardiac anomalies. This study determined the proportion of noncardiac anomalies among CHD cases in Alberta. METHODS: Records of infants and children born in Alberta between January 1, 1995, to December 31, 2002, were searched using multiple sources of ascertainment in addition to the Alberta Congenital Anomalies Surveillance System (ACASS) (Alberta Health and Wellness, 2012). Each case was assigned to one CHD category and was further categorized into one of the following groups: isolated CHD, syndromes, chromosomal, associations and sequences, teratogens, Mendelian, neoplasia, heterotaxy, multiple minor anomalies, and multiple major anomalies. RESULTS: Of all 3751 CHD cases (prevalence 12.42/1000 total births: confidence interval, 12.03-12.83), 75% were isolated, 10% had a chromosomal etiology, and 9% had multiple major anomalies. All other categories accounted for <2% each. The most commonly associated major noncardiac anomalies were musculoskeletal (MSK) (24%) followed by anomalies of the urinary tract (14%), gastrointestinal system (GI) (11%), and central nervous system (CNS) (11%). CONCLUSIONS: This is both a population-based and clinical study using a classification scheme that could help to determine possible etiologic factors contributing to CHD. By eliminating known etiologies such as chromosomal and single gene, future studies can focus on the remainder to evaluate possible preventive measures. The most commonly associated major noncardiac anomalies involve the MSK system, followed by the urinary, GI, and CNS systems.

Acardia: epidemiologic findings and literature review from the International Clearinghouse for Birth Defects Surveillance and Research.

Acardia is a severe, complex malformation of monozygotic twinning, but beyond clinical case series, very few epidemiologic data are available. The goals of this study were to assess the epidemiologic characteristics of acardia from birth defect registries in the International Clearinghouse for Birth Defects Surveillance and Research (Clearinghouse), and compare these findings to current literature. The study included 17 surveillance programs of the Clearinghouse representing 23 countries from North and South America, Europe, China, and Australia. Anonymized individual records with clinical and demographic data were reviewed centrally by clinical geneticists. A literature search was performed. A total of 164 cases of acardia were reported from an underlying cohort of 21.2 million births. Of these, 23% were elective pregnancy terminations. Rates did not vary significantly by maternal age. For many cases, information on pregnancy exposures and genetic testing was missing. However, these limited data did not suggest high rates of chronic illnesses (diabetes, seizure disorders) or lifestyle factors such as smoking. One case had trisomy 13. Major malformations were reported in 2.4% of co-twins. With some basic assumptions, the total prevalence of acardia was estimated at 1 in 50,000-70,000 births, and 1 in 200-280 monozygotic twins. In summary, acardia is a dramatic, probably underreported, and incompletely understood malformation. Studies on its epidemiology and etiology are challenging and still rare. An international collaboration of epidemiologists, clinicians, and geneticists is necessary to understand the etiology, pathogenesis, and occurrence of this severe malformation complex.

GJA1 mutations, variants, and connexin 43 dysfunction as it relates to the oculodentodigital dysplasia phenotype.

The predominantly autosomal dominant disorder, oculodentodigital dysplasia (ODDD) has high penetrance with intra- and interfamilial phenotypic variability. Abnormalities observed in ODDD affect the eye, dentition, and digits of the hands and feet. Patients present with a characteristic facial appearance, narrow nose, and hypoplastic alae nasi. Neurological problems, including dysarthria, neurogenic bladder disturbances, spastic paraparesis, ataxia, anterior tibial muscle weakness, and seizures, are known to occur as well as conductive hearing loss, cardiac defects, and anomalies of the skin, hair, and nails. In 2003, our analysis of 17 ODDD families revealed that each had a different mutation within the human gap junction alpha 1 (GJA1) gene which encodes the protein connexin 43 (Cx43). Since then at least 17 publications have identified an additional 26 GJA1 mutations and in this study, we present 28 new cases with 18 novel GJA1 mutations. We include tables summarizing the 62 known GJA1 nucleotide changes leading to Cx43 protein alterations and the phenotypic information available on 177 affected individuals from 54 genotyped families. Mutations resulting in ODDD occur in each of the nine domains of the Cx43 protein, and we review our functional experiments and those in the literature, examining the effects of 13 different Cx43 mutations upon gap junction activity.

Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry.

OBJECTIVES: Fortification of grain products with folic acid has been shown to significantly reduce the occurrence of neural tube defects (NTDs) in Canada and elsewhere. However, the impact on non-NTD anomalies has not been well studied. METHODS: Using the Alberta Congenital Anomalies Surveillance System (ACASS), we examined changes in occurrence of select congenital anomalies where folic acid supplementation with multivitamins had previously been suggested to have an effect. Anomalies documented in the ACASS 1992-1996 (pre-fortification) were compared to 1999-2003 (post-fortification). RESULTS: A significant decrease in spina bifida (OR 0.51, 95% CI 0.36-0.73) and ostium secundum atrial septal defects (OR 0.80, 95% CI 0.69-0.93) was evident, but there was a significant increase in obstructive defects of the renal pelvisand ureter (OR 1.45, 95% CI 1.24-1.70), abdominal wall defects (OR 1.40, 95% CI 1.04-1.88) and pyloric stenosis (OR 1.49, 95% CI 1.18-1.89). CONCLUSIONS: Consistent with other studies, a 50% reduction in spina bifida was associated with the post-fortification time period. Supporting the possibility that folic acid fortification may play a role in preventing other birth defects, a 20% reduction in atrial septal defects was also associated. The increase in abdominal wall defects, most notably gastroschisis, is likely related to pre-existing increasing trends documented in several regions around the world. The increase in pyloric stenosis and obstructive urinary tract defects was not expected and any causal relationship with folic acid fortification remains unclear. Similar studies by other birth defects surveillance systems in Canada and elsewhere are needed to confirm these trends.

Congenital anomalies surveillance in Canada.

Congenital anomalies (CA) are present in approximately 3% of all newborn babies and account for about 12% of paediatric hospital admissions. They represent an important public health problem. Surveillance is especially important so that preventive measures such as folic acid fortification can be properly assessed without resorting to a series of ad hoc studies. Canada's surveillance of CAs is weak, with only Alberta and British Columbia having established sytems. Most provinces have perinatal systems but their CA data are incomplete and they do not capture terminations of pregnancy. The same is true of the Public Health Agency of Canada's system. A new system, the Fetal Alert Network, has been proposed for Ontario, which represents a start but will require additional sources of ascertainment if it is to be a truly population-based system for Ontario.

Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) in seven patients.

We present a series of seven patients who were previously diagnosed with Proteus syndrome, but who do not meet published diagnostic criteria for this disorder and whose natural history is distinct from that of Proteus syndrome. This newly recognized phenotype comprises progressive, complex, and mixed truncal vascular malformations, dysregulated adipose tissue, varying degrees of scoliosis, and enlarged bony structures without progressive bony overgrowth. We have named this condition congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) on a heuristic basis. In contrast to the bony distortion so characteristic of Proteus syndrome, distortion in CLOVE syndrome occurs only following major or radical surgery. Here, we contrast differences and similarities of CLOVE syndrome to Proteus syndrome.

Stability of prevalence rates of anorectal malformations in the Alberta Congenital Anomalies Surveillance System 1990-2004.

BACKGROUND/PURPOSE: Anorectal malformations appeared to be increasing in the province of Alberta, Canada. To assess whether this was a significant trend, with the possibility of these having a teratogenic origin, we examined the frequency of anorectal malformations over a 15-year period. METHODS: We examined the records of the Alberta Congenital Anomaly Surveillance System, which is a semiactive surveillance system using the British Paediatric Association and the Royal College of Paediatrics and Child Health expansions of the International Classification of Diseases-Ninth Revision and the International Classification of Diseases-10th Revision. RESULTS: The overall rate was 1/2162 (4.63/10,000 total births) with a marked male predominance (1.7:1). Approximately two thirds of the 273 cases had 1 or more malformations. CONCLUSION: Although there was an increasing trend in the rate from 1999 especially for the multiples, this was not significant. In view of the advances in syndrome identification and molecular diagnostics, consideration should be given to a detailed review of the family history and appropriate testing not only for multiple cases but also for isolated ones.

Analysis of sperm karyotypes in a patient treated with griseofulvin.

Griseofulvin is known to interfere with chromosome segregation by binding to microtubule-associated proteins. Studies in mouse germ cells have demonstrated that griseofulvin can induce aneuploidy (numerical chromosome abnormalities) at therapeutic concentrations. The aim of this study was to determine if chronic griseofulvin treatment led to an increased frequency of sperm chromosome abnormalities in one male subject. We analyzed 290 full sperm karyotypes using the human sperm-hamster oocyte fusion system. The frequency of X- and Y-bearing sperm was equal. There was no increase in the frequency of numerical (1.7%) or structural (9.3%) abnormalities in the subject compared to unexposed controls. Although reassuring, this is the first report on this subject and future studies are needed to assess the risk of griseofulvin.

Reduction in neural-tube defects after folic acid fortification in Canada.

BACKGROUND: In 1998, folic acid fortification of a large variety of cereal products became mandatory in Canada, a country where the prevalence of neural-tube defects was historically higher in the eastern provinces than in the western provinces. We assessed changes in the prevalence of neural-tube defects in Canada before and after food fortification with folic acid was implemented. METHODS: The study population included live births, stillbirths, and terminations of pregnancies because of fetal anomalies among women residing in seven Canadian provinces from 1993 to 2002. On the basis of published results of testing of red-cell folate levels, the study period was divided into prefortification, partial-fortification, and full-fortification periods. We evaluated the relationship between baseline rates of neural-tube defects in each province and the magnitude of the decrease after fortification was implemented. RESULTS: A total of 2446 subjects with neural-tube defects were recorded among 1.9 million births. The prevalence of neural-tube defects decreased from 1.58 per 1000 births before fortification to 0.86 per 1000 births during the full-fortification period, a 46% reduction (95% confidence interval, 40 to 51). The magnitude of the decrease was proportional to the prefortification baseline rate in each province, and geographical differences almost disappeared after fortification began. The observed reduction in rate was greater for spina bifida (a decrease of 53%) than for anencephaly and encephalocele (decreases of 38% and 31%, respectively). CONCLUSIONS: Food fortification with folic acid was associated with a significant reduction in the rate of neural-tube defects in Canada. The decrease was greatest in areas in which the baseline rate was high.