Birth Defects: Etiology, screening, and detection (2017)

This issue of Birth Defects Research – Reviews focuses on the topic of “Birth Defects: Etiology, Screening, and Detection”, and contains seven reviews covering areas ranging from the detection and evaluation of the genetic and developmental origin of diseases to the imaging and structural assessment of birth defects. The authors have presented an array of approaches to observe, screen, detect and analyze the etiology as well as provided instructional and illustrative examples of birth defects that have both structural and physiological consequences. Huilin Wang and co-authors (Chromosome Copy Number Variants in Fetuses with Syndromic Malformations) address chromosome copy number variants (CNVs), which are gains and losses of DNA sequences >1 kb, a subset of which are responsible for the pathogenesis of major birth defects and cancer, as well as associated with neurodevelopmental disorders at birth. These microdeletions and microduplications are wide-spread throughout the genome and can occur in all pregnancies, and the spectrum of pathogenic CNVs in fetuses with syndromic malformations is not well studied in healthy individuals. These authors provide a contemporary review of the knowledge on CNVs, specifically the characteristics of pathogenic CNVs identified in fetuses with syndromic malformations, and present the commonly used CNV detection methods. Jinyu Li and colleagues (Screening, Genetics, Risk Factors, and Treatment of Neonatal Cataracts) present a fascinating review on neonatal cataracts, the most common cause of visual loss in children worldwide, which have diverse, and often unknown, etiologies. The review focuses on the detection, treatment, genetics, risk factors, and molecular mechanisms of congenital cataracts. Known etiologies include mutations in lens crystallins and membrane/cytoskeletal components. The authors point out the need for further understanding of the causes, progression, and pathology of neonatal cataracts in order to develop effective diagnostic criteria and appropriate interventions, such as the implantation of intraocular lenses, to ensure safety and improved visual outcomes for children. Progress in recent decades has demonstrated that many adult disorders, including hypertension, diabetes, obesity, cancer, and others, could be linked to poor development resulting from in utero insults, with utero-environments playing a critical role in fetal development. The concept of “fetal origins of health and diseases (FOAD)”, or “the invisible birth defect”, is the theme of the review by Xiang Li and co-authors (“Three Hits” Hypothesis for Developmental Origin of Health and Diseases in View of Cardiovascular Abnormalities). These authors propose the “Three Hits” hypothesis, which incorporates “congenital genetic factors inherited from parents or de novo genetic mutations” (First Hit), “adverse exposure in utero” (Second Hit), and “unhealthy living habits or conditions before and during adult stages” (Third Hit), to highlight the importance of intrauterine and early postnatal factors as contributors to FOAD, which could be significant for early prevention and treatments of FOAD. Small animal models, particularly mouse models, of human diseases have become an indispensable tool for biomedical research. These models have provided important insights into the etiology and pathogenesis of diseases and accelerated the development of therapeutic strategies. Critical for such studies is the ability to carry out detailed phenotypic characterization. Yijen Wu and Cecilia Lo (Diverse Application of Magnetic Resonance Imaging for Mouse Phenotyping) detail recent advancements in the application of magnetic resonance imaging (MRI) as a versatile and non-invasive imaging modality with excellent penetration depth, tissue coverage, and soft tissue contrast, particularly for phenotyping mutant models of structural birth defects. The authors survey and review a range of studies illustrating that the multi-modal imaging capability of MRI, together with proven imaging protocols and availability of good contrast agents, is ideally suited for phenotyping mutant mouse models. In another review authored by Xiaoqin Liu and colleagues (Diverse Application of Magnetic Resonance Imaging for Mouse Phenotyping), the application of non-invasive fetal ultrasound, coupled with micro-computed tomography (micro-CT) is introduced as an imaging technology for high throughput phenotyping of mice for congenital heart defects (CHD) and other developmental anomalies. Fetal ultrasound allows longitudinal scans to track the developmental profile of disease pathogenesis, including functional hemodynamic assessments with color flow and spectral Dopper imaging. In addition, micro-CT imaging may be used to obtain virtual necropsies. These authors also provide exciting application of a novel histological technique of episcopic confocal microscopy (ECM) to obtain rapid 3D reconstructions for accurate diagnosis of even the most complex anatomical defects. Combination of these imaging techniques enables high throughput mouse phenotyping of genetically engineered mice in the coming age of functional genomics. The application of ultrasound is further illustrated in the diagnosis of Cornelia de Lange syndrome (CdLS), which is an inherited human condition with a wide spectrum of phenotypic anomalies, consisting mainly of growth impairment, multi-organ abnormalities, and neurocognitive delay. Laura Avagliano and co-authors (Diverse Application of Magnetic Resonance Imaging for Mouse Phenotyping) summarize the main possible prenatal findings in CdLS, suggesting that a skilled ultrasound scan, in cases of intrauterine growth restriction associated with other fetal abnormalities, may improve the chance of prenatal diagnosis of CdLS, especially in families known to be at high risk. The final review in this issue is authored by Lucas Boer and colleagues (Sirenomelia: A Multi-Systemic Polytopic Field Defect with Ongoing Controversies), who have chosen to address Sirenomelia, a rare and highly unusual, multi-systemic polytopic birth defect with ongoing controversies. The most impressive phenotypic appearance of sirenomelia, which is also known as symmelia or mermaid syndrome, is the presence of a 180˚-rotated, axially positioned, single lower limb. Associated gastrointestinal and genitourinary anomalies are almost always present. This rare anomaly is still the subject of ongoing controversies concerning its nosology, pathogenesis, and possible genetic etiology, most likely involving different “primary field defects”, whether or not genetically based. Particularly noteworthy is the authors’ use of a third-trimester sirenomelic fetus from their anatomical museum collection to illustrate the VACTERL-H (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities – with hydrocephalus) associations with sirenomelia. Screening and detection of birth defects is a central focus of contemporary research on birth defects. Early, accurate, and precise knowledge of the structural and physiological characteristics of birth defects present the best opportunity for the development of treatment and management of such outcomes. It is the aim of the overviews and examples covered in this issue of Birth Defects Research – Reviews to present insights, approaches, technologies, and opportunities for ongoing and future investigations to advance our understanding, detection, and treatment of structural birth defects. Rocky S. Tuan* Center for Cellular and Molecular Engineering Department of Orthopaedic Surgery University of Pittsburgh School of Medicine Pittsburgh, PA 15219, U.S.A.