Congenital anomalies occur frequently and are estimated to be present in about 13% of all admissions to neonatal intensive care units in the developed countries. Data from large studies indicate that the burden of genetic diseases in neonates with congenital anomalies in intensive care settings is approximately 5% to 7%. Congenital anomalies are a leading cause of infant mortality in the United States, accounting for about 20% of all infant deaths. There are over 4500 Mendelian disorders that have a known genetic etiology at present, and a significant fraction of these present in the neonatal period. With the rapid advancement in diagnostic technologies and our increasing ability to decipher the genetic basis of birth defects, a substantial influence of genetic perturbation is recognized in infants with birth defects. Recognition of chromosomal syndromes, genomic disorders, and single-gene Mendelian diseases, as well as imprinting diseases presenting in the newborns, is paramount in this age of rapidly advancing diagnostic and treatment alternatives. While trisomy 21 (Down syndrome) remains the most common genetic condition associated with birth defects, with an estimated incidence of 1 in 700 live births, other genetic disorders play a correspondingly significant role and should be recognized by astute clinicians. Teratogens, such as warfarin, alcohol, maternal phenylketonuria, retinoic acid, and Zika virus have an important role in causing birth anomalies and should be distinguished from inherited genetic determinants. Approaching a newborn with birth defects not only requires a comprehensive evaluation to identify the underlying cause, but also involves elucidating the genetic variants in at-risk families to prevent recurrence of often serious and life-threatening congenital anomalies.
Understanding different terminologies relevant to birth defects is important to determine the etiology of causation, whether genetic or environmental.
Malformations result from an intrinsic abnormal development during organogenesis. Etiology includes both genetic and environmental factors. Malformations typically develop early, often in the first 8 weeks of gestation. Depending on the underlying cause, malformation could involve a single organ or multiple systems in the body. Malformations can be further divided into major malformations, such as congenital heart disease (CHD) and meningomyelocele, and minor malformations, which are generally of minimal significance, particularly if seen as an isolated finding.
A syndrome is defined as a pattern of malformations, whether major or minor, that occurs as a predictable constellation of features due to a single underlying etiology. The basis of a syndrome could be chromosomal, genomic structural change (eg, deletion or duplication also known as copy number variant [CNV]), monogenic, epigenetic, or teratogenic exposure. Some examples of syndromes include Down syndrome, DiGeorge/velocardiofacial syndrome (DGS/VCFS) due to 22q11.2 deletion, and Beckwith-Wiedemann syndrome (BWS).
An association is defined by the combination of several birth defects that occur more frequently together than would be expected by chance. VACTERL/VATER association (vertebral defects, anal atresia, cardiovascular anomalies, tracheoesophageal fistula with esophageal atresia, and radial/renal abnormalities) ...