Congenital Anomalies

Congenital Anomalies

Aditi S. Parikh and Anna L. Mitchell

Major anomalies are seen in about 2% of newborns, often prompting parental worry and urgent medical intervention soon after birth. In addition, they are a common cause of long-term illness and death. This chapter reviews some of the significant etiologic and epidemiologic aspects of congenital anomalies. It provides an approach to and a framework for the evaluation of the infant with congenital anomalies, with emphasis on conditions that are apparent in the delivery room. More detailed and complete differential diagnoses for each anomaly can be found in other sources.

General Clinical Approach

The neonatologist or perinatologist often is the first person to identify a congenital anomaly and initiate the necessary medical evaluations. In essence, the clinician observes an abnormal phenotype, which is a term used to describe the identifiable manifestation of a person’s genotype, or the genetic constitution of an individual. This observation is followed by the generation of possible causes, which are confirmed or refuted with further testing. Because the underlying defect or genotype is often not known, phenotype in clinical practice refers to a collection of specific traits, physical findings, and the results of medical tests, such as laboratory, pathologic, and radiologic studies.

A congenital anomaly is an internal or external structural defect that is identifiable at birth. Anomalies are deviations from the norm and are classified as major or minor. A major anomaly is a defect that requires significant surgical or cosmetic intervention, such as tetralogy of Fallot or cleft lip and palate, whereas a minor anomaly has no significant surgical or cosmetic importance. The clinician should be aware that minor anomalies often overlap with normal phenotypic variation, so a careful search for specific morphologic patterns is essential. It is important to classify an anomaly as major, minor, or normal because implications differ for both the infant and the family. It is also important to distinguish the concepts of congenital and genetic, terms that are often confused. Congenital merely indicates that the feature is present at birth and can have many genetic and nongenetic causes.

Anomalous external physical features are called dysmorphisms and can be clues to the underlying cause or developmental defect. A useful approach to determining the etiology of a congenital anomaly is to consider whether it represents a malformation, deformation, or disruption of normal development.57 In a study of 27,145 neonates with congenital anomalies, nearly 98% were caused by an underlying malformation, which is a primary structural defect in tissue formation such as a neural tube defect or a congenital heart defect.39 A malformation implies an abnormal morphogenesis of the underlying tissue owing to a genetic or teratogenic factor.

In contrast, a deformation results from abnormal mechanical forces acting on otherwise morphologically normal tissues.1,57 Deformations primarily result from mechanical forces, such as intrauterine constraint, on the growing fetus. A variety of maternal factors can cause fetal constraint, and common examples include breech or other abnormal positioning in utero, oligohydramnios, and uterine anomalies. Clubfoot and altered head shape are frequent anomalies that can result from constraint. Deformations occurring late in gestation often are reversible with changes in position or removal of the force. Observing the position the infant finds most comfortable, along with a careful obstetric history of fetal movement, position, and fluid volume, can be helpful in determining whether an anomaly could have been caused by a deforming force.

A disruption represents the destruction or interruption of intrinsically normal tissue, and it usually affects a body part rather than a specific organ. Vascular occlusion and amniotic bands are common causes of disruptions. Monozygotic twinning and prenatal cocaine exposure are common predisposing factors for disruptions on the basis of vascular interruption.

Malformations may predispose a fetus to additional deformations and multiple anomalies. A neural tube defect, a malformation, causes fetal deformations of hip dislocation and clubfoot, owing to lack of movement below the level of the lesion. If an infant has more than one anomaly, the clinician should then consider whether it is part of a sequence, association, or a known syndrome. Sequence refers to a pattern of multiple anomalies derived from a single known or presumed cause. An example is the oligohydramnios sequence, often referred to as Potter syndrome, which consists of limb deformations, pulmonary hypoplasia, and Potter facies of a beaked nose, infraorbital creases, and simple ears. These features are due to a lack of amniotic fluid during gestation, secondary to chronic leakage of amniotic fluid or lack of fetal urine (renal agenesis, a malformation).31,57 Another constellation of anomalies frequently seen by the neonatologist is the Pierre Robin sequence, consisting of micrognathia, cleft palate, and glossoptosis, in which the disproportionately small, malformed mandible causes the tongue to move backward and upward in the oral cavity during development, resulting in a cleft palate and potential airway obstruction.17,31 In these instances, the key to understanding the underlying cause of the secondary deformation anomalies lies with the primary malformation.

Multiple congenital anomalies in infants can also be seen as part of an association, which refers to a nonrandom occurrence of multiple malformations for which no specific or common etiology has been identified. An example is the VATER (or VACTERL) association, an acronym for a pattern of anomalies consisting of vertebral abnormalities, anal atresia, (cardiac anomalies), tracheoesophageal fistula, and renal and radial (limb) dysplasia.33,52 Although several conditions, such as maternal diabetes, are found in conjunction with VATER, a specific genetic link has not been proved. Over time the genetic cause for some idiopathic associations has been identified, as in the CHARGE association, now known as CHARGE syndrome. The acronym denotes multiple features of the syndrome (coloboma, heart anomalies, choanal atresia, restriction of growth and development, and genital and ear anomalies), and mutations in the CHD7 gene were found to be causative in over half of affected children, although the exact mechanism for the multiple malformations is not clear at this time.4 Further, many new genes have been identified for specific syndromes that have been recognized by dysmorphologists as Mendelian traits for many years. In genetic terms, a syndrome refers to a recognized pattern of anomalies with a specific, usually heritable, cause such as the Holt-Oram syndrome, in which radial dysplasia and cardiac defects occur as a consequence of an autosomal dominant TBX5 gene.2,53 The Cornelia de Lange syndrome is another example of this forward progress in genetic understanding of recognized malformation syndromes, in which at least five genetic loci, including the NIPBL gene, have been identified in patients with growth failure, microcephaly, limb anomalies, and characteristic facial dysmorphisms.13 It is expected that the discovery of new genetic defects will continue at a rapid pace, improving the diagnostic capability for infants with congenital anomalies in the future.

Although the underlying causes of congenital anomalies are heterogeneous, disruptions and isolated deformations are usually sporadic, with negligible or low recurrence risks. However, congenital malformations can also have more than one cause, often with different possible associated anomalies and different recurrence risks. Cleft lip and palate, for example, can be isolated or can be part of dozens of different syndromes due to monogenic, multifactorial, or complex, chromosomal, or teratogenic causes.22 The clinician should remember that the search for the underlying cause of a birth defect can be anxiety provoking for parents of newborns with congenital anomalies, as are the implications for future children and other family members. Evaluating the newborn for a pattern of major and minor anomalies will assist the clinician in more efficiently determining the appropriate tests and procedures for diagnosis and management of a congenital anomaly, and determining future recurrence risks for family members.

Epidemiology and Etiology

Major Malformations

About 2% of newborn infants have a serious anomaly that has surgical or cosmetic importance (Table 31-1).5 Most of these infants have a single anomaly, but this proportion is a minimum estimate because it is based only on the examination of newborn infants; additional anomalies are detected with increasing age.40 The most common anomalies are structural heart defects, cleft lip and palate, and neural tube defects, occurring in 5 to 7 per 1000, 1.5 per 1000, and 0.3 per 1000 live births, respectively.3,5,8,51 Identifying neonates with a major malformation is medically important because they have a fivefold increase in morbidity and, if identified in the prenatal setting, have a threefold increased risk for death in utero.36 From a genetic perspective, the etiology of malformations can be divided into broad categories: genetic (multifactorial, single gene [Mendelian], or chromosomal), environmental or teratogenic, and unknown.


Complex or Multifactorial.

Most congenital malformations (86%) are isolated and not associated with other anomalies.27 The most common and familiar birth defects fall into this category, including congenital heart defects, neural tube defects, cleft lip and palate, clubfoot, and congenital hip dysplasia (see Table 31-1). Most isolated malformations are believed to be the consequence of multifactorial inheritance, sometimes called complex inheritance, occurring when one or more genetic susceptibility factors combine with environmental factors and random developmental events.23 In most cases, multiple genetic components are involved, some with large effects and some with small contributions, the specifics of which continue to be studied. From a public health standpoint, the nongenetic effects have been harder to identify in most cases, although work has begun to link specific gene sequence variants to environmental factors. For example, epidemiologic studies have demonstrated that neural tube defects are associated with many maternal factors, such as hyperthermia, glucose levels, and folate intake.

Single Gene (Mendelian).

Single major genes are responsible for causing 0.4% of newborns to have major malformations. The most common mode of Mendelian inheritance for major malformations is autosomal dominant, with a minority of major malformations resulting from autosomal recessive or, rarely, X-linked genes. Limb anomalies, including postaxial polydactyly, syndactyly, and brachydactyly, constitute the most prevalent major localized malformations, and they are frequently the result of a dominant gene. Any type of malformation, however, may be under the control of a single gene, including multiple anomalies arising in different structures or organ systems. The mechanisms of monogenic malformation disorders are related to the dysfunction of the gene or disruption of the developmental pathway. For example, autosomal recessive Smith-Lemli-Opitz syndrome, characterized by genital abnormalities, syndactyly of the second and third toes, ptosis, wide alveolar ridges, hypotonia, inverted nipples, and abnormal fat distribution, has been found to be caused by a deficiency of the enzyme 7-dehydrocholesterol reductase in the cholesterol biosynthesis pathway.30,46 Since the genetic cause of this disorder was identified, other single gene disorders of cholesterol biosynthesis have been identified that result in multiple congenital anomalies.45 Although a biochemical or molecular basis increasingly is being recognized, specific diagnosis still relies heavily on the family history and clinical evaluation.


About 0.2% of newborns have a major malformation as a result of a chromosomal disorder, amounting to 10% of all the major congenital malformations (Table 31-2; see Chapter 11). The most prevalent malformation syndrome caused by an abnormal chromosomal constitution in newborns is Down syndrome, or trisomy 21, which occurs in about 1 in 660 births.28 The other common trisomies are trisomy 18 and trisomy 13, each occurring in about 1 in 10,000 births. All three autosomal trisomies, and the sex chromosome aneuploidies, 47,XXY and 47,XXX, occur more frequently with increased maternal age.

It is important to note, however, that although about 0.6% of newborns have chromosomal anomalies, the abnormalities are not detectable by physical examination at birth in 66% of these infants.28 Included among these early phenotypically undetectable chromosomal anomalies are common aneuploidies of the sex chromosomes, such as 47,XXY (Klinefelter syndrome) and 47,XXX. Neonates with these sex chromosome disorders may not have obvious malformations in the newborn period because the phenotype may develop over time.

In contrast, Turner syndrome (45,X) is present in 1 in 5000 female births, is often detected prenatally, and has a phenotype in a proportion at birth.

Many other types of chromosomal aberrations have been identified using standard karyotype and newer genomic technologies. In addition to detecting the gain or loss of a single chromosome, routine chromosome banding techniques can identify many translocations, inversions, ring chromosomes, marker chromosomes, and deletions.50 However, not all deletions are detectable by routine or even high-resolution (prometaphase) cytogenetic analysis, so that additional methodologies such as fluorescence in situ hybridization (FISH) or comprehensive genomic technologies should be considered. FISH uses fluorescently labeled DNA probes that identify deletions in specific locations on the chromosome metaphase spread, such as those associated with such conditions as 22q11 deletion syndrome/velocardiofacial/DiGeorge syndrome and Williams syndrome (long arm of chromosome 7).20

Newer genomic technologies simultaneously examine the entire structure of the chromosomes.14 Chromosomal microarray analysis targets known microdeletion syndromes, subtelomeres, and pericentric regions, and is more sensitive than routine karyotype analysis. In a relatively short period of time array analysis has revolutionized the diagnosis of neonates and children with multiple anomalies or developmental delay.14 One example is an analysis of 1176 cases evaluated by a clinical genetics laboratory in which 9.8% had pathogenic chromosomal imbalances identified by comparative genomic hybridization (CGH) array, compared with 2% using routine karyotyping.44 Other studies have shown that infants with multiple congenital anomalies may have a higher rate of imbalances. Lu et al. showed that 17% of 444 neonates with a variety of malformations had clinically significant aneuploidies found on microarray analysis.37 Furthermore, new microdeletion syndromes of developmental delay and multiple malformations have been identified, which suggests that whole genome analysis technologies of the future will improve diagnosis and expand our knowledge of clinically significant areas of the genome.55

However, karyotype remains the appropriate first-line test for suspected aneuploidy (trisomies 21, 18, and 13, and Turner and Klinefelter syndromes) and in cases of ambiguous genitalia, because of the rapid turnaround time and lower cost.

Environmental Exposure and Teratogens

A teratogen is anything external to the fetus that causes a structural or functional disability in prenatal or postnatal life (see Chapter 15). Teratogens can be drugs and chemicals, altered metabolic states in the mother, infectious agents, or mechanical forces. Known teratogenic factors cause only 5% to 10% of congenital anomalies despite the ever-expanding list of potential teratogens in our increasingly chemical environment (see Table 31-2).7 Before one can attribute malformations to a teratogenic agent, there must be one anomaly, only a few specific anomalies, or a recognizable pattern of anomalies found to occur at increased incidence over the background risk in infants exposed at the appropriate developmental stage (usually 2 to 12 weeks of gestation). With only a few exceptions, teratogenic agents do not affect every exposed infant, which is probably related to genetic susceptibility factors. Dose and timing of exposure also alter the potential of a specific teratogenic agent. To assess for specific drug teratogenic effects, multiple resources are available.25

Although beyond the scope of this chapter, pharmaceutical agents and environmental toxins are well documented to alter the development of the fetus.61 Although many drugs have teratogenic potential, the clinician should be aware of the teratogenic effect of some commonly used drugs and exposures. Alcohol is thought to be the most common teratogen to which a fetus may be exposed. Chronic maternal alcohol use during pregnancy is associated with increased perinatal mortality and intrauterine growth restriction, as well as congenital anomalies such as cardiac defects, microcephaly, short palpebral fissures, and other anomalies (Figure 31-1). Long-term effects include mental retardation and behavioral problems. Alcohol carries serious risks when it is used almost at any time during pregnancy in sufficient quantities, because the central nervous system continues to develop throughout pregnancy. For this reason it is recommended that women avoid alcohol, even in small amounts, throughout their pregnancies (see Chapter 53).

Anticonvulsants are a common category of teratogens to which a fetus is likely to be exposed. Although the medical literature is somewhat controversial, clinical geneticists, dysmorphologists, and clinical teratologists generally identify a variable but recognizable pattern of anomalies and developmental defects that occur at a significantly increased frequency among fetuses exposed to older classes of anticonvulsants. Studies have implied that newer classes of antiepileptic medications may not have the same effect on the developing fetus, although the clinician should be cautious in interpreting these studies.26

Some altered metabolic states in the mother also are known to have teratogenic potential. One of the most common is maternal diabetes mellitus. Infants of diabetic mothers are at two to three times the risk for congenital heart defects, caudal regression and sacral dysgenesis, and central nervous system abnormalities.16 In this population, there is about a threefold increase in congenital anomalies over those in the general population. The risk for congenital anomalies appears to be lower in offspring of diabetic mothers with better control of blood glucose, but this is not absolute, and factors other than blood glucose levels are thought to play a role in teratogenesis (see Chapters 19 and 95). Another example is untreated maternal phenylketonuria, in which the elevated levels of phenylalanine cause microcephaly, growth delay, and cardiac and neurologic abnormalities in the developing fetus.

Congenital anomalies also may be associated with certain infections during pregnancy. The most common and best understood infections are represented by the acronym TORCH, which stands for toxoplasmosis, other agents (including syphilis), rubella, cytomegalovirus, and herpes simplex. Although the sequelae of these infections may not be apparent until later, the clinician should consider these congenital infections in neonates with intrauterine growth restriction, microcephaly, chorioretinitis, intracranial calcification, microphthalmia, cataracts, or hearing loss. Confirmation of the specific diagnosis should be made by antibody studies and other evaluations such as ophthalmic examination and imaging studies.


About 66% of major malformations have no recognized etiology, if one includes those of presumed polygenic and multifactorial etiology (see Table 31-2).7 It is presumed that specific genetic or environmental causes of these congenital anomalies will be identified in the future as medical knowledge about the underlying biology of embryonic development and the technology for identifying gene-environment interaction improves. For example, folic acid has been recognized to decrease the risk for neural tube defects, thus implicating folic acid deficiency in the etiology of these anomalies.60

Anomalies in Aborted Fetuses

Spontaneously aborted fetuses have a higher incidence and severity of malformations than do newborns,36 which presumably represents a higher lethality of some developmental abnormalities. As in newborns, common anomalies, such as neural tube defects and cleft lip or palate, are also frequent in aborted fetuses, although these may be more severe. Other malformations, such as cloacal exstrophy, are relatively rare in newborns but are comparatively common in aborted fetuses.

In addition to these localized and single anomalies, multiple congenital anomalies commonly occur together in aborted fetuses, including well-recognized syndromes that are caused by single genes and chromosomal abnormalities (Table 31-3).12 It is estimated that about half of all pregnancy losses before 20 weeks of gestation have an underlying chromosomal abnormality. These losses include unrecognized early pregnancies and fetuses without an obvious structural anomaly. In this context, the most common single chromosomal abnormality is 45,X, followed by triploidy. Both conditions are more common in aborted fetuses than in newborns. The trisomies as a group account for more than 50% of all chromosomally abnormal pregnancy losses. The most frequent trisomy, accounting for almost one third of all trisomies, is trisomy 16, which is not found in newborns because it is lethal to the fetus.32,36 Trisomy 21, the most common trisomy in newborns, occurs in less than 10% of all recognized trisomic conceptions. Unbalanced translocations account for 2% to 4% of all chromosomally abnormal fetuses and are three to six times more frequent in aborted fetuses than in newborns. As with neonates, newer genomic technologies examining the chromosomes for small areas of genomic imbalance have shown an increased number of previously unrecognized deletions or amplifications of genetic material in fetuses with congenital anomalies. Analysis of the fetus’s parents could be helpful in determining whether the chromosomal microarray finding was diagnostic of the congenital anomaly.

Minor Anomalies and Phenotypic Variants

Although major malformations often are easy to identify, minor anomalies are, by nature, more subtle and may not be appreciated unless they are specifically sought. Minor anomalies, however, can be significant, particularly because they may be part of a characteristic pattern of malformations and thus may provide clues to a diagnosis. Also, their occurrence may be an indication of the presence of a more serious anomaly. In one large study of 4305 newborns, 19.6% of the 162 infants with major malformations had three or more minor anomalies.35 A single minor anomaly, however, was associated with a major malformation in only 3.7% of cases.35

Minor anomalies are most frequent in areas of complex and variable features, such as the face and distal extremities (Table 31-4).38 Among the most common features are lack of a helical fold of the pinna and complete or incomplete single transverse palmar crease patterns. Typical single transverse palmar crease occurs in almost 3% of normal newborns, but it appears in 45% of individuals with trisomy 21.31

Among the most frequent phenotypic variants, those present in 4% or more of the population, are a folded-over helix of the pinna and cerulean spots in blacks and Asians (Table 31-5).38 Before attributing medical significance to an apparent minor anomaly or phenotypic variation, it is useful to determine whether the anomaly is present in other family members or whether it is frequent in the patient’s ethnic group. It is common for isolated minor anomalies such as syndactyly of the second and third toes to be familial.

Jun 6, 2017 | Posted by in PEDIATRICS | Comments Off on Congenital Anomalies
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