Key Terms
Phenotype: all morphologic and functional attributes of an individual. The term may also refer to the organs, tissues, or cells of that individual, excluding the primary genome morphology.
Genotype: primary DNA sequence of an individual. It may also refer to the organs, tissues, or cells of the individual. Includes both nuclear and mitochondrial DNA.
Morphologic anomaly: macroscopic and/or microscopic anatomic phenotype representing a substantial departure from the population. A substantial departure implies that the anomaly is seen in a small fraction of the population, generally less than 2.5%. Malformations, deformations, disruptions, dysplasias, and sequences are types of morphologic anomalies. Morphologic anomalies can also be subdivided into major and minor.
Major morphologic anomaly: carries a significant consequence for the health or appearance of the individual.
Minor morphologic anomaly: carries minimal or no health consequence for the individual. However, it may have a modest impact on appearance.
Malformation: nonprogressive, congenital morphologic anomaly of a single organ or body part caused by alteration of a primary developmental process. Malformations typically arise during embryogenesis and are generally caused by gene mutation, teratogen exposure, or both.
Deformation: alteration in shape or position of a body part caused by aberrant mechanical force(s) distorting a normal structure. Deformations are causally heterogeneous and may occur as isolated phenomena or be a part of a broader malformation pattern, such as a syndrome. Deformations generally occur after organogenesis and may be seen at any time during pregnancy or postnatally. Deformations may be reversible.
Disruption: nonprogressive morphologic anomaly caused by breakdown of a body structure or organ with normal developmental potential.
Dysplasia: dynamic or ongoing alteration of cellular constitution, tissue organization, or function leading to a morphologic anomaly within a specific organ or tissue.
Syndrome: in dysmorphology, a syndrome represents a pattern of causally related anomalies, at least one of which is morphologic. These anomalies may not be pathogenetically related. Syndromes can be characterized by a combination of malformations, deformations, disruptions, sequences, and dysplasias. The multiple anomalies present in a syndrome are caused directly and independently by the underlying etiologic abnormality.
Sequence: one or more secondary morphologic anomalies that cascade from a single malformation, disruption, dysplasia, or deformation. The downstream anomalies are not necessarily directly attributable to the primary etiology.
Association: pattern of anomalies that occur together more often than expected by chance. At least two morphologic anomalies must be present. A causal relationship is not known.
Polytopic field defect: group of anomalies derived from disturbance of a single developmental field. A developmental field is a region or part of an embryo that responds as a unit to embryonic interactions, and results in complex or multiple anatomic structures.
Morphologic variant: mild anatomic phenotype that represents a small departure from the appropriate reference population. A small departure implies that the anomaly is found in approximately 2.5% to 10% of the appropriate reference population.
Based partially on work by the Elements of Morphology Consortium, 2013 revision. Hennekam RC, Biesecker LG, Allanson JE, et al. Elements of morphology: general terms for congenital anomalies. Am J Med Genet. 2013;161A(11):2726-2733.
The detection of anatomic congenital anomalies is one of the goals of prenatal care.1 Performing a correct prenatal diagnosis allows for adequate perinatal management, including the option of fetal intervention. The information required for diagnosis and management of the obstetrical patient with a fetal congenital anomaly demands knowledge in a variety of disciplines, including embryology, anatomy, genetics, obstetrics, pediatric surgery, teratology, and, certainly, diagnostic imaging. Many health care professionals involved in diagnostic imaging have had limited exposure to the other fields. The purpose of this chapter is to introduce the reader to congenital anomalies, and provide an overview of the definition and magnitude of the problem and pathogenic mechanisms of gross congenital anomalies. The principles of prenatal diagnosis with ultrasound, the use of ultrasound as a screening tool for the detection of congenital anomalies, and the management options once a congenital anomaly has been detected are also discussed.
A congenital anomaly consists of a departure from the normal anatomic architecture of an organ or system. Anomalies may result from an intrinsically abnormal primordium or anlage of an organ, or from a normal primordium that is affected during development by extrinsic forces. Interest in prenatal development, coupled with the need for a uniform nomenclature to refer to errors in morphogenesis, led an international working group to propose a set of terms useful in the classification of anatomic congenital anomalies.2-5 The proposed terminology was revised in 2013 and is summarized in ‘Key Terms’ box at the start of the chapter.6 Individual alterations of form or structure can therefore be classified as malformations, deformations, and disruptions. However, it should be stressed that it is not always possible to assign an anomaly to a specific class. In fact, malformations, deformations, and disruptions may overlap (see section on sequences).
A malformation is a morphologic defect of an organ, part of an organ, or a larger area of the body resulting from an intrinsically abnormal developmental process. The term intrinsically abnormal developmental process refers to an abnormality in the primordium (anlage) of the organ. This abnormality may not be identifiable in early stages of development. The typical example is a limb bud that appears normal in early embryonic life, but later develops an extra digit. Malformations can be considered the result of a developmental arrest of the primordium (incomplete morphogenesis), redundant morphogenesis, or aberrant morphogenesis (Figure 17-1). Examples of these types of malformations are listed in Table 17-1. Although malformations often occur during the embryonic period (until the ninth postmenstrual week), some may also arise during later stages of development.6 A general principle is that the earlier the malformation is initiated, the more complex the resulting anomaly (or anomalies).
| Types of Abnormal Morphogenesis | Examples of Malformation | Relative Frequency as a Class |
|---|---|---|
| Incomplete morphogenesis | Common | |
| Lack of development | Absent nostril, renal agenesis | |
| Hypoplasia | Microcephaly, micrognathia | |
| Incomplete closure | Cleft palate, iris coloboma | |
| Incomplete separation | Syndactyly | |
| Incomplete septation | Ventricular septal defect | |
| Incomplete migration | Exstrophy of the cloaca | |
| Incomplete rotation | Malrotated gut | |
| Incomplete resolution of early form | Choanal atresia, Meckel diverticulum | |
| Persistence of early location | Low-set ears, undescended testes | |
| Redundant morphogenesis | Supernumerary ear tag, polydactyly | Uncommon |
| Aberrant morphogenesis | Mediastinal thyroid gland, paratesticular spleen | Rare |
Deformation refers to an abnormal form, shape, or position of part of the body caused by nondisruptive mechanical forces. The primordium of the organ is normal, but development is affected by mechanical forces that are extrinsic or intrinsic to the fetus. For example, a clubfoot deformity (Figure 17-2) may be the result of intrauterine constraint due to oligohydramnios (extrinsic force) or lack of movement due to the neural defect associated with spina bifida (intrinsic force). Table 17-2 presents common forces leading to deformations. Four main factors influence the pathogenesis of deformations: pressure, fetal plasticity, fetal mobility, and the rate of fetal growth.7 Deformations tend to occur late in gestation because during this time there is rapid fetal growth in a potentially constraining intrauterine environment.7-10 Removal of the mechanical force responsible for the deformation results in normalization or improvement of the anomaly. Spontaneous resolution after birth occurs in approximately 90% of deformations.11 Table 17-3 compares malformations and deformations. Therefore, in general, the term malformation describes defects that are likely to have arisen during organogenesis, and the term deformation is reserved for defects arising after the embryonic period.
Extrinsic Maternal Small maternal size Small maternal pelvis Uterine malformation (eg, bicornuate uterus) Uterine leiomyoma |
Fetal Early pelvic engagement of the fetal head Unusual fetal position Oligohydramnios Large fetus, rapid growth Multiple fetuses |
Intrinsic Malformational Central nervous system malformations (eg, spina bifida) Urinary tract malformations (eg, bilateral renal agenesis or severe polycystic kidneys that may cause oligohydramnios and its sequence) Functional Congenital hypotonia secondary to neuromuscular disorders (eg, arthrogryposis) |
| Malformation | Deformation | |
|---|---|---|
| Time of occurrence | Embryonic period | Fetal period |
| Level of disturbance | Organ | Region |
| Incidence before 20th week | 5% (estimated) | 0.1% |
| Incidence after 28th week | 3.7% | 2.0% |
| Perinatal mortality | + (41%) | − (6%) |
| Spontaneous correction | — | + |
| Correction | — | + |
A disruption is a morphologic defect of an organ, part of an organ, or a larger region of the body resulting from breakdown of a body structure or organ with normal developmental potential. The term usually applies to events that occurred in utero. Disruptions can be isolated or a part of broader abnormal patterns such as syndromes. Vascular, mechanical, infectious, and teratogenic insults may cause disruptions.6 A typical example of this type of anomaly is digital amputation associated with amniotic band syndrome (Figure 17-3).12-14
Another concept frequently used by dysmorphologists is that of dysplasia, a term referring to abnormal organization of cells into tissue(s) and its morphologic result(s). The term dysplasia in pathology refers to an anaplastic process. Its use in dysmorphology is broader and refers to any type of tissue disorganization. Dysplasias may arise prenatally or postnatally. Since the term dysplasia implies that the tissue is abnormal, the clinical impact may persist or worsen as long as the tissue continues to grow or function. Dysplasias may be part of broader malformation patterns, such as a malformations, deformations, disruptions, and sequences.6 Osteogenesis imperfecta, for example, is a dysplasia in which the primary disorder affects collagen; accordingly, structures containing significant quantities of the particular type of defective collagen are affected.
A fetus may have multiple congenital anomalies. This association may occur simply by chance, or may be part of a pathogenetically related event. A set of terms has been coined to describe the relationship between coexistent anomalies: polytopic field defect, sequence, syndrome, and association.
A polytopic field defect is a group of anomalies derived from the disturbance of a single developmental field. A developmental field is a region or part of an embryo that responds as a unit to embryonic interactions and results in complex or multiple anatomic structures. Opitz discussed in detail the meaning and implications of the concept of developmental field defects.15,16 The embryo is omnipotent (the primary field) up to a certain time, during which further organization and differentiation occurs in a number of different developmental autonomous areas (secondary fields). Disturbances in a developmental field may result in multiple, and usually contiguous, anomalies (monotopic field defects) or multiple, distantly located anomalies (polytopic field defects). An example of a monotopic field defect is holoprosencephaly, where there are coexistent abnormalities of the central nervous system and face (Figures 17-4 and 17-5). Abnormalities in the acrorenal field are frequently cited as illustrative examples of polytopic field defects. There are at least 24 different genetic conditions in which both kidneys and limbs are involved, a fact that has been explained by invoking a relationship between the mesonephros and limb buds during embryogenesis. This concept is supported by the proximity between these 2 structures in early life, and by experiments showing an inductive effect of mesonephros on proliferation and differentiation of limb bud cartilage. A complete map of the developmental fields of the human embryo is not available, but could be constructed by classifying all human malformations and searching for causal heterogeneity among them. Opitz16 proposed that each time a certain malformation is seen in at least 2 causally different conditions, a developmental field has been identified because identical structure means identical development, independent of differences in causal mechanisms. Mammalian primordia have only a limited number of responses to various dysmorphogenetic insults. The existence of developmental fields limits the possibility of independent responses from different structures of the organism.
A sequence is a pattern of multiple anomalies derived from a single known or presumed prior anomaly or mechanical factor. Thus, there are malformations, deformations, and disruption sequences. The spectrum of anomalies of holoprosencephaly is an example of a malformation sequence. The precordal mesoderm is responsible for cleavage of the prosencephalon (forebrain) and normal development of the median facial structures. A primary defect of the precordal mesoderm leads to defects in both the brain and the face. In the brain, there is incomplete division of the cerebral hemispheres and underlying structures. Anomalies of the face include different degrees of hypoplasia of the median central structures (cyclopia, ethmocephaly, cebocephaly, and median cleft lip) (Figures 17-4, 17-5, 17-6, 17-7).
Figure 17-7.
Pathologic correlation of same fetus as Figure 17-6, showing the proboscis located above a midline orbit (cyclops).
Severe oligohydramnios may lead to intrauterine constraint and a typical deformation sequence that includes abnormal positioning of limbs (clubfoot) (Figure 17-8), breech presentation, Potter facies (Figure 17-9), growth deficiency, amnion nodosum, and pulmonary hypoplasia.17,18
Early amniotic rupture with the formation of amniotic bands may lead to a disruption sequence including amputations of fingers, bizarre facial clefts, and asymmetric encephaloceles (Figure 17-10).12,19
A syndrome is a pattern of multiple anomalies, at least one of which is morphologic, thought to be causally related and not known to represent a single sequence or a polytopic field defect. The term syndrome is frequently employed to refer to a single cause, such as Down syndrome. A syndrome can be characterized by several types of anomalies, including malformations, deformations, disruptions, sequences, and dysplasias.6 Please note that earlier definitions of the term syndrome required a single unifying cause for malformations that were part of the syndrome.2-5 However, advances in molecular genetics have shown that a mutation in a single gene can be the cause of multiple distinct conditions. Likewise, a single phenotype may be caused by mutations in more than one gene. Therefore, the most recent revision of the terminology to describe human congenital anomalies considers no longer appropriate to require “a single cause” to define a syndrome.
An association refers to a nonrandom occurrence in two or more individuals of at least two morphologic anomalies not known to represent a polytopic field defect, a sequence, or a syndrome. The term association carries a purely statistical connotation, and not a pathogenetic or causal implication. With increasing knowledge, associations may become syndromes or polytopic field defects.
Familiarity with these terms is important because correct classification of an anomaly has implications for clinical diagnosis, management, and genetic counseling.3,10 Disruptions are sporadic events and therefore do not tend to recur in future pregnancies. The recurrence rate of deformations depends on the cause of the mechanical force leading to the anomaly. If the etiology of the abnormal mechanical force is a fetal malformation (eg, spina bifida), the recurrence risk is different than if the abnormal force were related to a leiomyoma.9 As malformations result from intrinsic developmental processes, the cellular and molecular pathways involved in organogenesis can be altered by gene mutations, teratogens, or a combination thereof. Therefore, the diagnosis of a malformation suggests a chromosomal abnormality, a monogenic defect, teratogen exposure, or a multifactorial disorder.6,10,15 Table 17-420 presents a glossary of terms used to describe congenital anomalies, including some of the terms discussed previously.
| Anomaly | Deviation from the normal with regard to form, structure, or position |
| Aplasia | Complete absence of cellular proliferation |
| Hypoplasia | Results from insufficient or decreased cellular growth |
| Dysplasia | Abnormal growth or development of cells, causing disorganized cellular structure |
| Agenesis | Failure of a structure or organ to form |
| Dysgenesis | Defective development, resulting in some type of disorganization |
| Atrophy | Degeneration of cells that results in wasting or a decreased size |
| Hypotrophy | Undergrowth or the failure to reach the normal size |
| Hypertrophy | Overgrowth of a structure or organ |
| Genotype | Refers to an organism’s genetic composition |
| Phenotype | Outward physical appearance or genetic makeup of an individual; the direct result of the genotype and, in some cases, the environment |
| Congenital | Refers to conditions present at birth that may or may not be genetic |
| Genetic | An inherited but not always congenital condition |
| Malformation | A birth defect due to an intrinsic abnormality or incomplete development; can be genetic, environmental, or multifactorial and typically occurs before 10 weeks of gestation; cleft lip and/or cleft palate may be classified as malformations |
| Disruption | An interference with formation of an otherwise normal structure and a result from external forces such as amniotic bands or teratogens; may be the result of environmental agents or mechanical concerns |
| Deformation | In contrast to a disruption, a deformation occurs after the normal formation of an organ or structure; it is the result of compression, constriction, or immobility, eg, clubfeet due to oligohydramnios; in some cases, it may have a genetic cause |
| Etiology | Underlying cause of an anomaly |
| Pathogenesis | Specific mechanism by which an anomaly or disease occurs |
| Syndrome, genetic | A group of features seen together with common, specific etiology |
| Syndrome, complex | Composite of multiple features |
| Spectrum | Considered complex, with considerable variation |
| Association | Nonrandom occurrence of multiple features, with no known etiology, eg, VACTERL and CHARGE |
| Sequence | Pattern of anomalies from a single anomaly or factor, eg, Potter sequence versus syndrome |
| Teratogen | An environmental agent that causes a morphologic abnormality after fertilization but before delivery |
| Mendelian | Conditions, typically single gene, inherited in the manner conceived by Gregor Mendel |
| Multifactorial | Caused by both genetic and environmental factors |
| Sporadic | Occurring by chance, not hereditary |
Although there are several systems to classify congenital anomalies, an easy and practical method is to divide them into major and minor. A major anomaly is one that carries significant consequence for the health or appearance of the individual. A minor anomaly is one that carries minimal or no health consequence; however, it may have a modest impact on appearance.6 Obviously, this classification is subjective and arbitrary. In addition, there is an overlap between minor anomalies and morphologic variants. A morphologic variant is found in approximately 2.5% to 10% of the general population and is defined as a mild anatomic phenotype that represents a small departure from the reference population.6 Some ageneses, for example, are common enough to be considered “normal” anatomic variants (ie, absence of the muscle palmaris longus or upper lateral incisor). The importance of minor anomalies, however, is that they may serve as indicators of altered morphogenesis and more serious defects. Importantly, 90% of infants with 3 or more minor anomalies will have a major anomaly.21 Thus, the identification of several minor anomalies requires a careful search for hidden anomalies, in particular cardiac, renal, and vertebral disorders. Tables 17-5 and 17-6 have been compiled from the pediatric and genetic literature and display the most common major and minor anomalies, respectively.10,21-28
| Central Nervous System | |
Hydrocephalus Anencephaly Microcephaly Meningocele | Encephalocele Macrocephaly Cebocephaly |
| Craniofacial | |
Craniosynostosis Micrognathia Choanal atresia Hypertelorism, hypotelorism Protruding forehead Beaklike nose Absent ramus of mandible | Cleft lip or cleft palate Low nasal bridge Broad nasal bridge Prognathism Macroglossia Cranial asymmetry |
| Eye | |
Cataract or corneal opacity Coloboma of iris Microphthalmia Myopia Blue sclerae Glaucoma | Microcornea Retinal dysplasia Anophthalmos Cyclopia Aniridia |
| Auricle (Ear) | |
Low-set ear, severe Low ear canal | Severely malformed |
| Skin | |
Webbed neck | Multiple hemangiomas |
| Kidney | |
Polycystic kidney Hydronephrosis Horseshoe kidney Duplicated ureters Bilateral renal agenesis | Multicystic kidney disease Megaureter Prune-belly syndrome Ureteropelvic junction obstruction Posterior urethral valves |
| Heart | |
Atrial septal defect Ventricular septal defect Tetralogy of Fallot Atrioventricular septal defect Univentricular heart Hypoplastic left heart Hypoplastic right heart Complete transposition of the great arteries Corrected transposition of the great arteries Double outlet right ventricle Truncus arteriosus Coarctation and tubular hypoplasia of the aortic arch | Pulmonic stenosis Aortic stenosis Cardiomyopathies Total anomalous pulmonary venous return Ectopia cordis Tumors of the heart Single ventricle Supravalvular aortic stenosis Asymmetrical septal hypertrophy Endocardial fibroelastosis Ebstein’s anomaly Cardiosplenic syndromes |
| Gastrointestinal Tract | |
Intestinal atresia Imperforate anus Omphalocele Gastroschisis Hepatomegaly Splenomegaly | Pyloric stenosis Malrotation of colon Anal atresia with rectovestibular fistula Biliary atresia Megacystis–microcolon–intestinal hypoperistalsis syndrome |
| Genital Tract | |
Severe hypospadias Common cloaca Abdominal cryptorchidism Inguinal cryptorchidism Ambiguous genitalia Bifid scrotum Unicornuate uterus | Absence of uterus Double vagina Duplication or anomalous insertion of fallopian tubes Hypoplastic ovaries Uterine cysts Vaginal atresia Ovarian cysts |
| Skeleton | |
Absence of radius Absence of fibula Short femur Malleable bones Congenital dislocated hips Sacral agenesis Sirenomelia Hypoplasia of clavicles Small thoracic cages Rib defects | Scoliosis, kyphosis Short limbs Elbow dysplasia Narrow pelvis Joint limitation and/or contractures Absence of pubic rami Vertebral malformation Hemivertebrae Phocomelia Demineralization of bones |
| Hand | |
Polydactyly Syndactyly Clinodactyly Complete cutaneous syndactyly Absence of thumbs Short hands | Absence of all metacarpals Absence of distal phalanx Broad fingers Steeter’s bands and deformity Ectrodactyly Oligodactyly |
| Foot | |
Polydactyly Syndactyly Equinovarus/clubfoot | Severe calcaneovalgus Absence of nails |
| Other | |
Sacral teratoma | Absence of sternocleidomastoid muscle |
| Craniofacial | |
Borderline small mandible Flat occiput, bony occipital spur Prominent occiput Small or short nose Prominent nose Hypoplasia of nares Abnormal filtrum Prominent full lips | Lower lip pits Microstomia Macrostomia Cleft or irregular tongue Anodontia, hypodentia Irregular placement of teeth Neonatal teeth Dental cysts |
| Eye | |
Inner epicanthal folds Upward lateral slant of palpebral fissures Short palpebral fissures Small inner canthal distance Sparse eyebrows Shallow orbital ridges Prominent supraorbital ridges | Prominent eyes Ptosis of eyelid Strabismus Nystagmus Lens dislocation Retinal pigmentation Iris: unusual patterning or coloration |
| Ear | |
Lack of usual fold or helix Severe slant away from eye Preauricular or auricular skin tags Small ears, large ears, asymmetrical size Auricular sinus | Double lobules Incomplete helix Absent tragus Separate lobule |
| Heart | |
Premature atrial and ventricular contractions Supraventricular tachyarrythmias | Atrioventricular block |
| Abdominal | |
Unusual diastasis recti Umbilical hernia | Meckel’s diverticulum Heterotopic pancreatic or splenic tissue |
| Genital | |
Ectopic testicles in femoral locale Micropenis | Hypogenitalism Hypoplasia of labia majora |
| Skin | |
Hemangioma Pigmented nevi Mongoloid spots Café au lait High placed nipples Alopecia of scalp | Loose, redundant skin Cutis marmorate Telangiectasis Hirsutism Deep sacral dimple, pilonidal cyst Eczemalike skin disorder |
| Hand | |
Simian creases Other crease patterns Clinodactyly fifth finger | Rudimentary polydactyly Duplication of the thumb nail Clenched hand |
| Foot | |
Partial syndactyly Recessed fifth toes | Posterior prominence of heel Prominent calcaneous |
| Other Skeletal | |
Prominent sternum Depressed sternum Shieldlike chest | Genu recurvatum Cubitus valgus Joint hypermobility or lax ligaments |
A practical problem in clinical genetics is the classification of a “funny-looking kid” who has several dysmorphic features that may correspond to multiple minor anomalies, or multiple normal developmental variants. The two approaches that have been considered helpful are the analysis of family resemblance, and analysis of associated anomalies. On close inspection, the child with multiple phenotypic variants will resemble some other family members. By contrast, the child with multiple minor anomalies due to aneuploidy, for example, should not look like other family members. The child with multiple phenotypic anomalies also should not have other major external or internal anomalies.
Fetal anatomic defects observed by ultrasound may raise the suspicion of a more complex set of anomalies or chromosomal disorders. For example, a lemon-shaped head is commonly associated with spina bifida, whereas an atrioventricular canal defect is a major cardiac anomaly associated with Down syndrome.
Some minor anomalies and anatomical variants may also carry a higher risk of chromosomal disorders. They are collectively called markers. Sonographic markers are variations in normal anatomy that, except for their relationship to aneuploidy (especially trisomy 21 or Down syndrome), are unlikely to be clinically significant. Compared with structural anomalies, markers are often transient (eg, choroid plexus cysts) and nonspecific findings, which can also occur frequently in euploid fetuses. Some of the most common sonographic markers seen in the second trimester include echogenic intracardiac focus, choroid plexus cysts, shortened long bones, hyperechoic bowel, nuchal fold thickening, renal pyelectasis, clinodactyly, and hypoplastic or absent nasal bone.
A few markers, however, have such a strong association with chromosomal anomalies (eg, increased nuchal translucency thickness in the first trimester) that their identification per se is an indication for genetic counseling and further evaluation by noninvasive prenatal testing using cell-free DNA in the maternal blood, fetal karyotyping, or chromosomal microarray analysis.29,30 Other markers can be very common and are usually not associated with any handicap. For example, when echogenic intracardiac focus or choroid plexus cysts are found in isolation in a low-risk patient, they do not carry such a high risk for chromosomal anomalies to warrant the performance of an invasive procedure. It is important to remember, however, that the presence of these markers should prompt a thorough evaluation of the fetus for other anomalies, before considering the need for fetal karyotyping. As a general statement, as the number of identified markers increases, the risk for aneuploidy in the fetus increases as well. Table 17-7 presents a list of major anatomic defects and sonographic markers for chromosomal anomalies detectable by prenatal ultrasound.31 Table 17-8 lists the likelihood ratios for trisomy 21 for several ultrasonographic markers based on a meta-analysis of 48 studies.32
| Ultrasonographic Marker | Chromosomal Anomaly |
|---|---|
| Skull/brain | |
| Absent corpus callosum | Trisomy 18 |
| Brachycephaly | Trisomies 21, 18, 13 and monosomy 45,X0 |
| Choroid plexus cysts | Trisomies 18 and 21 |
| Enlarged cisterna magna | Trisomies 21, 18, and 13 |
| Holoprosencephaly | Trisomy 13 |
| Microcephaly | Trisomy 13, monosomy 45,X0 |
| Posterior fossa cyst | Trisomies 21, 18, and 13 |
| Strawberry-shaped head | Trisomy 18 |
| Ventriculomegaly | Trisomies 21 and 18 and triploidy |
| Face/neck | |
| Cystic hygroma | Monosomy 45,X0 |
| Facial cleft | Trisomies 18 and 13 |
| Increased nuchal translucency | Trisomies 21, 18, 13 and monosomy 45,X0 |
| Micrognathia | Trisomy 18 and triploidy |
| Nuchal edema | Trisomies 21, 18, and 13 |
| Chest | |
| Cardiac abnormality | Trisomies 21, 18, 13, triploidy and monosomy 45,X0 |
| Diaphragmatic hernia | Trisomies 18 and 13 |
| Echogenic foci in the heart | Trisomy 21 |
| Abdomen | |
| Collapsed stomach | Trisomies 21 and 18 |
| Duodenal atresia | Trisomy 21 |
| Hyperechogenic fetal bowel | Trisomy 21 |
| Omphalocele | Trisomies 18 and 13 |
| Urinary tract | |
| Mild hydronephrosis | Trisomies 21, 18, 13 and monosomy 45,X0 |
| Other renal anomalies | Trisomies 21, 18, 13 and triploidy |
| Other | |
| Hydrops | Trisomy 21 and monosomy 45,X0 |
| Small for gestational age | Trisomy 18, triploidy, and monosomy 45,X0 |
| Relatively short femur | Trisomies 21, 18, triploidy, and monosomy 45,X0 |
| Clinodactyly | Trisomy 21 |
| Overlapping fingers | Trisomy 18 |
| Polydactyly | Trisomy 13 |
| Syndactyly | Triploidy |
| Talipes | Trisomies 18 and 13 and triploidy |
| Marker | Likelihood Ratio* | ||
|---|---|---|---|
| Positive | Negative | Isolated Marker | |
| Thickened nuchal fold | 23.3 | 0.80 | 3.79 |
| Hyperechogenic bowel | 11.44 | 0.90 | 1.65 |
| Mild hydronephrosis | 7.63 | 0.92 | 1.08 |
| Short humerus | 4.81 | 0.74 | 0.78 |
| Short femur | 3.72 | 0.80 | 0.61 |
| Hyperechogenic intracardiac foci | 5.83 | 0.80 | 0.95 |
| Ventriculomegaly | 27.52 | 0.94 | 3.81 |
| Absent of hypoplastic nasal bone | 23.27 | 0.46 | 3.94 |
| Aberrant left subclavian artery | 21.48 | 0.71 | 6.58 |
| No marker | 0.12 | ||
The precise incidence of congenital anomalies is difficult to determine. Accurate documentation depends on many factors, including (1) age at examination (prenatal period, newborn period, infancy, or later in life);22,23,27 (2) the experience of the observer (eg, general pediatrician vs dysmorphologist);21 (3) the definition of an anomaly (major, minor, normal phenotypic variation);21,33,34 (4) the type of examination (body surface examination, extensive examination including evaluation of internal organs); and (5) ethnic, geographic, and social variations in the incidence of individual malformations.21,33,35-37 Follow-up of infants is also extremely important because only one-third of congenital anomalies are recognized in the newborn period.34
One of the first attempts to determine the incidence of major and minor congenital anomalies at birth was conducted by Marden et al.21 These investigators, particularly interested in dysmorphology, examined 4412 newborns during the first 2 days of life. A body surface examination, which did not include auscultation of the heart and abdominal palpation as standard procedures, was performed in all infants. A buccal smear for sex chromatin was also obtained. The incidence of major and minor anomalies was 2.04% and 14.7%, respectively. Importantly, among the 20 newborns having 2 or more minor defects, 90% had 1 or more major anomalies. Chromosomal aneuploidy was detected by buccal smear and phenotype examination in 4 of 1000 infants. Later, using data from the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, Chung and Myrianthopoulos reported the incidence of anomalies in a population of 52,332 liveborns.38 Table 17-9 shows the incidence of major, minor, and multiple anomalies, sequences, and syndromes, and Table 17-10 presents the incidence of congenital anomalies in live births, fetal deaths, and neonatal deaths.38 When all types of morphologic anomalies were considered, the incidence was 15% among liveborn infants. Males were affected more frequently than females. The excess was attributed to a differential incidence of major anomalies because the prevalence of minor anomalies was not different between the genders.
| n Individuals | n Malformations | % Malformations | |
|---|---|---|---|
| Live births | 51,096 | 7,856 | 15.27 |
| Fetal deaths | 1,004 | 82 | 8.17 |
| Neonatal deaths | 877 | 255 | 29.08 |
| Deaths from 28 days to 1 year | 417 | 98 | 23.50 |
| Total deaths | 2,298 | 435 | 18.93 |
More recently, the National Birth Defects Prevention Study, a large population-based multicenter case-control study of major birth defects, provided data regarding the relative frequency of major congenital anomalies among 10 birth defects surveillance programs in the United States. Table 17-11 provides the relative frequency of major structural birth defects seen in the study, in decreasing order of frequency.39
| Birth Defect | N | % |
|---|---|---|
| Atrial septal defect (ASD) | 7,280 | 12.0% |
| Cleft lip with and without cleft palate | 4,537 | 7.5% |
| Hypospadias (second- or third-degree) | 4,061 | 6.7% |
| Intestinal atresia or stenosis | 3,342 | 5.5% |
| Pulmonary stenosis (valvar) | 3,023 | 5.0% |
| Ventricular septal defect (VSD) | 2,693 | 4.4% |
| Craniosynostosis | 2,611 | 4.3% |
| Coarctation of the aorta | 2,464 | 4.1% |
| Cleft palate | 2,363 | 3.9% |
| Gastroschisis | 2,305 | 3.8% |
| Tetralogy of Fallot | 2,041 | 3.4% |
| Spina bifida | 1,854 | 3.0% |
| D-transposition great arteries/double outlet right ventricle | 1,731 | 2.8% |
| Limb deficiency (transverse) | 1,603 | 2.6% |
| Diaphragmatic hernia | 1,328 | 2.2% |
| Atrioventricular septal defect | 1,254 | 2.1% |
| Anencephaly, craniorachischisis | 1,164 | 1.9% |
| Anotia, microtia | 1,056 | 1.7% |
| Hypoplastic left heart syndrome | 1,034 | 1.7% |
| Esophageal atresia with and without esophageal fistula | 1,031 | 1.7% |
| Hydrocephalus | 995 | 1.6% |
| Anomalous pulmonary venous return | 993 | 1.6% |
| Aortic stenosis | 938 | 1.5% |
| Limb deficiency (longitudinal) | 895 | 1.5% |
| Omphalocele | 747 | 1.2% |
| Laterality defects, heterotaxia | 683 | 1.1% |
| Pulmonary atresia (not tetralogy of Fallot variant) | 679 | 1.1% |
| Cataracts | 668 | 1.1% |
| Amnion rupture sequence | 590 | 1.0% |
| Encephalocele, encephalomyelocele | 431 | 0.7% |
| Tricuspid atresia | 428 | 0.7% |
| Dandy-Walker malformation | 417 | 0.7% |
| Single ventricle | 413 | 0.7% |
| Anophthalmia, microphthalmia | 411 | 0.7% |
| Renal agenesis or hypoplasia (bilateral) | 366 | 0.6% |
| Ebstein malformation | 330 | 0.5% |
| Glaucoma, other anterior chamber eye defects | 323 | 0.5% |
| Holoprosencephaly | 321 | 0.5% |
| Biliary atresia | 315 | 0.5% |
| Truncus arteriosus | 309 | 0.5% |
| Choanal atresia | 262 | 0.4% |
| Sacral agenesis | 175 | 0.3% |
| Cloacal exstrophy, persistent cloaca | 142 | 0.2% |
| Bladder exstrophy | 105 | 0.2% |
| Limb deficiency (intercalary) | 103 | 0.2% |
| Total number of birth defects | 60,814 | 100.0% |
A substantial fall in maternal and infant mortality rates was achieved during the 20th century. Environmental interventions, improvements in nutrition, advances in clinical medicine, wider access to health care, increased surveillance and monitoring of disease, better education, and higher living standards contributed to this accomplishment. From 1915 through 1997, while the United States experienced a 93% drop in infant mortality (from approximately 100 per 1000 to 7.2 per 1000 live births),40 the relative contribution of congenital anomalies to the perinatal death rate increased. Indeed, the latest statistics provided by the Centers for Disease Control (CDC), based on data collected between 1980 and 2006, showed that, even with a 5% drop between 2000 and 2005,41 congenital anomalies have been consistently ranked as the leading cause of death for children less than 1 year of age. Furthermore, congenital malformations persist as a leading cause of death for children 1 to 4 years old, second only to unintentional injuries.42
In terms of morbidity, it has been estimated that at least 1% of all diseases requiring hospital admissions have a genetic basis or genetic contribution, as many as 1 of every 4 hospitalized children has a disease that is at least partly genetically determined, and approximately 1 of every 20 children is affected by a disorder that is completely genetic in origin.43
The birth of a congenitally malformed baby has implications for the use of health care resources. From a purely clinical and economic point of view, the birth of a baby with a lethal congenital abnormality will not place as large a burden on the health care system as would the birth of a baby with a condition associated with possible survival and long-term handicap.44 Chung and Myrianthopoulos reported the rates of postnatal mortality, neurologic abnormality at 7 years of follow-up, psychological deficit at age 7 years, and the requirement for major surgery for infants with different types of congenital anomalies (Table 17-12). Infants with anomalies detected within the first year had a significant increase in the risk of death, and in all parameters of evaluated postnatal morbidity. The authors estimated that if major congenital anomalies did not occur, a reduction of 16% in postnatal mortality to age 7 years could be achieved. In terms of economic impact, it has been estimated that birth defects account for more than 139,000 hospitalizations per year in the United States, with hospital costs totaling $2.6 billion. Approximately $1.4 billion is spent in the care of infants with congenital heart disease.45
| Postnatal Mortality to 7 Years | Neurologic Abnormality, 1–7 Years | Psychiatric Deficits at Age 7 Years | Major Surgery to 7 Years | |
|---|---|---|---|---|
| Total population | 0.030 | 0.054 | 0.183 | — |
| No anomaly | 0.026 | 0.035 | 0.049 | 0.162 |
| Minor only | 0.015* | 0.046† | 0.059‡ | 0.196* |
| Multiple major | 0.058* | 0.064* | 0.069* | 0.367* |
| Single major | 0.116* | 0.109* | 0.152* | 0.492* |
| Sequences | 0.442* | 0.211* | 0.159* | 0.583* |
| Syndromes | 0.288* | 0.733* | 0.720* | 0.378* |
| All anomalies | 0.052* | 0.069* | 0.078* | 0.292* |
| Major anomalies, sequences, syndromes | 0.087* | 0.092* | 0.097* | 0.386* |
The potential burden to the family nucleus is another important issue. The incidence of divorce and sibling social maladjustment, for example, is higher in families of children with spina bifida than in families of infants without congenital anomalies.46,47 A broader perspective is provided by a historical review and meta-analysis conducted by Risdal and Singer48 who investigated rates of marital adjustment/discord and divorce/separation among families of children with a wider range of disabilities, including mental retardation, autism, sensory impairment, spina bifida, Down syndrome, cerebral palsy, and phenylketonuria. The meta-analysis included 13 studies conducted between 1975 and 2003 and compared the prevalence of divorce and marital discord/satisfaction between parents of children with (n = 6270) and without disabilities (n = 48,254). The meta-analysis found a small but detectable negative impact of having a disabled child on marital adjustment (effect size d = 0.21) as well as a small increase in divorce rates (5.97%, range 2.9%-6.7%).
