Congenital Abnormalities and Dysmorphic Syndromes

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CHAPTER 16 Congenital Abnormalities and Dysmorphic Syndromes

The formation of a human being, a process sometimes known as morphogenesis, involves extremely complicated cell biology that, though only partially understood, is beginning to yield its mysteries (see Chapter 6). Given the complexity, it is not surprising that on occasion it goes wrong. Nor is it surprising that in many congenital abnormalities genetic factors can clearly be implicated. Approximately 2400 dysmorphic syndromes are described that are thought to be due to molecular pathology in single genes, and for at least 500 the genes have been identified and more than 200 mapped. A further 500 or so sporadically occurring syndromes are recognized, for which the precise cause remains elusive. In this chapter, we shall consider the overall impact of abnormalities in morphogenesis by reviewing the following.

Incidence

Newborn Infants

Surveys reviewing the incidence of both major and minor anomalies in newborn infants have been undertaken in many parts of the world. A major anomaly can be defined as one that has an adverse outcome on either the function or the social acceptability of the individual (Table 16.1). In contrast, minor abnormalities are of neither medical nor cosmetic importance (Box 16.1). However, the division between major and minor abnormalities is not always straightforward; for instance, an inguinal hernia occasionally leads to strangulation of bowel and always requires surgical correction, so there is a risk of serious sequelae.

Table 16.1 Examples of Major Congenital Structural Abnormalities

System and Abnormality Incidence per 1000 Births
Cardiovascular 10
Ventricular septal defect 2.5
Atrial septal defect 1
Patent ductus arteriosus 1
Tetralogy of Fallot 1
Central nervous system 10
Anencephaly 1
Hydrocephaly 1
Microcephaly 1
Lumbosacral spina bifida 2
Gastrointestinal 4
Cleft lip/palate 1.5
Diaphragmatic hernia 0.5
Esophageal atresia 0.3
Imperforate anus 0.2
Limb 2
Transverse amputation 0.2
Urogenital 4
Bilateral renal agenesis 2
Polycystic kidneys (infantile) 0.02
Bladder exstrophy 0.03

These surveys have consistently shown that 2% to 3% of all newborns have at least one major abnormality apparent at birth. The true incidence, taking into account abnormalities that present later in life, such as brain malformations, is probably close to 5%. Minor abnormalities are found in approximately 10% of all newborns. If two or more minor abnormalities are present in a newborn, there is a 10% to 20% risk that the baby will also have a major malformation.

The long-term outlook for a baby with a major abnormality obviously depends on the nature of the specific birth defect and whether it can be treated. The overall prognosis for this group of newborns is relatively poor, with 25% dying in early infancy, 25% having subsequent mental or physical disability, and the remaining 50% having a fair or good outlook after treatment.

Childhood Mortality

Congenital abnormalities make a significant contribution to mortality throughout childhood. During infancy, approximately 25% of all deaths are the result of major structural abnormalities, falling to 20% between 1 to 10 years of age, and to ∼7.5% between 10 to 15 years.

Collating the incidence data on abnormalities noted in early spontaneous miscarriages and newborns, at least 15% of all recognized human conceptions are structurally abnormal (Table 16.2), and genetic factors are probably implicated in at least 50% of these.

Table 16.2 Incidence of Structural Abnormalities

Incidence (%)
Spontaneous Miscarriages
First trimester 80–85
Second trimester 25
All Babies
Major abnormality apparent at birth 2–3
Major abnormality apparent later 2
Minor abnormality 10
Death in perinatal period 25
Death in first year of life 25
Death at 1–9 years 20
Death at 10–14 years 7.5

Definition and Classification of Birth Defects

So far in this chapter the terms congenital abnormality and birth defect have been used in a general sense to describe all types of structural abnormality that can occur in an embryo, fetus, or newborn infant. Although these terms are perfectly acceptable for the purpose of lumping together all these abnormalities when studying their overall incidence, they do not provide any insight into possible underlying mechanisms. More specific definitions have been devised that have the added advantage of providing a combined clinical and etiological classification.

Single Abnormalities

Single abnormalities may have a genetic or non-genetic basis. The system of terms used helps us to understand the different mechanisms that might be implicated, and these can be illustrated in schematic form (Figure 16.1).

Disruption

The term disruption refers to an abnormal structure of an organ or tissue as a result of external factors disturbing the normal developmental process. This used to be known as a secondary or extrinsic malformation, and includes ischemia, infection, and trauma. An example of a disruption is the effect seen on limb development when a strand or band of amnion becomes entwined around a baby’s forearm or digits (Figure 16.3). By definition a disruption is not genetic, although occasionally genetic factors can predispose to disruptive events. For example, a small proportion of amniotic bands are caused by an underlying genetically determined defect in collagen that weakens the amnion, making it more liable to tear or rupture spontaneously.

Deformation

A deformation is a defect resulting from an abnormal mechanical force that distorts an otherwise normal structure. Examples include dislocation of the hip and mild ‘positional’ talipes (‘clubfoot’) (Figure 16.4) resulting from reduced amniotic fluid (oligohydramnios) or intrauterine crowding from twinning or a structurally abnormal uterus. Deformations usually occur late in pregnancy and convey a good prognosis with appropriate treatment—for instance, gentle splinting for talipes, because the underlying organ is fundamentally normal in structure.

Multiple Abnormalities

Genetic Causes of Malformations

There are many recognized causes of congenital abnormality, although it is notable that in up to 50% of all cases no clear explanation can be established (Table 16.3).

Table 16.3 Causes of Congenital Abnormalities

Cause %
Genetic 30–40
Chromosomal 6
Single gene 7.5
Multifactorial 20–30
Environmental 5–10
Drugs and chemicals 2
Infections 2
Maternal illness 2
Physical agents 1
Unknown 50
Total 100

Chromosome Abnormalities

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