Multifactorial Causes

The genetic and environmental factors just discussed account for no more than half of human congenital anomalies. The causes of the vast majority of birth defects, including some

relatively common disorders such as cleft lip and cleft palate, remain unknown. In these anomalies, it would appear that inheritance of a certain number of mutant genes and their

interaction with the environment is required before the disorder is expressed. In the case of congenital dislocation of the hip, for example, depth of the acetabular socket and laxity of the

ligaments are believed to be genetically determined, whereas a significant environmental factor is believed to be frank breech position in utero, with hips flexed and knees extended. The

importance of environmental contribution to multifactorial inheritance is underscored by a dramatic reduction in the incidence of neural tube defects by periconceptional intake of folic acid

in the diet.[9] [10] The approximate frequency of some common congenital anomalies in the United States is presented in Table 10-3 . Both temporal and regional variability are common in

the reporting of many malformations. For example, between 1979 and 1989, there was a mean annual percent decrease in the incidence of anencephaly of 6.4 and a mean annual increase in

the incidence of atrial septal defect of 22.0.[11]

PATHOGENESIS OF CONGENITAL ANOMALIES

The pathogenesis of congenital anomalies is complex and still poorly understood, but certain general principles of

TABLE 10-3-- Approximate Frequency of the More Common Congenital Malformations in the United States

Malformation

Frequency per 10,000 Total

Births

Clubfoot without central nervous system anomalies 25.7

Patent ductus arteriosus 16.9

Ventricular septal defect 10.9

Cleft lip with or without cleft palate •9.1

Spina bifida without anencephalus •5.5

Congenital hydrocephalus without anencephalus •4.8

Anencephalus •3.9

Reduction deformity (musculoskeletal) •3.5

Rectal and intestinal atresia •3.4

Adapted from James LM: Maps of birth defects occurrence in the U.S., birth defects monitoring program (BDMP)/CPHA, 1970–1987. Teratology 48:551, 1993.

developmental pathology are relevant regardless of the etiologic agent.

The timing of the prenatal teratogenic insult has an important impact on the occurrence and the type of anomaly produced ( Fig. 10-5 ). The intrauterine development of humans can be

divided into two phases: (1) the embryonic period occupying the first 9 weeks of pregnancy and (2) the fetal period terminating at birth.

In the early embryonic period (first 3 weeks after fertilization), an injurious agent damages either enough cells to cause death and abortion or only a few cells, presumably allowing the

embryo to recover without developing defects. Between the third and the ninth weeks, the embryo is extremely susceptible to teratogenesis, and the peak sensitivity during this period

occurs between the fourth and the fifth weeks. During this period, organs are being crafted out of the germ cell layers. The fetal period that follows organogenesis is marked chiefly by the

further growth and maturation of the organs, with greatly reduced susceptibility to teratogenic agents. Instead the fetus is susceptible to growth retardation or injury to already formed

organs. It is therefore possible for a given agent to produce different anomalies if exposure occurs at different times of gestation.

Teratogens and genetic defects may act at several steps involved in normal morphogenesis. These include the following: [12]

• Proper cell migration to predetermined locations that influence the development of other structures

• Cell proliferation, which determines the size and form of embryonic organs

• Cellular interactions among tissues derived from different structures (e.g., ectoderm, mesoderm), which affect the differentiation of one or both of these tissues

• Cell-matrix associations, which affect growth and differentiation

• Programmed cell death (apoptosis), which, as we have seen, allows orderly organization of tissues and organs during embryogenesis ( Chapter 1 )

• Hormonal influences and mechanical forces, which affect morphogenesis at many levels.

The complex interplay between environmental teratogens and intrinsic genetic defects is underscored by the fact that features of dysmorphogenesis caused by environmental insults can be

recapitulated by certain genetic defects. This is exemplified in the relationship between the teratogen, retinoic acid (see below and Fig. 10-6 ), and two growth factors—transforming

growth factor (TGF) and fibroblast growth factor (FGF)—both involved in morphogenesis. As discussed later, retinoic acid can induce defects in palatal development (cleft lip and cleft

palate), possibly by impacting on multiple targets associated with secondary palatal development. In experimental models of retinoic acid teratogenesis, abnormal expression of TGF and

FGF has been reported in the developing palate.[13] [14] Not unexpectedly, therefore, rare single gene mutations in one or more of these growth factors or their receptors may also cause

palatal abnormalities. There is an association, for example, between rare mutations of the TGF-a gene and nonsyndromic cleft lip or cleft palate in humans;[15] in addition, loss of function

of the epidermal growth factor receptor, which acts as a receptor for TGF-a, can result in abnormal palatogenesis.[16] Disruption of TGF-b3 in mice also results in cleft palate.[17]

Figure 10-5Critical periods of development for various organ systems and the resultant malformations. (Modified and redrawn from Moore KL: The Developing Human, 5th ed.

Philadelphia, WB Saunders, 1993, p. 156.)

Figure 10-6Schematic representation of the postulated role of retinoic acid in normal development, the general features of its deficiency (vitamin A deficiency) (left) and retinoic acid

embryopathy (right). 1, Retinol in the maternal circulation is bound by retinol-binding protein (RBP), which is synthesized by the placenta and enters the fetal circulation. 2, Once in fetal

cells, retinol is bound by cytoplasmic retinol-binding protein (CRBP), which (3) regulates the conversion to retinoic acid and metabolites. The retinoic acid either remains in the cytoplasm

(bound to cytoplasmic/cellular retinoic acid-binding protein [CRABP]) or (4) enters the nucleus, where it is bound to nuclear retinoic acid receptors (RAR, RXR). The retinoic acid-receptor

complex acts as a transcriptional regulator of various patterning genes (e.g., HOX) that have the appropriate retinoic acid response element (RARE). Expression of the binding proteins and

receptors in various tissues and at various times during embryogenesis may be a mechanism of selectively modulating the action of retinoic acid. This differential expression may also

explain the pattern of abnormalities seen in vitamin A deficiency and retinoic acid embryopathy.

Figure 10-7Diagrammatic representation of constitutional chromosomal mosaicism. A, Generalized. B, Confined to the placenta. C, Confined to the embryo. (Modified and redrawn from

Kalousek DK: Confined placental mosaicism and intrauterine development. Pediatr Pathol 10:69, 1990.)

Figure 10-8Schematic diagrams of fetal lung maturation.

TABLE 10-4-- Evaluation of the Newborn Infant *

Sign 0 1 2

Heart rate Absent Below 100 Over 100

Respiratory effort Absent Slow, irregular Good, crying

Muscle tone Limp Some flexion of extremities Active motion

Response to catheter in nostril (tested after

oropharynx is clear)

No response Grimace Cough or sneeze

Color Blue, pale Body pink, extremities blue Completely pink

Data from Apgar V: A proposal for a new method of evaluation of the newborn infant. Anesth Analg 32:260, 1953.

*Sixty seconds after the complete birth of the infant (disregarding removal of the cord and placenta), the five objective signs are evaluated and each is given a score of 0, 1, or 2. A total

score of 10 indicates an infant in the best possible condition.

risk for birth injury, in particular those involving the skeletal system and peripheral nerves. We briefly discuss only injuries involving the head because they are the most ominous.

Intracranial hemorrhages are the most common important birth injury. These hemorrhages are generally related to excessive molding of the head or sudden pressure changes in its shape

as it is subjected to the pressure of forceps or sudden precipitate expulsion. Prolonged labor, hypoxia, hemorrhagic disorders, or intracranial vascular anomalies are important

predispositions. The hemorrhage may arise from tears in the dura or from rupture of vessels that traverse the brain. The substance of the brain may be torn or bruised, leading to

intraventricular hemorrhages or bleeding into the brain substance. The consequences of intracranial hemorrhages are mentioned later under germinal matrix hemorrhage.

Caput succedaneum and cephalhematoma are so common, even in normal uncomplicated births, that they hardly merit the designation birth injury. The first refers to progressive

accumulation of interstitial fluid in the soft tissues of the scalp, giving rise to a usually circular area of edema, congestion, and swelling at the site where the head begins to enter the lower

uterine canal. Hemorrhage may occur into the scalp, producing a cephalhematoma. Both forms of injury are of little clinical significance and are important only insofar as they must be

differentiated from skull fractures with attendant hemorrhage and edema. In approximately 25% of cephalhematomas, there is an underlying skull fracture. Such skull fractures may occur

in cases of precipitate delivery, inappropriate use of forceps, or prolonged labor with disproportion between the size of the fetal head and birth canal.

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