Multifactorial inheritance, which implies the interaction of environmental influences with two or more genes of small effect, is the most common genetic cause of congenital malformations. Included in this category are some relatively common malformations such as cleft lip and palate and neural tube defects. The importance of environmental contributions to multifactorial inheritance is underscored by the dramatic reduction in the incidence of neural tube defects by periconceptional intake of folic acid in the diet. The recurrence risks and mode of transmission of multifactorial disorders are described earlier in this chapter.
The pathogenesis of congenital anomalies is complex and still poorly understood, but two general principles are relevant regardless of the etiologic agent: 1. The timing of the prenatal teratogenic insult has an important impact on the occurrence and the type of anomaly produced.
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, with the peak sensitivity occurring 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.
2. The complex interplay between environmental teratogens and intrinsic genetic defects is exemplified by the fact that features of dysmorphogenesis caused by environmental insults often can be recapitulated by genetic defects in the pathways targeted by these teratogens. Some representative examples follow:
Cyclopamine is a plant teratogen. Pregnant sheep that feed on plants containing cyclopamine give birth to lambs that have severe craniofacial abnormalities including holoprosencephaly and cyclopia (single fused eye—hence the origin of the moniker cyclopamine). This compound is an inhibitor of Hedgehog signaling in the embryo, and, as stated previously, mutations of Hedgehog genes are present in subsets of fetuses with holoprosencephaly.
Valproic acid is an anti-epileptic and a recognized teratogen. Valproic acid disrupts expression of a family of highly conserved developmentally critical transcription factors known as homeobox (HOX) proteins. In vertebrates, HOX proteins have been implicated in the patterning of limbs, vertebrae, and craniofacial structures. Not surprisingly, mutations in the HOX gene family are responsible for congenital anomalies that mimic features observed in valproic acid embryopathy.