Deformations, like disruptions, also represent an extrinsic disturbance of development rather than an intrinsic error of morphogenesis. Deformations are common, affecting approximately 2% of newborn infants to various degrees. They are caused by localized or generalized compression of the growing fetus by abnormal biomechanical forces, leading eventually to a variety of structural abnormalities. The most common cause of deformations is uterine constraint. Between weeks 35 and 38 of gestation, rapid increase in the size of the fetus outpaces the growth of the uterus, and the relative amount of amniotic fluid (which normally acts as a cushion) also decreases. Thus, even the normal fetus is subjected to some degree of uterine constraint. However, several variables increase the likelihood of excessive compression of the fetus, including maternal conditions such as first pregnancy, small uterus, malformed (bicornuate) uterus, and leiomyomas. Causes relating to the fetus, such as presence of multiple fetuses, oligohydramnios, and abnormal fetal presentation, also may be involved.
Sequence refers to multiple congenital anomalies that result from secondary effects of a single localized aberration in organogenesis. The initiating event may be a malformation, deformation, or disruption. An excellent example is the oligohydramnios (or Potter) sequence (
Fig. 7.23A ). Oligohydramnios (decreased amniotic fluid) may be caused by a variety of maternal, placental, or fetal abnormalities, including chronic leakage of amniotic fluid because of rupture of the amnion; uteroplacental insufficiency resulting from maternal hypertension or severe toxemia; and renal agenesis in the fetus (because fetal urine is a major constituent of amniotic fluid). The fetal compression associated with oligohydramnios in turn results in a classic phenotype in the newborn infant consisting of flattened faces and positional abnormalities of the hands and feet (
Fig. 7.23B ). The hips may be dislocated. Growth of the chest wall and the lungs also is compromised, sometimes to such an extent that
Fig. 7.22 Disruptionduetoamnioticbands.Inthespecimenshown,theplacentaisattheright,andthebandofamnionextendsfromthetopportionoftheamnioticsactoencirclethelegofthefetus.(Courtesy of Dr.Theonia Boyd, Children’s Hospital of Boston, Boston, Massachusetts.) http://ebooksmedicine.net
Fig. 7.23 (A)Pathogenesisoftheoligohydramnios(Potter)sequence.
Known causes of errors in human malformations can be grouped into three major categories: genetic, environmental, and multifactorial (
Table 7.6 ). The cause has not been identified for almost half of the reported cases.
Genetic causes of malformations include all of the previously discussed mechanisms of genetic disease. Virtually all chromosomal syndromes are associated with congenital malformations. Examples are Down syndrome and other trisomies, Turner syndrome, and Klinefelter syndrome. Most chromosomal disorders arise during gametogenesis and hence are not familial. Single-gene mutations, characterized by mendelian inheritance, may underlie major malformations. For example, holoprosencephaly is the most common developmental defect of the forebrain and midface in humans (see Chapter 23). The Hedgehog signaling pathway plays a critical role in the morphogenesis of these structures, and loss-of-function mutations of individual components within this pathway are reported in families with a history of recurrent holoprosencephaly.
Environmental influences, such as viral infections, drugs, and radiation to which the mother was exposed during pregnancy, may cause fetal malformations (the appellation of “malformation” is used loosely in this context, because technically, these anomalies represent disruptions). Among the viral infections listed in
Table 7.6 , rubella was a major