Congenital Anomalies

Anirban Maitra MBBS

Vinay Kumar MD

Children are not merely little adults, and the diseases they get are not merely variants of adult diseases. Many childhood conditions are unique to, or at least take distinctive forms in, this

stage of life and so are discussed separately in this chapter. Diseases originating in the perinatal period are important in that they account for significant morbidity and mortality. As would

be expected, the chances for survival of live-born infants improve with each passing week. This differential represents, at least in part, a triumph of improved medical care. Better prenatal

care, more effective methods of monitoring the condition of the fetus, and judicious resort to cesarean section before term when there is evidence of fetal distress all contribute to bringing

into this "mortal coil" live-born infants who in past years might have been stillborn. These infants represent an increased number of high-risk infants. Nonetheless, the infant mortality rate

in the United States has shown a decline from a level of 20.0 deaths per 1000 live births in 1970 to about 6.9 deaths in 2000.[1] Although the death rate has continued

* The contributions of Dr. Deborah Scofield to this chapter in earlier editions are gratefully acknowledged.

to decline for all infants, American blacks continue to have an infant mortality rate more than twice (13.9 deaths per 1000 live births) that of American whites (6.0 deaths). Worldwide, the

infant mortality rates vary widely, from as low as 3 deaths per 1,000 live births in Sweden, to as high as 82 deaths in the Indian subcontinent.

Each stage of development of the infant and child is prey to a somewhat different group of disorders. The data available permit a survey of four time spans: (1) the neonatal period (the first

4 weeks of life), (2) infancy (the first year of life), (3) age 1 to 4 years, and (4) age 5 to 14 years.

The major causes of death in infancy and childhood are cited in Table 10-1 . Congenital anomalies, disorders relating to short gestation (prematurity) and low birth weight, and sudden

infant death syndrome (SIDS) represent the leading causes of death in the first 12 months of life. Once the infant survives the first year of life, the outlook brightens measurably. In the next

two age groups—1 to 4 years and 5 to 14 years—injuries resulting from accidents have become the leading cause of death (see Table 10-1 ). Among the natural diseases, in order of

importance, congenital anomalies and malignant neoplasms assume major significance. It would appear then that, in a sense, life is an obstacle course. For the great majority, the obstacles

are surmounted or, even better, bypassed. We now take a closer look at the specific conditions encountered during the various stages of infant and child development.

Congenital Anomalies

Congenital anomalies are morphologic defects that are present at birth, but some, such as cardiac defects and renal anomalies, may not become clinically apparent until years later. The

term congenital does not imply or exclude a genetic basis for the birth defect. It is estimated that about 3% of newborns have a major anomaly, defined as an anomaly having either

cosmetic or functional significance. As indicated in Table 10-1 , they are the most common cause of mortality in the first year of life and contribute significantly to morbidity and mortality

throughout the early years of life. In a real sense, anomalies found in live-born infants represent the less serious developmental failures in embryogenesis that are compatible with live birth.

Perhaps 20% of fertilized ova are so anomalous that they are blighted from the outset. Others may be compatible with early fetal development, only to lead to spontaneous abortion. Less

severe anomalies allow more prolonged intrauterine survival, with some disorders terminating in still-birth and those still less significant permitting live birth despite the handicaps

imposed.

DEFINITIONS

Before proceeding, we define some of the terms used for various kinds of errors in morphogenesis—malformations, disruptions, deformations, sequences, and syndromes.

• Malformations represent primary errors of morphogenesis, in other words there is an intrinsically abnormal developmental process ( Fig. 10-1 ). They are usually multifactorial

rather than the result of a single gene or chromosomal defect. Malformations may present in several patterns. Some, such as congenital heart defects and anencephaly (absence of

brain), involve single body systems, whereas in other cases multiple malformations involving many organs may coexist.

• Disruptions result from secondary destruction of an organ or body region that was previously normal in development; thus, in contrast to malformations, disruptions arise from an

extrinsic disturbance in morphogenesis. Amniotic

bands, denoting rupture of amnion with resultant formation of "bands"that encircle, compress, or attach to parts of the developing fetus, are the classic example of a disruption ( Fig. 10-2).

A variety of environmental agents may cause disruptions (see below). Understandably, disruptions are not heritable and hence are not associated with risk of recurrence in subsequent

pregnancies.

• Deformations, like disruptions, also represent an extrinsic disturbance of development rather than an intrinsic error of morphogenesis. Deformations are common problems,

affecting approximately 2% of newborn infants to varying degrees. Fundamental to the pathogenesis of deformations is localized or generalized compression of the growing fetus

by abnormal biomechanical forces, leading eventually to a variety of structural abnormalities. The most common underlying factor responsible for deformations is uterine

constraint. Between the 35th and 38th weeks 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 form of uterine constraint. Several factors increase the likelihood of excessive

compression of the fetus resulting in deformations. Maternal factors include first pregnancy, small uterus, malformed (bicornuate) uterus, and leiomyomas. Fetal or placental

factors include oligohydramnios, multiple fetuses, and abnormal fetal presentation. An example of a deformation is clubfeet, often a component of Potter sequence, described later.

• A sequence is a pattern of cascade anomalies. Approximately half the time, congenital anomalies occur singly; in the remaining cases, multiple congenital anomalies are

recognized. In some instances, the constellation of anomalies may be explained by a single, localized aberration in organogenesis (malformation, disruption, or deformation)

leading to secondary effects in other organs. A good example of a sequence is the oligohydramnios (or Potter) sequence ( Fig. 10-3 ). Oligohydramnios (decreased amniotic fluid)

may be caused by a variety of unrelated maternal, placental, or fetal abnormalities. 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 (as fetal urine is a major constituent of amniotic fluid) are all causes of

oligohydramnios. The fetal compression associated with significant oligohydramnios, in turn, results in a classic phenotype in the newborn infant, including flattened facies and positional

abnormalities of the hands and feet ( Fig. 10-4). The hips may be dislocated. Growth of the chest wall and the contained lungs is also compromised so that the lungs are frequently

hypoplastic, occasionally to the degree that they are the cause of fetal demise. Nodules in the amnion (amnion nodosum)are frequently present.

• A syndrome is a constellation of congenital anomalies, believed to be pathologically related, that, in contrast to a sequence, cannot be explained on the basis of a single, localized,

initiating defect. Syndromes are most often caused by a single etiologic agent, such as a viral infection or specific chromosomal abnormality, which simultaneously affects several

tissues.

TABLE 10-1-- Cause of Death Related with Age

Causes * Rate †

Under 1 Year: All Causes 727.4

Congenital malformations, deformations, and chromosomal anomalies

Disorders related to short gestation and low birth weight

Sudden infant death syndrome (SIDS)

Newborn affected by maternal complications of pregnancy

Newborn affected by complications of placenta, cord, and membranes

Respiratory distress of newborn

Accidents (unintentional injuries)

Bacterial sepsis of newborn

Intrauterine hypoxia and birth asphyxia

Diseases of the circulatory system

1–4 Years: All Causes 32.6

Accidents and adverse effects

Congenital malformations, deformations, and chromosomal abnormalities

Malignant neoplasms

Homicide and legal intervention

Diseases of the heart ‡

Influenza and pneumonia

5–14 Years: All Causes 18.5

Accidents and adverse effects

Malignant neoplasms

Homicide and legal intervention

Congenital malformations, deformations, and chromosomal abnormalities

Suicide

Diseases of the heart

15–24 Years: All Causes 80.7

Accidents and adverse effects

Homicide

Suicide

Malignant neoplasms

Diseases of the heart

*Causes are listed in decreasing order of frequency. All causes and rates are preliminary 2000 statistics. (Minino AM, Smith BL. Deaths: Preliminary data for 2000. National Vital Statistics

Report, 49:12, 2001).

†Rates are expressed per 100,000 population.

‡Excludes congenital heart disease.

Figure 10-1Malformations. Human malformations can range in severity from the incidental to the lethal. Polydactyly (one or more extra digits) and syndactyly (fusion of digits), both of

which are illustrated in A, have little functional consequence when they occur in isolation. Similarly, cleft lip (B), with or without associated cleft palate, is compatible with life when it

occurs as an isolated anomaly; in the present case, however, this child had an underlying malformation syndrome (trisomy 13) and expired because of severe cardiac defects. The stillbirth

illustrated in C represents a severe and essentially lethal malformation, where the midface structures are fused or ill-formed; in almost all cases, this degree of external dysmorphogenesis is

associated with severe internal anomalies such as maldevelopment of the brain and cardiac defects. (Pictures A and C courtesy of Dr. Reade Quinton, and B courtesy of Dr. Beverly

Rogers, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)

Figure 10-2Disruption. Disruptions occur in a normally developing organ because of an extrinsic abnormality that interferes with normal morphogenesis. Amniotic bands are a frequent

cause of disruptions. In the illustrated example, note the placenta at the right of the diagram and the band of amnion extending from the top portion of the amniotic sac to encircle the leg of

the fetus. (Courtesy of Dr. Theonia Boyd, Children's Hospital of Boston, MA.)

Figure 10-3Schematic diagram of the pathogenesis of the oligohydramnios sequence.

Figure 10-4Infant with oligohydramnios sequence. Note the flattened facial features and deformed right foot (talipes equinovarus).

TABLE 10-2-- Causes of Congenital Anomalies in Humans

Cause Frequency (%)

Genetic

Chromosomal aberrations 10–15

Mendelian inheritance •2–10

Environmental

Maternal/placental infections •2–3

••Rubella

••Toxoplasmosis

••Syphilis

••Cytomegalovirus

••Human immunodeficiency virus (HIV)

Maternal disease states •6–8

••Diabetes

••Phenylketonuria

••Endocrinopathies

Drugs and chemicals •1

••Alcohol

••Folic acid antagonists

••Androgens

••Phenytoin

••Thalidomide

••Warfarin

••13-cis-retinoic acid

••Others

Irradiations •1

Multifactorial (Multiple Genes ? Environment) 20–25

Unknown 40–60

Adapted from Stevenson RE, et al (eds): Human Malformations and Related Anomalies. New York, Oxford University Press, 1993, p. 115.

Single gene mutations of large effect may underlie major congenital anomalies, which, as expected, follow mendelian patterns of inheritance.[2] Of these, approximately 90% are inherited

in an autosomal dominant or recessive pattern, while the remainder segregates in an X-linked pattern. Not surprisingly, many of the mutations that give rise to birth defects involve

abrogation of function of genes involved in normal organogenesis and development. For example, holoprosencephaly is the most common developmental defect of the forebrain and

midface in humans (see Chapter 28 ); mutations of sonic hedgehog, a gene involved in developmental patterning (see below), have been reported in a subset of patients with

holoprosencephaly.[3] Similarly, mutations of a downstream target of sonic hedgehog signaling, GLI3, have been reported in patients with anomalies of digits, either conjoined digits

(syndactyly) or supernumerary digits (polydactyly).

Date: 2016-04-22; view: 922