10 Diesease of Infancy and Childhood

See TARGETED THERAPY available online at
www.studentconsult.com C H A P T ER
Diseases of Infancy
and Childhood
10
Anirban Maitra
C H A P T E R CO N T E N T S
Congenital Anomalies 452 Fetal Hydrops 461 Tumors and Tumor-like Lesions of
Definitions 452 Immune Hydrops 461 Infancy and Childhood 473
Causes of Anomalies 454 Nonimmune Hydrops 462 Benign Tumors and Tumor-like Lesions 473
Prematurity and Fetal Growth Inborn Errors of Metabolism and Other Malignant Tumors 475
Restriction 456 Genetic Disorders 464 Neuroblastic Tumors 475
Fetal Growth Restriction 456 Phenylketonuria 464 Wilms Tumor 479
Neonatal Respiratory Distress Syndrome 457 Galactosemia 465
Necrotizing Enterocolitis 459 Cystic Fibrosis (Mucoviscidosis) 466
Perinatal Infections 459 Sudden Infant Death Syndrome
Transcervical (Ascending) Infections 459 (SIDS) 471
Transplacental (Hematologic) Infections 460
Sepsis 460
Children are not merely little adults, and their diseases are dismayingly, the United States ranks thirty-first in infant
not merely variants of adult diseases. Many childhood con- mortality rates among developed nations in the Western
ditions are unique to, or at least take distinctive forms in, hemisphere.
this stage of life and so are discussed separately in this Each stage of development of the infant and child is
chapter. Diseases originating in the perinatal period are prey to a somewhat different group of disorders. The
important in that they account for significant morbidity data available permit a survey of four time spans: (1) the
and mortality. As would be expected, the chances for sur- neonatal period (the first 4 weeks of life), (2) infancy
vival of live-born infants improve with each passing week. (the first year of life), (3) age 1 to 4 years, and (4) age 5
This progress represents, at least in part, a triumph of to 14 years.
improved medical care. Better prenatal care, more effective The major causes of death in infancy and childhood are
methods of monitoring the condition of the fetus, and judi- listed in Table 10-1. Congenital anomalies, disorders relat-
cious resort to cesarean section before term when there is ing to short gestation (prematurity) and low birth weight,
evidence of fetal distress, have all contributed toward and sudden infant death syndrome (SIDS) represent the
bringing into this world live-born infants who in past years leading causes of death in the first 12 months of life. Once
might have been stillborn. This has resulted in an increased the infant survives the first year of life, the outlook bright-
number of high-risk infants in the population. Nonetheless, ens measurably. In the next two age groups—1 to 4 years
the infant mortality rate in the United States has shown a and 5 to 9 years—unintentional injuries resulting from
decline from a level of 20 deaths per 1000 live births in 1970 accidents have become the leading cause of death. Among
to about 6.1 deaths in 2010, the latest year for which com- the natural diseases, in order of importance, congenital
plete data are available. Although the death rate has con- anomalies and malignant neoplasms assume major signifi-
tinued to decline for all infants, African Americans continue cance. It would appear then that, in a sense, life is an
to have an infant mortality rate more than twice (12.4 obstacle course. Thankfully for the great majority, the
deaths per 1000 live births) that of American whites (5.3 obstacles are comfortably overcome.
deaths). Worldwide, infant mortality rates vary widely, The following discussion looks at specific conditions
from as low as 1.8 deaths per 1000 live births in Luxembourg, encountered during the various stages of infant and child
to as high as 180 deaths in the African subcontinent. Rather development.
451
452 C H A P T E R 10 Diseases of Infancy and Childhood
Table 10-1 Cause of Death Related with Age lead to spontaneous abortion. Less severe anomalies allow
Causes* Rate † more prolonged intrauterine survival, with some disorders
terminating in stillbirth and those still less significant per-
Younger than 1 year 660.6 mitting live birth despite the handicaps imposed.
Congenital malformations, deformations, and chromosomal
anomalies
Disorders related to short gestation and low birth weight
Definitions
Sudden infant death syndrome (SIDS)
The process of morphogenesis (organ and tissue develop-
Newborn affected by maternal complications of pregnancy
Accidents (unintentional injuries)
ment) can be impaired by a variety of different errors.
Newborn affected by complications of placenta, cord, and
membranes
• Malformations represent primary errors of morphogen-
esis, in which there is an intrinsically abnormal develop-
Bacterial sepsis of newborn
Respiratory distress of newborn
mental process (Fig. 10-1). Malformations can be the
Diseases of the circulatory system
result of a single gene or chromosomal defect, but are
Neonatal hemorrhage more commonly multifactorial in origin. Malformations
may present in several patterns. Some, such as congeni-
1-4 Years 28.3 tal heart defects and anencephaly (absence of the brain),
Accidents (unintentional injuries) involve single body systems, whereas in other cases
Congenital malformations, deformations, and chromosomal multiple malformations involving many organs may
abnormalities
coexist.
Assault (homicide)
Malignant neoplasms • Disruptions result from secondary destruction of an
Diseases of the heart‡ organ or body region that was previously normal in
development; thus, in contrast to malformations, dis-
5-9 Years 12.5 ruptions arise from an extrinsic disturbance in morphogen-
Accidents (unintentional injuries) esis. Amniotic bands, denoting rupture of amnion with
Malignant neoplasms resultant formation of “bands” that encircle, compress,
Congenital malformations, deformations, and chromosomal or attach to parts of the developing fetus, are the classic
abnormalities
example of a disruption (Fig. 10-2). A variety of envi-
Assault (homicide)
Influenza and pneumonia
ronmental agents may cause disruptions (see later).
Understandably, disruptions are not heritable and hence
10-14 Years 15.7 are not associated with risk of recurrence in subsequent
Accidents (unintentional injuries) pregnancies.
Malignant neoplasms
Intentional self-harm (suicide)
• Deformations, like disruptions, also represent an extrinsic
disturbance of development rather than an intrinsic error
Assault (homicide)
of morphogenesis. Deformations are common prob-
Congenital malformations, deformations, and chromosomal
anomalies
lems, affecting approximately 2% of newborn infants to
varying degrees. Fundamental to the pathogenesis of
*Causes are listed in decreasing order of frequency. All causes and rates are based on 2008
(final) and 2009 (preliminary) data. deformations is localized or generalized compression
†
‡
Rates are expressed per 100,000 population from all causes within each age group. of the growing fetus by abnormal biomechanical forces,
Excludes congenital heart disease. leading eventually to a variety of structural abnormali-
Data source: Centers for Disease Control and Prevention/NCHS, National Vital Statistics System:
mortality, 2009 and 2008 (www.cdc.gov/nchs/nvss/mortality_tables.htm). ties. The most common underlying factor responsible
for deformations is uterine constraint. Between the thirty-
fifth and thirty-eighth 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 nor-
Congenital Anomalies mally acts as a cushion) also decreases. Thus, even the
normal fetus is subjected to some form of uterine con-
Congenital anomalies are anatomic defects that are straint. Several factors increase the likelihood of exces-
present at birth, but some, such as cardiac defects and sive compression of the fetus resulting in deformations.
renal anomalies, may not become clinically apparent Maternal factors include first pregnancy, small uterus,
until years later. The term congenital means “born with,” malformed (bicornuate) uterus, and leiomyomas. Fetal
but it does not imply or exclude a genetic basis for the birth or placental factors include oligohydramnios, multiple
defect. It is estimated that about 120,000 (1 in 33) babies are fetuses, and abnormal fetal presentation. An example of
born with a birth defect each year in the United States. a deformation is clubfeet, often a component of Potter
They are the most common cause of mortality in the first sequence, described later.
year and contribute significantly to morbidity and mortal- • A sequence is a cascade of anomalies triggered by one
ity throughout the early years of life. In a sense, anomalies initiating aberration. Approximately half the time,
found in live-born infants represent the less serious congenital anomalies occur singly; in the remaining
developmental failures in embryogenesis that are compat- cases, multiple congenital anomalies are recognized. In
ible with live birth. Perhaps 20% of fertilized ova are so some instances the constellation of anomalies may be
anomalous that they are blighted from the outset. Others explained by a single, localized aberration in organo-
may be compatible with early fetal development, only to genesis (malformation, disruption, or deformation) that
Congenital anomalies 453
Figure 10-1 Examples of malformations. 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 neonate had an underlying malformation syndrome (trisomy 13) and died of severe cardiac defects.
C, The stillbirth illustrated represents a severe and essentially lethal malformation, wherein 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. (A and
C, Courtesy Dr. Reade Quinton; B, Courtesy Dr. Beverly Rogers, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.)
sets into motion secondary effects in other organs. A turn, results in a classic phenotype in the newborn
good example is the oligohydramnios (or Potter) sequence infant, including flattened facies and positional abnor-
(Fig. 10-3). Oligohydramnios (decreased amniotic fluid) malities of the hands and feet (Fig. 10-4). The hips may
may be caused by a variety of unrelated maternal, pla- be dislocated. Growth of the chest wall and the con-
cental, or fetal abnormalities. Causes of oligohydram- tained lungs is also compromised so that the lungs are
nios include chronic leakage of amniotic fluid because frequently hypoplastic, occasionally to the degree that
of rupture of the amnion, uteroplacental insufficiency they are the cause of fetal demise. Nodules in the amnion
resulting from maternal hypertension or severe toxemia, (amnion nodosum) are frequently present.
and renal agenesis in the fetus (because fetal urine is a • A malformation syndrome is a constellation of congenital
major constituent of amniotic fluid). The fetal compres- anomalies, believed to be pathologically related, that, in
sion associated with significant oligohydramnios, 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.
In addition to the aforementioned general definitions,
a few organ-specific terms should be defined. Agenesis
Renal Amniotic
agenesis leak Others
Amnion
nodosum OLIGOHYDRAMNIOS
FETAL COMPRESSION
Pulmonary Altered Positioning Breech

Figure 10-2 Disruption of morphogenesis by an amniotic band. Note the hypoplasia facies defects of presentation
feet, hands
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 Figure 10-3 Schematic diagram of the pathogenesis of the oligohydramnios
Dr. Theonia Boyd, Children’s Hospital of Boston, Boston, Mass.) sequence.
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
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
Figure 10-4 Infant with oligohydramnios sequence. Note the flattened facial Irradiations 1
features and deformed right foot (talipes equinovarus).
Multifactorial 20-25
Unknown 40-60
refers to the complete absence of an organ and its associ- Adapted from Stevenson RE, et al (eds): Human Malformations and related Anomalies.
New York, Oxford University Press, 1993, p 115.
ated primordium. A closely related term, aplasia, also
refers to the absence of an organ but one that occurs due
to failure of growth of the existing primordium. Atresia
describes the absence of an opening, usually of a hollow during gametogenesis and hence are not familial. Single-
visceral organ, such as the trachea and intestine. Hypoplasia gene mutations, characterized by mendelian inheritance,
refers to incomplete development or decreased size of an may underlie major malformations. For example, holo-
organ with decreased numbers of cells, whereas hyperplasia prosencephaly is the most common developmental defect
refers to the converse, that is, the enlargement of an organ of the forebrain and midface in humans; the Hedgehog
due to increased numbers of cells. An abnormality in an signaling pathway plays a critical role in the morphogen-
organ or a tissue as a result of an increase or a decrease in esis of these structures, and loss-of-function mutations of
the size (rather than the number) of individual cells defines individual components within this pathway are reported
hypertrophy or hypotrophy, respectively. Finally, dysplasia, in in families with a history of recurrent holoprosencephaly.
the context of malformations (versus neoplasia) describes an Environmental influences, such as viral infections, drugs,
abnormal organization of cells. and irradiation to which the mother was exposed during
pregnancy, may cause fetal anomalies. Among the viral
Causes of Anomalies infections listed in Table 10-2, rubella was a major scourge
of the nineteenth and early twentieth centuries. Fortunately,
At one time, it was believed that the presence of a visible, maternal rubella and the resultant rubella embryopathy
external anomaly was divine punishment for wickedness, have been virtually eliminated in developed countries as a
a belief that occasionally jeopardized the mother’s life. result of maternal rubella vaccination. A variety of drugs
Although we are learning a great deal about the molecular and chemicals have been suspected to be teratogenic,
bases of some congenital anomalies, the exact cause remains but perhaps less than 1% of congenital malformations
unknown in at least one half to three fourths of the cases. The are caused by these agents. The list includes thalidomide,
common known causes of congenital anomalies can be alcohol, anticonvulsants, warfarin (oral anticoagulant),
grouped into three major categories: genetic, environ- and 13-cis-retinoic acid, which is used in the treatment of
mental, and multifactorial (Table 10-2). severe acne. For example, thalidomide, once used as a tran-
Genetic causes of malformations include all of the previ- quilizer in Europe, causes an extremely high incidence
ously discussed mechanisms of genetic disease (Chapter (50% to 80%) of limb malformations. Alcohol, when con-
5). Virtually all chromosomal syndromes are associated sumed even in modest amounts during pregnancy, is an
with congenital malformations. Examples include Down important environmental teratogen. Affected infants show
syndrome and other trisomies, Turner syndrome, and prenatal and postnatal growth retardation, facial anoma-
Klinefelter syndrome. Most chromosomal disorders arise lies (microcephaly, short palpebral fissures, maxillary
Congenital anomalies 455
Embryonic Period (in weeks) Fetal Period (in weeks) Full Term
1 2 3 4 5 6 7 8 9 16 20-36 38
Period of dividing
zygote, implantation,
and bilaminar embryo
Critical periods of development (red denotes highly sensitive periods)
Central nervous system

Heart
Arms
Eyes
Usually not
Legs
susceptible
to teratogens Teeth
Palate
External genitalia
Ears
Prenatal death Major morphologic abnormalities Physiologic defects and minor morphologic abnormalities
Figure 10-5 Critical 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.)
hypoplasia), and psychomotor disturbances. These in com- Pathogenesis. The pathogenesis of congenital anomalies is
bination are labeled the fetal alcohol syndrome (also dis- complex and still poorly understood, but two general prin-
cussed in Chapter 9). While cigarette smoke-derived ciples of developmental pathology are relevant regardless
nicotine has not been convincingly demonstrated to be a of the etiologic agent.
teratogen, there is a high incidence of spontaneous abor-
tions, premature labor, and placental abnormalities in 1. The timing of the prenatal teratogenic insult has an important
pregnant smokers; babies born to mothers who smoke impact on the occurrence and the type of anomaly produced
often have a low birth weight and may be prone to the (Fig. 10-5). The intrauterine development of humans can
SIDS. In light of these findings, it is best to avoid nicotine expo- be divided into two phases: (1) the embryonic period
sure altogether during pregnancy. Among maternal condi- occupying the first 9 weeks of pregnancy and (2) the
tions listed in Table 10-2, diabetes mellitus is a common fetal period terminating at birth.
entity, and despite advances in antenatal obstetric monitor- • In the early embryonic period (first 3 weeks after fertil-
ing and glucose control, the incidence of major malforma- ization), an injurious agent damages either enough
tions in infants of diabetic mothers stands between 6% and cells to cause death and abortion or only a few cells,
10% in most series. Maternal hyperglycemia-induced fetal presumably allowing the embryo to recover without
hyperinsulinemia results in fetal macrosomia (organomeg- developing defects. Between the third and the ninth
aly and increased body fat and muscle mass); cardiac weeks, the embryo is extremely susceptible to teratogene-
anomalies, neural tube defects, and other central nervous sis, and the peak sensitivity during this period occurs
system (CNS) malformations are some of the major anoma- between the fourth and the fifth weeks. During this
lies seen in diabetic embryopathy. period organs are being crafted out of the germ cell
Multifactorial inheritance, which implies the interaction layers.
of environmental influences with two or more genes of • The fetal period that follows organogenesis is marked
small effect, is the most common genetic cause of congeni- chiefly by the further growth and maturation of
tal malformations. Included in this category are some rela- the organs, with greatly reduced susceptibility to
tively common malformations such as cleft lip, cleft palate teratogenic agents. Instead, the fetus is susceptible to
and neural tube defects. The importance of environmental growth retardation or injury to already formed
contributions to multifactorial inheritance is underscored organs. It is therefore possible for a given agent to
by the dramatic reduction of the incidence of neural tube produce different anomalies if exposure occurs at dif-
defects by periconceptional intake of folic acid in the diet. ferent times of gestation.
2. The interplay between environmental teratogens and pregnancies and is responsible for as many as a third of
intrinsic genetic defects is exemplified by the fact that all preterm deliveries. Rupture of membranes (ROM)
features of dysmorphogenesis caused by environmental insults before the onset of labor can be spontaneous or induced.
can often be recapitulated by genetic defects in the pathways PPROM refers to spontaneous ROM occurring before 37
targeted by these teratogens. This is illustrated by the fol- weeks’ gestation (hence the annotation “preterm”). In
lowing representative examples. contrast, PROM refers to spontaneous ROM occurring
• Cyclopamine is a plant teratogen and pregnant sheep after 37 weeks’ gestation. This distinction is important
who feed on this plant give birth to lambs that because after 37 weeks the associated risk to the fetus is
have severe craniofacial abnormalities including considerably decreased. Several clinical risk factors
holoprosencephaly and “cyclopia” (single fused eye, have been identified for PPROM, including a prior
hence the origin of the moniker cyclopamine). This history of preterm delivery, preterm labor and/or
compound is an inhibitor of Hedgehog signaling vaginal bleeding during the current pregnancy, mater-
in the embryo, and as stated earlier, mutations of nal smoking, low socioeconomic status, and poor mater-
Hedgehog genes are present in subsets of patients nal nutrition. The fetal and maternal outcome after
with holoprosencephaly. PPROM depends on the gestation age of the fetus
• Valproic acid is an antiepileptic and a recognized (second-trimester PPROM has a dismal prognosis), and
teratogen during pregnancy. Valproic acid disrupts the effective prophylaxis of infections in the exposed
expression of a family of highly conserved develop- amniotic cavity.
mentally critical transcription factors known as • Intrauterine infection: This is a major cause of preterm
homeobox (HOX) proteins. In vertebrates, HOX pro- labor with and without intact membranes. Intrauterine
teins have been implicated in the patterning of limbs, infection is present in approximately 25% of all preterm
vertebrae, and craniofacial structures. Not surpris- births, and the earlier the gestational age at delivery, the
ingly, mutations in HOX family of genes are respon- higher the frequency of intra-amniotic infection. The
sible for congenital anomalies that mimic features histologic correlates of intrauterine infection are inflam-
observed in valproic acid embryopathy. mation of the placental membranes (chorioamnionitis)
• The vitamin A (retinol) derivative all-trans-retinoic and inflammation of the fetal umbilical cord (funisitis).
acid is essential for normal development and differ- The most common microorganisms implicated in intra-
entiation, and its absence during embryogenesis uterine infections leading to preterm labor are Ureaplasma
results in a constellation of malformations affecting urealyticum, Mycoplasma hominis, Gardnerella vaginalis
multiple organ systems, including the eyes, genito- (the dominant organism found in “bacterial vaginosis,”
urinary system, cardiovascular system, diaphragm, a polymicrobial infection), Trichomonas, gonorrhea, and
and lungs (see Chapter 9 for effects of for vitamin A Chlamydia. In developing countries, malaria and HIV are
deficiency in the postnatal period). Conversely, exces- significant contributors to the burden of preterm labor
sive exposure to retinoic acid is also teratogenic. Infants and prematurity. Recent studies have begun to elucidate
born to mothers treated with retinoic acid for severe the molecular mechanisms of inflammation-induced
acne have a predictable phenotype (retinoic acid preterm labor. Endogenous Toll-like receptors (TLRs),
embryopathy), including CNS, cardiac, and craniofa- which bind bacterial components as natural ligands
cial defects, such as cleft lip and cleft palate. The latter (Chapter 6), have emerged as key players in this process.
may stem from retinoic acid–mediated deregulation It is postulated that signals produced by TLR engage-
of components of the transforming growth factor-β ment deregulate prostaglandin expression, which in
(TGF-β) signaling pathway, which is involved in turn induces uterine smooth muscle contractions.
palatogenesis. Mice with knockout of the Tgfb3 gene • Uterine, cervical, and placental structural abnormalities:
uniformly develop cleft palate, once again illustrat- Uterine distortion (e.g., uterine fibroids), compromised
ing the functional relationship between teratogenic structural support of the cervix (“cervical incompe-
exposure and signaling pathways in the causation of tence”), placenta previa, and abruptio placentae (Chapter
congenital anomalies. 22) are associated with an increased risk of prematurity.
• Multiple gestation (twin pregnancy).
The hazards of prematurity are manifold for the new-
Prematurity and Fetal born and may give rise to one or more of the following:
Growth Restriction • Neonatal respiratory distress syndrome, also known as
hyaline membrane disease
Prematurity, defined by a gestational age less than 37
weeks, is the second most common cause of neonatal • Necrotizing enterocolitis
mortality, behind only congenital anomalies (Table 10-1). • Sepsis
The American College of Obstetrics and Gynecology esti- • Intraventricular and germinal matrix hemorrhage
mates that 12% of all births in the United States are preterm
deliveries, and despite extensive research into this area, Fetal Growth Restriction
this rate has increased over the last two decades. The major Although preterm infants have low birth weights, it
risk factors for prematurity include: is usually appropriate once adjusted for their gestational
age. In contrast, as many as one third of infants who
• Preterm premature rupture of placental membranes weigh less than 2500 gm are born at term and are
(PPROM): PPROM complicates about 3% of all therefore undergrown rather than immature. These
Prematurity and fetal growth restriction 457
small-for-gestational-age (SGA) infants suffer from fetal The SGA infant faces a difficult course, not only during
growth restriction. Fetal growth restriction (FGR) may result the struggle for survival in the perinatal period, but also in
from fetal, maternal, or placental abnormalities, although childhood and adult life. Depending on the underlying
in many cases the specific cause is unknown. cause of FGR and, to a lesser extent, the degree of prema-
turity, there is a significant risk of morbidity in the form of
Fetal Abnormalities. Fetal influences are those that intrin- a major handicap, cerebral dysfunction, learning disability,
sically reduce growth potential of the fetus despite an or hearing and visual impairment.
adequate supply of nutrients from the mother. Prominent
among such fetal conditions are chromosomal disorders, con- Neonatal Respiratory Distress Syndrome
genital anomalies, and congenital infections. Chromosomal
abnormalities may be detected in up to 17% of fetuses There are many causes of respiratory distress in the
sampled for FGR and in up to 66% of fetuses with docu- newborn. The most common cause is respiratory distress
mented ultrasonographic malformations. Among the first syndrome (RDS), also known as hyaline membrane
group, the abnormalities include triploidy (7%), trisomy 18 disease because of the deposition of a layer of hyaline
(6%), trisomy 21 (1%), trisomy 13 (1%), and a variety of proteinaceous material in the peripheral airspaces of
deletions and translocations (2%). Fetal infection should be infants who succumb to this condition. Others include
considered in all infants with FGR. Those most commonly excessive sedation of the mother, fetal head injury during
responsible for FGR are the TORCH group of infections delivery, aspiration of blood or amniotic fluid, and intra-
(toxoplasmosis, rubella, cytomegalovirus, herpesvirus, uterine hypoxia brought about by coiling of the umbilical
and other viruses and bacteria, such as syphilis). Infants cord about the neck. An estimated 24,000 cases of RDS
who are SGA because of fetal factors usually have sym- are reported annually in the United States. Thankfully,
metric growth restriction (also referred to as proportionate improvements in management of this condition have
FGR), meaning that all organ systems are similarly affected. sharply decreased deaths due to respiratory insufficiency
from as many as 5000 per year a decade earlier to less than
Placental Abnormalities. During the third trimester of 900 cases per year currently.
pregnancy, vigorous fetal growth places particularly heavy In untreated infants (not receiving surfactant), RDS
demands on the uteroplacental blood supply. Therefore, generally presents in a stereotypical fashion, with charac-
the adequacy of placental growth in the preceding mid- teristic clinical findings. The infant is almost always
trimester is extremely important, and uteroplacental insuf- preterm but has weight appropriate for gestational age,
ficiency is an important cause of growth restriction. This and there are strong, but not invariable, associations with
insufficiency may result from umbilical-placental vascular male gender, maternal diabetes, and delivery by cesarean
anomalies (such as single umbilical artery, abnormal cord section. Resuscitation may be necessary at birth, but usually
insertion, placental hemangioma), placental abruption, pla- within a few minutes rhythmic breathing and normal color
centa previa, placental thrombosis and infarction, placental are reestablished. Soon afterward, often within 30 minutes,
infection, or multiple gestations (Chapter 22). In some cases breathing becomes more difficult, and within a few hours
the placenta may be small without any detectable underly- cyanosis becomes evident. Fine rales can now be heard
ing cause. Placental causes of FGR tend to result in asym- over both lung fields. A chest x-ray film at this time usually
metric (or disproportionate) growth retardation of the fetus reveals uniform minute reticulogranular densities, produc-
with relative sparing of the brain. Physiologically, this ing a so-called ground-glass picture. In the full-blown condi-
general type of FGR is viewed as a down-regulation of tion the respiratory distress persists, cyanosis increases,
growth in the latter half of gestation because of limited and even the administration of 80% oxygen by a variety of
availability of nutrients or oxygen. ventilatory methods fails to improve the situation. If
therapy staves off death for the first 3 or 4 days, however,
Maternal Abnormalities. By far the most common factors the infant has an excellent chance of recovery.
associated with SGA infants are maternal conditions that
result in decreased placental blood flow. Vascular diseases, Pathogenesis. Immaturity of the lungs is the most impor-
such as preeclampsia (toxemia of pregnancy) and chronic hyper- tant substrate on which RDS develops. It may be encoun-
tension, are often the underlying cause. Another class of tered in full-term infants but is much more frequent in
maternal diseases increasingly being recognized in the those “born before their time into this breathing world.”
setting of FGR are thrombophilias, such as the acquired anti- The incidence of RDS is inversely proportional to gesta-
phospholipid antibody syndrome (Chapter 6). Inherited tional age. It occurs in about 60% of infants born at less
diseases of hypercoagulability are also associated with than 28 weeks of gestation, 30% of those born between 28
recurrent early pregnancy losses. The list of other maternal to 34 weeks’ gestation, and less than 5% of those born after
conditions associated with SGA infants is long, but some 34 weeks’ gestation.
of the avoidable factors worth mentioning are maternal The fundamental defect in RDS is a deficiency of pul-
narcotic abuse, alcohol intake, and heavy cigarette smoking. monary surfactant. As described in Chapter 15, surfactant
Drugs causing FGR include both classic teratogens, such as consists predominantly of dipalmitoyl phosphatidylcho-
chemotherapeutic agents, and some commonly adminis- line (lecithin), smaller amounts of phosphatidylglycerol,
tered therapeutic agents, such as phenytoin (Dilantin). and two groups of surfactant-associated proteins. The first
Maternal malnutrition (in particular, prolonged hypoglyce- group is composed of hydrophilic glycoproteins SP-A and
mia) may also affect fetal growth, but the association SP-D, which play a role in pulmonary host defense (innate
between SGA infants and the nutritional status of the immunity). The second group consists of hydrophobic sur-
mother is complex. factant proteins SP-B and SP-C, which, in concert with the
surfactant lipids, are involved in the reduction of surface

tension at the air-liquid barrier in the alveoli of the lung.
With reduced surface tension in the alveoli, less pressure
is required to keep them patent and hence aerated. The
importance of surfactant proteins in normal lung function
can be gauged by the occurrence of severe respiratory
failure in neonates with congenital deficiency of surfactant
caused by mutations in the SFTPB or SFTBC genes.
Surfactant production by type II alveolar cells is acceler-
ated after the thirty-fifth week of gestation in the fetus. At
birth, the first breath of life requires high inspiratory pres-
sures to expand the lungs. With normal levels of surfactant,
the lungs retain up to 40% of the residual air volume after
the first breath; thus, subsequent breaths require far lower
inspiratory pressures. With a deficiency of surfactant, the
lungs collapse with each successive breath, and so infants
Figure 10-7 Hyaline membrane disease. There is alternating atelectasis and
must work as hard with each successive breath as they did dilation of the alveoli. Note the eosinophilic thick hyaline membranes lining
with the first. The problem of stiff atelectatic lungs is com- the dilated alveoli.
pounded by the soft thoracic wall that is pulled in as the
diaphragm descends. Progressive atelectasis and reduced
lung compliance then lead to a train of events as depicted Surfactant synthesis is modulated by a variety of hor-
in Figure 10-6, resulting in protein-rich, fibrin-rich exuda- mones and growth factors, including cortisol, insulin, pro-
tion into the alveolar spaces with the formation of hyaline lactin, thyroxine, and TGF-β. The role of glucocorticoids is
membranes. The fibrin-hyaline membranes are barriers particularly important. Conditions associated with intrauter-
to gas exchange, leading to carbon dioxide retention and ine stress and FGR that increase corticosteroid release
hypoxemia. The hypoxemia itself further impairs surfac- lower the risk of developing RDS. Surfactant synthesis can
tant synthesis, and a vicious cycle ensues. be suppressed by the compensatory high blood levels of
insulin in infants of diabetic mothers, which counteracts
the effects of steroids. This may explain, in part, why
infants of diabetic mothers have a higher risk of develop-
ing RDS. Labor is known to increase surfactant synthesis;
PREMATURITY
hence, cesarean section before the onset of labor may
increase the risk of RDS.
Reduced surfactant synthesis, storage, and release
MORPHOLOGY
Decreased alveolar surfactant
The lungs are distinctive on gross examination. Though of
normal size, they are solid, airless, and reddish purple, similar
Increased alveolar surface tension to the color of the liver, and they usually sink in water.
Microscopically, alveoli are poorly developed, and those that
Atelectasis are present are collapsed (Fig. 10-7). When the infant dies early
in the course of the disease, necrotic cellular debris can be seen
Uneven perfusion Hypoventilation in the terminal bronchioles and alveolar ducts. The necrotic
material becomes incorporated within eosinophilic hyaline
membranes lining the respiratory bronchioles, alveolar ducts,
Hypoxemia + CO2 retention and alveoli. The membranes are largely made up of fibrin
admixed with cell debris derived chiefly from necrotic type II
pneumocytes. The sequence of events that leads to the forma-
Acidosis
tion of hyaline membranes is depicted in Figure 10-6. There is
a remarkable paucity of neutrophilic inflammatory reaction
Pulmonary
vasoconstriction associated with these membranes. The lesions of hyaline mem-
brane disease are never seen in stillborn infants.
Increased In infants who survive more than 48 hours, reparative
Pulmonary hypoperfusion diffusion
gradient
changes occur in the lungs. The alveolar epithelium proliferates
under the surface of the membrane, and may detach into
the airspace where it undergoes partial digestion or phagocy-
Endothelial Epithelial
damage damage tosis by macrophages.
Clinical Features. The classic clinical presentation before

Plasma leak Fibrin + necrotic cells the era of treatment with exogenous surfactant was
into alveoli (hyaline membrane) described earlier. Currently, the actual clinical course
Figure 10-6 Schematic outline of the pathophysiology of respiratory distress and prognosis for neonatal RDS vary, depending on the
syndrome (see text). maturity and birth weight of the infant and the promptness
Perinatal infections 459
of institution of therapy. A major thrust in the control of The pathogenesis of necrotizing enterocolitis is uncer-
RDS focuses on prevention, either by delaying labor until the tain, but is in all likelihood multifactorial. In addition
fetal lung reaches maturity or by inducing maturation of the to prematurity, most cases are associated with enteral
lung in the fetus at risk. Critical to these objectives is feeding, suggesting that some postnatal insult (such as
the ability to assess fetal lung maturity accurately. Because introduction of bacteria) sets in motion the cascade culmi-
pulmonary secretions are discharged into the amniotic nating in tissue destruction. While infectious agents likely
fluid, analysis of amniotic fluid phospholipids provides play a role in the pathogenesis of necrotizing enterocolitis,
a good estimate of the level of surfactant in the alveolar no single bacterial pathogen has been linked to the disease.
lining. Prophylactic administration of exogenous surfac- A large number of inflammatory mediators have been
tant at birth to extremely premature infants (gestational associated with necrotizing enterocolitis, and their discus-
age < 28 weeks) has been shown to be very beneficial, sion is beyond the scope of this book. One particular medi-
such that it is now uncommon for infants to die of ator, platelet activating factor (PAF), has been implicated
acute RDS. in increasing mucosal permeability by promoting entero-
In uncomplicated cases, recovery begins to occur within cyte apoptosis and compromising intercellular tight junc-
3 or 4 days. In affected neonates, oxygen is required. tions, thus adding “fuel to the fire.” Stool and serum
However, high concentration of ventilator-administered samples of infants with necrotizing enterocolitis demon-
oxygen for prolonged periods is associated with two well- strate higher PAF levels than age-matched controls.
known complications: retrolental fibroplasia (also called reti- Ultimately, breakdown of mucosal barrier functions
nopathy of prematurity) in the eyes, and bronchopulmonary permits transluminal migration of gut bacteria, leading to
dysplasia. Fortunately, both complications are now infre- a vicious cycle of inflammation, mucosal necrosis, and
quent as a result of gentler ventilation techniques, antena- further bacterial entry, eventually culminating in sepsis
tal glucocorticoid therapy, and prophylactic surfactant and shock (Chapter 4).
treatments. The clinical course is fairly typical, with the onset of
bloody stools, abdominal distention, and development
• Retinopathy of prematurity has a two-phase pathogen- of circulatory collapse. Abdominal radiographs often
esis. During the hyperoxic phase of RDS therapy (phase
I), expression of the proangiogenic vascular endothelial demonstrate gas within the intestinal wall (pneumatosis
growth factor (VEGF) is markedly decreased, causing intestinalis).
endothelial cell apoptosis; VEGF levels rebound after
return to relatively hypoxic room air ventilation (phase MORPHOLOGY
II), inducing retinal vessel proliferation (neovasculariza-
tion) characteristic of the lesions in the retina. Necrotizing enterocolitis typically involves the terminal ileum,
cecum, and right colon, although any part of the small or large
• The major abnormality in bronchopulmonary dysplasia is intestines may be involved. The involved segment is distended,
striking decrease in alveolar septation (manifested as
large, simplified alveolar structures) and a dysmorphic friable, and congested, or it can be frankly gangrenous; intes-
capillary configuration. Thus, the current view is that tinal perforation with accompanying peritonitis may be seen.
bronchopulmonary dysplasia is caused by a potentially Microscopically, mucosal or transmural coagulative necrosis,
reversible impairment in the development of alveolar ulceration, bacterial colonization, and submucosal gas bubbles
septation at the so-called “saccular” stage. Multiple may be seen (Fig. 10-8). Reparative changes, such as the
factors—hyperoxemia, hyperventilation, prematurity, formation of granulation tissue and fibrosis, may begin shortly
inflammatory cytokines, and vascular maldevelop- after the acute episode. When detected early on, necrotizing
ment—contribute to bronchopulmonary dysplasia and enterocolitis can be often managed conservatively, but many
probably act additively or synergistically to promote cases (20% to 60%) require resection of the necrotic segments
injury. The levels of a variety of proinflammatory cyto- of bowel. Necrotizing enterocolitis is associated with high
kines (TNF, interleukin-1β [IL-1β], IL-6, and IL-8) are perinatal mortality; those who survive often develop post-
increased in the alveoli of infants who develop broncho- necrotizing enterocolitis strictures from fibrosis caused by the
pulmonary dysplasia, suggesting a role for these cyto- healing process.
kines in arresting pulmonary development.
Infants who recover from RDS are also at increased risk
for developing a variety of other complications associated Perinatal Infections
with preterm birth; most important among these are patent
ductus arteriosus, intraventricular hemorrhage, and necrotizing In general, fetal and perinatal infections are acquired
enterocolitis. Thus, although technologic advances help through one of two primary routes—transcervically (also
save the lives of many infants with RDS, it also brings to referred to as ascending) or transplacentally (hemato-
the surface the exquisite fragility of the immature neonate. logic). Occasionally, infections occur by a combination of
the two routes in that an ascending microorganism infects
Necrotizing Enterocolitis the endometrium and then invades the fetal bloodstream
via the chorionic villi.
Necrotizing enterocolitis is most common in premature
infants, with the incidence of the disease being inversely Transcervical (Ascending) Infections
proportional to the gestational age. It occurs in approxi-
mately 1 out of 10 very low birth weight infants (<1500 gm). Most bacterial and a few viral (e.g., herpes simplex II)
Approximately 2500 cases occur annually in the United infections are acquired by the cervicovaginal route. Such
States. infections may be acquired in utero or around the time of
Figure 10-8 Necrotizing enterocolitis (NEC). A, Postmortem examination in a severe case of NEC shows the entire small bowel is markedly distended with a
perilously thin wall (usually this implies impending perforation). B, The congested portion of the ileum corresponds to areas of hemorrhagic infarction and
transmural necrosis microscopically. Submucosal gas bubbles (pneumatosis intestinalis) can be seen in several areas (arrows).
birth. In general the fetus acquires the infection either by The TORCH group of infections (see earlier) are grouped
inhaling infected amniotic fluid into the lungs shortly together because they may evoke similar clinical and
before birth or by passing through an infected birth pathologic manifestations, including fever, encephalitis,
canal during delivery. As stated before, preterm birth is chorioretinitis, hepatosplenomegaly, pneumonitis, myocarditis,
a common and unfortunate consequence of infection. hemolytic anemia, and vesicular or hemorrhagic skin lesions.
Preterm birth due to infection may be related either to Such infections occurring early in gestation may also cause
damage and rupture of the amniotic sac as a direct conse- chronic sequelae in the child, including growth and mental
quence of the inflammation or to the induction of labor retardation, cataracts, congenital cardiac anomalies, and
by prostaglandins released from infiltrating neutrophils. bone defects.
Inflammation of the placental membranes and cord are
usually seen, but the presence or absence and severity of Sepsis
chorioamnionitis do not necessarily correlate with the
severity of the fetal infection. In the fetus infected by inha- Perinatal sepsis can be grouped clinically based on early
lation of amniotic fluid, pneumonia, sepsis, and meningitis onset (within the first 7 days of life) versus late onset
are the most common sequelae. (from 7 days to 3 months). Most cases of early-onset sepsis
are acquired at or shortly before birth and tend to result in
Transplacental (Hematologic) Infections clinical signs and symptoms of pneumonia, sepsis, and
occasionally meningitis within 4 or 5 days of life. Group B
Most parasitic (e.g., toxoplasma, malaria) and viral infec-
tions and a few bacterial infections (i.e., Listeria, Treponema)
gain access to the fetal bloodstream transplacentally via the
chorionic villi. This hematogenous transmission may occur
at any time during gestation or occasionally, as may be the
case with hepatitis B and HIV, at the time of delivery via
maternal-to-fetal transfusion. The clinical manifestations of
these infections are highly variable, depending largely on
the gestational timing and microorganism involved.
Parvovirus B19, which causes erythema infectiosum
or “fifth disease of childhood” in immunocompetent older
children, can infect 1% to 5% of seronegative (non-immune)
pregnant women, and the vast majority have a normal
pregnancy outcome. Adverse pregnancy outcomes in a
minority of intrauterine infections include spontaneous
abortion (particularly in the second trimester), stillbirth,
hydrops fetalis (see later), and congenital anemia.
Parvovirus B19 has a particular tropism for erythroid cells, Figure 10-9 Bone marrow from an infant infected with parvovirus B19. The
and diagnostic viral inclusions can be seen in early ery- arrows indicate two erythroid precursors with large homogeneous intranu-
throid progenitors in infected infants (Fig. 10-9). clear inclusions and a surrounding peripheral rim of residual chromatin.
Fetal hydrops 461
streptococcus is the most common cause of early-onset

sepsis as well as early-onset bacterial meningitis. Infections Rh– MOTHER
with Listeria and Candida have longer latent periods
Previously sensitized to Rh antigen by transfusion or Rh+ fetus
between the time of microorganism inoculation and the
appearance of clinical symptoms and present as late-onset IgM
Stimulate antibody
sepsis. production against
Rh antigen
IgG
Fetal Hydrops
PLACENTA
Fetal hydrops refers to the accumulation of edema fluid
in the fetus during intrauterine growth. Until recently,
hemolytic anemia caused by Rh blood group incompatibil- Rh+ antigen
ity between mother and fetus (immune hydrops) was the
most common cause, but with the successful prophylaxis
of this disorder during pregnancy, causes of nonimmune
hydrops have emerged as the principal culprits (Table 10-3). Rh+ erythrocytes Antibody attachment
The intrauterine fluid accumulation can be quite variable, to Rh+ erythrocytes
from progressive, generalized edema of the fetus (hydrops
fetalis), a usually lethal condition, to more localized degrees FETUS Removal and destruction
of edema, such as isolated pleural and peritoneal effusions, With Rh+ erythrocytes of erythrocyte-antibody complex
or postnuchal fluid accumulation (cystic hygroma, see later)
that are compatible with life.
Anemia Hemoglobin
degradation
Immune Hydrops
Immune hydrops is a hemolytic disease caused by blood Extramedullary Cardiac Bilirubin
group antigen incompatibility between mother and fetus. hematopoiesis decompensation
When the fetus inherits red cell antigenic determinants
from the father that are foreign to the mother, a maternal
Hydrops Jaundice Kernicterus
Table 10-3 Selected Causes of Nonimmune Fetal Hydrops Figure 10-10 Pathogenesis of immune hydrops fetalis (see text).
Cardiovascular
Malformations
Tachyarrhythmia immune reaction may occur. The major antigens known to
High-output failure induce clinically significant immunologic reactions are certain
of the Rh antigens and the ABO blood groups. The reaction
Chromosomal
occurs in second and subsequent pregnancies in an
Turner syndrome Rh-negative mother with an Rh-positive father.
Trisomy 21, trisomy 18
Thoracic Causes Etiology and Pathogenesis. The underlying basis of
Cystic adenomatoid malformation immune hydrops is the immunization of the mother by
Diaphragmatic hernia blood group antigens on fetal red cells and the free passage
Fetal Anemia of antibodies from the mother through the placenta to the
fetus (Fig. 10-10). Fetal red cells may reach the maternal
Homozygous α-thalassemia
circulation during the last trimester of pregnancy, when
Parvovirus B19
Immune hydrops (Rh and ABO) the cytotrophoblast is no longer present as a barrier, or
during childbirth itself. The mother thus becomes sensi-
Twin Gestation tized to the foreign antigen. The initial exposure to Rh
Twin-to-twin transfusion antigen evokes the formation of IgM antibodies,that unlike
Infection (excluding parvovirus) IgG antibodies, do not cross the placenta. Thus, Rh disease
is uncommon with the first pregnancy. Exposure during a
Cytomegalovirus
Syphilis subsequent pregnancy generally leads to a brisk IgG anti-
Toxoplasmosis body response and the risk of immune hydrops.
Of the numerous antigens included in the Rh system,
Genitourinary Tract Malformations only the D antigen is a major cause of Rh incompat-
Tumors ibility. Several factors influence the immune response
Genetic/Metabolic Disorders to Rh-positive fetal red cells that reach the maternal
The cause of fetal hydrops may be undetermined (“idiopathic”) in up to 20% of cases.
circulation.
Data from Machin GA: Hydrops, cystic hygroma, hydrothorax, pericardial effusions, and fetal
ascites. In Gilbert-Barness E, et al (eds): Potter’s Pathology of the Fetus, Infant, and Child.
St. Louis, Mosby, 2007, p 33.
• Concurrent ABO incompatibility protects the mother
against Rh immunization, because the fetal red cells
are promptly coated and removed from the maternal • Jaundice develops because hemolysis produces uncon-
circulation by anti-A or anti-B IgM antibodies that do jugated bilirubin (Chapter 18). Bilirubin also passes
not cross the placenta. through the infant’s poorly developed blood-brain
• The antibody response depends on the dose of immu- barrier. Being water insoluble, bilirubin blinds to lipids
nizing antigen; hence, hemolytic disease develops only in the brain, and can damage the CNS, causing kernic-
when the mother has experienced a significant transpla- terus (see Fig. 10-13).
cental bleed (>1 mL of Rh-positive fetal red cells).
Nonimmune Hydrops
The incidence of maternal Rh isoimmunization has
decreased significantly since the use of Rhesus immune The three major causes of nonimmune hydrops include
globulin (RhIg) containing anti-D antibodies. Admin- cardiovascular defects, chromosomal anomalies, and
istration of RhIg at 28 weeks and within 72 hours of deliv- fetal anemia (Table 10-3). Both structural and functional
ery to Rh-negative mothers significantly decreases the risk cardiovascular defects, such as congenital malformations
for hemolytic disease in Rh-positive neonates and in sub- and arrhythmias, may result in intrauterine cardiac failure
sequent pregnancies; RhIg is also administered following and hydrops. Among the chromosomal anomalies, 45,X
abortions, because these too can lead to immunization. karyotype (Turner syndrome) and the trisomies 21 and 18
Antenatal identification and management of the at-risk are associated with fetal hydrops because of the accompa-
fetus have been greatly facilitated by amniocentesis and nying structural cardiac anomalies. In Turner syndrome,
the advent of chorionic villus and fetal blood sampling. In abnormalities of lymphatic drainage from the neck may
addition, cloning of the RHD gene has resulted in efforts lead to postnuchal fluid accumulation (cystic hygromas) as
to determine fetal Rh status using maternal serum since it well. Fetal anemia, not caused by Rh- or ABO-associated
contains fetal DNA. When identified, cases of severe intra- antibodies, can also result in hydrops. In fact, in some parts
uterine hemolysis may be treated by fetal intravascular of the world (e.g., Southeast Asia), severe fetal anemia due
transfusions via the umbilical cord and early delivery. to homozygous α-thalassemia, resulting from deletion of
The pathogenesis of fetal hemolysis caused by maternal- all four α-globin genes, is probably the most common
fetal ABO incompatibility is slightly different from that cause of nonimmune hydrops (Chapter 14). Transplacental
caused by differences in the Rh antigens. ABO incompati- infection by parvovirus B19 is rapidly emerging as an
bility occurs in approximately 20% to 25% of pregnancies, important cause of hydrops (see earlier). The virus gains
but laboratory evidence of hemolytic disease occurs in only preferential entry into erythroid precursors (normoblasts),
1 in 10 of such infants, and the hemolytic disease is severe where it replicates, leading to apoptosis of red cell progeni-
enough to require treatment in only 1 in 200 cases. Several tors and isolated red cell aplasia. Parvoviral intranuclear
factors account for this. First, as mentioned, most anti-A inclusions can be seen within circulating and marrow
and anti-B antibodies are of the IgM type and hence do not erythroid precursors (Fig. 10-9). Approximately 10% of
cross the placenta. Second, neonatal red cells express blood cases of nonimmune hydrops are related to monozygous
group antigens A and B poorly. Third, many cells other twin pregnancies and twin-to-twin transfusion occurring
than red cells express A and B antigens and thus absorb through anastomoses between the two circulations.
some of the transferred antibody. ABO hemolytic disease
occurs almost exclusively in infants of group A or B who
are born of group O mothers. For reasons unknown, certain
group O women possess IgG antibodies directed against MORPHOLOGY
group A or B antigens (or both) even without prior
The anatomic findings in fetuses with intrauterine fluid accumu-
sensitization. Therefore, the firstborn may be affected.
lation vary with both the severity of the disease and the underly-
Fortunately, even with transplacentally acquired antibod-
ing etiology. As previously noted, hydrops fetalis represents the
ies, lysis of the infant’s red cells is minimal. There is no
most severe and generalized manifestation (Fig. 10-11), and
effective protection against ABO reactions.
lesser degrees of edema such as isolated pleural, peritoneal, or
There are two consequences of excessive destruction of
postnuchal fluid collections can occur. Accordingly, infants may
red cells in the neonate (Fig. 10-10). The severity of these
be stillborn, die within the first few days, or recover completely.
changes varies considerably, depending on the degree of
The presence of dysmorphic features suggests a chromosomal
hemolysis and the maturity of the infant.
abnormality; postmortem examination may reveal an underlying
cardiac anomaly.
• Anemia is a direct result of red cell loss. If hemolysis
In hydrops associated with fetal anemia, both fetus and
is mild, increased red cell production may suffice to
placenta are characteristically pale; in most cases the liver
maintain near normal levels of red cells. However, with
and spleen are enlarged from cardiac failure and congestion.
more severe hemolysis, progressive anemia develops
Additionally, the bone marrow demonstrates compensatory
and may result in hypoxic injury to the heart and liver.
hyperplasia of erythroid precursors (parvovirus-associated red
Because of liver injury, plasma protein synthesis
cell aplasia being a notable exception), and extramedullary
decreases, and levels of these proteins may drop to as
hematopoiesis is present in the liver, spleen, and lymph nodes,
low as 2 to 2.5 mg/dL. Cardiac hypoxia may lead to
and possibly other tissues such as the kidneys, lungs, and even
cardiac decompensation and failure. The combination of
the heart. The increased hematopoietic activity accounts for the
reduced plasma oncotic pressure and increased hydro-
presence in the peripheral circulation of large numbers of imma-
static pressure in the circulation (secondary to cardiac
ture red cells, including reticulocytes, normoblasts, and eryth-
failure) results in generalized edema and anasarca, cul-
roblasts (erythroblastosis fetalis) (Fig. 10-12).
minating in hydrops fetalis.
Fetal hydrops 463
A B
Figure 10-11 Hydrops fetalis. A, There is generalized accumulation of fluid in the fetus. B, Fluid accumulation is particularly prominent in the soft tissues of
the neck, and this condition has been termed cystic hygroma. Cystic hygromas are characteristically seen, but not limited to, constitutional chromosomal
anomalies such as 45,X karyotypes. (Courtesy Dr. Beverly Rogers, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.)
infants display pallor, possibly accompanied by hepato-

The most serious threat in fetal hydrops is CNS damage, splenomegaly (to which may be added jaundice with
known as kernicterus (Fig. 10-13). The affected brain is more severe hemolytic reactions), whereas the most gravely
enlarged and edematous and, when sectioned, has a bright ill neonates present with intense jaundice, generalized
yellow color, particularly the basal ganglia, thalamus, cerebel- edema, and signs of neurologic injury. These infants
lum, cerebral gray matter, and spinal cord. The precise level of may be supported by a variety of measures, including
bilirubin that induces kernicterus is unpredictable, but neural phototherapy (visual light oxidizes toxic unconjugated
damage usually requires a blood bilirubin level greater than bilirubin to harmless, readily excreted, water-soluble
20 mg/dL in term infants; in premature infants this threshold dipyrroles) and, in severe cases, total exchange transfusion
may be considerably lower. of the infant.
Clinical Features. The clinical manifestations of fetal

hydrops vary with the severity of the disease and can be
inferred from the preceding discussion. Minimally affected
Figure 10-12 Numerous islands of extramedullary hematopoiesis (small blue Figure 10-13 Kernicterus. Note the yellow discoloration of the brain paren-
cells) are scattered among mature hepatocytes in the liver of this infant with chyma due to bilirubin accumulation, which is most prominent in the basal
nonimmune hydrops fetalis. ganglia deep to the ventricles.
Phenylalanine
Inborn Errors of Metabolism and + O2
Tetrahydro-
biopterin
NAD
Other Genetic Disorders Phenylalanine (BH4) Dihydropteridine

hydroxylase reductase
Inborn errors of metabolism are well-characterized genetic (PAH) (DHPR)
abnormalities that give rise to metabolic disorders. Since Tyrosine Dihydro- NADH
Sir Archibald Garrod coined the term in 1908, the number + H2O biopterin
of such diseases that have been recognized has increased
Figure 10-14 The phenylalanine hydroxylase system. Deficiency of PAH and
exponentially and a comprehensive discussion of these dis- DHPR can give rise to phenylketonuria.
eases is beyond the scope of this chapter. Most inborn errors
of metabolism are rare diseases that are generally inherited
as autosomal recessive or X-linked traits (Chapter 5). Mito- Phenylketonuria (PKU) is an autosomal recessive
chondrial disorders (Chapter 5) form a distinct entity by disorder caused by a severe deficiency of the enzyme
themselves. Some of the clinical features that suggest an phenylalanine hydroxylase (PAH) and the resultant
underlying metabolic disorder in a neonate are listed in hyperphenylalaninemia. Affected infants are normal at
Table 10-4. Three genetic disorders of metabolism, phenyl- birth but within a few weeks develop a rising plasma phe-
ketonuria (PKU), galactosemia, and cystic fibrosis, are nylalanine level, which impairs brain development. Usually
selected for discussion here. PKU and galactosemia by 6 months of life severe mental retardation becomes evident;
are reviewed because their early diagnosis (via neonatal fewer than 4% of untreated phenylketonuric children have
screening programs) is particularly important and with IQs greater than 50 or 60. About one third of these children
appropriate dietary regimens early death or mental retar- are never able to walk, and two thirds cannot talk. Seizures,
dation can be prevented. Cystic fibrosis is included because other neurologic abnormalities, decreased pigmentation of
it is one of the most common, potentially lethal diseases hair and skin, and eczema often accompany the mental retar-
occurring in individuals of Caucasian descent. dation in untreated children. Hyperphenylalaninemia and
the resultant mental retardation can be avoided by restrict-
Phenylketonuria ing phenylalanine intake early in life. Hence, several
screening procedures are routinely performed to detect
There are several variants of this inborn error of metabo- PKU in the immediate postnatal period.
lism, which affects 1 in 10,000 live-born Caucasian infants. Many female PKU patients, if treated with dietary re-
The most common form, referred to as classic phenylketon- striction early in life, reach childbearing age and are
uria, is quite common in persons of Scandinavian descent clinically asymptomatic. Most of them have marked hyper-
and is distinctly uncommon in African American and phenylalaninemia, because dietary treatment is discontin-
Jewish populations. ued after they reach adulthood. Between 75% and 90% of
children born to such women are mentally retarded and
microcephalic, and 15% have congenital heart disease,
Table 10-4 Abnormalities Suggesting Inborn Errors of Metabolism even though the infants themselves are heterozygotes. This
General syndrome, termed maternal PKU, results from the terato-
Dysmorphic features genic effects of phenylalanine or its metabolites that cross
Deafness the placenta and affect specific fetal organs during devel-
Self-mutilation opment. The presence and severity of the fetal anomalies
Abnormal hair directly correlate with the maternal phenylalanine level,
Abnormal body or urine odor (“sweaty feet”; “mousy or musty”; “maple syrup”) so it is imperative that maternal dietary restriction of phenylala-
Hepatosplenomegaly; cardiomegaly nine be initiated before conception and continued throughout
Hydrops
pregnancy.
Neurologic The biochemical abnormality in PKU is an inability to
Hypotonia or hypertonia convert phenylalanine into tyrosine. In normal children,
Coma less than 50% of the dietary intake of phenylalanine is
Persistent lethargy necessary for protein synthesis. The remainder is converted
Seizures to tyrosine by the phenylalanine hydroxylase system (Fig.
Gastrointestinal 10-14). When phenylalanine metabolism is blocked because
Poor feeding
of a lack of PAH enzyme, minor shunt pathways come into
Recurrent vomiting play, yielding several intermediates that are excreted in
Jaundice large amounts in the urine and in the sweat. These impart
a strong musty or mousy odor to affected infants. It is be-
Eyes
lieved that excess phenylalanine or its metabolites contrib-
Cataract ute to the brain damage in PKU. Concomitant lack of
Cherry red macula
tyrosine (Fig. 10-14), a precursor of melanin, is responsible
Dislocated lens
Glaucoma for the light color of hair and skin.
At the molecular level, approximately 500 mutant alleles
Muscle, Joints of the PAH gene have been identified, only some of which
Myopathy cause a severe deficiency of the enzyme and thus result in
Abnormal mobility classic PKU. Infants with mutations resulting in a complete
Adapted from Barness LA, Gilbert-Barness E: Metabolic diseases. In Gilbert-Barness E, et al lack of PAH activity present with the classic features of
(eds): Potter’s Pathology of the Fetus, Infant, and Child. St. Louis, Mosby, 2007.
PKU, while those with up to 6% residual activity present
Inborn errors of metabolism and other genetic disorders 465
Galactokinase
REACTION 1 Galactose + ATP Galactose-1-phosphate + ADP
Galactose-1-phosphate
uridyl transferase
REACTION 2 Galactose-1-phosphate UDP-galactose + glucose-1-phosphate
+
UDP-glucose
UDP-galactose-4-epimerase
REACTION 3 UDP-galactose UDP-glucose
Figure 10-15 Pathways of galactose metabolism. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; UDP, uridine diphosphate.
with milder disease. Moreover, some mutations result in been variously imputed to these metabolic intermediates.
only modest elevations of blood phenylalanine levels Heterozygotes may have a mild enzyme deficiency but are
without associated neurologic damage. This latter condi- spared the clinical and pathologic consequences of the
tion, referred to as benign hyperphenylalaninemia, is impor- homozygous state.
tant to recognize, because these individuals may well have The clinical picture is variable, probably reflecting the
positive screening tests but do not develop the stigmata of heterogeneity of mutations in the galactose-1-phosphate
classic PKU. Because of the numerous disease-causing uridyl transferase gene. The liver, eyes, and brain bear the
alleles of the phenylalanine hydroxylase gene, molecular brunt of the damage. The early-to-develop hepatomegaly is
diagnosis is not feasible, and measurement of serum phe- due largely to fatty change, but in time widespread scar-
nylalanine levels is necessary to differentiate benign hyper- ring that closely resembles the cirrhosis of alcohol abuse
phenylalaninemia from PKU; the levels in the latter are may supervene (Fig. 10-16). Opacification of the lens (cataract)
typically five-fold or more above normal. Once a biochemi- develops, probably because the lens absorbs water and
cal diagnosis is established, the specific mutation causing swells as galactitol, produced by alternative metabolic
PKU can be determined. With the identification of the pathways, accumulates and increases osmotic pressure.
mutation, carrier testing of at-risk family members can be Nonspecific alterations appear in the CNS, including loss
performed. of nerve cells, gliosis, and edema, particularly in the dentate
While 98% of PKU is attributable to mutations in PAH, nuclei of the cerebellum and the olivary nuclei of the medulla.
approximately 2% occur due to abnormalities in synthesis Similar changes may occur in the cerebral cortex and white
or recycling of the cofactor tetrahydrobiopterin BH4 (Fig. matter.
10-14). It is clinically important to recognize these variant forms These infants fail to thrive almost from birth. Vomiting
of PKU, because they cannot be treated by dietary restriction of and diarrhea appear within a few days of milk ingestion.
phenylalanine. Jaundice and hepatomegaly usually become evident during
the first week of life and may seem to be a continuation of
Galactosemia the physiologic jaundice of the newborn. The cataracts
develop within a few weeks, and within the first 6 to 12
Galactosemia is an autosomal recessive disorder of galac- months of life mental retardation may be detected. Even in
tose metabolism resulting from accumulation of galac-
tose-1-phosphate in tissues. Normally, lactose, the major
carbohydrate of mammalian milk, is split into glucose and
galactose in the intestinal microvilli by lactase. Galactose
is then converted to glucose in three steps (Fig. 10-15). Two
variants of galactosemia have been identified. In the more common
variant there is a total lack of galactose-1-phosphate uridyl trans-
ferase (also known as GALT) involved in reaction 2. The rare
variant arises from a deficiency of galactokinase, involved in
reaction 1. Because galactokinase deficiency leads to a
milder form of the disease not associated with mental
retardation, it is not considered in this discussion. As a
result of the transferase deficiency, galactose-1-phosphate
accumulates in many locations, including the liver, spleen,
lens of the eye, kidneys, heart muscle, cerebral cortex, and
erythrocytes. Alternative metabolic pathways are acti-
vated, leading to the production of galactitol (a polyol
metabolite of galactose) and galactonate, an oxidized Figure 10-16 Galactosemia. The liver shows extensive fatty change and a
by-product of excess galactose, both of which also accumu- delicate fibrosis. (Courtesy Dr. Wesley Tyson, The Children’s Hospital,
late in the tissues. Long-term toxicity in galactosemia has Denver, Colo.)
untreated infants, however, the mental deficit is usually Cl–

not as severe as that seen in PKU. Accumulation of galac- Agonist
Glycosylation
tose and galactose-1-phosphate in the kidney impairs
amino acid transport, resulting in aminoaciduria. There is
an increased frequency of fulminant Escherichia coli septice-
mia, possibly arising from depressed neutrophil bacteri-
cidal activity. Hemolysis and coagulopathy in the newborn
period can occur as well. N R
NBD
Many of the clinical and morphologic changes of galac- domain NORMAL NBD
tosemia can be prevented or ameliorated by early removal CFTR
of galactose from the diet for at least the first 2 years of life. ATP C
P
Control instituted soon after birth prevents the cataracts ATP
and liver damage and permits almost normal develop-
cAMP
ment. Even with dietary restrictions, however, it is now ATP
established that older patients are frequently affected
by a speech disorder and gonadal failure (especially pre- Protein kinase A CFTR
mature ovarian failure) and, less commonly, ataxia.
Processing
Cystic Fibrosis (Mucoviscidosis)
Golgi
Cystic fibrosis is an inherited disorder of ion transport
that affects fluid secretion in exocrine glands and in the
epithelial lining of the respiratory, gastrointestinal, and
reproductive tracts. In many individuals this disorder
leads to abnormally viscous secretions that obstruct organ
passages, resulting in most of the clinical features of this
Chromosome 7
disorder, such as chronic lung disease secondary to recurrent
infections, pancreatic insufficiency, steatorrhea, malnutrition, Nucleus
hepatic cirrhosis, intestinal obstruction, and male infertility.
These manifestations may appear at any point in life from Figure 10-17 Top, Normal cystic fibrosis transmembrane conductance regu-
before birth to much later in childhood or even in lator (CFTR) structure and activation. CFTR consists of two transmembrane
domains, two nucleotide-binding domains (NBDs), and a regulatory R
adolescence.
domain. Agonists (e.g., acetylcholine) bind to epithelial cells and increase
With an incidence of 1 in 2500 live births, cystic fibrosis cyclic adenosine monophosphate (cAMP), which activates protein kinase A,
is the most common lethal genetic disease that affects Caucasian the latter phosphorylating the CFTR at the R domain using ATP. This results
populations. The carrier frequency in the United States is 1 in opening of the chloride channel. Bottom, CFTR from gene to protein. The
in 20 among Caucasians but significantly lower in African most common mutation in the CFTR gene results in defective protein folding
Americans, Asians, and Hispanics. Although cystic fibrosis in the Golgi/endoplasmic reticulum and degradation of CFTR before it
follows an autosomal recessive transmission pattern, recent reaches the cell surface. Other mutations affect synthesis of CFTR, NBDs,
data suggest that even heterozygote carriers have a higher inci- and R domains, as well as membrane-spanning domains. (See text for
details.)
dence of respiratory and pancreatic diseases as compared with
the general population. In addition, despite the classifica-
tion of cystic fibrosis as a “mendelian” disorder, there is a
wide degree of phenotypic variation that results from phosphorylates the R domain. Adenosine triphosphate
diverse mutations in the gene associated with cystic fibro- (ATP) binding and hydrolysis occurs at the NBD and
sis, the tissue-specific effects of the encoded gene product, is essential for the opening and closing of the channel
and the influence of so-called modifier genes. pore in response to cAMP-mediated signaling. Several
important facets of CFTR function have emerged in recent
Cystic Fibrosis Gene: Normal Structure and Function. In years:
normal duct epithelia, chloride is transported by plasma
membrane channels (chloride channels). The primary • CFTR regulates multiple additional ion channels and cellular
defect in cystic fibrosis results from abnormal function processes. Although initially characterized as a chloride-
of an epithelial chloride channel protein encoded by the conductance channel, it is now recognized that CFTR
cystic fibrosis transmembrane conductance regulator can regulate multiple ion channels and cellular pro-
(CFTR) gene on chromosome 7q31.2. The 1480-amino acid cesses, primarily through interactions involving its
polypeptide encoded by CFTR has two transmembrane NBDs. These include so-called outwardly rectified chlo-
domains (each containing six α-helices), two cytoplasmic ride channels, inwardly rectified potassium channels
nucleotide-binding domains (NBDs), and a regulatory (Kir6.1), the epithelial sodium channel (ENaC), gap
domain (R domain) that contains protein kinase A and C junction channels, and cellular processes involved in
phosphorylation sites (Fig. 10-17). The two transmembrane ATP transport and mucus secretion. Of these, the inter-
domains form a channel through which chloride passes. action of CFTR with the ENaC has possibly the most
Activation of the CFTR channel is mediated by agonist- pathophysiologic relevance in cystic fibrosis. The ENaC
induced increases in cyclic adenosine monophosphate is situated on the apical surface of exocrine epithelial
(cAMP), followed by activation of a protein kinase A that cells and is responsible for sodium uptake from the
LUMEN OF SWEAT DUCT

NORMAL CYSTIC FIBROSIS
Cl– Na+ Cl– Na+
CFTR ENaC
Epithelial cells
AIRWAY
NORMAL CYSTIC FIBROSIS
Normal mucus Dehydrated mucus
Cl– Na+ H2O Cl– Na+ H2O

Epithelial cells
Figure 10-18 Chloride channel defect in the sweat duct (top) causes increased chloride and sodium concentration in sweat. In the airway (bottom), patients
with cystic fibrosis have decreased chloride secretion and increased sodium and water reabsorption leading to dehydration of the mucus layer coating epithelial
cells, defective mucociliary action, and mucus plugging of airways. CFTR, Cystic fibrosis transmembrane conductance regulator; ENaC, epithelial sodium
channel.
luminal fluid, rendering it (the luminal fluid) hypotonic. there is no difference in the salt concentration of the
The ENaC is inhibited by normally functioning CFTR; surface fluid layer coating the respiratory and intestinal
hence, in cystic fibrosis, ENaC activity increases, markedly mucosal cells in normal individuals versus those with
augmenting sodium uptake across the apical membrane. The cystic fibrosis. Instead, the pathogenesis of respiratory and
importance of this phenomenon is discussed later in the intestinal complications in cystic fibrosis seems to stem from
context of pulmonary and gastrointestinal pathology in an isotonic but low-volume surface fluid layer. In the lungs,
cystic fibrosis. The one exception to this rule happens to this dehydration leads to defective mucociliary action
be the human sweat ducts, where ENaC activity decreases and the accumulation of hyperconcentrated, viscid
as a result of CFTR mutations; therefore, a hypertonic secretions that obstruct the air passages and predispose
luminal fluid containing high sweat sodium chloride to recurrent pulmonary infections.
(the sine qua non of classic cystic fibrosis) is formed. This • CFTR regulates transport of bicarbonate ions. The bicarbon-
is the basis for the “salty” sweat that mothers can often ate transport function of CFTR is mediated by reciprocal
detect in their affected infants. interactions with a family of anion exchangers called
• The functions of CFTR are tissue-specific; therefore, the SLC26, which are co-expressed on the apical surface
impact of a mutation in CFTR is also tissue-specific. The with CFTR. In some CFTR mutants chloride transport is
major function of CFTR in the sweat gland ducts is to completely or substantially preserved, while bicarbonate
reabsorb luminal chloride ions and augment sodium transport is markedly abnormal. Alkaline fluids are secreted
reabsorption via the ENaC (see earlier). Therefore, in the by normal tissues, in contrast fluids that are acidic (due
sweat ducts, loss of CFTR function leads to decreased to absence of bicarbonate ions) are secreted by epithelia
reabsorption of sodium chloride and production of harboring these mutant CFTR alleles. The acidity of
hypertonic sweat (Fig. 10-18). However, in the respira- secretions results in decreased luminal pH that can lead
tory and intestinal epithelium, the CFTR is one of the most to a variety of adverse effects such as increased mucin
important avenues for active luminal secretion of chloride. precipitation and plugging of ducts, and increased
At these sites, CFTR mutations result in loss or reduc- binding of bacteria to plugged mucins. Pancreatic insuf-
tion of chloride secretion into the lumen (Fig. 10-18). ficiency, a feature of classic cystic fibrosis, is virtually always
Active luminal sodium absorption is increased (due to present when there are CFTR mutations with abnormal bicar-
loss of inhibition of ENaC activity), and both of these bonate conductance.
ion changes increase passive water reabsorption from
the lumen, lowering the water content of the surface fluid Cystic Fibrosis Gene: Mutational Spectra and Genotype-
layer coating mucosal cells. Thus, unlike the sweat ducts, Phenotype Correlation. Since the CFTR gene was cloned
Sweat test Clinical phenotype Molecular phenotype

Positive Classical Cystic Fibrosis Severe
Bronchiectasis; pancreatic insufficiency;
male infertility; hepatic cirrhosis
Meconium ileus; pancreatic insufficiency;

mild lung disease
Bronchiectasis; pancreatic
insufficiency; male infertility
Abnormal
Mild lung disease; polyposis; CFTR
pancreatic insufficiency
Sinusitis; absent
vas deferens
Azoospermia
(Normal
female)
Negative Mild
Figure 10-19 The many clinical manifestations of mutations in the cystic fibrosis gene, from most severe to asymptomatic. (Redrawn from Wallis C: Diagnosing
cystic fibrosis: blood, sweat, and tears. Arch Dis Child 76:85, 1997.)
in 1989, more than 1800 disease-associated mutations have regulation of multiple distinct cellular ion channels, of
been identified. The mutations can be grouped into six which its role in regulating bicarbonate secretion
classes based on their effect on the CFTR protein: through relevant apical channels is required for main-
taining luminal pH balance. Mutations in this class
• Class I: Defective protein synthesis. These mutations are
affect the regulatory role of CFTR. In some cases, a given
associated with complete lack of CFTR protein at the
apical surface of epithelial cells. mutation affects the conductance by CFTR as well as
regulation of other ion channels. For example, the ΔF508
• Class II: Abnormal protein folding, processing, and traffick-
mutation is both a class II and class VI mutation.
ing. These mutations result in defective processing of
the protein from the endoplasmic reticulum to the Golgi
Because cystic fibrosis is an autosomal recessive disease,
apparatus; the protein does not become fully folded and
affected individuals harbor mutations on both alleles.
glycosylated and is instead degraded before it reaches
However, the nature of mutations on each of the two alleles
the cell surface. The most common class II mutation is
can have a remarkable effect on the overall phenotype, as
a deletion of three nucleotides coding for phenylalanine
well as on organ-specific manifestations (Fig. 10-19). Thus,
at amino acid position 508 (ΔF508). Worldwide, this
two “severe” mutations (for example, a combination of
mutation can be found in approximately 70% of cystic
Class I, II or III mutations in any permutation) that produce
fibrosis patients. Class II mutations are also associated
virtual absence of membrane CFTR function are associated
with complete lack of CFTR protein at the apical surface
with the classic cystic fibrosis phenotype (pancreatic insuf-
of epithelial cells.
ficiency, sinopulmonary infections, and gastrointestinal
• Class III: Defective regulation. Mutations in this class symptoms), while the presence of a “mild” (class IV or V)
prevent activation of CFTR by abrogating ATP binding mutation on one or both alleles results in a less severe
and hydrolysis, an essential prerequisite for ion trans- phenotype. This general dictum of genotype-phenotype
port (see earlier). Thus, there is a normal amount of correlation is most consistent for pancreatic disease,
CFTR on the apical surface, but it is nonfunctional. wherein the presence of one allele with a mild mutation
• Class IV: Decreased conductance. These mutations typi- associated with some CFTR activity can prevent the
cally occur in the transmembrane domain of CFTR, pancreatic insufficiency that is virtually always seen
which forms the ionic pore for chloride transport. There with homozygosity for “severe” mutations. By contrast,
is a normal amount of CFTR at the apical membrane, genotype-phenotype correlations are far less consistent in
but with reduced function. This class is usually associ- pulmonary disease, due to the effect of secondary modifi-
ated with a milder phenotype. ers (see later). As genetic testing for CFTR mutations has
• Class V: Reduced abundance. These mutations typically expanded, it has become evident that some patients who present
affect intronic splice sites or the CFTR promoter, such with clinical features apparently unrelated to cystic fibrosis may
that there is a reduced amount of normal protein. As also harbor CFTR mutations. These include individuals with
discussed subsequently, class V mutations are also asso- idiopathic chronic pancreatitis, late-onset chronic pulmonary
ciated with a milder phenotype. disease, idiopathic bronchiectasis, and obstructive azoospermia
• Class VI: Altered function in regulation of ion channels. caused by bilateral absence of the vas deferens (see detailed
As previously described, CFTR is involved in the discussion of individual phenotypes later). Most of these
patients do not demonstrate other features of cystic

fibrosis, despite the presence of bi-allelic CFTR mutations;
these patients are classified as having nonclassic or atypical
cystic fibrosis. Identifying these individuals is important not
only for subsequent management, but also for genetic
counseling.
Genetic and Environmental Modifiers. Although cystic

fibrosis remains one of the best-known examples of the
“one gene, one disease” axiom, there is now considerable
evidence that genes other than CFTR modify the
frequency and severity of certain organ-specific mani-
festations, especially pulmonary manifestations and
neonatal meconium ileus. Not surprisingly, polymor-
phisms in genes whose products modulate neutrophil
function in response to bacterial infections act as modifier
Figure 10-20 Pancreas in cystic fibrosis. The ducts are dilated and plugged
loci for the severity of pulmonary disease in cystic fibrosis. with eosinophilic mucin, and the parenchymal glands are atrophic and
Examples of such modifier genes include mannose binding replaced by fibrous tissue.
lectin 2 (MBL2), transforming growth factor β1 (TGFB1)
and interferon related developmental regulator 1 (IFRD1). It
is postulated that polymorphisms in these genes regulate
development. In others, the pancreatic involvement is severe
the resistance of the lungs to exogenous infections with
and impairs intestinal absorption because of the pancreatic
virulent microbes (see later), thus modifying the natural
insufficiency (Chapter 19), and so malabsorption stunts devel-
history of cystic fibrosis. Similarly, several other genetic
opment and post-natal growth. In others, the mucus secretion
modifiers appear to influence the incidence of meconium
defect leads to defective mucociliary action, obstruction of
ileus in cystic fibrosis, although the degree of association
bronchi and bronchioles, and crippling fatal pulmonary infec-
is less stringent than that observed for pulmonary
tions. In all variants, the sweat glands are morphologically
manifestations.
unaffected.
Environmental modifiers may also explain the signifi-
Pancreatic abnormalities are present in approximately
cant phenotypic differences between individuals who
85% to 90% of patients with cystic fibrosis. In the milder cases,
share the same CFTR genotype. This is best exemplified in
there may be only accumulations of mucus in the small ducts
pulmonary disease, where CFTR genotype and phenotype
with some dilation of the exocrine glands. In more severe cases,
correlations can be perplexing. As stated earlier, defective
usually seen in older children or adolescents, the ducts are
mucociliary action because of deficient hydration of the
completely plugged, causing atrophy of the exocrine glands
mucus results in an inability to clear bacteria from the
and progressive fibrosis (Fig. 10-20). Atrophy of the exocrine
airways. Pseudomonas aeruginosa species, in particular,
portion of the pancreas may occur, leaving only the islets within
colonize the lower respiratory tract, first intermittently
a fibrofatty stroma. The loss of pancreatic exocrine secretion
and then chronically. Concurrent viral infections predis-
impairs fat absorption, and the associated avitaminosis A may
pose to such colonization. The static mucus creates a
contribute to squamous metaplasia of the lining epithelium of
hypoxic microenvironment in the airway surface fluid,
the ducts in the pancreas, which are already injured by the
which in turn favors the production of alginate, a mucoid
inspissated mucus secretions. Thick viscid plugs of mucus
polysaccharide capsule, by the colonizing bacteria. Alginate
may also be found in the small intestine of infants. Sometimes
production permits the formation of a biofilm that protects
these cause small-bowel obstruction, known as meconium
the bacteria from antibodies and antibiotics, allowing
ileus.
them to evade host defenses, and produce a chronic
The liver involvement follows the same basic pattern. Bile
destructive lung disease. Antibody- and cell-mediated
canaliculi are plugged by mucus material, accompanied by
immune reactions induced by the organisms result in
ductular proliferation and portal inflammation. Hepatic steato-
further pulmonary destruction, but are ineffective against
sis is not an uncommon finding in liver biopsies. Over time,
the organism. It is evident, therefore, that in addition to
focal biliary cirrhosis develops in approximately a third of
genetic factors (e.g., class of mutation), a plethora of envi-
patients (Chapter 18), which can eventually involve the entire
ronmental modifiers (e.g., virulence of organisms, efficacy
liver, resulting in diffuse hepatic nodularity. Such severe hepatic
of therapy, intercurrent and concurrent infections by other
involvement is encountered in less than 10% of patients.
organisms, exposure to tobacco and allergens) can influ-
The salivary glands frequently show histologic changes
ence the severity and progression of lung disease in cystic
similar to those described in the pancreas: progressive dilation
fibrosis.
of ducts, squamous metaplasia of the lining epithelium, and
glandular atrophy followed by fibrosis.
The pulmonary changes are the most serious complica-
MORPHOLOGY tions of this disease (Fig. 10-21). These stem from the viscous
mucus secretions of the submucosal glands of the respiratory
The anatomic changes are highly variable in distribution and tree leading to secondary obstruction and infection of the
severity. In individuals with nonclassic cystic fibrosis, the disease air passages. The bronchioles are often distended with thick
is quite mild and does not seriously disturb their growth and mucus associated with marked hyperplasia and hypertrophy of
quadrant pain sometimes associated with a palpable mass

of meconium, with or without associated intussusception,
in the right iliac fossa.
Exocrine pancreatic insufficiency occurs in the majority
(85% to 90%) of patients with cystic fibrosis and is associ-
ated with “severe” CFTR mutations on both alleles (e.g.,
ΔF508/ΔF508), whereas 10% to 15% of patients with one
“severe” and one “mild” CFTR mutation (ΔF508/R117H)
or two “mild” CFTR mutations retain enough pancreatic
exocrine function so as not to require enzyme supplemen-
tation (pancreas-sufficient phenotype). Pancreatic insuffi-
ciency is associated with protein and fat malabsorption
and increased fecal loss. Manifestations of malabsorption
(e.g., large, foul-smelling stools, abdominal distention, and
poor weight gain) may appear during the first year of life.
The faulty fat absorption may induce deficiency of the
fat-soluble vitamins, resulting in manifestations of avita-
minosis A, D, or K. Hypoproteinemia may be severe
enough to cause generalized edema. Persistent diarrhea
may result in rectal prolapse in up to 10% of children with
this disease. The pancreas-sufficient phenotype is usually
not associated with other gastrointestinal complications,
and in general, these individuals demonstrate excellent
Figure 10-21 Lungs of a patient dying of cystic fibrosis. There is extensive growth and development. A subset of patients with
mucus plugging and dilation of the tracheobronchial tree. The pulmonary
parenchyma is consolidated by a combination of both secretions and
pancreas-sufficient cystic fibrosis have recurrent bouts of
pneumonia—the green color associated with Pseudomonas infections. pancreatitis associated with acute abdominal pain and
(Courtesy Dr. Eduardo Yunis, Children’s Hospital of Pittsburgh, Pittsburgh,
Pa.) Table 10-5 Clinical Features and Diagnostic Criteria for Cystic Fibrosis
Clinical Features of Cystic Fibrosis
the mucus-secreting cells. Superimposed infections give rise 1. Chronic sinopulmonary disease manifested by
to severe chronic bronchitis and bronchiectasis (Chapter 15). a. Persistent colonization/infection with typical cystic fibrosis pathogens,
In many instances, lung abscesses develop. Staphylococcus including Staphylococcus aureus, nontypeable Haemophilus influenzae,
aureus, Haemophilus influenzae, and Pseudomonas aeruginosa mucoid and nonmucoid Pseudomonas aeruginosa, Burkholderia
are the three most common organisms responsible for lung cepacia
infections. As mentioned earlier, a mucoid form of P. aeruginosa b. Chronic cough and sputum production
(alginate-producing) is particularly frequent and causes chronic c. Persistent chest radiograph abnormalities (e.g., bronchiectasis,
atelectasis, infiltrates, hyperinflation)
inflammation. Even more sinister is the increasing frequency of
d. Airway obstruction manifested by wheezing and air trapping
infection with another group of pseudomonads, the Burkholderia e. Nasal polyps; radiographic or computed tomographic abnormalities of
cepacia complex, which includes at least nine different species; paranasal sinuses
of these, infections with B. cenocepacia are the most common f. Digital clubbing
in cystic fibrosis patients. This opportunistic bacterium is 2. Gastrointestinal and nutritional abnormalities, including
particularly hardy, and infection with this organism has been a. Intestinal: meconium ileus, distal intestinal obstruction syndrome, rectal
associated with fulminant illness (“cepacia syndrome”), longer prolapse
hospital stays, and increased mortality. Other opportunistic b. Pancreatic: pancreatic insufficiency, recurrent acute pancreatitis,
chronic pancreatitis
bacterial pathogens include Stenotrophomonas maltophilia and
c. Hepatic: chronic hepatic disease manifested by clinical or histologic
nontuberculous mycobacteria; allergic bronchopulmonary evidence of focal biliary cirrhosis, or multilobular cirrhosis, prolonged
aspergillosis also occurs with increased frequency in cystic neonatal jaundice
fibrosis. d. Nutritional: failure to thrive (protein-calorie malnutrition),
Azoospermia and infertility are found in 95% of the males hypoproteinemia, edema, complications secondary to fat-soluble
who survive to adulthood; congenital bilateral absence of vitamin deficiency
the vas deferens is a frequent finding in these patients. In 3. Salt-loss syndromes: acute salt depletion, chronic metabolic alkalosis
4. Male urogenital abnormalities resulting in obstructive azoospermia
some males, bilateral absence of the vas deferens may be the
(congenital bilateral absence of vas deferens)
only feature suggestive of an underlying CFTR mutation.
Criteria for Diagnosis of Cystic Fibrosis
One or more characteristic phenotypic features,
Clinical Features. Few childhood diseases are as protean OR a history of cystic fibrosis in a sibling,
as cystic fibrosis in clinical manifestations (Table 10-5). The OR a positive newborn screening test result
symptoms are extremely varied and may appear at birth AND
to years later, and involve one organ system or many. An increased sweat chloride concentration on two or more occasions
Approximately 5% to 10% of the cases come to clinical OR identification of two cystic fibrosis mutations,
attention at birth or soon after because of meconium ileus. OR demonstration of abnormal epithelial nasal ion transport
Distal intestinal obstruction can also occur in older indi- Adapted with permission from Rosenstein BJ, Cutting GR: The diagnosis of cystic fibrosis: a
consensus statement. J Pediatr 132:589, 1998.
viduals, manifesting as recurrent episodes of right lower
Sudden infant death syndrome (SIDS) 471
occasionally, life-threatening complications. These patients suggestive clinical findings or family history (or both),
have other features of classic cystic fibrosis, such as pulmo- genetic analysis may be warranted.
nary disease. By contrast, “idiopathic” chronic pancreatitis There have been major improvements in the manage-
can also occur as an isolated late-onset finding in the ment of acute and chronic complications for cystic fibrosis,
absence of other stigmata of cystic fibrosis (Chapter 19); including more potent antimicrobial therapies, pancreatic
bi-allelic CFTR mutations (usually one “mild,” one enzyme replacement, and bilateral lung transplantation.
“severe”) are demonstrable in the majority of these indi- New treatment modalities for restoring mutant CFTR func-
viduals who have nonclassic or atypical cystic fibrosis. tion are being tested in clinical trials. For example, the
Endocrine pancreatic insufficiency (i.e., diabetes) is uncom- first-in-class of a group of agents known as CFTR “poten-
mon in cystic fibrosis and is caused by severe destruction tiators” has been recently approved for use in a minority
of pancreatic parenchyma including the islets. (~3%-5%) of cystic fibrosis patients that harbor a G155D
Cardiorespiratory complications, such as persistent lung mutation in the CFTR gene. This particular mutation is a
infections, obstructive pulmonary disease, and cor pulmo- class IV alteration, in which functionally defective CFTR
nale, are the most common cause of death (~80%) in patients is present in otherwise normal amounts at the cell mem-
in the United States. By age 18, 80% of patients with classic brane; the orally bioavailable CFTR “potentiator” partially
cystic fibrosis harbor P. aeruginosa, and 3.5% harbor B. restores the critical ion transport functions to the defective
cepacia. With the indiscriminate use of antibiotic prophy- channel. Overall, improvements in the management of
laxis against Staphylococcus, there has been an unfortunate cystic fibrosis has extended the median life expectancy to
resurgence of resistant strains of Pseudomonas in many close to 40 years and increasingly, a lethal disease of child-
patients. Individuals who carry one “severe” and one hood is changing into a chronic disease of adults.
“mild” CFTR mutation may develop late-onset mild pul-
monary disease, another example of nonclassic or atypical
cystic fibrosis. Patients with mild pulmonary disease Sudden Infant Death Syndrome (SIDS)
usually have little or no pancreatic disease. Adult-onset
“idiopathic” bronchiectasis, has been linked to CFTR muta- According to the National Institute of Child Health and
tions in a subset of cases. Recurrent sinonasal polyps can Human Development, SIDS is defined as “the sudden
occur in 10% to 25% of individuals with cystic fibrosis; death of an infant under 1 year of age which remains
hence, children who present with this finding should be unexplained after a thorough case investigation, includ-
tested for cystic fibrosis. ing performance of a complete autopsy, examination of
Significant liver disease occurs late in the natural history the death scene, and review of the clinical history.” It is
of cystic fibrosis and is gaining in clinical importance as important to emphasize that many cases of sudden death in
life expectancies increase. In fact, after cardiopulmonary infancy may have an unexpected anatomic or biochemical
and transplantation-related complications, liver disease is basis discernible at autopsy (Table 10-6), and these should
the most common cause of death in cystic fibrosis. Most not be labeled as SIDS, but rather as sudden unexpected
studies suggest that symptomatic or biochemical liver infant death (SUID). The Centers for Disease Control and
disease has its onset at or around puberty, with a preva- Prevention estimates that SIDS accounts for approximately
lence of approximately 13% to 17%. However, asymptomatic half of the cases of SUID in the United States. An aspect of
hepatomegaly may be present in up to a third of individuals. SIDS that is not stressed in the definition is that the infant
Obstruction of the common bile duct may occur due to usually dies while asleep, mostly in the prone or side posi-
stones or sludge; it presents with abdominal pain and the tion, hence the pseudonyms of crib death or cot death.
acute onset of jaundice. As previously noted, diffuse biliary
cirrhosis develops in less than 10% of individuals with Epidemiology. As infantile deaths due to nutritional prob-
cystic fibrosis. lems and infections have come under control in developed
Approximately 95% of males with cystic fibrosis are countries, SIDS has assumed greater importance, including
infertile, as a result of obstructive azoospermia. As men- in the United States. SIDS is the leading cause of death
tioned earlier, this is most commonly due to congenital between age 1 month and 1 year in this country and the
bilateral absence of the vas deferens, which is caused in third leading cause of death overall in infancy, after con-
80% of cases by bi-allelic CFTR mutations. genital anomalies and diseases of prematurity and low
In most cases, the diagnosis of cystic fibrosis is based birth weight. Mostly because of nationwide SIDS aware-
on persistently elevated sweat electrolyte concentrations ness campaigns by organizations such as the American
(often the mother makes the diagnosis by recognizing Academy of Pediatrics, there has been a significant drop in
her infant’s abnormally salty sweat), characteristic clinical SIDS-related mortality in the past decade, from an esti-
findings (sinopulmonary disease and gastrointestinal mated 120 deaths per 100,000 live births in 1992 to 54 per
manifestations), an abnormal newborn screening test, or a 100,000 in 2005. This number translates to about 2000
family history. A minority of patients with cystic fibrosis, deaths due to SIDS in the US. Worldwide, in countries
especially those with at least one “mild” CFTR mutation, where unexpected infant deaths are diagnosed as SIDS
may have a normal or near-normal sweat test (<60 mM/L). only after postmortem examination, the death rates from
Measurement of nasal transepithelial potential difference SIDS range from 10 per 100,000 live births in the Netherlands
in vivo can be a useful adjunct under these circumstances; to 80 per 100,000 in New Zealand.
individuals with cystic fibrosis demonstrate a significantly Approximately 90% of all SIDS deaths occur during the
more negative baseline nasal potential difference than con- first 6 months of life, most between ages 2 and 4 months.
trols. Sequencing the CFTR gene is the gold standard for This narrow window of peak susceptibility is a unique
diagnosis of cystic fibrosis. Therefore, in patients with characteristic that is independent of other risk factors (to
Table 10-6 Risk Factors and Postmortem Findings Associated with

Sudden Infant Death Syndrome
MORPHOLOGY
Parental In infants who have died of suspected SIDS, a variety of findings
Young maternal age (age younger than 20 years) have been reported at postmortem examination. They are
Maternal smoking during pregnancy usually subtle and of uncertain significance and are not present
Drug abuse in either parent, specifically paternal marijuana and maternal in all cases. Multiple petechiae are the most common finding
opiate, cocaine use (~80% of cases); these are usually present on the thymus,
Short intergestational intervals visceral and parietal pleura, and epicardium. Grossly, the lungs
Late or no prenatal care are usually congested, and vascular engorgement with or
Low socioeconomic group without pulmonary edema is demonstrable microscopically in
African-American and American Indian ethnicity (? socioeconomic factors)
the majority of cases. These changes possibly represent agonal
Infant events, because they are found with comparable frequencies
Brain stem abnormalities, associated with delayed development of arousal in explained sudden deaths in infancy. Within the upper respira-
and cardiorespiratory control tory system (larynx and trachea), there may be some histologic
Prematurity and/or low birth weight evidence of recent infection (correlating with the clinical symp-
Male sex toms), although the changes are not sufficiently severe to
Product of a multiple birth
account for death and should not detract from the diagnosis of
SIDS in a prior sibling
Antecedent respiratory infections
SIDS. The CNS demonstrates astrogliosis of the brain stem and
Germline polymorphisms in autonomic nervous system genes cerebellum. Sophisticated morphometric studies have revealed
quantitative brain-stem abnormalities such as hypoplasia of the
Environment arcuate nucleus or a decrease in brain-stem neuronal popula-
Prone or side sleep position tions in several cases; these observations are not uniform,
Sleeping on a soft surface however. Nonspecific findings include frequent persistence of
Hyperthermia
hepatic extramedullary hematopoiesis and periadrenal brown
Co-sleeping in first 3 months of life
fat; it is tempting to speculate that these latter findings relate to
Postmortem Abnormalities Detected in Cases of Sudden Unexpected chronic hypoxemia, retardation of normal development, and
Infant Death (SUID)* chronic stress. Thus, autopsy usually fails to provide a clear
Infections cause of death, and this may well be related to the etiologic
Viral myocarditis heterogeneity of SIDS. The importance of a postmortem exami-
Bronchopneumonia nation rests in identifying other causes of SUID, such as unsus-
Unsuspected congenital anomaly pected infection, congenital anomaly, or a genetic disorder
Congenital aortic stenosis
(Table 10-6), the presence of any of which would exclude a
Anomalous origin of the left coronary artery from the pulmonary artery
Traumatic child abuse diagnosis of SIDS; and in ruling out the unfortunate possibility
Intentional suffocation (filicide) of traumatic child abuse.
Genetic and metabolic defects
Long QT syndrome (SCN5A and KCNQ1 mutations)
Fatty acid oxidation disorders (MCAD, LCHAD, SCHAD mutations) Pathogenesis. The circumstances surrounding SIDS have
Histiocytoid cardiomyopathy (MTCYB mutations) been explored in great detail, and it is generally accepted
Abnormal inflammatory responsiveness (partial deletions in C4a and C4b) that it is a multifactorial condition, with a variable mixture
*SIDS is not the only cause of SUIDs, but rather is a diagnosis of exclusion. Therefore, perfor- of contributing factors. A “triple-risk” model of SIDS has
mance of an autopsy may often reveal findings that would explain the cause of an SUID. These
cases should not, strictly speaking, be labeled as “SIDS.” SCN5A, sodium channel, voltage- been proposed, which postulates the intersection of three
gated, type V, alpha polypeptide; KCNQ1, potassium voltage-gated channel, KQT-like subfam- overlapping factors: (1) a vulnerable infant, (2) a critical
ily, member 1; MCAD, medium-chain acyl coenzyme A dehydrogenase; LCHAD, long-chain developmental period in homeostatic control, and (3) an
3-hydroxyacyl coenzyme A dehydrogenase; SCHAD, short-chain 3-hydroxyacyl coenzyme A
dehydrogenase; MTCYB, mitochondrial cytochrome b; C4, complement component 4. exogenous stressor. According to this model, several
factors make the infant vulnerable to sudden death during
the critical developmental period (i.e., the first 6 months of
be described) and the geographic locale. Most infants who life). These vulnerability factors may relate to the parents
die of SIDS die at home, usually during the night after a or the infant, while the exogenous stressor(s) are environ-
period of sleep. For many years, prolonged apnea was mental (Table 10-6).
considered to be a risk factor for SIDS. Infants who devel- While numerous factors have been proposed to account
oped a so-called “apparent life-threatening event” (ALTE), for a vulnerable infant, the most compelling hypothesis is
characterized by some combination of apnea, marked that SIDS reflects a delayed development of “arousal” and
change in color or muscle tone, choking or gagging, were cardiorespiratory control. The brain stem, and in particular
considered at risk for subsequent SIDS. However, the medulla oblongata, plays a critical role in the body’s
epidemiologic studies have demonstrated that these “life- “arousal” response to noxious stimuli such as episodic
threatening events” and SIDS have different risk factors hypercarbia, hypoxia, and thermal stress encountered
and ages of onset, and are probably unrelated entities. during sleep. The serotonergic (5-HT) system of the
Children experiencing ALTEs are often premature or have medulla is implicated in these “arousal” responses, as well
a mechanical basis for respiratory compromise. This dis- as regulation of other critical homeostatic functions such
tinction might explain why home apnea monitors, which as respiratory drive, blood pressure, and upper airway
have proliferated among American families for “SIDS pre- reflexes. Abnormalities in serotonin-dependent signaling
vention,” have had minimal impact on reducing the risk in the brain stem may be the underlying basis for SIDS in
of SIDS. some infants.
Tumors and tumor-like lesions of infancy and childhood 473
Epidemiologic and genetic studies have identified addi- acid oxidation disorders, characterized by defects in
tional vulnerability factors for SIDS in the “triple-risk” mitochondrial fatty acid oxidative enzymes, may be
model. Infants who are born before term or who are low responsible for as many as 5% of SUIDs. Other newly
birth weight are at increased risk, and risk increases with emerging genetic causes of sudden death are listed in
decreasing gestational age or birth weight. As stated, male Table 10-6.
sex is associated with a slightly greater incidence of SIDS.
SIDS in a prior sibling is associated with a fivefold relative
risk of recurrence, highlighting the importance of a genetic
predisposition; traumatic child abuse must be carefully excluded Tumors and Tumor-like Lesions
under these circumstances. Most SIDS babies have an imme- of Infancy and Childhood
diate prior history of a mild respiratory tract infection, but
no single causative organism has been isolated. These Only 2% of all malignant tumors occur in infancy and
infections may predispose an already vulnerable infant to childhood; nonetheless, cancer (including leukemia)
even greater impairment of cardiorespiratory control and accounts for about 9% of deaths in the United States in
delayed arousal. In this context, laryngeal chemoreceptors children older than age 4 and up to age 14 years, and only
have emerged as a putative “missing link” between upper accidents cause significantly more deaths. Benign tumors
respiratory tract infections, the prone position, and SIDS. are even more common than cancers. Most benign tumors
When stimulated, these laryngeal chemoreceptors typi- are of little concern, but on occasion they cause serious
cally elicit an inhibitory cardiorespiratory reflex. Stimulation complications by virtue of their location or rapid increase
of the chemoreceptors is augmented by respiratory tract in size.
infections, which increase the volume of secretions, and by It is sometimes difficult to separate, on morphologic
the prone position, which impairs swallowing and clearing grounds, true tumors or neoplasms from tumor-like lesions
of the airways even in healthy infants. In a previously in the infant and child. In this context, two special catego-
vulnerable infant with impaired arousal, the resulting ries of tumor-like lesions should be distinguished from
inhibitory cardiorespiratory reflex may prove fatal. Genetic true tumors.
vulnerability factors in the infant include polymorphisms
of genes related to serotonergic signaling and autonomic • The term heterotopia (or choristoma) is applied to micro-
scopically normal cells or tissues that are present in
innervation, pointing to the importance of these processes
abnormal locations. Examples of heterotopias include
in the pathophysiology of SIDS.
a rest of pancreatic tissue found in the wall of the
In addition to infant vulnerability factors, several mater-
stomach or small intestine, or a small mass of adrenal
nal risk factors have also been identified. Maternal smoking
cells found in the kidney, lungs, ovaries, or elsewhere.
during pregnancy has consistently emerged as a risk factor
These heterotopic rests are usually of little significance,
in epidemiologic studies of SIDS, with children exposed
but they can be confused clinically with neoplasms.
to in utero nicotine having more than double the risk of
Rarely, they are sites of origin of true neoplasms, pro-
SIDS as compared with children born to nonsmokers.
ducing paradoxes such as an adrenal carcinoma arising
Young maternal age, frequent childbirths, and inadequate
in the ovary.
prenatal care are all risk factors associated with increased
incidence of SIDS in the offspring. • The term hamartoma refers to an excessive, focal over-
Among the potential “environmental stressors,” prone growth of cells and tissues native to the organ in which
or side sleeping positions, sleeping with parents in the first it occurs. Although the cellular elements are mature and
3 months, sleeping on soft surfaces, and thermal stress are identical to those found in the remainder of the organ,
probably the most important modifiable risk factors for they do not reproduce the normal architecture of the
SIDS. The prone or side positions predispose an infant to surrounding tissue. The line of demarcation between a
one or more recognized noxious stimuli (hypoxia, hyper- hamartoma and a benign neoplasm is often unclear,
carbia, and thermal stress) during sleep. The side position since both lesions can be clonal. Hemangiomas, lymph-
was considered a reliable alternative to the prone sleeping angiomas, rhabdomyomas of the heart, adenomas of the
position, but the American Academy of Pediatrics now recog- liver, and developmental cysts within the kidneys,
nizes the supine sleeping position as the only safe position that lungs, or pancreas are interpreted by some as hamarto-
reduces the risk of SIDS. This “Back to Sleep” campaign has mas and by others as true neoplasms. Their unequivo-
resulted in substantial reductions in SIDS-related deaths cally benign histology, however, does not preclude
since its inception in 1994. bothersome and rarely life-threatening clinical prob-
As has been stated, SIDS is far from the only cause lems in some cases.
of SUIDs. In fact, SIDS is a diagnosis of exclusion, requir-
ing careful examination of the death scene and a com- Benign Tumors and Tumor-Like Lesions
plete postmortem examination. The latter can reveal
an unsuspected cause of sudden death in as many as 20% Virtually any tumor may be encountered in children, but
or more of “SIDS” babies. Infections (e.g., viral myocarditis within this wide array hemangiomas, lymphangiomas,
or bronchopneumonia) are the most common causes fibrous lesions, and teratomas deserve special mention.
of sudden “unexpected” death, followed by unsuspected You will notice that the most common neoplasms of child-
congenital anomalies. In part as a result of advance- hood are so-called soft-tissue tumors of mesenchymal deri-
ments in molecular diagnostics and knowledge of the vation. This contrasts with adults, in whom the most
human genome, several genetic causes of sudden “unex- common tumors, benign or malignant, have an epithelial
pected” infant death have emerged. For example, fatty origin. Benign tumors of various tissues are described in
as lymphangiectasis. The lymphangiomas are usually charac-

terized by cystic and cavernous spaces. Lesions of this
nature may occur in the skin but are more often encoun-
tered in the deeper regions of the neck, axilla, media-
stinum, retroperitoneal tissue, and elsewhere. Although
histologically benign, they tend to increase in size after
birth, owing to the accumulation of fluid and the budding
of preexisting spaces. In this manner they may encroach on
vital structures, such as those in the mediastinum or nerve
trunks in the axilla, and give rise to clinical problems.
Lymphangiectasis, in contrast, usually presents as a diffuse
swelling of part or all of an extremity; considerable dis-
tortion and deformation may occur as a consequence of
the spongy, dilated subcutaneous and deeper lymphatics.
The lesion is not progressive, however, and does not
extend beyond its original location. Nonetheless, it creates
cosmetic problems that are often difficult to correct
surgically.
Fibrous Tumors. Fibrous tumors occurring in infants and

children range from sparsely cellular proliferations of
spindle-shaped cells (designated as fibromatosis) to richly
cellular lesions indistinguishable from fibrosarcomas
occurring in adults (designated as congenital-infantile fibro-
sarcomas). Biologic behavior cannot be predicted based on
histology alone, however, in that despite their histologic
similarities with adult fibrosarcomas, the congenital-
infantile variants have an excellent prognosis. A character-
istic chromosomal translocation, t(12;15)(p13;q25), has been
described in congenital-infantile fibrosarcomas, which results in
generation of an ETV6-NTRK3 fusion transcript. The normal
ETV6 gene product is a transcription factor, while the
Figure 10-22 Congenital capillary hemangioma at birth (A) and at age NTRK3 gene product (also known as TRKC) is a tyrosine
2 years (B) after spontaneous regression. (Courtesy Dr. Eduardo Yunis, kinase. Like other tyrosine kinase fusion proteins found
Children’s Hospital of Pittsburgh, Pittsburgh, Pa.) in human neoplasms, ETV6-TRKC is constitutively active
and stimulates signaling through the oncogenic RAS
and PI-3K/AKT pathways (Chapter 7). Among soft-tissue
greater detail in appropriate chapters; here a few com- tumors, the ETV6-NTRK3 fusion transcript is unique to
ments are made about their special features in childhood. infantile fibrosarcomas, making it a useful diagnostic
marker.
Hemangioma. Hemangiomas are the most common tumors of
infancy (Chapter 11). Architecturally, they do not differ Teratomas. Teratomas illustrate the relationship of histo-
from those occurring in adults. Both cavernous and capil- logic maturity to biologic behavior. Teratomas may occur
lary hemangiomas may be encountered, although the latter as benign, well-differentiated cystic lesions (mature terato-
are often more cellular than in adults, a feature that is mas), as lesions of indeterminate potential (immature tera-
deceptively worrisome. In children, most are located in the tomas), or as unequivocally malignant teratomas (usually
skin, particularly on the face and scalp, where they produce admixed with another germ cell tumor component such as
flat to elevated, irregular, red-blue masses; some of the flat, endodermal sinus tumor) (Chapter 21). They exhibit two
larger lesions (considered by some to represent vascular peaks in incidence: the first at approximately 2 years of age
ectasias) are referred to as port-wine stains. Hemangiomas and the second in late adolescence or early adulthood. The
may enlarge along with the growth of the child, but in first peak is congenital neoplasms; the later occurring
many instances they spontaneously regress (Fig. 10-22). In lesions may also be of prenatal origin but are more slowly
addition to their cosmetic significance, they can represent growing. Sacrococcygeal teratomas are the most common
one facet of the hereditary disorder von Hippel-Lindau teratomas of childhood, accounting for 40% or more of
disease (Chapter 28). A subset of CNS cavernous heman- cases (Fig. 10-23). They occur with a frequency of 1 in
giomas can occur in the familial setting; these families 20,000 to 40,000 live births, and are four times more
harbor mutations in one of three cerebral cavernous malfor- common in girls than boys. In view of the overlap in the
mation (CCM) genes. mechanisms underlying teratogenesis and oncogenesis, it
is interesting that approximately 10% of sacrococcygeal
Lymphatic Tumors. A wide variety of lesions are of lym- teratomas are associated with congenital anomalies, pri-
phatic origin. Some of them—lymphangiomas—are hamar- marily defects of the hindgut and cloacal region and
tomatous or neoplastic, whereas others seem to represent other midline defects (e.g., meningocele, spina bifida)
abnormal dilations of preexisting lymph channels known not believed to result from local effects of the tumor.
Neoplasms that exhibit sharp peaks in incidence in

children younger than age 10 years include (1) leukemia
(principally acute lymphoblastic leukemia), (2) neuroblas-
toma, (3) Wilms tumor, (4) hepatoblastoma, (5) retinoblas-
toma, (6) rhabdomyosarcoma, (7) teratoma, (8) Ewing
sarcoma, and posterior fossa neoplasms—principally (9)
juvenile astrocytoma, (10) medulloblastoma, and (11)
ependymoma. Other forms of cancer are also common in
childhood but do not have the same striking early peak.
The approximate age distribution of these cancers is indi-
cated in Table 10-7. Within this large array, leukemia alone
accounts for more deaths in children younger than age 15
years than all of the other tumors combined.
Histologically, many of the malignant non-hematopoi-
etic pediatric neoplasms are unique. In general, they tend
to have a more primitive (embryonal) undifferentiated
appearance, are often characterized by sheets of cells with
small, round nuclei, and frequently show features of
organogenesis specific to the site of tumor origin. Because
Figure 10-23 Sacrococcygeal teratoma. Note the size of the lesion compared
of this latter characteristic, these tumors are frequently des-
with that of the stillbirth.
ignated by the suffix -blastoma, for example, nephroblas-
toma (Wilms tumor), hepatoblastoma, and neuroblastoma.
Because of their primitive histologic appearance, many
Approximately 75% of these tumors are mature teratomas, childhood tumors have been collectively referred to as
and about 12% are unequivocally malignant and lethal. small round blue cell tumors. The differential diagnosis
The remainder is immature teratomas; their malignant of such tumors includes neuroblastoma, Wilms tumor,
potential correlates with the amount of immature tissue, lymphoma (Chapter 13), rhabdomyosarcoma (Chapter
usually immature neuroepithelial elements, that are 27), Ewing sarcoma/primitive neuroectodermal tumor
present. Most of the benign teratomas are encountered in (Chapter 26), medulloblastoma (Chapter 28), and retino-
younger infants (<4 months), whereas children with malig- blastoma (Chapter 29). If the anatomic site of origin is
nant lesions tend to be somewhat older. Other sites for known, diagnosis is usually possible on histologic grounds
teratomas in childhood include the testis (Chapter 21), alone. Occasionally, a combination of chromosome analy-
ovaries (Chapter 22), and various midline locations, such sis, immunoperoxidase stains, or electron microscopy is
as the mediastinum, retroperitoneum, and head and neck. required. Two of these tumors are particularly illustrative
and are discussed here: the neuroblastic tumors, specifi-
Malignant Tumors cally neuroblastoma, and Wilms tumor. The remaining
tumors are discussed in their respective organ-specific
Cancers of infancy and childhood differ biologically and histo- chapters.
logically from their counterparts occurring later in life. The
main differences, some of which have already been alluded Neuroblastic Tumors
to, include the following: The term neuroblastic tumor includes tumors of the sym-
pathetic ganglia and adrenal medulla that are derived
• Incidence and type of tumor from primordial neural crest cells populating these sites.
• Relatively frequent demonstration of a close relation- As a family, neuroblastic tumors demonstrate certain char-
ship between abnormal development (teratogenesis)
and tumor induction (oncogenesis) acteristic features including spontaneous or therapy-induced
• Prevalence of underlying familial or genetic aberrations Table 10-7 Common Malignant Neoplasms of Infancy and Childhood
spontaneously
• Tendency of fetal and neonatal malignancies to regress 0 to 4 Years 5 to 9 Years 10 to 14 Years
or differentiate spontaneously Leukemia Leukemia
• Improved survival or cure of many childhood tumors, Retinoblastoma Retinoblastoma
so that more attention is now being devoted to minimiz- Neuroblastoma Neuroblastoma
ing the adverse delayed effects of chemotherapy and Wilms tumor
radiation therapy in survivors, including the develop-
ment of second malignancies Hepatoblastoma Hepatocellular Hepatocellular
carcinoma carcinoma
Soft tissue sarcoma (especially Soft tissue Soft-tissue sarcoma
Incidence and Types. The most frequent childhood cancers rhabdomyosarcoma) sarcoma
arise in the hematopoietic system, nervous tissue (includ-
Teratomas
ing the central and sympathetic nervous system, adrenal
medulla, and retina), soft tissues, bone, and kidney. This Central nervous system tumors Central nervous Osteogenic sarcoma
is in sharp contrast to adults, in whom the skin, lung, system tumors
breast, prostate, and colon are the most common sites of Ewing sarcoma Thyroid carcinoma
Lymphoma Hodgkin disease
tumors.
differentiation of primitive neuroblasts into mature elements,

spontaneous tumor regression, and a wide range of clinical
behavior and prognosis, which often mirror the extent of
histologic differentiation. Neuroblastoma is the most
important member of this family. It is the most common
extracranial solid tumor of childhood, and the most fre-
quently diagnosed tumor of infancy. The prevalence is
about one case in 7000 live births, and there are approxi-
mately 700 cases diagnosed each year in the United States.
The median age at diagnosis is 18 months; approximately
40% of cases are diagnosed in infancy. Most neuroblasto-
mas occur sporadically, but 1% to 2% are familial, and in
such cases the neoplasms may involve both of the adrenals
or multiple primary autonomic sites. Germline mutations
in the anaplastic lymphoma kinase (ALK) gene (Chapter 13)
have recently been identified as a major cause of familial
predisposition to neuroblastoma. Somatic gain-of-function
ALK mutations are also observed in less than 10% of spo-
radic neuroblastomas. Tumors harboring ALK mutations
in either the germline or somatic setting may be amenable
to treatment using small molecule inhibitors that target the
activity of this kinase. Figure 10-24 Adrenal neuroblastoma in a 6-month-old child. The hemor-
Despite the remarkable progress made in the therapy of rhagic, partially encapsulated tumor has displaced the opened left kidney and
is impinging on the aorta and left renal artery. (Courtesy Dr. Arthur Weinberg,
this disease, long-term prognosis for the high-risk subsets
University of Texas Southwestern Medical School, Dallas, Texas.)
remains modest, with a 5-year survival in the range of 40%.
As will be evident later, age and stage have a remarkable
effect on prognosis, and, in general, children younger than
18 months of age tend to have a significantly better prog-
nosis than older individuals at comparable disease burdens.
MORPHOLOGY
In childhood about 40% of neuroblastomas arise in the
adrenal medulla. The remainder occur anywhere along
the sympathetic chain, with the most common locations being
the paravertebral region of the abdomen (25%) and posterior
mediastinum (15%). Tumors may arise in numerous other sites,
including the pelvis, the neck, and within the brain (cerebral
neuroblastomas).
Neuroblastomas range in size from minute nodules (so-called
in situ lesions) to large masses more than 1 kg in weight (Fig.
10-24). In situ neuroblastomas are reported to occur 40 times
more frequently than clinically overt tumors. The great majority Figure 10-25 Adrenal neuroblastoma. This tumor is composed of small cells
embedded in a finely fibrillar matrix.
of these silent lesions spontaneously regress, leaving only a
focus of fibrosis or calcification in the adult; this has led some
to question the neoplastic connotation for the in situ lesions,
arguing instead in favor of labeling them as developmental fibrillary material (neuropil) that corresponds to neuritic pro-
anomalies (“rests”). cesses of the primitive neuroblasts. Typically, rosettes (Homer-
Some neuroblastomas are often sharply demarcated by a Wright pseudorosettes) can be found in which the tumor cells
fibrous pseudo-capsule, but others are far more infiltrative and are concentrically arranged about a central space filled with
invade surrounding structures, including the kidneys, renal vein, neuropil (Fig. 10-25). Other helpful features include positive
and vena cava, and envelop the aorta. On transection, they are immunohistochemical reactions for neuron-specific enolase
composed of soft, gray-tan, tissue. Larger tumors have areas and ultrastructural demonstration of small, membrane-bound,
of necrosis, cystic softening, and hemorrhage. Occasionally, cytoplasmic catecholamine-containing secretory granules; the
foci of punctate intra-tumoral calcification can be palpated. latter contain characteristic central dense cores surrounded by
Histologically, classic neuroblastomas are composed of a peripheral halo (dense core granules). Some neoplasms show
small, primitive-appearing cells with dark nuclei, scant cyto- signs of maturation that can be spontaneous or therapy-
plasm, and poorly defined cell borders growing in solid sheets. induced. Larger cells having more abundant cytoplasm, large
Such tumors may be difficult to differentiate morphologically vesicular nuclei, and a prominent nucleolus, representing gan-
from other small round blue cell tumors. Mitotic activity, nuclear glion cells in various stages of maturation, may be found in
breakdown (“karyorrhexis”), and pleomorphism may be promi- tumors admixed with primitive neuroblasts (ganglioneuroblas-
nent. The background often demonstrates a faintly eosinophilic toma). Even better differentiated lesions contain many more
• Stage 3: Unresectable unilateral tumor infiltrating across the

midline with or without regional lymph node involvement; or
localized unilateral tumor with contralateral regional lymph
node involvement.
• Stage 4: Any primary tumor with dissemination to distant
lymph nodes, bone, bone marrow, liver, skin, and/or other
organs (except as defined for stage 4S).
• Stage 4S (“S” = special): Localized primary tumor (as defined
for stages 1, 2A, or 2B) with dissemination limited to skin,
liver, and/or bone marrow; stage 4S is limited to infants
younger than 1 year.
Unfortunately, most (60% to 80%) children present with stage
3 or 4 tumors, and only 20% to 40% present with stage 1, 2A,
2B, or 4S neuroblastomas. The staging system is of paramount
importance in determining prognosis.
Clinical Course and Prognostic Features. In young chil-

Figure 10-26 Ganglioneuromas, arising from spontaneous or therapy- dren, under age 2 years, neuroblastomas generally present
induced maturation of neuroblastomas, are characterized by clusters of large
with large abdominal masses, fever, and possibly weight
cells with vesicular nuclei and abundant eosinophilic cytoplasm, representing
neoplastic ganglion cells (arrow). Spindle-shaped Schwann cells are present loss. In older children, they may not come to attention
in the background stroma. until metastases produce manifestations, such as bone
pain, respiratory symptoms, or gastrointestinal complaints.
Neuroblastomas may metastasize widely through the
large cells resembling mature ganglion cells with few if any hematogenous and lymphatic systems, particularly to
residual neuroblasts; such neoplasms merit the designation liver, lungs, bones, and bone marrow. Proptosis and ecchy-
ganglioneuroma (Fig. 10-26). Maturation of neuroblasts into mosis may also be present, due to spread to the periorbital
ganglion cells is usually accompanied by the appearance of region, a common metastatic site. Bladder and bowel dys-
Schwann cells. In fact, the presence of a so-called schwann- function may be caused by paraspinal neuroblastomas that
ian stroma composed of organized fascicles of neuritic pro- impinge on nerves. In neonates, disseminated neuroblas-
cesses, mature Schwann cells, and fibroblasts is a histologic tomas may present with multiple cutaneous metastases
prerequisite for the designation of ganglioneuroblastoma and
ganglioneuroma; ganglion cells in and of themselves do not fulfill
the criteria for maturation. The origin of Schwann cells in neu- Table 10-8 Prognostic Factors in Neuroblastomas
roblastoma remains an issue of contention; some investigators
Variable Favorable Unfavorable
believe they represent a reactive population recruited by the
Stage* Stage 1, 2A, 2B, 4S Stage 3, 4
tumor cells. However, studies using microdissection techniques
have demonstrated that the Schwann cells harbor at least a Age* <18 months >18 months
subset of the same genetic alterations found in neuroblasts, Histology*
and therefore are a component of the malignant clone. Evidence of schwannian Present Absent
Irrespective of histogenesis, documenting the presence of stroma and
schwannian stroma is essential, because its presence is associ- gangliocytic
ated with a favorable outcome (Table 10-8). differentiation†
Metastases, when they develop, appear early and widely. In Mitosis-karyorrhexis <200/5000 cells >200/5000 cells
addition to local infiltration and lymph node spread, there is a index‡
pronounced tendency to spread through the bloodstream to DNA ploidy* Hyperdiploid (whole Near-diploid (Segmental
the liver, lungs, bone marrow, and bones. chromosomal chromosomal losses;
Staging. The International Neuroblastoma Staging System, gains) chromothripsis)
which is the most widely used staging scheme worldwide, is MYCN* Not amplified Amplified
detailed here:
Chromosome 1p loss Absent Present
• Stage 1: Localized tumor with complete gross excision, with Chromosome 11q loss Absent Present
or without microscopic residual disease; representative ipsi-
TRKA expression Present Absent
lateral nonadherent lymph nodes negative for tumor (nodes
adherent to the primary tumor may be positive for tumor). TRKB expression Absent Present
• Stage 2A: Localized tumor with incomplete gross resection; Mutations of Absent Present
representative ipsilateral nonadherent lymph nodes negative neuritogenesis genes
for tumor microscopically. *Corresponds to the most commonly used parameters in clinical practice for assessment of
prognosis and risk stratification.
• Stage 2B: Localized tumor with or without complete gross †
It is not only the presence but also the amount of schwannian stroma that confers the designa-
excision; ipsilateral nonadherent lymph nodes positive for tion of a favorable histology. At least 50% or more schwannian stroma is required before a
neoplasm can be classified as ganglioneuroblastoma or ganglioneuroma.
tumor; enlarged contralateral lymph nodes, which are nega- ‡
Mitotic karyorrhexis index (MKI) is defined as the number of mitotic or karyorrhectic cells per
tive for tumor microscopically. 5000 tumor cells in random foci.
that cause deep blue discoloration of the skin (earning the

unfortunate designation of “blueberry muffin baby”). About
90% of neuroblastomas, regardless of location, produce cate-
cholamines (similar to the catecholamines associated with
pheochromocytomas), which are an important diagnostic
feature (i.e., elevated blood levels of catecholamines and
elevated urine levels of the metabolites vanillylmandelic
acid [VMA] and homovanillic acid [HVA]). Despite the
elaboration of catecholamines, hypertension is much less
frequent with these neoplasms than with pheochromocy-
tomas (Chapter 24). Ganglioneuromas, unlike their malig-
nant counterparts, tend to produce either asymptomatic
mass lesions or symptoms related to compression.
The course of neuroblastomas is extremely variable.
Several clinical, histopathologic, molecular, and biochemi- A
cal factors have been identified that have a bearing on
prognosis (Table 10-8); based on the collection of prognos- 1
tic factors present in a given patient, they are classified 0.9
either as “low,” “intermediate,” or “high” risk. With No amplification
improvements in therapy, long-term survival exceeds 90% 0.8
of patients in the first two groups, while less than 50% of
% Event-free survival
0.7
patients in the high-risk category are long-term survi-
vors. The most pertinent prognostic factors include the 0.6
following: 0.5
• Age and stage are the most important determinants of 0.4

outcome. Neuroblastomas at stages 1, 2A, or 2B tend to 0.3
have an excellent prognosis, irrespective of age (“low”
or “intermediate” risk); the one notable exception to this 0.2
MYCN amplification
rule are tumors exhibiting amplification of the MYCN 0.1
oncogene. Infants with localized primary tumors and
widespread metastases to the liver, bone marrow, and 0
0 1 2 3 4 5 6 7 8
skin (stage 4S) represent a special subtype, wherein it is
not uncommon for the disease to regress spontaneously. B Years from diagnosis
The biologic basis of this welcome behavior is not clear. Figure 10-27 A, Fluorescence in situ hybridization using a fluorescein-labeled
The age of 18 months has emerged as a critical point of cosmid probe for N-myc on a tissue section. Note the neuroblastoma cells
dichotomy in terms of prognosis. Children younger than 18 on the upper half of the photo with large areas of staining (yellow-green); this
corresponds to amplified N-MYC in the form of homogeneously staining
months of age, and especially those in the first year of
regions. Renal tubular epithelial cells in the lower half of the photograph show
life, have an excellent prognosis regardless of the stage no nuclear staining and background (green) cytoplasmic staining. B, A
of the neoplasm. Children older than 18 months fall into Kaplan-Meier survival curve of infants younger than 1 year of age with meta-
at least the “intermediate” risk category, while those static neuroblastoma. The 3-year event-free survival of infants whose tumors
with higher stage tumors or with confounding unfavor- lacked MYCN amplification was 93%, whereas those with tumors that had
able prognostic variables like MYCN amplification in MYCN amplification had only a 10% event free survival. (A, Courtesy Dr.
the neoplastic cells are considered “high” risk. Timothy Triche, Children’s Hospital, Los Angeles, Calif.; B, Reproduced with
permission from Brodeur GM: Neuroblastoma: biological insights into a clini-
• Morphology is an independent prognostic variable in neuro- cal enigma. Nat Rev Cancer 3:203-216; 2003.)
blastic tumors. An age-linked morphologic classification
of neuroblastic tumors has recently been proposed that
divides them into favorable and unfavorable histologic presenting as advanced-stage disease, and the degree of
subtypes. The specific morphologic features that bear on amplification correlates with worse prognosis. MYCN
prognosis are listed in Table 10-8. amplification is currently the most important genetic
• Amplification of the MYCN oncogene in neuroblastomas is a abnormality used in risk stratification of neuroblastic
molecular event that has possibly the most profound impact tumors (see later).
on prognosis, particularly when it occurs in tumors that • Ploidy of the tumor cells correlates with outcome in chil-
would otherwise portend a good outcome. The presence dren less than 2 years of age but loses its independent
of MYCN amplification “bumps” the tumor into a prognostic significance in older children. Broadly, neu-
“high”-risk category, irrespective of age, stage, or histol- roblastomas can be divided into two categories: near-
ogy. MYCN is located on the distal short arm of chromo- diploid and hyper-diploid (whole chromosome gains), with
some 2 (2p23-p24). Amplification of MYCN does not the latter being associated with a better prognosis. It
karyotypically manifest at the resident 2p23-p24 site, is postulated that neuroblastomas with hyperdiploidy
but rather as extrachromosomal double minute chromo- have an underlying defect in the mitotic machinery,
somes or homogeneously staining regions on other leading to nondisjunction and whole chromosome
chromosomes (Fig. 10-27). MYCN amplification is gains, but otherwise relatively banal karyotypes. On
present in about 20% to 30% of primary tumors, most the contrary, the more aggressive near-diploid tumors
harbor generalized genomic instability, with multiple focused on tumors harboring activating ALK mutations
segmental chromosomal aberrations that result in a because they are potentially susceptible to targeted inhibi-
complex karyotype with adverse prognostic implica- tors of the encoded kinase, and such agents are currently
tions. One peculiar form of segmental aberration undergoing evaluation in clinical trials.
described recently in aggressive neuroblastomas is Finally, we should mention the current status of screen-
called chromothripsis (Chapter 7), which involves local- ing programs for neuroblastoma. Because the vast majority
ized fragmentation of a chromosome segment followed of neuroblastomas release catecholamines into the circu-
by random assembly of the fragments. In a subset of lation, detection of catecholamine metabolites (VMA and
neuroblastomas, chromothripsis can result in amplifica- HVA) in urine could, in principle, form the basis for screen-
tion of MYCN or other oncogenes, or losses in tumor ing for asymptomatic tumors in children. However,
suppressor loci. two large studies in Europe and North America have
failed to demonstrate improved mortality rates with popu-
While age, stage, histology,, MYCN status, and DNA ploidy lation screening, because most tumors detected had favor-
are currently the “core” criteria used for the purposes of able biologic characteristics. Therefore, community-based
formal risk stratification and therapeutic decision, several screening programs for neuroblastomas are not currently
emerging molecular variables have been described with advocated.
prognostic implications. The most pertinent ones include
the following: Wilms Tumor
Wilms tumor afflicts approximately 1 in every 10,000 chil-
• Hemizygous deletion of the distal short arm of chromosome 1 dren in the United States, making it the most common
in the region of band p36 has been demonstrated in 25%
to 35% of primary tumors. Loss of 1p36 in neuroblasto- primary renal tumor of childhood and the fourth most
mas has a strong correlation with MYCN amplification, common pediatric malignancy in the United States. The
as well as advanced disease stage, and is associated with peak incidence for Wilms tumor is between 2 and 5 years
an increased risk of disease relapse in localized tumors. of age, and 95% of tumors occur before the age of 10 years.
Hemizygous loss of chromosome 11q genetic material is Approximately 5% to 10% of Wilms tumors involve both
another adverse prognostic factor, and may be the most kidneys, either simultaneously (synchronous) or one after
common deletion event in neuroblastomas. the other (metachronous). Bilateral Wilms tumors have a
median age of onset approximately 10 months earlier than
• The expression of specific neurotrophin receptors is also a tumors restricted to one kidney, and these patients are
prognostic marker for neuroblastoma. The neurotrophin
receptors are a family of tyrosine kinase receptors, presumed to harbor a germline mutation in one of the
notably TrkA, TrkB, and TrkC (also known as NTRK3, Wilms tumor-predisposing genes (see later). The biology
see earlier), that regulate the growth, survival, and dif- of this tumor illustrates several important aspects of child-
ferentiation of neural cells. High TrkA expression is a hood neoplasms, such as the relationship between malfor-
favorable prognostic factor in neuroblastomas, gener- mations and neoplasia, the histologic similarities between
ally associated with low-stage tumors lacking MYCN organogenesis and oncogenesis, the two-hit theory of recessive
amplification that occur in younger patients. In contrast, tumor suppressor genes (Chapter 7), the role of premalig-
elevated TrkB expression is associated with unfavorable nant lesions, and perhaps most importantly, the potential
biological characteristics, including MYCN amplifica- for judicious treatment modalities to dramatically affect prog-
tion and a higher disease stage. nosis and outcome. Improvements in the cure rates for
Wilms tumor (from as low as 30% a few decades ago, to
• Lastly, the application of next generation sequencing approximately 90% currently) represent one of the greatest
techniques to unravel the neuroblastoma genome has
successes of pediatric oncology.
identified recurrent mutations in genes whose products
are involved in neuritogenesis (a process in neuronal dif- Pathogenesis and Genetics. The risk of Wilms tumor is
ferentiation which includes the sprouting of neurites increased with at least three recognizable groups of congenital
that will subsequently lead to the formation of axons). malformations associated with distinct chromosomal loci.
Selected examples of mutated genes within this func- Although Wilms tumors arising in this setting account
tional class include alpha thalassemia / mental retardation, for no more than 10% of cases, these syndromic tumors
X-linked (ATRX) and protein tyrosine phosphatase, receptor have provided important insight into the biology of this
type D (PTPRD). Mutations of neuritogenesis associated neoplasm.
genes were generally present in more aggressive, higher-
stage neuroblastomas (including those arising in the • The first group of patients has the WAGR syndrome,
characterized by Wilms tumor, aniridia, genital anoma-
absence of MYCN amplification), and these alterations lies, and mental retardation. Their lifetime risk of devel-
are postulated to lead to defects in neuronal differentia- oping Wilms tumor is approximately 33%. Individuals
tion within the neoplastic cells, likely underlying their with WAGR syndrome carry constitutional (germline)
poorly differentiated histology. deletions of 11p13. Studies on these patients led to the
Although discussion of the treatment modalities for identification of the first Wilms tumor-associated gene,
neuroblastoma is beyond the scope of this book, we men- WT1, and a contiguously deleted autosomal dominant
tion in passing two promising experimental approaches. gene for aniridia, PAX6, both located on chromosome
The first involves the use of retinoids as an adjunct therapy 11p13. Patients with deletions restricted to PAX6, with
for inducing the differentiation of neuroblastoma. Recall normal WT1 function, develop sporadic aniridia, but
that the retinoic acid pathway plays a critical role in cel- they are not at increased risk for Wilms tumors.
lular differentiation during embryogenesis. The second is The presence of germline WT1 deletions in WAGR
syndrome represents the “first hit”; the development of this region—insulin-like growth factor-2 (IGF2) —is
Wilms tumor in these patients frequently correlates normally expressed solely from the paternal allele, while
with the occurrence of a nonsense or frameshift muta- the maternal allele is silenced by imprinting. In some
tion in the second WT1 allele (“second hit”). Wilms tumors, loss of imprinting (i.e., re-expression of
• A second group of patients at much higher risk for the maternal IGF2 allele) can be demonstrated, leading
Wilms tumor (~90%) have the Denys-Drash syndrome, to overexpression of the IGF-2 protein. In other instances
which is characterized by gonadal dysgenesis (male pseu- there is a selective deletion of the imprinted maternal
dohermaphroditism) and early-onset nephropathy leading allele, combined with duplication of the transcription-
to renal failure. The characteristic glomerular lesion in ally active paternal allele in the tumor (uniparental pater-
these patients is a diffuse mesangial sclerosis (Chapter 20). nal disomy), which has an identical functional effect in
As in patients with WAGR, these patients also demon- terms of overexpression of IGF-2. Because the IGF-2
strate germline abnormalities in WT1. In patients with protein is an embryonal growth factor, it could conceiv-
the Denys-Drash syndrome, however, the genetic abnor- ably explain the features of overgrowth associated with
mality is a dominant-negative missense mutation in the BWS, as well as the increased risk for Wilms tumors in
zinc-finger region of the WT1 protein that affects its these patients. Of all the “WT2” genes, imprinting
DNA-binding properties. This mutation interferes with abnormalities of IGF2 have the strongest relationship to
the function of the remaining wild-type allele, yet tumor predisposition in BWS. A subset of patients with
strangely, it is sufficient only in causing genitourinary BWS harbor mutations of the cell cycle regulator
abnormalities, but not tumorigenesis; Wilms tumors CDKN1C (also known as p57 or KIP2); however, these
arising in Denys-Drash syndrome demonstrate bi-allelic patients have a significantly lower risk for developing
inactivation of WT1. In addition to Wilms tumors, these Wilms tumors. In addition to Wilms tumors, patients
individuals are also at increased risk for developing with BWS are also at increased risk for developing
germ cell tumors called gonadoblastomas (Chapter 21), hepatoblastoma, pancreatoblastoma, adrenocortical
almost certainly a consequence of disruption in normal tumors, and rhabdomyosarcomas.
gonadal development.
WT1 encodes a DNA-binding transcription factor Recent genetic studies have also elucidated the role of
that is expressed within several tissues, including the β-catenin in Wilms tumor. It will be recalled (Chapter 7)
kidney and gonads, during embryogenesis. The WT1 that β-catenin belongs to the developmentally important
protein is critical for normal renal and gonadal develop- WNT (wingless) signaling pathway. Gain-of-function muta-
ment. WT1 has multiple binding partners, and the tions of the gene encoding β-catenin have been demon-
choice of this partner can affect whether WT1 functions strated in approximately 10% of sporadic Wilms tumors;
as a transcriptional activator or repressor in a given cel- there is a significant overlap between the presence of WT1
lular context. Numerous transcriptional targets of WT1 and β-catenin mutations, suggesting a synergistic role for
have been identified, including genes encoding glomer- these events in the genesis of Wilms tumors.
ular podocyte-specific proteins and proteins involved in
induction of renal differentiation. Despite the impor- Nephrogenic rests are putative precursor lesions of Wilms
tance of WT1 in nephrogenesis and its unequivocal role tumors and are seen in the renal parenchyma adjacent to
as a tumor suppressor gene, only about 10% of patients approximately 25% to 40% of unilateral tumors; this fre-
with sporadic (nonsyndromic) Wilms tumors demon- quency rises to nearly 100% in cases of bilateral Wilms
strate WT1 mutations, suggesting that the majority of tumors. In many instances the nephrogenic rests share
these tumors are caused by mutations in other genes. genetic alterations with the adjacent Wilms tumor, point-
• A third group, that is clinically distinct from these previ- ing to their preneoplastic status. The appearance of neph-
ous two groups of patients but also with an increased rogenic rests varies from expansile masses that resemble
risk of developing Wilms tumor are children with Wilms tumors (hyperplastic rests) to sclerotic rests consist-
Beckwith-Wiedemann syndrome (BWS), characterized by ing predominantly of fibrous tissue and occasional admixed
enlargement of body organs (organomegaly), macro- immature tubules or glomeruli. It is important to docu-
glossia, hemihypertrophy, omphalocele, and abnormal ment the presence of nephrogenic rests in the resected
large cells in the adrenal cortex (adrenal cytomegaly). specimen, because these patients are at an increased risk of
BWS has served as a model for a nonclassical mecha- developing Wilms tumors in the contralateral kidney and
nism of tumorigenesis in humans—genomic imprinting require frequent and regular surveillance for many years.
(Chapter 5). The chromosomal region implicated in
BWS has been localized to band 11p15.5 (“WT2”), distal
to the WT1 locus. This region contains multiple genes MORPHOLOGY
that are normally expressed from only one of the
Grossly, Wilms tumor tends to present as a large, solitary, well-
two parental alleles, with transcriptional silencing
circumscribed mass, although 10% are either bilateral or mul-
(i.e., imprinting) of the other parental homologue by
ticentric at the time of diagnosis. On cut section, the tumor is
methylation of the promoter region. Unlike WAGR or
soft, homogeneous, and tan to gray with occasional foci of
Denys-Drash syndromes, the genetic basis for BWS
hemorrhage, cyst formation, and necrosis (Fig. 10-28).
is considerably more heterogeneous in that no single
Microscopically, Wilms tumors are characterized by recogniz-
11p15.5 gene is involved in all cases. Moreover, the
able attempts to recapitulate different stages of nephrogenesis.
phenotype of BWS, including the predisposition to
The classic triphasic combination of blastemal, stromal,
tumorigenesis, is influenced by the specific “WT2”
and epithelial cell types is observed in the vast majority
imprinting abnormalities present. One of the genes in
Suggested readings 481
of lesions, although the percentage of each component

is variable (Fig. 10-29A). Sheets of small blue cells with few
distinctive features characterize the blastemal component.
Epithelial differentiation is usually in the form of abortive tubules
or glomeruli. Stromal cells are usually fibrocytic or myxoid in
nature, although skeletal muscle differentiation is not uncom-
mon. Rarely, other heterologous elements are identified,
including squamous or mucinous epithelium, smooth muscle,
adipose tissue, cartilage, and osteoid and neurogenic tissue.
Approximately 5% of tumors reveal anaplasia, defined as the
presence of cells with large, hyperchromatic, pleomorphic
nuclei and abnormal mitoses (Fig. 10-29B). The presence of
anaplasia correlates with the presence of TP53 mutations and
the emergence of resistance to chemotherapy. Recall that p53
elicits pro-apoptotic signals in response to DNA damage
(Chapter 7). The loss of p53 function might explain the
relative unresponsiveness of anaplastic cells to cytotoxic
chemotherapy.
Clinical Features. Most children with Wilms tumors

present with a large abdominal mass that may be unilateral
or, when very large, may extend across the midline and
down into the pelvis. Hematuria, pain in the abdomen after
some traumatic incident, intestinal obstruction, and appear-
ance of hypertension are other patterns of presentation. In
a considerable number of these patients, pulmonary metas-
tases are present at the time of primary diagnosis.
As stated, most patients with Wilms tumor can expect
to be cured of their malignancy. Anaplastic histology
remains a critical determinant of adverse prognosis. Even
anaplasia restricted to the kidney (i.e., without extra-renal
spread) confers an increased risk of recurrence and death,
emphasizing the need for accurate identification of this
histologic feature. Molecular parameters that correlate
with adverse prognosis include loss of genetic material on Figure 10-29 A, Wilms tumor with tightly packed blue cells consistent with
chromosomes 11q and 16q, and gain of chromosome 1q in the blastemal component and interspersed primitive tubules, representing
the tumor cells. Along with the increased survival of indi- the epithelial component. Although multiple mitotic figures are seen, none
viduals with Wilms tumor have come reports of an are atypical in this field. B, Focal anaplasia was present in this Wilms tumor
increased risk of developing second primary tumors, in other areas, characterized by cells with hyperchromatic, pleomorphic
including bone and soft-tissue sarcomas, leukemia and nuclei, and abnormal mitoses.
lymphomas, and breast cancers. While some of these neo-

plasms result from the presence of a germline mutation in
a cancer predisposition gene, others are a consequence of
therapy, most commonly radiation administered to the
cancer field. This tragic, albeit uncommon, outcome has
mandated that radiation therapy be used judiciously in the
treatment of this and other childhood cancers.
SUGGESTED READINGS
Congenital Anomalies
Bellini C, Hennekam RC: Non-immune hydrops fetalis: a short review
of etiology and pathophysiology. Am J Med Genet A 158A:597-605,
2012. [A well written review on non-immune hydrops, which accounts
for the overhwelming majority of fetal hydrops in the Western world.]
de Jong EP, Walther FJ, Kroes AC, et al: Parvovirus B19 infection in
pregnancy: new insights and management. Prenat Diagn 31:419-25,
2011. [A comprehesive review that discusses the epidemiology, natural
history, and complications of intrauterine Parvovirus B19 infection,
along with diagnostic and treatment guidelines.]
Figure 10-28 Wilms tumor in the lower pole of the kidney with the charac- Kochanek KD, Kirmeyer SE, Martin JA, et al: Annual summary of vital
teristic tan-to-gray color and well-circumscribed margins. statistics: 2009. Pediatrics 129:338-48, 2012. [A periodically updated

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Pulmonary Altered Positioning Breech

Table 10-2 Causes of Congenital Anomalies in Humans

Critical periods of development (red denotes highly sensitive periods)

Central nervous system

surfactant lipids, are involved in the reduction of surface

Clinical Features. The classic clinical presentation before

streptococcus is the most common cause of early-onset

infants display pallor, possibly accompanied by hepato-

Clinical Features. The clinical manifestations of fetal

Other Genetic Disorders Phenylalanine (BH4) Dihydropteridine

untreated infants, however, the mental deficit is usually Cl–

LUMEN OF SWEAT DUCT

Normal mucus Dehydrated mucus

Cl– Na+ H2O Cl– Na+ H2O

Sweat test Clinical phenotype Molecular phenotype

Meconium ileus; pancreatic insufficiency;

patients do not demonstrate other features of cystic

Genetic and Environmental Modifiers. Although cystic

quadrant pain sometimes associated with a palpable mass

Table 10-6 Risk Factors and Postmortem Findings Associated with

as lymphangiectasis. The lymphangiomas are usually charac-

Fibrous Tumors. Fibrous tumors occurring in infants and

Neoplasms that exhibit sharp peaks in incidence in

differentiation of primitive neuroblasts into mature elements,

• Stage 3: Unresectable unilateral tumor infiltrating across the

Clinical Course and Prognostic Features. In young chil-

that cause deep blue discoloration of the skin (earning the

• Age and stage are the most important determinants of 0.4

of lesions, although the percentage of each component

Clinical Features. Most children with Wilms tumors

lymphomas, and breast cancers. While some of these neo-

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