Chapter 10 Diseases of Infancy and Childhood PDF

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Diseases of Infancy and Childhooda...

See TARGETED THERAPY available online at www.studentconsult.com C H A P T E R Diseases of Infancy and Childhooda Aliya N. Husain Selene C. Koo 10 CHAPTER CONTENTS Congenital Anomalies 453 Fetal Hydrops 462 Sudden Infant Death Syndrome 473 Definitions 454 Immune Hydrops 462 Tumors and Tumorlike Lesions of Causes of Anomalies 455 Nonimmune Hydrops 463 Infancy and Childhood 475 Prematurity and Fetal Growth Inborn Errors of Metabolism and Benign Tumors and Tumorlike Restriction 457 Other Genetic Disorders 464 Lesions 475 Fetal Growth Restriction 458 Phenylketonuria 465 Hemangioma 476 Maternal Abnormalities 458 Galactosemia 466 Fibrous Tumors 476 Fetal Abnormalities 458 Cystic Fibrosis (Mucoviscidosis) 466 Teratomas 476 Placental Abnormalities 458 Cystic Fibrosis Gene: Normal Structure and Malignant Tumors 477 Neonatal Respiratory Distress Function 467 Neuroblastic Tumors 477 Syndrome 459 Cystic Fibrosis Gene: Mutational Spectrum Wilms Tumor 480 Necrotizing Enterocolitis 460 and Genotype-Phenotype Correlation 468 Perinatal Infections 461 Genetic and Environmental Modifiers 470 Transcervical (Ascending) Infections 461 Transplacental (Hematologic) Infections 461 Sepsis 462 Children are not merely little adults, and their diseases are 12 months of life. Once the infant survives the first year not merely variants of adult diseases. Many childhood of life, the outlook brightens measurably. In the next two conditions are unique to, or at least take distinctive forms age groups—1 to 4 years and 5 to 9 years—unintentional in, this stage of life and so are discussed separately in this injuries resulting from accidents are the leading cause of chapter. Diseases originating in the perinatal period are death. Among the natural diseases, in order of importance, important in that they account for significant morbidity and congenital anomalies and malignant neoplasms assume mortality. The chances for survival of infants improve with major significance. In the 10- to 14-year age group, accidents, each passing week. The infant mortality rate in the United malignancies, suicide, homicide, and congenital malforma- States has shown a decline from a level of 20 deaths per tions are the leading causes of death. 1000 live births in 1970 to 5.8 in 2014. Although the death The following discussion looks at specific conditions rate has continued to decline for all infants, African Ameri- encountered during the various stages of infant and child cans continue to have an infant mortality rate more than development. twice (11 deaths per 1000 live births) that of American whites (4.9 deaths). Worldwide, infant mortality rates vary widely, from as low as 1.8 deaths per 1000 live births in Slovenia, CONGENITAL ANOMALIES to as high as 110.6 deaths in Afghanistan. Rather dismayingly, the United States ranks thirtieth in infant mortality rate Congenital anomalies are anatomic defects that are present among high income nations in the Western hemisphere. at birth, but some, such as cardiac defects and renal Each stage of development of the infant and child is prey anomalies, may not become clinically apparent until years to a somewhat different group of disorders: (1) the neonatal later. The term congenital means “born with,” but it does period (the first 4 weeks of life), (2) infancy (the first year not imply or exclude a genetic basis for the birth defect. It of life), (3) 1 to 4 years of age, and (4) 5 to 14 years of age. is estimated that about 120,000 (1 in 33) babies are born Congenital anomalies, prematurity and low birth weight, with a birth defect each year in the United States. In a sense, sudden infant death syndrome, and maternal complications anomalies found in live-born infants represent the less serious and injuries represent the leading causes of death in the first developmental failures in embryogenesis as they are compat- ible with live birth. Perhaps 20% of fertilized ova are so a The prior contributions of Dr. Anirban Maitra to this chapter are anomalous that they are blighted at early stages. Others gratefully acknowledged. may be compatible with early fetal development, only to 453 454 C H A P T E R 10 Diseases of Infancy and Childhood Figure 10.1 Examples of malformations. (A) Polydactyly (one or more extra digits) and syndactyly (fusion of digits) 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, Tex.) lead to spontaneous abortion. Less severe anomalies allow to varying degrees. Fundamental to the pathogenesis of more prolonged intrauterine survival, with some disorders deformations is localized or generalized compression of terminating in stillbirth and those still less significant permit- the growing fetus by abnormal biomechanical forces, ting live birth despite the handicaps imposed. leading eventually to a variety of structural abnormalities. The most common underlying factor responsible for Definitions deformations is uterine constraint. Between 35 and 38 weeks of gestation, rapid increase in the size of the fetus The process of morphogenesis (organ and tissue develop- outpaces the growth of the uterus, and the relative amount ment) can be impaired by a variety of different errors. of amniotic fluid (which normally acts as a cushion) Malformations represent primary errors of morphogen- decreases. Thus, even the normal fetus is subjected to esis, in which there is an intrinsically abnormal some degree of uterine constraint. Several factors increase developmental process (Fig. 10.1). Malformations can be the result of a single gene or chromosomal defect, but are more commonly multifactorial in origin. Develop- mental anomalies may present in several patterns. Some, such as congenital heart defects and anencephaly (absence of part or all of the brain), involve single body systems, whereas in other cases multiple malformations involving many organs may coexist. Disruptions result from secondary destruction of an organ or body region that was previously normal in development; thus, in contrast with malformations, disruptions arise from an extrinsic disturbance in mor- phogenesis. Amniotic bands, denoting rupture of amnion with resultant formation of “bands” that encircle, com- press, or attach to parts of the developing fetus, are the classic example of a disruption (Fig. 10.2). A variety of environmental agents may cause disruptions (see later). Disruptions are not heritable, hence they are not associated with increased risk of recurrence in subsequent pregnancies. Deformations, like disruptions, represent an extrinsic Figure 10.2 Disruption of morphogenesis by an amniotic band. Note the disturbance of development rather than an intrinsic placenta at the right of the diagram and the band of amnion extending error of morphogenesis. Deformations are common from the top portion of the amniotic sac to encircle the leg of the fetus. problems, affecting approximately 2% of newborn infants (Courtesy Dr. Theonia Boyd, Boston Children’s Hospital, Boston, Mass.)  Congenital anomalies 455 the likelihood of excessive compression of the fetus resulting in deformations. Maternal factors include first pregnancy, small uterus, malformed (e.g., bicornuate) uterus, and leiomyomas. Fetal or placental factors include oligohydramnios, multiple fetuses, and abnormal fetal presentation. For example, clubfeet can occur as a com- ponent of Potter sequence, described later. A sequence is a cascade of anomalies triggered by one initiating aberration. Approximately one-half the time, congenital anomalies occur singly; in the remaining cases, multiple congenital anomalies are recognized. In some instances, the constellation of anomalies may be explained by a single localized aberration in organogenesis (mal- formation, disruption, or deformation) that sets into motion secondary effects in other organs. A good example is the oligohydramnios (or Potter) sequence (Fig. 10.3). Oligohydramnios (decreased amniotic fluid) may be caused by a variety of unrelated maternal, placental, or fetal abnormalities. The most common cause of oligohy- dramnios is chronic leakage of amniotic fluid due to rupture of fetal membranes. Other causes include renal agenesis and urinary tract obstruction in the fetus (because fetal urine is a major constituent of amniotic fluid), and uteroplacental insufficiency resulting from maternal hypertension or severe preeclampsia. The fetal compres- sion associated with significant oligohydramnios, in turn, Figure 10.4 Infant with oligohydramnios sequence. Note the flattened results in a classic phenotype in the newborn infant, facial features and deformed right foot (talipes equinovarus). including flattened facies, positional abnormalities of the hands, and clubfeet (Fig. 10.4). The hips may be dislocated. Growth of the chest wall and the contained lungs is also compromised so that the lungs are frequently hypoplastic, primordium. A closely related term, aplasia, also refers to and may cause fetal demise. Nodules in the amnion the absence of an organ but one that occurs due to failure (amnion nodosum) are frequently present. of growth of the existing primordium. Atresia describes the A malformation syndrome is a constellation of congenital absence of an opening, usually of a hollow visceral organ, anomalies, believed to be pathologically related, that, in such as the trachea or intestine. Hypoplasia refers to incom- contrast to a sequence, cannot be explained on the basis plete development or decreased size of an organ with of a single, localized, initiating defect. Syndromes are decreased numbers of cells, whereas hyperplasia refers to most often caused by a single etiologic agent, such as a the converse, that is, the enlargement of an organ due to viral infection or specific chromosomal abnormality, which increased numbers of cells. An abnormality in an organ or simultaneously affects several tissues. a tissue as a result of an increase or a decrease in the size (rather than the number) of individual cells defines hyper- In addition to the aforementioned general definitions, a trophy or hypotrophy, respectively. Finally, dysplasia in the few organ-specific terms should be defined. Agenesis refers context of malformations (versus neoplasia) describes an to the complete absence of an organ and its associated abnormal organization of cells. Causes of Anomalies Renal Amniotic Although we are learning a great deal about the molecular agenesis leak Others bases of some congenital anomalies, the exact cause remains unknown in 40% to 60% of cases. The era of molecular Amnion medicine promises to bring additional insights into the nodosum OLIGOHYDRAMNIOS mechanisms by which malformations occur. The common known causes of congenital anomalies can be grouped into three major categories: genetic, environmental, and multi- FETAL COMPRESSION factorial (Table 10.1). Genetic causes of malformations include all of the previ- ously discussed mechanisms of genetic disease (Chapter 5). Pulmonary Altered Positioning Breech Virtually all chromosomal syndromes are associated with hypoplasia facies defects of presentation congenital malformations. Examples include Down syndrome feet, hands and other trisomies, Turner syndrome, and Klinefelter Figure 10.3 Schematic diagram of the pathogenesis of the syndrome. Most chromosomal disorders arise during oligohydramnios sequence. gametogenesis and hence are not familial. Single-gene 456 C H A P T E R 10 Diseases of Infancy and Childhood Table 10.1 Causes of Congenital Anomalies in disturbances. These in combination are labeled the fetal Live-Born Infants alcohol syndrome (also discussed in Chapter 9). Although Cause Frequency (%) cigarette smoke–derived nicotine has not been convincingly Genetic demonstrated to be a teratogen, there is a high incidence of spontaneous abortion, premature labor, and placental Chromosomal aberrations 10–15 abnormalities in pregnant women who smoke, babies born Mendelian inheritance 2–10 to mothers who smoke often have a low birth weight and Environmental may be prone to sudden infant death syndrome (discussed Maternal/placental infections 2–3 later). In light of these findings, it is best to avoid nicotine Rubella exposure altogether during pregnancy. Among maternal Toxoplasmosis conditions listed in Table 10.1, diabetes mellitus is a common Syphilis entity, and despite advances in antenatal obstetric monitoring Cytomegalovirus and glucose control, the incidence of major malformations Human immunodeficiency virus in infants of diabetic mothers stands between 6% and Maternal disease states 6–8 10% in most series. Maternal hyperglycemia-induced fetal Diabetes hyperinsulinemia results in fetal macrosomia (organomegaly Phenylketonuria Endocrinopathies, including severe obesity and increased body fat and muscle mass); cardiac anomalies, neural tube defects, and other central nervous system (CNS) Drugs and chemicals 1 Alcohol, smoking malformations are some of the major anomalies seen in Folic acid antagonists diabetic embryopathy. Androgens Multifactorial inheritance, which implies the interaction of Phenytoin environmental influences with two or more genes of small Thalidomide effect, is the most common genetic etiology of congenital Warfarin malformations. Examples include relatively common malfor- 13-cis-retinoic acid mations such as cleft lip, cleft palate, and neural tube defects. Others The dramatic reduction in incidence of neural tube defects Irradiation 1 by periconceptional intake of folic acid is one case where Multifactorial 20–25 understanding the environmental stimuli has prevented Unknown 40–60 development of multifactorial malformations even though Modified from Stevenson RE, Hall JG, Everman DB, Solomon B, editors: Human contributing genes have not been eliminated. Malformations and Related Anomalies, ed 3, New York, 2016, Oxford University Press, p 12. Pathogenesis The pathogenesis of congenital anomalies is complex and still poorly understood, but two general principles of developmental pathology are relevant regardless of the mutations, characterized by Mendelian inheritance, may etiologic agent. underlie some major malformations. For example, holopros- 1. The timing of the prenatal teratogenic insult has an encephaly is the most common developmental defect of the important impact on the occurrence and the type of forebrain and midface in humans; the Hedgehog signaling anomaly produced (Fig. 10.5). The intrauterine develop- pathway plays a critical role in the morphogenesis of these ment of humans can be divided into two phases: (1) the structures, and loss-of-function mutations of individual early embryonic period occupying the first 9 weeks of components within this pathway are reported in families pregnancy and (2) the fetal period terminating at birth. with a history of recurrent holoprosencephaly. In the early embryonic period (first 3 weeks after fertiliza- Environmental influences, such as viral infections, drugs, tion), an injurious agent damages either enough cells and maternal irradiation, may cause fetal anomalies. Among to cause death and abortion or only a few cells, presum- the viral infections listed in Table 10.1, rubella was a major ably allowing the embryo to recover without develop- scourge of the nineteenth and early twentieth centuries. ing defects. Between the third and the ninth weeks, Fortunately, maternal rubella and the resultant rubella the embryo is extremely susceptible to teratogenesis; embryopathy have been virtually eliminated in high income peak sensitivity occurs between the fourth and the countries as a result of maternal rubella vaccination. A variety fifth weeks. During this period, organs are being crafted of drugs and chemicals have been suspected to be teratogenic, out of the germ cell layers. but perhaps less than 1% of congenital malformations are The fetal period that follows organogenesis is marked caused by these agents. The list includes thalidomide, alcohol, chiefly by further growth and maturation of the organs, anticonvulsants, warfarin (oral anticoagulant), and 13-cis- with greatly reduced susceptibility to teratogenic retinoic acid, which is used in the treatment of severe acne. agents. Instead, the fetus is susceptible to growth For example, thalidomide, once used as a tranquilizer in restriction or injury to already formed organs. Thus Europe, causes an extremely high incidence (50% to 80%) of a given agent may produce different anomalies if limb malformations. Alcohol, when consumed even in modest exposure occurs at different times of gestation. amounts during pregnancy, is an important environmental 2. The interplay between environmental teratogens and teratogen. Affected infants show prenatal and postnatal intrinsic genetic defects is exemplified by the fact that growth restriction, facial anomalies (microcephaly, short features of dysmorphogenesis caused by environmental palpebral fissures, maxillary hypoplasia), and psychomotor insults can often be recapitulated by genetic defects in  Prematurity and fetal growth restriction 457 Embryonic Period (in weeks) Fetal Period (in weeks) Full Term 1 2 3 4 5 6 7 8 9 16 32 38 Period of dividing zygote, implantation, and bilaminar embryo Morula Critical periods of development (red denotes highly sensitive periods) Neural tube defects Intellectual disability CNS Blastocyst Embryonic TA, ASD, VSD Heart disc Amelia/meromelia Upper limb Amelia/meromelia Lower limb Low-set malformed ears and deafness Ears Usually not Microphthalmia, cataracts, glaucoma Eyes susceptible to teratogens Enamel hypoplasia Teeth Cleft palate Palate Masculinization External genitalia Prenatal death Major morphologic abnormalities Physiologic defects and minor 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, ed 10, Philadelphia, 2016, WB Saunders, p 474.) the pathways targeted by these teratogens. This is to retinoic acid is also teratogenic. Infants born to illustrated by the following representative examples. mothers treated with retinoic acid for severe acne Cyclopamine is a plant teratogen contained in the corn have a predictable phenotype (retinoic acid embry- lily; pregnant sheep who feed on this plant give birth opathy) including CNS, cardiac, and craniofacial to lambs with severe craniofacial abnormalities includ- defects, such as cleft lip and cleft palate. The latter ing holoprosencephaly and “cyclopia” (single fused may stem from retinoic acid–mediated deregulation eye, hence the origin of the moniker cyclopamine). of components of the transforming growth factor-β This compound is an inhibitor of Hedgehog signaling (TGF-β) signaling pathway, which is involved in pala- in the embryo, and, as stated earlier, mutations of togenesis. Mice with knockout of the Tgfb3 gene uni- Hedgehog genes are present in subsets of patients formly develop cleft palate, once again illustrating the with holoprosencephaly. functional relationship between teratogenic exposure Valproic acid is an antiepileptic and a recognized and signaling pathways in the causation of congenital teratogen during pregnancy. Valproic acid disrupts anomalies. expression of a family of highly conserved develop- mentally critical transcription factors known as homeobox (HOX) proteins. In vertebrates, HOX proteins PREMATURITY AND FETAL GROWTH have been implicated in the patterning of limbs, RESTRICTION vertebrae, and craniofacial structures. Not surprisingly, mutations in the HOX family of genes are responsible Prematurity, defined by a gestational age less than 37 for congenital anomalies that mimic features observed weeks, is the second most common cause of neonatal in valproic acid embryopathy. mortality, behind only congenital anomalies. The Centers The vitamin A (retinol) derivative all-trans-retinoic acid for Disease Control and Prevention (CDC; cdc.gov/ is essential for normal development and differentia- reproductivehealth) report that in 2016, preterm birth affected tion, and its absence during embryogenesis results about 1 in 10 infants born in the United States. Preterm in a constellation of malformations affecting multiple birth rates decreased from 2007 to 2014 due, in part, to organ systems, including the eyes, genitourinary declines in the number of births to teens and young mothers; system, cardiovascular system, diaphragm, and lungs however, the rate among African-American women (14%) (see Chapter 9 for effects of vitamin A deficiency in remains greater than that in white women (9%). The major the postnatal period). Conversely, excessive exposure risk factors for prematurity include the following: 458 C H A P T E R 10 Diseases of Infancy and Childhood Preterm premature rupture of membranes (PPROM): PPROM than 2500 g are born at term and are therefore undergrown complicates about 3% of all pregnancies and is responsible rather than immature. These small-for-gestational-age (SGA) for as many as one-third of all preterm deliveries. Rupture infants suffer from fetal growth restriction (FGR),which may of membranes (ROM) before the onset of labor can be result from maternal, fetal, or placental abnormalities, spontaneous or induced. PPROM refers to spontaneous although in many cases the specific cause is unknown. ROM occurring before 37 weeks of gestation (hence the annotation “preterm”). In contrast, PROM refers to Maternal Abnormalities spontaneous ROM occurring after 37 weeks of gestation. By far the most common factors associated with SGA infants This distinction is important because after 37 weeks the are maternal conditions that result in decreased placental associated risk to the fetus is considerably decreased. blood flow. Vascular diseases such as preeclampsia (toxemia Several clinical risk factors have been identified for of pregnancy) and chronic hypertension are often the PPROM, including a prior history of preterm delivery, underlying cause. The list of other maternal conditions preterm labor and/or vaginal bleeding during the current associated with SGA infants is long, but some of the avoidable pregnancy, maternal smoking, low socioeconomic status, factors worth mentioning are maternal narcotic abuse, alcohol and poor maternal nutrition. The fetal and maternal intake, and heavy cigarette smoking. Drugs causing FGR outcome after PPROM depends on the gestational age include both classic teratogens, such as chemotherapeutic of the fetus (second-trimester PPROM has a dismal agents, and some commonly administered therapeutic agents, prognosis) and the effective prophylaxis of infections in such as phenytoin (Dilantin). Maternal malnutrition (in the exposed amniotic cavity. particular, prolonged hypoglycemia) may also affect fetal Intrauterine infection: This is a major cause of preterm growth. labor with and without intact membranes. Intrauterine infection is present in approximately 25% of all preterm Fetal Abnormalities births, and the earlier the gestational age at delivery, the Fetal influences are those that intrinsically reduce growth higher the frequency of intra-amniotic infection. The potential of the fetus despite an adequate supply of nutrients histologic correlates of intrauterine infection are inflam- from the mother. Prominent among such fetal conditions mation of the placental membranes (chorioamnionitis) are chromosomal disorders, congenital anomalies, and and inflammation of the fetal umbilical cord (funisitis). congenital infections. Chromosomal abnormalities may be The most common microorganisms implicated in intra- detected in up to 17% of fetuses sampled for FGR and in uterine infections leading to preterm labor are Ureaplasma up to 66% of fetuses with documented ultrasonographic urealyticum, Mycoplasma hominis, Gardnerella vaginalis (the malformations. Among the first group, the abnormalities dominant organism found in “bacterial vaginosis,” a include triploidy (7%), trisomy 18 (6%), trisomy 21 (1%), polymicrobial infection), Trichomonas, gonorrhea, and trisomy 13 (1%), and a variety of deletions and translocations Chlamydia. In low income countries, malaria and HIV (2%). Fetal infection should be considered in all infants with are significant contributors to the burden of preterm labor FGR. Those most commonly responsible for FGR are the and prematurity. Recent studies have begun to elucidate TORCH group of infections (toxoplasmosis, other viruses the molecular mechanisms of inflammation-induced and bacteria such as syphilis, rubella, cytomegalovirus, and preterm labor. Endogenous Toll-like receptors (TLRs), herpesvirus). Infants who are SGA because of fetal factors which bind bacterial components as natural ligands usually have symmetric growth restriction (also referred to (Chapter 6), have emerged as key players in this process. as proportionate FGR), meaning that all organ systems are It is postulated that signals produced by TLR engagement similarly affected. deregulate prostaglandin expression, which, in turn, induces uterine smooth muscle contractions. Placental Abnormalities Uterine, cervical, and placental structural abnormalities: During the third trimester of pregnancy, vigorous fetal Uterine distortion (e.g., uterine fibroids), compromised growth places particularly heavy demands on the utero- structural support of the cervix (“cervical incompetence”), placental blood supply. Therefore, the adequacy of placental placenta previa, and abruptio placentae (Chapter 22) are growth in the preceding midtrimester is extremely important, associated with an increased risk of prematurity. and uteroplacental insufficiency is an important cause of Multiple gestation (twin pregnancy) growth restriction. This insufficiency may result from umbilical-placental vascular anomalies (such as single The hazards of prematurity are manifold for the newborn umbilical artery and abnormal cord insertion), placental and may give rise to one or more of the following: abruption, placenta previa, placental thrombosis and infarc- Neonatal respiratory distress syndrome, also known as hyaline tion, chronic villitis of unknown etiology, placental infection, membrane disease or multiple gestations (Chapter 22). In some cases the Necrotizing enterocolitis (NEC) placenta (and the baby) may be small without any detectable Sepsis underlying cause. Placental causes of FGR tend to result in Intraventricular and germinal matrix hemorrhage asymmetric (or disproportionate) growth restriction of the fetus with relative sparing of the brain. Physiologically, this Fetal Growth Restriction general type of FGR is viewed as a down-regulation of growth in the latter half of gestation because of limited Although preterm infants have low birth weights, it is usually availability of nutrients or oxygen. appropriate once adjusted for their gestational age. In The SGA infant faces a difficult course, not only during contrast, as many as one-third of infants who weigh less the struggle for survival in the perinatal period, but also in  Prematurity and fetal growth restriction 459 childhood and adult life. Depending on the underlying cause PREMATURITY of FGR and, to a lesser extent, the degree of prematurity, there is a significant risk of morbidity in the form of a major handicap such as cerebral dysfunction, learning disability, Reduced surfactant synthesis, storage, and release or hearing and visual impairment. Decreased alveolar surfactant Neonatal Respiratory Distress Syndrome There are many causes of respiratory distress in the Increased alveolar surface tension newborn. The most common cause is neonatal respiratory distress syndrome (RDS), also known as hyaline membrane Atelectasis disease because of the deposition of a layer of hyaline proteinaceous material in the peripheral airspaces of infants Uneven perfusion Hypoventilation who succumb to this condition. Others include excessive sedation of the mother, fetal head injury during delivery, aspiration of blood or amniotic fluid, and intrauterine Hypoxemia + CO2 retention hypoxia brought about by coiling of the umbilical cord about the neck. The incidence of RDS increases with decreasing Acidosis gestational age, being 1% at 37 weeks, 10.5% at 34 weeks, and 93% in extremely preterm infants (28 weeks or below). Pulmonary vasoconstriction Pathogenesis Increased The fundamental defect in RDS is pulmonary immaturity Pulmonary hypoperfusion diffusion and deficiency of surfactant. As described in Chapter 15, gradient surfactant consists predominantly of dipalmitoyl phospha- tidylcholine (lecithin), smaller amounts of phosphatidyl­ Endothelial Epithelial glycerol, and two groups of surfactant-associated proteins. damage damage The first group is composed of hydrophilic glycoproteins SP-A and SP-D, which play a role in pulmonary host defense (innate immunity). The second group consists of hydrophobic Plasma leak Fibrin + necrotic cells surfactant proteins SP-B and SP-C, which, in concert with into alveoli (hyaline membrane) the surfactant lipids, are involved in the reduction of surface tension at the air-liquid barrier in the alveoli of the lung. Figure 10.6 Schematic outline of the pathophysiology of respiratory distress syndrome (see text). 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 intrauterine stress and FGR that increase corticosteroid in neonates with congenital deficiency of surfactant caused release lower the risk of developing RDS. Surfactant synthesis by mutations in the SFTPB or SFTPC genes. can be suppressed by the compensatory high blood levels Surfactant production by type II alveolar cells is acceler- of insulin in infants of diabetic mothers, which counteracts ated after the 35th week of gestation in the fetus. At birth, the effects of steroids. This may explain, in part, why infants the first breath of life requires high inspiratory pressures of diabetic mothers have a higher risk of developing RDS. to expand the lungs. With normal levels of surfactant, the Labor is known to increase surfactant synthesis; hence, lungs retain up to 40% of the residual air volume after the cesarean delivery before the onset of labor may increase first breath; thus, subsequent breaths require far lower the risk of RDS. inspiratory pressures. With a deficiency of surfactant, the lungs collapse with each successive breath, so infants must work as hard with each successive breath as they did with MORPHOLOGY the first. The problem of stiff atelectatic lungs is compounded The lungs are distinctive on gross examination. Though of normal by the soft thoracic wall that is pulled in as the diaphragm size, they are solid, airless, and reddish purple, similar to the color descends. Progressive atelectasis and reduced lung compli- of the liver, and they usually sink in water, indicating the relative ance then lead to a chain of events as depicted in Fig. 10.6, absence of entrapped air. Microscopically, alveoli are poorly resulting in protein-rich, fibrin-rich exudation into the developed, and those that are present are collapsed (Fig. 10.7). alveolar spaces with the formation of hyaline membranes. When the infant dies early in the course of the disease, necrotic The fibrin-hyaline membranes are barriers to gas exchange, cellular debris can be seen in the terminal bronchioles and alveolar leading to carbon dioxide retention and hypoxemia. The ducts. The necrotic material becomes incorporated within hypoxemia itself further impairs surfactant synthesis, and eosinophilic hyaline membranes lining the respiratory a vicious cycle ensues. bronchioles, alveolar ducts, and alveoli. The membranes are largely Surfactant synthesis is modulated by a variety of made up of fibrin admixed with cell debris derived chiefly from hormones and growth factors, including cortisol, insulin, necrotic type II pneumocytes. The sequence of events that leads prolactin, thyroxine, and TGF-β. The role of glucocorticoids to the formation of hyaline membranes is depicted in Fig. 10.6. is particularly important. Conditions associated with 460 C H A P T E R 10 Diseases of Infancy and Childhood provides a good estimate of the level of surfactant in the alveolar lining. Prophylactic administration of exogenous surfactant at birth to extremely premature infants (gestational age