Pathology_Robbins

Pathology_Robbins. An inherited deficiency of any one of the enzymes involved in glycogen synthesis or degradation can result in excessive accumulation of glycogen or some abnormal form of glycogen in various tissues. The type of glycogen stored, its intracellular location, and the tissue distribution of the affected cells vary depending on the specific enzyme deficiency. Regardless of the tissue or cells affected, the glycogen most often is stored within the cytoplasm, or sometimes within nuclei. One variant, Pompe disease, is a form of lysosomal storage disease, because the missing enzyme is localized to lysosomes. Most glycogenoses are inherited as autosomal recessive diseases, as is common with “missing enzyme” syndromes. Approximately a dozen forms of glycogenoses have been described in association with specific enzyme deficiencies. Based on pathophysiologic findings, they can be grouped into three categories ( Table 7.4


Pathology_Robbins

Pathology_Robbins. Table 7.4 Hepatic type. Liver contains several enzymes that synthesize glycogen for storage and also break it down into free glucose. Hence, a deficiency of the hepatic enzymes involved in glycogen metabolism is associated with two major clinical effects: enlargement of the liver due to storage of glycogen and hypoglycemia due to a failure of glucose production ( Fig. 7.12 ). Von Gierke disease (type I glycogenosis), resulting from a lack of glucose-6phosphatase, is the most important example of the hepatic form of glycogenosis ( Table 7.4


Pathology_Robbins

Pathology_Robbins. Fig. 7.12 ). Von Gierke disease (type I glycogenosis), resulting from a lack of glucose-6phosphatase, is the most important example of the hepatic form of glycogenosis ( Table 7.4 Myopathic type. In striated muscle, glycogen is an important source of energy. Not surprisingly, most forms of glycogen storage disease affect muscles. When enzymes that are involved in glycolysis are deficient, glycogen storage occurs in muscles and there is an associated muscle weakness due to impaired energy production. Typically, the myopathic forms of glycogen storage diseases are marked by muscle cramps after exercise, myoglobinuria, and failure of exercise to induce an elevation in blood lactate levels because of a block in glycolysis. McArdle disease (type V glycogenosis), resulting from a deficiency of muscle phosphorylase, is the prototype of myopathic glycogenoses.


Pathology_Robbins

Pathology_Robbins. Type II glycogenosis (Pompe disease) is caused by a deficiency of lysosomal acid maltase and is associated with deposition of glycogen in virtually every organ, but cardiomegaly is most prominent. Most affected patients die within 2 years of onset of cardiorespiratory failure. Therapy with the missing enzyme (glucosidase) can reverse cardiac muscle damage and modestly increase longevity. http://ebooksmedicine.net Inheriteddeficiencyofenzymesinvolvedinglycogenmetabolismcanresultinstorageofnormalorabnormalformsofglycogen,predominantlyinliverormusclesorinalltissues. Inthehepaticform(vonGierkedisease),livercellsstoreglycogenbecauseofalackofhepaticglucose-6-phosphatase. Thereareseveralmyopathicforms,includingMcArdledisease,inwhichlackofmusclephosphorylasegivesrisetostorageinskeletalmusclesandcrampsafterexercise. InPompediseasethereislackoflysosomalacidmaltase,andallorgansareaffected,butheartinvolvementispredominant.


Pathology_Robbins

Pathology_Robbins. InPompediseasethereislackoflysosomalacidmaltase,andallorgansareaffected,butheartinvolvementispredominant. As detailed in Chapter 6, two classes of genes, protooncogenes and tumor suppressor genes, regulate normal cell growth. Mutations affecting these genes, most often in somatic cells, are involved in the pathogenesis of tumors. In approximately 5% to 10% of all cancers, however, mutations affecting certain tumor suppressor genes are present in all cells of the body, including germ cells, and hence can be transmitted to the offspring. These mutant genes predispose the offspring to hereditary tumors, a topic discussed in greater detail in Chapter 6. A few salient examples of familial neoplasms arising in children are discussed later in this chapter.


Pathology_Robbins

Pathology_Robbins. Complex multigenic disorders—so-called “multifactorial or polygenic disorders”—are caused by interactions between genetic variants and environmental factors. A genetic variant that occurs in at least 1% of the population is called a polymorphism. According to the common disease–common variant hypothesis, complex multigenic disorders occur when many polymorphisms, each with a modest effect and low penetrance, are coinherited. Two additional important facts have emerged from studies of common complex disorders such as type 1 diabetes: • Although complex disorders result from the collective inheritance of many polymorphisms, different polymorphisms vary in significance. For example, of the 20 to 30 genes implicated in type 1 diabetes, 6 or 7 are most important, and a few HLA alleles contribute more than 50% of the risk (Chapter 20). http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 7.12 (Top) Asimplifiedschemeofnormalglycogenmetabolismintheliverandskeletalmuscles.(Middle) Theeffectsofaninheriteddeficiencyofhepaticenzymesinvolvedinglycogenmetabolism.(Bottom) Theconsequencesofageneticdeficiencyintheenzymesthatmetabolizeglycogeninskeletalmuscles. Some polymorphisms are common to multiple diseases of the same type, whereas others are disease-specific. This observation is well illustrated in immune-mediated inflammatory diseases (Chapter 5). Many of the disease-associated polymorphisms are in noncoding regions so they likely affect epigenetic regulation of gene expression.


Pathology_Robbins

Pathology_Robbins. Several normal phenotypic characteristics are governed by multigenic inheritance, such as hair color, eye color, skin color, height, and intelligence. These characteristics (also known as quantitative trait loci [QTLs]) show a continuous variation within, as well as across, all population groups. Environmental influences, however, significantly modify the phenotypic expression of complex traits. For example, type 2 diabetes mellitus has many of the features of a complex multigenic disorder. It is well recognized clinically that affected persons often first exhibit clinical manifestations of this disease after weight gain. Thus, obesity, as well as other environmental influences, unmasks the diabetic genetic trait. Assigning a disease to this mode of inheritance must be done with caution. Such attribution depends on many factors but first on familial clustering and the exclusion of mendelian and chromosomal modes of transmission. A range of levels of severity of a disease is suggestive


Pathology_Robbins

Pathology_Robbins. attribution depends on many factors but first on familial clustering and the exclusion of mendelian and chromosomal modes of transmission. A range of levels of severity of a disease is suggestive of a complex multigenic disorder, but, as pointed out earlier, variable expressivity and reduced penetrance of single mutant genes also may account for this phenomenon. Because of these issues, it is sometimes difficult to distinguish between mendelian and multifactorial disorders.


Pathology_Robbins

Pathology_Robbins. Chromosomal abnormalities occur much more frequently than is generally appreciated. It is estimated that approximately 1 in 200 newborn infants has some form of chromosomal abnormality. The figure is much higher in fetuses that do not survive to term; in as many as 50% of first-trimester spontaneous abortions, the fetus may have a chromosomal abnormality. Cytogenetic disorders result from alterations in the number or structure of chromosomes and may affect autosomes or sex chromosomes.


Pathology_Robbins

Pathology_Robbins. Before embarking on a discussion of chromosomal aberrations, it is appropriate to review karyotyping as the basic tool of the cytogeneticist. A karyotype is a photographic representation of a stained metaphase spread in which the chromosomes are arranged in order of decreasing length. A variety of techniques for staining chromosomes has been developed. With the widely used Giemsa stain (G banding) technique, each chromosome set can be seen to possess a distinctive pattern of alternating light and dark bands of variable widths ( Fig. 7.13 ). The use of banding techniques allows identification of each chromosome, and can detect and localize structural abnormalities large enough to produce changes in banding pattern (described later).


Pathology_Robbins

Pathology_Robbins. In humans, the normal chromosome count is 46 (i.e., 2n = 46). Any exact multiple of the haploid number (n) is called euploid. Chromosome numbers such as 3n and 4n are called polyploid. Polyploidy generally results in a spontaneous abortion. Any number that is not an exact multiple of n is called aneuploid. The chief cause of aneuploidy is nondisjunction of a homologous pair of chromosomes at the first meiotic division or a failure of sister chromatids to separate during the second meiotic division. The latter also may occur during mitosis in somatic cells, leading to the production of two aneuploid cells. Failure of pairing of homologous chromosomes followed by random assortment (anaphase lag) also can lead to aneuploidy. When nondisjunction occurs at the time of meiosis, the gametes formed have either an extra chromosome (n + 1) or one less chromosome (n − 1). Fertilization of such gametes by normal gametes would result in two types of zygotes: trisomic, with an extra chromosome (2n


Pathology_Robbins

Pathology_Robbins. have either an extra chromosome (n + 1) or one less chromosome (n − 1). Fertilization of such gametes by normal gametes would result in two types of zygotes: trisomic, with an extra chromosome (2n + 1), or monosomic (2n − 1). Monosomy involving an autosome is incompatible with life, whereas trisomies of certain autosomes and monosomy involving sex chromosomes are compatible with life. These, as we shall see, are associated with variable degrees of phenotypic abnormality. Mosaicism is a term used to describe the presence of two or more populations of cells with different complements of chromosomes in the same individual. In the context of chromosome numbers, postzygotic mitotic nondisjunction would result in the production of a trisomic and a monosomic daughter cell; the descendants of these cells would then produce a mosaic. As discussed later, mosaicism affecting sex chromosomes is common, whereas autosomal mosaicism is not.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 7.13 G-bandedkaryotypefromanormalmale(46,XY).AlsoshownisthebandingpatternoftheX-chromosomewithnomenclatureofarms,regions,bands,andsubbands.(Karyotype courtesy of Dr. Stuart Schwartz, Department of Pathology, University of Chicago, Chicago, Illinois.) 2 3 2211112323456781 3 3 4 2 2 2 1 1 1 2 2 3 3 X-CHROMOSOME 1 1 Arm Region Band Sub-band p q 1 1 6 13 19 20 21 22 X Y 14 15 16 17 18 7 8 9 10 11 12 2 3 4 5 1 2 Structural changes in the chromosomes typically result from chromosomal breakage followed by loss or rearrangement of material. Such changes usually are designated using a cytogenetic shorthand in which p (French, petit) denotes the short arm of a chromosome, and q, the long arm. Each arm is then divided into numbered regions (1, 2, 3, and so on) from centromere outward, and within each region the bands are numerically ordered (


Pathology_Robbins

Pathology_Robbins. Fig. 7.13 ). Thus, 2q34 indicates chromosome 2, long arm, region 3, band 4. The patterns of chromosomal rearrangement after breakage ( Fig. 7.14 ) are as follows: • Translocation implies transfer of a part of one chromosome to another chromosome. The process is usually reciprocal (i.e., fragments are exchanged between two chromosomes). In genetic shorthand, translocations are indicated by t followed by the involved chromosomes in numeric order—for example, 46,XX,t(2;5)(q31;p14). This notation would indicate a reciprocal translocation involving the long arm (q) of chromosome 2 at region 3, band 1, and the short arm of chromosome 5, region 1, band 4. When the entire broken fragments are exchanged, the resulting balanced reciprocal translocation (


Pathology_Robbins

Pathology_Robbins. Fig. 7.14 ) is not harmful to the carrier, who has the normal number of chromosomes and the full complement of genetic material. However, during gametogenesis, abnormal (unbalanced) gametes are formed, resulting in abnormal zygotes. A special pattern of translocation involving two acrocentric chromosomes is called centric fusion type, or robertsonian, translocation. The breaks typically occur close to the centromere, affecting the short arms of both chromosomes. Transfer of the segments leads to one very large chromosome and one extremely small one ( Fig. 7.14 ). The short fragments are lost, and the carrier has 45 chromosomes. Because the short arms of all acrocentric chromosomes carry highly redundant genes (e.g., ribosomal RNA genes), such loss is compatible with survival. However, difficulties arise during gametogenesis, resulting in the formation of unbalanced gametes that could lead to abnormal offspring.


Pathology_Robbins

Pathology_Robbins. • Isochromosomes result when the centromere divides horizontally rather than vertically. One of the two arms of the chromosome is then lost, and the remaining arm is duplicated, resulting in a chromosome with only two short arms or two long arms. The most common isochromosome present in live births involves the long arm of the X chromosome and is designated i(Xq). When fertilization occurs by a gamete that contains a normal X chromosome, the result is monosomy for genes on Xp and trisomy for genes on Xq. http://ebooksmedicine.net Fig. 7.14 Typesofchromosomalrearrangements. Deletion involves loss of a portion of a chromosome. A single break may delete a terminal segment. Two interstitial breaks, with reunion of the proximal and distal segments, may result in loss of an internal segment. The isolated fragment, which lacks a centromere, almost never survives, and thus many genes are lost.


Pathology_Robbins

Pathology_Robbins. Inversions occur when there are two interstitial breaks in a chromosome, and the segment reunites after a complete turnaround. ring chromosome is a variant of a deletion. After loss of segments from each end of the chromosome, the arms unite to form a ring. Chromosomal disorders may be associated with absence (deletion, monosomy), excess (trisomy), or abnormal rearrangements (translocations) of chromosomes. In general, a loss of chromosomal material produces more severe defects than does a gain of chromosomal material. Excess chromosomal material may result from a complete chromosome (as in trisomy) or from part of a chromosome (as in Robertsonian translocation). Imbalances of sex chromosomes (excess or loss) are tolerated much better than are similar imbalances of autosomes. Sex chromosomal disorders often produce subtle abnormalities, sometimes not detected at birth. Infertility, a common manifestation, cannot be diagnosed until adolescence.


Pathology_Robbins

Pathology_Robbins. Sex chromosomal disorders often produce subtle abnormalities, sometimes not detected at birth. Infertility, a common manifestation, cannot be diagnosed until adolescence. In most cases, chromosomal disorders result from de novo changes (i.e., parents are normal, and risk of recurrence in siblings is low). The translocation form of Down syndrome (described later) exhibits an uncommon but important exception to this principle. Some specific examples of diseases involving changes in the karyotype are presented next. Three autosomal trisomies (21, 18, and 13) and one deletion syndrome (cri du chat syndrome), which results from partial deletion of the short arm of chromosome 5, were the first chromosomal abnormalities identified. More recently, several additional trisomies and deletion syndromes (such as those affecting 22q) have been described. Most of these disorders are quite uncommon, but their clinical features should permit ready recognition ( Fig. 7.15


Pathology_Robbins

Pathology_Robbins. Fig. 7.15 Only trisomy 21 and 22q11.2 deletions occur with sufficient frequency to merit further consideration. Down syndrome, characterized by extra copy of genes on chromosome 21, is the most common of the chromosomal disorders. About 95% of affected persons have trisomy 21, so their chromosome count is 47. As mentioned earlier, the most common cause of trisomy, and therefore of Down syndrome, is meiotic nondisjunction. The parents of such children are normal in all respects. Maternal age has a strong influence on the incidence of Down syndrome. It occurs in 1 in 1550 live births in women younger than 20 years, in contrast with 1 in 25 live births in women older than 45 years. The correlation with maternal age suggests http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Mental retardation Prominent occiput Mental retardation Micrognathia Low set ears Epicanthic folds and flat facial profile Congenital heart defects Intestinal stenosis Gap between first and second toe Umbilical hernia Hypotonia Abundant neck skin Simian crease Predisposition to leukemia TRISOMY 21: DOWN SYNDROME Incidence: 1 in 700 births Karyotypes: Trisomy 21 type: 47,XX, +21 Translocation type: 46,XX,der(14;21)(q10;q10),+21 Mosaic type: 46,XX/47,XX, +21 TRISOMY 13: PATAU SYNDROME Incidence: 1 in 15,000 births Karyotypes: Trisomy 13 type: 47,XX, +13 Translocation type: 46,XX,+13,der(13;14)(q10;q10) Mosaic type: 46,XX/47,XX, +13 TRISOMY 18: EDWARDS SYNDROME Incidence: 1 in 8000 births Karyotypes: Trisomy 18 type: 47,XX, +18 Mosaic type: 46,XX/47,XX, +18 Short neck Overlapping fingers Congenital heart defects Renal malformations Limited hip abduction Microphthalmia Polydactyly Cardiac defects Umbilical hernia Rocker-bottom feet Microcephaly and mental retardation Cleft lip and palate


Pathology_Robbins

Pathology_Robbins. heart defects Renal malformations Limited hip abduction Microphthalmia Polydactyly Cardiac defects Umbilical hernia Rocker-bottom feet Microcephaly and mental retardation Cleft lip and palate Renal defects Rocker-bottom feet


Pathology_Robbins

Pathology_Robbins. Fig. 7.15 Clinicalfeaturesandkaryotypesofthethreemostcommonautosomaltrisomies. http://ebooksmedicine.net that in most cases the meiotic nondisjunction of chromosome 21 occurs in the ovum. Indeed, in 95% of cases the extra chromosome is of maternal origin. The reason for the increased susceptibility of the ovum to nondisjunction with aging is not fully understood. No effect of paternal age has been found in those cases in which the extra chromosome is derived from the father.


Pathology_Robbins

Pathology_Robbins. In about 4% of all patients with trisomy 21, the extra chromosomal material is present as a translocation of the long arm of chromosome 21 to chromosome 22 or 14. Such cases frequently (but not always) are familial, and the translocated chromosome is inherited from one of the parents, who typically is a carrier of a Robertsonian translocation. Approximately 1% of patients with trisomy 21 are mosaics, usually having a mixture of 46-and 47-chromosome cells. These cases result from mitotic nondisjunction of chromosome 21 during an early stage of embryogenesis. Clinical manifestations in such cases are variable and milder, depending on the proportion of abnormal cells. The diagnostic clinical features of this condition—flat facial profile, oblique palpebral fissures, and epicanthic folds (


Pathology_Robbins

Pathology_Robbins. The diagnostic clinical features of this condition—flat facial profile, oblique palpebral fissures, and epicanthic folds ( Fig. 7.15 )—are usually readily evident, even at birth. Down syndrome is a leading cause of severe mental retardation; approximately 80% of those afflicted have an IQ of 25 to 50. By contrast, some mosaics with Down syndrome have mild phenotypic changes and normal or near-normal intelligence. In addition to the phenotypic abnormalities and the mental retardation already noted, some other clinical features are worthy of mention: Approximately 40% of the patients have congenital heart disease, most commonly defects of the endocardial cushion, including atrial septal defects, atrioventricular valve malformations, and ventricular septal defects (Chapter 11). Cardiac problems are responsible for a majority of the deaths in infancy and early childhood. Several other congenital malformations, including atresias of the esophagus and small bowel, also are common.


Pathology_Robbins

Pathology_Robbins. Children with trisomy 21 have a tenfold-to twentyfold increased risk of developing acute leukemia. Both acute lymphoblastic leukemias and acute myeloid leukemias occur (Chapter 12). Virtually all patients with trisomy 21 older than age 40 develop neuropathologic changes characteristic of Alzheimer disease, a degenerative disorder of the brain (Chapter 23). Patients with Down syndrome demonstrate abnormal immune responses that predispose them to serious infections, particularly of the lungs, and to thyroid autoimmunity (Chapter 20). Although several abnormalities, affecting mainly T cell functions, have been reported, the basis for the immunologic disturbances is not clear.


Pathology_Robbins

Pathology_Robbins. Despite all of these problems, improved medical care has increased the longevity of persons with trisomy 21. Currently the median age at death is 60 years (up from 25 years in 1983). Although the karyotype of Down syndrome has been known for decades, the molecular basis for this disease remains elusive. Studies of humans with partial trisomy of chromosome 21 and mouse models of trisomy have identified the critical region of human chromosome 21 that is involved in the pathogenesis. Based on these studies, several gene clusters, each of which is predicted to participate in the same biologic pathway, have been implicated. For example, 16 genes are involved in the mitochondrial energy pathway, several are likely to influence CNS development, and one group is involved in folate metabolism. It is not known how each of these groups of genes is related to Down syndrome. Adding complexity is the fact that several miRNA genes reside on chromosome 21 that can shut down translation of genes that


Pathology_Robbins

Pathology_Robbins. is not known how each of these groups of genes is related to Down syndrome. Adding complexity is the fact that several miRNA genes reside on chromosome 21 that can shut down translation of genes that map elsewhere in the genome.


Pathology_Robbins

Pathology_Robbins. Much progress is being made in the molecular diagnosis of Down syndrome prenatally. Approximately 5% to 10% of the total cell free DNA in maternal blood is derived from the fetus and can be identified by polymorphic genetic markers. By using next-generation sequencing, the gene dosage of chromosome 21-linked genes in fetal DNA can be determined with great precision. This has emerged as a sensitive and specific noninvasive method (“liquid biopsy”) for prenatal diagnosis of trisomy 21 as well as other trisomies. Currently, all cases of trisomy 21 identified by such liquid biopsies are confirmed by conventional cytogenetics on fetal cells obtained by amniocentesis. 22q11.2 Deletion Syndrome


Pathology_Robbins

Pathology_Robbins. The 22q11.2 deletion syndrome encompasses a spectrum of disorders that result from a small interstitial deletion of band 11 on the long arm of chromosome 22. The clinical features of this syndrome include congenital heart disease affecting the outflow tracts, abnormalities of the palate, facial dysmorphism, developmental delay, thymic hypoplasia with impaired T cell immunity (Chapter 5), and parathyroid hypoplasia resulting in hypocalcemia (Chapter 20). Previously, these clinical features were believed to represent two different disorders: DiGeorge syndrome and velocardiofacial syndrome. However, it is now known that both are caused by 22q11.2 deletion. Variations in the size and position of the deletion are thought to be responsible for the differing clinical manifestations. When T cell immunodeficiency and hypocalcemia are the dominant features, the patients are said to have DiGeorge syndrome, whereas patients with the so-called velocardiofacial syndrome have mild immunodeficiency


Pathology_Robbins

Pathology_Robbins. immunodeficiency and hypocalcemia are the dominant features, the patients are said to have DiGeorge syndrome, whereas patients with the so-called velocardiofacial syndrome have mild immunodeficiency and pronounced dysmorphology and cardiac defects. In addition to these malformations, patients with 22q11.2 deletion are at high risk for schizophrenia and bipolar disorder. In fact, it is estimated that schizophrenia develops in approximately 25% of adults with this syndrome. Conversely, deletions of the region can be found in 2% to 3% of individuals with childhood-onset schizophrenia. The molecular basis for this syndrome is not fully understood. The affected region of chromosome 11 encodes many genes. Among these, a transcription factor gene called TBX1 is suspected to be one of the responsible candidates, because its loss seems to correlate with the occurrence of DiGeorge syndrome. Clearly there are other genes that contribute to the behavioral and psychiatric disorders that remain to


Pathology_Robbins

Pathology_Robbins. candidates, because its loss seems to correlate with the occurrence of DiGeorge syndrome. Clearly there are other genes that contribute to the behavioral and psychiatric disorders that remain to be identified.


Pathology_Robbins

Pathology_Robbins. The diagnosis of this condition may be suspected on clinical grounds but can be established only by detection of the deletion, typically by fluorescence in situ hybridization (FISH) (see Fig. 7.38B http://ebooksmedicine.net Downsyndromeisassociatedwithanextracopyofgenesonchromosome21,mostcommonlyduetotrisomy21andlessfrequentlyfromtranslocationofextrachromosomalmaterialfromchromosome21tootherchromosomesorfrommosaicism. PatientswithDownsyndromehaveseverementalretardation,flatfacialprofile,epicanthicfolds,cardiacmalformations,higherriskofleukemiaandinfections,andprematuredevelopmentofAlzheimerdisease. Deletionofgenesatchromosomallocus22q11.2givesrisetomalformationsaffectingtheface,heart,thymus,andparathyroids.Theresultingdisordersarerecognizedas(1)DiGeorgesyndrome(thymichypoplasiawithdiminishedT-cellimmunityandparathyroidhypoplasiawithhypocalcemia),and(2)velocardiofacialsyndrome(congenitalheartdiseaseinvolvingoutflowtracts,facialdysmorphism,anddevelopmentaldelay).


Pathology_Robbins

Pathology_Robbins. A number of abnormal karyotypes involving the sex chromosomes, ranging from 45,X to 49,XXXXY, are compatible with life. Indeed, phenotypically normal males with two and even three Y chromosomes have been identified. Such extreme karyotypic deviations are not encountered with the autosomes. In large part, this latitude relates to two factors: lyonization of X chromosomes and the small amount of genetic information carried by the Y chromosome. The consideration of lyonization must begin with Mary Lyon, who in 1962 proposed that in females, only one X chromosome is genetically active. X inactivation occurs early in fetal life, about 16 days after conception. Either the paternal or the maternal X chromosome is randomly inactivated in each cell of the developing embryo. Once inactivated, the same X chromosome remains inactive in all of the progeny of these cells. Moreover, all but one X chromosome is inactivated, and so a 48,XXXX female has only one active X chromosome. This phenomenon


Pathology_Robbins

Pathology_Robbins. same X chromosome remains inactive in all of the progeny of these cells. Moreover, all but one X chromosome is inactivated, and so a 48,XXXX female has only one active X chromosome. This phenomenon explains why normal females do not have a double dose (compared with males) of phenotypic attributes encoded on the X chromosome. The Lyon hypothesis also explains why normal females are in reality mosaics, containing two cell populations: one with an active maternal X, the other with an active paternal X. The molecular basis of X inactivation involves a long non–coding RNA that is encoded by the XIST gene. This non–coding RNA is retained in the nucleus, where it “coats” the X chromosome that it is transcribed from and silences the genes on that chromosome. The other XIST allele is switched off in the active X, allowing genes encoded one one X chromosome to be expressed.


Pathology_Robbins

Pathology_Robbins. Although essentially accurate, the Lyon hypothesis subsequently has been somewhat modified. Most important, the initial presumption that all of the genes on the inactive X are “switched off” has been revised, as roughly 21% of genes on Xp, and a smaller number (3%) on Xq, escape X inactivation. This observation has implications for monosomic X chromosome disorders, or Turner syndrome, as discussed later. Extra Y chromosomes are readily tolerated because the only information known to be carried on the Y chromosome seems to relate to male differentiation. Of note, whatever the number of X chromosomes, the presence of a Y invariably dictates the male phenotype. The gene for male differentiation (SRY, sex-determining region of Y chromosome) is located on the short arm of the Y. Described briefly next are two disorders, Klinefelter syndrome and Turner syndrome, that result from aberrations of sex chromosomes.


Pathology_Robbins

Pathology_Robbins. Described briefly next are two disorders, Klinefelter syndrome and Turner syndrome, that result from aberrations of sex chromosomes. Klinefelter syndrome is defined as male hypogonadism that develops when there are at least two X chromosomes and one or more Y chromosomes. It is the most common cause of hypogonadism in males. Most affected patients have a 47,XXY karyotype. This karyotype results from non-disjunction of sex chromosomes during meiosis. The extra X chromosome may be of either maternal or paternal origin. Advanced maternal age and a history of irradiation in either parent may contribute to the meiotic error resulting in this condition. Approximately 15% of the patients show mosaic patterns, including 46,XY/47,XXY, 47,XXY/48,XXXY, and variations on this theme. The presence of a 46,XY line in mosaics usually is associated with a milder clinical condition.


Pathology_Robbins

Pathology_Robbins. Klinefelter syndrome is associated with a wide range of clinical manifestations. In some persons it may be expressed only as hypogonadism, but most patients have a distinctive body habitus with an increase in length between the soles and the pubic bone, which creates the appearance of an elongated body. Also characteristic is eunuchoid body habitus. Reduced facial, body, and pubic hair and gynecomastia also are frequently seen. The testes are markedly reduced in size, sometimes to only 2 cm in greatest dimension. In keeping with the testicular atrophy, the serum testosterone levels are lower than normal, and urinary gonadotropin levels are elevated.


Pathology_Robbins

Pathology_Robbins. Only rarely are patients with the Klinefelter syndrome fertile, and presumably such persons are mosaics with a large proportion of 46,XY cells. The sterility is due to impaired spermatogenesis, sometimes to the extent of total azoospermia. Histologic examination shows hyalinization of tubules, which appear as ghostlike structures on tissue section. By contrast, Leydig cells are prominent, as a result of either hyperplasia or an apparent increase related to loss of tubules. Although Klinefelter syndrome may be associated with mental retardation, the degree of intellectual impairment typically is mild, and in some cases, no deficit is detectable. The reduction in intelligence is correlated with the number of extra X chromosomes. Klinefelter syndrome is associated with a higher frequency of several disorders, including breast cancer (seen 20 times more commonly than in normal males), extragonadal germ-cell tumors, and autoimmune diseases such as systemic lupus erythematosus.


Pathology_Robbins

Pathology_Robbins. Turner syndrome, characterized by primary hypogonadism in phenotypic females, results from partial or http://ebooksmedicine.net complete monosomy of the short arm of the X chromosome. With routine cytogenetic methods, the entire X chromosome is found to be missing in 57% of patients, resulting in a 45,X karyotype. These patients are the most severely affected, and the diagnosis often can be made at birth or early in childhood. Typical clinical features associated with 45,X Turner syndrome include growth retardation, leading to abnormally short stature (below the third percentile); swelling of the nape of the neck because of distended lymphatic channels (in infancy) that is seen as webbing of the neck in older children; low posterior hairline; cubitus valgus (an increase in the carrying angle of the arms); shieldlike chest with widely spaced nipples; high-arched palate; lymphedema of the hands and feet; and a variety of congenital malformations such as horseshoe kidney, bicuspid aortic


Pathology_Robbins

Pathology_Robbins. of the arms); shieldlike chest with widely spaced nipples; high-arched palate; lymphedema of the hands and feet; and a variety of congenital malformations such as horseshoe kidney, bicuspid aortic valve, and coarctation of the aorta (


Pathology_Robbins

Pathology_Robbins. Fig. 7.16 ). Cardiovascular abnormalities are the most common cause of death in childhood. In adolescence, affected girls fail Coarctation of aorta Broad chest Streak ovaries, infertility, amenorrhea Incidence: 1 in 3000 female births Karyotypes: Classic: 45,X Defective second X chromosome: 46,X,i(Xq) 46,XXq– 46,XXp– 46,X, r(X) Mosaic type: 45,X/46,XX Fig. 7.16 ClinicalfeaturesandkaryotypesofTurnersyndrome.


Pathology_Robbins

Pathology_Robbins. Fig. 7.16 ClinicalfeaturesandkaryotypesofTurnersyndrome. to develop normal secondary sex characteristics; the genitalia remain infantile, breast development is minimal, and little pubic hair appears. Most patients have primary amenorrhea, and morphologic examination shows transformation of the ovaries into white streaks of fibrous stroma devoid of follicles. The mental status of these patients usually is normal, but subtle defects in visual–spatial information processing have been noted. Curiously, hypothyroidism caused by autoantibodies occurs, especially in women with isochromosome Xp. As many as 50% of these patients develop clinical hypothyroidism. In adult patients, a combination of short stature and primary amenorrhea should prompt strong suspicion for Turner syndrome. The diagnosis is established by karyotyping.


Pathology_Robbins

Pathology_Robbins. Approximately 43% of patients with Turner syndrome either are mosaics (one of the cell lines being 45,X) or have structural abnormalities of the X chromosome. The most common is deletion of the short arm, resulting in the formation of an isochromosome of the long arm, 46,X,i(X) (q10). The net effect of the associated structural abnormalities is to produce partial monosomy of the X chromosome. Combinations of deletions and mosaicism also occur. It is important to appreciate the karyotypic heterogeneity associated with Turner syndrome because it is responsible for significant variations in the phenotype. In contrast with the patients with monosomy X, those who are mosaics or have deletion variants may have an almost normal appearance and may present only with primary amenorrhea.


Pathology_Robbins

Pathology_Robbins. The molecular pathogenesis of Turner syndrome is not completely understood, but studies have begun to shed some light. As mentioned earlier, both X chromosomes are active during oogenesis and are essential for normal development of the ovaries. During normal fetal development, ovaries contain as many as 7 million oocytes. The oocytes gradually disappear so that by menarche their numbers have dwindled to a mere 400,000, and when menopause occurs fewer than 10,000 remain. In Turner syndrome, fetal ovaries develop normally early in embryogenesis, but the absence of the second X chromosome leads to an accelerated loss of oocytes, which is complete by age 2 years. In a sense, therefore, “menopause occurs before menarche,” and the ovaries are reduced to atrophic fibrous strands, devoid of ova and follicles (streak ovaries). Because patients with Turner syndrome also have other (nongonadal) abnormalities, it follows that genes required for normal growth and development of somatic tissues


Pathology_Robbins

Pathology_Robbins. and follicles (streak ovaries). Because patients with Turner syndrome also have other (nongonadal) abnormalities, it follows that genes required for normal growth and development of somatic tissues also must reside on the X chromosome. Among the genes involved in the Turner phenotype is the short stature homeobox (SHOX) gene at Xp22.33. This is one of the genes that remain active in both X chromosomes and is unique in having an active homologue on the short arm of the Y chromosome. Thus, both normal males and females have two active copies of this gene. Loss of one copy of SHOX gives rise to short stature. Indeed, deletions of the SHOX gene are noted in 2% to 5% of otherwise normal children with short stature. Whereas loss of one copy of SHOX can explain the growth deficit in Turner syndrome, it cannot explain other important clinical features such as cardiac malformations and endocrine abnormalities. Clearly, several other genes located on the X chromosome also are involved.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Infemales,oneXchromosome,maternalorpaternal,israndomlyinactivatedduringdevelopment(Lyonhypothesis). InKlinefeltersyndrome,therearetwoormoreXchromosomeswithoneYchromosomeasaresultofnondisjunctionofsexchromosomes.Patientshavetesticularatrophy,sterility,reducedbodyhair,gynecomastia,andeunuchoidbodyhabitus.Itisthemostcommoncauseofmalesterility. InTurnersyndrome,thereispartialorcompletemonosomyofgenesontheshortarmoftheXchromosome,mostcommonlycausedbytheabsenceofoneXchromosome(45,X)andlesscommonlybymosaicism,orbydeletionsinvolvingtheshortarmoftheXchromosome.Shortstature,webbingoftheneck,cubitusvalgus,cardiovascularmalformations,amenorrhea,lackofsecondarysexcharacteristics,andfibroticovariesaretypicalclinicalfeatures. Three groups of diseases resulting from mutations affecting single genes do not follow the mendelian rules of inheritance: Diseases associated with alteration of imprinted regions of the genome


Pathology_Robbins

Pathology_Robbins. Three groups of diseases resulting from mutations affecting single genes do not follow the mendelian rules of inheritance: Diseases associated with alteration of imprinted regions of the genome Fragile X syndrome is the prototype of diseases in which the causative mutation occurs in a long repeating sequence of three nucleotides. Other examples of diseases associated with trinucleotide repeat mutations are Huntington disease and myotonic dystrophy. This type of mutation is now known to cause about 40 diseases, and all disorders discovered so far are associated with neurodegenerative changes. In each of these conditions, amplification of specific sets of three nucleotides within the gene disrupts its function. Certain unique features of trinucleotide repeat mutations, described later, are responsible for the atypical pattern of inheritance of the associated diseases.


Pathology_Robbins

Pathology_Robbins. Fragile X syndrome results from a mutation in the FMR1 gene, which maps to Xq27.3 and is the second most common genetic cause of mental retardation, after Down syndrome. It has a frequency of 1 in 1550 for males and 1 in 8000 for females. The syndrome derives its name from the karyotypic appearance of the X chromosome in the original method of diagnosis. Culturing patient cells in a folate-deficient medium typically showed a discontinuity of staining or constriction in the long arm of the X chromosome. This method has now been supplanted by DNA-based analysis of triplet repeat size, as discussed later. Clinically affected males have moderate to severe mental retardation, although the extent of impairment is highly variable. It is not unusual for some children to initially be diagnosed with autism-like symptoms. The typical physical phenotype includes a long face with a large mandible, large everted ears, and large testicles (macroorchidism). Although characteristic of fragile X


Pathology_Robbins

Pathology_Robbins. with autism-like symptoms. The typical physical phenotype includes a long face with a large mandible, large everted ears, and large testicles (macroorchidism). Although characteristic of fragile X syndrome, these abnormalities are not always present or may be quite subtle. The only distinctive physical abnormality that can be detected in at least 90% of postpubertal males with fragile X syndrome is macroorchidism.


Pathology_Robbins

Pathology_Robbins. As with all X-linked diseases, fragile X syndrome predominantly affects males. Analysis of several pedigrees, however, shows some patterns of transmission not typically associated with other X-linked recessive disorders ( Fig. 7.17 ). These include the following: Carrier males. Approximately 20% of males who, by pedigree analysis, are known to carry a fragile X mutation do not manifest the typical neurological symptoms or physical characteristics of fragile X during childhood. As discussed below, these carrier males (also known as “transmitting males”) harbor a detectable molecular abnormality at the FMR1 locus but not the full-fledged mutation observed in symptomatic children.


Pathology_Robbins

Pathology_Robbins. Affected females. From 30% to 50% of carrier women with the fragile X mutation on one chromosome might show features of mild cognitive impairment or other behavioral disturbances. Approximately 20% develop features of premature reproductive failure (see below). The presence of symptoms in carrier females, albeit mild, is unusual for an X-linked recessive disease. Anticipation. This term refers to the phenomenon whereby clinical features of fragile X syndrome worsen with each successive generation, as if the mutation becomes increasingly deleterious as it is transmitted from a man to his grandsons and great-grandsons.


Pathology_Robbins

Pathology_Robbins. These unusual features have been related to the dynamic nature of the mutation. In the normal population, the number of repeats of the sequence CGG in the FMR1 gene is small, averaging around 29, whereas affected persons have 200 to 4000 repeats. These so-called “full mutations” are believed to arise through an intermediate stage of premutations characterized by 52 to 200 CGG repeats. Carrier males and females have premutations. During oogenesis (but not spermatogenesis), the premutations can be converted to full mutations by further amplification of the CGG repeats, which can then be transmitted to both the sons and the daughters of the carrier female. These observations provide an explanation for why some carrier males are unaffected (they have premutations), and certain carrier females are affected (they inherit full mutations).


Pathology_Robbins

Pathology_Robbins. The molecular basis for fragile X syndrome is beginning to be understood and relates to silencing of the product of the FMR1 gene, familial mental retardation protein (FMRP). The normal FMR1 gene contains CGG repeats in its 5′ untranslated region. When the number of trinucleotide repeats exceeds approximately 230, the DNA of the entire 5′ region of the gene becomes abnormally methylated. Methylation also extends upstream into the promoter region of the gene, resulting in transcriptional suppression of FMR1. The resulting absence of FMRP is believed to cause the http://ebooksmedicine.net


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Pathology_Robbins. Fig. 7.17 FragileXpedigree.XandYchromosomesareshown.Notethatinthefirstgeneration,allsonsarenormalandallfemalesarecarriers(harborapremutation).Duringoogenesisinthecarrierfemale,premutationexpandstofullmutation;hence,inthenextgeneration,allmaleswhoinherittheXwithfullmutationareaffected.However,only50%offemaleswhoinheritthefullmutationareaffected,andoftenonlymildly.(Based on an original sketch courtesy of Dr. Nancy Schneider,Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.) phenotypic changes. FMRP is widely expressed in normal tissues, but higher levels are found in the brain and the testis. It is an RNA-binding protein that is transported from the cytoplasm to the nucleus, where it binds specific mRNAs and transports them to the axons and dendrites (


Pathology_Robbins

Pathology_Robbins. Fig. 7.18 ). It is in the synapses that FMRP–mRNA complexes perform critical roles in regulating the translation of specific mRNAs involved in control of synaptic functions. The absence of this finely coordinated “shuttle” function seems to underlie the fragile X syndrome.


Pathology_Robbins

Pathology_Robbins. Although initially assumed to be innocuous, CGG premutations in the FMR1 gene can cause a disease that is phenotypically different from fragile X syndrome through a distinct mechanism involving a toxic “gain-offunction.” This disease was discovered when it was noted that approximately 20% of females carrying the premutation (carrier females) have mild cognitive impairment and premature ovarian failure (before the age of 40 years), and more than 50% of premutation-carrying males (transmitting males) exhibit a progressive neurodegenerative syndrome starting in their sixth decade. This syndrome, referred to as fragile X tremor/ataxia, is characterized by intention tremors and cerebellar ataxia and may progress to parkinsonism.


Pathology_Robbins

Pathology_Robbins. How do premutations cause disease? In these patients, the FMR1 gene instead of being methylated and silenced continues to be transcribed. CGG-containing FMR1 mRNAs so formed are “toxic.” They accumulate in the nucleus and form intranuclear inclusions. In this process the aggregated mRNA recruits RNA-binding proteins. Fig. 7.18 Amodelfortheactionoffamilialmentalretardationprotein(FMRP)inneurons.FMRPplaysacriticalroleinregulatingthetranslationofaxonalproteinsfromboundRNAs.Theselocallyproducedproteins,inturn,playdiverserolesinthemicroenvironmentofthesynapse.(Adapted from Hin P, Warren ST: New insights into fragile X syndrome: from molecules to neu-robehavior, TrendsBiochemSci28:152, 2003.) FMRP Ribosomes Axonal proteins Dendritic proteins Ribosomes FMRP-mRNA complex AXON DENDRITE http://ebooksmedicine.net Perhaps sequestration of these proteins at abnormal locations leads to events that are toxic to the cell.


Pathology_Robbins

Pathology_Robbins. Perhaps sequestration of these proteins at abnormal locations leads to events that are toxic to the cell. As noted, earlier many other neurodegenerative diseases related to trinucleotide repeat expansions are recognized. Some general principles follow: In all cases, gene functions are altered by an expansion of the repeats, but the precise threshold at which premutations are converted to full mutations differs with each disorder. Whereas the expansion in fragile X syndrome occurs during oogenesis, in other disorders such as Huntington disease, premutations are converted to full mutations during spermatogenesis. The expansion may involve any part of the gene, and the range of possibilities can be divided into two broad categories: those that affect untranslated regions (as in fragile X syndrome) and those that affect coding regions (as in Huntington disease) (


Pathology_Robbins

Pathology_Robbins. Fig. 7.19 ). When mutations affect noncoding regions, there is “loss of function,” because protein synthesis is suppressed (e.g., FMRP). By contrast, mutations involving translated parts of the gene give rise to misfolded proteins (e.g., Huntington disease). Many of these so-called “toxic gain-offunction” mutations involve CAG repeats that encode polyglutamine tracts, and the resultant diseases are sometimes referred to as polyglutamine diseases, affecting primarily the nervous system. Accumulation of mis-folded proteins in aggregates within the cytoplasm is a common feature of such diseases. Pathologicamplificationoftrinucleotiderepeatscausesloss-of-function(fragileXsyndrome)orgain-of-functionmutations(Huntingtondisease).Mostsuchmutationsproduceneurodegenerativedisorders. FragileXsyndromeresultsfromlossofFMR1 genefunctionandischaracterizedbymentalretardation,macroorchidism,andabnormalfacialfeatures.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Mitochondria contain several genes that encode enzymes involved in oxidative phosphorylation. Inheritance of mitochondrial DNA differs from that of nuclear DNA in that the former is associated with maternal inheritance. The reason for this peculiarity is that ova contain the normal complement of mitochondria within their abundant cytoplasm, whereas spermatozoa contain few, if any, mitochondria. The mitochondrial DNA of the zygote is therefore derived entirely from the ovum. Thus, only mothers transmit mitochondrial genes to their offspring, both male and female.


Pathology_Robbins

Pathology_Robbins. Diseases caused by mutations in mitochondrial genes are rare. Because mitochondrial DNA encodes enzymes involved in oxidative phosphorylation, diseases caused by mutations in such genes affect organs most dependent on oxidative phosphorylation (CNS, skeletal muscle, cardiac muscle, liver, and kidney). Leber hereditary optic neuropathy is the prototypical disorder in this group. This neurodegenerative disease manifests as progressive bilateral loss of central vision that leads in due course to blindness. DiseasesCausedbyAlterationsofImprintedRegions:Prader-WilliandAngelmanSyndromes


Pathology_Robbins

Pathology_Robbins. DiseasesCausedbyAlterationsofImprintedRegions:Prader-WilliandAngelmanSyndromes All humans inherit two copies of each gene (except, of course, the sex chromosome genes in males), carried on homologous maternal and paternal chromosomes. It was long assumed that there was no difference between normal homologous genes derived from the mother and the father. Indeed, this is true for most genes. It has been established, however, that functional differences exist between the paternal and the maternal copies of some genes. The differences arise from an epigenetic process called genomic imprinting, whereby certain homologous genes are differentially “inactivated” during paternal and maternal


Pathology_Robbins

Pathology_Robbins. Fig. 7.19 Sitesofexpansionandtheaffectedsequenceinselecteddiseasescausedbynucleotiderepeatmutations.UTR, Untranslatedregion.*Althoughnotstrictlyatrinucleotide-repeatdisease,progressivemyoclonusepilepsyiscaused,likeothersinthisgroup,byaheritableDNAexpansion.Theexpandedsegmentisinthepromoterregionofthegene. http://ebooksmedicine.net gametogenesis. Thus, maternal imprinting refers to transcriptional silencing of the maternal allele, whereas paternal imprinting implies that the paternal allele is inactivated. At the molecular level, imprinting is associated with methylation of the gene promoter, as well as related events such as modification of DNA-binding histone proteins, the sum total effect of which is to silence the gene. Imprinting occurs in ova or sperm and is then stably transmitted to all somatic cells derived from the zygote. Genomic imprinting is best illustrated by considering two uncommon genetic disorders, Prader-Willi syndrome and Angelman syndrome.


Pathology_Robbins

Pathology_Robbins. Mental retardation, short stature, hypotonia, obesity, small hands and feet, and hypogonadism characterize Prader-Willi syndrome. In 60% to 75% of cases, an interstitial deletion of band q12 in the long arm of chromosome 15—del(15)(q11;q13)—can be detected. In many patients without a detectable cytogenetic abnormality, FISH analysis shows smaller deletions within the same region. It is striking that in all cases, the deletion affects the paternally derived chromosome 15. In contrast to Prader-Willi syndrome, patients with the phenotypically distinct Angelman syndrome are born with a deletion of the same chromosomal region derived from their mothers. Patients with Angelman syndrome also are mentally retarded, but in addition they present with ataxic gait, seizures, and inappropriate laughter. Because of the laughter and ataxia, this syndrome has been called the happy puppet syndrome. A comparison of these two syndromes clearly demonstrates the “parent-oforigin” effects on gene


Pathology_Robbins

Pathology_Robbins. laughter. Because of the laughter and ataxia, this syndrome has been called the happy puppet syndrome. A comparison of these two syndromes clearly demonstrates the “parent-oforigin” effects on gene function. If all the paternal and maternal genes contained within chromosome 15 were expressed in an identical fashion, clinical features resulting from these deletions would be expected to be identical regardless of the parental origin of chromosome 15.


Pathology_Robbins

Pathology_Robbins. The molecular basis of these two syndromes can be understood in the context of imprinting (


Pathology_Robbins

Pathology_Robbins. Fig. 7.20 ). A set of genes on the maternal chromosome at 15q12 is imprinted (and hence silenced), so the paternal chromosome provides the only functional alleles. When these are lost as a result of a deletion (in the paternal chromosome), the patient develops Prader-Willi syndrome. Among the set of genes that are deleted in Prader-Willi syndrome, the most likely culprit is believed to be a gene cluster encoding multiple distinct small nucleolar RNAs (snoRNAs), which are involved in messenger RNA processing. Conversely, a distinct gene, UBE3A, that also maps to the same region of chromosome 15 isimprinted on thepaternalchromosome. UBE3A encodes for a ubiquitin ligase, a family of enzymes that targets other cellular proteins for proteasomal degradation (Chapter 1) through the addition of ubiquitin moieties. Only the maternally derived allele of the gene normally is active. Deletion of this maternal gene on chromosome 15 gives rise to the Angelman syndrome. The neurologic manifestations


Pathology_Robbins

Pathology_Robbins. moieties. Only the maternally derived allele of the gene normally is active. Deletion of this maternal gene on chromosome 15 gives rise to the Angelman syndrome. The neurologic manifestations of Angelman are principally because of a lack of UBE3A expression in specific regions of the brain.


Pathology_Robbins

Pathology_Robbins. Molecular studies of cytogenetically normal patients with Prader-Willi syndrome have shown that in some cases, both of the structurally normal copies of chromosome 15 are derived from the mother. Inheritance of both chromosomes of a pair from one parent is called uniparental disomy. The net effect is the same (i.e., the patient does not have a functional set of genes from the [nonimprinted] paternal chromosome 15). Angelman syndrome, as might be expected, also can result from uniparental disomy of paternal chromosome 15. Site of deletion Site of deletion Imprinted Angelman Active Angelman gene gene Fig. 7.20 GeneticsofAngelmanandPrader-Willisyndromes. http://ebooksmedicine.net •Imprintinginvolvestranscriptionalsilencingofthepaternalormaternalcopiesofcertaingenesduringgametogenesis.Forsuchgenesonlyonefunctionalcopyexistsintheindividual.Lossofthefunctionalallele(notimprinted)bydeletionsgivesrisetodiseases.


Pathology_Robbins

Pathology_Robbins. As mentioned earlier and as illustrated by several examples, many diseases of infancy and childhood are of genetic origin. Others, although not genetic, either are unique to children or take distinctive forms in this patient population and thus merit the designation pediatric diseases. During each stage of development, infants and children are prey to a somewhat different group of diseases ( Table 7.5 ). Clearly, diseases of infancy (i.e., in the first year of life) pose the highest risk of death. During this phase, the neonatal period (the first 4 weeks of life) is unquestionably the most hazardous time. After the infant survives the first year of life, the outlook brightens considerably. However, it is sobering to note that between 1 year and 14 years of age, injuries resulting from accidents are the leading cause of death. Not all conditions listed in


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Pathology_Robbins. Table 7.5 are described in this chapter; only a select few that are most common are considered here. Although general principles of neoplastic disease and specific tumors are discussed elsewhere, a few tumors of children are described, to highlight the differences between pediatric and adult neoplasms. Table 7.5 Causes of Death by Age Prader-Willisyndromeresultsfromdeletionofpaternalchromosomalregion15q12andischaracterizedbymentalretardation,shortstature,hypotonia,obesity,andhypogonadism. Angelmansyndromeresultsfromdeletionofmaternalchromosomalregion15q12andischaracterizedbymentalretardation,ataxia,seizures,andinappropriatelaughter.


Pathology_Robbins

Pathology_Robbins. Angelmansyndromeresultsfromdeletionofmaternalchromosomalregion15q12andischaracterizedbymentalretardation,ataxia,seizures,andinappropriatelaughter. Congenital anomalies are structural defects that are present at birth, although some, such as cardiac defects and renal anomalies, may not become clinically apparent until years later. As will be evident from the ensuing discussion, the term congenital does not imply or exclude a genetic basis. It is estimated that about 120,000 babies are born with a birth defect each year in the United States, an incidence of 1 in 33. As indicated in Table 7.5 , congenital anomalies are an important cause of infant mortality. Moreover, they continue to be a significant source of illness, disability, and death throughout the early years of life. Before considering the etiology and pathogenesis of congenital anomalies, it is essential to define some of the terms used to describe errors in morphogenesis.


Pathology_Robbins

Pathology_Robbins. Before considering the etiology and pathogenesis of congenital anomalies, it is essential to define some of the terms used to describe errors in morphogenesis. • Malformations are primary errors of morphogenesis. In other words, there is an intrinsically abnormal developmental process. Malformations usually are multifactorial, rather than the result of a single gene or chromosomal defect. *Causesarelistedindecreasingorderoffrequency.Allcausesandratesarebasedon2008(final)and2009(preliminary)data. †Ratesareexpressedper100,000populationfromallcauseswithineachagegroup. ‡Excludescongenitalheartdisease.Datasource:CentersforDiseaseControlandPrevention/NCHS,NationalVitalStatisticsSystem:mortality,2014. www.cdc.gov/nchs/data/dvs/lcwk1_2014.pdf http://ebooksmedicine.net


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Pathology_Robbins. www.cdc.gov/nchs/data/dvs/lcwk1_2014.pdf http://ebooksmedicine.net Fig. 7.21 Examplesofmalformations.Malformationscanrangeinseverityfromtheincidentaltothelethal.(A)Polydactyly(oneormoreextradigits)andsyndactyly(fusionofdigits)havelittlefunctionalconsequencewhentheyoccurinisolation.(B)Similarly,cleftlip,withorwithoutassociatedcleftpalate,iscompatiblewithlifewhenitoccursasanisolatedanomaly;inthiscase,however,thechildhadanunderlyingmalformationsyndrome(trisomy13)andexpiredbecauseofseverecardiacdefects.(C)Stillbirthassociatedwithalethalmalformation,inwhichthemidfacestructuresarefusedorill-formed;inalmostallcases,thisdegreeofexternaldysmorphogenesisisassociatedwithsevereinternalanomaliessuchasmaldevelopmentofthebrainandcardiacdefects.(A and C, Courtesy of Dr. Reade Quinton, Department of Pathology, University of Texas Southwestern Medical Center, Dallas,Texas. B, Courtesy of Dr. Beverly Rogers, Department of Pathology,University of Texas Southwestern Medical Center,Dallas,Texas.)


Pathology_Robbins

Pathology_Robbins. They may manifest in any of several patterns. In some presentations, such as congenital heart diseases, single body systems may be involved, whereas in others, multiple malformations involving many organs and tissues may coexist ( Fig. 7.21 • 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 morphogenesis. Amniotic bands, stemming from rupture of amnion with resultant formation of “bands” that encircle, compress, or attach to parts of the developing fetus, constitute the classic example of a disruption ( Fig. 7.22 ). A variety of environmental agents may cause disruptions (see later). Disruptions are not heritable, of course, and thus are not associated with risk of recurrence in subsequent pregnancies.


Pathology_Robbins

Pathology_Robbins. Deformations, like disruptions, also represent an extrinsic disturbance of development rather than an intrinsic error of morphogenesis. Deformations are common, affecting approximately 2% of newborn infants to various degrees. They are caused by localized or generalized compression of the growing fetus by abnormal biomechanical forces, leading eventually to a variety of structural abnormalities. The most common cause of deformations is uterine constraint. Between weeks 35 and 38 of gestation, rapid increase in the size of the fetus outpaces the growth of the uterus, and the relative amount of amniotic fluid (which normally acts as a cushion) also decreases. Thus, even the normal fetus is subjected to some degree of uterine constraint. However, several variables increase the likelihood of excessive compression of the fetus, including maternal conditions such as first pregnancy, small uterus, malformed (bicornuate) uterus, and leiomyomas. Causes relating to the fetus, such as presence


Pathology_Robbins

Pathology_Robbins. excessive compression of the fetus, including maternal conditions such as first pregnancy, small uterus, malformed (bicornuate) uterus, and leiomyomas. Causes relating to the fetus, such as presence of multiple fetuses, oligohydramnios, and abnormal fetal presentation, also may be involved.


Pathology_Robbins

Pathology_Robbins. Sequence refers to multiple congenital anomalies that result from secondary effects of a single localized aberration in organogenesis. The initiating event may be a malformation, deformation, or disruption. An excellent example is the oligohydramnios (or Potter) sequence ( Fig. 7.23A ). Oligohydramnios (decreased amniotic fluid) may be caused by a variety of maternal, placental, or fetal abnormalities, including chronic leakage of amniotic fluid because of rupture of the amnion; uteroplacental insufficiency resulting from maternal hypertension or severe toxemia; and renal agenesis in the fetus (because fetal urine is a major constituent of amniotic fluid). The fetal compression associated with oligohydramnios in turn results in a classic phenotype in the newborn infant consisting of flattened faces and positional abnormalities of the hands and feet (


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Pathology_Robbins. Fig. 7.23B ). The hips may be dislocated. Growth of the chest wall and the lungs also is compromised, sometimes to such an extent that Fig. 7.22 Disruptionduetoamnioticbands.Inthespecimenshown,theplacentaisattheright,andthebandofamnionextendsfromthetopportionoftheamnioticsactoencirclethelegofthefetus.(Courtesy of Dr.Theonia Boyd, Children’s Hospital of Boston, Boston, Massachusetts.) http://ebooksmedicine.net Fig. 7.23 (A)Pathogenesisoftheoligohydramnios(Potter)sequence. Known causes of errors in human malformations can be grouped into three major categories: genetic, environmental, and multifactorial ( Table 7.6 ). The cause has not been identified for almost half of the reported cases.


Pathology_Robbins

Pathology_Robbins. Table 7.6 ). The cause has not been identified for almost half of the reported cases. Genetic causes of malformations include all of the previously discussed mechanisms of genetic disease. Virtually all chromosomal syndromes are associated with congenital malformations. Examples are Down syndrome and other trisomies, Turner syndrome, and Klinefelter syndrome. Most chromosomal disorders arise during gametogenesis and hence are not familial. Single-gene mutations, characterized by mendelian inheritance, may underlie major malformations. For example, holoprosencephaly is the most common developmental defect of the forebrain and midface in humans (see Chapter 23). The Hedgehog signaling pathway plays a critical role in the morphogenesis of these structures, and loss-of-function mutations of individual components within this pathway are reported in families with a history of recurrent holoprosencephaly.


Pathology_Robbins

Pathology_Robbins. Environmental influences, such as viral infections, drugs, and radiation to which the mother was exposed during pregnancy, may cause fetal malformations (the appellation of “malformation” is used loosely in this context, because technically, these anomalies represent disruptions). Among the viral infections listed in Table 7.6 , rubella was a major Table 7.6 Causes of Congenital Malformations in Humans (B)Infantwitholigohydramnios(Potter)sequence.Noteflattenedfacialfeaturesanddeformedfoot(talipesequinovarus). survival is not possible. If the embryologic connection between these defects and the initiating event is not recognized, a sequence may be mistaken for a malformation syndrome.


Pathology_Robbins

Pathology_Robbins. survival is not possible. If the embryologic connection between these defects and the initiating event is not recognized, a sequence may be mistaken for a malformation syndrome. Malformation syndrome refers to the presence of several defects that cannot be explained on the basis of a single localizing initiating error in morphogenesis. Syndromes most often arise from a single causative condition (e.g., viral infection or a specific chromosomal abnormality) that simultaneously affects several tissues. In addition to these global definitions, some general terms are applied to organ-specific malformations. Agenesis refers to the complete absence of an organ or its anlage, whereas aplasia and hypoplasia indicate incomplete development and underdevelopment, respectively. Atresia describes the absence of an opening, usually of a hollow visceral organ or duct such as intestines and bile ducts.


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Pathology_Robbins. *Livebirths.DatafromStevensonRE,HallJG,GoodmanRM,editors:Human malformations and related anomalies, NewYork,1993,OxfordUniversityPress,p115.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net scourge of the 19th and early 20th centuries. Fortunately, maternal rubella and the resultant rubella embryopathy have been virtually eliminated in developed countries as a result of vaccination. As mentioned later, maternal infection with Zika Virus can give rise to severe malformations of the central nervous system. A variety of drugs and chemicals have been suspected to be teratogenic, but perhaps less than 1% of congenital malformations are caused by these agents. The list includes thalidomide, alcohol, anticonvulsants, warfarin (oral anti-coagulant), and 13-cisretinoic acid, which is used in the treatment of severe acne. For example, thalidomide, formerly used as a tranquilizer in Europe and currently used for treatment of certain cancers, causes an extremely high incidence (50% to 80%) of limb malformations. Alcohol, perhaps the most widely used agent today, is an important environmental teratogen. Infants born of mothers who abuse alcohol show prenatal


Pathology_Robbins

Pathology_Robbins. high incidence (50% to 80%) of limb malformations. Alcohol, perhaps the most widely used agent today, is an important environmental teratogen. Infants born of mothers who abuse alcohol show prenatal and postnatal growth retardation, facial anomalies (microcephaly, short palpebral fissures, maxillary hypoplasia), and psychomotor disturbances. These features in combination are designated the fetal alcohol syndrome. Although cigarette smoke–derived nicotine has not been convincingly demonstrated to be a teratogen, there is a high incidence of spontaneous abortions, premature labor, and placental abnormalities among pregnant smokers, and babies born to mothers who smoke often have a low birth weight and may be prone to the sudden infant death syndrome (SIDS). In light of these findings, it is best to avoid nicotine exposure altogether during pregnancy. Among maternal conditions listed in


Pathology_Robbins

Pathology_Robbins. Table 7.6, diabetes mellitus is a common entity, and despite advances in antenatal obstetric monitoring and glucose control, the incidence of major malformations in infants of diabetic mothers stands between 6% and 10% in most reported series. Maternal hyperglycemia–induced fetal hyperinsulinemia results in fetal macrosomia (organomegaly and increased body fat and muscle mass); cardiac anomalies, neural tube defects, and other CNS malformations are some of the major anomalies seen in diabetic embryopathy.


Pathology_Robbins

Pathology_Robbins. Multifactorial inheritance, which implies the interaction of environmental influences with two or more genes of small effect, is the most common genetic cause of congenital malformations. Included in this category are some relatively common malformations such as cleft lip and palate and neural tube defects. The importance of environmental contributions to multifactorial inheritance is underscored by the dramatic reduction in the incidence of neural tube defects by periconceptional intake of folic acid in the diet. The recurrence risks and mode of transmission of multifactorial disorders are described earlier in this chapter. The pathogenesis of congenital anomalies is complex and still poorly understood, but two general principles are relevant regardless of the etiologic agent: 1. The timing of the prenatal teratogenic insult has an important impact on the occurrence and the type of anomaly produced.


Pathology_Robbins

Pathology_Robbins. The intrauterine development of humans can be divided into two phases: (1) the embryonic period, occupying the first 9 weeks of pregnancy, and (2) the fetal period, terminating at birth. In the early embryonic period (first 3 weeks after fertilization), an injurious agent damages either enough cells to cause death and abortion or only a few cells, presumably allowing the embryo to recover without developing defects. Between the third and the ninth weeks, the embryo is extremely susceptible to teratogenesis, with the peak sensitivity occurring between the fourth and the fifth weeks. During this period organs are being crafted out of the germ-cell layers.


Pathology_Robbins

Pathology_Robbins. The fetal period that follows organogenesis is marked chiefly by the further growth and maturation of the organs, with greatly reduced susceptibility to teratogenic agents. Instead, the fetus is susceptible to growth retardation or injury to already formed organs. It is therefore possible for a given agent to produce different anomalies if exposure occurs at different times of gestation. 2. The complex interplay between environmental teratogens and intrinsic genetic defects is exemplified by the fact that features of dysmorphogenesis caused by environmental insults often can be recapitulated by genetic defects in the pathways targeted by these teratogens. Some representative examples follow:


Pathology_Robbins

Pathology_Robbins. Cyclopamine is a plant teratogen. Pregnant sheep that feed on plants containing cyclopamine give birth to lambs that have severe craniofacial abnormalities including holoprosencephaly and cyclopia (single fused eye—hence the origin of the moniker cyclopamine). This compound is an inhibitor of Hedgehog signaling in the embryo, and, as stated previously, mutations of Hedgehog genes are present in subsets of fetuses with holoprosencephaly. Valproic acid is an anti-epileptic and a recognized teratogen. Valproic acid disrupts expression of a family of highly conserved developmentally critical transcription factors known as homeobox (HOX) proteins. In vertebrates, HOX proteins have been implicated in the patterning of limbs, vertebrae, and craniofacial structures. Not surprisingly, mutations in the HOX gene family are responsible for congenital anomalies that mimic features observed in valproic acid embryopathy.


Pathology_Robbins

Pathology_Robbins. • The vitamin A (retinol) derivative all-trans-retinoic acid is essential for normal development and differentiation, and its absence during embryogenesis results in a constellation of malformations affecting multiple organ systems, including the eyes, genitourinary system, cardiovascular system, diaphragm, and lungs (see Chapter 8 for vitamin A deficiency in the postnatal period). Conversely, excessive exposure to retinoic acid also is teratogenic. Infants born to mothers treated with retinoic acid for severe acne have a predictable phenotype (retinoic acid embryopathy), including CNS, cardiac, and craniofacial defects, such as cleft lip and cleft palate. The last entity may stem from retinoic acid–mediated deregulation of components of the transforming growth factor-β (TGF-β) signaling pathway, which is involved in palatogenesis. Mice with knockout of the TGFB3 gene uniformly develop cleft palate, once again illustrating the functional relationship between teratogenic exposure and


Pathology_Robbins

Pathology_Robbins. pathway, which is involved in palatogenesis. Mice with knockout of the TGFB3 gene uniformly develop cleft palate, once again illustrating the functional relationship between teratogenic exposure and signaling pathways in the causation of congenital anomalies.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Congenitalanomaliesresultfromintrinsicabnormalities(malformations)aswellasextrinsicdisturbances(deformations,disruptions). Congenitalanomaliescanresultfromgenetic(chromosomalabnormalities,genemutations),environmental(infections,drugs,alcohol),andmultifactorialcauses. Thetimingoftheinuteroinsulthasprofoundinfluenceontheextentofcongenitalanomalies,withearliereventsusuallyhavinggreaterimpact. Theinterplaybetweengeneticandenvironmentalcausesofanomaliesisemphasizedbythefactthatteratogensoftentargetsignalingpathwaysinwhichmutationshavebeenreportedasacauseforthesameanomalies. Infections of the fetus and neonate may be acquired transcervically (ascending infections) or transplacentally (hematologic infections).


Pathology_Robbins

Pathology_Robbins. Infections of the fetus and neonate may be acquired transcervically (ascending infections) or transplacentally (hematologic infections). Transcervical, or ascending, infections are caused by spread of microbes from the cervicovaginal canal and may be acquired in utero or during birth. Most bacterial infections (e.g., α-hemolytic streptococcal infection) and a few viral infections (e.g., herpes simplex) are acquired in this manner. In general, the fetus acquires the infection by “inhaling” infected amniotic fluid into the lungs or by passing through an infected birth canal during delivery. Fetal infection usually is associated with inflammation of the placental membranes (chorioamnionitis) and inflammation of the umbilical cord (funisitis). This mode of spread is typical for pneumonia and, in severe cases, sepsis and meningitis.


Pathology_Robbins

Pathology_Robbins. Transplacental infections gain access to the fetal bloodstream by crossing the placenta via the chorionic villi, and may occur at any time during gestation or occasionally, as may be the case with hepatitis B and human immunodeficiency virus, at the time of delivery via maternal-to-fetal transfusion. Most parasitic (e.g., toxoplasma, malaria) and viral infections, and a few bacterial infections (i.e., Listeria and Treponema), follow this mode of hematogenous transmission. The clinical manifestations of these infections are highly variable, depending largely on the gestational timing and the microorganism involved. The most important trans-placental infections can be conveniently remembered by the acronym TORCH. The elements of the TORCH complex are Toxoplasma (T), rubella virus (R), cytomegalovirus (C), herpesvirus (H), and any of a number of other (O) microbes such as Treponema pallidum. These agents are grouped together because they may evoke similar clinical and pathologic


Pathology_Robbins

Pathology_Robbins. cytomegalovirus (C), herpesvirus (H), and any of a number of other (O) microbes such as Treponema pallidum. These agents are grouped together because they may evoke similar clinical and pathologic manifestations. TORCH infections occurring early in gestation may cause chronic sequelae in the child, including growth restriction, mental retardation, cataracts, and congenital cardiac anomalies, whereas infections later in pregnancy result primarily in tissue injury accompanied by inflammation (encephalitis, chorioretinitis, hepatosplenomegaly, pneumonia, and myocarditis). More recently, Zika virus has emerged as another agent that can be transmitted by pregnant females to their offspring with devastating consequences such as microcephaly and brain damage.


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Pathology_Robbins. Prematurity is defined by a gestational age less than 37 weeks and is the second most common cause of neonatal mortality (second only to congenital anomalies). As might be expected, infants born before completion of gestation also weigh less than normal (<2500 gm). The major risk factors for prematurity include preterm premature rupture of membranes; intrauterine infection leading to inflammation of the placental membranes (chorioamnionitis); structural abnormalities of the uterus, cervix, and placenta; and multiple gestation (e.g., twin pregnancy). Children born before completion of the full period of gestation have higher morbidity and mortality rates than full-term infants. The immaturity of organ systems in preterm infants makes them especially vulnerable to several important complications: Respiratory distress syndrome, also called hyaline membrane disease Long-term sequelae, including developmental delay


Pathology_Robbins

Pathology_Robbins. Respiratory distress syndrome, also called hyaline membrane disease Long-term sequelae, including developmental delay Although birth weight is low in preterm infants, it usually is appropriate after adjustment for gestational age. By contrast, as many as one-third of infants who weigh less than 2500 gm are born at term and are therefore under-grown rather than immature. These small-for-gestationalage (SGA) infants suffer from fetal growth restriction. Fetal growth restriction may result from fetal, maternal, or placental abnormalities, although in many cases the specific cause is unknown.


Pathology_Robbins

Pathology_Robbins. Fetal abnormalities: This category consists of conditions that intrinsically reduce growth potential of the fetus despite an adequate supply of nutrients from the mother. Prominent among such fetal conditions are chromosomal disorders, congenital anomalies, and congenital infections. Chromosomal abnormalities may be detected in as many as 17% of fetuses evaluated for fetal growth restriction and in as many as 66% of fetuses with documented ultrasonographic malformations. Fetal infection should be considered in all growth-restricted neonates, with the TORCH group of infections (see earlier) being a common cause. When the causation is intrinsic to the fetus, fetal growth restriction is symmetric (i.e., affects all organ systems equally).


Pathology_Robbins

Pathology_Robbins. Placental abnormalities: Placental causes include any factor that compromises the uteroplacental blood supply. Examples include placenta previa (low implantation of the placenta), placental abruption (separation of placenta from the decidua by a retroplacental clot), or placental infarction. With placental (and maternal) abnormalities, the fetal growth restriction is asymmetric http://ebooksmedicine.net (i.e., the brain is spared relative to visceral organs such as the liver).


Pathology_Robbins

Pathology_Robbins. • Maternal factors: This category comprises by far the most common causes of the growth deficit in SGA infants. Important examples are vascular diseases such as preeclampsia (“toxemia of pregnancy”) (Chapter 19) and chronic hypertension. Another class of maternal diseases increasingly being recognized in the setting of fetal growth restriction is acquired or inherited diseases of hypercoagulability (i.e., thrombophilias) (Chapter 4). The list of other maternal conditions associated with fetal growth restriction is long, but some of the avoidable influences are maternal narcotic abuse, alcohol intake, and heavy cigarette smoking (as noted previously, many of these same causes also are involved in the pathogenesis of congenital anomalies). Drugs causing fetal growth restriction in similar fashion include teratogens, such as the commonly administered anti-convulsant phenytoin (Dilantin), as well as nonteratogenic agents. Maternal malnutrition (in particular, prolonged hypoglycemia) also


Pathology_Robbins

Pathology_Robbins. include teratogens, such as the commonly administered anti-convulsant phenytoin (Dilantin), as well as nonteratogenic agents. Maternal malnutrition (in particular, prolonged hypoglycemia) also may affect fetal growth.


Pathology_Robbins

Pathology_Robbins. Not only is the growth-restricted infant handicapped in the perinatal period, but the deficits persist into childhood and adult life. Affected persons are thus more likely to have cerebral dysfunction, learning disabilities, and sensory (i.e., visual and hearing) impairment.


Pathology_Robbins

Pathology_Robbins. The most common cause of respiratory distress in the newborn is respiratory distress syndrome (RDS), also know as hyaline membrane disease because of the formation of “membranes” in the peripheral air spaces observed in infants who succumb to this condition. An estimated 24,000 cases of RDS are reported annually in the United States. Improvements in management of this condition have sharply decreased deaths due to respiratory insufficiency from as many as 5000 per year a decade ago to fewer than 900 cases yearly. It is primarily a disorder of premature infants. Less common causes include excessive sedation of the mother, fetal head injury during delivery, aspiration of blood or amniotic fluid, and intrauterine hypoxia secondary to compression from coiling of the umbilical cord about the neck.


Pathology_Robbins

Pathology_Robbins. RDS occurs in about 60% of infants born at less than 28 weeks’ gestation, 30% of those born between 28 to 34 weeks’ gestation, and less than 5% of those born after 34 weeks’ gestation. There are also strong though not invariable associations with male gender, maternal diabetes, and delivery by cesarean section.


Pathology_Robbins

Pathology_Robbins. The fundamental defect in RDS is the inability of the immature lung to synthesize sufficient surfactant. Surfactant is a complex of surface-active phospholipids, principally dipalmitoylphosphatidylcholine (lecithin) and at least two groups of surfactant-associated proteins. The importance of surfactant-associated 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 corresponding genes. Surfactant is synthesized by type II pneumocytes and, with the healthy newborn’s first breath, rapidly coats the surface of alveoli, reducing surface tension and thus decreasing the pressure required to keep the alveoli open. In a lung deficient in surfactant, alveoli tend to collapse, and a relatively greater inspiratory effort is required with each breath to open the alveoli. The infant rapidly tires from breathing and generalized atelectasis sets in. The resulting hypoxia sets


Pathology_Robbins

Pathology_Robbins. and a relatively greater inspiratory effort is required with each breath to open the alveoli. The infant rapidly tires from breathing and generalized atelectasis sets in. The resulting hypoxia sets into motion a sequence of events that leads to epithelial and endothelial damage and eventually to the formation of hyaline membranes (


Pathology_Robbins

Pathology_Robbins. Fig. 7.24 ). As discussed later, this classical picture of surfactant deficiency is greatly modified by surfactant treatment. Hormones regulate surfactant synthesis. Corticosteroids stimulate the formation of surfactant lipids and associated proteins. Therefore, conditions associated with intrauterine stress and fetal growth restriction, which increase corticosteroid release, lower the risk of developing RDS. Conversely, the compensatory high blood levels of insulin in infants of diabetic mothers can suppress surfactant synthesis, counteracting the effects of steroids. This may explain, in part, why infants of diabetic mothers are at higher risk for developing RDS. Labor is known to increase surfactant synthesis; accordingly, cesarean section performed before the onset of labor also may be associated with increased risk for RDS.


Pathology_Robbins


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Pathology_Robbins. The classic clinical presentation before the era of treatment with exogenous surfactant was described earlier. Currently, the actual clinical course and prognosis for neonatal RDS vary, depending on the maturity and birth weight of the infant and the promptness of therapy. The control of RDS focuses on prevention, either by delaying labor until the fetal lung reaches maturity or by inducing maturation of the lung in the at-risk fetus. Critical to these objectives is the ability to assess fetal lung maturity accurately. Because pulmonary secretions are discharged into the amniotic fluid, analysis of amniotic fluid phospholipids http://ebooksmedicine.net Reduced surfactant synthesis, storage, and release Fig. 7.24 Pathophysiologyofrespiratorydistresssyndrome(seetext). Fig. 7.25 Hyalinemembranedisease(hematoxylin-eosinstain).Alternatingatelectasisanddilationofthealveolicanbeseen.Notetheeosinophilicthickhyalinemembranesliningthedilatedalveoli.


Pathology_Robbins

Pathology_Robbins. Fig. 7.25 Hyalinemembranedisease(hematoxylin-eosinstain).Alternatingatelectasisanddilationofthealveolicanbeseen.Notetheeosinophilicthickhyalinemembranesliningthedilatedalveoli. provides a good estimate of the level of surfactant in the alveolar lining. Prophylactic administration at birth of exogenous surfactant to extremely premature infants (born before 28 weeks’ gestational age) has proven very beneficial, such that it is now uncommon for infants to die of acute RDS.


Pathology_Robbins

Pathology_Robbins. In uncomplicated cases, recovery begins to occur within 3 or 4 days. In affected infants, oxygen is required. Use of high concentrations of ventilator-administered oxygen for prolonged periods, however, is associated with two well-known complications: retrolental fibroplasia (also called retinopathy of prematurity) in the eyes; and bronchopulmonary dysplasia. Fortunately, both complications are now significantly less common as a result of gentler ventilation techniques, antenatal glucocorticoid therapy, and prophylactic surfactant treatments. Hence they are described briefly:


Pathology_Robbins

Pathology_Robbins. Retinopathy of prematurity has a two-phase pathogenesis. During the hyperoxic phase of RDS therapy (phase I), expression of the proangiogenic vascular endothelial growth factor (VEGF) is markedly decreased, causing endothelial cell apoptosis. VEGF levels rebound after return to relatively hypoxic room air ventilation (phase II), inducing retinal vessel proliferation (neovascularization) characteristic of the lesions in the retina. The major abnormality in bronchopulmonary dysplasia is a striking decrease in alveolar septation (manifested as large, simplified alveolar structures) and a dysmorphic capillary configuration. Multiple factors—hyperoxemia, hyperventilation, prematurity, inflammatory cytokines, and vascular maldevelopment—contribute to bronchopulmonary dysplasia and probably act additively or synergistically to promote injury.


Pathology_Robbins

Pathology_Robbins. Infants who recover from RDS also are at increased risk for developing a variety of other complications associated with preterm birth; most important among these are patent ductus arteriosus, intraventricular hemorrhage, and necrotizing enterocolitis. Thus, although technologic advances help save the lives of many infants with RDS, they also bring to the surface the exquisite fragility of the immature neonate. NeonatalRDS(hyalinemembranedisease)isadiseaseofprematurity;mostcasesoccurinneonatesbornbefore28weeks’gestationalage. ThefundamentalabnormalityinRDSisinsufficientpulmonarysurfactant,whichresultsinfailureoflungstoinflateafterbirth. ThecharacteristicmorphologicpatterninRDSisthepresenceofhyalinemembranes(consistingofnecroticepithelialcellsandplasmaproteins)liningtheairways. RDScanbeamelioratedbyprophylacticadministrationofsteroids,surfactanttherapy,andbyimprovedventilationtechniques.


Pathology_Robbins

Pathology_Robbins. Necrotizing enterocolitis (NEC) most commonly occurs in premature infants, with the incidence of the disease being inversely proportional to the gestational age. It http://ebooksmedicine.net occurs in approximately 1 of 10 very-low-birth-weight infants (<1500 gm). In addition to prematurity, most cases are associated with enteral feeding, suggesting that some postnatal insult (such as the introduction of bacteria) sets in motion the cascade culminating in tissue destruction. Although infectious agents are likely to play a role in NEC pathogenesis, no single bacterial pathogen has been linked to the disease. A large number of inflammatory mediators have been associated with pathogenesis of NEC. One particular mediator, platelet-activating factor, has been implicated in increasing mucosal permeability by promoting enterocyte apoptosis and compromising intercellular tight junctions, thereby “adding fuel to the fire.”


Pathology_Robbins

Pathology_Robbins. NEC typically involves the terminal ileum, cecum, and right colon, although any part of the small or large intestine may be involved. The involved segment typically is distended, friable, and congested ( Fig. 7.26 ), or it can be frankly gangrenous; intestinal perforation with accompanying peritonitis may be seen. On microscopic examination, mucosal or transmural coagulative necrosis, ulceration, bacterial colonization, and submucosal gas bubbles are all features associated with NEC. Evidence of reparative changes, such as granulation tissue and fibrosis, may be seen shortly after resolution of the acute episode.


Pathology_Robbins

Pathology_Robbins. The clinical course is fairly typical, with the onset of bloody stools, abdominal distention, and development of circulatory collapse. Abdominal radiographs often demonstrate gas within the intestinal wall (pneumatosis intestinalis). When detected early, NEC often can be managed conservatively, but many cases (20% to 60%) require operative intervention including resection of the necrotic segments of bowel. NEC is associated with high perinatal mortality; infants who survive often develop post-NEC strictures from fibrosis caused by the healing process.


Pathology_Robbins

Pathology_Robbins. According to the National Institute of Child Health and Human Development, SIDS is defined as “the sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history.” It is important to emphasize that many cases of sudden death in infancy are found to have an anatomic or biochemical basis at autopsy (


Pathology_Robbins

Pathology_Robbins. Table 7.7 ); these should not be labeled as SIDS, but rather as sudden unexpected infant death (SUID). The Centers for Disease Control and Prevention estimates that SIDS accounts for approximately half of the cases of SUID in the United States. An aspect of SIDS that is not stressed in the definition is that the infant usually dies while asleep—hence the lay terms crib death and cot death. SIDS is the leading cause of death between the ages of 1 month and 1 year in U.S. infants, and the third leading cause of death overall in this age group, after congenital anomalies and diseases of prematurity and low birth weight. In 90% of cases, the infant is younger than 6 months; most are between the ages of 2 and 4 months. SIDS in an earlier sibling is associated with a fivefold relative risk of recurrence; traumatic child abuse must be carefully excluded under these circumstances.


Pathology_Robbins

Pathology_Robbins. SIDS is multifactorial condition, with a mixture of contributing causes in a given case. Three interacting variables have been proposed: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control, and (3) one or more exogenous stressors. According to this model, several factors make the infant vulnerable to sudden Fig. 7.26 Necrotizingenterocolitis.(A)Atpostmortemexaminationinaseverecase,theentiresmallbowelwasmarkedlydistendedandperilouslythin(usuallythisappearanceimpliesimpendingperforation).(B)Thecongestedportionoftheileumcorrespondstoareasofhemorrhagicinfarctionandtransmuralnecrosis.Submucosalgasbubbles(pneumatosisintestinalis)canbeseeninseveralareas(arrows). http://ebooksmedicine.net Table 7.7 Factors Associated With Sudden Infant Death Syndrome (SIDS) Drugabuseineither parent,specificallypaternalmarijuanaandmaternalopiate,cocaineuse Brainstemabnormalities,associatedwithdelayeddevelopmentofarousalandcardiorespiratorycontrol


Pathology_Robbins

Pathology_Robbins. Drugabuseineither parent,specificallypaternalmarijuanaandmaternalopiate,cocaineuse Brainstemabnormalities,associatedwithdelayeddevelopmentofarousalandcardiorespiratorycontrol Fattyacidoxidationdisorders(MCAD,LCHAD,SCHAD mutations) as respiratory drive, blood pressure, and upper airway reflexes. Abnormalities in serotonin-dependent signaling in the brain stem may be the underlying basis for SIDS in some infants.


Pathology_Robbins

Pathology_Robbins. Among the potential environmental causes, prone sleeping position, sleeping on soft surfaces, and thermal stress are possibly the most important modifiable risk factors for SIDS. Many studies have clearly shown increased risk for SIDS in infants who sleep in a prone position, prompting the American Academy of Pediatrics to recommend placing healthy infants on their backs when laying them down to sleep. This “Back to Sleep” campaign has resulted in substantial decreases in SIDS-related deaths since its inception in 1994. The prone position increases the infant’s vulnerability to one or more recognized noxious stimuli (hypoxia, hypercarbia, and thermal stress) during sleep. In addition, the prone position also is associated with decreased arousal responsiveness compared with the supine position.


Pathology_Robbins

Pathology_Robbins. Of note, SIDS is not the only cause of sudden unexpected death in infancy. Therefore, SIDS is a diagnosis of exclusion, requiring careful examination of the death scene and a complete postmortem examination. The latter can show an unsuspected cause of sudden death in as many as 20% or more of babies presumed to have died of SIDS (


Pathology_Robbins

Pathology_Robbins. Table 7.7 ). Infections (e.g., viral myocarditis or bronchopneumonia) are the most common causes of SUID, followed by a congenital anomaly. As a result of advancements in molecular diagnostics, several genetic causes of SUID have emerged. For example, fatty acid oxidation disorders, characterized by defects in mitochondrial fatty acid oxidative enzymes, may be responsible for as many as 5% of sudden deaths in infancy; of these, a deficiency in medium-chain acylcoenzyme A dehydrogenase is the most common. Retrospective analyses in cases of sudden infant death originally designated SIDS also have revealed mutations of cardiac sodium and potassium channels, which result in a form of cardiac arrhythmia characterized by prolonged QT intervals; these cases account for no more than 1% of SUIDs.


Pathology_Robbins

Pathology_Robbins. C4b)*SIDSisnottheonlycauseofSUIDs,butratherisadiagnosis of exclusion.Therefore, performanceofanautopsymayoftenshowfindingsthatwouldexplainthecauseofanSUID.Thesecasesshouldnot,strictlyspeaking,belabeledas“SIDS.”SCN5A, Sodiumchannel,voltage-gated,typeV,alphapolypeptide;KCNQ1, potassiumvoltage-gatedchannel,KQT-likesubfamily,member1;MCAD, medium-chainacylcoenzymeAdehydrogenase;LCHAD, long-chain3-hydroxyacylcoenzymeAdehydrogenase;SCHAD, short-chain3-hydroxyacylcoenzymeAdehydrogenase;MTCYB, mitochondrialcytochromeb;C4, complementcomponent4. death during the critical developmental period (i.e., 1 month to 1 year). These vulnerability factors may be specific to the parents or the infant, whereas the exogenous stressor or stressors are attributable to the environment (


Pathology_Robbins

Pathology_Robbins. Table 7.7 ). Although numerous factors have been proposed to account for a vulnerable infant, the most compelling hypothesis is that SIDS reflects a delayed development of arousal and cardiorespiratory control. The brain stem and, in particular, the medulla oblongata play a critical role in the body’s “arousal” response to noxious stimuli such as episodic hypercarbia, hypoxia, and thermal stress encountered during sleep. The serotonergic (5-HT) system of the medulla is implicated in these “arousal” responses as well as regulation of other critical homeostatic functions such


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net ThemostlikelybasisforSIDSisadelayeddevelopmentofarousalreflexesandcardiorespiratorycontrol. Numerousenvironmentalriskfactorshavebeenproposed,ofwhichthepronesleepingpositionisbestrecognized—hencethesuccessofthe“BacktoSleep”programinreducingtheincidenceofSIDS. Fetal hydrops refers to the accumulation of edema fluid in the fetus during intrauterine growth. The causes of fetal hydrops are manifold; the most important are listed in