Dysplasias are defects of tissue differentiation or defects of histogenesis. These involve principally connective tissue, bone, blood vessels, skin. Dysplasias are characterized by the abnormal growth of tissues. They are frequently caused by autosomal dominantmutations, rarely by the homozygous state of recessive mutations. Occasionally caused by teratogens, dysplasias are not biochemically defined. They are primarily expressed as extensive, multiple, or generalized abnormalities of one type of tissue.
CONNECTIVE TISSUE DYSPLASIAS
Neurofibromatosis (von Recklinghausen Disease) (OMIM *162200)
Neurofibromatosis is inherited as an autosomal dominant trait; 50% represent a new mutation.
Type I, peripheral neurofibromatosis, affects 1 in 4,000 live births; the gene is on chromosome 17. It is associated with the presence of six or more caféau- lait spots more than 5 mm in diameter in children; neurofibromas and plexiform neurofibromas occur along nerves (Figures 9.1 to 9.7 and Tables 9.1 to 9.3). Hamartomatous lesions include lipomas, angiomas, optic gliomas, iris hamartomas, sphenoid dysplasia, and frequently local overgrowth and hemihypertrophy. Malignant change occurs in approximately 3 – 15%. Anintestinal formmay involve the length of the gastrointestinal tract.
Type 2, central neurofibromatosis, has an incidence of 1 in 50,000. The gene is on chromosome 22. It includes acoustic schwannomas, neurofibromas, meningiomas, gliomas, schwannomas, and lenticular opacity.
Type 3 is the intermediate type with neurofibromas limited to the gastrointestinal tract.
Type 4 is a variant form.
Tuberous Sclerosis (See Also Renal Chapter) (TS) (OMIM # 191100)
This is an autosomal dominant mutation; approximately 60% are new mutations.
A horseshoe kidney is a single, midline, horseshoe-shaped kidney.
The kidney is formed by an interaction between the ureteric bud and the metanephric blastema (Figures 19.1 to 19.3). If the ureteric buds are located more medially than normal or if the inducible metanephric blastema is continuous at the lower pole, then a fused horseshoe kidney may develop.
The horseshoe kidney is usually at a lower level than normal kidneys. Its renal pelves are displaced anteriorly and its ureters usually course across the anterior surfaces of the kidney. Dysplastic development may occur in the fused portion of the kidney.
The ureters may be duplicated or angulated, so that obstruction, which leads to hydronephrosis, occurs.
A kidney is ectopic when it is in the pelvis and not in its usual location. Ureter duplication is a double ureter that can be unilateral or bilateral. Ectopic kidney and ureter duplication usually are not functionally important in the prenatal period. Their frequency is increased in chromosome aneuploidies.
In bilateral renal agenesis, both kidneys and ureters are absent (Table 19.1).
Bilateral renal agenesis is rare, occurring in 1/3,000 to 1/4,000 live borns (Figure 19.4). Unilateral agenesis occurs in 1/1,000 newborns; it is more common in males.
It is postulated that renal agenesis is caused by the failure of the ureteric bud to develop. The ureteric bud normally induces the metanephric blastema to become a kidney.
Bone is formed from collagen. Bone dysplasias predominantly involve one type of collagen (Figure 15.1). Terms used in the description of bone dysplasias according to the defect in collagen are shown in Table 15.1.
The normal growth plate or physis consists of four zones:
zone of provisional calcification.
The revised international classification of osteochondrodysplasias encompasses those disorders that are perinatally lethal and/or amenable to prenatal diagnosis (Table 15.2). Prenatal diagnosis has been made in most of the lethal forms of ostechondrodysplasia (Table 15.3). The osteochondrodysplasias include the infant or fetus with dwarfism. Most are lethal. For most convenience in diagnosis they can be divided into the following groups:
■ Osteochondrodysplasias with platyspondyly
■ Osteochondrodysplasias with short trunk
■ Short rib osteochondrodysplasias
■ Osteochondrodysplasias with defective bone density
■ Miscellaneous group
Osteochondrodysplasias with Platyspondyly (Table 15.4)
Although the trunk of the infants in this group is not significantly short, the vertebral bodies in the radiograph are markedly flattened. Histopathologically the physeal growth zones are usually disorganized and may be retarded, but the resting cartilage is mostly unremarkable.
SEBORRHEA AND DRY DESQUAMATION
Secretion of sweat normally exudes from the glands but occasionally collects in the gland ducts, distending them so that they are visible at birth as discrete pinpoint elevations known as milia crystalline (Figure 21.1). They usually disappears during the first week of life. They are most often visible on the forehead, cheeks, and sides of the nose. Microscopically a keratinous plug and an intra- or subcorneal vesicle communicates with the underlying sweat duct, sometimes with a mild inflammatory infiltrate. When the process is deeper, prickly heat (miliaria rubra) occurs.
Milia are pearly yellow 1 to 3-mm papules on the face, chin, and forehead of 50% of newborns. Occasionally they erupt on the trunk and extremities. Although milia usually resolve without treatment during the first month of life, they may persist for several months. Microscopically they are miniature epidermal inclusion cysts, which arise from the pilosebaceous apparatus of vellus hairs.
The scalp is most often affected in the newborn and is often associated with incomplete removal of the vernix caseosa. The lesions are poorly defined, yellowred salmon-colored patches covered by waxy, greasy, easily removed scales.
Acanthosis, edema, and occasional perivascular infiltration of leukocytes are present as well as spongiosis of the basal layer seen microscopically (Figure 21.2).
Congenital tumors are often composed of persistent embryonal or fetal tissues, suggesting a failure of proper cytodifferentiation or maturation during early life. Neuroblastoma develops from neural crest cells that migrate into the gland during embryonic and fetal life. Normally, these cells mature to ganglion cells.
Morphologic features of embryonic neoplasms include retinoblastoma, peripheral primitive neuroectodermal tumor (PNET), hepatoblastoma, yolk sac tumor of the testis, and embryonal rhabdomyosarcoma. Some teratomas show proliferation ofembryonic tissues that fail tomature. Anumberof tumors in the young are associated with congenital malformations and growth disturbances.
Some embryonic tumors have a benign course despite a malignant microscopic appearance such as stage IV-S neuroblastoma, congenital fibrosarcoma, and nephroblastomatosis. These tumors may undergo cytodifferentiation and spontaneous regression. Malignant neoplasms are seldom seen in the newborn and only infrequently are responsible for neonatal death or spontaneous abortion. Chromosomal abnormalities associated with childhood tumors are shown in Table 20.1.
Hemangiomas are the most common tumors of the skin and soft tissues in infants (Figure 20.1).
Capillary hemangioma usually manifests at birth, grows steadily for 68 months, then stabilizes, and eventually regresses, although complete disappearance may take several years. It is composed of capillaries separated by stroma. It may present as a raised subcutaneous nodule that blanches under pressure. Because childhood hemangiomas are tumors that evolve in time, a capillary hemangioma is thought to originate from a more primitive form.
The source of developmental anomalies lies within deviations from the normal pathways of embryogenesis.
Early stages ofembryonic development can be studiedby identification of developmental genes and their products, using in situhybridization and immuno chemistry and computerized three-dimensional reconstruction of aborted sectioned human embryos.
The most frequent craniofacial anomalies are clefts of the upper lip and palate that can now be diagnosed prenatally.
Clefts of the lip and palate are among the most common congenital anomalies, occurring in ±1.7 per 1,000 births in Asians, approximately 1 per 1,000 Caucasian births, and approximately 1 per 2,500 births in those of African lineage (Figures 14.1 to 14.5 and Tables 14.1 and 14.2). The frequency of cleft lip /palate is highest in Native Americans, occurring in over 3.6 per 1,000 births and showing a 2:1 female-to-male frequency. Unilateral cleft lips are more frequent on the left than the right and are least frequent bilaterally in the respective ratios of 6:3:1. Isolated cleft palate is distinguished from combined cleft lip and palate; the former occurs about twice as frequently as the combination. Some 2050% of cleft palates are associated with other anomalies. About 5% of facial clefting is syndromic, with over 250 cleft-associated syndromes.
Pathology of Cleft Lip. If the embryo is examined shortly after Carnegie Stage 18 and autolysis is severe, the newly fused tissue may degenerate and an artifactual cleft may appear. Thus, cleft lip cannot be diagnosed in a severely autolyzed embryo.
Amniotic fluid can be tested for phospholipid components of fetal lung surfactant.
The lecithin-to-sphingomyelin (L/S) ratio is the most widely used index. An L/S of >2.0 indicates fetal lung maturity in most cases. An L/S of <2 does not reliably exclude lung maturity.
The presence of phosphatidylglycerol (PG), a late-appearing surfactant component, has greater positive predictive value than the L/S ratio in determining fetal lung maturity. However, PG has lower sensitivity. A positive PG is helpful when the L/S is marginal.
RESPIRATORY TRACT ABNORMALITIES Choanal atresia
Choanal atresia is the failure of communication between the posterior nasal sacs and the oral cavity.
Laryngeal stenosis is a narrowing of the laryngeal cavity (Figure 17.1).
Laryngeal cleft is incomplete formation of the larynx (Figure 17.2).
The incidence of tracheoesophageal fistula (TEF) with or without esophageal atresia is 1/1,000 to 1/2,500 births (Figures 17.3 and 17.4 and Table 17.1). TEF is rarely familial and there are at least six anatomic types. More than 85% of all cases are of type 1 esophageal atresiawith fistula fromthe trachea or carina to the lower esophageal segment. Type 2 – esophageal atresia with TEF – is the next most common. The other types are shown in Figure 17.1.
Stillbirth or fetal death is the delivery of an infant with no signs of life between 20 weeks gestational age and term. The infant does not breathe or show any evidence of life: heart beat, pulsation of the umbilical cord, or definitemovement of voluntary muscles.
Perinatal death includes stillbirths and early neonatal deaths (less than 7 completed days from birth) (Tables 2.1 and 2.2). World Health Organization national statistics include fetal deaths with a fetus weighing 500 g or more, or gestation > 22 weeks, or crown-heel length > 25 cm. International statistics include fetal deaths with a fetus weighing > 1,000 g, gestation > 28 weeks, or crown-heel length > 35 cm.
Late intrauterine fetal death with stillbirth accounts for 1% of pregnancies.
PLACENTAL ABNORMALITIES ASSOCIATED WITH LATE FETAL DEATH
■ Cord accidents comprise 15-18% of fetal demise.
■ Long cord – entanglement around a fetal part, cord prolapse, cord compression, true knots, and excessive spiraling (sometimes may be a postmortem artifact) (Figure 2.1).
■ Short cord may indicate a central nervous system abnormality; it is more frequent with congenital anomalies. Delay in completion of the second stage of labor, abruption, inversion of the uterus, or cord rupture at delivery may be complications (Figures 2.2 to 2.4).
■ Nuchal cord may cause fetal strangulation – functionally significant if two or more loops are around the neck, with associated plethora of the face and scalp.
STAGES OF EMBRYONIC DEVELOPMENT
Carnegie staging in the development of the human embryo categorizes 23 stages.
Fertilization and Implantation (Stages 1-3)
Embryonic development commences with fertilization between a spermand a secondary oocyte (Tables 1.1 to 1.5). The fertilization process requires about 24 hours and results in the formation of a zygote – a diploid cell with 46 chromosomes containing genetic material from both parents. This takes place in the ampulla of the uterine tube.
The embryo's sex is determined at fertilization. An X chromosome-bearing spermproduces an XX zygote, which normally develops into a female, whereas fertilization by a Y chromosome-bearing spermproduces an XY zygote, which normally develops into a male.
The zygote passes down the uterine tube and undergoes rapid mitotic cell divisions, termed cleavage. These divisions result in smaller cells – the blastomeres. Three days later, after the developing embryo enters the uterine cavity, compaction occurs, resulting in a solid sphere of 12-16 cells to form the morula.
At 4 days, hollow spaces appear inside the compact morula and fluid soon passes into these cavities, allowing one large space to formand thus converting the morula into the blastocyst (blastocyst hatching). The blastocyst cavity separates the cells into an outer cell layer, the trophoblast, which gives rise to the placenta, and a group of centrally located cells, the inner cell mass, which gives rise to both embryo and extraembryonic tissue.
The zona pellucida hatches on day 5 and the blastocyst attaches to the endometrial epithelium.
Minor hydrops is common, particularly in premature infants. Severe hydrops is generalized edema of 7.5 mm subcutaneous edema in a third-trimester fetus with an effusion of at least one body cavity, usually accompanied by polyhydramnios and edema of the placenta.
Amniotic fluid volume is approximately 800 mL at term. The volume is increased by fetal urine and is simultaneously removed by fetal swallowing. Fetal anomalies that interfere with swallowing are associated with polyhydramnios, while a decrease of fetal renal function and production of urine result in oligohydramnios. The volume of amniotic fluid falls rapidly after 40weeks gestation to about 400 mL at 42 weeks and 200 mL at 44 weeks. Polyhydramnios is the presence of an excess of 1,500 mL of amniotic fluid at term and is present in up to 1% of pregnancies.
Causes of polyhydramnios
A. Diabetes and gestational diabetes
II. Fetal anomalies
B. Esophageal atresia
C. Small intestinal obstruction
D. Diaphragmatic hernia
E. Central nervous system malformations
F. Chromosomal defects
FETAL HYDROPS (FH)
Hydrops fetalis (HF) has a mortality rate in excess of 90% (Tables 12.1 to 12.5).
Intrauterine diagnosis of hydrops by ultrasound may allow successful treatment and reversal in selected cases, but the majority die without an established causative diagnosis.
The symptoms and signs and laboratory findings in congenital infections are listed in Table 22.1.
Bacterial infections in the fetus (Figure 22.1) are more frequently recognized than viral, parasitic, or fungal infections. In most cases acquisition of the organism is believed to be from the maternal genital tract by an ascending route. Premature rupture of membranes or a sudden spontaneous abortion may be the first indication of intrauterine infection.
Other routes of infection are:
Hematogenous spread of maternal infection
Iatrogenic infections introduced during prenatal procedures such as amniocentesis
Direct infection from the maternal peritoneal cavity.
In addition, bacteria can be carried asymptomatically in the male urogenital tractandcan infect the conceptusby the ascending route after sexual intercourse in pregnancy.
Infection may occur by access secondary to rupture of membranes. Once bacteria are in the amniotic sac, they incite maternal leukocyte migration from the intervillous space toward the amniotic cavity (Tables 22.1 and 22.2). The accumulation of neutrophils leads to a loss of translucency of the membranes, which become creamy yellow. Most bacteria infect the membranes diffusely. Inhalation and ingestion of infected amniotic fluid by the fetus (amniotic infection syndrome) can be diagnosed microscopically by sectioning of the fetal lungs and stomach, which will contain neutrophils from the amniotic fluid. Infection of the amniotic fluid can result in intrauterine aspiration pneumonia in the fetus or the development of septicemia particularly if the organism is strongly virulent aswith group B streptococci (Figures 22.2 and 22.3). Oranisms most frequently resulting in chorioamnionitis are shown in Table 22.2.
APPENDIX 1. CYTOGENETIC TERMINOLOGY
Aneuploid. An unbalanced state that arises through loss or addition of whole or pieces of chromosomes; always considered deleterious.
Chromosome. The location of hereditary (genetic) material within the cell. This hereditary material is packaged in the formof a very long, double-stranded molecule of DNA surrounded by and complexed with several different forms of protein. Genes are found arranged in a linear sequence along chromosomes, as is also a large amount of DNA of unknown function.
Confined placental mosaicism. A viable mutation in trophoblast or extraembryonic progenitor cells of the inner cell mass resulting in dichotomy between the chromosomal constitution of the placenta and the embryo or fetus.
Deletion. Pieces of chromosomes are missing in persons having 46 chromosomes.
Diploid (2n). The whole set of 46 chromosomes in a somatic cell.
Duplications. Extra pieces of chromosomes occur in individuals with 46 chromosomes.
Endomitosis. Duplication of the chromosomeswithout accompanying spindle formation or cytokinesis, resulting in a polyploid nucleus.
The normal anatomy of the adult and child are similar; however, the perinatal autopsy is significantly different. The variety and complexity of the congenital anomalies found in perinatal and fetal autopsies is endless and the prosector must be prepared to spend the necessary time demonstrating these anomalies. This detailed procedure can be altered to preserve any anomaly encountered without deforming the body itself. Most of the anomalies found in this population never survive to adulthood. Together with the clinical information this meticulous examination provides the necessary information to educate the families about future pregnancies.
PLACENTAL CHANGES AFTER FETAL DEATH
After the intrauterine death of the fetus, the placenta remains vital until it is expelled. However, changes occur that resemble vascular insufficiency but are diffuse, affecting fetal structure and all villi (Figure 3.1). Focal lesions suggest a preexisting abnormality (Tables 3.1).
Fetal death results in complete interruption of the fetal circulation. Vascular spaces within the villi are empty and collapsed. Within weeks, ingrowth of fibroblasts ultimately completely obliterate the vessels. Thrombosis does not occur and if present indicates preexistent pathology.
Calcificationmay be observed in addition to fibrosis as a postmortemchange within villi. It presents as fine granules deposited along the basal membrane of the trophoblast, sometimes almost in linear fashion. The fine granules contrast with the coarse deposits that sometimes occur in villi during physiological maturation. After fetal death, there are excessive syncytial knots that are diffuse. Primary vascular insufficiency is usually focal.
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