Infection (excluding parvovirus)

Cytomegalovirus

Syphilis

Toxoplasmosis

Major Malformations

Tumors

Metabolic disorders

Note: The cause of fetal hydrops may be undetermined ("idiopathic") in up to 20% of cases. Data from Machin GA: Hydrops, cystic hygroma, hydrothorax, pericardial effusions, and

fetal ascites, In Gilbert-Barness E (ed): Potter's Pathology of Fetus and Infant. St. Louis, Mosby-Year Book, 1997.

IMMUNE HYDROPS

Immune hydrops is defined as a hemolytic disease in the newborn caused by blood-group incompatibility between mother and child. When the fetus inherits red cell antigenic determinants

from the father that are foreign to the mother, a maternal immune reaction may occur, leading to hemolytic disease in the infant. Any of the numerous red cell antigenic systems may

theoretically be involved, but the major antigens known to induce clinically significant immunologic disease are the ABO and certain of the Rh antigens. The incidence of immune hydrops

in urban populations has declined remarkably, owing largely to the current methods of preventing Rh immunization in at-risk mothers. Successful prophylaxis of this disorder has resulted

directly from an understanding of its pathogenesis.

Etiology and Pathogenesis.

The underlying basis of immune hydrops is the immunization of the mother by blood group antigens on fetal red cells and the free passage of antibodies from the mother through the

placenta to the fetus ( Fig. 10-14 ). Fetal red cells may reach the maternal circulation during the last trimester of pregnancy, when the cytotrophoblast is no longer present as a barrier, or

during childbirth itself. The mother thus becomes sensitized to the foreign antigen.

Of the numerous antigens included in the Rh system, only the D antigen is the major cause of Rh incompatibility. Several

Figure 10-14Pathogenesis of immune hydrops fetalis (see text).

Figure 10-15Numerous islands of extramedullary hematopoiesis (small blue cells) are scattered among mature hepatocytes in this infant with nonimmune hydrops fetalis.

Figure 10-16Kernicterus. Severe hyperbilirubinemia in the neonatal period, for example, secondary to immune hemolysis, results in deposition of bilirubin pigment in the brain

parenchyma. This occurs because the blood-brain barrier is less well developed in the neonatal period than it is in adulthood. Infants who survive develop long-term neurologic sequelae.

TABLE 10-6-- Abnormalities Suggesting Inborn Errors of Metabolism

General

Dysmorphic features

Deafness

Self-mutilation

Abnormal hair

Abnormal body or urine odor ("sweaty feet"; "mousy or musty"; "maple syrup")

Hepatosplenomegaly; cardiomegaly

Hydrops

Neurologic

Hypotonia or hypertonia

Coma

Persistent lethargy

Seizures

Gastrointestinal

Poor feeding

Recurrent vomiting

Jaundice

Eyes

Cataract

Cherry red macula

Dislocated lens

Glaucoma

Muscle, Joints

Myopathy

Abnormal mobility

Adapted from Barness LA and Gilbert-Barness E: Metabolic diseases, In Gilbert-Barness E (ed): Potter's Pathology of Fetus and Infant. St. Louis, Mosby-Year Book, 1997.

Homozygotes with this autosomal recessive disorder classically have a severe deficiency of phenylalanine hydroxylase, leading to hyperphenylalaninemia and its pathologic consequences.

Affected infants are normal at birth but within a few weeks develop a rising plasma phenylalanine level, which in some way impairs brain development. Usually by 6 months of life severe

mental retardation becomes evident; fewer than 4% of untreated PKU children have intelligence quotient values greater than 50 or 60. About one third of these children are never able to

walk, and two thirds cannot talk. Seizures, other neurologic abnormalities, decreased pigmentation of hair and skin, and eczema often accompany the mental retardation in untreated

children. Hyperphenylalaninemia and the resultant mental retardation can be avoided by restriction of phenylalanine intake early in life. Hence, a number of screening procedures are

routinely used for detection of PKU in the immediate postnatal period.

Many clinically normal female PKU patients who are treated with dietary control early in life reach childbearing age. Most of them discontinue dietary treatment and have marked

hyperphenylalaninemia. Between 75% and 90% of children born to such women are mentally retarded and

microcephalic, and 15% have congenital heart disease, even though the infants themselves are heterozygotes. This syndrome, termed maternal PKU, results from the teratogenic effects of

phenylalanine or its metabolites that cross the placenta and affect specific fetal organs during development.[62] The presence and severity of the fetal anomalies directly correlate with the

maternal phenylalanine level, so it is imperative that maternal dietary restriction of phenylalanine is initiated before conception and continues throughout the pregnancy.

The biochemical abnormality in PKU is an inability to convert phenylalanine into tyrosine. In normal children, less than 50% of the dietary intake of phenylalanine is necessary for protein

synthesis. The rest is irreversibly converted to tyrosine by a complex hepatic phenylalanine hydroxylase system ( Fig. 10-17 ), which, in addition to the enzyme phenylalanine hydroxylase,

has two other components: the cofactor tetrahydrobiopterin (BH4 ) and the enzyme dihydropteridine reductase, which regenerates BH4 . Although neonatal hyperphenylalaninemia can be

caused by deficiencies in any of these components, 98% to 99% of cases are attributable to abnormalities in phenylalanine hydroxylase. With a block in phenylalanine metabolism owing to

lack of phenylalanine hydroxylase, minor shunt pathways come into play, yielding phenylpyruvic acid, phenyllactic acid, phenylacetic acid, and o-hydroxyphenylacetic acid, which are

excreted in large amounts in the urine in PKU. Some of these abnormal metabolites are excreted in the sweat, and phenylacetic acid in particular imparts a strong musty or mousy odor to

affected infants. It is believed that excess phenylalanine or its metabolites contribute to the brain damage in PKU.

At the molecular level, several mutant alleles of the phenylalanine hydroxylase gene have been identified. Each mutation induces a particular alteration in the enzyme resulting in a

corresponding quantitative effect on residual enzyme activity ranging from complete absence to 50% of normal values. The degree of hyperphenylalaninemia and clinical phenotype is

inversely related to the amount of residual enzyme activity. Infants with mutations resulting in a lack of phenylalanine hydroxylase activity present with the classic features of PKU, while

those with up to 6% residual activity present with milder disease. Moreover, some mutations result in only modest elevations of phenylalanine levels, and the affected children have no

neurologic damage. This latter condition, referred to as benign hyperphenylalaninemia, or mild PKU, is important to recognize because the individuals may well test positive in screening

tests but do not develop the stigmata of classic PKU.[63] Measurement of serum phenylalanine levels differentiates benign hyperphenylalaninemia and classic PKU.

Although dietary restriction of phenylalanine is relatively successful in reducing or preventing the mental retardation associated with PKU, there are problems with long-term compliance

(resulting in a decline in mental or behavioral status)

Figure 10-17The phenylalanine hydroxylase system.

Figure 10-18Pathways of galactose metabolism.

Figure 10-19Galactosemia. The liver shows extensive fatty change and a delicate fibrosis. (Courtesy of Dr. Wesley Tyson, The Children's Hospital, Denver, CO.)

Figure 10-20Top, Normal cystic fibrosis transmembrane conductance regulator (CFTR) structure and activation. CFTR consists of two transmembrane domains, two nucleotide-binding

domains (NBD), and a regulatory R domain. Agonists (e.g., acetylcholine) bind to epithelial cells and increase cAMP, which activates protein kinase A, the latter phosphorylating the

CFTR at the R domain, resulting in opening of the chloride channel. Bottom, CFTR from gene to protein. The most common mutation in the CFTR gene results in defective protein folding

in the Golgi/ER and degradation of CFTR before it reaches the cell surface. Other mutations affect synthesis of CFTR, nucleotide-binding and R domains, and membrane-spanning

domains.

Figure 10-21Chloride channel defect in the sweat duct (top) causes increased chloride and sodium concentration in sweat. In the airway (bottom), cystic fibrosis patients have decreased

chloride secretion and increased sodium and water reabsorption leading to dehydration of the mucus layer coating epithelial cells, defective mucociliary action, and mucus plugging of

airways. CFTR, Cystic fibrosis transmembrane conductance regulator; EnaC, Epithelial sodium channel.

Figure 10-22The many clinical manifestations of mutations in the cystic fibrosis gene, from most severe to asymptomatic. (Redrawn from Wallis C: Diagnosing cystic fibrosis: blood,

sweat, and tears. Arch Dis Child 76:85, 1997.)

Figure 10-23Lungs of a patient dying of cystic fibrosis. There is extensive mucus plugging and dilation of the tracheobronchial tree. The pulmonary parenchyma is consolidated by a

combination of both secretions and pneumonia—the green color associated with Pseudomonas infections. (Courtesy of Dr. Eduardo Yunis, Children's Hospital of Pittsburgh, Pittsburgh,

PA.)

Figure 10-24Mild to moderate cystic fibrosis changes in the pancreas. The ducts are dilated and plugged with eosinophilic mucin, and the parenchymal glands are atrophic and replaced by

fibrous tissue.

TABLE 10-7-- Clinical Features and Diagnostic Criteria for Cystic Fibrosis

1. Chronic sinopulmonary disease manifested by

•••a. Persistent colonization/infection with typical cystic fibrosis pathogens, including Staphylococcus aureus, nontypeable Hemophilus influenzae, mucoid and nonmucoid Pseudomonas

aeruginosa, Burkholderia cepacia

•••b. Chronic cough and sputum production

•••c. Persistent chest radiograph abnormalities (e.g., bronchiectasis, atelectasis, infiltrates, hyperinflation)

•••d. Airway obstruction manifested by wheezing and air trapping

•••e. Nasal polyps; radiographic or computed tomographic abnormalities of paranasal sinuses

•••f. Digital clubbing

2. Gastrointestinal and nutritional abnormalities, including

•••a. Intestinal: meconium ileus, distal intestinal obstruction syndrome, rectal prolapse

•••b. Pancreatic: pancreatic insufficiency, recurrent pancreatitis

•••c. Hepatic: chronic hepatic disease manifested by clinical or histologic evidence of focal biliary cirrhosis, or multilobular cirrhosis

•••d. Nutritional: failure to thrive (protein-calorie malnutrition), hypoproteinemia, edema, complications secondary to fat-soluble vitamin deficiency

3. Salt-loss syndromes: acute salt depletion, chronic metabolic acidosis

4. Male urogenital abnormalities resulting in obstructive azoospermia (congenital bilateral absence of vas deferens)

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