It is difficult to precisely identify the diseases of infancy and childhood because many disorders that begin in childhood become clinically evident in adulthood if a long period of time is required to generate a pathologic lesion. The topics chosen for inclusion in this chapter are disorders presenting almost exclusively in childhood. However, they obviously represent only a small fraction of “childhood disorders.” Many disorders in other sections of this book, such as hemophilia and numerous infections, occur or are diagnosed primarily in childhood. The chapter begins with an overview of prenatal and neonatal laboratory testing.

Prenatal Testing and Screening

The disorders that can be diagnosed before birth number in the thousands. In families in which there is a history of a particular disorder, it is not uncommon to test prenatally for that particular disorder, often with DNA-based diagnostic tests. However, for the vast majority of families without a history of a specific illness, prenatal screening may also be undertaken. A screen differs from a test in that it does not provide a definitive diagnosis but rather an assessment of the risk of a diagnosis. For most of these families, screening is preferred as an initial step because it is less invasive; for example, there are several maternal serum screening assays (see below) for fetal Down syndrome (also known as trisomy 21), but testing for fetal Down syndrome requires an invasive procedure such as chorionic villus sampling or collection of amniotic fluid. The decision to screen is a personal one for families and includes considerations such as parental age and desire to avoid having a diseased child.

Neonatal Screening

Neonatal screening was originally developed to detect diseases such as phenylketonuria (PKU) and congenital hypothyroidism, for which early detection and intervention could prevent catastrophic consequences such as intellectual disability (mental retardation). Improvements in assay methodology, such as decreases in cost and the availability of tandem mass spectrometry for single assay detection of many abnormalities, have expanded the neonatal screening menu to include assays for diseases that are not preventable but are often treatable. All 50 US states screen for over 26 disorders, including amino acidurias (such as PKU and maple syrup urine disease), organic acidemias (such as isovaleric acidemia), fatty acid disorders (such as medium-chain acyl-CoA dehydrogenase [MCAD] deficiency), hemoglobinopathies associated with hemoglobin S, congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, and classical galactosemia, among others. As new methods and new assays are developed, some variation between states’ neonatal screening menus will inevitably continue to exist; these variations are tracked on a Web site maintained by the National Newborn Screening & Global Resource Center.

As with any screening program, positive results require follow-up confirmation testing; false-positives do occur. Suggested actions and algorithms for neonatal screen positives are published on the Web by the American College of Medical Genetics and Genomics (ACMG). Urgent intervention is required for some of these disorders, to preserve life or prevent intellectual disability.

Neonatal Testing

The laboratory evaluation of an infant who appears clinically well in the first 24 hours of life but develops signs of illness on the second or third day may include:

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  Blood gases to detect metabolic acidosis/alkalosis

  
  
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  Urinalysis to detect ketonuria

  
  
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  Complete blood count to detect abnormalities in blood cells

  
  
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  A blood glucose test to detect hypoglycemia

  
  
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  A blood ammonia test to detect elevated ammonia

  
  
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  Liver function tests to detect hepatic dysfunction

  
  
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  Prothrombin time and partial thromboplastin time to detect coagulopathies

  
  
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  Blood lactate to detect lactic acidosis

Table 7–1 lists a number of screening laboratory tests that are typically ordered when there is suspicion that a neonate (or older child) is suffering from an inborn error of metabolism.

The results of these tests only suggest specific disorders, with additional testing required to identify a specific metabolic defect. Definitive tests to make a conclusive diagnosis of a metabolic disorder often involve the measurement of specific enzyme activities or various metabolites in a pathway. Because sepsis is often suspected, it must be ruled out in the sick infant if there are any signs or symptoms of infection.

Description

A major cause of neonatal mortality and morbidity is prematurity, defined as birth prior to 37 weeks of gestation. When preterm labor or premature rupture of membranes causes prematurity, the underlying etiology is not often apparent, although it is believed to be commonly associated with infection or inflammation. Maternal correlates of prematurity include diabetes, obesity, intervention for infertility, genital or urinary infection, periodontal disease, low socioeconomic status, and other factors. Conflicting information exists about the value of intervention such as use of antibiotics for infection or infection risk.

Another cause of prematurity is iatrogenic, when the medical condition of the mother and/or fetus compels intervention to produce early delivery. The timing of such elective intervention for early delivery is influenced by the risk for fetal organ immaturity. Principal among these concerns is lung immaturity that is associated with the development of respiratory distress syndrome in the newborn.

Diagnosis

Risk of preterm delivery can be assessed by measurement of fetal fibronectin in cervical or vaginal fluid. This glycoprotein is produced by fetal membranes and appears in the cervix and vagina early in pregnancy as implantation develops, but normally disappears by week 20. Its reappearance in the third trimester often precedes labor and delivery. Its chief clinical value lies in its negative predictive value, that is, patients thought to be at risk for preterm labor who are negative for fetal fibronectin in their cervicovaginal fluid are very unlikely to deliver within 1 week of the laboratory result. The major barrier to the widespread use of the fetal fibronectin test, when positive, is that clinical interventions to end preterm labor are only partially successful.

In those instances when fetal or maternal health dictates early delivery, there are several tests available to assess fetal lung maturity. A simple and inexpensive test is to count lamellar bodies in amniotic fluid, using the platelet channel in a conventional hematology automated analyzer. These lamellar bodies are surfactant-containing products of Type II pneumocytes. The finding of greater than 50,000 lamellar bodies per microliter of amniotic fluid predicts lung maturity. If fewer bodies are present, further testing on the amniotic fluid sample is warranted. Other tests include identification of the presence of phosphatidylglycerol (PG), and determination of the ratio of lecithin to sphingomyelin (L/S ratio). (See Chapter 14 for additional information.)

Description

Down syndrome is the most commonly encountered, clinically significant autosomal chromosome aberration affecting individuals beyond infancy. This genetic defect, which can be detected by cytogenetic analysis, is trisomy 21. More than 90% of Down cases occur as a result of meiotic nondisjunction. Down syndrome is characterized by intellectual disability, cardiac malformations, malformations of the digestive tract, eyes, and ears, and the development of an Alzheimer-like disease process in later life.

The overall birth prevalence of Down syndrome is approximately 1 in 1000 births. However, a woman’s individual risk to deliver an infant with Down syndrome depends substantially on her age. The risk increases significantly past age 35 years, with an incidence in the range of 1:270 to 1:100 by age 40 years.

Screening and Diagnosis

The neonatal diagnosis of Down syndrome is clinical, with metaphase chromosome analysis on peripheral blood serving merely to confirm the diagnosis.

Noninvasive fetal screening for Down syndrome involves many more tests (Table 7–2) that are used in combination to develop a risk assessment of Down syndrome during pregnancy. Definitive diagnosis of fetal Down syndrome during pregnancy is established by an invasive test, namely, metaphase analysis of cells from either chorionic villus sampling (typically limited to first trimester) or amniotic fluid collection. The decision to engage in fetal screening for Down syndrome or to move from screening tests to invasive diagnostic testing once a risk assessment is completed depends on patient preference. The invasive tests to assess for Down syndrome during pregnancy do carry a risk of miscarriage.