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Neonatal Screening Tests

Almost all of the diseases detected in neonatal screening programs have a very low prevalence, and for the most part, the tests are quantitative rather than qualitative. In general, the strategy is to use the initial screening test to separate a highly suspect group of patients from normal infants (i.e., to increase the prevalence) and then to follow this suspect group aggressively. There are 2 common strategies used to detect congenital hypothyroidism, 1 uses thyroid-stimulating hormone for the initial screen and the other uses thyroxine. In the thyroxine strategy for congenital hypothyroidism, which has a prevalence of 25/100,000 liveborn infants, the initial test performed is for thyroxine in whole blood. Infants with the lowest 10% of test results are considered suspect. If all infants with hypothyroidism were included in the suspect group, the prevalence of disease in this group would be 250/100,000 infants. The original samples obtained from the suspect group are retested for thyroxine and are tested for thyroid-stimulating hormone. This 2nd round of testing results in an even more highly suspect group composed of 0.1% of the infants screened and having a prevalence of hypothyroidism of 25,000/100,000 subjects. This final group is aggressively pursued for further testing and treatment. Even with a 1,000-fold increase in prevalence, 75% of the aggressively tested population is euthyroid. The justifications advanced for the program are that treatment is easy and effective and that the alternative, if congenital hypothyroidism is undetected and untreated—long-term custodial care—is both unsatisfactory and expensive.

At its inception, newborn screening was driven by the selection of genetic diseases whose clinical manifestations developed postnatally, such as phenylketonuria, galactosemia, and hypothyroidism. Diseases selected for screening typically had to meet certain criteria. The prevalence of disease had to meet a minimum, typically 1 in 100,000. Disease selection required demonstrated reduction in morbidity and mortality in the neonatal period. Effective therapies needed to be available, and the cost of screening and the feasibility of laboratory testing were also considerations in this selection process.

More common diseases have also become targets for neonatal screening programs. Sickle cell disease, easily detected using liquid chromatography or isoelectric focusing, can be treated more effectively if it is diagnosed before clinical signs appear. In addition, the results of neonatal screening for cystic fibrosis (CF) show that there are clear benefits associated with preclinical diagnosis, but also that there are some inherent difficulties associated with genetic screening for complex autosomal recessive diseases that are common and are caused by a rather large number of mutations (>1,500) of a single gene. The definitive diagnostic test for CF is the measurement of concentrations of chloride in sweat, a test that is not practical during the 1st wk of life. Neonates with CF generally have elevations in whole blood trypsinogen. This test allows the identification of a group of neonates at risk for CF. Unfortunately trypsinogen as an initial screening test has a high false-positive rate, a unfavorable characteristic that creates unnecessary anxiety among newborn parents and families, and is costly due to the time and expense for medical follow up. Performing DNA analysis for common mutations that cause CF reduces the size of the suspect group and identifies neonates with a higher likelihood of disease. This 2-tiered strategy identifies a manageable number of infants on whom to perform sweat tests. Problems include the following: (1) uncommon mutations are not included in the screening panel (thus, cases of CF caused by these mutations can be missed); (2) common mutations that cause clinically innocent elevations of whole blood trypsinogen in heterozygous neonates cause potentially alarming false-positive findings; and (3) CF in patients with normal sweat test results is rare, but is likely to be missed.

Tandem mass spectrometry (MS/MS) is a technically advanced method in which many compounds are initially fragmented and separated by molecular weight. Each compound is then fragmented again. Identification of compounds is based upon characteristic fragments. The process requires roughly 2 min/sample and can detect 20 or more inborn errors of metabolism. The effects of prematurity, neonatal illness, and intensive neonatal management on metabolites in blood complicate the interpretation of results. The PV of a positive screening result is likely to be <10%; that is, 90% of positive results are not indicative of a genetic disorder of metabolism. Nonetheless, MS/MS permits a diagnosis to be made before clinical illness develops, and has revolutionized the purpose and ability of newborn screening. MS/MS is not directed toward diseases defined as treatable, but toward all of the diseases, each of which is rare, that the technique can identify.

Electrospray tandem mass spectrometry permits the detection of rare inborn errors of metabolism and has been introduced as a newborn screening tool all around the world. In the 4 yr since mass spectrometry was implemented in Australia, the rate of detection per 100,000 births was 15.7, significantly higher than the rate of 8.6-9.5 in the 6 preceding 4-yr periods. Disorders of fatty acid oxidation, particularly medium-chain acyl coenzyme A dehydrogenase deficiency, accounted for the majority of increased diagnoses.

Expanded newborn screening programs using MS/MS increase the detection of inherited metabolic disorders. As of 2009, 49 U.S. states use MS/MS in their neonatal screening programs. The remaining state has required expanded newborn screening, but has not yet implemented the testing. However, the metabolic conditions screened for by states using MS/MS vary, ranging from <10 to >29.

In an attempt to standardize newborn screening programs, the American College of Medical Genetics recommends that every baby born in the USA be screened for a core panel of 29 disorders (Table 707-3). An additional 25 conditions were recommended as secondary targets because they may be identified while screening for the core panel disorders. The March of Dimes and the American Academy of Pediatrics also endorse the recommendation by the American College of Medical Genetics. However, expansion of the screening test menu raises several issues. For example, the cost of implementation can be significant because many states will need multiple MS/MS systems. In addition, staffing the laboratory with qualified technical personnel to run the MS/MS system and qualified clinical scientists to interpret the profiles can be a challenge. A number of false-positive results will also be obtained with these newborn screening programs. Many of these findings are due to parenteral nutrition, biologic variation, or treatment, and are not the result of an inborn error of metabolism. Therefore, qualified staff will be needed to ensure that patients with abnormal results are contacted and receive follow-up testing and counseling, if needed. Even with these concerns, the American College of Medical Genetics report is a step in the right direction toward standardizing guidelines for state newborn screening programs.

Table 707-3   — ACMG CORE PANEL

   Glutaricaciduria type 1
   Multiple CoA carboxylase deficiency
   Methylmalonicacidemia (mutase deficiency)
   3-Methylcrotonyl CoA carboxylase deficiency
   Methymalonicacidemia (Cbl A,B)
   β-Ketothiolase deficiency
   Medium-chain acyl-CoA dehydrogenase deficiency
   Very long chain acyl-CoA dehydrogenase deficiency
   Long-chain l-3-hydroxy acyl-CoA dehydrogenase deficiency
   Trifunctional protein deficiency
   Carnitine uptake deficiency
   Maple syrup urine disease
   Homocystinuria (due to CBS deficiency)
   Tyrosinemia type 1
   Sickle cell anemia (Hb SS disease)
   Hb S/b-thalassemia
   Hb S/C disease
   Congenital hypothyroidism
   Biotinidase deficiency
   Congenital adrenal hyperplasia (21-hydroxylase deficiency)
   Classical galactosemia
   Hearing loss
   Cystic fibrosis

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