Prevention of illness and promotion of good health have long been keystones of pediatric practice. Anticipation of potential problems, assessment of risk of future illness, and discussion of mese concerns with parents are the stock in trade of pediatric practitioners. As we enter the 21st century, we recognize that genes play a significant role in health and disease in infancy and childhood. Interest in using this knowledge to identify health risks in infancy and childhood is expanding at a rapid pace. Principles derived from three decades of experience with newborn screening programs can provide guidance in this new era. Pediatricians are eager for new tools that enhance the lives and health of children (Table 1).
This issue of Pediatric Annals discusses new directions in newborn screening that will provide such tools. Nevertheless, reconsidering old tools in the light of new knowledge is useful, and so this issue also focuses attention on the use of the family history as a genetic screening tool. In addition, new knowledge about genetic causes of disease raises important concerns about when genetic screening is appropriate in children. Such a discussion raises ethical, legal, and social issues. This issue explores and reviews ways that pediatricians can bring the benefits of genetic screening to children.
Principles of and Issues in Newborn Screening
LESSONS FROM NEWBORN SCREENING
Newborn screening for phenylketonuria (PKU) began in 19621 and opened the door for a new level of prevention of mental retardation in children. Presymptomatic diagnosis of PKU provided treatment that could prevent the mental retardation associated with this disorder. The success depended on new understanding of a biochemical cause of mental retardation, a treatment based on this biochemical understanding, and a testing method that could be applied to large numbers of newborns at a modest cost. For 30 years, these programs uncovered a complexity in both the disorder sought and the delivery of definitive diagnosis and treatment that earlier experience did not predict.
Lessons learned from newborn screening for PKU led to a paradigm shift in pediatric diagnosis, and new diseases were rapidly added to the newborn screening protocols. Now all 50 states and Puerto Rico perform newborn screening for PKU and hypothyroidism.2'3 More than 40 states screen for sickle cell disease and galactosemia. In addition, many states test for other metabolic or endocrine disorders such as homocystinuria, branched-chain ketoaciduria (ie, maple syrup urine disease [MSUD]), biotinidase deficiency, and congenital adrenal hyperplasia. Newborn screening is also provided by the Uniformed Services.
The outcome in the diseases identified by newborn screening has been strikingly successful.3 The intelligence quotient (IQ) of children with PKU is within a few points of the IQ of unaffected siblings when treated with a phenylalanine-restricted diet in the first few weeks of life. Mortality from complications of sickle cell disease among infants diagnosed early and treated with prophylactic penicillin is now low at approximately 1%.4 Although no good case-control studies exist, birth certificate data collected before newborn screening suggest that this is a significant decrease. Congenital hypothyroidism presenting as classic cretinism is a thing of the past. The lives of children with congenital adrenal hyperplasia have been saved. Biotinidase deficiency no longer ravages undiagnosed children with seizures when identified by newborn screening and promptly treated.
Opportunities and Challenges in Newborn Screening
Newborn screening programs have not been an unqualified success; we still face challenges (Table 2).5,6 Outcome in PKU is still not ideal, as there remains an incidence of learning disability, and uniform management guidelines have yet to be established in the United States.5 Early treatment of galactosemia clearly prevents death in neonatal life.7 However, ovarian failure is nearly universal in affected women and learning disability is common in affected children despite early treatment. The mortality rate in MSUD remains high, despite early diagnosis and treatment.3
Practitioners must be alert to changes in health care that impact screening test strategies. This is particularly true in the analyte-based testing done for inborn errors of metabolism. Timing may be a factor in the identification of normal ranges for analytes measured in screening for PKU8 and the other amino acid disorders, hypothyroidism, and congenital adrenal hyperplasia. Transfusion may hamper the diagnosis of red blood cell analytes such as hemoglobin, and gal-l-P and GALT (galactose 1 -phosphate uridyltransferase).3
Positive and negative predictive value of tests varies with strategy. Particularly with rare diseases, one missed case represents failure. Both technical and biological reasons account for missed cases. A positive test result creates anxiety in a parent, so false-positive results represent a potential source of unnecessary distress. Any screening program must try to decrease the number of false-positive results.
The methods of testing are precise enough for some conditions that they identify heterozygous carriers for recessive genetic disorders and identify affected infants.9 This has implications for future pregnancies in the family and for other family members that are different from testing that identifies affected infants. What is different is the numbers involved, because heterozygosity ranges from 1 in 10 African Americans for sickle cell disease to 1 in 100 for the rarest metabolic conditions. Distinguishing heterozygosity, which has genetic implications, from an affected child, who requires treatment,9 is important for the practitioner.
Current Issues in Genetic Screening in Children
Some basic principles that apply to new tools for screening for disease in children derive from the experience in newborn screening for PKU and other disorders. Screening for PKU identified the important fact that PKU does not have a single, simple phenotype.5 The degree of genetic heterogeneity now recognized in PKU is large. More than 500 mutations have been identified and genotype-phenotype correlations are being established. Similar clinical heterogeneity characterizes all of the other disorders that newborn screening programs identify. Different mutations at the locus of the disease mutation, contributions of other genes, and environmental factors contribute to this heterogeneity. As we screen for new disorders and use new diagnostic tools, we must expect heterogeneity and build the testing and counseling aspects of the programs to consider it.
The addition of new tests to the screening battery depends on several criteria (Table 3).10 The first principle in the application of screening tests is that the information has use for the person being tested.11 Usually, this means that methods of treatment are established enough to allow development of an effective treatment program for patients identified by the testing. In addition, the pediatric community must have adequate educational information prior to the institution of testing. Public participation in decision making about additional newborn screening tests also has value. Expanded newborn screening for disorders of organic acid metabolism and fatty acid oxidation exemplifies these issues.12
Consent for testing is a controversial issue.13 Generally, the principle of informed consent has stood the test of time for the usual medical testing. The first newborn screening programs introduced newborn screening as a public health measure, and, as such, mandated testing for all infants. However, the screening community has revisited the issue of consent for testing. Nevertheless, newborn screening has been established in most states as a public health measure, and most programs do not require parental consent. Informed dissent may provide a solution to the problem of obtaining informed consent for an increasing variety of screening tests.
Classic newborn screening programs that test for biochemical analytes collect blood samples on newborn screening filter paper cards. The dried blood spots on these cards can provide a source of blood and of DNA for further testing for both genetic conditions and toxic exposures. They have been useful for postmortem diagnosis of unidentified inborn errors of metabolism.14 The Council on Regional Networks for Genetics Services suggested guidelines for retention, storage, and use of the dried blood spots on these cards.15 They recommend that guidelines be in place for using these samples as sources of genetic material.
The testing phase of a pediatric screening program does not stand alone.5,11 The identification of an abnormal screening result is only the beginning of the process (Figure). Accurate methods must exist to track the children identified by a screening program so that follow-up, definitive diagnosis, and treatment, if indicated, occur without delay. Treatment protocols and programs need to be in place and accessible. The pediatric practice community needs educational information to act promptly on the report of an abnormal screening result.
No program can ignore cost. Several cost-benefit studies done in the early days of newborn screening have attested to the favorable cost-benefit ratio of current newborn screening programs.16 New programs must also review costs and benefits as they are implemented.
Although many disorders subject to screening are genetic, not all of them are. Most hypothyroidism, for example, is not the result of a known genetic change.2 The issues raised by the genetic concerns are unique in that they raise the possibility of risk to others in the family besides the infant being tested.13 However, they can provide a forum for discussion of wider social and ethical concerns.
How can these lessons provide guidance for new questions in screening infants and children for genetic risk? Genetic testing for increased risk of development of cancer is playing a significant role in adult medicine. More than 50 kinds of cancer show familial clustering.17 Current estimates suggest that between 4% and 10% of childhood cancer results from single gene mutations.18 Single gene mutations also confer risk in children for retinoblastoma, familial adenomatous polyps, LiFraumeni syndrome, multiple endocrine neoplasia, and hereditary nonpolyposis colon cancer. Guidelines are being developed for genetic testing for cancer risk in adults,17 but genetic testing for cancer risk in children is still in its infancy. Scientific, social, and ethical concerns will all play a role in the development of these guidelines. Basic principles derived from the newborn screening experience will again prove useful and highlight the special concerns for children being tested, the use of the test for the child's health, and the degree to which the test result predicts outcome.
Figure. Follow-up for a newborn screening test with abnormal results.
A review of developments in newborn screening for biochemical disorders is particularly timely.1012 We now have prospects of vastly expanding the number of disorders that can be identified by new technology. Although this provides opportunities for prevention of illness and death, full appreciation of the scope and limitations of methodology is crucial. As we know from the classic newborn screening programs, a newborn screening program does not end with the development of a new test. The tracking and treatment part of the program is crucial to its success.
Newborn screening for hearing disorders uses principles of newborn screening, but the methods are entirely different from the classic biochemical approach. In addition, both genetic and nongenetic risks for hearing disability are addressed.19 Nevertheless, these programs build on principles learned in newborn screening for metabolic disorders. Gear diagnosis, explanation to the family, and provision for follow-up treatment determine the success or failure of the program, and pediatricians will need to play an active role in performing these.
Not all genetic screening uses new technology. Family history is a well-known genetic screening tool in pediatrics. However, in this expanding world of new genetic knowledge, its use and interpretation need to rise in importance for pediatricians. It is not just about cancer, diabetes, and heart disease, although those have not decreased in importance. Pediatricians will need to think about the key elements of family history as it relates to genetic disease, and we will need to continue to develop efficient ways to incorporate this tool into regular pediatric practice.
Children are not suitable candidates for screening for some genetic risks. Major concerns exist about presymptomatic screening of children for known gene mutations that cause disease.20 We need to think about the criteria for electing to test children for mutations associated with disease. Again, newborn screening programs provide lessons. A cardinal principle in selecting disorders for newborn screening has been that a treatment or an intervention that makes a difference follows the screening diagnosis.
The new century promises expanded knowledge of genetic contribution to health and disease in children. Pediatricians increasingly will use screening methods to detect children at risk, will need to know whether genetic risk is part of the picture, and will need to provide information and establish treatment to optimize outcome in these children.
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2. American Academy of Pediatrics Committee on Genetics. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics. 1993;91:1203-1209.
3. American Academy of Pediatrics Committee on Genetics. Newborn screening fact sheets. Pediatrics. 1996; 98:473-501.
4. Centers for Disease Control and Prevention. Mortality among children with sickle cell disease identified by newborn screening during 19901994: California, Illinois, and New York. JAMA. 1998;279:1059-1060.
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6. Seashore MR, Wappner R, Cho S, de la Cruz R Development of guidelines for treatment of children with phenylketonuria: report of a meeting at the National Institute of Child Health and Human Development. Pediatrics. 1999;104:e67. Available at: ww w.pediatrics. org / cgi / content / full/99/ 104/ 6/e67.
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13. Alonso C. Ethical reflections concerning genetic services: a paradigm for the future? J Inherit Metab Dis. 1996;19:424-431.
14. Boles RG, Buck EA, Blitzer MG, et al. Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life. J Pediatr. 1998;132:924-933.
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18. Nichols KE, Li FP, Haber DA, Diller L. Childhood cancer predisposition: applications of molecular testing and future implications. J Pediatr. 1998; 132:389-397.
19. Downs MP. Universal newborn hearing screening: the Colorado story. Int J Pediatr Otorhinolaryngol. 1995;32:257-259.
20. Natowicz MR, Alper JS. Genetic screening: triumphs, problems, and controversies. J Public Health Policy. 1991;12:475-491.
Principles of and Issues in Newborn Screening
Opportunities and Challenges in Newborn Screening
Current Issues in Genetic Screening in Children