Screening for genetic disorders

Recent additions to genetic screening programs include DNA testing to identify carriers of certain disorders, presymptomatic detection of certain disorders, newborn screening for hemoglobinopathies, and maternal serum alpha fetoprotein screening during pregnancy. Purposes and limitations of each of these new screening programs are discussed. Responsibilities of nurse practitioners for educating clients about genetic screening tests is emphasized.     

Ethical issues in newborn screening and the impact of new technologies

Medical ethics is an integral part of medical practice. The general principles are well known: autonomy (the right to choose), beneficence (do good), non-maleficence (do no harm), and justice (be fair and equitable). In newborn screening these principles must be especially carefully applied, as the intervention, screening, has not been sought by the patient, but is a form of preventive medicine. In proposing a screening programme questions to be asked are: should we do it? (is there enough benefit, not too much harm?); can we do it? (do we have the technology and skill to find the cases sought); can we afford it? The first question, with its ethical implications, is often ignored. New issues have arisen with new technology, but underlying ethical themes are the same. Tandem mass spectrometry can be used to detect about 30 very rare disorders in a single test. Proving the benefit of this (and other screening tests) is difficult because randomised controlled trials seem impractical, because of power considerations, long follow-up time, and because there is already a perceived benefit. Best possible evidence of a lower order must be sought. In future, DNA microarray technology is likely to become sufficiently inexpensive to apply to newborn screening. It is difficult to predict all the future possibilities of DNA technology in this fast-moving field. Major ethical problems are likely with the ability to detect adult-onset disorders or susceptibility to these in babies. Under what circumstances would this be ethical? We need to start debating these issues.     

The call from the newborn screening laboratory: frustration in the afternoon

Newborn screening programs in the United States are evolving in concert with technologic advances in analytic chemistry and medicine. Many more disorders are being identified on dried filter paper blood spots without fundamentally altering the basic principles first put forward in the 1960s. Some disorders have been added without researchers knowing if there is a true benefit to early diagnosis and treatment; some disorders currently being detected will merit little or no follow-up in the future. The general principles underlying newborn screening are discussed, as are the individual disorders screened in most programs. The expanding and evolving impact of tandem mass spectrometry on newborn screening is also explored.     

State-of-the-art for DNA technology in newborn screening

Just as metabolites, hormones and proteins are measured in newborn screening tests, DNA has become an analyte that is important in the screens for certain disorders. DNA confirmatory testing on the original dried blood specimen reduces the age at diagnostic confirmation and antibiotic prophylaxis initiation for neonates with sickle cell disease. Molecular genetic analysis of the initial specimens from newborns with elevated immunoreactive trypsinogen (IRT) for cystic fibrosis (CF) screening permits reduction of the IRT threshold value, improving specificity without compromising sensitivity. Because of this cost reduction, CF neonatal screening programs routinely incorporate DNA confirmatory testing into their initial CF screening algorithm. DNA analysis is also a valuable adjunct in screening programs for congenital adrenal hyperplasia (CAH), improving sensitivity and specificity. Incorporation of DNA into newborn screening programs will continue to be stimulated by development of robust, high throughput technologies for evaluation of this analyte. New paradigms for neonatal screening are evolving, including hearing screening in the newborn nursery. DNA testing, such as for mutations in the connexin 26 gene, may have a role in the evaluation of those screened positive. Newborn screening dried blood specimens are DNA databases. Therefore, there are significant ethical, legal and social issues that must be considered in the storage and utilization of neonatal screening specimens.     

Lessons from the past--looking to the future. Newborn screening

It is safe to predict that we are still at an early stage of newborn screening. There is a high probability that in the future, MS/MS or a similar technology will be applied to screening for many additional disorders, both metabolic and non-metabolic. The ability to examine DNA in the Guthrie specimen, currently used in second-tier screening, has opened up opportunities for primary screening of a huge array of potential disorders that previously could not be identified in the newborn. Among the possibilities under current discussion are type I diabetes, severe combined immunodeficiency, fragile X syndrome, hereditary hemochromatosis, and lymphoblastic leukemia. The major problems with these considerations, however, are that preventive treatment is not yet possible for most of these disorders, and for many, the abnormal finding determines only susceptibility for and not certainty of disease. Our experiences in the past with such newborn screening as that for histidinemia, which was found not to produce disease, and alpha 1-antitrypsin deficiency, which was not medically beneficial and had negative psychological effects, are lessons that must be taken seriously when considering new avenues of screening. Beyond further application to the Guthrie blood specimen and testing in a centralized laboratory is the broader concept of newborn screening exemplified by universal screening for hearing impairment. This screening is conducted directly on the newborn in the newborn nursery. This type of in-hospital universal screening may have wider application in the future. Much activity is underway to develop a consensus on appropriate newborn screening. This activity has been led by the Genetic Disease Branch of the federal Maternal and Child Health Bureau (MCHB), Health Resources and Services Administration (HRSA), in collaboration with the American Academy of Pediatrics and, currently, in collaboration with the American College of Medical Genetics through a committee to promulgate criteria for inclusion in newborn screening. The aphorism, "good judgment comes from experience, and experience comes from bad judgment," may be applied to newborn screening. Our challenge now is to use the experience we have from the previous bad judgements to guarantee future good judgements.     

50 Jahre Neugeborenenscreening in Deutschland

Background

In Germany newborn screening for phenylketonuria was started in single regions in 1964 and implemented nationwide in 1969. In the following decades additional disorders have been included in the screening panel.

Objective

Evaluation of the number of patients with inborn metabolic or endocrine disorders who have been identified by newborn screening in Germany.

Material and methods

Results of former evaluations of newborn screening, nationwide screening reports, and data from the newborn screening laboratory in Heidelberg were used to evaluate how many patients have been detected by newborn screening in Germany since its implementation. For individual years with a lack of systematic data, estimations are performed using the respective birth rate for Germany, participation rate of newborn screening and disease prevalence established for the other years.

Results

In the past 50 years newborn screening has been performed for more than 34,000,000 children in Germany. For more than 11,000 children, and in consideration of estimations even more than 14,000 children, this resulted in early diagnosis of a metabolic or endocrine disorder allowing for early treatment and prevention of severe handicap or death. The actual number of patients who could so far benefit from newborn screening is presumably even higher, as patients with additional disorders have been identified in pilot studies, which are not included in this survey.

Conclusion

New diagnostic and therapeutic measures will allow further extension of the screening panel, which is currently investigated in pilot studies, and will allow even more children to benefit from newborn screening. Systematic tracking of positive results and transition of patients into adult patient care are important current challenges.

     

State-of-the-art for DNA technology in newborn screening

Just as metabolites, hormones and proteins are measured in newborn screening tests, DNA has become an analyte that is important in the screens for certain disorders. DNA confirmatory testing on the original dried blood specimen reduces the age at diagnostic confirmation and antibiotic prophylaxis initiation for neonates with sickle cell disease. Molecular genetic analysis of the initial specimens from newborns with elevated immunoreactive trypsinogen (IRT) for cystic fibrosis (CF) screening permits reduction of the IRT threshold value, improving specificity without compromising sensitivity. Because of this cost reduction, CF neonatal screening programs routinely incorporate DNA confirmatory testing into their initial CF screening algorithm. DNA analysis is also a valuable adjunct in screening programs for congenital adrenal hyperplasia (CAH), improving sensitivity and specificity. Incorporation of DNA into newborn screening programs will continue to be stimulated by development of robust, high throughput technologies for evaluation of this analyte. New paradigms for neonatal screening are evolving, including hearing screening in the newborn nursery. DNA testing, such as for mutations in the connexin 26 gene, may have a role in the evaluation of those screened positive. Newborn screening dried blood specimens are DNA databases. Therefore, there are significant ethical, legal and social issues that must be considered in the storage and utilization of neonatal screening specimens.     

Newborn screening for lysosomal storage disorders

Newborn screening is a public health programme aimed at identifying treatable conditions in pre-symptomatic newborns to avoid premature mortality, morbidity and disabilities. With the advent of successful treatment options for an increasing number of lysosomal storage disorders (LSDs), such as enzyme replacement or bone marrow transplantation, inclusion of these disorders into newborn screening programmes seems reasonable. However, the success of these programmes depends on the availability of testing methods that are suitable for population screening, have high sensitivity and a low false-positive rate. In recent years, two methods have been proposed for newborn screening of LSDs, which enable assessment of more than one LSD from a single blood spot sample. One applies tandem mass spectrometry, the other microbead array technology. Now, prospective studies are needed to determine the most effective approach to newborn screening that will identify those patients who require treatment. CONCLUSION: With the advent of high-throughput assays for the detection of LSDs, newborn screening for these disorders may soon become a reality. However, careful prospective studies are required to optimize this process before it is used on a larger scale.     

Neonatal screening for haematological disorders

Neonatal screening for haematological disorders has advanced over the last decade in England, with the phased implementation of a universal screening programme for the detection of sickle cell disease. Glucose-6-phosphate dehydrogenase deficiency and haemoglobin H disease are included in the universal newborn screening programmes in some parts of the world. Selective screening for haematological diseases should be considered in neonates with unexplained or prolonged hyperbilirubinaemia. Additionally, selective screening for haemostatic disorders is recommended in neonates at risk of hereditary bleeding disorders, although the majority of haemostatic abnormalities detected in the newborn are acquired. This review will give an introduction to the above disorders and discuss the role and procedures in place for newborn screening.     

The future of newborn screening belongs to obstetricians

Newborn screening has been a mainstay of genetic testing for several decades. Molecular biological techniques, pervasive in genetics and in medicine, are shifting the focus of such testing from enzymology to molecular diagnosis. Concomitant developments in the isolation of fetal cells from maternal blood enable molecular analysis to be performed not just postnatally, but in fact as early as the late first trimester. Potential advantages of first trimester prenatal diagnosis of those disorders currently performed postnatally include more reproductive options for couples, and, in selected cases, the fact that certain genetic disorders can be treated much earlier in development, thereby potentially ameliorating the sequelae of these disorders. Thus, the future of newborn screening will belong as much to the obstetrician as to the pediatrician, if not more so.     

The future of newborn screening belongs to obstetricians

Newborn screening has been a mainstay of genetic testing for several decades. Molecular biological techniques, pervasive in genetics and in medicine, are shifting the focus of such testing from enzymology to molecular diagnosis. Concomitant developments in the isolation of fetal cells from maternal blood enable molecular analysis to be performed not just postnatally, but in fact as early as the late first trimester. Potential advantages of first trimester prenatal diagnosis of those disorders currently performed postnatally include more reproductive options for couples, and, in selected cases, the fact that certain genetic disorders can be treated much earlier in development, thereby potentially ameliorating the sequelae of these disorders. Thus, the future of newborn screening will belong as much to the obstetrician as to the pediatrician, if not more so.     

Newborn screening: a literature review

Newborn screening is the largest genetic testing effort for newborns in the U.S. Its purpose is to identify newborns who are at risk for metabolic, endocrine, or hematologic disorders. A review of the literature was conducted to determine the benefits of newborn screening; specimen collection timing and handling; ethical considerations of screening; as well as current practices regarding consent, notification of results, and follow-up procedures. The use of tandem mass spectrometry for expanded newborn screening and postmortem diagnosis of unexplained infant death was also reviewed. This article is intended to educate health care providers in the areas of controversy that surround the U.S. newborn screening program, with the hope of encouraging further research in this mportant area of newborn care.     

Newborn screening for medium chain acyl-CoA dehydrogenase deficiency: evaluating the effects on outcome

Although individually rare, inborn errors of metabolism represent a potentially preventable cause of death and disability. Tandem mass spectrometry allows a number of these disorders to be detected in a single step. Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most important of these disorders. However, public health decisions on whether or not to implement new screening programmes rely on evidence regarding benefits and harms. This article reviews existing published evidence for newborn screening for MCADD and highlights where further information is required for public health decision making. This review reveals that important uncertainties remain about performance and outcome, including criteria and thresholds for defining a positive screening result, diagnostic criteria, test performance and longer-term outcome. Notably, despite a combined experience of screening well over one million infants, there has been no report of a systematic follow-up of longer-term outcome in affected infants detected by screening. Prospective data on mortality, neurological outcome, and cognitive function are required to assess the effectiveness of screening. Additionally, the impact of screening and treatment on the families of infants with true, borderline, and false positive diagnoses needs to be taken into account.     

Introduction to the newborn screening fact sheets

Newborn screening fact sheets were last revised in 1996 by the Committee on Genetics of the American Academy of Pediatrics. These fact sheets have been revised again because of advances in the field, including technologic innovations such as tandem mass spectrometry, as well as greater appreciation of ethical issues such as informed consent. The fact sheets provide information to assist pediatricians and other professionals who care for children in performing their essential role within the newborn screening public health system. The newborn screening system consists of 5 parts: (1) newborn testing; (2) follow-up of abnormal screening results to facilitate timely diagnostic testing and management; (3) diagnostic testing; (4) disease management, which requires coordination with the medical home and genetic counseling; and (5) continuous evaluation and improvement of the newborn screening system. The following disorders are reviewed in the newborn screening fact sheets (which are available at www.pediatrics.org/cgi/content/full/118/3/e934): biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia,homocystinuria, maple syrup urine disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, phenylketonuria, sickle cell disease and other hemoglobinopathies,and tyrosinemia.     

Welche Rolle bleibt dem selektiven Screening auf Stoffwechselstörungen angesichts des Neugeborenenscreening mit Tandemmassenspektrometrie?

For several decades general neonatal screening for inborn metabolic and endocrine disorders through the examination of dried blood spots has been available in Germany and Austria. More recently, this newborn screening has been extended in these two countries to include tandem mass spectrometry analyses. The extended neonatal screening and its potential have rightly attracted major attention, but the heavy emphasis placed on its potential has also made some pediatricians uncertain about the further need for organic acid/amino acid analyses and other assays performed as selective screening tests for inborn errors of metabolism. We therefore give an introduction to routine and selective newborn screening and present signs, symptoms and laboratory data that can prompt selective metabolic screening.     

Arguments for early screening: a clinician's perspective

Recent technological advances have led to an expansion in inborn errors that can be detected in the newborn period. Further developments in newborn screening will increase this number further. There are two main arguments put forward to support the developments of an expanded newborn screening programme. Firstly there may be an improvement in patient outcome. The early detection of disorders either in the pre-symptomatic or early symptomatic phase should, with treatment, result in the prevention of severe illness. This is evident for phenylketonuria and generally accepted for homocystinuria and medium-chain acyl-CoA dehydrogenase deficiency, disorders which have a long pre-symptomatic phase. However, other inborn errors may present within the first 10 days of life with severe illness, particularly neonatal encephalopathy. In order to effectively stop the rapid progression of these disorders, screening must be undertaken early although where severe metabolic decompensation occurs within 2 to 3 days of birth, newborn screening programmes are unlikely to be of direct benefit. Secondly an early diagnosis, even when this does not affect that individual's prognosis, may allow for accurate genetic advise to be given to the family and the opportunity to have prenatal diagnosis for future pregnancies. CONCLUSION: For the clinician, the introduction of an expanded and early newborn screening presents opportunities for improved patient and family care. However, it is important to be aware of possible detrimental effects on families of early screening. Screening tests must have adequate sensitivity and high specificity. Furthermore with early screening, close liaison between the laboratory, clinicians and community services is essential.     

Neonatal screening for cystic fibrosis: present and future

Despite there being effective tests for detecting cystic fibrosis (CF) using newborn screening blood samples, screening in neonates has not had universal approval because of uncertainty about its benefits. After up to 18 y experience, at a recent conference in Caen several aspects attracted universal agreement. There is still major delay in clinical diagnosis after the onset of symptoms. There is short-term benefit in early diagnosis by screening, with reduced morbidity in the first 2 y, evidence of significant nutritional benefits up to the age of 10 y, and probable respiratory benefit over this time frame. There is great potential for research into treatment modalities and no evidence of significant psychological harm to CF babies from early diagnosis. With a screening protocol that includes a DNA test there is some unwanted carrier detection and careful genetic counselling is needed. There is no evidence yet that screening will extend the life of CF patients, so some doubts remain as to its overall effectiveness, and there have been no good studies on comparative costs in screened and unscreened cohorts. Even so, the weight of evidence suggests very worthwhile advantages for screened babies and their families. Because of this, it is unlikely that further trials will take place. It may be that the onus now is on those who do not support screening to justify this stance to parents who may favour it.     

Neonatal screening for cystic fibrosis: present and future

Despite there being effective tests for detecting cystic fibrosis (CF) using newborn screening blood samples, screening in neonates has not had universal approval because of uncertainty about its benefits. After up to 18 y experience, at a recent conference in Caen several aspects attracted universal agreement. There is still major delay in clinical diagnosis after the onset of symptoms. There is short-term benefit in early diagnosis by screening, with reduced morbidity in the first 2 y, evidence of significant nutritional benefits up to the age of 10 y, and probable respiratory benefit over this time frame. There is great potential for research into treatment modalities and no evidence of significant psychological harm to CF babies from early diagnosis. With a screening protocol that includes a DNA test there is some unwanted carrier detection and careful genetic counselling is needed. There is no evidence yet that screening will extend the life of CF patients, so some doubts remain as to its overall effectiveness, and there have been no good studies on comparative costs in screened and unscreened cohorts. Even so, the weight of evidence suggests very worthwhile advantages for screened babies and their families. Because of this, it is unlikely that further trials will take place. It may be that the onus now is on those who do not support screening to justify this stance to parents who may favour it.     

National newborn screening program — Still a hype or a hope now?

The year 2013 marks 50 years of both newborn screening and the Indian Academy of Pediatrics. India has seen a lot of change in terms of motivation, evolution and implementation of newborn screening as pilot projects for few disorders. Facilities for implementing screening using tandem mass spectrometry or what is termed as ‘expanded newborn screening’ have also become available. We attempt to discuss the evolution of newborn screening and the way to carry it forward in the country. The current strengths, the major obstacles and gritty challenges are enlisted. No moment could be so opportune than this year to discuss the rainbow of hope with all its colors with respect to newborn screening in our country.     

Universal newborn hearing screening

The present statement reviews the evidence for universal newborn hearing screening (UNHS). A systematic review of the literature was conducted using Medline and using search dates from 1996 to the third week of August 2009. The following search terms were used: neonatal screening AND hearing loss AND hearing disorders. The key phrase "universal newborn hearing screening" was also searched. The Cochrane Central Register of Controlled Trials and systematic reviews was searched. Three systematic reviews, one controlled non-randomized trial and multiple cohort studies were found. It was determined that there was satisfactory evidence to support UNHS. The results of the available literature are consistent and indicate clear evidence that without UNHS, delayed diagnosis leads to significant harm for children and their families; with UNHS, diagnosis and intervention occur earlier; earlier intervention translates to improved language outcomes; and in well-run programs, there is negligible harm from screening.