CHAPTER 25
Newborn Screening
Henry J. Lin, MD, and Moin Vera, MD, PhD
CASE STUDY
A 1-week-old boy is brought to the pediatrician’s office for a positive newborn screening test result for congenital adrenal hyperplasia. The baby was a product of a 38-week gestation and was born by normal spontaneous vaginal delivery to a 30-year-old gravida 2, para 2 woman with an unremarkable pregnancy. Birth weight was 3,300 g (116.4 oz), and the baby is feeding and acting appropriately. Family history is unremarkable, and the physical examination is normal.
Questions
1. What are the proposed benefits of newborn screening?
2. Which newborn screening tests are most commonly performed?
3. How are the results of newborn screening tests reported to physicians?
4. How should a patient with an abnormal newborn screening result be managed?
5. What are the most common causes of false-positive and false-negative results?
6. What are the ethical issues and future challenges surrounding newborn screening?
Newborn screening programs are designed to identify neonates at risk for catastrophic outcomes from treatable illnesses. Technologic advances in the past 50 to 60 years, such as tandem mass spectrometry, have made it possible to test for more than 50 metabolic disorders from a single blood spot. New techniques in molecular biology, including high-throughput DNA sequencing, allow for rapid diagnostic testing of conditions such as cystic fibrosis.
From the inception of newborn screening in the 1960s until 2005, each state in the United States chose a different set of conditions for its newborn screening program, based on disease prevalence, cost, availability of treatment, and false-positive rates. In 2005, an expert panel from the American College of Medical Genetics and Genomics recommended 29 core disorders for which newborn screening was most effective, as well as 25 secondary disorders that are in the differential diagnosis of a core disorder. In 2010, severe combined immunodeficiency (SCID) was added to the core list. Screening for critical congenital heart disease (by pulse oximetry) was endorsed by the American Academy of Pediatrics in 2011. By the end of 2013, all states offered testing for the 29 original core disorders, although screening for secondary disorders and SCID was variable.
Since 2015, development of federal recommendations for newborn screening has been the responsibility of the Advisory Committee on Heritable Disorders in Newborns and Children (under the US Department of Health and Human Services). The conditions on the Recommended Uniform Screening Panel include metabolic disorders, hemoglobinopathies and thalassemias, congenital hypothyroidism, SCID, hearing screening (see Chapter 88), and critical congenital heart disease. Advances in treatment (eg, enzyme replacement therapy) have resulted in recent expansion of the panel. As of July 2018, the latest additions to the Core Conditions list were disease type II (ie, Pompe disease), mucopolysaccharidosis type I (ie, Hurler syndrome), X-linked adrenoleukodystrophy, and spinal muscular atrophy (caused by homozygous deletion of exon 7 in SMN1; Table 25.1). The Recommended Uniform Screening Panel also has a list of Secondary Conditions, based on the earlier recommendations (Box 25.1).
Primary care physicians have 3 crucial roles in newborn screening. First, they provide education to parents about the newborn screening process. Second, they ensure that specimens are drawn under proper circumstances and that the results are promptly followed up. Finally, they provide medical follow-up and referral in cases of positive test results. All physicians must have contact information for state newborn screening programs and local pediatric subspecialists. Contact information for these groups is listed in Table 25.2.
Epidemiology
More than 4 million newborns are screened each year in the United States. The National Newborn Screening 2006 Incidence Report shows that newborn screening identifies 1 in 3,200 newborns with a metabolic disorder, 1 in 2,200 with congenital hypothyroidism, 1 in 2,200 with sickle cell disease or a related hemoglobinopathy, and 1 in 29,000 with congenital adrenal hyperplasia. Several disorders are more common in particular ethnic groups. For example, cystic fibrosis has an incidence of 1 in 2,500 in whites, and sickle cell disease has an incidence of 1 in 400 in blacks.
Clinical Presentation
Most neonates with disorders detected on newborn screening are clinically asymptomatic in the first 2 weeks after birth, but others may have significant signs and symptoms (see Table 25.1). The presence of such features may require a more urgent work-up or even hospitalization. Unfortunately, severe forms of some metabolic disorders may cause coma and encephalopathy by 48 hours of age. In these cases, newborn screening results are critical, because they will suggest a probable diagnosis and allow early optimization of therapy.
| Table 25.1. Recommended Uniform Screening Panel Core Conditionsa | ||
| Type of Disorder | Core Condition | Possible Signs and Symptoms in Neonates |
| Metabolic: Organic acid | Propionic acidemia | Lethargy, vomiting, hypoglycemia, ketoacidosis, hyperammonemia, neutropenia, thrombocytopenia |
| Methylmalonic acidemia (ie, methylmalonyl-CoA mutase) Methylmalonic acidemias (ie, cobalamin disorders) | Same as above | |
| Isovaleric acidemia | Lethargy, vomiting, odor of sweaty feet, hyperammonemia | |
| 3-Methylcrotonyl-CoA carboxylase deficiency | Lethargy, vomiting; may be asymptomaticb | |
| 3-Hydroxy-3-methylglutaricaciduria | Lethargy, vomiting, hypoglycemia, hyperammonemia, elevated transaminases | |
| Holocarboxylase synthetase deficiency | Lethargy, vomiting, hypoglycemia, ketoacidosis, hyperammonemia | |
| ß-Ketothiolase deficiency | Lethargy, vomiting; may be asymptomaticb | |
| Glutaric acidemia type 1 | Macrocephaly possible; otherwise asymptomaticb | |
| Metabolic: Fatty acid oxidation | Carnitine uptake defect/carnitine transport defect | Lethargy, cardiac decompensation, hypotonia, hypoglycemia, liver dysfunction; may be asymptomaticb |
| Medium-chain acyl-CoA dehydrogenase deficiency | Lethargy, coma, sudden death, hypoglycemia, liver dysfunction, arrhythmias, symptoms similar to those of Reye syndrome; may be asymptomaticb | |
| Very-long-chain acyl-CoA dehydrogenase deficiency | Lethargy, cardiac decompensation, coma, sudden death, hypoglycemia; may be asymptomaticb | |
| Long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency | Lethargy, cardiac decompensation, hypoglycemia, liver dysfunction; may be asymptomaticb | |
| Trifunctional protein deficiency | Same as above | |
| Metabolic: Amino acid | Argininosuccinicaciduria | Lethargy, vomiting, seizures, coma, hyperammonemia |
| Citrullinemia type I | Lethargy, vomiting, seizures, coma, hyperammonemia | |
| Maple syrup urine disease | Lethargy, vomiting, seizures, coma, maple syrup odor | |
| Homocystinuria | Asymptomaticb | |
| Classic phenylketonuria | Asymptomaticb | |
| Tyrosinemia type I | Vomiting, diarrhea, liver dysfunction (jaundice, bleeding, hypoglycemia), boiled cabbage odor; may be asymptomaticb | |
| Endocrine | Primary congenital hypothyroidism | May be asymptomaticb; umbilical hernia, enlarged fontanelle, macroglossia, jaundice |
| Congenital adrenal hyperplasia | Virilization in females, salt-wasting crisis | |
| Hemoglobin | SS disease (ie, sickle cell anemia) | Asymptomaticb, dactylitis |
| S ß-thalassemia (ie, sickle ß-thalassemia) | Asymptomaticb | |
| SC disease (ie, hemoglobin C sickle cell disease) | Asymptomaticb | |
| Other | Biotinidase deficiency | Lethargy, hypotonia, seizures; may be asymptomaticb |
| Critical congenital heart disease | Hypoxemia | |
| Cystic fibrosis | Meconium ileus, intestinal obstruction | |
| Classic galactosemia | Lethargy, vomiting, diarrhea, jaundice, hepatomegaly, cataracts, sepsis (Escherichia coli) | |
| Glycogen storage disease type II (ie, Pompe disease) | Hypotonia, hypertrophic cardiomyopathy; may be asymptomaticb | |
| Hearing loss | Deafness, speech delay | |
| Severe combined immunodeficiencies | Recurrent infections | |
| Mucopolysaccharidoses type I | Inguinal hernia, upper respiratory tract infection; may be asymptomaticb | |
| X-linked adrenoleukodystrophy | Asymptomaticb | |
| Spinal muscular atrophy caused by homozygous deletion of exon 7 in SMN1 | Impaired motor function | |
Abbreviations: CoA, coenzyme A; SMN1, survival of motor neuron 1.
a As of July 2018.
b Asymptomatic covers the first month after birth and does not exclude very rare case reports of neonatal presentations.
Adapted from Advisory Committee on Heritable Disorders in Newborns and Children. Recommended Uniform Newborn Screening Panel Core Conditions (as of July 2018). Washington, DC: U.S. Department of Health & Human Services; 2018 www.hrsa.gov/sites/default/files/hrsa/advisory-committees/heritable-disorders/rusp/rusp-uniform-screening-panel.pdf.
Box 25.1. Recommended Uniform Screening Panel Secondary Conditionsa
Organic Acid Disorders
•Methylmalonic acidemia with homocystinuria
•Malonic acidemia
•Isobutyrylglycinuria
•2-Methylbutyrylglycinuria
•3-Methylglutaconicaciduria
•2-Methyl-3-hydroxybutyricaciduria
Fatty Acid Oxidation Disorders
•Short-chain acyl-CoA dehydrogenase deficiency
•Medium/short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency
•2,4-Dienoyl-CoA reductase deficiency
•Carnitine palmitoyltransferase type I deficiency
•Carnitine palmitoyltransferase type II deficiency
•Carnitine acylcarnitine translocase deficiency
Amino Acid Disorders
•Argininemia
•Citrullinemia type II
•Hypermethioninemia
•Benign hyperphenylalaninemia
•Biopterin defect in cofactor biosynthesis
•Biopterin defect in cofactor regeneration
•Tyrosinemia type II
•Tyrosinemia type III
Hemoglobin Disorders
•Various other hemoglobinopathies
Other Disorders
•Galactoepimerase deficiency
•Galactokinase deficiency
•T-cell related lymphocyte deficiencies
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