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Newborn Screening

Inborn errors of metabolism include a vast array of disorders that are caused by deficiencies of specific enzymes or transport proteins. The goal of newborn screening is the presymptomatic diagnosis of disorders for which early treatment can reduce morbidity and mortality. State mandated newborn screening was initiated in the early 1960s to identify infants affected with phenylketonuria (PKU). Screening programs have gradually expanded to include additional inborn errors, but state mandated programs are not uniform across the United States. Until recently, the Missouri Department of Health has screened for five disorders including phenylketonuria, congenital hypothyroidism, congenital adrenal hyperplasia, galactosemia and hemoglobinopathy.

During the last decade, tandem mass spectrometry has been adapted for supplemental newborn screening because it is amenable to population-wide testing for more than 30 disorders of fatty acid, organic acid and amino acid metabolism.

The complete list includes:

  • Congenital hypothyroidism
  • Congenital adrenal hyperplasia
  • Hemoglobinopathy
  • Galactosemia
  • Cystic Fibrosis
  • BIotinidase deficiency
  • Fatty Acid Disorders
    • Carnitine/acylcarnitine translocase deficiency (CAT)
    • Carnitine palmitoyl transferase deficiency (CPT)
    • Long-chain hydroxy acyl-CoA dehydrogenase deficiency (LCHAD)
    • Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)
    • Multiple acyl-CoA dehydrogenase deficiency (MAD)
    • Short-chain acyl-CoA dehydrogenase deficiency (SCAD)
    • Trifunctional protein deficiency (TFP)
    • Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD)
  • Organic Acid Disorders
    • Glutaric acidemia, type 1 (GA-1)
    • Isovaleric acidemia (IVA)
    • Methylmalonic acidemia (MMA)
    • Propionic acidemia (PA)
    • 3-hydroxy-3-methylglutaryl CoA lyase deficiency (HMG)
    • 3-methylcrotonyl CoA carboxylase deficiency (3MCC)
  • Amino Acid Disorders
    • Argininosuccinic aciduria
    • Citrullinemia
    • Homocystinuria
    • Hypermethioninemia
    • Maple Syrup Urine Disease (MSUD)
    • Phenylketonuria (PKU)
    • Tyrosinemia, type II


Results of the screening tests will be reported as normal or abnormal. If the result is abnormal, a quantitative result will be reported along with the expected ranges. Each abnormal result will also be accompanied by an interpretive comment indicating whether it is considered to be slightly elevated, elevated, or highly elevated and the suggested follow-up. In general, slightly elevated results require prompt repeat newborn screening, or if clinically indicated, diagnostic testing. For elevated and highly elevated results, the immediate diagnostic testing and consultation with a referral center are recommended.

Newborn cystic fibrosis screening is performed by utilizing a fluroimmunoassay to measure immunoreactive trypsinogen (IRT). Newborns with cystic fibrosis have persistently elevated IRT levels, whereas unaffected infants may have transiently elevated levels at birth that return to normal after the first week of life. A repeat screen is requested for all infants that have elevated IRT levels on the initial newborn screen. If IRT levels are elevated on the repeat screen, the physician of record will be contacted by a cystic fibrosis center for additional follow up testing.

Biotinidase deficiency is an autosomal recessive disorder that results in multiple carboxylase deficiencies. Individuals with profound biotinidase deficiency have less than 10% of mean normal serum biotinidase enzyme activity, while individuals with partial biotinidase deficiency have 10%-30%. Both profound and partial biotinidase deficiencies are usually identified by newborn screening. The estimated incidence of profound and partial deficiencies is 1 in 60,000 births.

Infants with profound biotinidase deficiency appear normal at birth but develop one or more of the following symptoms after the first few weeks of life: seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities such as alopecia, skin rash and candidiasis. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress. Children with biotinidase deficiency identified by newborn screening should remain asymptomatic if biotin therapy is instituted early and continuously maintained.

An abnormal biotinidase screening test should be confirmed by measuring biotinidase enzyme activity in serum or plasma. Biotinidase test results should be abnormal in all infants with profound or partial deficiency even if the specimen is obtained before formula or milk feeding or collected before 24 hours of age. A newborn screen should be collected prior to transfusion since transfusion may mask the deficiency.

The pros and cons of supplemental newborn screening by tandem mass spectrometry are being hotly debated. Pro-active groups, such as, and parents of infants born with treatable diseases have spearheaded the development of supplemental newborn screening programs. Recent studies have associated 5% of SIDS to metabolic disorders that can be detected by supplemental screening.

However, many experts believe that tandem mass spectrometry should not be used in newborn screening until more is known about its sensitivity and specificity. Given the low prevalence of these metabolic disorders in the general population, the number of false positive results will greatly exceed the number of true positives. Sufficient resources need to be available to handle the increased number of abnormal results that will need to be further investigated. In most newborn screening programs, 75% or more of staff time is devoted to follow-up of false positive results. Once an abnormal result is obtained, additional confirmatory testing will need to be performed. Another concern is that there may not be enough pediatric specialists in the United States to evaluate all of the newborns with abnormal results in a timely manner. The issue of informed consent for supplemental screening is complicated, in part because uniformly effective therapies have not been developed for all the conditions that can be detected and because expanded screening may detect previously unrecognized disorders. Reimbursement is also problematic. Supplemental screening costs vary from $25 to $60, but consultation and confirmatory testing are much more expensive. Presently, it is unclear whether private insurance or state and federal programs will cover any of these costs.

Second Tier Follow-up Testing for Congenital Adrenal Hyperplasia

Newborn screening includes testing for congenital adrenal hyperplasia (CAH), which is an autosomal recessive disorder that affects approximately 1 in 10,000 newborns and results in deficient secretion of cortisol. Decreased cortisol synthesis leads to elevated ACTH levels, which produces adrenal hyperplasia. Five different enzyme deficiencies can cause CAH, but deficiency of 21-alpha-hydroxylase accounts for more than 90% of cases. Impaired 21-hydroxylase activity causes deficient production of cortisol and aldosterone. Depending on the extent of the enzyme deficiency, CAH may present as either a salt losing (75% of cases) or a non-salt losing disorder during the newborn period. Both types of CAH are associated with genital abnormalities because 21-hydroxylase deficiency prevents precursor hormones, such as 17-hydroxyprogesterone (17-OHP), from entering the cortisol metabolic pathway. These precursors accumulate and spill over into the androgen metabolic pathway, forming androstenedione and testosterone.

CAH screening is performed by measuring levels of 17-OHP in dried blood spots. Levels of <50 ng/mL are considered normal for a normal weight infant of 2250 grams or greater. A significant problem with CAH screening programs, is that 17-OHP levels are elevated in very low birth weight (<1500 grams) and extremely low birth weight (< 1000 grams) infants, resulting in many falsely positive results. Second Tier CAH testing is recommended for all newborns with abnormal 17-OHP screening results.

Second tier testing by tandem mass spectrometry simultaneously measures 17-OHP, androstenedione and cortisol. Patients with CAH have elevated androstenedione and low or absent cortisol. Findings of elevated 17-0HP values (>10.2 ng/mL) and a high 17-OHP + androstenedione/cortisol ratio (>2.5) support the initial abnormal screening result. 

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