Newborn screening (NBS) programs are state mandated to ensure that all infants are screened for specific conditions at birth, providing the opportunity for early intervention and prevention of adverse outcomes such as neurologic dysfunction, developmental disability, and death.1 Screening for phenylketonuria (PKU) began in the 1960s.2 Since then, genomic medicine and technological advancements have expanded the capacity to screen for over 60 conditions.3

The Recommended Uniform Screening Panel (RUSP) forms a standardized list of disorders endorsed by the Advisory Committee on Heritable Disorders in Newborns and Children and recommended by the Secretary of the Department of Health and Human Services. While most states screen for the majority of disorders on the RUSP, states have the authority to determine which conditions are included in their state universal NBS program.1

Categories of Diseases Included in the NBS

The goal of newborn screening is to prevent morbidity and mortality through cost-effective early diagnosis of treatable disorders. Disorders listed on the RUSP are classified as either core conditions or secondary conditions. Treatment is available for all core conditions on the RUSP list. The NBS is specifically designed to detect core conditions and it is recommended that they be included in every state NBS program.4

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Secondary conditions are considered clinically significant and may be detected while screening for core conditions or during confirmatory testing of an abnormal core condition result, but some secondary conditions may lack appropriate medical therapy to affect long-term outcomes.1, 5, 6 Core and secondary conditions are further broken down into the type of disorder: metabolic, endocrine, hemoglobin, and other.

As of July 2018, 35 core conditions and an additional 26 secondary conditions were on the recommended uniform screening panel.4 In-born errors of metabolism account for 20 of the core conditions on the current RUSP, the most of any category, and are categorized as either organic acid metabolism disorders (n=9), fatty acid metabolism disorders (n=5), or amino acid metabolism disorders (n=6). In addition, endocrine and hemoglobin disorders account for 2 and 3 RUSP core conditions, respectively. Ten other various core conditions round out the list. 

Clinical findings may be helpful in the differential diagnosis of some disorders. For example, infant tone and activity such as urine odors, dysmorphic features, stooling patterns, quality of cry, laboratory findings, and feeding progress, may alert the practitioner of abnormalities before NBS results are known and may also serve as a reminder to check results of pending screens.7-11 Management of specific disorders depends on the underlying cause for the condition. Table 1 lists some of the more common conditions from the RSUP, their frequency, clinical features, and management strategies.

Table 1. Select Conditions From the Recommended Uniform Screening Panel Core Conditions4,7-11

Core ConditionType of DisorderFrequencyClinical FeaturesManagement  
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiencyMetabolic1 in 17,000  Neonatal: usually asymptomatic
Later: anorexia, vomiting lethargy, seizures, hyoketotic hypoglycemia
Prevention of hypoglycemia; no fasting; heart healthy diet with  ≤30% fat; carnitine supplementation
Citrullinemia, type IMetabolic  1 in 57,000Neonatal: Anorexia, vomiting, lethargy, seizures, coma, hyperammonemiaDietary protein restriction; essential amino acid supplementation
Classic phenylketonuriaMetabolic  1 in 10,000-15,000    Neonatal: vomiting, poor feeding, hyperactivity, irritability
Later: seizures, musty urine odor
Untreated: severe intellectual disability, developmental delays, seizures
Dietary protein restriction; select amino acid restriction (special formula without phenylalanine)
Holocarboxylase synthase deficiencyMetabolic  1 in 87,000    Neonatal: lethargy, hypotonia, seizures, ketoacidosis, hyperammonemia
Later: rash, impaired T-cell immunity, developmental delay
Biotin supplementation
Primary congenital hypothyroidismEndocrine1 in 2000-4000Neonatal: lethargy, hypotonia, periorbital edema, large fontanelles, feeding difficulty, respiratory distress, pallor, prolonged jaundice, hoarse crying, constipation, hypothermiaThyroid hormone replacement
Sickle cell diseaseHemoglobin1 in 500
(Black infants)
1 in 1000-1400 (Hispanic infants) 
Early childhood: anemia, repeat infections, episodic painTreat pain; prevent complications; stem cell transplant
Cystic fibrosisOther1 in 2500-3000 (White infants)
1 in 17,000
(Black infants)
1 in 31,000
(Asian infants)
1 in 9200
(Hispanic infants)
Neonatal: meconium ileus, intestinal atresia, prolonged jaundice, abdominal or scrotal calcifications
Early childhood: digestive symptoms or failure to thrive, pulmonary infections
High energy and fat diet; hydrolyzed protein formula with MCT; pancreatic enzyme, vitamin, mineral supplementation;  breastfeeding encouraged
Classic galactosemiaOther    1 in 30,000-60,000      Neonatal: lethargy and poor feeding, jaundice with hepatic dysfunction, possible sepsis
Chronic: growth failure, cirrhosis, intellectual disabilities, cataracts
Strict avoidance of dietary galactose
MCT; medium-chain triglyceride