Newborn screening is a highly effective public health program saving the lives of thousands of babies nationwide every year. Although most pediatricians are familiar with their state’s newborn screening program, they may not be aware of how new conditions are added.
To encourage uniformity, in 2006 the American College of Medical Genetics and the Health Resources and Services Administration published the results of an expert panel review of conditions under consideration for newborn screening. Conditions were ranked on feasibility of screening from the newborn blood spot and availability of interventions. The conditions identified by this consensus method became the Recommended Uniform Screening Panel (RUSP). All states screen for the 29 original RUSP core conditions.
A process also was developed for adding conditions to the RUSP. As technologies advance in treatment and detection, more conditions have been considered for the RUSP, which now includes 34 core conditions and 26 secondary conditions; secondary conditions are detected during screening for core conditions but do not reach the evidence threshold for inclusion as a primary target for screening.
Three new conditions recently were added to the RUSP: Pompe disease, mucopolysaccharidosis type I (MPS I, Hurler syndrome) and X-linked adrenoleukodystrophy (X-ALD). As these conditions were reviewed, further complexities regarding variability of severity and onset of clinical symptoms as well as the efficacy of treatment needed to be considered. Ethical considerations also play a prominent role in the committee’s deliberations.
Infantile-onset Pompe disease, which impacts about 1 in 28,000 newborns in the U.S., (acid alpha glucosidase deficiency, glycogen storage disease type II) presents in the first two months of life with hypotonia, generalized muscle weakness, cardiomegaly and hypertrophic cardiomyopathy, feeding difficulties, failure to thrive, respiratory distress and hearing loss. Untreated infantile-onset Pompe disease commonly results in death in the first year of life from progressive left ventricular outflow obstruction.
Non-classical infantile-onset Pompe disease presents in the first year of life with motor delays and slowly progressive muscle weakness, resulting in death from ventilatory failure in early childhood.
Late-onset Pompe disease is characterized by proximal muscle weakness and respiratory insufficiency. Treatment requires lifelong enzyme replacement therapy (ERT). Immunomodulary therapy may be required for patients on ERT due to the development of antibodies to the infused enzyme.
There is a spectrum of phenotypes in MPS I (alpha-L-iduronidase deficiency) patients. The condition impacts about 1 in 100,000 individuals; infants with severe MPS I appear normal at birth. Coarsening of facial features is not apparent until after age 1. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal. By age 3 years, linear growth decreases. Loss of cognition is progressive, and hearing loss is common. Death usually occurs within the first 10 years of life without treatment. Hematopoietic stem cell transplantation (HSCT) increases survival and improves visceral symptoms but has less impact on the skeletal and joint manifestations or corneal clouding.
In attenuated MPS I, the severity and rate of disease progression range from death in the second to third decades to a normal lifespan complicated by progressive joint manifestations and cardiorespiratory disease. Clinical onset is usually between ages 3 and 10 years. Hearing loss and cardiac valvular disease are common. Lifelong treatment with ERT for non-central nervous system manifestations of MPS I improves liver size, linear growth, joint mobility and breathing for patients with attenuated disease.
In X-ALD, which impacts about 1 in 17,000 individuals, affected males develop progressive neurologic and adrenal cortex dysfunction. There is a spectrum of phenotypes in this condition as well.
Childhood cerebral ALD (approximately 35% of affected X-ALD males) is the most severe with onset commonly between 4 and 10 years of age. Progressive neurologic deterioration occurs involving cognition, behavior, vision, hearing and motor function resulting in total disability within two years of symptom presentation. HSCT at the onset of leukodystrophy detection (by MRI) has been reported to stop progression of neurologic decline and prolong life.
Adrenomyeloneuropathy (AMN) accounts for 40%-45% of affected males who often present in their late 20s with progressive motor dysfunction and adrenal insufficiency or adrenal cortical insufficiency only (10%).
Most female carriers have normal endocrine function. Approximately 20% of female carriers develop neurologic manifestations that resemble AMN but have later onset (age 35 years or older) and milder disease than affected males. Genetic counseling for this X-linked condition is critical for these families.
Dr. Freedenberg is a member of the AAP Section on Genetics and Birth Defects and the Committee on Genetics. Dr. Berry is a member of the section’s executive committee.
