Missed CF cases in New Jersey lead to expansion of newborn screening
5 newborns missed in CF screening went on to have severe lung disease
A newborn screening program in New Jersey failed to identify cystic fibrosis (CF) in five children, all of whom went on to have severe lung disease, a new study reports.
Based on the findings, New Jersey’s newborn screening program has been updated to include screening for many more disease-causing mutations, as well as new cutoff values on lab tests used in the screening.
“This case series provides examples of patients who suffered from being missed because of their early development of life-threatening lung disease. But these observations have led to an incrementally improved algorithm in 2022–23,” researchers wrote in the study “Severe lung disease in children with cystic fibrosis missed in newborn screening,” which was published in Pediatric Pulmonology.
CF is caused by mutations in the CFTR gene. Everyone inherits two copies of this gene, and CF develops if both copies are mutated. The disease is characterized by thick, sticky mucus, which builds up and causes damage to organs such as the lungs and pancreas.
In the modern medical era, most people with CF are diagnosed within the first few weeks of life by newborn screening programs, where all babies are routinely checked for genetic disorders such as CF.
New Jersey was 4th U.S. state to implement newborn screening program
New Jersey was the fourth U.S. state to implement a newborn screening program in 2001. The program used a two-step screening method that was state-of-the-art at the time. First, a blood sample was tested for levels of immunoreactive trypsinogen (IRT), a protein made by the pancreas that is typically elevated in the blood of people with CF.
If IRT levels were high, babies then underwent genetic testing for F508del, which is the most common type of CF-causing mutation. Roughly 9 in 10 CF patients carry at least one copy of the F508del mutation, though this mutation is more common in people of European ancestry.
Although the New Jersey program successfully diagnosed many children with CF, a few children who’d had negative results on newborn screening went on to be diagnosed with CF. In the new study, researchers reviewed data on five such cases.
In all five cases, the children carried one copy of the F508del mutation, but a different CF-causing mutation on the other copy of the CFTR gene. Their IRT values were not high enough to prompt additional testing.
The researchers noted IRT values are often low in babies with CF who experience meconium ileus, a type of intestinal obstruction. Since meconium ileus specifically can be difficult to recognize, newborns with any type of intestinal obstruction should undergo sweat testing to check for signs of CF, the findings highlight.
In all five missed cases, the children went on to develop severe lung disease. Collectively, these results “demonstrate clearly that false negative tests can result in dangerous delays in diagnosis and treatment that are potentially associated with increased mortality,” the researchers wrote.
New Jersey’s newborn screening program largely unchanged since 2001
Since it was launched in 2001, New Jersey’s newborn screening program has remained largely unchanged.
“Once a region like New Jersey begins with a screening protocol … it is difficult to change as other screening methods evolve,” the researches wrote. “The challenges are multidimensional and include financial, staffing, facilities, administrative/leadership, and even political constraints.”
Spurred by cases like these, several of the co-authors of this study were active in a recent effort to modernize the program. Steps have been taken to lower the cutoff value used in IRT testing from 90 nanograms (ng)/mL to 70 ng/mL in order to reduce the risk of false-negative results, and the program is expanding to test for 139 different CF-causing mutations.
“New Jersey’s quality improvement change will help address our goal of achieving equity. Although our sequential action plan will require some additional time to complete, the transformation in New Jersey CF NBS [newborn screening] will advance CF NBS there to the current standard as was originally achieved in 2001,” the researchers concluded.
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