Cystic Fibrosis Newborn Screening

Evans Machogu, MD, FAAP, and Clement L. Ren, MD, MS

Introduction

•The starting point for cystic fibrosis (CF) newborn screening (NBS) is currently the initial identification of a high level of immunoreactive trypsinogen (IRT) in the neonatal dried blood spot collected on a Guthrie card.

•Blockage of pancreatic ducts causes an increase of trypsinogen, a precursor for trypsin, in the blood of most newborns with CF.

•Because IRT levels can fluctuate throughout the year, the cutoff level is set by individual state NBS programs in which the newborn is tested as a percentile of that day’s results (eg, the top 5% of specimens), although some states also set an absolute threshold for a very high IRT level.

•IRT levels may be increased for reasons unrelated to CF, such as neonatal asphyxia, chronic fetal distress, perinatal infection, or biological and genetic variability.

•On the other hand, false-negative NBS results may occur if the IRT level does not reach the set cutoff value, even in newborns who may actually have CF.

•CF NBS has been universally available in the United States since 2010.

Testing Algorithms for CF NBS

•IRT is a very sensitive test because levels are increased in almost all neonates with CF. However, it is not very specific, since many neonates without CF may also have a transiently increased IRT level. Therefore, a second stage of testing must be conducted.

•IRT level may be falsely decreased in neonates with CF who present with meconium ileus, but in this case, the diagnosis of CF should be already suspected on clinical grounds.

•Three strategies are currently used to improve the specificity of an increased IRT level in identifying newborns with CF. The specific choice of strategy varies by state.

—IRT DNA strategy

▪This strategy is followed by most states.

▪The specific choice of mutations in the panel varies by state.

~Because of its diverse population, the state of California chose to incorporate gene sequencing in its IRT DNA algorithm.

▪Infants with 1 or 2 CFTR panel mutations are considered to have positive screening results and are referred for sweat testing.

—IRT-IRT strategy ▪IRT level testing is repeated in a second sample obtained from the neonate at about 2 weeks of age.

▪If the second IRT level is increased, a sweat test is performed.

—IRT–IRT DNA strategy

▪The IRT-IRT strategy is followed.

▪Newborns with an increased repeat IRT finding undergo CFTR mutation panel testing.

~Only infants with 1 or 2 CFTR mutations are then referred for sweat testing.

~This reduces the number of patients with false-positive results who are sent for sweat testing.

Reporting of CF NBS Results

Negative NBS results

•NBS results will be reported as “screen negative,” and no further testing or follow-up is required when the initial IRT value does not meet the state-specific cutoff value.

•Likewise, a “screen-negative” result is reported in cases of an initial increased IRT level but negative CFTR DNA analysis findings. No further testing or follow-up is required.

•As previously noted, all newborns with meconium ileus should undergo