No one can argue that newborn screening for cystic fibrosis (CF) has improved health outcomes. However, like any screening test, some infants may screen positive and have unclear diagnostic test results. When this does happen, this can be stressful for parents and clinicians. Should these children be considered as having CF or not? What does this mean for a family who is not sure whether their child will subsequently develop classical CF in the years to come? Are there predictors that can help when there is a variant of uncertain significance?
To answer these questions, Gonska et al (10.1542/peds.2021-051740) analyzed data from a prospective, longitudinal multicenter cohort study that began in 2008 performed across Canada identifying 115 infants who were CF screen positive with an inconclusive diagnosis (CFSPID)—meaning a positive CF newborn screen and either a sweat chloride value of less than 30 with 2 CF Transmembrane Conductance Regulator (CFTR) gene mutations (with one having unclear phenotypic consequences) or with an intermediate sweat chloride of 30-59 mmol/L and 1 or 0 CF variants. The children in this study were followed for an average of 7.7 years and 24 (21%) were subsequently diagnosed as actually having CF. Most notable was the authors attempt to predict how these 24 might be better identified early—and the key finding in this study is that the best predictor of CF is if the sweat chloride is ≥ 40 mmol/L. The good news is that for as long as the investigators were able to follow the children into school age years, the remaining 91 demonstrated normal growth and pulmonary function compared to healthy controls.
Are we ready to tell families with an infant with CFSPID families and a sweat chloride <40 mmol/L that they can stop sweating about their child having CF? Not quite yet according to an accompanying commentary from Drs. Chakraborty, Potter, and Hayeems, from Ontario (10.1542/peds.2021-052822), who note the strengths but also some key limitations of the Gonska et al study and also give us hope that newer technologies such as CFTR sequencing may help further predict which children with CFSPID might have CF. Unfortunately, even CFTR sequencing can have its problems by uncovering variants of unknown significance that will require further longitudinal studies to better understand their significance as children get older. Still, remembering the sweat chloride threshold of 40 mmol/L can be helpful if there is a question after diagnostic evaluation for infants with a positive newborn screen for CF.