Newborn Cystic Fibrosis Diagnoses May Change Over Time

Source: Sciortino S, Graham S, Bishop T. Diagnostic transitions of cystic fibrosis and CRMS compared after 12 years of newborn screening in California. J Pediatr. 2025:276:114287; doi: 10.1016/j.jpeds.2024.114287.Investigators from the California Department of Public Health, Richmond, CA, conducted a longitudinal study to determine long-term diagnostic characterization of newborns with a positive newborn screen (NBS) for cystic fibrosis (CF). In CA, initial screening consists of an assay for immunoreactive trypsinogen (IRT), followed by testing for variants of the cystic fibrosis trans-membrane conductance regulator (CFTR) protein gene. As part of the screening program, children with a positive screen are followed by CF specialists for 5 years or longer. A child is diagnosed with CF if they have an abnormal sweat chloride test (SCT) and/or positive fecal elastase test, and/or physician-observed signs and symptoms or family history. Patients with a positive newborn screen but normal SCT and fecal elastase tests and no clinical signs of CF are initially diagnosed with CFTR-related metabolic syndrome (CRMS). During the follow-up period, some children initially diagnosed with CRMS transition to a diagnosis of CF (CRMS2CF), and some from CF to CRM (CF2CRMS). Finally, for the study, patients with CF were subdivided by the number of SCT obtained before the diagnosis was made, including CF-1 (initial SCT abnormal), CF-2+ (2 or more SCT obtained), or CF-0 (SCT attempted but no results). The study participants in these groups were characterized by growth during the first 6 months of life, fecal elastase tests, positive respiratory tract cultures for Pseudomonas aeruginosa, pancreatic insufficiency diagnosed, and hospitalizations. These characteristics among children with CRMS only were compared to those of patients in the other groups with regression analyses.Among 5,944,888 newborns with NBS results, 99,433 (1.67%) were IRT screen-positive, with 694 initially diagnosed with CF and 1,257 with CRMS. There were 66 children initially diagnosed with CRMS who transitioned to a diagnosis of CF (5.3%) at a mean age of 3.3 years (95% confidence interval [CI], 2.8, 3.8); 36 patients transitioned from CF to CRMS at a mean age of 1.8 years. Compared to children with CRMS only, those in the CF-1 group had significantly lower weight in the first 6 months of life (odds ratio [OR], 0.04), a significantly higher number of hospitalizations (OR, 3.40), and significantly higher rates of Pseudomas aeruginosa cultures, pancreatic insufficiency, and positive fecal elastase tests. There also were multiple significant differences between those in the CR-2+ group, those in the CF-0 group, and children with CRMS only. Conversely, compared to those with CRMS only, there were no significant differences for percentile weight, hospitalizations, or pancreatic insufficiency among those in the CRMS2CF group. The only significant difference for those with CRMS2CF was the rate of a positive fecal elastase test (OR, 23.17; 95% CI, 3.02, 177.6).The authors conclude that transition from a diagnosis of CRMS to CF was made on the basis of biochemical tests rather than clinical symptoms.Dr Chan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.CF is a chronic and progressive condition that benefits from early diagnosis and intervention.1 IRT is a protein elevated in infants with CF and has been on the NBS for all 50 states since 2009.2 In 2007, the California Genetic Disease Screening Program started performing a CFTR variant panel if the IRT result was greater than a cutoff and sequencing if only 1 variant was identified on the panel. As such, there have been more variants of unknown significance (VUS) identified. With the implementation of more widespread genetic testing, new CFTR-phenotypes and diagnostic codes were created. CRMS describes infants with elevated IRT but intermediate SCT results and fewer than 2 CF disease-causing mutations, potentially including VUS.The authors of the current study sought to compare and describe the diagnostic transition of CRMS to CF (CRMS2CF) alongside diagnosed CF and CRMS cases. They performed a retrospective analysis of a 12-year cohort with 5 years of follow-up data. The authors found that 62.1% of CRMS2CF cases eventually had a positive SCT or positive fecal elastase test. However, compared to CRMS-only cases, there were no obvious signs or symptoms. They also noted that the majority of CRMS2CF cases had known variants of varying clinical consequence among the second variant.Strengths of the study include an in-depth analysis of the genetic, biochemical, and clinical presentations of CF, CRMS, and CRMS2CF children. Limitations include incomplete data collection that often is unavoidable in these types of studies.Children with CRMS2CF transition often lack obvious clinical symptoms and are more likely to develop positive biomarkers over time.For the pediatrician caring for a newborn with a positive NBS for CF rather than a definitive diagnosis of a condition with significant morbidity, the ultimate prognosis is extremely variable. Further testing and sometimes years of observation are required for clear delineation.