Introduction
Newborn screening (NBS) for cystic fibrosis (CF) is a successful public health strategy allowing for early recognition of affected infants. When combined with early multidisciplinary care at CF centers, NBS improves nutrition and cognitive outcomes, thereby reducing morbidity and mortality.1,2 However, the universal implementation of screening led to a new and complex diagnostic dilemma of infants who are screen-positive with inconclusive sweat chloride tests and/or DNA results.3 These infants have been designated as cystic fibrosis transmembrane conductance regulator (CFTR) – related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis in other countries (CRMS/CFSPID).4 Although the first cases of this new diagnosis were recognized in mid-2000s in US and Europe and this population is now entering adolescence, there remains limited guidance to families regarding prognosis, which is unsettling for medical providers and parents.5,6
Although most children with the CRMS/CFSPID designation will remain healthy and asymptomatic, some will develop signs and symptoms of CF. The rates of reclassification from CRMS/CFSPID to CF have been reported from 6% to 48%, varying based on NBS algorithm, number of CFTRvariants identified and their interpretations, population heterogeneity, and length of follow up.3,7 The criteria for reclassification include reassignment of CFTR variants as CF-causing, clinical features of CF that may surface with age, and/or sweat chloride concentration (sw[Cl-]) above the diagnostic threshold of 60 mmol/L in repeat assessments. Early recognition of phenotypic patterns that are characteristic of reclassification would promote early diagnosis and interventions; however, risk factors that lead to reclassification to CF are unknown.
To determine the factors associated with reclassification from CRMS/CFSPID to CF, we collected retrospective and cross-sectional data in a cohort of children aged 2 months to 13 years old who had a positive CF NBS in California, where extensive genetic testing is part of the NBS algorithm. Findings from this work will help CF providers recognize risk factors early, thereby minimizing long-term morbidity. These observations will improve guidance to providers and decrease the uncertainty for families of children with CRMS/CFSPID.