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.