Complex Family of CFTR-Associated Disorders

While most clinicians are familiar with cystic fibrosis (CF), much fewer are familiar with a group of disorders related to the cystic fibrosis transmembrane conductance regulator (CFTR) that do not meet the criteria for cystic fibrosis.  A summary of these disorders is provided in a recent editorial (Levy H, Farrell PM. J Pediatrics 2015; 166: 1337-40).  In addition, the editorial provides insight into a related study: Groves T et al.. J Pediatrics 2015; 166: 1469-74.

The editorialists note that new disorders have been created due to newborn screening and due to the use of CF mutation analysis.  New disorders:

  • CRMS -CFTR-related metabolic syndrome.  CRMS describes infants with elevated immunoreactive trypsinogen and inconclusive sweat testing and DNA results.  Inconclusive sweat testing includes sweat tests 30-59 mmol/L if age <6 months or 40-59 mmol/L if >6 months on at least 2 occasions.  DNA testing is inconclusive if there are fewer than 2 CF disease-related mutations identified.  DNA testing is also considered inconclusive if there are 2 CFTR mutations but sweat testing is normal.
  • CFTR-RD -CFTR related disease.  CFTR-RD describes symptomatic individuals beyond infancy who have sweat testing <60 mmol/L and up to 2 CFTR mutations, at least one of which is not clearly categorized as a CF-causing mutation.  Thus, these individuals do not fulfill criteria for CF but could have congenital bilateral absence of vas deferens, acute recurrent or chronic pancreatitis, or disseminated bronchiectasis.
  • Delayed CF -Delayed CF describes patients eventually diagnosed with CF who had initially intermediate sweat chloride values.  Over time, their condition evolves to fulfill the criteria for CF.  In the retrospective study by Groves et al, 14 of 29 (48%) evolved to a diagnosis of CF.  These patients with delayed CF had less pancreatic insufficiency (OR 0.06), milder obstructive lung disease, less colonization with Pseudomonas aeruginosa (OR 0.04), and overall disease severity as measured by Shwachman scores at 2 years.
  • Nutritional outcomes were improved at 2 years in this Delayed CF cohort in comparison to 28 matched patients diagnosed with CF in the newborn period, but did not persist to later ages.

The editorial notes that nearly 20% of patients with CF are being enrolled in the CF foundation patient registry without sweat chloride testing results.  They do not favor this approach because the diagnosis of CF requires proof of CFTR dysfunction, not simply CF DNA mutations.

Take-home message: Patients who do not meet the criteria for CF  but who have intermediate sweat testing or abnormal CF DNA mutations need to be followed.  Some will fulfill the criteria with time and others may develop other clinical problems even without having CF.