CFTR-Related Metabolic Syndrome
Evans Machogu, MD, FAAP, and Clement L. Ren, MD, MS
•Cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) is a term first proposed in 2009 to describe a group of infants found through newborn screening (NBS) to have increased immunoreactive trypsinogen (IRT) levels, in whom CF could be diagnosed or excluded on the basis of inconclusive sweat chloride concentration and/or extended DNA testing.
•Although CRMS is not a true metabolic disorder, the designation was proposed by a CF Foundation (CFF) guidelines committee to provide a name that could be associated with an International Classification of Diseases, 10th Revision (ICD-10), code (E88.9; metabolic disorder, unspecified) to facilitate coding and billing of services for this group of individuals.
•In 2015, the European Cystic Fibrosis Society proposed use of the term CF screen positive, inconclusive diagnosis (CFSPID) to define the infant with a positive NBS finding and inconclusive second-tier testing results.
•The term CRMS will be used for the remainder of this chapter.
•An infant is determined to have CRMS if he or she is asymptomatic, with a positive NBS test result and either of the following (Figure 69-1):
—A sweat chloride level of 30–59 mmol/L on at least 2 occasions and fewer than 2 CF disease-causing mutations
—A normal sweat chloride level (×30 mmol/L) and 2 CFTR mutations, of which no more than 1 is known to cause CF disease
Testing Algorithm Recommended by the CFF Diagnosis Consensus Conference
•The initial NBS sweat chloride level may be ×30 mmol/L with 2 CFTR mutations detected (no more than 1 determined to cause CF disease) or 30–59 mmol/L with 0, 1, or more CFTR mutations (no more than 1 determined to cause CF disease).
•This results in an inconclusive diagnosis of CF, and a repeat sweat chloride test is recommended by 2 months of age.
Figure 69-1. Identification of infants with CFTR-related metabolic syndrome. * = Group A, cystic fibrosis (CF)-causing; Group B, CFTR-related disorder; Group D, unknown or uncertain clinical relevance. ** = Multimutation method, gene scanning or sequencing, duplication and deletion testing, and evaluation for IVS-8 TG repeats; consider family evaluation for phasing to confirm that mutations are trans.