title: Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis.
abstract: An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS test but inconclusive diagnostic testing. These infants are classified as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis (CFSPID) in other countries. Diagnostic and management decisions of these infants are challenges for CF healthcare professionals and stressful situations for families. As CF NBS has become more widespread across the world, increased information about the epidemiology and outcomes of these infants is becoming available. These data were reviewed at the 2015 CF Foundation Diagnosis Consensus Conference, and a harmonized definition of CRMS and CFSPID was developed.
  
  
  
  At the consensus conference, participants reviewed published and unpublished studies of CRMS/CFSPID and used a modified Delphi methodology to develop a harmonized approach to the definition of CRMS/CFSPID.
  
  
  
  Several studies of CRMS/CFSPID from populations around the world have been published in the past year. Although the studies vary in the number of infants studied, study design, and outcome measures, there have been some consistent findings. CRMS/CFSPID occurs relatively frequently, with CF:CRMS that ranges from 3 to 5 cases of CF for every 1 case of CRMS/CFSPID in regions where gene sequencing is not used. The incidence varies by NBS protocol used, and in some regions more cases of CRMS/CFSPID are detected than cases of CF. The majority of individuals with CRMS/CFSPID do not develop CF disease or progress to a diagnosis of CF. However, between 10% and 20% of asymptomatic infants can develop clinical features concerning for CF, such as a respiratory culture positive for Pseudomonas aeruginosa. Most studies have only reported short-term outcomes in the first 1-3 years of life; the long-term outcomes of CRMS/CFSPID remain unknown. The European CF Society definition of CFSPID and the CF Foundation definition of CRMS differ only slightly, and the consensus conference was able to create a unified definition of CRMS/CFSPID.
  
  
  
  CRMS/CFSPID is a relatively common outcome of CF NBS, and clinicians need to be prepared to counsel families whose NBS test falls into this classification. The vast majority of infants with CRMS/CFSPID will remain free from disease manifestations early in life. However, a small proportion may develop clinical features concerning for CF or demonstrate progression to a clinical phenotype compatible with a CF diagnosis, and their long-term outcomes are not known. A consistent international definition of CRMS/CFSPID will allow for better data collection for study of outcomes and result in improved patient care.
authors.affiliation: Section of Pediatric Pulmonology, Allergy, and Sleep Medicine, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN.
authors.forename: Clement L
authors.initials: CL
authors.lastname: Ren
authors.affiliation: Clinical Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY.
authors.forename: Drucy S
authors.initials: DS
authors.lastname: Borowitz
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, and Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gonska
authors.affiliation: Section of Pediatric Pulmonology, Allergy, and Sleep Medicine, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Howenstine
authors.affiliation: Division of Pulmonary Medicine, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
authors.forename: Hara
authors.initials: H
authors.lastname: Levy
authors.affiliation: Department of Respiratory Medicine, Royal Children's Hospital. and Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Massie
authors.affiliation: Center for Excellence in Pulmonary Biology, Stanford University, Palo Alto, CA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Milla
authors.affiliation: Centres de Ressources et de Compétences pour la Mucoviscidose, Hôpital Robert Debre, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Munck
authors.affiliation: Department for Women's and Children's Health, University of Liverpool, Institute in the Park, Alder Hey Children's Hospital, Liverpool, United Kingdom.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Southern
mesh_terms: D003550:Cystic Fibrosis / Q000150:complications* / Q000175:diagnosis*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005820:Genetic Testing; D006801:Humans; D007231:Infant, Newborn; D024821:Metabolic Syndrome / Q000175:diagnosis* / Q000209:etiology*; D015997:Neonatal Screening
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: immunoreactive trypsinogen; intestinal current measurement; nasal potential difference; newborn screening; sweat chloride