title: Inconclusive diagnosis of cystic fibrosis after newborn screening.
abstract: OBJECTIVE
  To prospectively study infants with an inconclusive diagnosis of cystic fibrosis (CF) identified by newborn screening (NBS; "CF screen positive, inconclusive diagnosis" [CFSPID]) for disease manifestations.
  
  
  METHODS
  Infants with CFSPID and CF based on NBS from 8 CF centers were prospectively evaluated and monitored. Genotype, phenotype, repeat sweat test, serum trypsinogen, and microbiology data were compared between subjects with CF and CFSPID and between subjects with CFSPID who did (CFSPID→CF) and did not (CFSPID→CFSPID) fulfill the criteria for CF during the first 3 years of life.
  
  
  RESULTS
  Eighty-two subjects with CFSPID and 80 subjects with CF were enrolled. The ratio of CFSPID to CF ranged from 1:1.4 to 1:2.9 in different centers. CFTR mutation rates did not differ between groups; 96% of subjects with CFSPID and 93% of subjects with CF had 2 mutations. Subjects with CFSPID had significantly lower NBS immunoreactive trypsinogen (median [interquartile range]:77 [61-106] vs 144 [105-199] μg/L; P < .0001) than did subjects with CF. Pseudomonas aeruginosa and Stenotrophomonas maltophilia were isolated in 12% and 5%, respectively, of subjects with CFSPID. CF was diagnosed in 9 of 82 (11%) subjects with CFSPID (genotype and abnormal sweat chloride = 3; genotype alone = 4; abnormal sweat chloride only = 2). Sweat chloride was abnormal in CFSPID→CF patients at a mean (SD) age of 21.3 (13.8) months. CFSPID→CF patients had significantly higher serial sweat chloride (P < .0001) and serum trypsinogen (P = .009) levels than did CFSPID→CFSPID patients.
  
  
  CONCLUSIONS
  A proportion of infants with CFSPID will be diagnosed with CF within the first 3 years. These findings underscore the need for clinical monitoring, repeat sweat testing at age 2 to 3 years, and extensive genotyping.
authors.affiliation: Discipline of Pediatrics, School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, Australia; Sydney Children's Hospital Randwick, Sydney, Australia; Division of Gastroenterology, Hepatology, and Nutrition.
authors.forename: Chee Y
authors.initials: CY
authors.lastname: Ooi
authors.affiliation: Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy;
authors.forename: Carlo
authors.initials: C
authors.lastname: Castellani
authors.affiliation: Physiology and Experimental Medicine, Research Institute.
authors.forename: Katherine
authors.initials: K
authors.lastname: Keenan
authors.affiliation: Physiology and Experimental Medicine, Research Institute.
authors.forename: Julie
authors.initials: J
authors.lastname: Avolio
authors.affiliation: Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy;
authors.forename: Sonia
authors.initials: S
authors.lastname: Volpi
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, and.
authors.forename: Margaret
authors.initials: M
authors.lastname: Boland
authors.affiliation: Division of Respirology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada;
authors.forename: Tom
authors.initials: T
authors.lastname: Kovesi
authors.affiliation: Division of Respiratory Medicine, Department of Pediatrics, University of Calgary, Alberta Children's Hospital, Calgary, Alberta, Canada;
authors.forename: Candice
authors.initials: C
authors.lastname: Bjornson
authors.affiliation: Division of Pediatric Respiratory Medicine, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Chilvers
authors.affiliation: Pediatric Cystic Fibrosis Clinic, Windsor Regional Hospital, Windsor, Ontario, Canada;
authors.forename: Lenna
authors.initials: L
authors.lastname: Morgan
authors.affiliation: Department of Pediatrics, School of Medicine, Queen's University, Kingston, Ontario, Canada;
authors.forename: Richard
authors.initials: R
authors.lastname: van Wylick
authors.affiliation: Victoria General Hospital, Victoria, British Columbia, Canada; and.
authors.forename: Steven
authors.initials: S
authors.lastname: Kent
authors.affiliation: Children's Hospital of Western Ontario, London, Ontario, Canada.
authors.forename: April
authors.initials: A
authors.lastname: Price
authors.affiliation: Division of Clinical and Metabolic Genetics, and.
authors.forename: Melinda
authors.initials: M
authors.lastname: Solomon
authors.affiliation: Division of Clinical and Metabolic Genetics, and.
authors.forename: Karen
authors.initials: K
authors.lastname: Tam
authors.affiliation: Division of Clinical and Metabolic Genetics, and.
authors.forename: Louise
authors.initials: L
authors.lastname: Taylor
authors.affiliation: Discipline of Pediatrics, School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, Australia;
authors.forename: Kylie-Ann
authors.initials: KA
authors.lastname: Malitt
authors.affiliation: Physiology and Experimental Medicine, Research Institute, Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada;
authors.forename: Felix
authors.initials: F
authors.lastname: Ratjen
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Physiology and Experimental Medicine, Research Institute.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Physiology and Experimental Medicine, Research Institute, tanja.gonska@sickkids.ca.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gonska
mesh_terms: D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D015997:Neonatal Screening; D011237:Predictive Value of Tests; D011446:Prospective Studies; D015203:Reproducibility of Results