title: Negative sweat test in hypertrypsinaemic infants with cystic fibrosis carrying rare CFTR mutations.
abstract: Persistent hypertrypsinaemia in newborn screening for cystic fibrosis (CF) recognises subjects at high risk to be affected. Diagnosis is confirmed by a positive sweat test and/or by the presence of two mutations in the cystic fibrosis transmembrane regulator gene. The aim of the present study was to evaluate the occurrence of a negative sweat test (chloride < 60 mmol/l) during the first months of life, in hypertrypsinaemic infants, which would lead to a delayed diagnosis. We reviewed clinical charts of CF patients born between January 1993 and September 1998, when the neonatal screening programme consisted of an immunoreactive trypsinogen (IRT)/DNA (F508del) + IRT strategy. Laboratory and clinical data were collected for patients diagnosed after 12 months of life. Out of 446,492 newborns, 104 CF patients were diagnosed giving an overall incidence of 1:4293. Of these, six had a blood IRT level above the cut off value (99th percentile) and a negative sweat test in the first trimester of life. At a mean age of 3.5years, the patients were again referred to our CF Centre for re-evaluation in order to confirm or exclude the disorder. Molecular analysis identified the following genotypes: F508del/A309D, F508del/3849 + 10kbC-->T, F508del/R117H (in two patients), R117H/ L997F, and F508del/R117L.
  
  
  CONCLUSIONS
  Infants with cystic fibrosis bearing a spectrum of mild cystic fibrosis transmembrane regulator gene mutations may present as hypertrypsinaemic newborns with a sweat chloride within the normal range. Reference values for normal sweat test during the first months of life should be revised. A wide molecular genetic analysis is recommended for newborns presenting persistent hypertrypsinaemia and a sweat test result > 30 mmol/l in order to diagnose atypical forms of the disease.
authors.affiliation: Cystic Fibrosis Centre, A O Istituti Clinici di Perfezionamento, Milano, Italy. rita.padoan@unimi.it
authors.forename: Rita
authors.initials: R
authors.lastname: Padoan
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bassotti
authors.forename: Manuela
authors.initials: M
authors.lastname: Seia
authors.forename: Carlo
authors.initials: C
authors.lastname: Corbetta
mesh_terms: D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000032:analysis; D003550:Cystic Fibrosis / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000032:analysis* / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D013542:Sweat / Q000737:chemistry*; D014357:Trypsin / Q000097:blood; D014362:Trypsinogen / Q000097:blood
chemical_list: C505032:CFTR protein, human; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014362:Trypsinogen; D014357:Trypsin