title: Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up.
abstract: The neonatal screening protocol for cystic fibrosis (CF) is based on a first determination of blood immunoreactive trypsin (IRT1), followed by a first level genetic test that includes the 31 worldwide most common mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (DNA31), and a second determination of blood immunoreactive trypsin (IRT2). This approach identifies, in addition to affected subjects, a high proportion of newborns with hypertrypsinaemia at birth, in whom only one mutation is identified and who have a negative or borderline sweat test and pancreatic sufficiency. Although it has been suggested that hypertrypsinaemia may be caused by a single CFTR mutation, whether such neonates should be merely considered as healthy carriers remains a matter of debate as hypertrypsinaemia at birth may be a biochemical marker of a CFTR malfunction because of a second mild mutation. We analyzed, by means of an extended sequencing protocol, 32 newborns who tested positive at an IRT1/DNA31/IRT2 screening protocol and in whom only one CFTR mutation was found. The results obtained demonstrate that 62.5% of these newborns were also carrying a second mild CFTR mutation. The high proportion of compound heterozygous subjects, combined with the results of a 4-year follow-up in nine of these subjects all of whom displaying initial CF clinical symptoms, suggest that it may be possible to use the IRT1/DNA31/IRT2 protocol of neonatal screening to identify newborns with atypical forms of CF. In view of these findings, an extended genetic search for subjects with compound heterozygosity and a periodic clinical assessment should be considered.
authors.affiliation: Department of Paediatrics, Cystic Fibrosis Centre, University of Rome La Sapienza, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Narzi
authors.forename: G
authors.initials: G
authors.lastname: Ferraguti
authors.forename: A
authors.initials: A
authors.lastname: Stamato
authors.forename: F
authors.initials: F
authors.lastname: Narzi
authors.forename: S B
authors.initials: SB
authors.lastname: Valentini
authors.forename: A
authors.initials: A
authors.lastname: Lelli
authors.forename: I
authors.initials: I
authors.lastname: Delaroche
authors.forename: M
authors.initials: M
authors.lastname: Lucarelli
authors.forename: R
authors.initials: R
authors.lastname: Strom
authors.forename: S
authors.initials: S
authors.lastname: Quattrucci
mesh_terms: D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005500:Follow-Up Studies; D005820:Genetic Testing; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015997:Neonatal Screening; D014357:Trypsin / Q000097:blood; D014362:Trypsinogen / Q000097:blood
chemical_list: C505032:CFTR protein, human; C064831:PRSS2 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014362:Trypsinogen; C489303:PRSS1 protein, human; D014357:Trypsin