Gomez Lira et al. (2000) postulated that there might be particular CFTR gene mutations involved in pancreatic ductular obstruction, as manifested in idiopathic pancreatitis or in neonatal hypertrypsinemia. Following up on this hypothesis, they performed a complete screening of the CFTR gene in a group of 32 patients with idiopathic pancreatitis (14 of whom carried the 5T variant CF mutation (602421.0086) or had a borderline sweat chloride level, and 18 of whom were without common CF mutations or any other CF characteristic) and in 49 newborns with hypertrypsinemia and normal sweat chloride (32 of whom had a common CF mutation, and 17 of whom did not have a common CF mutation). Rare mutations were found in 9 of 32 patients with idiopathic pancreatitis and in 21 of 49 newborns with hypertrypsinemia. Of these rare mutations, leu997 to phe (L997F) was identified in 4 (12.5%) of 32 patients with idiopathic pancreatitis and in 4 (8%) of 39 newborns with hypertrypsinemia. L997 is a highly conserved residue in transmembrane domain 9.
Since most neonatal screening programs for cystic fibrosis combine the assay of immunoreactive trypsinogen (IRT) with analysis for the most common mutations of the CFTR gene, the identification of heterozygotes among neonates because of increased IRT is considered a drawback. Scotet et al. (2001) assessed the heterozygosity frequency among children with hypertrypsinemia detected during a CF screening program in Brittany (France) 10 years previously. A total of 160,019 babies were screened for CF between 1992 and 1998. Of the 1,964 newborns with increased IRT (1.2%), 60 had CF and 213 were carriers. Heterozygosity frequency was 12.8%, or 3 times greater than in the general population (3.9%). A high proportion of mild mutations or variants was observed in carriers. The allelic frequency of the 5T variant (5.6%) was not increased. The study was consistent with previous ones in finding a significantly higher rate of heterozygotes than expected among neonates with hypertrypsinemia.
Kabra et al. (2000) identified the L997F mutation in a Pakistani patient with cystic fibrosis (219700), but did not identify the second mutation.
Derichs et al. (2005) reported a child, born of consanguineous Turkish parents, who was homozygous for the L997F substitution. The child showed normal development with no evidence of pancreatic insufficiency or cystic fibrosis. Sweat chloride tests and intestinal chloride secretion were normal. Derichs et al. (2005) concluded that the L997F mutation does not cause cystic fibrosis.
