Pancreatic phenotype in infants with cystic fibrosis identified by mutation screening

Objective

To determine the pancreatic phenotype of infants with cystic fibrosis (CF) diagnosed in the first week of life by a combined immunoreactive trypsin/mutation screening program.

Design

A prospective evaluation of pancreatic function in infants with CF at the time of neonatal diagnosis and up to the age of 12.

Setting

Two different centres (Verona, Italy and Westmead, Australia) to enable comparison of results between two regions where <60% or ?90% of patients, respectively, have at least one single ΔF508 a mutation.

Patients

315 children with CF including 149 at Verona and 166 at Westmead.

Interventions

Fat balance studies over 3–5?days and pancreatic stimulation tests with main outcome measures being faecal fat or pancreatic colipase secretion. Patients with malabsorption are pancreatic insufficient (PI) or with normal absorption and pancreatic sufficient (PS).

Results

34 infants (23%) at Verona and 46 (28%) at Westmead were PS at diagnosis. 15% of those with two class I, II or III “severe” mutations and 26/28 (93%) of those with class IV or V mutations were PS at this early age. Of the 80 infants with PS, 20 became PI before the age of 12. All 20 had two severe mutations.

Conclusion

Neonatal mutational screening programs for CF are less likely to detect PS patients with non‐ΔF508 mutations. Of PS patients who are detected, those with two severe class I, II or III mutations are at particularly high risk of becoming PI during early childhood.Neonatal screening for cystic fibrosis (CF) began in the early 1980s with measurement of immunoreactive trypsin (IRT) assays on dried blood spots obtained from infants in the first 4–6?weeks of life.^1,2 Questions were raised about the reliability of these programs as they had not been validated for the 10%–15% of patients with normal fat absorption (pancreatic sufficient or PS).³ Subsequently however, 37% of screened infants were found to be PS,^4,5 that is 2–3?times the 10%–15% observed in older patients.³ Furthermore, follow‐up studies demonstrated that nearly 50% of the infants with PS near birth developed fat malabsorption (pancreatic insufficient or PI) in later childhood, thus accounting for the lower proportion of PS patients at an older age. It is significant that all those who transitioned from being PS to PI had two “severe” class I, II or III cystic fibrosis transmembrane conductance regulator (CFTR) mutations,⁶ as defined previously,^7,8 whereas those with persistent PS had at least one class IV or V “mild” mutation.Following the discovery of the CFTR gene,⁹ most screening programs have modified their screening strategy.¹⁰ In regions where more than 90% of patients with CF have at least one ΔF508 mutation, analysis for ΔF508 is performed on week 1 neonatal blood spots with an elevated IRT level.¹¹ This strategy has been further modified in regions (particularly southern Europe) where ΔF508 is only present in 40%–60% of patients, by screening for an extended panel of non‐ΔF508 mutations (usually severe class I, II or III) common to that region.^12,13 These IRT/DNA screening strategies are, however, not without problems. For instance, in regions where ΔF508 is responsible for CF in over 90% of cases, up to 10% of patients have non‐ΔF508 mutations with a preponderance of PS patients¹⁴ and therefore screening for ΔF508 alone would not detect such patients.Currently, only limited data are available on the pancreatic phenotype of infants with CF diagnosed by IRT/DNA screening from a study¹⁵ restricted to 27 infants with only class I or II mutations. The present study was thus undertaken, firstly to determine the pancreatic phenotype of infants in either a ΔF508 predominant or non‐dominant region, and secondly, to determine what proportion of infants initially with PS later transitioned to being PI and whether this was determined by the presence of two severe mutations.