Duplication of a 303 kb Locus Containing PRSS1 and PRSS2 is Associated With Hereditary Pancreatitis in a Spanish Kindred

Abstract

Background:Etiologies of recurrent pancreatitis include anatomical anomalies, hereditary, metabolic and autoimmune disorders. A significant number of patients remain with a diagnosis of idiopathic pancreatitis. The advent of genetic analysis and electrophysiologic testing may further assist in the diagnostic process. Evidence has shown that specific genetic mutations in the cationic trypsinogen gene PRSS1 and the SPINK1 gene for pancreatic secretory trypsin inhibitor cause pancreatitis; furthermore cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have been associated with pancreatitis. Aims :To present the work-up of patients with recurrent pancreatitis referred for genetic analysis and electrophysiological testing. Methods : Patients with recurrent, acute pancreatitis with no known etilology were referred to the Electrophysiology Laboratory, Division of Pediatric GI at Hadassah University Hospital for PRSS1 and SPINK1 gene mutations as well as evaluation of CFTR function by Nasal Potential Difference (NPD) testing. Results: A total of 42 patients with recurrent pancreatitis were evaluated; the mean age was 21 years ±14.9 years (range 2-54 yrs). A third (33%) of the patients was of Ashkenazi ancestry, 41% of mainly Sephardic ancestry, 24% of Arab ancestry and the remaining 2% of other ethnic background. There was a family history in 8 patients. The patients had a mean of 4 episodes (range 1-25). 6 (14%) patients showed PRSS1 genemutation (p.R112H and p.K23R) including 2 sets of siblings of Georgian Jewish ancestry with p.K23R. No SPINK1 mutation was found in the 26 patients submitted for testing. 3 patients out of 21 submitted for CFTR gene testing showed mutations (5T, F508del/p.L997F and D1152H/5T). 26 (61%) patients underwent sweat testing, with 13 patients with results >40 mmol/L. 35 (83%) patients had Nasal Potential Difference testing, 4 (11.5%) with abnormal results: 3 had sweat chloride>60mmol/L with no CFTR mutations found but one patient with D1152H/5T had a sweat test of 30 mmol/L. None of the 6 patients with PRSS1 gene mutation showed any concomitant CFTR dysfunction (by NPD or sweat testing) or gene mutation.Conclusion:This is the first study on recurrent pancreatitis in Israel examining both the presence of susceptibility gene mutations for pancreatitis and CFTR dysfunction. A prospective study with a larger number of patients may further clarify the impact of genetic mutations and CFTR dysfunction on the clinical presentation and outcome of recurrent pancreatitis.