Background and aims: The prevalence and natural history of hereditary pancreatitis (HP) remain poorly documented. The aims of this study were to assess genetic, epidemiological, clinical and morphological characteristics of HP in an extensive national survey. Methods: A cohort comprising all HP patients was constituted by contacting all gastroenterologists and paediatricians (response rate 84%) and genetics laboratories (response rate 100%) in France (60 200 000 inhabitants). Inclusion criteria were the presence of mutation in the cationic trypsingen gene (PRSS1 gene), or chronic pancreatitis in at least two first-degree relatives, or three second-degree relatives, in the absence of precipitating factors for pancreatitis. Results: 78 families and 200 patients were included (181 alive, 6673 person-years, males 53%, alcoholism 5%, smoking 34%). The prevalence was 0.3/100 000 inhabitants. PRSS1 mutations were detected in 68% (R122H 78%, N29I 12%, others 10%). Penetrance was 93%. Median age at first symptom, diagnosis and date of last news, were 10 (range 1-73), 19 (1-80) and 30 (1-84) years, respectively. HP was responsible for pancreatic pain (83%), acute pancreatitis (69%), pseudocysts (23%), cholestasis (3%), pancreatic calcifications (61%), exocrine pancreatic insufficiency (34%, median age of occurrence 29 years), diabetes mellitus (26%, median age of occurrence 38 years) and pancreatic adenocarcinoma (5%, median age 55 years). No differences in clinical and morphological data according to genetic status were observed. 19 patients died, including 10 directly from HP (8 from pancreatic adenocarcinoma). Conclusion: The prevalence of HP in France is at least 0.3/100 000. PRSS1 gene mutations are found in 2/3 with a 93% penetrance. Mutation type is not correlated with clinical/morphological expression. Pancreatic adenocarcinoma is the cause of nearly half the deaths.

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.