Patients with hereditary pancreatitis caused by pathogenic variants of the PRSS1 gene experience high rates of exocrine and endocrine complications across their lifespan and face a markedly elevated risk of pancreatic ductal adenocarcinoma (PDAC), according to a nationwide French cohort study presented at Digestive Disease Week® (DDW) 2026.
“This study provides the most comprehensive nationwide description to date of the natural history of hereditary pancreatitis caused by pathogenic trypsinogen gene variants,” study author Guillaume Cléry, MD, told GI & Hepatology News. “It includes nearly three decades of follow-up and, importantly, incorporates individuals identified through family screening before symptom onset, allowing a more accurate estimation of disease penetrance and long-term complications. Because genetic testing for this condition is centralized in France, we were also able to obtain a reliable estimate of prevalence at the population level. Finally, our results confirm the increased risk of pancreatic cancer with greater precision than previous studies, with narrower confidence intervals reflecting the robustness of this large national cohort.”
For the PARADISIO-1 study, Dr. Cléry, a pancreatologist in the Department of Pancreatology and Digestive Oncology at Beaujon University Hospital, AP-HP Nord – Université Paris Cité, Clichy, France, and colleagues constructed the cohort using exhaustive listings from the three French genetic laboratories that perform PRSS1 testing nationwide. Eligible patients carried a confirmed pathogenic variant of PRSS1 identified between 1996 — the year the gene was first described — and 2025. Both living and deceased patients were included, with informed consent obtained from patients or their relatives. Data collection was carried out by the attending clinician for each patient.
Across France, 726 patients had been diagnosed with a pathogenic PRSS1 variant since 1996, corresponding to a cumulative prevalence of 1.1 cases per 100,000 inhabitants. Of these, 455 were enrolled in the study between October 2024 and October 2025, representing 4,380 person-years of follow-up. The estimated penetrance, defined by a clinical or morphological manifestation attributable to the PRSS1 mutation, was 77.6%. Median age at symptom onset was 12.5 years. The most prevalent variant was R122H, identified in 178 patients (39.1%).
Mean age at diagnosis was 32.3 years for pancreatic exocrine insufficiency (PEI) and 42.7 years for diabetes mellitus. By age 50, the cumulative incidence of PEI was 27.5% and the cumulative incidence of diabetes was 20.4%. The R122H and N29I variants were linked to an elevated risk of developing diabetes, with hazard ratios (HRs) of 2.2 and 3.3, respectively.
Nineteen cancers were identified in the cohort, at a median age at diagnosis of 63.8 years. The standardized incidence ratio (SIR) for PDAC was 32.2 compared with the general population. The cumulative incidence of PDAC remained low through the first four decades of life and rose steeply thereafter, reaching 2% by age 50, 5.9% by age 60, 12.9% by age 70, and 14.5% by age 75. Diabetes was associated with a markedly increased risk of PDAC, with an HR of 6.75.
Dr. Cléry pointed to several findings he considered particularly noteworthy. “One finding that stood out was the high proportion of patients with a history of smoking, despite the known association between smoking and pancreatic cancer risk in hereditary pancreatitis,” he said. “This highlights an important opportunity for preventive interventions in this population. Another notable observation was that many individuals identified through family screening, although initially asymptomatic, developed pancreatic abnormalities or metabolic complications over time, reinforcing the importance of systematic follow-up even in apparently unaffected carriers.”
The genotype–phenotype patterns observed in the cohort may also help explain why certain PRSS1 variants dominate clinical case series, he said. “[An] interesting observation was that the most frequent PRSS1 variants, particularly p.R122H and p.N29I, were associated with a higher risk of pancreatic insufficiency. This may partly explain why these variants are more commonly identified in clinical cohorts, as their greater clinical impact likely increases the probability of genetic testing and diagnosis.”
Dr. Cléry said the data argue for sustained monitoring across the full mutation-carrier population, not only those with overt pancreatic disease. “Our results support the need for long-term follow-up of all individuals carrying pathogenic trypsinogen gene variants, not only those with chronic pain or recurrent pancreatitis. Pancreatic exocrine insufficiency and diabetes occur frequently and can have significant consequences such as malnutrition and bone disease if not recognized early. In addition, the observed increase in pancreatic cancer risk after age 60 years, particularly in patients with diabetes, suggests that surveillance strategies could be adapted according to individual risk profiles while maintaining monitoring throughout adulthood.”
Limitations of the analysis are inherent to retrospective, registry-based work, including reliance on clinician-entered data and the possibility of residual confounding in genotype–phenotype comparisons. The investigators noted that the size and completeness of the national cohort yielded narrower confidence intervals around the PDAC risk estimate than had been reported in earlier studies of hereditary pancreatitis.
“This study illustrates the value of nationwide collaboration in rare diseases,” Dr. Cléry said. “By combining genetic and clinical data collected over several decades, we were able to provide a more complete picture of disease evolution across the full spectrum of mutation carriers, including those identified before symptom onset. We hope these findings will help improve genetic counselling, patient education, and long-term management strategies for hereditary pancreatitis.”
Dr. Cléry reported having no relevant disclosures.
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