{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:02:39Z","timestamp":1790697759553,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chronic pancreatitis (CP) is a clinically heterogeneous condition that may occur with a broad clinical spectrum, including cases of cystic fibrosis (CF), cystic fibrosis transmembrane regulator (CFTR)-related disorder (CFTR-RD), acute recurrent pancreatitis (ARP), and CP, including cases of idiopathic CP (iCP) and hereditary pancreatitis (HP). The specific contribution of CFTR variants and pancreatitis-predisposing genes (PPG), i.e., genes responsible for intrapancreatic activation of trypsinogen or pancreatic secretion pathways to CP susceptibility in these different contexts remains incompletely understood. We investigated the occurrence of CP and mutations in PPG genes in: (i) 377 subjects with CF and (ii) 217 subjects with CFTR-RD (including cases expressing with CP alone). Moreover, we studied 136 subjects with iCP. CP occurred in 33\/377 subjects (8.8%) with CF carrying CFTR genotypes other than homozygous p.Phe508del and was mainly associated with pancreatic sufficiency (24\/33, 72.7%) and at least one residual-function CFTR variant (25\/33, 75.8%). Chronic pancreatitis also occurred in 8 CF subjects carrying both CFTR mutations classified as no residual function, and 7 of them also had PPG variants. Subjects with CFTR-RD expressing with ARP\/CP alone (n = 92) are genetically indistinguishable from CFTR-RD subjects with diffuse bronchiectasis (n = 45) or congenital bilateral absence of vas deferens (n = 92). In fact, all CFTR-RD subjects had at least one residual-function CFTR variant, all had pancreatic sufficiency, and the sweat chloride was not significantly different between the three subgroups. Finally, 66\/136 (48.5%) subjects with iCP harbored pathogenic variants in PPG, with 26\/66 cases (i.e., 39.4%) with multiple gene mutations (consistent with a potential role of oligogenic inheritance in CP susceptibility). Idiopathic CP subjects with mutations in PPG (48.5% in our series) are known to be at higher risk to develop pancreatic adenocarcinoma. Our study revealed such mutations also in subjects with CF (with both CFTR mutations classified as no residual function and with pancreatic insufficiency) and in subjects with CFTR-RD, supporting the use of multigene testing and genetic counselling. To conclude: The early diagnosis of CF by NBS enhanced the number of CF subjects who develop ARP and\/or CP, independently by the pancreatic status and by the CFTR genotype. Mutations in PGP genes further increase such risk. Thus, we suggest: (i) to test for PGP genes and counseling all cases of CF with pancreatitis; (ii) large multicenter studies to investigate why a subset of CFTR-RD appear with ARP\/CP alone; and (iii) a careful investigation of familiarity and the analysis of a large panel of PPG genes to better define the profile of risk for HP in all cases of idiopathic ARP\/CP.<\/jats:p>","DOI":"10.3390\/ijms27198620","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8620","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and Genetic Interplay Between Chronic Pancreatitis, Cystic Fibrosis and CFTR-Related Disorders"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4246-6883","authenticated-orcid":false,"given":"Carnovale","family":"Vincenzo","sequence":"first","affiliation":[{"name":"Centro di Riferimento Regionale Campano CF Adulti, Dipartimento di Scienze Mediche Traslazionali, Universit\u00e0 di Napoli Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tosco","family":"Antonella","sequence":"additional","affiliation":[{"name":"Centro di Riferimento Regionale per La Cura della Fibrosi Cistica Pediatrico, Dipartimento Materno-Infantile, Azienda Ospedaliera Universitaria Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8446-0861","authenticated-orcid":false,"given":"Castaldo","family":"Alice","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"},{"name":"SC di Pneumologia e UTSIR, AORN Santobono-Pausilipon, 80129 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3642-8928","authenticated-orcid":false,"given":"Fevola","family":"Cristina","sequence":"additional","affiliation":[{"name":"Centro di Riferimento Regionale Toscano sulla Fibrosi Cistica, Azienda Ospedaliera Universitaria Meyer IRCCS, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8008-2557","authenticated-orcid":false,"given":"Comegna","family":"Marika","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"},{"name":"Centro di Riferimento Regionale Campano CF, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 di Napoli Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1500-0746","authenticated-orcid":false,"given":"Gelzo","family":"Monica","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"},{"name":"Centro di Riferimento Regionale Campano CF, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 di Napoli Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8909-9726","authenticated-orcid":false,"given":"Iacotucci","family":"Paola","sequence":"additional","affiliation":[{"name":"Centro di Riferimento Regionale Campano CF Adulti, Dipartimento di Scienze Mediche Traslazionali, Universit\u00e0 di Napoli Federico II, 80131 Naples, Italy"},{"name":"Dipartimento di Scienze Biomediche Avanzate, Universit\u00e0 di Napoli Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sepe","family":"Angela","sequence":"additional","affiliation":[{"name":"Centro di Riferimento Regionale per La Cura della Fibrosi Cistica Pediatrico, Dipartimento Materno-Infantile, Azienda Ospedaliera Universitaria Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1106-4424","authenticated-orcid":false,"given":"Terlizzi","family":"Vito","sequence":"additional","affiliation":[{"name":"Centro di Riferimento Regionale Toscano sulla Fibrosi Cistica, Azienda Ospedaliera Universitaria Meyer IRCCS, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Castaldo","sequence":"additional","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"},{"name":"Centro di Riferimento Regionale Campano CF, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 di Napoli Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1001\/jama.2019.19411","article-title":"Diagnosis and management of chronic pancreatitis: A 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