{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T19:23:38Z","timestamp":1781810618414,"version":"3.54.5"},"reference-count":27,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T00:00:00Z","timestamp":1752192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJNS"],"abstract":"<jats:p>Cystic Fibrosis Screen Positive Inconclusive Diagnosis\/CFTR-related Metabolic Syndrome (CFSPID\/CRMS) presents a significant clinical challenge due to its variable diagnostic outcomes and uncertain disease progression. Current diagnostic strategies, including sweat chloride testing and genetic analysis fall short in delivering clear guidance for clinical decision-making and risk assessment. Here, we comment on the potential of CFTR functional tests in patient-derived intestinal organoids (PDIOs) to enhance early risk stratification in CFSPID\/CRMS cases. Using four hypothetical cases based on real-world data, we illustrate diverse clinical trajectories: diagnosis of cystic fibrosis (CF), reclassification as a CFTR-related disorder (CFTR-RD), non-CF designation, and persistent diagnostic uncertainty. Organoid-based assays\u2014such as forskolin-induced swelling (FIS), steady-state lumen area (SLA) analysis, and rectal organoid morphology analysis (ROMA)\u2014offer functional insights into CFTR activity and drug responsiveness. Compared to existing CFTR functional tests, such as Intestinal Current Measurement (ICM) and Nasal Potential Difference (NPD), these assays are more accessible, highly reproducible, and when needed support personalized medicine approaches. PDIO-based assays could help identify infants at high risk of disease progression, facilitating earlier interventions while minimizing unnecessary follow-ups for those unlikely to develop CF-related symptoms. Although not yet widely implemented, these assays hold promise for refining CFSPID diagnostics and management. Future research should focus on establishing standardized protocols allowing validation of clinical utility.<\/jats:p>","DOI":"10.3390\/ijns11030052","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T12:46:33Z","timestamp":1752237993000},"page":"52","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Promising Role of Intestinal Organoids in the Diagnostic Work-Up of Cystic Fibrosis Screen Positive Inconclusive Diagnosis\/CFTR-Related Metabolic Syndrome (CFSPID\/CRMS)"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7076-0767","authenticated-orcid":false,"given":"Noelia","family":"Rodriguez Mier","sequence":"first","affiliation":[{"name":"CF Research Lab, Woman and Child Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium"},{"name":"Department of Paediatrics, Paediatric Pulmonology, University Hospital Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9951-3591","authenticated-orcid":false,"given":"Marlies","family":"Destoop","sequence":"additional","affiliation":[{"name":"Department of Paediatric Pulmonology, Wilhelmina Children\u2019s Hospital, University Medical Centre Utrecht, Utrecht University, 3585 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha","family":"Spelier","sequence":"additional","affiliation":[{"name":"Department of Paediatric Pulmonology, Wilhelmina Children\u2019s Hospital, University Medical Centre Utrecht, Utrecht University, 3585 CX Utrecht, The Netherlands"},{"name":"Department of Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3585 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3143-3661","authenticated-orcid":false,"given":"Anabela Santo","family":"Ramalho","sequence":"additional","affiliation":[{"name":"CF Research Lab, Woman and Child Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Beekman","sequence":"additional","affiliation":[{"name":"Department of Paediatric Pulmonology, Wilhelmina Children\u2019s Hospital, University Medical Centre Utrecht, Utrecht University, 3585 CX Utrecht, The Netherlands"},{"name":"Department of Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3585 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Vermeulen","sequence":"additional","affiliation":[{"name":"CF Research Lab, Woman and Child Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium"},{"name":"Department of Paediatrics, Paediatric Pulmonology, University Hospital Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0666-3983","authenticated-orcid":false,"given":"Karin M.","family":"de Winter-de Groot","sequence":"additional","affiliation":[{"name":"Department of Paediatric Pulmonology, Wilhelmina Children\u2019s Hospital, University Medical Centre Utrecht, Utrecht University, 3585 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5576-9517","authenticated-orcid":false,"given":"Marijke","family":"Proesmans","sequence":"additional","affiliation":[{"name":"CF Research Lab, Woman and Child Unit, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium"},{"name":"Department of Paediatrics, Paediatric Pulmonology, University Hospital Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S2213-2600(16)00053-9","article-title":"Newborn screening for cystic fibrosis","volume":"4","author":"Castellani","year":"2016","journal-title":"Lancet Respir. 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