{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T10:03:18Z","timestamp":1791453798124,"version":"4.3.3"},"reference-count":32,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,8]],"date-time":"2020-08-08T00:00:00Z","timestamp":1596844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Newborn screening (NBS) early-identifies cystic fibrosis (CF), but in CF-screening positive inconclusive diagnosis (CF-SPID) the results of immunoreactive trypsinogen (IRT), molecular analysis and sweat test (ST) are discordant. A percentage of CF-SPID evolves to CF, but data on long-term monitoring are lacking. We describe the follow-up of all CF and CF-SPID identified between 2008 and 2019. Methods: NBS was performed by IRT followed by molecular analysis and ST between 2008 and 2014; double IRT followed by molecular analysis and ST after 2014. Results: NBS revealed 47 CF and 99 CF-SPID newborn, a ratio 1:2.1\u2014the highest reported so far. This depends on the identification by gene sequencing of the second variant with undefined effect in 40 CF-SPID that otherwise would have been defined as carriers. Clinical complications and pulmonary infections occurred more frequently among CF patients than among CF-SPID. Two CF-SPID cases evolved to CF (at two years), while eight evolved to CFTR-related disorders (CFTR-RD), between one and eight years, with bronchiectasis (two), recurrent pneumonia (four, two with sinonasal complications), recurrent pancreatitis (two). No clinical, biochemical or imaging data predicted the evolution. Conclusion: Gene sequencing within the NBS reveals a higher number of CF-SPID and we first describe an approach to early identify CFTR-RD, with relevant impact on their outcome.<\/jats:p>","DOI":"10.3390\/diagnostics10080570","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T05:07:23Z","timestamp":1597036043000},"page":"570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Cystic Fibrosis-Screening Positive Inconclusive Diagnosis: Newborn Screening and Long-Term Follow-Up Permits to Early Identify Patients with CFTR-Related Disorders"],"prefix":"10.3390","volume":"10","author":[{"given":"Alice","family":"Castaldo","sequence":"first","affiliation":[{"name":"Department of Translational Medical Sciences, Cystic Fibrosis Centre, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cimbalo","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Cystic Fibrosis Centre, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raimondo J.","family":"Castaldo","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Cystic Fibrosis Centre, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella","family":"D\u2019Antonio","sequence":"additional","affiliation":[{"name":"CEINGE-Advanced Biotechnology, Via Gaetano Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Scorza","sequence":"additional","affiliation":[{"name":"CEINGE-Advanced Biotechnology, Via Gaetano Salvatore 486, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Salvadori","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Cystic Fibrosis Centre, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Sepe","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Cystic Fibrosis Centre, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Raia","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Cystic Fibrosis Centre, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Tosco","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Cystic Fibrosis Centre, University Federico II, Via Sergio Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.jcf.2015.03.003","article-title":"Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy","volume":"14","author":"Cantin","year":"2015","journal-title":"J. Cyst. Fibros."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Terlizzi, V., Lucarelli, M., Salvatore, D., Angioni, A., Bisogno, A., Braggion, C., Buzzetti, R., Carnovale, V., Casciaro, R., and Castaldo, G. (2018). Clinical expression of cystic fibrosis in a large cohort of Italian siblings. BMC Pulm. Med., 18.","DOI":"10.1186\/s12890-018-0766-6"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1111\/ped.14173","article-title":"Clinical characteristics and genetic analysis of cystic fibrosis transmembrane conductance receptor-related disease","volume":"62","author":"Kilinc","year":"2020","journal-title":"Pediatr. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S86","DOI":"10.1016\/S1569-1993(11)60014-3","article-title":"Recommendations for the classification of diseases as CFTR-related disorders","volume":"10","author":"Bombieri","year":"2011","journal-title":"J. Cyst. Fibros."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jmoldx.2011.09.001","article-title":"Extensive molecular analysis of patients bearing CFTR-Related disorders","volume":"14","author":"Amato","year":"2012","journal-title":"J. Mol. Diagn."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S106","DOI":"10.1016\/j.jpeds.2009.09.003","article-title":"Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond","volume":"155","author":"Borowitz","year":"2009","journal-title":"J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.jcf.2015.01.001","article-title":"Cystic Fibrosis screen positive Inconclusive Diagnosis (CFSPID): A new designation end management recommendations for infants with an inconclusive diagnosis following newborn screening","volume":"14","author":"Munck","year":"2015","journal-title":"J. Cyst. Fibros."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jpeds.2016.09.066","article-title":"Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis","volume":"181","author":"Ren","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.jcf.2007.12.004","article-title":"Epidemiology and a novel procedure for large scale analysis of CFTR rearrangements in classic and atypical CF patients: A multicentric Italian study","volume":"7","author":"Tomaiuolo","year":"2008","journal-title":"J. Cyst. Fibrosis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1515\/cclm-2017-0553","article-title":"Multicenter validation study for the certification of a CFTR gene scanning method using next generation sequencing technology","volume":"56","author":"Bergougnoux","year":"2018","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eS13","DOI":"10.1016\/S0929-693X(20)30045-2","article-title":"Variant classifications, databases and genotype-phenotype correlations","volume":"27","author":"Raynal","year":"2020","journal-title":"Arch. Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jpeds.2016.09.063","article-title":"Applying Cystic Fibrosis Transmembrane Conductance Regulator Genetics and CFTR2 Data to Facilitate Diagnoses","volume":"181","author":"Sosnay","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1373\/clinchem.2008.119545","article-title":"Three novel CFTR polymorphic repeats improve segregation analysis for cystic fibrosis","volume":"55","author":"Elce","year":"2009","journal-title":"Clin. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.jpeds.2016.09.064","article-title":"Diagnosis of cystic fibrosis: Consensus guidelines from the Cystic Fibrosis Foundation","volume":"181","author":"Farrell","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1515\/CCLM.2004.148","article-title":"Quality assessment in cytogenetic and molecular genetic testing: The experience of the Italian project on standardisation and quality assurance","volume":"42","author":"Taruscio","year":"2004","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1097\/MPG.0b013e31824f1516","article-title":"Definitions of pediatric pancreatitis and survey of current clinical practices: Report from insppire (international study group of pediatric pancreatitis: In search for a cure)","volume":"55","author":"Morinville","year":"2012","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S1569-1993(02)00141-8","article-title":"Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients","volume":"2","author":"Lee","year":"2003","journal-title":"J. Cyst. Fibros."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Castaldo, A., Iacotucci, P., Carnovale, V., Cimino, R., Liguori, R., Comegna, M., Raia, V., Corso, G., Castaldo, G., and Gelzo, M. (2020). Salivary cytokines and airways disease severity in patients with cystic fibrosis. Diagnostics (Basel), 10.","DOI":"10.3390\/diagnostics10040222"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1515\/cclm-2015-1151","article-title":"absorption and enhanced synthesis of cholesterol in patients with cystic fibrosis: A preliminary study of plasma sterols","volume":"54","author":"Gelzo","year":"2016","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"371","DOI":"10.23736\/S0026-4946.19.05509-9","article-title":"Inhaled medications in cystic fibrosis beyond antibiotics","volume":"71","author":"Sepe","year":"2019","journal-title":"Minerva Pediatr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.jcf.2019.04.002","article-title":"Cystic Fibrosis screen positive inconclusive diagnosis (CFSPID): Experience in Tuscany, Italy","volume":"18","author":"Terlizzi","year":"2019","journal-title":"J. Cyst. Fibros."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.jcf.2014.12.012","article-title":"Clinical expression of patients with the D1152H CFTR mutation","volume":"14","author":"Terlizzi","year":"2015","journal-title":"J. Cyst. Fibros."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1542\/peds.2014-2081","article-title":"Inconclusive diagnosis of cystic fibrosis after newborn screening","volume":"135","author":"Ooi","year":"2015","journal-title":"Pediatrics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1177\/0969141317692611","article-title":"Optimization of the French cystic fibrosis newborn screening programme by a centralized tracking process","volume":"25","author":"Munck","year":"2018","journal-title":"J. Med. Screen."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.jcf.2018.07.008","article-title":"Newborn blood spot screening for cystic fibrosis with a four-step screening strategy in the Netherlands","volume":"18","author":"Bouva","year":"2019","journal-title":"J. Cyst. Fibros."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1002\/ppul.24634","article-title":"Phenotype of children with inconclusive cystic fibrosis diagnosis after newborn screening","volume":"55","author":"Munck","year":"2020","journal-title":"Pediatr. Pulmonol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1080\/17476348.2016.1240032","article-title":"Clinical approach to the diagnosis and treatment of cystic fibrosis and CFTR-related disorders","volume":"10","author":"Michl","year":"2016","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1002\/jgc4.1170","article-title":"Practice variation of genetic counselor engagement in the cystic fibrosis newborn screen-positive diagnostic resolution process","volume":"28","author":"Raraigh","year":"2019","journal-title":"J. Genet. Couns."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ooi, C.Y., Sutherland, R., Castellani, C., Keenan, K., Boland, M., Reisman, J., Bjornson, C., Chilvers, M.A., Van Wylick, R., and Kent, S. (2019). Immunoreactive trypsinogen levels in newborn screened infants with an inconclusive diagnosis of cystic fibrosis. BMC Pediatr., 19.","DOI":"10.1186\/s12887-019-1756-4"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1073\/pnas.1914912117","article-title":"Cystic Fibrosis Carriers Are at Increased Risk for a Wide Range of Cystic Fibrosis-Related Conditions","volume":"117","author":"Miller","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5806","DOI":"10.1038\/s41598-020-62747-9","article-title":"TAS2R38 is a novel modifier gene in patients with cystic fibrosis","volume":"10","author":"Castaldo","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1136\/jmedgenet-2016-103985","article-title":"Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles","volume":"54","author":"Terlizzi","year":"2017","journal-title":"J. Med. Genet."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/10\/8\/570\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:58:16Z","timestamp":1760176696000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/10\/8\/570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,8]]},"references-count":32,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["diagnostics10080570"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics10080570","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,8]]}}}