Skip to main content

Advertisement

SpringerLink
Log in

Cystic fibrosis and CFTR-related disorder with electrolyte imbalance at diagnosis: clinical features and outcome in an Italian cohort

  • RESEARCH
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

There is limited information available on the clinical data, sweat test trends, and outcomes of individuals with cystic fibrosis (CF) who present with an isolated episode of hypoelectrolytemia with metabolic alkalosis (HMA). This study describes a cohort of Italian individuals with HMA as presenting symptom. The study is a retrospective multicenter analysis of individuals who presented with HMA as an initial symptom and was followed at 8 Italian CF Centers, from March 1988 to March 2022. Demographic, clinical, microbiological, biochemical, and genetic data were extracted from local health records. Ninety-three individuals were enrolled in the study. At first evaluation, 82 (88.2%) were diagnosed with CF, and 11 received a CFTR-Related Disorder (CFTR-RD) diagnostic label. Twenty-three (85.1%) out of the 27 subjects who underwent CF neonatal screening (NBS) resulted falsely negative. After a mean observational period of 11.5 years, most of subjects had a mild pulmonary phenotype, pancreatic sufficiency, and rarely CF-related complications. Four CFTR-RD changed to a CF diagnosis during the study period, resulting in 86 (92.4%) subjects classified as CF.

Conclusions: Most CF patients presenting with isolated HMA have a mild course of disease and rarely CF-related complications.

What is Known:

• Isolated episode of hypoelectrolytemia with metabolic alkalosis is a well-known onset symptom of Cystic Fibrosis in infancy.

• There is limited information available on the clinical data and outcomes of individuals with Cystic Fibrosis who present with electrolyte imbalance at diagnosis.

What is New:

• Most patients with Cystic Fibrosis presenting with isolated hypoelectrolytemia and metabolic alkalosis have a mild course of disease and rarely CF-related complications.

• Electrolyte imbalance at diagnosis of Cystic Fibrosis is a common symptom in children not screened for CF at birth, or in those who received a false negative result from newborn screening.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data availability

Data supporting the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, Burgel PR, Tullis E, Castaños C, Castellani C et al (2020) The future of cystic fibrosis care: a global perspective. Lancet Respir Med 8:65–124

    Article  CAS  PubMed  Google Scholar 

  2. Shamsuddin AKM, Quinton PM (2019) Concurrent absorption and secretion of airway surface liquids and bicarbonate secretion in human bronchioles. Am J Physiol Lung Cell Mol Physiol 316:L953–L960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Farrell PM, White TB, Ren CL, Hempstead SE, Accurso F, Derichs N, Howenstine M, McColley SA, Rock M, Rosenfeld M et al (2017) Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation. J Pediatr 181S:S4-S15.e1

  4. Bombieri C, Claustres M, De Boeck K, Derichs N, Dodge J, Girodon E, Sermet I, Schwarz M, Tzetis M, Wilschanski M et al (2011) Recommendations for the classification of diseases as CFTR-related disorders. J Cyst Fibros 10(Suppl 2):S86-102

    Article  CAS  PubMed  Google Scholar 

  5. Castellani C, De Boeck K, De Wachter E, Sermet-Gaudelus I, Simmonds NJ, Southern KW, ECFS (2022) Diagnostic Network Working Group. ECFS standards of care on CFTR-related disorders: updated diagnostic criteria. J Cyst Fibros 21:908–921

    Article  CAS  PubMed  Google Scholar 

  6. Salvatore D, Dell’Edera D, Colangelo C, Smaldore G (2016) Salt depletion syndrome as the initial presentation of cystic fibrosis in a toddler with the rare p.Ala309Gly (A309G) CFTR variant. Clin Genet 90:186–187

    Article  CAS  PubMed  Google Scholar 

  7. Ballestero Y, Hernandez MI, Rojo P, Manzanares J, Nebreda V, Carbajosa H, Infante E, Baro M (2006) Hyponatremic dehydration as a presentation of cystic fibrosis. Pediatr Emerg Care 22:725–727

    Article  PubMed  Google Scholar 

  8. Sosnay PR, White TB, Farrell PM, Ren CL, Derichs N, Howenstine MS, Nick JA, De Boeck K (2017) Diagnosis of cystic fibrosis in nonscreened populations. J Pediatr 181S:S52-S57.e2

  9. Fustik S, Pop-Jordanova N, Slaveska N, Koceva S, Efremov G (2022) Metabolic alkalosis with hypoelectrolytemia in infants with cystic fibrosis. Pediatr Int 44:289–292

    Article  Google Scholar 

  10. Terlizzi V, Di Lullo AM, Comegna M, Centrone C, Pelo E, Castaldo G, Raia V, Braggion C (2018) S737F is a new CFTR mutation typical of patients originally from the Tuscany region in Italy. Ital J Pediatr 44:2

    Article  PubMed  PubMed Central  Google Scholar 

  11. Taccetti G, Botti M, Terlizzi V, Cavicchi MC, Neri AS, Galici V, Mergni G, Centrone C, Peroni DG, Festini F (2020) Clinical and genotypical features of false-negative patients in 26 years of cystic fibrosis neonatal screening in Tuscany. Italy Diagnostics (Basel) 10:446

    Article  CAS  PubMed  Google Scholar 

  12. Wathen JE, MacKenzie T, Bothner JP (2004) Usefulness of the serum electrolyte panel in the management of pediatric dehydration treated with intravenously administered fluids. Pediatrics 114:1227–1234

    Article  PubMed  Google Scholar 

  13. Terlizzi V, Padoan R (2022) Infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis and acute recurrent pancreatitis: what definition? J Med Screen 29:64–65

    Article  PubMed  Google Scholar 

  14. Poli P, De Rose DU, Timpano S, Savoldi G, Padoan R (2019) Should isolated Pseudo-Bartter syndrome be considered a CFTR-related disorder of infancy? Pediatr Pulmonol 54:1578–1583

    Article  PubMed  Google Scholar 

  15. Terlizzi V, Claut L, Tosco A, Colombo C, Raia V, Fabrizzi B, Lucarelli M, Angeloni A, Cimino G, Castaldo A et al (2021) A survey of the prevalence, management and outcome of infants with an inconclusive diagnosis following newborn bloodspot screening for cystic fibrosis (CRMS/CFSPID) in six Italian centres. J Cyst Fibros 20:828–834

    Article  CAS  PubMed  Google Scholar 

  16. Asfuroglu P, Sismanlar Eyuboglu T, Aslan AT, Gursoy TR, Emiralioglu N, Yalcin E et al (2022) The success of the cystic fibrosis registry of Turkey for improvement of patient care. Pediatr Pulmonol 57:1245–1252

    Article  PubMed  Google Scholar 

  17. Scurati-Manzoni E, Fossali EF, Agostoni C, Riva E, Simonetti GD, Zanolari-Calderari M, Bianchetti MG, Lava SA (2014) Electrolyte abnormalities in cystic fibrosis: systematic review of the literature. Pediatr Nephrol 29:1015–1023

    Article  PubMed  Google Scholar 

  18. Il Test del Sudore: Raccomandazioni del Gruppo di Lavoro SIFC (2022) (Aprile 2022; https://www.sifc.it/)

  19. Borowitz D (2005) Update on the evolution of pancreatic exocrine status in cystic fibrosis. Curr Opin Pulm Med 11:524–527

    Article  PubMed  Google Scholar 

  20. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson JL, Ip MS, Zheng J et al (2012) Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 40:1324–1343

    Article  PubMed  PubMed Central  Google Scholar 

  21. Flume PA, O’Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, Bujan J, Finder J, Lester M, Quittell L et al (2007) Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 176:957–969

    Article  CAS  PubMed  Google Scholar 

  22. Castellani C, Duff AJA, Bell SC, Heijerman HGM, Munck A, Ratjen F, Sermet-Gaudelus I, Southern KW, Barben J, Flume PA et al (2018) ECFS best practice guidelines: the 2018 revision. J Cyst Fibros 17:153–178

    Article  PubMed  Google Scholar 

  23. Lee TW, Brownlee KG, Conway SP, Denton M, Littlewood JM (2003) Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J Cyst Fibros 2:29–34

    Article  PubMed  Google Scholar 

  24. Terlizzi V, Lucarelli M, Salvatore D, Angioni A, Bisogno A, Braggion C, Buzzetti R, Carnovale V, Casciaro R, Castaldo G et al (2018) Clinical expression of cystic fibrosis in a large cohort of Italian siblings. BMC Pulm Med 18:196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Terlizzi V, Carnovale V, Castaldo G, Castellani C, Cirilli N, Colombo C, Corti F, Cresta F, D’Adda A, Lucarelli M et al (2015) Clinical expression of patients with the D1152H CFTR mutation. J Cyst Fibros 14:447–452

    Article  CAS  PubMed  Google Scholar 

  26. Munck A, Berger DO, Southern KW, Carducci C, de Winter-de Groot KM, Gartner S, Kashirskaya N, Linnane B, Proesmans M, Sands D et al (2022) European survey of newborn bloodspot screening for CF: opportunity to address challenges and improve performance. J Cyst Fibros S1569–1993(22):00689

    Google Scholar 

  27. Sermet-Gaudelus I, Mayell SJ, Southern KW; European Cystic Finrosis Society (ECFS), Neonatal Screening Working Group (2010) Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening. J Cyst Fibros 9:323–329

    Article  Google Scholar 

  28. UK Cystic Fibrosis Registry 2020 Annual Data Report

  29. Cystic Fibrosis Foundation Patient Registry (2020) Annual Data Report Bethesda, Maryland

  30. Sismanlar Eyuboglu T, Dogru D, Çakır E, Cobanoglu N, Pekcan S, Cinel G, Yalçın E, Kiper N, Sen V, Selimoglu Sen H et al (2020) Clinical features and accompanying findings of Pseudo-Bartter Syndrome in cystic fibrosis. Pediatr Pulmonol 55:2011–2016

    Article  PubMed  Google Scholar 

  31. French Cystic Fibrosis Registry Annual Data Report 2020 (2022)

  32. Campagna G, Amato A, Majo F, Ferrari G, Quattrucci S, Padoan R, Floridia G, Salvatore D, Carnovale V, Puppo Fornaro G et al (2022) Gruppo di lavoro RIFC. Registro italiano Fibrosi Cistica (RIFC). Rapporto 2019–2020 [Italian Cystic Fibrosis Registry (ICFR). Report 2019–2020]. Epidemiol Prev 46(4 Suppl 2):1–38

  33. Barben J, Castellani C, Dankert-Roelse J, Gartner S, Kashirskaya N, Linnane B, Mayell S, Munck A, Sands D, Sommerburg O et al (2017) The expansion and performance of national newborn screening programmes for cystic fibrosis in Europe. J Cyst Fibros 16:207–213

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Vito Terlizzi and Rita Padoan contributed equally to this work.

Authors and Affiliations

  1. Department of Paediatric Medicine, Meyer Children’s Hospital IRCCS, Cystic Fibrosis Regional Reference Center, Florence, Italy

    Vito Terlizzi, Giovanni Taccetti & Cristina Fevola

  2. Scientific Board, Italian Cystic Fibrosis Registry, Rome, Italy

    Rita Padoan & Donatello Salvatore

  3. Pediatric Cystic Fibrosis Centre, Azienda Universitaria Ospedaliera Consorziale Policlinico, Bari, Italy

    Giuseppina Leonetti

  4. Cystic Fibrosis Support Center, Ospedale G. Tatarella di Cerignola, Cerignola, Italy

    Pamela Vitullo

  5. Paediatric Unit, Department of Translational Medical Sciences, Cystic Fibrosis Regional Reference Center, University of Naples Federico II, Naples, Italy

    Antonella Tosco

  6. Cystic Fibrosis Center, Ospedale Giovanni Di Cristina, Palermo, Italy

    Francesca Ficili

  7. Cystic Fibrosis Center, Hospital San Carlo, Potenza, Italy

    Angela Pepe & Donatello Salvatore

  8. Department of Pediatrics, Cystic Fibrosis Regional Support Center, University of Brescia, ASST Spedali Civili Brescia, Brescia, Italy

    Piercarlo Poli

  9. Department of Pathophysiology and Transplantation, Cystic Fibrosis Regional Reference Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

    Laura Claut & Valeria Daccò

Authors
  1. Vito Terlizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rita Padoan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppina Leonetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pamela Vitullo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonella Tosco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giovanni Taccetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cristina Fevola
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Francesca Ficili
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Angela Pepe
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Piercarlo Poli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Laura Claut
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Valeria Daccò
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Donatello Salvatore
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: V.T. and D.S. Methodology: V.T, R.P, D.S. Validation: V.T, R.P. D.S. Formal analysis: V.T, C.F., D.S. Investigation: V.T, R.P, D.S. Resources: V.T, R.P, G.L, P.V, A.T, G.T, F.F, A.P, P.P, L.C, C.C, D.S. Data curation: V.T, R.P, C.F, D.S. Writing-original draft preparation: V.T, R.P, D.S. Writing-review and editing: V.T, R.P, D.S. Project administration: V.T, D.S. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Vito Terlizzi.

Ethics declarations

Ethics approval

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the CF coordinator center (Florence, Ethics Committee number 134/2022). Informed consent was obtained from all patients (or from their legal guardians) for the use of anonymous clinical data for research purposes.

Informed consent

Informed consent was obtained from all subjects involved in the study or from the patients to publish this paper.

Conflict of interest

The authors declare no competing interests.

Additional information

Communicated by Peter de Winter

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOC 175 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Terlizzi, V., Padoan, R., Leonetti, G. et al. Cystic fibrosis and CFTR-related disorder with electrolyte imbalance at diagnosis: clinical features and outcome in an Italian cohort. Eur J Pediatr 182, 5275–5283 (2023). https://doi.org/10.1007/s00431-023-05193-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-023-05193-9

Keywords

Search

Navigation