Elsevier

Gene

Volume 540, Issue 2, 1 May 2014, Pages 183-190
Gene

CFTR genotype and clinical outcomes of adult patients carried as cystic fibrosis disease

https://doi.org/10.1016/j.gene.2014.02.040Get rights and content

Highlights

  • Cystic fibrosis has CFTR mutation associated with patient age groups.

  • To determine the complete genotype of adult cystic fibrosis that is complex.

  • The cystic fibrosis is a “disease” of each patient.

Abstract

Background

There are nearly 2000 cystic fibrosis transmembrane regulator (CFTR) mutations that cause cystic fibrosis (CF). These mutations are classified into six classes; on the one hand, the first three classes cause severe disease involvement in early childhood, on the other hand, the Class IV, V and VI mutations cause minor severe disease in the same age. Nowadays, with therapeutic advances in CF management and competence of pediatricians, physicians of adults have to deal with two groups of CF patients: (i) adults diagnosed in childhood with severe mutations and (ii) adults who initiated symptoms in adulthood and with Class IV, V and VI mutations. The aim of this study was to analyze adults from a clinical center, treated as CF disease, screening the CFTR genotype and evaluating the clinical characteristics.

Methods

Thirty patients followed as CF disease at the University Hospital were enrolled. After a complete molecular CFTR negative screening and sweat test levels between 40 and 59 mEq/L, five patients were characterized as non-CF disease and were excluded. Molecular screening was performed by CFTR gene sequencing/MLPA or by specific mutation screening. Clinical data was obtained from medical records. The patients were divided into three groups: (1) patients with Class I, II and III mutations in two CFTR alleles; (2) genotype with at least one allele of Class IV, V or VI CFTR mutations and, (3) non-identified CFTR mutation + one patient with one allele with CFTR mutation screened (Class I).

Results

There was an association of CFTR class mutation and sodium/chloride concentration in the sweat test (sodium: p = 0.040; chloride: p = 0.016), onset of digestive symptoms (p = 0.012), lung function parameter (SpO2 — p = 0.016), Bhalla score (p = 0.021), age at diagnosis (p = 0.008) and CF-related diabetes (p = 0.029). There was an association between Pseudomonas aeruginosa chronic colonization (as clinical marker for the lung disease status) and lung impairment (FEV1% — p = 0.027; Bhalla score — p = 0.021), CF-related diabetes (p = 0.040), chloride concentration in the sweat test (p = 0.040) and chronic infection by microorganisms (Staphylococcus aureus — p = 0.039; mucoid P. aeruginosa — p = 0.001). There is no positive association with the status of other clinical markers and the CFTR genotype groups. For clinical association with pancreatic insufficiency (as clinical marker for digestive symptoms), no association was related.

Conclusion

The adults with CF diagnosed by sweat test have specific clinical and genotypic characteristics, being a population that should be studied to cause better future management. Some patients treated as CF disease by clinical symptoms, showed no disease, taking into account the sweat test and complete exon sequencing/MLPA screening.

Introduction

Cystic fibrosis (CF) is a common autosomal recessive disorder within the Caucasian population with high lethality and morbidity (Farrel, 2000). It is caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR; ENSG00000001626) gene which encodes a chloride channel expressed on the surface of epithelial cells (Riordan et al., 1989). Nearly more than 2000 mutations have been described (http://www.genet.sickkids.on.ca/cftr) and divided into six categories depending on their effects on protein production and activity (Zielenski and Tsui, 1995, Haardt et al., 1999). I, II and III CFTR-class mutations are associated with a severe clinical status since there is no production of an active CFTR protein, while CFTR gene mutation Classes IV, V and VI are associated with a better prognosis since the channel has residual activity (Amaral and Kunzelmann, 2007). When CF disease was first described, patient's life was short and painful. However, antibiotics began to be widely used and pancreatic supplements became available, providing an aggressive treatment of symptoms, with higher life expectancy and quality of life improvement. In 2005, more than 35% of CF patients were over 18 years old (Davis, 2006) and it was expected that CF patients who were born in the 90s could live up to their 40s, while those who are born currently are expected to live 50 years of age (Cystic Fibrosis Foundation, 2008). Nowadays, as CF patients have bigger life expectancy, the adult population requiring medical care increased (Tuchman et al., 2010).

Around the world the transition process to adult life takes places at the end of adolescence or the first phase of adulthood. In these CF life phases, the pulmonary function should be decreasing, and both, load of treatment and multisystemic complications derived from the disease are increasing (Cystic Fibrosis Foundation, 2008, Dobbin and Bye, 2003, Konstan et al., 2009). Within this new perspective, studies that characterize this growing group are important.

Actually, with therapeutic advances in CF management and the competence of pediatricians, adults' physicians have to deal with two groups of patients: (i) adults diagnosed in childhood with severe mutations and (ii) adults who initiated symptoms in adulthood and with Class IV, V and VI mutations. In this context, the aim of this study was to analyze adults from a clinical center, carried as CF disease, screening the CFTR genotype, performing the sweat test and evaluating the clinical characteristics.

Section snippets

Patients and method

Cross-sectional study enrolled 30 patients carried as CF disease, older than 18 years old from State University of Campinas (Unicamp).

All patients showed clinical symptoms of CF, and received the treatment. All patients had done the sweat test and had a diagnosis of CF. The positive case of CF was considered as patients with two doses of sodium and chloride from the sweat with values greater than 60 mEq/L or two CFTR gene mutation identified by molecular technique.

Local Ethics Committees approved

Description of CF patients

From the patients carried as CF in the Center, five have normal sweat test and no CFTR mutation screened. For the clinical characterization and the associations, only patients with positive results screened in sweat test and/or CFTR mutation determined were enrolled. The complete patient's characteristics for sweat tests and CFTR genotype were described in Table 1. The clinical markers achieved in our data were shown in Table 2. The 25 CF patients had diagnosis performed in the first ages (mean =

Discussion

The study of typical CF disease is an important and knowledgeable area of medicine. Nowadays, CF can be considered as a disease for each patient, and a particular population needs to be analyzed: the adult CF patients. In our center, patients are treated in adults' clinical as CF patients, taking into account the clinical markers. To understand this particular sample, the present work performed the screening of CFTR mutations and analyzed the patient's records.

In our data, five patients had no

Conflict of interest

The authors declare that they have no competing interests.

Authors' contributions

LCB: made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; involved in drafting the manuscript or revising it critically for important intellectual content.

FALM: made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; involved in drafting the manuscript or revising it critically for important intellectual content.

JDR/IPA/MPC/AFR: has been involved in drafting the

Acknowledgments

Bruna Favetta — English review. Maria Angela Ribeiro — spirometry analysis. www.laboratoriomultiusuario.com.br by technical contribution. Anabela S. Ramalho to collaborate with CFTR mutation identification.

Financial support: Fapesp and CNPq.

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