Phenotypic characterization of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis

Christophe Goubau ¹, Michael Wilschanski ², Veronika Skalická ³, Patrick Lebecque ⁴, Kevin Southern ⁵, Isabelle Sermet ⁶, Anne Munck ⁷, Nico Derichs ⁸, Peter G Middleton ⁹, Lena Hjelte ¹⁰, Rita Padoan ¹¹, Maire Vasar ¹² and Christiane A De Boeck ^1*

¹ University of Leuven, Belgium
² Hadassah University Hospital, Israel
³ Faculty Hospital Motol, Czech Republic
⁴ Universit? Catholique de Louvain, Belgium
⁵ Royal Liverpool Children's Hospital, United Kingdom
⁶ H?pital Necker-Enfants Malades, France
⁷ H?pital Robert Debr?, France
⁸ Medizinische Hochschule Hannover, Germany
⁹ Ludwig Engel Centre for Respiratory Research, Westmead Millennium Institute, Australia
¹⁰ Karolinska University Hospital Huddinge, Sweden
¹¹ Ospedale dei Bambini, Italy
¹² Children's Clinic of Tartu University Clinics, Estonia

^* To whom correspondence should be addressed. E-mail: christiane.deboeck{at}uz.kuleuven.ac.be.

Accepted 12 March 2009

Abstract

Background: In patients with symptoms suggestive of cystic fibrosis and intermediate sweat chloride values (30-60mmol/L) extensive CFTR gene mutation analysis and nasal potential difference (NPD) measurement are used as additional diagnostic tests and a positive result in either test provides evidence of CFTR dysfunction. To define the phenotype of such patients and confirm the validity of grouping them, we compared patients with intermediate sweat chloride values in whom either additional CF diagnostic test was abnormal with subjects in whom this was not the case and patients with classic CF.

Methods: Phenotypic features were compared in 4 groups: 59 patients with CFTR dysfunction, 46 patients with an intermediate sweat chloride concentration but no evidence of CFTR dysfunction (CF unlikely), 103 CF pancreatic sufficient patients (CF-PS), 62 CF pancreatic insufficient patients (CF-PI).

Results: The CFTR dysfunction group had more lower respiratory tract infections (p=0.01), more isolation of CF pathogens (p<0.001) and clubbing (p=0.001) compared with the CF unlikely group but less frequent respiratory tract infections with CF pathogens than CF-PS group (p=0.05). CF-PS patients had a milder phenotype than those with PI. Many features, showed stepwise changes through the patient groups.

Conclusion: Patients with intermediate sweat chloride values and 2 CFTR mutations or an abnormal nasal PD measurement have a CF like phenotype compatible with CFTR dysfunction and –as a group- differ phenotypically from patients with intermediate sweat chloride values in whom further CF diagnostic tests are normal as well as from CF-PS and CF-PI patients.