The CF-CIRC study: a French collaborative study to assess the accuracy of cystic fibrosis diagnosis in neonatal screening.
BACKGROUND
Cystic fibrosis (CF) is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR) protein, which acts as a chloride channel after activation by cyclic AMP (cAMP). Newborn screening programs for CF usually consist of an immunoreactive trypsinogen (IRT) assay, followed when IRT is elevated by testing for a panel of CF-causing mutations. Some children, however, may have persistent hypertrypsinogenemia, only one or no identified CFTR gene mutation, and sweat chloride concentrations close to normal values. In vivo demonstration of abnormal CFTR protein function would be an important diagnostic aid in this situation. Measurements of transepithelial nasal potential differences (NPD) in adults accurately characterize CFTR-related ion transport. The aim of the present study is to establish reference values for NPD measurements for healthy children and those with CF aged 3 months to 3 years, the age range of most difficult-to-diagnose patients with suspected CF. The ultimate goal of our study is to validate NPD testing as a diagnostic tool for children with borderline results in neonatal screening.


METHODS
We adapted the standard NPD protocol for young children, designed a special catheter for them, used a slower perfusion rate, and shortened the protocol to include only measurement of basal PD, transepithelial sodium (Na+) transport in response to the Na+ channel inhibitor amiloride, and CFTR-mediated chloride (Cl-) secretion in response to isoproterenol, a beta-agonist in a Cl- free solution. The study will include 20 children with CF and 20 healthy control children. CF children will be included only if they carry 2 CF-causing mutations in the CFTR gene or have sweat chloride concentrations > 60 mEq/L or both. The healthy children will be recruited among the siblings of the CF patients, after verification that they do not carry the familial mutation.


CONCLUSIONS
A preliminary study of 3 adult control subjects and 4 children older than 12 years with CF verified that the new protocol was well tolerated and produced NPD measurements that did not differ significantly from those obtained with the standard protocol. This preliminary study will provide a basis for interpreting NPD measurements in patients with suspected CF after neonatal screening. Earlier definitive diagnosis should alleviate parental distress and allow earlier therapeutic intervention and genetic counseling.
Sermet-Gaudelus
Isabelle
I
Service de Pédiatrie Générale and CRCM, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743, Paris, France. isabelle.sermet@nck.aphp.fr
Roussel
Delphine
D
Bui
Stéphanie
S
Deneuville
Eric
E
Huet
Frédéric
F
Reix
Philippe
P
Bellon
Gabriel
G
Lenoir
Gérard
G
Edelman
Aleksander
A
D000584:Amiloride / Q000494:pharmacology; D002404:Catheterization; D002675:Child, Preschool; D002712:Chlorides / Q000032:analysis / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000453:epidemiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004553:Electric Conductivity; D004567:Electrodes, Implanted; D004867:Equipment Design; D005260:Female; D005602:France / Q000453:epidemiology; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017136:Ion Transport / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D015997:Neonatal Screening / Q000379:methods; D010477:Perfusion / Q000379:methods; D011237:Predictive Value of Tests; D012016:Reference Values; D012107:Research Design; D012680:Sensitivity and Specificity; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D040521:Subcutaneous Tissue; D013542:Sweat / Q000737:chemistry; D013566:Sympathomimetics / Q000494:pharmacology
C505032:CFTR protein, human; D002712:Chlorides; D026941:Sodium Channel Blockers; D013566:Sympathomimetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000584:Amiloride; D012964:Sodium; D007545:Isoproterenol