title: Familial concordance of phenotype and microbial variation among siblings with CF.
abstract: The clinical spectrum of cystic fibrosis (CF) is influenced by the cystic fibrosis transmembrane conductance regulator (CFTR) genotype. However, variable courses of the disease were demonstrated among patients with identical genotypes. Since siblings share identical CFTR mutations and environmental factors, they can serve as a model to assess the effect of modifier genes on disease expression, and also to evaluate cross-infection. The aim of this study was to compare disease expression among siblings with CF. All sibling pairs treated at 7 CF centers in Israel were included in the study. Data were collected from patients' medical charts. Fifty families with at least 2 siblings were identified. As expected, the second-born sibling was diagnosed at an earlier age compared to the first-born. The mode of CF presentation at diagnosis showed significant familial concordance. In the families where the first sibling presented with gastrointestinal manifestations, 79% of the second siblings also presented with gastrointestinal manifestations. When gastrointestinal manifestations were absent in the first sibling, only 12% of the second siblings presented with gastrointestinal manifestations (P < 0.0001). Likewise, when the first sibling presented with respiratory symptoms, 60% of the second siblings presented with the similar symptoms. However, when the first sibling presented without respiratory symptoms, only 12% of the second siblings presented with respiratory symptoms (P < 0.001). Meconium ileus (MI) was present in 20 patients (21%). In 10 families where the first-born sibling had MI, 8 (80%) of the subsequent siblings had MI. On the other hand, in the 39 families where the first-born sibling did not have MI, only 2 (5%) subsequent siblings had MI (P < 0.001). Pancreatic insufficiency (PI) also had high familial concordance (P < 0.0001). Percentile growth for weights and heights and lung function (FVC, FEV(1), and FEF(25-75)) at ages 7 and 10 years were similar between siblings. P. aeruginosa grew from sputum in 89% of our study patients. When P. aeruginosa was isolated from the first-born patient, 91% of the second siblings were also positive for P. aeruginosa, whereas when the initial sibling was not a carrier of P. aeruginosa, only 50% of subsequent siblings were positive (P < 0.0001). This familial concordance was not observed for S. aureus. By contrast, the age of first isolation of P. aeruginosa and S. aureus was significantly earlier in the second sibling than in the first for the two bacteria: 10.3 +/- 5.1 vs. 7.3 +/- 5.2 years (P < 0.05) for P. aeruginosa, and 11.5 +/- 5.4 years vs. 6.8 +/- 5.1 years (P < 0.05) for S. aureus. CF siblings tend to share similar phenotypes that are not mutation-dependent. The lack of variability between siblings in mode of initial CF presentation, rates of MI, pulmonary function, and nutritional status supports the role of modifier genes in the determination of these factors.
authors.affiliation: Department of Pediatric Respiratory Medicine, Cystic Fibrosis Center, Shaare Zedek Medical Center, Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Elie
authors.initials: E
authors.lastname: Picard
authors.forename: Micha
authors.initials: M
authors.lastname: Aviram
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Yahav
authors.forename: Joseph
authors.initials: J
authors.lastname: Rivlin
authors.forename: Hanna
authors.initials: H
authors.lastname: Blau
authors.forename: Lea
authors.initials: L
authors.lastname: Bentur
authors.forename: Avraham
authors.initials: A
authors.lastname: Avital
authors.forename: Yael
authors.initials: Y
authors.lastname: Villa
authors.forename: Shepard
authors.initials: S
authors.lastname: Schwartz
authors.forename: Batsheva
authors.initials: B
authors.lastname: Kerem
authors.forename: Eitan
authors.initials: E
authors.lastname: Kerem
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007223:Infant; D007557:Israel; D009154:Mutation; D010641:Phenotype; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D012189:Retrospective Studies; D035781:Siblings
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator