Clinical expression of cystic fibrosis in a large cohort of Italian siblings

BMC Pulm Med. 2018 Dec 22;18(1):196. doi: 10.1186/s12890-018-0766-6.


Background: A clinical heterogeneity was reported in patients with Cystic Fibrosis (CF) with the same CFTR genotype and between siblings with CF.

Methods: We investigated all clinical aspects in a cohort of 101 pairs of siblings with CF (including 6 triplets) followed since diagnosis.

Results: Severe lung disease had a 22.2% concordance in sib-pairs, occurred early and the FEV1% at 12 years was predictive of the severity of lung disease in the adulthood. Similarly, CF liver disease occurred early (median: 15 years) and showed a concordance of 27.8% in sib-pairs suggesting a scarce contribution of genetic factors; in fact, only 2/15 patients with liver disease in discordant sib-pairs had a deficiency of alpha-1-antitrypsin (a known modifier gene of CF liver phenotype). CF related diabetes was found in 22 pairs (in 6 in both the siblings). It occurred later (median: 32.5 years) and is strongly associated with liver disease. Colonization by P. aeruginosa and nasal polyposis that required surgery had a concordance > 50% in sib-pairs and were poorly correlated to other clinical parameters. The pancreatic status was highly concordant in pairs of siblings (i.e., 95.1%) but a different pancreatic status was observed in patients with the same CFTR mutations. This suggests a close relationship of the pancreatic status with the "whole" CFTR genotype, including mutations in regulatory regions that may modulate the levels of CFTR expression. Finally, a severe course of CF was evident in a number of patients with pancreatic sufficiency.

Conclusions: Physicians involved in care of patients with CF and in genetic counseling must be aware of the clinical heterogeneity of CF even in sib-pairs that, at the state of the art, is difficult to explain.

Keywords: CFTR; FEV1; Genotype; Modifier genes; Phenotype; Pseudomonas aeruginosa.

MeSH terms

  • Adolescent
  • Adult
  • Carrier State / microbiology*
  • Child
  • Cystic Fibrosis / complications
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / physiopathology*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Diabetes Mellitus / etiology*
  • Exocrine Pancreatic Insufficiency / etiology*
  • Female
  • Forced Expiratory Volume
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Italy
  • Liver Diseases / etiology*
  • Male
  • Meconium Ileus / etiology*
  • Middle Aged
  • Mutation
  • Nasal Polyps / complications
  • Nasal Polyps / surgery
  • Oropharynx / microbiology
  • Phenotype
  • Pseudomonas aeruginosa
  • Severity of Illness Index
  • Siblings*
  • Sputum / microbiology
  • Young Adult
  • alpha 1-Antitrypsin / genetics


  • CFTR protein, human
  • alpha 1-Antitrypsin
  • Cystic Fibrosis Transmembrane Conductance Regulator