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

Abstract

BackgroundA clinical heterogeneity was reported in patients with Cystic Fibrosis (CF) with the same CFTR genotype and between siblings with CF.MethodsWe investigated all clinical aspects in a cohort of 101 pairs of siblings with CF (including 6 triplets) followed since diagnosis.ResultsSevere 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.ConclusionsPhysicians 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.Electronic supplementary materialThe online version of this article (10.1186/s12890-018-0766-6) contains supplementary material, which is available to authorized users.

TAS2R38 is a novel modifier gene in patients with cystic fibrosis

“…P. aeruginosa expresses a series of specific virulence factors and, through adaptive mutations and antimicrobial resistance, causes chronic colonization via the development of biofilms 22 . In our study on CF sibling pairs 4 , we found chronic colonization by P. aeruginosa in 92/208 (44.2%) patients with CF and 21/101 cases in which only one sibling was colonized; 11/21 of these patients lived in the same environment suggesting that the environment has a limited role in P. aeruginosa colonization. Modifier genes, inherited independently by CFTR, may predispose to colonization of P. aeruginosa 23 .…”

“…Interestingly, our data relate the TAS2R38 genotype to the age of onset of NP requiring surgery, indicating that CF patients with nonfunctional alleles would develop NP requiring surgery at a younger age than CF patients with functional alleles. Thus, TAS2R38 can be considered a novel CF modifier gene, that modulates the severity of sinonasal disease contributing to explaining the known discordance for sinonasal severity observed in CF patients with the same CFTR genotype and in some pairs of CF patients 4 .…”

“…It is still unclear why only a small subgroup of patients with CF progress to such phase of the sinonasal disease [17][18][19][20] , even though the severity of CFTR mutations as well as previous sinus surgery may predict an increased risk 11 . Interestingly, in a recent study on 101 CF sibling-pairs 4 we found NP requiring surgery in both the siblings of 13 pairs and in only one sibling from 12 sibling pairs. The poor correlation of NP to the CFTR genotype and to other clinical manifestations such as the pancreatic status and the severity of lung disease suggest that modifier genes play a role in determining nasal polyposis 21 .…”

“…The clinical manifestation of cystic fibrosis (CF) is highly heterogeneous also depending on the functional effect of the CFTR genotype 1,2 . However, patients with the same CFTR genotype may display a clinical discordance 3 and a percentage of sibling pairs affected by CF display a discordant clinical manifestation 3,4 reinforcing the concept that complex alleles (i.e., additional mutations on the same allele 5 ), non-coding regions of CFTR 6,7 or other genes, inherited independently of CFTR, modulate the clinical manifestation and complications of patients with CF 8 . Patients with CF frequently show different degrees of chronic rhinosinusitis 9,10 with poor perception of sinonasal symptoms 11 and pulmonary colonization by Pseudomonas aeruginosa and other opportunistic bacteria 12,13 .…”

Salivary Cytokines and Airways Disease Severity in Patients with Cystic Fibrosis

“…Lung disease was classified as severe, moderate, or mild, considering both the age and the most recent forced expiratory volume in 1 s (FEV1) of patients while they were clinically stable [23]. The FEV1 was expressed as the percentage of predicted value (% pred) for age, according to standardized reference equations for spirometry [24].…”