Is there evidence for correct diagnosis in cystic fibrosis registries?

BACKGROUND: Cystic fibrosis (CF) spans a wide spectrum. Therefore, benchmarking between registries implies comparing similar cohorts. OBJECTIVE AND METHODS: Explore patient characteristics in Belgian (B), French (F), German (G) and Dutch (NL) registries (total N=13,122) and determine whether they fulfill predefined diagnostic criteria. RESULTS: Using as case definition sweat chloride >60mmol/L or 2 CFTR mutations identified, CF diagnosis was not documented in 2.8, 5.7, 6.5 and 21.6% of subjects in the F, B, NL, and G registries. Restricting CFTR mutation interpretation to 124 CF causing mutations in CFTR2, these numbers rose to 10.5, 10.4, 14.5 and 24.3% respectively. Excluding these subjects impacted on outcomes. The impact differed between countries; the largest changes seen were a decrease in % adults from 51.9 to 47.8% in G, a decrease in % pancreas sufficiency from 17.0 to 13.0 in F, an increase in % homozygous for F508del from 55.3 to 63.7 in NL and a decrease of % with sweat chloride ≤60mmol/L from 8.4 to 1.1 in B. CONCLUSION: CF diagnosis is not documented in 10 to 24% of patients included in CF registries. Excluding these patients for analyses leads to significant changes in outcomes.

Novel de novo large deletion in cystic fibrosis transmembrane conductance regulator gene results in a severe cystic fibrosis phenotype.

We identified c.1521_1523delCTT and c.1679+94_2619+986del8118 in trans in a 6-year-old boy with a severe cystic fibrosis phenotype. The first deletion was inherited maternally, but the latter had arisen de novo.

[Genetic risk markers of low bone mineral density in cystic fibrosis children]. / Genetyczne markery ryzyka wystapienia obnizonej gestosci mineralnej tkanki kostnej u dzieci z mukowiscydoza.

THE AIM OF THE STUDY: Verification of the hypothesis concerning the association between polymorphic variants of the following genes: COLIA1, VDR and CALCR considered to be risk factors of bone metabolism disturbances and decreased bone mineral density (BMD) in children with cystic fibrosis (CF). MATERIAL AND METHODS: Clinical evaluation of CF phenotype progression in 101 patients was assessed according to the Shwachman-Kulczycki score. In the project the best value of forced expiratory volume of one second (FEV1) from the six months before densitometric measurements was used. Evaluation of bone tissue condition parameters was always correlated with the analysis of calcium-phosphate metabolism and bone turnover parameters. Densitometric measurements of L1-L4 lumbar spine were made using Lunar DPX IQ 2898. Age and sex of examined persons were standardized in respect to clinical and biochemical parameters. Molecular analysis was performed in CF patients with the following genotypes: F508del/F508del--55 persons, F508del/m--37 persons, m/m--9 persons. In this project 102 persons formed the control group. Presence of polymorphisms in studied genes was compared with bone tissue parameters. RESULTS: Low bone mineral density (Z-score < -1 SD) was observed in 53.5% patients and in 26.7% of them BMD was below -2 SD. Patients with low BMD had worse BMI, FEV1 and more severe symptoms of CF. Allele T (Ball) in COLIA I and allele C (L447P) in CALCR were found to be more frequent in CF patients than in the control group. Allele C in CALCR gene was associated with reduced bone mass. No significant correlation was found between COLIA1 and VDR polymorphisms and BMD. CONCLUSIONS: Process of bone loss in CF patients starts in early childhood and recurrent respiratory infection, malnutrition and corticosteroid therapy are the main factors disturbing metabolic balance of bone tissue. There is a correlation between bone mass loss in CF patients and the appearance of defined gene alleles of bone metabolism. However, we have to emphasize that this type of study needs confirmation on larger groups of patients.

[On the way to gene therapy in cystic fibrosis]. / Na drodze do terapii genowej mukowiscydozy.

Cystic fibrosis (CF) is the most common recessively inherited lethal disease among the Caucasian population. CF is caused by mutations in the CFTR gene. Although several organs and tracts are affected, severe lung disease is the cause of the most of the morbidity and mortality in CF individuals. Current treatment is aimed at slowing the inevitable progression of lung disease, rather than halting it, or preventing its onset. The isolation of the gene responsible for CF suggested the feasibility of new therapeutic possibilities based on the CFTR gene transfer to CF patients. At present, somatic CF gene therapy clinical trials, using mostly animals but also CF patients, are being conducted. Gene therapy development is restricted by the lack of the appropriate gene vector systems, which could be successfully used to transfer in vivo and protect the therapeutic gene. This is because of the many extracellular, intracellular and immunological barriers, which protect living organisms against invasion of foreign genetic material. Future improvement in gene therapy depends on the more effective ways of the gene transfer methods, creation animal models of the human diseases and development of strategies involved in the new gene construct formulation, which facilitate to control gene transcription activity.

[Genetic markers in the pathogenesis of osteopenia and osteoporosis in cystic fibrosis]. / Genetyczne markery osteopenii i osteoporozy w mukowiscydozie.

Cystic fibrosis (CF) is the most common recessive autosomal disorder in the Caucasian population. Advancements in treatment of CF patients have increased life expectancy from approximately 2 to over 30 years. Complex approach to the health status and management of CF children increased the interest in osteoarticular system pathology in these patients. This particularly concerns osteopenia and osteoporosis. Multiple studies indicate that osteoporosis is a genetic disease in which the phenotype is determined by both environmental and genetic factors and by mutual interactions between them. It is postulated that osteoporosis occurs as the result of mutations and/or polymorphisms in many different genes. The evidence for the genotype-phenotype correlation came from the analysis of mutations and polymorphisms in Collagen Type I Alpha 1 (COL1A1), Vitamin D Receptor (VDR) and Calcitonin receptor (CALCR) genes. Determination of osteoporotic genetic background may lead to better understanding of the pathomechanism of osteoporosis in CF patients and to help further define treatment guidelines.

Analysis of CFTR, SPINK1, PRSS1 and AAT mutations in children with acute or chronic pancreatitis.

OBJECTIVES: Defects of PRSS1, SPINK1, CFTR and AAT are considered causative or predisposing to pancreatitis. The aim of this study was to evaluate the impact of these defects into molecular pathology of chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP). METHODS: Ninety-two children with CP or ARP, 55 family members and 50 controls were investigated. The subjects were screened for PRSS1 mutations: R122H, R122C, A16V, N29I; SPINK1 N34S variant; panel of 14 CFTR defects: INNOLiPA CFTR12, CFTRdele2,3 and IVS8-T variant or panel of 3 CFTR defects-F508del, CFTRdele2,3 and IVS8-T; AAT mutations: E264V, E342K. RESULTS: We identified 1 mutated allele in at least 1 of 4 genes in 31 of 92 patients and 12 of 50 controls (P = 0.157). Mutations in SPINK1 and PRSS1 were most frequent. PRSS1 mutations were identified mainly in CP patients (9.6% of CP vs 2.5% of ARP alleles, P = 0.094), whereas N34S SPINK1 mutation was present with comparable frequency in CP and ARP patients (7.7% vs 10.0%, P = 0.768). The frequency of mutations in CFTR alleles was similar to controls (4.9% vs 5%, P = 0.587). Overall frequency of AAT mutations was lower than in the controls. Family studies showed that defects in the examined genes did not always segregate with disease. CONCLUSIONS: PRSS1 defects seem to be causative for pancreatitis, whereas defects in SPINK1 are suggested to be associated with the disease. No association between CFTR mutations and pancreatitis was observed. The importance of AAT variants remains speculative.