Cluster of cystic fibrosis cases in a limited area of Brittany (France)

Cystic fibrosis in the northern sector of the French "département" of Finistère is 1:1787 live births. Within this sector a concentration of the disease was found in a small area. The minimal frequency in this area, from 1946 to 1972, was calculated as 1 per 377 live births, the gene frequency being 0.0515. Genealogic analysis, going back to the beginning of the 18th century, showed a relationship between 8 of the 10 families to which the patients belonged. The origin of the deleterious genes may be explained by at least five primary ancestral couples living in the 18th century. Random drift is the most probable explanation for the concentration of cystic fibrosis in this region.     

Reproductive behavior of individuals with increased risk of having a child with retinoblastoma

To investigate reproductive behavior of individuals at increased risk of having a child with retinoblastoma (Rb), we conducted a cross-sectional questionnaire survey among 118 counselees visiting the Clinical Genetics Department of the National Rb Center in the Netherlands. The recurrence risk for counselees ranged from <1% to 50%. The response rate was 69%. Of 43 respondents considering having children after becoming aware of their increased risk, Rb influenced reproductive behavior for 25 (58%), of whom 14 had a recurrence risk <3%. Twenty of these 25 decided against having more children and 5 used prenatal diagnosis. Eighteen of the 43 respondents did not use any of the alternative reproductive options and had children (or more children), although half indicated having had doubts about their decisions. Multiple logistic regression showed that only perceived risk (p = 0.003) was significantly associated with Rb influencing reproductive behavior. Of 17 respondents planning children (or more children), 11 (65%) considered using one of the alternative reproductive options. We conclude that reproductive behavior is greatly influenced by Rb and that perceived risk, not objective risk, is the most important factor of influence. It is important to offer individuals at increased risk continued access to genetic counseling, even when this risk is small.     

Parents' perspective on having a child with Down Syndrome in France

In 2011, Skotko, Levine, and Goldstein asked parents who had children with Down Syndrome (DS) in the United States how they felt about having a child with DS. The purpose of the present study was to ask the same questions to parents living in France so that this information could be shared with new and expectant parents. The results were also compared to the findings of Skotko, Levine, and Goldstein (2011a) to see whether some parental feelings might be universally shared and to discuss the differences observed. This web‐based survey was shared with a number of DS organizations and online DS communities. Of the 369 respondents living in France, 99% indicated that they loved their son or daughter with DS; 98% were proud of their child with DS; 78% felt that their outlook on life was more positive because of their son or daughter with DS; 12% felt embarrassed by their child with DS; and 7% expressed regret for having a child with DS. A significant number of respondents admitted that raising a child with DS was not without challenges. Nevertheless, most respondents indicated that their son or daughter with DS had had a positive impact on their life and that of their family and that they were happy to have their child.     

Screening for cystic fibrosis mutations in southern France: identification of a frameshift mutation and two missense variations.

In the search for mutations in the cystic fibrosis gene in patients from the Mediterranean area, we have analysed exons 4, 9, 10, 19, and 21 by the single-strand conformation polymorphism (SSCP) technique in 50 patients with at least one non-delta F508 chromosome. Ten samples demonstrated a shifted band, four in exon 19 and six in exon 21. Sequencing of the PCR fragments has led to the identification of three new sequence alterations, two in exon 19 (3737 delA and I1234V), and one in exon 21 (N1303H). We also analysed the frequency of two known intronic polymorphisms in front of exon 19 (C to A change at nucleotide 3601-65) and exon 21 (G to A change at position 4006-200).     

Cystic fibrosis with homozygous R553X mutation in a Taiwanese child

It has been reported that cystic fibrosis is very rare in Asians, and its clinical expression and genetic mutations are different from those found in Caucasians. We report the case of a boy who had chronic diarrhea with failure to thrive and frequent respiratory tract infections beginning at the age of 2 months. He developed bronchiectasis with chronic severe hypoxemia and pancreatic insufficiency by the age of 3 years and 5 months, which raised the consideration of cystic fibrosis. DNA analysis revealed a homozygous R553X mutation, and both his parents were subsequently proven to be R553X carriers. This case is the first report in a Taiwanese with cystic fibrosis attributable to a mutation commonly seen in Caucasians. However, the age of onset was much younger and the clinical course was more severe than those associated with Western patients. We reviewed the eight reported Taiwanese patients with cystic fibrosis, including the present case. We believe that the incidence of cystic fibrosis in Taiwan may be underestimated. Both genetic and environmental factors may play a role in the phenotypic disparity between Asians and Caucasians.     

Renin-like (angiotensinogenase) activity in sweat of patients with cystic fibrosis and controls

Summary Using bioassay method (rat blood pressure technique) as well as the radioimmunoassay, renin-like activity (RLA) was measured in eccrine sweat of patients with cystic fibrosis of the pancreas (CF) and of controls. Sweat-formation was induced by pilocarpine-iontophoresis or by local injection of carbamylcholine (Doryl®). RLA-values between 0 (not measurable) and 460 ng/ml·h were measured. With increasing sweat flow-rate a tendency to lower RLA-values was detected. No significant difference was observed between CF and controls. From the observation that RLA of sweat is up to 30 times higher than that of plasma, it is concluded that RLA is probably released not from plasma but from the sweat glands themselves, where it is stored or synthesized.This work was supported by the Deutsche Forschungsgemeinschaft     

Prenatal diagnosis of cystic fibrosis by using linked DNA markers in 138 pregnancies at l-in-4 risk

Prenatal diagnosis was carried out in 138 pregnancies at 1-in-4 risk for cystic fibrosis (CF) by using closely linked DNA markers, including XV-2c and KM-19. In fully informative families, 25 of 123 (20%) fetuses were predicted to be affected; 16 of these 25 pregnancies were terminated and 9 were continued. Postnatal sweat tests are completed in 42 cases; the diagnoses were confirmed in 4 of 4 infants predicted to be affected and in 37 of 38 infants predicted to be unaffected. One infant predicted to be a carrier had an abnormal sweat test after birth, but the mother also had an abnormal sweat test, and there was no evidence of an error in linkage analysis. The data indicate that prenatal diagnosis using linkage analysis is fully informative in most families and is highly reliable with either chorionic villus sampling or amniocentesis. Although Outcome data are available on only 42 pregnancies, based on our experience, on general principles of linkage of the known DNA markers with CF we recommend that DNA analysis replace microvillar intestinal enzyme analysis for 1-in-4 risk pregnancies when DNA is available from the propositus.     

Factors associated with mucoid transition of Pseudomonas aeruginosa in cystic fibrosis patients

Although the mucoid form of Pseudomonas aeruginosa (Pa) is largely responsible for the progression of lung disease in cystic fibrosis (CF), the relationship between factors relating daily-care regimes to mucoidy acquisition are as yet poorly investigated. Fifty-two CF patients registered at the CF centre of Dijon, France, were retrospectively evaluated from the date of Pa colonization either to the first -positive sputum culture for mucoid Pa (n = 26) or to the last culture in which the Pa remained non-mucoid (n = 26). All clinical, pathological and therapeutic events were recorded. The association between the parameters collected and mucoid transition of Pa was assessed in a Cox model with time-dependant covariables. The mean follow-up was 4.7 ± 4.3 years. Three independent parameters were associated with the higher risk of mucoid transition of Pa: persistence of Pa in sputum (OR 7.89; p <0.01), use of inhaled bronchodilators (OR 3.40; p = 0.04), and the use of inhaled colimycin (OR 4.04; p = 0.02). Isolation of Staphylococcus aureus, Haemophilus influenzae or Streptococcus pneumoniae in sputum was associated with a lower risk (OR 0.24; p < 0.01). Mucoid transition of Pa was associated with variables that reflected the severity of both lung disease and Pa colonization. Although they do not lead to prophylactic measures, these results corroborate the need to avoid Pa persistence.     

Prevalence and dynamics of Lactobacillus sp. in the lower respiratory tract of patients with cystic fibrosis

No prevalence or dynamics analysis of Lactobacilli in the lung of cystic fibrosis (CF) patients has yet been conducted. In order to use them as probiotics in the treatment of Pseudomonas aeruginosa infection, we describe their lung epidemiology.Over a period of 8 months, we analyzed 279 sputum samples from 124 CF patients classified according to their P. aeruginosa Leeds status of colonization. A total of 137 strains belonging to 11 species were isolated. The prevalence of carriage was 61%. No difference in species diversity or frequency was observed according to Leeds criteria. The next step will be to focus on the strain level.     

Phage therapy against Achromobacter xylosoxidans lung infection in a patient with cystic fibrosis: a case report

Respiratory infections can lead to serious complications in CF patients, especially when infected with antibiotic resistant bacteria. Alternative treatments for these infections are being sought out to help address this problem. We present a clinical case of a cystic fibrosis (CF) patient, with multi-drug resistant (MDR) Achromobacter xylosoxidans chronic lung infection who was successfully managed with bacteriophage therapy.     

Direct sputum analysis of Pseudomonas aeruginosa macrorestriction fragment genotypes in patients with cystic fibrosis

The distribution of bacterial populations in the airways of 13 patients with cystic fibrosis who were colonized for 6 – 23 years with Pseudomonas aeruginosa was investigated by genotyping of bacterial chromosomes directly isolated from 21 sputa. After removal of host material from sputum by hypotonic cell lysis and repetitive washing and centrifugation steps, agarose-embedded bacterial cells were lysed, residual eukaryotic DNA separated by field inversion gel electrophoresis, and the purified bacterial chromosomes subjected to macrorestriction fragment pattern and Southern analyses. Bacterial populations consisted of a single P. aeruginosa clone in 17 sputa, of which more than one clonal variant was apparent in two SpeI fragment fingerprints. Two clones of P. aeruginosa and another species co-existed in four samples. Genomically homogeneous populations of P. aeruginosa are characteristic for chronically colonized lungs in most cases of cystic fibrosis. Received: 25 April 1997     

Linkage relationships of paraoxonase (PON) with other markers: indication of PON-cystic fibrosis synteny

The linkage relationships of the serum arylesterase paraoxonase (PON) was examined in our Danish material of normal families and in Danish and English cystic fibrosis families. Highest lod scores were found between PON and cystic fibrosis. The combined lod score for this relationship was z = 2.69 at theta = 0.07 in males and theta = 0.00 in females. When scored in accordance with a tentative three allele model for PON, the score was z = 3.70 at the same theta values. Linkage studies for PON against 64 other polymorphic marker systems did not give any lod score above +1.3 and PON still remains chromosomally unassigned. By the present screening about 2/3 of the genome could tentatively be excluded as the region of PON and cystic fibrosis.     

Screening for CF mutations in adult cystic fibrosis patients with a directed and optimized SSCP strategy

Twenty adolescent and adult cystic fibrosis (CF) patients have been studied for the presence of mutations in the CFTR gene. Mutations other than deltaFSOS have been detected by comparison to the single-stranded conformation polymorphism (SSCP) pattern of known mutations in eight exons, in which 80% of the more common mutations are present. Each mutation was confirmed by direct sequencing. For each of the analyzed exons, optimal SSCP conditions have been determined that allow all available known mutations in that exon to be distinguished from each other. This approach allowed mutations to be defined in 75% of the non deltaF508 alleles and 92% of all CF alleles in this cohort. © 1994 Wiley-Liss, Inc.     

Inquilinus limosus isolated from a patient with chronic cystic fibrosis. First report in Mexico and evidence that co-infection with Pseudomonas aeruginosa promotes the accelerated and increased formation of extracellular neutrophil traps

Cystic fibrosis is characterized by abnormal mucous secretions in the lungs that favor the proliferation of colonizing bacteria, with Pseudomonas aeruginosa and Staphylococcus aureus being the most isolated, however, other less known species could also have an impact on the health of the patient. Here we demonstrate the isolation and antibiotic resistance profiles of Inquilinus limosus, a rarely reported multidrug resistant bacterium, and compare them to a co-infectant strain of Pseudomonas aeruginosa. Likewise, we found that co-infection with both bacteria promotes increased formation of neutrophil extracellular traps, which can have an impact on the disease severity and make treatment difficult.     

Does a primary host defense abnormality involving monocytes-macrophages underlie the pathogenesis of lung disease in cystic fibrosis?

The primary cause of morbidity and mortality in cystic fibrosis (CF) patients is chronic pulmonary disease. Pulmonary disease in CF is characterized in part by: (a) obstruction of the bronchi and bronchioles by inspissated secretions (mucus is hypersecreted and may also be abnormal), (b) recurrent or persistent bacterial infections, and (c) a chronic inflammatory state. We propose herein that much of the pathophysiology of lung disease in CF stems from a genetically inherited metabolic defect in monocyte-macrophages (M-MØ), and we review evidence which indicates that CF M-MØ are innately metabolically abnormal. Once activated by various stimuli, CF M-MØ become metabolically hyperactive and hypersecretory as evidenced by the production of excessive levels of a variety of mediators which could have definite roles in both the initiation of pulmonary obstruction and the accelerated development of a chronic inflammatory response in CF. Evidence is also reviewed which indicates that other CF M-MØ functions crucial to the afferent and efferent phases of the immune response to bacterial infections in the lung may be adversely affected. Mechanisms proposed to explain the abnormal production of mediators by CF M-MØ are discussed, and it is concluded that hyperproduction of mediators by CF M-MØ and their metabolic hyperactivity probably result from a defect in autoregulation. The nature of the metabolic defect in CF M-MØ indicates that CF should be classified as a “new” primary host defense abnormality or alternatively as a “new” primary immune deficiency disease.     

Nine mutations in the cystic fibrosis (CF) gene account for 80% of the CF chromosomes in French patients

Thirteen mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been screened in a French sample of 185 cystic fibrosis (CF) patients, together with their respective associated RFLP haplotypes at the linked D7S23 locus (XV2C and KM19 markers). The respective frequencies of the mutations showed that 9 of them account for 80% of the CF chromosomes. Implications for prenatal diagnosis and heterozygote detection are defined and discussed. The well-known great excess of RFLP B marker within CF chromosomes is partially explained by two already characterized mutations highly associated with haplotype B: delta F508 and G542X. Similarly, the excess of haplotype D within CF chromosomes is partially explained by the association between delta I507 and this haplotype. These results may suggest the existence of two still untested or uncharacterized mutations, whose frequencies could be near 1%, one which would be associated with haplotype B and a second which would be associated with haplotype D. The possible cause of the specific association between most of the main different CF mutations and the RFLP haplotype B is discussed.     

Detection of more than 94% cystic fibrosis mutations in a sample of belgian population and identification of four novel mutations

We have analysed 194 Belgian CF chromosomes using a variety of techniques: ΔF508 was detected by polyacrylamide gel electrophoresis; dot blotting of PCR products was used to identify the mutations G542X, 1717-1 G → A, and N1303K; molecular defects in exons 2, 3, 4, 5, 6b, 7, 11, 12, 13, 14a, 14b, 17b, 19, 20, and 21 were screened for by DGGE. We identified 17 mutations, which accounted for 94.3% of the Belgian CF chromosomes. Four novel mutations and a novel polymorphism were characterized. The detection of such a high proportion of Belgian CF mutations is important in understanding the functional role of the molecule and in improving prenatal and genetic diagnosis of CF. © 1993 Wiley-Liss, Inc.