Formerly known as cystic fibrosis of the pancreas, this entity has increasingly been labeled simply 'cystic fibrosis.' Manifestations relate not only to the disruption of exocrine function of the pancreas but also to intestinal glands (meconium ileus), biliary ... Formerly known as cystic fibrosis of the pancreas, this entity has increasingly been labeled simply 'cystic fibrosis.' Manifestations relate not only to the disruption of exocrine function of the pancreas but also to intestinal glands (meconium ileus), biliary tree (biliary cirrhosis), bronchial glands (chronic bronchopulmonary infection with emphysema), and sweat glands (high sweat electrolyte with depletion in a hot environment). Infertility occurs in males and females. For discussion of a phenotype consisting of bronchiectasis with or without elevated sweat chloride caused by mutation in the genes encoding the 3 subunits of the epithelial sodium channel, see BESC1 (211400).
Boue et al. (1986) reported on prenatal diagnostic studies in 200 pregnancies with a presumed 1-in-4 risk of recurrence of cystic fibrosis. The method involved measurement of total enzymes and isoenzymes of gamma-glutamyl-transpeptidase, aminopeptidase M, and alkaline phosphatase ... Boue et al. (1986) reported on prenatal diagnostic studies in 200 pregnancies with a presumed 1-in-4 risk of recurrence of cystic fibrosis. The method involved measurement of total enzymes and isoenzymes of gamma-glutamyl-transpeptidase, aminopeptidase M, and alkaline phosphatase in amniotic fluid in the second trimester. The recurrence rate of cystic fibrosis was 22.5% in 147 cases in which the index case had cystic fibrosis without meconium ileus at birth but was 47.5% when the index case had meconium ileus. The authors speculated on the mechanism of the 50% recurrence rate and favored the view that 1 parent was in fact a homozygote for a mild allele. With use of their method, the authors suggested 98% accuracy in prenatal diagnosis of cystic fibrosis. Allan et al. (1981), Super (1987), and Boue et al. (1986) found that in families in which a CF child did not have meconium ileus the observed recurrence rate agreed with the expected 1-in-4 risk, but that in families with a history of meconium ileus in the index case the recurrence rate was much higher, 43.7% in the study of Boue et al. (1986). Mornet et al. (1989) found different haplotype associations in the 2 types of families. A distortion of the segregation ratio was suggested to explain the high recurrence rate. Estivill et al. (1987) pointed out that individuals with haplotypes A and C as determined by their cosmid library, whether homozygous or heterozygous, have a considerably reduced risk of being carriers as compared to the 1 in 20 average risk in the British population. On the other hand, a homozygote for haplotype B had a risk of about 1 in 7 of being a carrier. It appears that about 85% of cases of CF in northern Europeans have 1 particular haplotype and the rest a second haplotype. CF with or without meconium ileus may be different entities. Baxter et al. (1988) stated that the meconium ileus form of CF is often lethal so that families with this form are underrepresented in linkage studies. On the other hand, couples who seek prenatal diagnosis often have had children with this problem. Harris et al. (1988) found that 30 of 37 British CF families were sufficiently informative with 3 RFLP probes to enable prenatal diagnosis. They also used linkage analysis to exclude CF in 2 cases in which diagnosis of the disease was equivocal in the sib of an affected child. Strain et al. (1988), Krawczak et al. (1988), and Beaudet et al. (1989) discussed the use of linkage disequilibrium between CF and DNA markers in genetic risk calculation. Handyside et al. (1992) achieved preimplantation diagnosis. In vitro fertilization techniques were used to recover oocytes from each of 3 women and fertilize them with the husband's sperm. Both members of the 3 couples carried the delF508 mutation. Three days after insemination, embryos in the cleavage stage underwent biopsy with removal of 1 or 2 cells for DNA amplification and analysis. In 2 of the women the oocytes produced noncarrier, carrier, and affected embryos. Both couples chose to have 1 noncarrier embryo and 1 carrier embryo transferred. One woman became pregnant and gave birth to a girl free of the deletion in both chromosomes. Curnow (1994) used cystic fibrosis to illustrate how, in genetic counseling, one can calculate carrier risk for recessive diseases when not all the mutant alleles are detectable. Dean (1995) reviewed the 5 main methods used for detecting mutations at the time. Savov et al. (1995) demonstrated the presence of 2 different mutations carried by the same CF allele in 4 out of 44 Bulgarian CF patients during a systematic search of the entire coding sequence of the CFTR gene. Two of the double mutant alleles include 1 nonsense and 1 missense mutation, and although the nonsense mutation could be considered to be the main defect, the amino acid substitutions are candidates for disease-causing mutations as well. Savov et al. (1995) suggested that double mutant alleles may be more common than expected and could account for some of the problems in phenotype-genotype correlations. Stern (1997) reviewed the diagnosis of cystic fibrosis. He presented a table of conditions, all readily distinguishable from cystic fibrosis, that can cause moderately elevated sweat electrolytes. With mutation analysis, in approximately 1% of cases no abnormal gene can be found and in about 18% more only 1 abnormal gene will be identified. Stern (1997) pointed out, however, that even if both genes were abnormal, the patient could have an ameliorating or neutralizing second mutation elsewhere. For example, patients homozygous for delF508 (602421.0001) have normal sweat electrolyte concentrations if a second mutation, R553Q (602421.0121), is also present. - Screening Under the chairmanship of Beaudet and Kazazian (1990), a workshop at the National Institutes of Health laid down guidelines concerning screening for the cystic fibrosis gene. The following points were emphasized: screening should be voluntary, and confidentiality must be assured; screening requires informed consent; providers of screening services have an obligation to ensure adequate education and counseling; quality control in all aspects of testing is required; and there should be equal access to testing. Newborn babies with CF have abnormally high levels of immunoreactive trypsin (IRT) in serum, which has been the basis for a screening test. Hammond et al. (1991) reported on the results of a Colorado statewide test of the feasibility and efficacy of measuring immunoreactive trypsinogen in blood spots to screen for neonatal cystic fibrosis. They found an incidence of cystic fibrosis of 1 in 3,827 (0.26 per 1,000), with 3.2 newborns per 1,000 requiring repeat measurements. When adjusted for race and compliance with testing, the incidence among the white infants (1 in 2,521) was close to the expected incidence. They concluded that screening was feasible and could be implemented with acceptable rates of repeat testing and false positive and false negative results. Laroche and Travert (1991) found 9 F508 deletion heterozygotes among 149 infants with neonatal transitory mild hypertrypsinemia. Dumur et al. (1990) found an increased frequency of heterozygosity for the same mutation in adults with chronic bronchial hypersecretion. Observing that many patients with cystic fibrosis are malnourished by the time the diagnosis is made, Farrell et al. (1997) sought to determine whether newborn screening and early treatment might prevent the development of nutritional deficiency. A total of 650,341 newborn infants were screened by measuring immunoreactive trypsinogen on dried blood spots (from April 1985 through June 1991) or by combining the trypsinogen test with DNA analysis (from July 1991 through June 1994). Of 325,171 infants assigned to an early-diagnosis group, cystic fibrosis was diagnosed in 74 infants, including 5 with negative screening tests. Excluding infants with meconium ileus, Farrell et al. (1997) evaluated nutritional status for up to 10 years by anthropometric and biochemical methods in 56 of the infants who received an early diagnosis and in 40 of the infants in whom the diagnosis was made by standard methods (the control group). Pancreatic insufficiency was managed with nutritional interventions that included high-calorie diets, pancreatic enzyme therapy, and fat-soluble vitamin supplements. The diagnosis of cystic fibrosis was confirmed by a positive sweat test at a younger age in the early-diagnosis group than in the control group (mean age, 12 vs 72 weeks). At the time of diagnosis, the early-diagnosis group had significantly higher height and weight percentiles and a higher head circumference percentile. The early-diagnosis group also had significantly higher anthropometric indices during the follow-up, especially the children of pancreatic insufficiency and those who were homozygous for the delta-F508 mutation. Dankert-Roelse and te Meerman (1997) raised the question of whether the time had not arrived for adoption of routine neonatal screening for cystic fibrosis. Farrell et al. (2001) reported findings of the continuation of their longitudinal study of children with CF detected by neonatal screening or standard clinical methods (control). Because sequential analysis of nutritional outcome measures revealed significantly better growth in screened patients, the authors accelerated the unblinding of the control group and identified 9 additional CF patients. After each member of this cohort had been enrolled for at least 1 year, Farrell et al. (2001) performed another statistical analysis of anthropometric indices. They found that severe malnutrition persisted after delayed diagnosis of CF and questioned whether catch-up growth is possible. Muller et al. (1998) studied 209 fetuses with hyperechogenic bowel diagnosed at routine ultrasonography and with no family history of cystic fibrosis. Seven of the 209 fetuses (3.3%) were subsequently given the diagnosis of cystic fibrosis. Muller et al. (1998) pointed out that this incidence is 84 times the estimated risk of cystic fibrosis in the general population, and concluded that screening for cystic fibrosis should be offered to families in which fetal hyperechogenic bowel is diagnosed at routine ultrasonography. Boyne et al. (2000) demonstrated that of 88 neonates with transient hypertrypsinemia shown to carry a delta-F508 mutation, 20 (22%) carried a second CFTR mutation. In 45% of cases, the second mutation was R117H (602421.0005). Forty-one percent of delta-F508 heterozygous neonates with greater than 25 ng IRT/ml in the 27th day blood sample possessed a second mutation, compared to approximately 6% of those with less than 25 ng/ml. Boyne et al. (2000) concluded that the IRT level at 27 days is a useful marker to refine the risk of finding a second CFTR mutation in delta-F508 heterozygotes with hypertrypsinemia. Castellani et al. (2001) studied 47 neonates with hypertrypsinemia and normal sweat chloride. Thirty-two of the newborns had 1 identified CFTR mutation. Further analysis by DGGE identified additional mutations in 14 of the 32 babies in whom a mutation had previously been found. In 1 case, 2 more CFTR gene mutations were identified. Mutations were identified in 8 of the 15 babies in whom a mutation had previously not been identified. Castellani et al. (2001) pointed out that it is impossible to predict the clinical outcome of these newborns and suggested that in some cases these findings might represent CFTR-related disease even in the presence of normal sweat chloride. They therefore advocated close clinical follow-up of neonates in this group. Scotet et al. (2002) evaluated the prenatal detection of CF by ultrasound in more than 346,000 pregnancies in Brittany, France, where the incidence of CF is very high. The authors found that the incidence of CF in fetuses with echogenic bowel was 9.9%, significantly higher than in the general population. Only severe mutations were identified in these fetuses. The ultrasound examination enabled diagnosis of 11% of affected fetuses. Scotet et al. (2002) concluded that CF screening based on ultrasound examination is effective, particularly in populations where the disease is frequent. Dequeker et al. (2009) provided an update on the best practice guidelines for the molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders, as established at a 2006 conference in Manchester, U.K. The report included methods for CFTR mutation testing, indications for CFTR testing, and guidelines for interpretation. De Becdelievre et al. (2011) reported on an 18-year experience of documenting comprehensive CFTR genotypes and correlations with ultrasound patterns in a series of 694 cases of fetal bowel anomalies. A total of 30 CF fetuses and 8 cases compatible with CFTR-related disorders were identified. CFTR rearrangements were found in 5 of the 30 CF fetuses. A second rare mutation indicative of CF was found in 21.2% of fetuses carrying a frequent mutation. The frequency of CF among fetuses with no frequent mutation was 0.43%. Correlation with ultrasound patterns revealed a significant frequency of multiple bowel anomalies in CF fetuses. The association of at least 2 signs of bowel anomaly on ultrasound, including hyperechogenic bowel, loop dilatation, and/or nonvisualization of gallbladder, was observed in 14 of 30 CF fetuses (46.7%) as compared with 61 of 422 (14.5%) non-CF fetuses (P less than 10(-3)). The rare triad of hyperechogenic bowel, loop dilatation, and nonvisualization of the gallbladder was of the highest diagnostic value, with a likelihood ratio of 31.40. Fetuses demonstrating this triad of bowel anomalies should have extensive CFTR sequencing and a search for rearrangements, even if no common mutation is detected.
The mildest extreme of CF is represented by patients not diagnosed until middle age (Scully et al., 1977). The phenotypic variability in CF was analyzed by Sing et al. (1982). In an inbred kindred in North Carolina, a ... The mildest extreme of CF is represented by patients not diagnosed until middle age (Scully et al., 1977). The phenotypic variability in CF was analyzed by Sing et al. (1982). In an inbred kindred in North Carolina, a mild form of cystic fibrosis was described by Knowles et al. (1989). There was 1 instance of mother-daughter involvement, the mother being related to her husband. One of the presumed homozygotes was a 62-year-old woman. Another was her 52-year-old sister, the mother of the affected proposita. The daughter was an intensive care nurse, the mother of a normal daughter. Manifestations in the family were predominantly pulmonary; pancreatic exocrine insufficiency was not a conspicuous feature, especially in the older patients. The 2 subgroups defined by the A and C haplotypes of polymorphisms closely linked to the CF locus on chromosome 7, reported by Estivill et al. (1987), have clinical differences in terms of the frequency of meconium ileus, pseudomonas infections, and pancreatic disease (Woo, 1988). Gasparini et al. (1990) described a RFLP DNA marker closely linked to the CF locus which showed an allelic correlation with severity of the disorder: the genotype 2/2 was associated with severe disease; the genotype 1/2 was overrepresented in patients with very mild clinical manifestations, including pancreatic insufficiency, absence of meconium ileus, and absence of Pseudomonas colonization. - Meconium Ileus Allan et al. (1981) showed that sibs tend to show recurrence of meconium ileus as a feature of cystic fibrosis. The distal intestinal obstruction syndrome is a 'meconium ileus equivalent' that occurs in adolescents and adults with CF. It is the consequence of the abnormally viscid mucofeculant material in the terminal ileum and right colon, where the fecal stream is normally liquid.Typical features are recurrent episodes of RLQ pain with palpable mass in the right iliac fossa. Symptoms are exacerbated by eating. Mornet et al. (1988) determined the haplotype associated with cystic fibrosis in 41 families using 4 DNA probes, all of which are tightly linked to the CF gene. In 17 of the families an affected child had meconium ileus, and in the other 24 families there was a child without meconium ileus. A different haplotype was associated with the 2 types of families, suggesting that multiple allelism, i.e., different mutations at the same locus, accounts for CF with or without meconium ileus. - Liver Disease Gaskin et al. (1988) found that 96% of patients with cystic fibrosis and evidence of liver disease had biliary tract obstruction, usually a stricture of the distal common bile duct. All patients without liver disease had normal intrahepatic and common-duct excretion of tracer. Bilton et al. (1990) described a case of cystic fibrosis complicated by common bile duct stenosis. Gabolde et al. (2001) showed that the presence of cirrhosis in patients with cystic fibrosis is significantly associated with either homozygous or compound heterozygous mutations in the MBL2 gene (154545), which encodes mannose-binding lectin (MBL). The authors compared 216 patients homozygous for the delta-F508 mutation (602421.0001) and found that 5.4% of those homozygous or compound heterozygous for wildtype mannose-binding lectin had cirrhosis, while 30.8% of those homozygous or compound heterozygous for mutant alleles had cirrhosis (p = 0.008). Approximately 3 to 5% of patients with cystic fibrosis develop severe liver disease defined as cirrhosis with portal hypertension. Bartlett et al. (2009) performed a 2-stage case control study enrolling patients with CF and severe liver disease with portal hypertension from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America. In the first stage, 124 patients with CF and severe liver disease, enrolled between January 1999 and December 2004, and 843 control patients without CF-related liver disease (all assessed at greater than 15 years of age) were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the 2 genes that were positive from the first stage were tested in an additional 136 patients with CF-related liver disease, enrolled between January 2005 and February 2007, and in 1,088 with no CF-related liver disease. The combined analysis of the initial and replication studies by logistic regression showed CF-related liver disease to be associated with the SERPINA1 Z allele (107400.0011) (odds ratio = 5.04; 95% confidence interval, 2.88-8.83; p = 1.5 x 10(-8)). Bartlett et al. (2009) concluded that the SERPINA1 Z allele is a risk factor for liver disease in CF. Patients carrying the Z allele are at greater risk (odds ratio = approximately 5) of developing severe liver disease with portal hypertension. - Pancreatic Insufficiency Approximately 15% of CF patients do not have pancreatic insufficiency, i.e., are 'pancreatic sufficient.' Kerem et al. (1989) performed linkage disequilibrium and haplotype association studies of patients in 2 clinical subgroups, one pancreatic insufficient (PI) and the other pancreatic sufficient (PS). Significant differences were found in allelic and haplotype distributions in the 2 groups. The data suggested that most of the CF-PI patients were descendants of a single mutational event at the CF locus, whereas the CF-PS patients resulted from multiple, different mutations. Corey et al. (1989) commented on the intrafamilial concordance for pancreatic insufficiency in CF. Devoto et al. (1989) studied the allele and haplotype frequencies of 5 polymorphic DNA markers near the CF locus in 355 CF patients from Belgium, the German Democratic Republic, Greece, and Italy who were divided into 2 groups according to whether or not they were taking supplementary pancreatic enzymes. The distributions of alleles and haplotypes revealed by 2 of the probes were always different in patients with or without pancreatic insufficiency in all the populations studied. In the case of 1 haplotype that was present in 73% of all the CF chromosomes in their sample, they found homozygosity in only 28% of patients without pancreatic insufficiency as contrasted with 64% who were homozygous and had pancreatic insufficiency. Like other workers, they concluded that this indicated that pancreatic insufficiency and sufficiency are associated with different mutations at the CF locus. Ferrari et al. (1990) studied the distribution of haplotypes based on 8 polymorphic DNA markers linked to CF in 163 Italian patients and correlated the findings with clinical presentation. Among 19 pancreatic sufficient patients, 6 (31.6%) showed at least 1 copy of a rare phenotype which was present in only 16 of 138 patients (11.6%) with pancreatic insufficiency. In addition, only 5 pancreatic sufficient patients were homozygous for the common 2,1 haplotype as compared with 88 patients (63.8%) with pancreatic insufficiency. Kristidis et al. (1992) likewise found intrafamilial consistency of the pancreatic phenotype, whether pancreatic sufficient or insufficient. Furthermore, the PS phenotype occurred in patients who had 1 or 2 mild CFTR mutations, such as arg117-to-his (602421.0005), arg334-to-trp (602421.0034), arg347-to-pro (602421.0006), ala455-to-glu (602421.0007), and pro574-to-his (602421.0018), whereas the PI phenotype occurred in patients with 2 severe alleles, such as phe508-to-del (602421.0001), ile507-to-del (602421.0002), gln493-to-ter (602421.0003), gly542-to-ter (602421.0009), arg553-to-ter (602421.0014), and trp1282-to-ter (602421.0022). Borgo et al. (1993) commented on the phenotypic intrafamilial heterogeneity displayed by an Italian family in which 3 sibs, 2 of whom were dizygotic twins, were compound heterozygotes for the delF508 (602421.0001) and the 1717,-1,G-A splicing mutation (602421.0008). While close intrafamilial concordance was found for exocrine pancreatic phenotype, the pulmonary phenotype varied widely. They suggested that interaction of the CFTR protein with tissue-specific proteins or the action of modifier loci (which may be operationally identical possibilities) plays a role in intrafamilial variability. Barreto et al. (1991) concluded that the father of a girl with severe CF also had CF but was mildly affected. The child was homozygous for the delta-F508 mutation associated with haplotype B; the father was a compound heterozygote for this mutation and a second CF mutation associated with haplotype C. Perhaps it should not be surprising that some patients with cystic fibrosis have no pancreatic lesions (Oppenheimer, 1972). Sharer et al. (1998) and Cohn et al. (1998) demonstrated that heterozygosity for CFTR mutations can lead to 'idiopathic' chronic pancreatitis, especially when the mutation is associated with the 5T allele of the variable number of thymidines in intron 8 of the CFTR gene. - Pulmonary Disease Pier et al. (1996) provided an experimental explanation for the susceptibility of CF patients to chronic Pseudomonas aeruginosa lung infections. They found that cultured human airway epithelial cells expressing the delta-F508 allele of the CFTR gene were defective in uptake of P. aeruginosa compared with cells expressing the wildtype allele. P. aeruginosa lipopolysaccharide-core oligosaccharide was identified as the bacterial ligand for epithelial cell ingestion; exogenous oligosaccharide inhibited bacterial ingestion in a neonatal mouse model, resulting in increased amounts of bacteria in the lungs. The authors concluded that CFTR may normally contribute to a host-defense mechanism that is important for clearance of P. aeruginosa from the respiratory tract. Ernst et al. (1999) identified unique lipopolysaccharide structures synthesized by P. aeruginosa within CF patient airways. P. aeruginosa synthesized lipopolysaccharide with specific lipid A structures, indicating unique recognition of the CF airway environment. CF-specific lipid A forms containing palmitate and aminoarabinose were associated with resistance to cationic antimicrobial peptides and increased inflammatory responses, indicating that they are likely to be involved in airway disease. Because mannose-binding lectin (MBL), encoded by the MBL2 gene (154545), is a key factor in innate immunity, and lung infections are a leading cause of morbidity and mortality in CF, Garred et al. (1999) investigated whether MBL variant alleles, which are associated with recurrent infections, might be risk factors for CF patients. In 149 CF patients, different MBL genotypes were compared with respect to lung function, microbiology, and survival to end-stage CF (death or lung transplantation). The lung function was significantly reduced in carriers of MBL variant alleles when compared with normal homozygotes. The negative impact of variant alleles on lung function was especially confined to patients with chronic Pseudomonas aeruginosa infection. Burkholderia cepacia infection was significantly more frequent in carriers of variant alleles than in homozygotes. The risk of end-stage CF among carriers of variant alleles increased 3-fold, and the survival time decreased over a 10-year follow-up period. Moreover, by using a modified life table analysis, Garred et al. (1999) estimated that the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes. Davies et al. (2000) found that MBL binds to Burkholderia cepacia, an important pathogen in patients with CF, and leads to complement activation, but that this was not the case for Pseudomonas aeruginosa, the more common colonizing organism in CF. Davies et al. (2000) suggested that patients with CF and mannose-binding lectin deficiency would be at a particularly high risk of B. cepacia colonization. The lack of binding to P. aeruginosa suggests that the effect of this organism on lung function in patients with MBL-deficient CF reflects a role for MBL, either in intercurrent infections with other organisms, or in the inflammatory process. In an association study involving 112 patients with cystic fibrosis, Yarden et al. (2004) found that patients with the MBL2 A/O or O/O genotypes were more likely to have a more severe pulmonary phenotype than patients with the A/A genotype (p = 0.002). No association was found between the MBL2 genotype and the age at first infection with P. aeruginosa. Yarden et al. (2004) concluded that it is very likely that MBL2 is a modulating factor in cystic fibrosis. Tarran et al. (2001) stated that there is controversy over whether abnormalities in the salt concentration or volume of airway surface liquid (ASL) initiate CF airway disease. Using CF mouse nasal epithelia, they showed that an increase in goblet cell number was associated with decreased ASL volume rather than abnormal Cl- concentration. Aerosolization of osmolytes in vivo failed to raise ASL volume. Osmolytes and pharmacologic agents were effective in producing isotonic volume responses in human airway epithelia but were typically short acting and less effective in CF cultures with prolonged volume hyperabsorption and mucus accumulation. These data showed that therapies can be designed to normalize ASL volume without producing deleterious compositional changes in ASL, and that therapeutic efficacy will likely depend on development of long-acting pharmacologic agents and/or an increased efficiency of osmolyte delivery. In 69 Italian patients with CF due to homozygosity for the delF508 mutation in the CFTR gene (F508del; 602421.0001), De Rose et al. (2005) found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients. Emond et al. (2012) used exome sequencing and an extreme phenotype study design to discover genetic variants influencing Pseudomonas aeruginosa infection in cystic fibrosis. Forty-three individuals with early age of onset of chronic P. aeruginosa infection (all below the tenth percentile of age at onset), and the 48 oldest individuals who had not reached chronic P. aeruginosa infection (all past the mean age of onset) were sequenced. After Bonferroni adjustment, a single gene, DCTN4, was significantly associated with time to chronic P. aeruginosa infection (naive P = 2.2 x 10(-6); adjusted P = 0.025). Twelve of the 43 individuals in the early extreme sample carried a missense variant in DCTN4, 9 a phe349-to-leu substitution (F349L; dbSNP rs11954652) and 3 a tyr270-to-cys substitution (Y270C; dbSNP rs35772018). None of the 48 individuals in the late P. aeruginosa extreme sample had either missense variant. Subsequently, 696 individuals with varied CFTR genotypes were studied. Seventy-eight participants were heterozygous and 9 were homozygous for the F349L (614758.0001) mutation; 15 were heterozygous for the Y270C (614758.0002) mutation; 1 individual was heterozygous for both mutations. The presence of at least 1 DCTN4 missense variant was significantly associated with both early age of first P. aeruginosa-positive culture (p = 0.01, hazard ratio = 1.4) and with early age of onset of chronic P. aeruginosa infection (p = 0.004, hazard ratio = 1.9). The risk was highest in individuals with less selective bias toward a P. aeruginosa-negative history, i.e., children enrolled before 1.5 years of age and 103 enrollees who participated in the study despite a history of P. aeruginosa-positive cultures. No significant interaction was found between CFTR genotypes and DCTN4 mutations, although power to detect such an interaction was low. - Infertility Oppenheimer et al. (1970) suggested that characteristics of cervical mucus may account for infertility in females with cystic fibrosis. Congenital bilateral absence of the vas deferens (CBAVD; 277180) is a usual cause of male infertility in cystic fibrosis. It also occurs with CFTR mutations in heterozygous state, especially when associated with the polymorphic number of thymidines in intron 8, specifically the 5T allele. - Carcinoma Siraganian et al. (1987) pointed to adenocarcinoma of the ileum in 3 males with cystic fibrosis. The diagnosis was made between ages 29 and 34 years. From a pancreatic adenocarcinoma developing in a 26-year-old patient with cystic fibrosis due to the phenylalanine-508 deletion, Schoumacher et al. (1990) established a cell line in which the cells showed morphologic and chemical characteristics typical of pancreatic duct cells and showed physiologic properties of CF cells. Schoumacher et al. (1990) suggested that the cell line, which had been stable through more than 80 passages over a 2-year period, could serve as a continuous cell line for studies of the CF defect. Bradbury et al. (1992) demonstrated that the CFTR protein is involved in cAMP-dependent regulation of endocytosis and exocytosis. In a study of pancreatic cancer cells derived from a CF patient, they found that plasma membrane recycling did not occur until normal CFTR was provided. Neglia et al. (1995) performed a retrospective cohort study of the occurrence of cancer in 28,511 patients with cystic fibrosis from 1985 through 1992 in the United States and Canada. The number of cases observed was compared with the number expected, calculated from population-based data on the incidence of cancer. They also analyzed proportional incidence ratios to assess the association between specific cancers and cystic fibrosis in Europe. The final results indicated that although the overall risk of cancer in patients with cystic fibrosis is similar to that of the general population, there is an increased risk of digestive tract cancers. They recommended that persistent or unexplained gastrointestinal symptoms in CF patients should be carefully investigated. Patients with cystic fibrosis have altered levels of plasma fatty acids. Affected tissues from cystic fibrosis knockout mice show elevated levels of arachidonic acid and decreased levels of docosahexaenoic acid. Freedman et al. (2004) performed studies of fatty acids in nasal and rectal biopsy specimens, nasal epithelial scrapings, and plasma from 38 patients with cystic fibrosis, and found alterations in fatty acids similar to those in the knockout mice. - Other Features Delayed puberty is common among individuals with cystic fibrosis and is usually attributed to chronic disease and/or poor nutrition. However, delayed puberty has been reported as a feature of CF even in the setting of good nutritional and clinical status (Johannesson et al., 1997).
Wine (1992) pointed out that CFTR mutations associated with pancreatic sufficiency, milder pulmonary disease, and improved sweat gland function are associated with residual CFTR chloride-ion channel function. He questioned the disruptive effects proposed for the delF508 mutation because ... Wine (1992) pointed out that CFTR mutations associated with pancreatic sufficiency, milder pulmonary disease, and improved sweat gland function are associated with residual CFTR chloride-ion channel function. He questioned the disruptive effects proposed for the delF508 mutation because variation in homozygotes for this mutation is very large. At the same time, those homozygous for stop codons have been severely affected, showing pancreatic insufficiency and pulmonary function values (FEV1) in the same range as those of delF508 subjects. Disruptive effects of delF508 would be expected to give rise to a dominant pattern of inheritance. Wine (1992) concluded that the observations are consistent with the recessive nature of CF and with the likelihood that gene or protein replacement therapy for CF will be effective on their own, without requiring concomitant silencing of the delF508 gene. Sheppard et al. (1993) found that some CFTR mutations, such as delF508, which disrupt normal processing and hence are missing from the apical membrane, generate no chloride current and are associated with severe disease. Other mutants, such as R117H (602421.0005), R334W (602421.0034), and R347P (602421.0006), which are correctly processed and retain significant apical chloride channel function, are associated with a milder form of the disease. Thus, the CF genotype determines the biochemical abnormality, which determines the clinical phenotype. Because these 3 'mild' mutants have normal regulation, interventions designed to increase the activity of mutant CFTR may have therapeutic efficacy in patients with these mutations. Studying 267 children and adolescents with CF who were regularly seen at the same center, Kubesch et al. (1993) found that the age-specific colonization rates with Pseudomonas aeruginosa were significantly lower in pancreatic sufficient than in pancreatic insufficient patients. The missense and splice site mutations that were 'mild' CF alleles with respect to exocrine pancreatic function were also 'low risk' alleles for the acquisition of P. aeruginosa. On the other hand, the proportion of P. aeruginosa-positive patients increased most rapidly in the pancreatic insufficient delF508 compound heterozygotes who were carrying a termination mutation in the nucleotide binding fold-encoding exons. Kulczycki et al. (2003) stated that their oldest patient was a 71-year-old white male who was diagnosed with CF at the age of 27 years because of recurrent nasal polyposis, elevated sweat sodium and chloride, and a history of CF in his 20-year-old sister. The man was married but childless, and practiced as an attorney. Urologic examination revealed CBAVD. Nutritional and pulmonary status were almost normal. At the age of 60 years, genetic testing indicated 2 mutations in the CFTR gene: his1282 to ter (H1282X; 602421.0129), which is associated with severe CF, and ala445 to glu (A445E; 602421.0130), which is associated with mild CF.
For an extensive discussion of the molecular genetics of cystic fibrosis and a listing of allelic variants of the CFTR gene, see 602421.
Collins (1992) gave an update concerning the molecular biology of CF and the ... For an extensive discussion of the molecular genetics of cystic fibrosis and a listing of allelic variants of the CFTR gene, see 602421. Collins (1992) gave an update concerning the molecular biology of CF and the therapeutic implications thereof. O'Sullivan and Freedman (2009) reviewed the clinical features, pathogenesis, diagnosis, molecular genetics, and current state of gene therapy in CF.
Attempting total ascertainment of cases in white children born alive in Ohio during the years 1950 through 1953, Steinberg and Brown (1960) estimated the phenotype frequency to be about 1 in 3,700, a value only about one-fourth that ... Attempting total ascertainment of cases in white children born alive in Ohio during the years 1950 through 1953, Steinberg and Brown (1960) estimated the phenotype frequency to be about 1 in 3,700, a value only about one-fourth that of some earlier estimates. Cystic fibrosis even at this lower estimate is the most frequent lethal genetic disease of childhood. The gene frequency was estimated to be about 0.016, and about 3% of white persons are heterozygotes. Klinger (1983) found an incidence of 1 in 569 among 10,816 live births in the Old Order Amish of Holmes County, Ohio. The gene frequency was estimated to be at least 0.042. On the other hand, not a single case was found among 4,448 live births in the Geauga County, Ohio, Amish. In Connecticut, Honeyman and Siker (1965) arrived at higher phenotype frequency estimates of 1 in 489 (maximal) and 1 in 1,863 (minimal). Bois et al. (1978) reported a frequency of at least 1 in 377 births in an area of Brittany, France. Scotet et al. (2002) retrospectively registered all 520 CF patients born in Brittany since 1960. The birthplace of the patients, the spectrum of CFTR mutations, and the spatial distribution of the mutations across Brittany were determined. The incidence of CF was 1 in 2,630, with a west/east gradient that was confirmed over time (1 in 2,071 in the west, 1 in 3,286 in the east). At the time of study, the incidence of CF was decreasing, mainly as a result of prenatal diagnosis. A mutation detection rate of 99.7% was obtained. Western Brittany presented a specific spectrum of mutations, whereas the eastern region showed a spectrum more similar to the overall picture in France. In Italy, to estimate the incidence of CF, Romeo et al. (1985) used the increase in first- and second-cousin parentage, as compared with the general level of consanguinity indicated by the archive of consanguineous marriages maintained by the Catholic Church. The incidence was estimated to be about 1/2000. The data were consistent with a single gene locus; consanguinity would have been higher if more than one were present. The segregation ratio in 624 CF sibships was 0.252. In Hutterite families with cystic fibrosis, Ober et al. (1987) found close linkage to chromosome 7 markers as in non-Hutterite families. Because 3 different chromosome 7 haplotypes carried the CF mutation in these families, they suggested that the CF gene may have been introduced into the Hutterite population by as many as 3 different ancestors. Fujiwara et al. (1989) confirmed these observations. From studies in Caucasian families in Utah, Jorde and Lathrop (1988) concluded that fertility differences are unlikely to account for the observed Caucasian CF gene frequency. They compared 143 grandparent couples of Utah CF cases with 20 replicate sets of matched control couples drawn from the Utah Genealogical Database. Before ascertainment correction was applied, CF carriers appeared to manifest a significant fertility advantage over controls. After the correction formula (not used in previous studies) was applied, this difference disappeared. Also, no differences were found between carriers and controls in the length of intervals between births. In the Hutterites, Klinger et al. (1990) demonstrated that 1 of the 3 previously identified CF haplotypes carries the phe508 deletion. The other 2 Hutterite CF haplotypes are generally rare in Caucasian populations and must carry different CF mutations. Thus, there must have been at least 3 original carriers of CF mutations among the founders of the Hutterite population. They found 1 Hutterite CF patient who had both of the haplotypes that do not carry the phe508 deletion. From a study in Northern Ireland, Hill et al. (1989) concluded that the CF locus is in strong linkage disequilibrium with KM19 and Xv-2C, as it is in other Caucasian populations. These findings indicate that CF in northern European populations may have resulted from a single ancestral mutation. A further finding was preferential inheritance of the paternal CF allele (22 of 28) as opposed to the maternal CF allele (6 of 28) with no significant difference in the sex of the children inheriting these alleles. Cutting et al. (1989) concluded from the analysis of closely linked DNA marker haplotypes that the majority of CF mutations in the Caucasian population arose from a single mutational event. Similar analysis in American black families suggested that multiple mutant alleles are found in this population. Although CF had been thought to be very rare in Arabs, Nazer et al. (1989) documented CF in 13 children in Saudi Arabia. El-Harith et al. (1998) reported that 6 mutations, detectable by PCR with subsequent restriction enzyme digestion, would allow detection of 70% of Saudi CFTR mutations. Estivill et al. (1989) reported that in Spanish and Italian populations, deletion of phe508 is present in only 46.2% of CF chromosomes. In all cases, it occurred with haplotype 2, which accounts for about 75% of southern European CF chromosomes; thus, at least 2 independent mutations must have occurred on this haplotype. McIntosh et al. (1989) found a frequency of 74.4% for the phe508 deletion in Scotland. Colten (1990) indicated that one-third of the more than 15,000 patients listed in the registry of the North American National Cystic Fibrosis Foundation are older than 21 years. Using PCR and hybridization with allele-specific oligonucleotides, Lemna et al. (1990) found the phe508 deletion in 75.8% of 439 cystic fibrosis chromosomes. The 3-base deletion was found in only 30.3% of cystic fibrosis chromosomes from Ashkenazi families. In 5 southern European populations (Albanian, Greek, Italian, Spanish, and Yugoslavian), Nunes et al. (1991) found that, apart from delF508, the most frequent mutations were G542X (602421.0009), 6.04%; R1162X (602421.0033), 3.61%; and N1303K (602421.0032), 3.24%. Of the 14 mutations tested, 7 others had frequencies of less than 1% and 4 mutations were not found at all. Ten Kate et al. (1991) demonstrated that consanguinity, even if present, may be irrelevant: a family with 2 brothers with cystic fibrosis whose parents were consanguineous, being members of an isolated religious group, were found to have inherited different mutations from the parents. They presented a diagram relating the likelihood of 'autozygosity,' depending on gene frequency with consanguinity of various degrees. In a systematic study of 365 CF chromosomes in the Celtic population in Brittany, Ferec et al. (1992) identified more than 98% of the cystic fibrosis gene mutations. By use of the denaturing gradient gel electrophoresis (DGGE) method, they detected 19 different CFTR mutations located in 9 exons. Nine new mutations were found. Kerem et al. (1995) reported that the incidence of CF and the frequency of disease-causing mutations varies considerably among the Jewish ethnic subgroups in Israel. Among Ashkenazi Jews, the frequency of CF is 1:3300, which is similar to the frequency in most Caucasian populations. Among non-Ashkenazi Jews, the disease occurs at a similar frequency among Jews from Libya (1:2700), Georgia (1:2700), Greece and Bulgaria (1:2400), but is rare in Jews from Yemen (1:8800), Morocco, (1:15000), Iraq (1:32000), and Iran (1:39000). To that point, only 12 mutations had been identified in Israeli Jews, and this enabled the identification of 91% of the CF chromosomes in the entire Jewish CF population. However, in each Jewish ethnic group, the disease is caused by a different repertoire of mutations. In a study in the Netherlands, de Vries et al. (1997) tested for the carrier frequency of the delta-F508 mutation by analyzing mouthwashes and matched blood samples from 11,654 blood donors from all over the country. They detected a delF508 carrier frequency of 1 in 42 (95% CI 1/37-1/47). By assuming that the relative frequency of the delF508 mutation among carriers and patients is comparable in the Netherlands, they estimated the overall CF carrier frequency as 1 in 32, significantly less than 1 in 25, the usual figure cited. An increase in carrier frequency with increasing distance from the northeastern region of the country was observed, thus confirming that there is a gradient in gene frequency with low frequencies in the northeastern part of the country and high frequencies in the southern part. Brock et al. (1998) studied a total of 27,161 women enrolled in prenatal clinics in Scotland between 1990 and 1997. All 27,161 were screened for the delta-F508 (602421.0001), G551D (602421.0013), and G542X (602421.0009) mutations. In 14,360 women R117H was also measured. In addition, 183 patients with cystic fibrosis were studied for the presence of these mutations. Based on their data, the authors estimated that the incidence of CF in the Scottish population is 1 in 1984, with 95% confidence intervals between 1 in 1,692 to 1 in 2,336. Macek et al. (1997) reported a large-scale study for mutation identification in African American CF patients. The entire coding and flanking intronic sequence of the CFTR gene was analyzed by denaturing gradient-gel electrophoresis (DGGE) and sequencing in 82 African American CF chromosomes. One novel mutation, 3120+1G-A (602421.0120), occurred with a frequency of 12.3% and was also detected in a native African patient. To establish gene frequencies, an additional group of 66 African American CF chromosomes were screened for mutations identified in 2 or more African American patients. Screening for 16 'common Caucasian' mutations identified 52% of CF alleles in African Americans, while screening for 8 'common African' mutations accounted for an additional 23%. The combined detection rate of 75% was comparable to the sensitivity of mutation analysis in Caucasian CF patients. These results indicated that African Americans have their own set of 'common' CF mutations that originated from the native African population. To examine whether the 3120+1G-A mutation has a common origin in the diverse populations in which it has been observed or whether its widespread distribution is the result of recurrent mutational events, Dork et al. (1998) analyzed DNA samples obtained from 17 unrelated CF patients in 4 different populations and from 8 unrelated African CF carriers. They found identical extended CFTR haplotypes for the 3120+1G-A alleles in Arab, African, and African American patients, strongly suggesting that the mutation had a common origin. This finding was not surprising in the case of Africans and African Americans; it was not as easy to explain the presence of the 3120+1G-A mutation in African and Saudi Arab patients. Recent ethnic admixture accounts for a few percent of Africans in Saudi Arabia; however, this was considered an unlikely explanation of the finding, since none of the Saudi families with the mutation had any anthropomorphologic signs of an African descent. In the past, a continuous gene flow between Arab and African populations probably persisted for many centuries, in association with trading and with the spread of the Islamic religion. Thus far, the Greeks are the only Caucasian population in which the 3120+1G-A mutation has been identified. A recurrent mutational event seems to be unlikely, because the Greek haplotype differs from the others in only minor respects. Historical contacts, e.g., under Alexander the Great or during the ancient Minoan civilization, may provide an explanation for the common ancestry of the disease mutation in these ethnically diverse populations. Dork et al. (1998) concluded that 3120+1G-A is an ancient mutation that may be more common than previously thought in populations of the tropical and subtropical belt, where CF probably is an underdiagnosed disorder. Padoa et al. (1999) screened 1,152 unrelated, healthy African blacks from southern, western, and central Africa, and 9 black CF patients for the 3120+1G-A mutation. The mutation was found to have a carrier frequency of 1 in 91 for South African blacks, with a 95% confidence interval of 1 in 46 to 1 in 197. A subset of those studied were also screened for the A559T, S1255X, and 444delA mutations. These mutations were not found in any of the patients or in over 373 healthy subjects tested. Padoa et al. (1999) concluded that the corrected CF carrier frequency in South African blacks would be between 1 in 14 and 1 in 59 and, hence, that the incidence of CF would be predicted to be between 1 in 784 and 1 in 13,924 in this population. Padoa et al. (1999) speculated as to why the observed incidence in this population is lower than that which they predicted. Restrepo et al. (2000) used a reverse dot-blot detection kit to examine the frequency of 16 CFTR mutations among 192 cystic fibrosis alleles in Mexico, Colombia, and Venezuela. The detection efficacy of the panel used was 47.9% in this population. The most prevalent CF allele was delF508 (39.6%). The most common alleles among the others were G542X, N1303K and 3849+10kbC-T (602421.0062). The authors compared their results to population studies from Spain and concluded that an important Spanish contribution is present in CFTR mutations in these 3 countries, but that important regional differences in allele prevalence exist. Kabra et al. (2000) analyzed CFTR mutations in 24 children with CF from the Indian subcontinent. Of the mutant chromosomes, 33.3% had the delF508 mutation. The authors screened 16 exons of the CFTR gene by SSCP and heteroduplex analysis, but mutations were not identified in 46% of chromosomes. The authors also reported novel mutations in their population: 3622insT (602421.0125) and 3601-20T-C (602421.0126). Wang et al. (2000) found that 7 of 29 Hispanic patients with CF were heterozygous for a single-basepair deletion at nucleotide 3876 resulting in a frameshift and termination at residue 1258 of the CFTR gene (602421.0127). This mutation therefore accounted for 10.3% of mutant alleles in this group. The patients with this mutation had a severe phenotype as determined by age of diagnosis, high sweat chloride, presence of allergic bronchopulmonary aspergillosis, pancreatic insufficiency, liver disease, cor pulmonale, and early death. Wang et al. (2000) also noted that this mutation had not been reported in any other ethnic group. Considering that the haplotype background of the mutations that most often cause cystic fibrosis in Europe is different from that of non-CF chromosomes, Mateu et al. (2002) reasoned that these haplotype backgrounds might be found at high frequencies in populations in which CF was currently not common; thus, such populations would be candidates for the place of origin of CF mutations. In a worldwide survey of normal chromosomes, they found a very low frequency or absence of the most common CF haplotypes in all populations analyzed, and a strong genetic variability and divergence, among various populations, of the chromosomes that carry disease-causing mutations. They suggested that the depth of the gene genealogy associated with disease-causing mutations may be greater than that of the evolutionary process that gave rise to the current human populations. The concept of 'population of origin' lacks either spatial or temporal meaning for mutations that are likely to have been present in Europeans before the ethnogenesis of the current populations. Subsequent population processes may have erased the traces of their geographic origin. In Brittany, France, Scotet et al. (2003) reviewed the results of a neonatal screening program for CF begun in 1989 to determine the prevalence of CF at birth and to review data from prenatal diagnoses carried out in the region, first in families related to a CF child and also those made following the detection of an echogenic bowel upon routine ultrasound examination performed during pregnancy. The prevalence of CF at birth was estimated to be 1 in 2,838 in the region from 1992 to 2001. By including the 54 CF-affected pregnancies that were terminated during those 10 years, the corrected birth prevalence of CF was 1 in 1,972. Prenatal diagnosis was therefore responsible for a decrease in CF prevalence at birth of 30.5%. Quint et al. (2005) described the mutation spectrum in Jewish CF patients living in Israel. Using a panel of 12 CFTR mutations, they identified 99% of CF alleles in Ashkenazi Jewish patients, 91% in Jews of North African origin, and 75% in Jewish patients from Iraq. In a survey of 495 blood samples of randomly selected healthy individuals in Hanoi, Vietnam, Nam et al. (2005) found no instance of the delta-F508 mutation. Among 1,482 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 32 heterozygotes and no homozygotes for the phe508del mutation in the CFTR gene (dbSNP rs113993960; 602421.0001), for a frequency of 0.022, or 1 in 45.5. This frequency is lower than that for the general population for this mutation, which is 1 in 30. They identified the met1101-to-lys mutation (602421.0137) in 108 heterozygotes and 6 homozygotes among 1,473 screened, for a carrier frequency of 0.073 (1 in 13.5). Among 23,369 ethnically diverse individuals screened for cystic fibrosis carrier status, Lazarin et al. (2013) identified 842 carriers (3.6%), for an estimated carrier frequency of approximately 1 in 28. Twenty-seven 'carrier couples' were identified. Nine individuals were identified as homozygotes or compound heterozygotes. Among 12,870 individuals of northwestern European origin, the carrier frequency was 1 in 23. A carrier frequency of 1 in 40 was found among 1,122 south Asians screened, supporting reports that cystic fibrosis is underreported in this population.