Clinical characteristics.

Cystic fibrosis (CF) is a multisystem disease affecting epithelia of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and exocrine sweat glands. Morbidities include progressive obstructive lung disease with bronchiectasis, frequent hospitalizations for pulmonary disease, pancreatic insufficiency and malnutrition, recurrent sinusitis and bronchitis, and male infertility. Pulmonary disease is the major cause of morbidity and mortality in CF. Meconium ileus occurs at birth in 15%-20% of newborns with CF. More than 95% of males with CF are infertile.

Congenital absence of the vas deferens (CAVD) is generally identified during evaluation of infertility or as an incidental finding at the time of a surgical procedure. Hypoplasia or aplasia of the vas deferens and seminal vesicles may occur either bilaterally or unilaterally. Testicular development and function and spermatogenesis are usually normal.

Diagnosis/testing.

The diagnosis of CF is established in a proband with one or more characteristic phenotypic features and evidence of an abnormality in cystic fibrosis transmembrane conductance regulator (CFTR) function (e.g., 2 elevated sweat chloride values, biallelic CFTR pathogenic variants, or transepithelial nasal potential difference measurement characteristic of CF). The diagnosis of CF is established in an infant with elevated trypsinogen on newborn screening and identification of biallelic CFTR pathogenic variants or an elevated sweat chloride.

The diagnosis of CAVD is established in a male with azoospermia and absence of the vas deferens on palpation or identification of biallelic CAVD-causing CFTR pathogenic variants.

Management.

Treatment of manifestations: Treatment of respiratory complications using inhaled dornase alfa, inhaled hypertonic saline, antibiotics, anti-inflammatory agents, ivacaftor, ivacaftor/lumacaftor combined therapy, lung or heart/lung transplant; topical steroids, antibiotics and/or surgical intervention for nasal/sinus symptoms; treatment of exocrine pancreatic insufficiency using oral pancreatic enzyme replacement, special infant formulas, supplemental nutrition, fat-soluble vitamin supplements and zinc; management of CF-related diabetes mellitus (CFRD) by an endocrinologist; surgical management for meconium ileus; oral ursodiol for biliary sludging/obstruction, liver transplant when indicated; assisted reproductive technologies (ART) for male infertility.

Prevention of primary complications: Airway clearance techniques, dornase alpha, hypertonic saline, antibiotics to prevent chronic airway infection, immunizations including anti-RSV monoclonal antibody; physical activity to maintain bone health and improve airway clearance; nutritional support for pancreatic insufficiency; extra salt and water in hot, dry climates.

Surveillance: Frequent visits to CF care providers to monitor for changes in symptoms and physical examination; cultures of respiratory tract secretions at least four times yearly; pulmonary function studies, chest radiographic examination, annual electrolytes, fat-soluble vitamin levels and IgE levels; bronchoscopy and chest CT examination when indicated; monitor weight gain and caloric intake in infants until age six months; fecal elastase when indicated; annual oral glucose tolerance test in individuals older than age ten years; evaluation of bone mineral density starting in adolescence; annual liver function tests and liver ultrasound to monitor progression of liver disease.

Agents/circumstances to avoid: Respiratory irritants; individuals with respiratory infections; dehydration.

Evaluation of relatives at risk: Molecular genetic testing of at-risk sibs if the pathogenic variants in the family are known or sweat chloride testing of at-risk sibs if the pathogenic variants in the family are not known, to identify as early as possible those who should be referred to a cystic fibrosis center for initiation of treatment and preventive measures.

Therapies under investigation: Prophylactic ursodiol therapy; CF corrector VX-661; inhaled dry powder mannitol; CFTR gene therapy.

Genetic counseling.

CF and CAVD are inherited in an autosomal recessive manner. At conception, each sib of an affected individual with CF and brothers of a male with CAVD have a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the CFTR pathogenic variants in the family are known.

Suggestive Findings

Cystic fibrosis (CF) should be suspected in individuals with the following features:

• Chronic sinopulmonary disease including chronic cough and sputum production, chronic wheeze and air trapping, obstructive lung disease on pulmonary function tests, persistent colonization with pathogens commonly found in individuals with CF, persistent chest radiograph abnormalities, nasal polyps, chronic pan sinusitis, and digital clubbing
• Gastrointestinal/nutritional abnormalities such as meconium ileus, rectal prolapse, malabsorption/pancreatic insufficiency, steatorrhea, distal intestinal obstructive syndrome, recurrent acute pancreatitis, chronic pancreatitis, prolonged neonatal jaundice, chronic hepatic disease manifested by clinical or histologica evidence of focal biliary cirrhosis or multilobular cirrhosis, failure to thrive (protein-calorie malnutrition), hypoproteinemia and edema, complications secondary to fat-soluble vitamin deficiencies
• Obstructive azoospermia
• Salt-loss syndromes including acute salt depletion, chronic metabolic alkalosis, and hyponatremic hypochloremic dehydration
• In infants: elevated immunoreactive trypsinogen (IRT) on newborn screening

Congenital absence of the vas deferens (CAVD) should be suspected in males with the following:

• Severe oligospermia or azoospermia
• A low volume of ejaculated semen with a specific chemical profile (low pH, elevated citric acid concentration, elevated acid phosphatase concentration, low fructose concentration, and failure to coagulate)
• Evidence of abnormalities of seminal vesicles or vas deferens on rectal ultrasound examination

Establishing the Diagnosis

The diagnosis of CF is established in a proband with the following:

• One or more characteristic phenotypic features of CF and evidence of an abnormality in cystic fibrosis transmembrane conductance regulator (CFTR) function based on ONE of the following:
  • Two abnormal quantitative pilocarpine iontophoresis sweat chloride values (>60 mEq/L in infants age > 6 months). Click here (pdf) for more specific information on this test.
  • Identification of biallelic pathogenic or likely pathogenic variants in CFTR (see Table 1)
  • Transepithelial nasal potential difference measurements characteristic of CF. Click here (pdf) for more specific information on this test.
• In an infant: elevated trypsinogen on newborn screening immunoreactive trypsinogen (IRT) assay AND
  • Identification of biallelic CF-causing pathogenic variants in CFTR
    OR
  • An abnormal sweat chloride value ≥60 mEq/L (see ACMG Newborn Screening ACT Sheet)

The diagnosis of CAVD is established in a male with the following features:

• Azoospermia
  AND
• Absence of the vas deferens on palpation (rarely, a thin fibrous cord representing a rudimentary vas deferens may be present)
  OR
• Identification of biallelic CAVD-causing CFTR pathogenic variants (establishes the diagnosis if clinical features are inconclusive; see Table 1)

Molecular genetic testing approaches include single-gene testing and use of a multigene panel.

Single-gene testing

• Targeted analysis for CFTR pathogenic variants can be performed first.
  Note: The American College of Medical Genetics recommended panel includes the 23 pathogenic variants listed in Table 6 and has a detection rate of 97% in Ashkenazi Jewish, 88.3% in non-Hispanic whites, 69% in African Americans, and 57% in Hispanic Americans; detection rate in Asian Americans is unknown [Grody et al 2001, Palomaki et al 2002, Watson et al 2004].
  Note: A panel that includes more than 129 pathogenic variants would detect approximately 96% of pathogenic variants in affected individuals (see www.cftr2.org) [Sosnay et al 2013].
• Sequence analysis of CFTR – followed by gene-targeted deletion/duplication analysis – is performed if only one or no pathogenic variant is found.
  Note: Sequence analysis of CFTR, followed by gene-targeted deletion/duplication analysis, is the initial diagnostic test for:
  • Individuals of an ethnicity for which the sensitivity of targeted analysis is low;
  • Prenatal testing in a high-risk fetus;
  • Prenatal testing in a low-risk fetus with echogenic bowel identified on prenatal ultrasound examination;
  • An infant with an elevated IRT assay on newborn screening and a sweat chloride of 30-59 mEq/L (intermediate result);
  • A symptomatic infant (e.g., infant with meconium ileus) who is too young to produce adequate volumes of sweat.

A multigene panel that includes CFTR and other genes of interest (see Differential Diagnosis) may also be considered. Notes: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Cystic fibrosis (CF) affects the epithelia in several organs resulting in a complex, multisystem disease that involves the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, male genital tract, and exocrine sweat glands. Morbidities include progressive obstructive lung disease with bronchiectasis, frequent hospitalizations for pulmonary disease, pancreatic insufficiency and malnutrition, recurrent sinusitis and bronchitis, and male infertility. The overall median predicted survival is estimated at 40.7 years (95% confidence intervals, 37.7- 44.1 yrs) [CFF Patient Registry 2013].

• Respiratory. Pulmonary disease remains the major cause of morbidity and mortality in CF. Early manifestations are chronic cough, intermittent sputum production, and exertional dyspnea. Bronchiectasis is now known to develop early, detectable in infants as young as age ten weeks, and is persistent and progressive [Sly et al 2013]. Failure of lung defenses leads to bacterial endobronchitis (most commonly Staphylococcus aureus and Pseudomonas aeruginosa) with resulting airway obstruction and intense neutrophilic inflammation. Progression of lung disease results in chronic endobronchitis and structural injury to the airways. End-stage lung disease is characterized by extensive damage to the airways (cysts/abscesses) and accompanying fibrosis of lung parenchyma adjacent to airways.
  Other respiratory causes of morbidity include recurrent sinusitis and nasal polyposis.
• Exocrine pancreatic insufficiency with malabsorption occurs in the great majority of individuals with CF, although median body mass index percentiles have steadily increased [CFF Patient Registry 2013]. Pancreatic insufficiency is caused by inspissation of secretions within the pancreatic ducts and ultimately interstitial fibrosis. The clinical manifestations are steatorrhea and poor growth related to fat malabsorption. Acute or chronic recurrent pancreatitis can be a presenting manifestation of CF, and is much more common among those with pancreatic sufficiency (10% prevalence) than those with pancreatic insufficiency (0.5% prevalence) [De Boeck et al 2005]. Hemolytic anemia, defective coagulation, or skin rashes related to deficiencies of fat-soluble vitamins and zinc may occasionally be seen.
  Cystic fibrosis-related diabetes (CFRD) can occur at any age, but prevalence increases with age, estimated in 20% of adolescents and 40%-50% of adults [Moran et al 2009, Moran et al 2014]. CFRD is distinctive from type 1 and type 2 diabetes and requires its own approach to both diagnosis and management [Moran et al 2014]. Glucose metabolism in CFRD is impaired by a loss of total islet cells leading to an absence of insulin and glucagon, and fluctuating insulin resistance occurs from chronic and acute inflammation. CFRD is diagnosed if the fasting glucose level is ≥126 mg/dL (7.0 mmol/L) or the two-hour oral glucose tolerance test glucose level is ≥200 mg/dL (11.1 mmol/L). CFRD can be diagnosed during a pulmonary exacerbation if fasting glucose levels of ≥126 mg/dL (7.0 mmol/L) or the two-hour post prandial levels of ≥200 mg/dL (11.1 mmol/L) persist for 48 hours [Moran et al 2010].
• Gastrointestinal. Meconium ileus occurs in 15%-20% of newborns diagnosed with CF.
• Liver disease typically presents by age ten years and is defined as the presence of at least two of the following: hepatomegaly, elevated serum hepatic enzyme levels, and/or liver ultrasound abnormalities other than hepatomegaly [Leeuwen et al 2014]. Liver disease is reported in approximately 10% of individuals [CFF Patient Registry 2013]. Approximately 5%-10% develop clinically significant liver disease with multilobar cirrhosis and portal hypertension [Debray et al 2011]. Progression is variable. Individuals with CF may develop focal biliary cirrhosis from progressive portal fibrosis and biliary obstruction. Complications include variceal bleeding, ascites, hypersplenism, hepatic encephalopathy, and rarely liver synthetic failure. Liver disease is the cause of mortality in 2.9% of individuals with CF [CFF Patient Registry 2013].
• Fertility. More than 95% of males with CF are infertile as a result of azoospermia caused by altered vas deferens, which may be absent, atrophic, or fibrotic.
  Women with CF are fertile, although a few females have abnormal cervical mucus that may contribute to infertility. Others with severe illness and reduced body mass index may be anovulatory. The rate of live births among females with CF age 14-45 years is 1.6 per 100 [CFF Patient Registry 2011].

Congenital absence of the vas deferens (CAVD) is generally identified during evaluation of infertility or as an incidental finding at the time of a surgical procedure, such as orchidopexy. CAVD accounts for 1.2%-1.7% of male infertility. Hypoplasia or aplasia of the vas deferens and seminal vesicles may occur either bilaterally or unilaterally. Testicular development and function and spermatogenesis are usually normal.

Genotype-Phenotype Correlations

The Clinical and Functional Translation of CFTR website provides information about CFTR pathogenic variants including sweat chloride, lung function, pancreatic status, and pseudomonas infection rates in individuals with specific pathogenic variants.

Cystic fibrosis. The best correlation between genotype and phenotype is seen in the context of pancreatic function. The most common pathogenic variants have been classified as pancreatic sufficient (PS) or pancreatic insufficient. Individuals with pancreatic sufficiency usually have either one or two PS alleles, indicating that PS alleles are dominant with respect to pancreatic phenotype.

The severity of pulmonary disease among individuals with identical genotypes varies widely. Limited genotype-phenotype correlations include:

Compound heterozygotes for p.Phe508del/p.Ala455Glu have better pulmonary function than individuals who are homozygous for p.Phe508del [De Braekeleer et al 1997].

• The severity of lung disease in individuals heterozygous or homozygous for p.Arg117His depends on the presence of a variation in the poly T tract of intron 9, c.1210-12T[5_9] [Massie et al 2001]. Individuals with a CF-causing variant plus the 5T variant in cis with p.Arg117His usually develop the lung disease of CF, but those individuals with p.Arg117His and the 7T variant or the 9T variant have a highly variable phenotype that can range from no symptoms to mild lung disease [Kiesewetter et al 1993, Chmiel et al 1999].
• Because p.Ala455Glu and p.Arg117His are associated with pancreatic sufficiency, the less severe lung disease seen in individuals with these pathogenic variants could be the consequence of better nutritional status.

CAVD. CAVD usually results from compound heterozygosity of a classic (severe, loss-of-function) CFTR pathogenic variant with a mild (retaining some function) CFTR pathogenic variant (e.g., the 5T allele; Table 2). However, some overlap exists between the CAVD phenotype and a very mild CF phenotype, with a small percentage of individuals with CAVD also reporting respiratory or pancreatic problems [Dörk et al 1997, Gilljam et al 2004]. The 5T allele may be associated with lung disease in adult females with CF-like clinical features [Noone et al 2000]. Thus, caution must be exercised in attempting to use genotype to predict the future course of individuals initially diagnosed with CAVD only.

Nomenclature

Atypical cystic fibrosis, a term originally proposed to describe a disorder that presents with cystic fibrosis-like symptoms but is not caused by CFTR dysfunction, is sometimes used to denote mild or non-classic CF. However, use of the term in this way is confusing and strongly discouraged.

Prevalence

CF is the most common life-limiting autosomal recessive disorder in individuals of northern European background. The disease incidence of CF is 1:3,200 live births in this population [Rosenstein & Cutting 1998]. Approximately 30,000 affected persons live in the United States. The carrier frequency of individuals of northern European ancestry living in North America is 1:28 (see Table 3).

CF occurs with lower frequency in other ethnic and racial populations (1:15,000 African Americans, and 1:31,000 Asian Americans) [Rosenstein & Cutting 1998].

Cystic Fibrosis (CF)

Primary dysphagia with chronic descending tracheal aspiration and primary gastroesophageal reflux (GER) with or without ascending tracheal aspiration. Both conditions can cause chronic cough in infancy and may be associated with failure to thrive. However, in infants without CF, the cough is often temporally associated with feedings; and steatorrhea is not associated with primary dysphagia or primary GER.

Severe combined immunodeficiency and other immunodeficiency disorders. Individuals with immunodeficiency may present with recurrent respiratory infections and chronic diarrhea in infancy. These individuals are also prone to non-respiratory infections (e.g., otitis media, cellulitis) not specifically associated with CF.

Asthma. CF and asthma both present with chronic cough and persistent wheeze following respiratory viral infections, allergen exposure, or exertion. However, individuals with asthma typically improve on asthma therapy, do not experience recurrent pneumonia, are not colonized with CF-related bacteria, have normal growth and weight gain, and do not have steatorrhea.

Congenital airway anomalies can cause chronic cough and wheezing during infancy similar to CF. Gastrointestinal or nutritional manifestations that are typically present in infants with CF are not seen in children with congenital airway anomalies. Stridor is not common in CF.

Primary ciliary dyskinesia (PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic oto-sino-pulmonary disease. Individuals with PCD present with respiratory distress in infancy, cough and sputum production with recurrent pneumonias that may progress to chronic bronchiectasis, Pseudomonas aeruginosa or other opportunistic bacterial pathogens that may be cultured from airway secretions, and chronic sinus disease. Situs inversus is present in 50% of individuals with PCD; steatorrhea and failure to thrive are not associated with PCD. PCD is associated with pathogenic variants in multiple genes encoding different structural components of cilia and is inherited in an autosomal recessive manner.

Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure. SDS can be distinguished from CF by the presence of hematologic abnormalities with single- or multilineage cytopenias, susceptibility to myelodysplasia syndrome (MDS) and acute myelogenous leukemia (AML), and skeletal abnormalities (most commonly chondrodysplasia or asphyxiating thoracic dystrophy). SDS is caused by biallelic pathogenic variants in SBDS and is inherited in an autosomal recessive manner.

Primary biliary atresia. Rarely, individuals with CF may present in infancy with symptoms of biliary obstruction without other clinically apparent GI or respiratory manifestations. Serum levels of immunoreactive trypsinogen and stool levels of elastase should be normal in primary biliary atresia, whereas CF liver disease is invariably associated with evidence of pancreatic duct obstruction.

Bronchiectasis with or without elevated sweat chloride. Pathogenic variants in SCNN1A, SCNN1B, and SCNN1G encoding the beta subunit of the epithelial sodium channel cause a non-classic CF phenotype [Sheridan et al 2005]. Individuals with SCNN1A, SCNN1B, or SCNN1G pathogenic variants may also have mild lung disease and elevated sweat chloride concentration.

Isolated hyperchlorhidrosis, characterized by elevated sweat chloride levels and failure to thrive, is caused by pathogenic variants in CA12, which encodes carbonic anhydrase XII [Feldshtein et al 2010].

Congenital Absence of the Vas Deferens (CAVD)

CAVD is part of the differential diagnosis of obstructive azoospermia, caused by obstruction to sperm outflow from the testes or ductular system. Obstructive azoospermia may be part of a syndrome or may be an isolated finding. Syndromes with obstructive azoospermia include the following:

• Young syndrome (OMIM 279000), a progressive obstruction of the epididymis by inspissated secretions in males with chronic sinopulmonary infection. Males with Young syndrome do not have malformations of the vas deferens or epididymis. Molecular testing of individuals with Young syndrome indicates that this disorder is not caused by pathogenic variants in CFTR [Friedman et al 1995].
• Hereditary urogenital adysplasia (OMIM 277000), an autosomal dominant disorder of variable expressivity and reduced penetrance. Females have a range of uterine anomalies; males may have Wolffian duct anomalies including unilateral or bilateral absence of the vas deferens; males and females may have unilateral or bilateral renal agenesis.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with cystic fibrosis (CF) the following evaluations are recommended.

Respiratory

• Sinus CT to assess for pan sinusitis in individuals with chronic nasal congestion and/or recurrent sinusitis
• Pulmonary function testing (PFT), including infant PFT at specialized centers
• Chest radiographic examination to screen for bronchiectasis, or chest computed tomography (CT) examination as indicated for worsening symptoms or concern for progression
• Sputum culture in affected individuals who can expectorate a sputum sample, or culture of deep oropharyngeal swab in those who cannot
• Bronchoscopy with bronchoalveolar lavage to evaluate lower airway microbiology and inflammation as indicated

Exocrine pancreatic insufficiency

• Fecal elastase
• Fecal fat content based on 72-hour stool collection
• Vitamin A, D, and E serum concentrations
• Prothrombin time and international normalized ratio (INR)
• Random glucose

Overall clinical status / extent of disease

• CBC with differential and cell count
• Serum electrolytes, BUN, creatinine
• Liver function tests (ALT, AST)
• Consultation with a genetic counselor

To establish the extent of disease and needs in an individual diagnosed with congenital absence of the vas deferens (CAVD) referral to a urologist is recommended.

Treatment of Manifestations

Prevention of Primary Manifestations – Cystic Fibrosis

Respiratory

• A variety of airway clearance techniques (ACTs) can mobilize airway secretions, minimize airway obstruction, and reduce airway infections. ACTs include manual chest percussion with postural drainage, hand-held devices (e.g., flutter valve, or Acapella^®), and inflatable vest therapy devices that vibrate the chest wall. These treatments are most effective when used at least twice daily.
• Dornase alfa and hypertonic saline help mobilize airway secretions in individuals age six years or older.
• Airway clearance should be used in conjunction with inhaled medications given in a standard sequence:

  1.

  Bronchodilator

  2.

  Hypertonic saline

  3.

  Dornase alfa

  4.

  Airway clearance

  5.

  Inhaled corticosteroids and/or long-acting beta agonist (for select individuals)

  6.

  Aerosolized antibiotic

  The rationale for this sequence is to open the airway, decrease sputum viscosity, promote expectoration of secretions, and then deliver anti-inflammatory treatments and/or antibiotics as widely and deeply as possible within the bronchial tree.
• Aggressive antibiotic treatment at the time of initial isolation of P. aeruginosa from cultured airway secretions helps prevent chronic airway infection.
• All routine immunizations should be given at the recommended times. Especially important are vaccines that protect against microorganisms associated with pulmonary manifestations, including pertussis, measles, varicella, Haemophilus influenzae type B, and Streptococcus pneumoniae.
• Influenza vaccine should be administered annually in infants age six months and older. Note: (1) Because the influenza vaccine may not be fully protective, consider immunizing an affected individual's entire family. (2) CF individuals with suspected influenza should receive anti-viral medications targeted toward influenza A and B.
• Anti-RSV monoclonal antibody (Synagis^®) should be considered for infants up to age 12 months for the duration of the local RSV season, particularly in individuals with ongoing pulmonary symptoms.
• Physical activity, exercise, and conditioning help maintain bone health and improve airway clearance.

Exocrine pancreatic insufficiency

• Pancreatic enzyme replacement and supplementation of fat-soluble vitamins
• High-calorie, high-fat nutritional supplements
• Consultation with a nutritionist specializing in CF
• Extra salt and water for hydration and salt losses in hot, dry climates

Surveillance – Cystic Fibrosis

Respiratory

• Newborns are examined monthly by a CF care provider for the first six months of life and then bimonthly until age one year.
• Individuals age one year and older should be examined quarterly by a CF care provider to monitor for subtle changes in physical examination that are not yet manifest as symptoms.
• Culture respiratory tract secretions at least four times yearly. Some individuals may benefit from more frequent visits and respiratory tract surveillance cultures (see Therapies Under Investigation).
• Pulmonary function studies, chest radiographic examination, and at least annual blood tests for electrolytes, fat soluble vitamin levels, and IgE levels are appropriate.
• Bronchoscopy and chest CT examination are indicated for individuals with symptoms and signs of lung disease who fail to respond to intervention.

Exocrine pancreatic insufficiency

• Weight gain and caloric intake are monitored monthly in newborns until age six months.
• Fecal elastase may need to be repeated during the first year of life, particularly if infants have signs or symptoms of malabsorption or inadequate weight gain.
• Measure oral glucose tolerance annually after age ten years during a period of stable health. Plasma glucose is measured fasting and two hours after an oral glucose load of 1.75 g/kg, or 75 g maximum.
• Evaluate bone mineral density in adolescence.

Liver disease. Annual screening of liver function tests and liver ultrasound to monitor progression of liver disease is appropriate.

Agents/Circumstances to Avoid – Cystic Fibrosis

Avoid the following:

• Respiratory irritants (e.g., smoke, dust)
• Individuals with respiratory infections
• Dehydration; add extra salt and water to diet in hot, dry climates because of perspiration-related salt losses (see Prevention of Primary Manifestations).

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband/at-risk relatives in order to identify as early as possible those who should be referred to a cystic fibrosis center for initiation of treatment and preventive measures.

Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Sweat chloride testing if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancies are well tolerated with improved nutrition, improved pulmonary treatment, aggressive management of infections, and a multidisciplinary care team, especially in women with mild to moderate disease. Pregnancy is not associated with an increased risk of death [Goss et al 2003]. In all studies published to date, the most important predictors of pregnancy outcome are the severity of maternal pulmonary impairment and nutritional status; deterioration during pregnancy may precipitate preterm delivery.

• Females with CF of reproductive age should receive preconception counseling and take steps to optimize health prior to pregnancy.
• The management of pregnancy and the immediate postpartum period for a woman with CF requires a dietician, members of the CF team, and a maternal fetal medicine specialist.
• Maternal nutritional status and weight gain should be monitored and optimized aggressively and pulmonary exacerbations should be treated early.
• Traditional screening paradigms for gestational diabetes mellitus may not be useful in pregnancies of women with CF; therefore, screening at each trimester of pregnancy has been suggested to improve the detection of diabetes mellitus.
• As in pregnancies of women with other forms of diabetes mellitus, fetal outcome is optimized when glycemic control is achieved prior to pregnancy.
• Mode of delivery is based on usual obstetric indications.

Therapies Under Investigation

Ursodeoxycholic acid may be cytoprotective and increase bile flow to improve hepatic enzyme levels, bile drainage, liver histology, and nutritional status [Desmond et al 2007, Cheng et al 2012, Leeuwen et al 2014]. However, whether ursodiol therapy can prevent progression of liver disease in the subset of individuals with CF who are at risk for this complication is uncertain [Brigman & Feranchak 2006, Leeuwen et al 2014].

CFTR pathogenic variant-specific candidate drugs:

• CF correctors such as VX-661 are small-molecule therapies being developed to increase the quantity of functional CFTR protein at the cell surface in individuals with specific CFTR pathogenic variants (including the most common CF variant, p.Phe508del).
• Inhaled dry powder mannitol has demonstrated relative sustained improvement in lung function in both European and American trials [Bilton at al 2011, Aiken et al 2012].
• Alternate ion channel regulation is being investigated as a strategy to restore airway surface liquid.

Gene therapy. Gene therapy is in early clinical trials. Gene therapy is not able to control or treat the symptoms related to CF at this time [Prickett & Jain 2013]

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

While there has been much interest in developing active and passive immunization strategies against Pseudomonas aeruginosa, an effective vaccine against P. aeruginosa has not yet been developed.

Mode of Inheritance

Cystic fibrosis (CF) and congenital absence of the vas deferens (CAVD) are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband with CF

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one CFTR pathogenic variant).
• Heterozygotes (carriers) are generally asymptomatic.
• On rare occasions, a parent may be diagnosed as affected subsequent to the diagnosis of the child.

Sibs of a proband with CF

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are generally asymptomatic.

Offspring of a proband with CF

• Females with CF can be fertile.
• Males with CF may conceive children through assisted reproductive technologies (ART).
• Offspring of a male or female proband with CF inherit one CFTR pathogenic variant from their affected parent.
• The risk that a child will inherit a second CFTR pathogenic variant depends on the reproductive partner's genetic status. If the reproductive partner is heterozygous for a CFTR pathogenic variant, offspring are at a 50% risk of being affected and a 50% risk of being obligate heterozygotes.

Parents, sibs, and offspring of a proband with CAVD

• Males with CAVD may conceive children through assisted reproductive technologies (ART).
• The risk to the relatives of a proband with CAVD depends on the parental genotypes and cannot readily be predicted without this information.
• Molecular genetic testing is most informative when the CAVD-causing CFTR variants have been identified in the proband. Men with CAVD may have only one identifiable CFTR variant, complicating the testing and interpretation of results in their family members.

Other family members. Each sib of an individual known to be heterozygous for a CFTR pathogenic variant is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the CFTR pathogenic variants in the family.

If the proband is deceased and molecular testing was not performed, it is appropriate to attempt to obtain an available tissue sample for CFTR molecular testing. If molecular testing cannot be done on the proband's tissue, it is appropriate to offer molecular testing to at-risk family members. Individuals in whom a CFTR pathogenic variant is not identified have a reduced carrier risk (see Table 4).

5T and TG tract typing should not be included in a routine carrier screen. The 5T/TG tract analysis is not able to provide a specific risk figure for developing symptoms or having a child who develops symptoms of non-classic CF or CAVD; it is able to assign risk as "increased" or "decreased."

If an individual has the p.Arg117His pathogenic variant, reflex testing for the variants 5T/7T/9T is recommended. If the individual has the 5T allele, family studies are recommended to determine if the 5T allele is in cis configuration or trans configuration with the p.Arg117His allele. An individual with p.Phe508del and 5T/11TG is highly unlikely to develop non-classic CF. An individual with p.Phe508del and 5T/12TG or p.Phe508del and 5T/13TG may rarely develop CAVD or non-classic CF [Groman et al 2004].

Multiple naming systems are still in use for CFTR pathogenic variants. When ordering targeted testing for familial CFTR variants, it is important to know whether a particular variant is named using the legacy or HGVS convention (see Berwouts et al [2011] for review).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of carrier testing, potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Population Screening

Screening for CF carrier status is offered to some couples as part of routine prenatal care. The ACMG Subcommittee on Cystic Fibrosis Screening recommends offering CF carrier screening to individuals of northern European background and Ashkenazi Jews, and making carrier screening available to other ethnic groups. The Subcommittee recommends a pan ethnic panel including 23 pathogenic variants that includes the majority of CF-causing pathogenic variants with an allele frequency of greater than 0.1% in the general US population (Table 6) [Grody et al 2001] (full text).

The NSGC Practice Guideline recommends that carrier testing for CF be offered to all women of reproductive age, regardless of ancestry; preferably before conception. Pan ethnic panels that include pathogenic variants more commonly identified in minority populations are appropriate to consider for individuals of non-northern European descent. See Carrier Detection for information on interpretation of results of CF carrier testing.

Individuals with no family history of CF and negative carrier testing have a reduced carrier risk. Table 5 provides calculations of the residual risk of being a carrier based on the pathogenic variant detection rate of the test method used and the individual's a priori risk of being a carrier. The laboratory should be provided with complete and accurate information regarding the patient's ethnicity and family history of CF to facilitate accurate calculation of residual risk.

For more information, see the American College of Medical Genetics Carrier Screening ACT Sheets CFTR Mutations except R117H, Cystic Fibrosis R117H, and No Mutations Detected by Carrier Screening.

Prenatal Testing and Preimplantation Genetic Diagnosis

High-risk pregnancies. Once the CFTR pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CF are possible.

Indeterminate-risk pregnancies. Amniotic fluid digestive enzyme analysis may be helpful for prenatal diagnosis in pregnancies of indeterminate risk following CFTR analysis [Oca et al 2009].

Low-risk pregnancies. The finding of fetal echogenic bowel and/or dilated bowel on ultrasound examination is associated with an increased risk for CF in a pregnancy previously not known to be at increased risk for CF. Scotet et al [2010] found a 6.7% incidence of CF in 289 fetuses with the prenatal diagnosis of Grade 3 echogenic bowel, defined as echogenicity similar to or greater than that of surrounding fetal bone and/or intestinal dilation. In this situation, genetic counseling of the parents regarding the risk for CF is appropriate, followed by CFTR molecular genetic testing of the parents and/or the fetus, depending on the gestational age of the pregnancy and the decision of the parents. Based on the pathogenic variant detection rate of the test method used, the risk for CF when only one pathogenic variant is identified in the fetus can be calculated [Bosco et al 1999, Hodge et al 1999].

Genetic Modifiers of CF Phenotype

CFTR, 5T/TG tract analysis. A poly T tract, a string of thymidine bases located in intron 8 of CFTR, can be associated with CFTR-related disorders depending on its size. The three common variants of the poly T tract are 5T, 7T, and 9T. Both 7T and 9T are considered polymorphic variants and 5T is considered a variably penetrant variant. The 5T variant is thought to decrease the efficiency of intron 8 splicing. Poly T testing is appropriate as a reflex test when an Arg117His variant is detected or an adult male is being evaluated for CAVD (see Related Genetic Counseling Issues).

A TG tract lies just 5' of the poly T tract. It consists of a short string of TG repeats that commonly number 11, 12, or 13. A longer TG tract (12 or 13) in conjunction with a shorter poly T tract (5T) has the strongest adverse effect on proper intron 8 splicing [Cuppens et al 1998, Groman et al 2004, Sun et al 2006].

There are ongoing investigations of genetic modifiers of CF nutritional status, liver disease, diabetes, and lung disease. Heritability of several of these traits is high, indicating a significant role for non-CFTR genetic modifiers [Knowles & Drumm 2012]. To date, the association of several genes has been replicated in multiple studies:

• MBL2, EDNRA, and TGF-β1 in lung function
• MBL2 in age at first P. aeruginosa infection
• MSRA in meconium ileus
• TCF7L2 in CF-related diabetes [Knowles & Drumm 2012]
• SERPINA1 in CF-related liver disease [Bartlett et al 2009]

While these genes/variants may be targeted for future therapeutic interventions, no genetic modifier is well established enough at the time of this update to offer clinical testing or change clinical management based on non-CFTR genotype.

Published Guidelines/Consensus Statements

• Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ (Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Services Committee, ACMG). Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Available online. 2001. Accessed 7-26-18. [PubMed: 11280952]
• Langfelder-Schwind E, Karczeski B, Strecker MN, Redman J, Sugarman EA, Zaleski C, Brown T, Keiles S, Powers A, Ghate S, Darrah R. Molecular Testing for Cystic Fibrosis Carrier Status Practice Guidelines: Recommendations of the National Society of Genetic Counselors. Available online. 2014. Accessed 7-26-18. [PubMed: 24014130]
• National Institutes of Health. Consensus statement on genetic testing for cystic fibrosis. Available online. 1997. Accessed 7-26-18.
• Wilson RD, Davies G, Desilets V, Reid GJ, Shaw D, Summers A, Wyatt P, Young D, Crane J, Armson A, de la Ronde S, Farine D, Leduc L, Van Aerde J., Society of Obstetricians and Gynaecologists of Canada. Cystic fibrosis carrier testing in pregnancy in Canada. J Obstet Gynaecol Can. 2002;24:644–51. [PubMed: 12196844]

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Suggested Reading

• Moskowitz SM, Gibson RL, Effmann EL. Cystic fibrosis lung disease: genetic influences, microbial interactions, and radiological assessment. Pediatr Radiol. 2005;35:739–57. [PubMed: 15868140]
• Rubenstein RC. Novel, mechanism-based therapies for cystic fibrosis. Curr Opin Pediatr. 2005;17:385–92. [PubMed: 15891431]
• Welsh MJ, Ramsey BW, Accurso F, Cutting GR. Cystic fibrosis. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill.

Author History

Edith Cheng, MS, MD (2001-present)
James F Chmiel, MD; Case Western Reserve University School of Medicine (2008-2017)
Garry R Cutting, MD (2001-present)
Ronald L Gibson, MD, PhD; University of Washington (2001-2008)
Barbara A. Karczeski, MS, CGC, MA (2017-present)
Susan G Marshall, MD (2001-2004; 2017-present)
Samuel M Moskowitz, MD; Massachusetts General Hospital (2004-2017)
Thida Ong, MD (2017-present)
Darci Sternen, MS, LGC (2001-present)
Jonathan F Tait, MD, PhD; University of Washington (2001-2004)

Revision History

• 2 February 2017 (sw) Comprehensive update posted live
• 19 February 2008 (me) Comprehensive update posted to live Web site
• 24 August 2005 (cd) Revision: changes to ACMG-recommended mutation panel
• 24 August 2004 (me) Comprehensive update posted to live Web site
• 26 March 2001 (me) Review posted to live Web site
• 6 October 1998 (jt) Original submission