A 9-month-old girl presents to her pediatrician for persistent cough, failure to gain weight and a bulging mass from her rectum. Her mother reports that the girl has had two episodes of “pneumonia” requiring hospitalization at the age of 3 and 5 months. Since that time, she has not gained much weight and is noted to be at the 10th percentile for weight and length. On examination, the patient has course breath sounds and wheezes throughout the lung fields, and has rectal prolapse (Figure 51-1). The pediatrician suspects cystic fibrosis and orders a sweat chloride test, which is 120 mEq/L. This confirms the suspected diagnosis, as a result greater than 60 mEq/L is diagnostic for cystic fibrosis. The family is referred to a comprehensive cystic fibrosis center.

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  Cystic fibrosis (CF) is an autosomal recessive disorder caused by a mutation in the CF transmembrane conductance regular gene that alters the composition of mucus secreted in the lungs, pancreas, sweat glands, digestive tract, and vas deferens. This leads to obstructive lung disease and pancreatic insufficiency leading to malabsorption and malnutrition in affected children.

CF, fibrocystic disease of pancreas, mucoviscidosis.

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  Incidence of CF is 1 in 3200 newborns in the US.¹

  
  
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  CF is the most common fatal inherited disorder among Caucasians.

  
  
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  Current median life expectancy of patients diagnosed with CF in the US is between 30 to 40 years.²

  
  
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  CF is most common among Caucasians; 4 to 5 percent of Caucasians in North America are heterozygous for CF.^1,3

  
  
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  CF incidence among Hispanics ranges from 1:9200 to 1:13500 individuals.⁴

  
  
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  CF has an incidence of 1:15,000 in African Americans and 1:31,000 in Asian Americans.³

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  CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7.

  
  
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  The CFTR gene is a 250 kb, 27 exon gene encoding an ATP binding cassette transporter found on the apical surface of mucosal epithelial cells. This protein is responsible for regulating chloride entrance into mucosal cells.⁵

  
  
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  Mutations in CFTR are divided into several classes:^3,5

  
  
  
  
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    Class 1 mutations—Premature transcription termination signal leading to a defective protein.

    
    
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    Class 2 mutations—Protein misfolding leading to premature degradation of CFTR and absence of CFTR expression at the apical surface of mucosal epithelial cells.

    
    
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    Class 3 mutations—Defective regulation of CFTR at the apical surface despite intact ability to traffic CFTR to the cell surface.

    
    
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    Class 4 mutations—Defective CFTR channel conductance of chloride.

    
    
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    Class 5 mutations—Decreased synthesis of functional CFTR due to splicing abnormalities.

    
    
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    Class 6 mutations—Increased turnover of CFTR at the apical surface.

  
  
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  Class 1, 2, and 3 mutations are associated with more severe disease, while class 4 and 5 mutations tend to demonstrate pancreatic insufficiency and milder pulmonary disease.³

  
  
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  The most common mutation in CF is ∆F508, a class 2 mutation that is present in 70 percent of CF patients.¹

  
  
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  The pathophysiology of CF lies in the importance of CFTR in regulating the chloride conductance across the apical membrane of mucosal cells, which impacts sodium and water transport. The end result is a thick, viscous mucus that leads to inflammation, obstruction, and finally fibrosis of organs expressing CFTR in its mucosal cells.⁶

  
  
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  Pulmonary manifestations of CF are due to increased viscosity of the airway surface liquid, which leads to impaired ciliary beating and thus decreased mucociliary clearance.⁵

  
  
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  In addition to alteration of the airway surface liquid, pulmonary disease in CF is also characterized by an impaired immune response to pathogens because of decreased opsonization, decreased pH, and inactivation of antimicrobial peptides.^5,7

  
  
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  CFTR protein is also hypothesized to serve as a binding site for Pseudomonas aeruginosa which leads to phagocytosis and clearance via desquamation.⁵

  
  
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  Another important manifestation of CF is pancreatic insufficiency, which results from thickened secretions from epithelial mucosal cells in the pancreas and leads to destruction of pancreatic β cells. Although insulin secretion is decreased, there is still some endogenous production, preventing the development of ketosis. In addition, the inflammation in the pancreas also reduces α cell mass, which leads to decreased glucagon. Insulin resistance is present in some patients with more severe disease, possibly due to increased inflammation. As patients develop diabetes, slight peripheral insulin resistance also develops.⁶

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  Family history of CF or carrier state.

  
  
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  Caucasian.

Clinical Features

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  Pulmonary symptoms are the most common presenting manifestations of CF. Thick airway mucus and impaired clearance of pathogens leads to colonization of the airways and inflammation. This culminates in obstructive lung disease, specifically bronchiectasis, and leads to clinical findings such as diminished breath sounds, tachypnea, and increased chest diameter.¹

  
  
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  Common pathogens colonizing the airways early in life include Staphylococcus aureus and Haemophilus influenzae.

  
  
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  Eventually, almost all patients acquire and become permanently colonized with P aeruginosa.

  
  
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  Patients with more severe disease may also be colonized with Burkholderia cepacia, which is associated with a poor prognosis.

  
  
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  Pulmonary complications, although uncommon, can become life threatening and include massive hemoptysis, spontaneous pneumothorax, and pulmonary hypertension.

  
  
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  Digital clubbing is apparent even with only mildly reduced lung function (Figure 51-2).

  
  
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  Pancreatic disease in children with CF is characterized by obstruction of pancreatic ducts, which can lead to pancreatitis and eventual loss of pancreatic exocrine function. Consequently, children are unable to digest fat and protein, leading to greasy, foul-smelling stool, abdominal distention, and cramping. This can also lead to malnutrition and failure to thrive. Loss of pancreatic endocrine function can also lead to diminished insulin secretion and thus diabetes.⁶

  
  
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  Twenty to thirty percent of newborns with CF present with meconium ileus due to obstruction from thick intestinal secretions. Older infants and children can develop distal intestinal obstruction syndrome (DIOS) when stool becomes firm and accumulates at the ileocecal valve.

  
  
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  Rectal prolapse occurs in about 20 percent of infants and children and usually occurs early in life (Figure 51-1). This is caused by bowel obstruction, malnutrition, and loss of anal sling musculature.

  
  
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  Hepatobiliary disease occurs from thickened biliary secretions which can lead to acalculous cholecystitis. Liver disease occurs in about a third of children who have CF and a small percentage of them will develop cirrhosis and eventual liver failure.

  
  
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  Pansinusitis is present in almost all children, while nasal polyposis occurs in about 25 percent children with CF. Children less than 12 years of age who have nasal polyposis should be screened for CF.

  
  
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  Infertility is common in males due to absence of the vas deferens. Women with CF may also have decreased fertility due to thickened mucus obstructing the cervix.

Laboratory Testing

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  Newborn screening is increasingly used in the US to identify newborns with CF. Newborns are identified by testing for immunoreactive trypsinogen (IRT), an inactive pancreatic enzyme that is elevated in the serum of infants with CF. Infants who are positive on this initial screen will then undergo either a DNA mutation analysis (IRT/DNA) or a second IRT (IRT/IRT), depending on state policy.⁸

  
  
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  Infants who have a positive newborn screen (2 positive IRT screens or a positive IRT screen and DNA mutation analysis) should be referred to a CF center and undergo sweat chloride testing or definitive genetic testing to confirm the diagnosis.

  
  
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  Sweat chloride testing remains the gold standard for diagnosis and involves using quantitative pilocarpine iontoelectrophoresis. Pilocarpine is applied to stimulate sweat glands. Sweat is collected and analyzed for chloride content.

  
  
  
  
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    A chloride concentration greater than 60 mEq/L is diagnostic for CF, whereas a concentrations less than 40 mEq/L is normal. A concentration between 40–60 mEq/L (30–60 mEq/L in infants less than 2 months) is considered indeterminate.

    
    
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    Infants and children with indeterminate tests should undergo genotype analysis.

  
  
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  DNA testing for known CF mutations can also be used to diagnose CF. This requires identifying two known CF-causing mutations in the CFTR gene. Current DNA tests identify >90 percent CFTR mutations. Thus, a diagnosis of CF cannot be totally excluded using genetic testing. Uncharacterized CFTR mutations are more common in non-Caucasian CF patients. Thus, DNA testing may be more likely to miss a mutation in these patients.¹

  
  
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  In general, genetic testing for CF should be reserved for patients in whom sweat testing is logistically difficult or has yielded indeterminate results.

  
  
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  The function of the CFTR protein in respiratory epithelium can also be assessed directly in vivo by measuring the bioelectric voltage difference across nasal epithelium (the “nasal potential difference”), which is available in a few specialized CF centers.⁹ This test can be used for children who have clinical symptoms of CF but who have normal sweat chloride and genetic testing.