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36 AJN ▼ June 2014 ▼ Vol. 114, No. 6 ajnonline.com

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Cystic fibrosis (CF) is the second most common potentially life-shortening genetic disorder affecting U.S. children.1 Like sickle cell dis- ease, the most common serious inherited disorder of childhood onset, CF is an autosomal recessive dis- order. Although CF occurs in most racial and ethnic groups, it is most common among white Americans, with an incidence of one per 2,500 live births in this population, and both ethnic and geographic distribu- tion vary widely (see Table 11-3).4-6 Currently, there is no cure for CF, but recent advances in genomic tech- nology have given rise to treatments that increase life expectancy and quality of life for people with CF. In the 1930s, infants born with CF seldom lived past four months of age. Today, patients with CF can be expected to live beyond the fourth or fifth decade. At many CF centers, the number of adult patients exceeds the number of pediatric patients.7 As a re- sult, nurses are now more likely to encounter pa- tients with CF in a variety of settings, including adult and pediatric primary care centers, specialty clinics, tertiary care settings, and schools. To optimize the care of these patients, nurses need to understand CF

genetics, CF manifestations, and recent genomic de- velopments that have advanced CF treatment.

This article describes recent genetic discoveries in the area of CF; the spectrum of genetic variants and phenotypic clinical presentations; the impact of new genomic advances on CF diagnosis and treatment; and implications for nursing practice, education, and research. It summarizes findings from salient research of the past 10 years, as well as from earlier seminal articles in the CF literature, and provides a glossary of common genetic terms (see Table 2).

PATHOPHYSIOLOGY OF CF CF is caused by mutations in the cystic fibrosis trans- membrane conductance regulator (CFTR) gene, which regulates the hydration of epithelial cells throughout the body by controlling chloride and sodium trans- port. Defects in the chloride channel alter the trans- port of electrolytes across the cell membrane, resulting in excessive secretion of chloride and sodium in the sweat and abnormally thick secretions in exocrine glands, most notably, the lungs, pancreas, and repro- ductive organs. Consequently, the most common

2.3

OVERVIEW: Cystic fibrosis (CF) is an autosomal recessive disorder that was long considered a terminal illness. Recent genetic discoveries and genomic innovations, however, have transformed the diagnosis, classifica- tion, and treatment of this multisystem condition. For affected patients, these breakthroughs offer hope for significantly greater longevity and quality of life and, perhaps, for a future cure. This article reviews empirical research on CF, filling a critical gap in the nursing literature regarding recent findings in the study of CF ge- netics and their implications for patient teaching, diagnosis, and treatment.

Keywords: cystic fibrosis, cystic fibrosis transmembrane conductance regulator gene, genetics, genomics, patient education

The nursing implications of recent genetic discoveries and technologic advances.

Genomic Breakthroughs in the Diagnosis and Treatment of Cystic Fibrosis

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By Stephanie J. Nakano, BSN, RN, and Audrey Tluczek, PhD, RN

problems associated with CF are chronic bacterial infections in the lungs and progressive obstructive pulmonary disease, both resulting from decreased mucociliary clearance, and malnutrition resulting from pancreatic insufficiency. Men tend to be infertile owing to congenital bilateral absence of the vas deferens. Al- though many women with CF can become pregnant, CF may thicken cervical mucus, thereby obstructing the sperm’s entry and reducing fertility.

GENETIC IMPLICATIONS Because CF is inherited in an autosomal recessive pattern, a person must inherit two mutations in the CFTR gene, one from each parent, in order to mani- fest symptoms. Those who inherit only one mutation are classified as carriers and are not expected to de- velop CF symptoms. A child has a one in four chance of having CF if both parents are carriers, and a one in two chance if one parent has CF and the other is a carrier (see Figure 1). For a given couple, the risk of inheritance remains the same with each preg- nancy.

The CFTR gene is located on the long arm of chro- mosome 7. As of this writing, genomic advances have led to the identification of 1,965 CFTR mutations, though the number continues to rise.8 There is evi- dence that 127 mutations sufficiently impair CFTR function to produce CF symptoms.9 Of the remaining mutations, 225 are known to produce no symptoms, and the others are of unknown clinical significance.10

A project called the Clinical and Functional Transla- tion of CFTR (www.cftr2.org) is dedicated to docu- menting all CFTR mutations and associated clinical presentations.

Symptom-causing mutations interfere with the protein responsible for transporting chloride across the cell membrane. Based on the means by which they disrupt CFTR protein production or function, there are six classes of CF mutations, which are not mutually exclusive (see Table 38, 11-14). Patients with class I and II mutations, which result in very limited or no CFTR protein production, are more likely to manifest typical CF symptoms, including pulmonary disease and pancreatic insufficiency, in infancy or early childhood. Patients with classes III, IV, V, and VI mutations have some protein production. Patients who have class IV mutations, in which protein pro- duction is normal, tend to have milder symptoms than patients with two class I or II mutations, even if they also have a single class I or II mutation.12

Although information on the correlation between patients’ genotype and phenotype is limited, clinical symptoms usually reflect the degree to which CFTR protein function is lost.12 Clinical presentation of CF, particularly pulmonary symptoms, varies widely, even among patients who have the same CFTR gene mutations. These variations suggest that environmen- tal factors such as medical treatment and adherence to prescribed recommendations, or genetic factors such as modifier genes (non-CFTR alleles that can

2 out of 4 have CF (50%)

2 out of 4 are carriers

(50%)

1 out of 4

has CF (25%)

2 out of 4 are carriers (50%)

1 out of 4 does not have CF (25%)

= Both chromosomes with CFTR mutation (CF diagnosis)

= 1 chromosome with CFTR mutation (CF carrier)

= Neither chromosome with CFTR mutation (neither CF carrier nor CF diagnosis)

Figure 1. The Autosomal Recessive Inheritance Pattern in Cystic Fibrosis. CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator.

38 AJN ▼ June 2014 ▼ Vol. 114, No. 6 ajnonline.com

affect CFTR function), may play a significant role in symptom manifestation and disease progression.5, 15, 16

NEWBORN SCREENING AND DIAGNOSIS Newborn screening for CF was first introduced as a pilot project—in Colorado in 1982 and in Wisconsin in 1985.1 These early screening programs measured the pancreatic enzyme immunoreactive trypsinogen (IRT), which is usually elevated in CF, to identify in- fants at risk. With the discovery of the CF gene in 1989 and related advances in molecular genetics, DNA analysis was added to the screening procedure. In 1991, DNA analysis for F508del, the gene muta- tion responsible for most cases of CF, was added to the newborn screening panel in Wisconsin. This mile- stone marked the first time DNA testing had been ap- plied to population-based newborn screening in the United States. Later, additional CF symptom-causing mutations were added to screening panels. Today, throughout the United States and in most industri- alized countries, newborns are screened for CF.

Research has shown that early di- agnosis and prompt treatment im- prove nutrition and growth and can thus be expected to improve overall health and survival.

Newborn screening involves ob- taining a blood specimen through a heel prick and sending it to a CF- screening laboratory for analysis. Most such laboratories screen for CF by measuring IRT, and if levels are elevated, following up with a second test that may include repeat- ing the IRT measurement or analyz- ing DNA for CFTR mutations. Algorithms for CF newborn screen- ing vary by state or jurisdiction (for one example, see Figure 25, 10, 17, 18). The Cystic Fibrosis Foundation rec- ommends that newborn screening panels include the 23 most com- mon symptom-causing mutations.10 Since the ethnic composition of the population screened affects the frequency and distribution of mu- tations, gene panels may vary by geographic region. For example, the screening panel recommended by the American College of Medical Genet- ics for screening white Americans identifies only 68.5% of mutations that are associated with CF in His- panic Americans.10 The frequency of F508del mutation in people with CF is 72% among white Americans, only 31% to 44% among black Ameri- cans, and 18% among Iranians.19

Newborn screening is considered positive (abnor- mal) if the IRT is elevated and the DNA analysis indi- cates one or two symptom-causing CFTR mutations. Positive screening is followed by a diagnostic sweat test. When multimutation panels are used, about 97% of infants found to have only one CF mutation through newborn screening have normal sweat test results, indicating that they do not have CF.17 Because of the ethnically diverse population of California, the state’s newborn screening procedure includes three steps: IRT and DNA analysis followed by gene se- quencing, which searches for CFTR mutations not on the screening panel. Consequently, only infants found to have two mutations are referred for a con- firmatory sweat test in California.5 Genetic counsel- ing is recommended for all families with infants found to have one or two CFTR mutations, regard- less of the screening algorithm used.20

A CF diagnosis requires the presence of clinical symptoms and evidence of a CFTR defect, which is reflected in elevated sweat chloride levels, or the

Newborn screening for CF

Elevated IRT levels

Elevated IRT levels CFTR mutations found

Normal IRT levels No CFTR mutations found

Abnormal screen

Results communicated to provider and/or family

Sweat chloride test

CF diagnosis confirmed (chloride

≥ 60 mEq/L)

Intermediate result

(chloride 30–59 mEq/L)

Normal result CF ruled out

(chloride < 30 mEq/L)

Negative screen for CF

Repeat IRT or DNA analysis and/or

gene sequencing

Normal IRT levels

Figure 2. A Cystic Fibrosis Newborn Screening Algorithm.5, 10, 17, 18 CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; IRT = immunoreac- tive trypsinogen.

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confirmation of CF-causing mutations on both al- leles. A sweat test that uses pilocarpine iontophore- sis is considered the gold standard for diagnosis. A sweat chloride value of 60 mEq/L or higher confirms a CF diagnosis in all age groups; a value between 30 and 59 mEq/L in infants younger than six months, or between 40 and 59 mEq/L in children and adults, is considered an “intermediate” result, which is in- conclusive; and a value below 30 mEq/L in infants younger than six months, or 39 mEq/L or lower in children and adults, rules out a CF diagnosis.10 If sweat test results are intermediate, the test may be repeated and additional DNA analysis may be per- formed to establish the individual’s diagnostic sta- tus.

THE CF SPECTRUM With the implementation of genetic testing in new- born screening came the inevitable consequence of identifying infants in the intermediate range of CF diagnosis. Clinical evidence, diagnostic test results, and the number and type of CFTR mutations deter- mine where a patient’s diagnosis falls along the CF spectrum (see Figure 310, 15, 21, 22). The classifications within the spectrum guide clinicians in determining the treatment and frequency and type of monitoring the patient requires.

Those with a clear CF diagnosis have evidence of two symptom-causing mutations confirmed by the presence of pulmonary involvement, pancreatic in- sufficiency, or both, as well as diagnostic sweat chlo- ride levels in the clinical range.15, 23 Patients with CF may or may not have a family history of CF.

Some people do not meet these diagnostic criteria but have evidence of multisystem disease in addition

to an intermediate sweat chloride value or a CFTR mutation that may or may not have known clinical relevance. These patients are classified as having CFTR-related disease (CFTR-RD). They tend to have some CFTR function and present atypically compared with patients who have a clear CF diag- nosis.15, 23 These patients usually have less severe lung disease and are less likely to have pancreatic insufficiency. Conditions that can be associated with CFTR-RD include congenital bilateral absence of the vas deferens, disseminated bronchiectasis, and recurrent acute pancreatitis or chronic pancreatitis.15, 23

CFTR-related metabolic syndrome (CRMS) is in- dicated by fewer than two CF-causing CFTR muta- tions and an intermediate sweat chloride value, or two CFTR mutations, of which no more than one is CF causing, and a normal sweat chloride value.22 This classification is generally associated with a more favorable prognosis and less need for aggressive treat- ment than a CF diagnosis. Even so, affected patients should be followed closely because they may develop clinical symptoms of CF.

CF Carrier

1 CFTR mutation Normal sweat chloride:

< 30 mEq/L

CRMS

< 2 CF-causing CFTR mutations

Intermediate sweat chloride: 30–59 mEq/L

OR 2 CFTR mutations

(1 CF causing) Normal sweat chloride:

T

Reduced Diminished Mild symptoms or delayed onset of typical symptoms

Class VI Functional protein present at membrane for a shorter than normal period

Unknown Q1412X Normal Diminished Mild symptoms or delayed onset of typical symptoms

Table 3. Classification of Cystic Fibrosis8, 11-14, a

CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator. a The authors acknowledge Patrick Sosnay, MD, of Johns Hopkins University for reviewing this table on behalf of the CFTR2 project. b Most common CFTR mutation; at least one copy is found in approximately 90% of CF cases worldwide.

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Research. Recent genetic discoveries related to CF raise issues that call for additional nursing re- search. The widespread use of newborn screening allows parents to learn a child’s carrier status in in- fancy. Little is known about the optimal time or way in which to inform children that they are CF carriers. There is also a dearth of information on the effects of the new CF diagnostic classifications on parents’ perceptions of their children’s health or on their parenting styles. Some data, for example, sug- gest that parents of children found to be CF carriers through newborn screening might view their chil- dren as being more susceptible to illness or more “fragile” than noncarriers.33 One of us (AT) is cur- rently collecting data for a study that will shed light on this issue. Empirical evidence will be critical in identifying the most effective approaches to commu- nicating genetic test results and educating patients and their families. ▼

Stephanie J. Nakano is a staff nurse in the Department of Nurs- ing and Patient Services and works in the pediatric ICU of Amer- ican Family Children’s Hospital, Madison, WI. Audrey Tluczek is an associate professor at the University of Wisconsin–Madison School of Nursing. Contact author: Audrey Tluczek, atluczek@ wisc.edu. The authors and planners have disclosed no potential conflicts of interest, financial or otherwise.

REFERENCES 1. Grosse SD, et al. Newborn screening for cystic fibrosis: eval-

uation of benefits and risks and recommendations for state newborn screening programs. MMWR Recomm Rep 2004; 53(RR-13):1-36.

2. Cutting GR. Genetic epidemiology and genotype/phenotype correlations. In: Genetic testing for cystic fibrosis. Program and abstracts. Bethesda, MD: National Institutes of Health; 1997. p. 19-22. NIH Consensus Development Conference on Genetic Testing for Cystic Fibrosis, April 14-16, 1997. http://consensus.nih.gov/1997/1997GeneticTestCysticFibrosis 106Program.pdf#page=24.

3. Grebe TA. Cystic fibrosis among Native Americans of the Southwest. In: Genetic testing for cystic fibrosis. Program and abstracts. Bethesda, MD: National Institutes of Health; 1997. p. 87-90. NIH Consensus Development Conference on Genetic Testing for Cystic Fibrosis, April 14-16, 1997. http://consensus.nih.gov/1997/1997GeneticTestCysticFibrosis 106Program.pdf#page=92.

4. Cohen-Cymberknoh M, et al. Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med 2011;183(11):1463-71.

5. Sharp JK, Rock MJ. Newborn screening for cystic fibrosis. Clin Rev Allergy Immunol 2008;35(3):107-15.

6. Voter KZ, Ren CL. Diagnosis of cystic fibrosis. Clin Rev Al- lergy Immunol 2008;35(3):100-6.

7. Ratjen F. Recent advances in cystic fibrosis. Paediatr Respir Rev 2008;9(2):144-8.

8. Hospital for Sick Children, Cystic Fibrosis Centre. Cystic fi- brosis mutation database. 2011. http://www.genet.sickkids. on.ca/cftr/app.

9. Sosnay PR, et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet 2013;45(10):1160-7.

10. Farrell PM, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Founda- tion consensus report. J Pediatr 2008;153(2):S4-S14.

11. Cystic Fibrosis Foundation. Patient registry. Annual data report 2011. Bethesda, MD; 2012. http://www.cff.org/ UploadedFiles/research/ClinicalResearch/2011-Patient- Registry.pdf.

12. Kreindler JL. Cystic fibrosis: exploiting its genetic basis in the hunt for new therapies. Pharmacol Ther 2010;125(2): 219-29.

13. Rowntree RK, Harris A. The phenotypic consequences of CFTR mutations. Ann Hum Genet 2003;67(Pt 5): 471-85.

14. Thursfield RM, Davies JC. Cystic fibrosis: therapies target- ing specific gene defects. Paediatr Respir Rev 2012;13(4): 215-9.

15. Bombieri C, et al. Recommendations for the classification of diseases as CFTR-related disorders. J Cyst Fibros 2011; 10Suppl2:S86-S102.

16. Knowles MR. Gene modifiers of lung disease. Curr Opin Pulm Med 2006;12(6):416-21.

17. Rock MJ, et al. Newborn screening for cystic fibrosis in Wisconsin: nine-year experience with routine trypsinogen/ DNA testing. J Pediatr 2005;147(3 Suppl):S73-S77.

18. Montgomery GS, Howenstine M. Cystic fibrosis. Pediatr Rev 2009;30(8):302-9.

19. Rohlfs EM, et al. Cystic fibrosis carrier testing in an ethnically diverse US population. Clin Chem 2011;57(6): 841-8.

20. Clinical and Laboratory Standards Institute (CLSI). Newborn screening for cystic fibrosis; approved guideline (NBS05-A, formerly I/LA35-A). Wayne, PA; 2011 Nov. http://shopping. netsuite.com/s.nl/c.1253739/it.A/id.978/.f.

21. Dungan JS. Carrier screening for cystic fibrosis. Obstet Gy- necol Clin North Am 2010;37(1):47-59.

22. Ren CL, et al. Clinical outcomes in infants with cystic fi- brosis transmembrane conductance regulator (CFTR) re- lated metabolic syndrome. Pediatr Pulmonol 2011;46(11): 1079-84.

23. Knowles MR, Durie PR. What is cystic fibrosis? N Engl J Med 2002;347(6):439-42.

24. Wang X, et al. Increased prevalence of chronic rhinosinusitis in carriers of a cystic fibrosis mutation. Arch Otolaryngol Head Neck Surg 2005;131(3):237-40.

25. Cohn JA, et al. Increased risk of idiopathic chronic pancre- atitis in cystic fibrosis carriers. Hum Mutat 2005;26(4): 303-7.

26. de Cid R, et al. Independent contribution of common CFTR variants to chronic pancreatitis. Pancreas 2010;39(2): 209-15.

27. Accurso FJ, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 2010;363(21):1991-2003.

28. Ramsey BW, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365(18): 1663-72.

29. Barnes B. Approval of Kalydeco bodes well for new CF drugs targeting genetic defects. CFRI News 2012. http:// www.cfri.org/pdf/2012CFRInewsSpringIssue.pdf.

30. Cystic Fibrosis Foundation. About cystic fibrosis: what you need to know. n.d. http://www.cff.org/aboutcf.

31. Tluczek A, et al. Psychosocial consequences of false-positive newborn screens for cystic fibrosis. Qual Health Res 2011;21(2):174-86.

32. Eakin MN, Riekert KA. The impact of medication adher- ence on lung health outcomes in cystic fibrosis. Curr Opin Pulm Med 2013;19(6):687-91.

33. Tluczek A, et al. Factors associated with parental perception of child vulnerability 12 months after abnormal newborn screening results. Res Nurs Health 2011;34(5):389-400.

For five additional continuing nursing educa- tion activities on genomics topics, go to www. nursingcenter.com/ce.

mailto:atluczek@wisc.edu
mailto:atluczek@wisc.edu
http://consensus.nih.gov/1997/1997GeneticTestCysticFibrosis106Program.pdf#page=24
http://consensus.nih.gov/1997/1997GeneticTestCysticFibrosis106Program.pdf#page=24
http://consensus.nih.gov/1997/1997GeneticTestCysticFibrosis106Program.pdf#page=92
http://consensus.nih.gov/1997/1997GeneticTestCysticFibrosis106Program.pdf#page=92
http://www.genet.sickkids.on.ca/cftr/app
http://www.genet.sickkids.on.ca/cftr/app
http://www.cff.org/UploadedFiles/research/ClinicalResearch/2011-Patient-Registry.pdf
http://www.cff.org/UploadedFiles/research/ClinicalResearch/2011-Patient-Registry.pdf
http://www.cff.org/UploadedFiles/research/ClinicalResearch/2011-Patient-Registry.pdf
http://shopping.netsuite.com/s.nl/c.1253739/it.A/id.978/.f
http://shopping.netsuite.com/s.nl/c.1253739/it.A/id.978/.f
http://www.cfri.org/pdf/2012CFRInewsSpringIssue.pdf
http://www.cfri.org/pdf/2012CFRInewsSpringIssue.pdf
http://www.cff.org/aboutcf.
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