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2002 Selected Articles

Cystic Fibrosis Screening in Current Practice

Owen P. Phillips, MD; Lee P. Shulman, MD; Sherman Elias, MD

Cystic fibrosis (CF) is a disorder of exocrine glands that is inherited in autosomal recessive fashion and is characterized by thickened, viscid secretions that lead to multisystem dysfunction, failure, and death. CF is the most common autosomal recessive condition in white populations; its frequency among whites in North America is approximately 1 in 2,500, with a carrier, or heterozygote, frequency of 1 in 29. In nonwhite communities, the frequency of CF is considerably less.¹ This article, the first in a two-part series, addresses prenatal screening guidelines of CF in current practice. The second part of this series will focus on screening specific ethnic and racial groups.

In 1997, the National Institutes of Health (NIH) Consensus Development Conference on Genetic Testing for Cystic Fibrosis recommended that CF screening be offered to the following populations: individuals with a positive family history of CF, partners of individuals with CF, and couples currently planning a pregnancy or seeking prenatal care.² An NIH workshop later that year reviewed the implementation of the recommendations of the NIH conference. Recognizing that successful implementation would necessitate the collaboration of several organizations and societies, the American College of Obstetricians and Gynecologists (ACOG), the American College of Medical Genetics, and the NIH convened a steering committee to create and review the various aspects of such a screening process.³ Their work, and that of others, is now the focus of the new CF screening protocol for clinicians and patients.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION

CF is a multisystem disorder caused by the absence or dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Pulmonary disease is the major manifestation of CF; the increasingly viscid secretions in the bronchopulmonary system lead to airway obstruction and dyspnea and an increased predisposition to infection, bronchial obstruction, and pulmonary fibrosis. Pulmonary disease ranges from very mild symptoms to severe, progressive chronic bronchopulmonary disease; chronic progressive bronchopulmonary disease leading to bronchopulmonary infection is the major cause of morbidity and mortality in affected individuals.⁴

Thick secretions lead to dysfunction in other vital organs as well. About 85% of individuals with CF are affected by various degrees of pancreatic and intestinal malfunction. Thus, individuals with CF may exhibit progressive loss of pancreatic function with an increased incidence of diabetes mellitus.⁵

In the gastrointestinal tract, the lack of digestive enzymes leads to malabsorption of fats and protein with the presence of thickened mucus increasing the risk for bowel obstruction.⁶ The gastrointestinal effects of CF can sometimes be identified in utero by ultrasonographic detection of hyperechogenic bowel in the developing fetus resulting from meconium ileus.⁷

In affected individuals, sweat electrolytes are usually characterized by elevated levels of sodium and chloride as a result of CFTR absence or dysfunction. Patients commonly report heat intolerance and may become hyponatremic and alkalotic as a result of hypochloremic metabolic alkalosis. There are neither unique nor typical dysmorphic features. In addition, no particular central nervous system, intelligence, or psychiatric disorder is associated with CF.¹

Diagnosis of CF can be accomplished by a sweat chloride test and, more recently, confirmation by DNA analysis. A cure is not yet available; symptomatic management remains the mainstay of therapy and includes chest physical therapy, mucolytic agents, antibiotics, anti-inflammatory drugs for pulmonary complications, and pancreatic enzyme replacement and nutritional support for pancreatic and gastrointestinal manifestations. Gene therapy is currently being investigated but does not appear to be readily available in the near future.¹

Advances in the medical treatment of CF have considerably improved the prognosis for affected individuals over the past decade. The median age at diagnosis is 6 to 8 months. In the US, median survival has increased to 31.1 years for men and 28.3 years for women. Survival of affected individuals into their fourth and fifth decades is no longer uncommon.⁸

MOLECULAR AND GENETIC CONSIDERATIONS

CF results from mutations in the CF gene, a gene that has been mapped to chromosome 7, band q31, and codes for the CFTR protein.⁹ When CFTR is not produced or is altered in structure or function as result of mutations in the CF gene, viscid secretions are produced that primarily affect the respiratory and gastrointestinal systems.⁴

More than 800 mutations have been identified in the CF gene. Because of the large number of mutations in the CF gene, as well as other molecular, cellular, and environmentally modifying effects, the clinical presentation and course of affected individuals can be highly variable. The first CF mutation identified, delta F508 (ΔF508), is a deletion of 3 base pairs in exon 10 that code for phenylalanine at the 508th amino acid of the CFTR protein.^10,11 The highest frequency for ΔF508 is observed in white populations, especially of northern and central European origins, where it accounts for 70% to 75% of mutant CF alleles. ΔF508 mutation accounts for 48% of mutant CF alleles in blacks, 46% in Latinos, and 30% in Asian Americans. Among Ashkenazi Jews, the ΔF508 mutation along with the W1282X mutation accounts for approximately 95% of all CF mutations.¹

Clinical severity of CF is influenced by the particular mutation(s) present. There is a correlation with genotype and phenotype regarding pancreatic and gastrointestinal abnormalities; however, no such correlation exists with regard to pulmonary manifestations.¹² Homozygosity for ΔF508 frequently leads to the severe CF phenotype. However, different mutations and combinations of mutations (compound heterozygosity) can result in different and varied degrees of protein dysfunction and, thus, disease presentation. Individuals who are compound heterozygotes possess two different CF mutations. Compound heterozygosity is relatively common because of the large number of mutations that have been reported. The presence of two different mutations in an individual may result in an unpredictable phenotype and makes phenotype-genotype correlations difficult.

FERTILITY AND PREGNANCY

Women with CF have menstrual disorders and decreased fertility. Affected women frequently have delayed onset of menses and increased risk of anovulation and secondary amenorrhea; these conditions are believed to be linked to the adverse nutritional status of many women with CF.¹³ However, cervical factors theoretically contribute to the higher rates of infertility because the thickened cervical mucus can serve as an effective barrier to sperm penetration and capacitation.

As individuals with CF are living well into their reproductive years, more women with CF are requesting contraception, infertility management, and obstetrical care. Although no formal studies have been performed, there does not appear to be any contraindications to reversible sex-steroid contraceptive methods for women with CF. Accordingly, low-dose oral contraceptives and combination sex-steroid injectable methods provide effective and reversible contraception and help restore regular menstrual cyclicity.¹⁴ Conversely, for those women who desire pregnancy and are unable to conceive, ovulation stimulation and assisted reproductive technologies are now able to effectively influence the hormonal milieu and mucus-related problems that could assist many women with CF in their desire to become pregnant.

CARRIER SCREENING

Ideally, carrier screening should be offered to couples before they become pregnant so that they can consider the complete range of reproductive options. Nonetheless, carrier screening for CF is accomplished by directly evaluating individuals for specific CFTR mutations, regardless of the timing of the screening. As stated earlier, more than 800 mutations have thus far been identified, with theΔF508 mutation being the most common mutation causing CF. However, its relative frequency varies among different ethnic and racial groups. Approximately 30 mutations account for 85% of CF alleles, again with the frequency dependent on the specific ethnic or racial group. Most of the remaining mutations occur infrequently and are considered “private” mutations that occur in particular families.¹⁵

Recognition of the particular frequencies of CF mutations in specific populations allows for more precise screening of individuals. In several populations, the combination of ΔF508 with several additional CFTR mutations allows for high detection rates. For example,ΔF508 accounts for only 30% of mutations among Ashkenazi Jews. The W1282X mutation is far more common in this population; when both mutations are included in a CF screening panel, CF carrier detection rates for Ashkenazi Jews rise to approximately 95%.¹⁶

The higher the rate of mutation detection for individuals of a particular group, the more precise the counseling. If an individual is screened for a panel of CF mutations and none is found, it does not totally exclude that individual from being a CF carrier, since a mutation not included in the panel could still be present. This information should be used to adjust the estimated risk for CF carrier status during genetic counseling.

ACOG recommends that the following groups be offered carrier screening:

• Adults with a positive family history of CF
• Partners of individuals with CF
• White couples of European and Ashkenazi Jewish heritage planning a pregnancy
• White couples of European and Ashkenazi Jewish heritage seeking prenatal care

Couples who are in lower-risk racial or ethnic groups (eg, blacks, Asian Americans) where there is no known admixture with higher-risk groups, CF screening should be made available, but not actively offered, by providing written materials about the risks of having a child with CF and the sensitivity and limitations of carrier screening in their racial or ethnic group.

Counseling for CF screening may include personal interaction with a knowledgeable health care provider, written materials and possibly video, Internet, and interactive media. CF screening counseling should include a description of the clinical manifestations of CF, the purpose and voluntary nature of screening, factors to consider in the decision to undergo or forego CF screening, the genetics of CF and estimates for carrier status for the individual receiving counseling, and the meaning and implications of positive and negative screening outcomes.¹

There are several screening strategies to consider. Sequential screening involves the screening of one partner, with the other partner being tested only if the first partner is found to carry a mutant gene. Concurrent screening involves the screening of both partners at the same time. Both strategies carry potential benefits and pitfalls; however, patient, couple, and logistical issues may supercede the screening strategy in any given venue. Nonetheless, issues concerning positive and negative screening results, particularly for those couples in which one partner tests positive and the other tests negative, should be reviewed. Known as intermediate risk, this will require detailed genetic counseling, and may lead to considerable anxiety and fear rather than the intended purpose of genetic screening and testing to reduce such anxiety and fear. In such cases, referral to an expert in this field may be warranted.³

Ideally, carrier screening for couples who have been identified as carriers of CF, should be offered prenatal diagnosis by either chorionic villus sampling or amniocentesis. For couples who elect prenatal diagnosis, counseling should communicate that the presence of specific CF mutations in the fetus cannot be used to fully predict the severity of pulmonary complications.

CONCLUSION

It is now incumbent upon health care providers to offer CF screening to all appropriate higher risk women and couples, or to refer such individuals for counseling and screening by qualified professionals. Accordingly, CF counseling and screening should be offered in a fashion similar to second-trimester maternal serum screening–nondirective counseling describing an elective screening protocol with risks, benefits and limitations for those who choose to undergo or forego the screening. As with other genetic-related issues, referral to and consultation with local/regional geneticists who have special expertise in CF screening, diagnosis, and treatment should be considered in situations when the obstetrician or primary care provider may not be comfortable in identifying at-risk individuals or in providing counseling or screening.

Owen P. Phillips, MD, is an associate professor, Department of Obstetrics and Gynecology, and chief, genetics, both at the University of Tennessee, Memphis; Lee P. Shulman, MD, is a professor of obstetrics and gynecology and molecular genetics, director, Division of Reproductive Services, and deputy head, Department of Obstetrics and Gynecology, all at the University of Illinois at Chicago; Sherman Elias, MD, is professor and chair, Department of Obstetrics and Gynecology, and professor of molecular genetics, both at the University of Illinois at Chicago.

This work is based on the article “Cystic Fibrosis,” authored by Lee P. Shulman and Sherman Elias and found in the Metabolic and Genetic Screening edition of Clinics in Perinatology, Volume 28, No. 2, June 2001.

REFERENCES

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