Information on the following diseases can be found in the Related Disorders section of this report:

• None

Associated symptoms may vary in range and severity among affected individuals. This is due, in part, to the fact that the disease may result from many different mutations of the cystic fibrosis gene. The disorder is often apparent shortly after birth, but when symptoms are not severe, it may not be detected until years later.

In some newborns with cystic fibrosis, associated symptoms may include abdominal bloating (distension), and blockage of the small intestine with meconium, the thick, dark material that forms a newborn's first stools. Affected infants often fail to grow and gain weight at the expected rate (failure to thrive), may continue to have abdominal bloating, and may have abnormally large, loose, foul smelling stools that contain an excess of fat (steatorrhea) and other nutrients due to malabsorption.

During childhood or adolescence, associated characteristics may include a chronic cough; wheezing; breathlessness; chronic inflammation of the lung's airways (bronchitis); and recurrent lung infections. As the disease progresses, there is increasing lung damage and, eventually, respiratory failure, and death.

Cystic fibrosis is transmitted as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes for any specific condition, one received from the father and one from the mother.

In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, that person will be "a carrier" for the disease but usually will not show symptoms. When both parents are carriers for a recessive disorder, the risk of transmitting the disease to their children is 25 percent. The risk that their children will be carriers of the disorder, but not likely to exhibit symptoms, is 50 percent. There is a 25 percent likelihood that children of such a couple will receive both normal genes, one from each parent, and be genetically normal (for that particular trait). The probabilities remain the same for each pregnancy.

CF results from changes (mutations) of a gene known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene. More than 1000 mutations of this gene have been identified. The CFTR gene is located on the long arm (q) of chromosome 7 (7q31.2). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered.

The CFTR gene is primarily expressed in cells lining the airways, pancreas, sweat glands, and other exocrine glands. The gene controls the production of a protein that regulates the transfer of chloride and sodium across cell membranes. Accordingly, investigators speculate that inheritance of two mutated copies of the CFTR gene results in disruption of chloride and sodium transfer, ultimately leading to low levels of certain bodily fluids (dehydration), abnormalities of glandular secretions, and impaired glandular functioning.
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There are about 30,000 cases of CF in the United States. One thousand new cases are diagnosed each year. The disorder occurs predominately among Caucasians, occurring in approximately one of every 3,200 live Caucasian births compared to one in 3,900 live births of all Americans. Among African Americans, CF is manifest in about one in 17,000 live births. There is also a small but significant number of Americans of Asian descent who are affected by the disorder. Most individuals are diagnosed by age three. However, nearly 10 percent of those affected do not receive a diagnosis until age 18 or older.
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Diagnosis
The standard diagnostic test for cystic fibrosis is the sweat test, a painless and simple procedure that measures the amount of salt in the sweat. Genetic testing can identify carriers of the defective gene. In May 2005, the U.S. Food and Drug Administration (FDA) approved the first DNA-based blood test to help detect cystic fibrosis. The Tag-It Cystic Fibrosis Kit directly analyzes human DNA to find genetic variations indicative of the disease. It will be used to help diagnose cystic fibrosis in children and to identify adults who are carriers of the gene variations. The kit is manufactured by a Canadian firm, the Bioscience Corporation of Toronto.

Treatment
There is at present no cure for cystic fibrosis. Treatment depends upon the stage of the disease and which organs are involved. Various forms of chest physical therapy, such as applying cupped hands vigorously to the back and chest, may help to dislodge thick mucus from the lungs and maintain clear airways. Antibiotics may be used to treat lung infections. In addition, inhaling particular medications via nebulizers may help to wet and thin the mucus secretions.

When the gastrointestinal system is involved, patients may need to eat an enriched diet and/or take replacement vitamins. Also, studies have shown that neonatal screening may provide an opportunity to prevent malnutrition in infants with cystic fibrosis. Pancreatic insufficiency may be treated by enzyme replacement therapy and diet.

The drug dornase alfa (Pulmozyme) inhalation solution was approved by the FDA for the treatment of CF in 1993. It was the first new drug therapy to be developed exclusively for CF in 30 years. In clinical trials, this mucus-thinning drug reduced the rate of respiratory infection and improved pulmonary function. FDA approval is limited to those over the age of five years. Pulmozyme is manufactured by Genentech, Inc.

The antibiotic drug tobramycin solution for inhalation (TOBI) has been approved by the FDA for the treatment of bronchopulmonary infections of Pseudomonas aeruginosa in individuals with cystic fibrosis. It is manufactured by Chiron.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Research using various approaches, including gene therapy and improved drugs, is being carried out at several locations to identify causes, treatments, and, ultimately, a cure for cystic fibrosis.

Currently (2006) the Clinical Trials web site lists more than 40 studies investigating potential treatments for cystic fibrosis.

The Cystic Fibrosis Foundation maintains a current database of investigational therapies and clinical trials for CF at its Web site at www.cff.org. The organization maintains an active clinical research program, and can be contacted directly for information on current studies at (800) 344-4823

A Phase II trial of the orphan drug PTC124 began in 2005. PTC Therapeutics manufactures this drug. For a certain percentage of CF patients, the cause of the disease is due to a nonsense mutation that stops or slows the production of CFTR protein. It is hoped that this drug will increase the production of this protein. This trial is sponsored by PTC Therapeutics and the Cystic Fibrosis Foundation, and it is listed on www.clinicaltrials.gov. Information is also available from PTC Therapeutics at www.ptcbio.com.

In June 2004, Vertex Pharmaceuticals discovered two new classes of compounds that, in laboratory studies, partially restore the function of the defective cell membrane protein that is responsible for the progression of cystic fibrosis. These compounds act upon the protein via two different mechanisms of action. This research is being sponsored by the Cystic Fibrosis Foundation.

In gene therapy, scientists make normal genes in the laboratory. Then, using innovative delivery systems, such as modified viruses, they deposit these healthy genes in damaged cystic fibrosis cells with the hope that the healthy genes will correct the problem.

Research strategies are aimed at improving the cystic fibrosis gene delivery mechanisms, and circumventing the body's defensive immune mechanisms. Through these studies, scientists expect to increase the quantity of cells that can be treated and the length of time they are corrected.

The antibiotic, azithromycin, appeared to be effective in a phase III trial and is currently (2004) in an observational follow-up trial sponsored by the Cystic Fibrosis Foundation.

In 2002, the U.S. Food and Drug Administration (FDA) granted orphan status for aztreonam (formulated for inhalation) and SPI-8811. Both of these substances are in phase II clinical trials (2004).

Other categories of promising CF investigational therapies include protein-assist therapies, such as phenylbuterate and gentamicin, which attempt to correct the activity of the abnormal CFTR protein, and ion-transport therapies, such as INS 37217 and duramycin, which stimulate alternative mechanisms for chloride to escape the cell.

In 2002, the U.S. Food and Drug Administration (FDA) granted orphan drug status to INS 37217, manufactured by Inspire Pharmaceuticals. A Phase II study was completed in April 2004. Additional study is needed of the safety and efficacy of INS 37217 in treating cystic fibrosis. For information, contact:

Mary Bennett
Senior Vice President, Operations & Communications
Inspire Pharmaceuticals, Inc.
(919) 941-9777

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 219700; Last Update: 4/11/02. See also: Entry No: 602421; Last Update: 4/10/02.

TEXTBOOKS
Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2366-71.

Berkow R, ed. The Merck Manual-Home Edition. Whitehouse Station, NJ: Merck Research Laboratories; 1997:201-04, 1209.

Larson DE, ed. Mayo Clinic Family Health Book. New York, NY: William Morrow and Company, Inc; 1996:720-21.

REVIEW ARTICLES
Johnson L. Retroviral approaches to gene therapy of cystic fibrosis. Ann N Y Acad Sci. 2001;953:43-52

Koletzko S, Reinhardt D. Nutritional challenges of infants with cystic fibrosis. Early Hum Dev. 2001;65 Suppl:S53-61.

Davies JC, Geddes DM, Alton EW. Prospects for gene therapy in lung disease. Curr Opin Pharmacol. 2001;1:272-77.

Flotte TR. Recombinant adeno-associated virus vectors for cystic fibrosis gene therapy. Curr Opin Mol Ther. 2001;3:497-502.

Kunzelmann K, Mall M. Pharmacotherapy of the ion transport defect in cystic fibrosis. Clin Exp Pharmacol Physiol. 2001;28:857-67.

Smyth A, Walters S. Prophylactic antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2001;(3):CD001912.

Jaffe A, Bush A. Cystic fibrosis: review of the decade. Monaldi Arch Chest Dis. 2001;56:240-47.

Singh MP. Tobramycin (Cystic Fibrosis Foundation/PathoGenesis) Curr Opin Investig Drugs. 2001;2:755-65.

Pai VB, Nahata MC. Efficacy and safety of aerosolized tobramycin in cystic fibrosis. Pediatr Pulmonol. 2001;32:314-27.

Hulka GF. Head and neck manifestations of cystic fibrosis and ciliary dyskinesia. Otolaryngol Clin North Am. 2000;33:1333-41.