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Cystic fibrosis

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Cystic fibrosis
   Classifications and external resources

     ICD- 10   E 84.
     ICD- 9    277
      OMIM     219700
   DiseasesDB  3347
   MedlinePlus 000107
    eMedicine  ped/535

   Cystic fibrosis (CF) is a common hereditary disease that affects the
   entire body, causing progressive disability and early death. Difficulty
   breathing is the most common symptom and results from frequent lung
   infections, which are treated, though not always cured, by antibiotics
   and other medications. A multitude of other symptoms, including sinus
   infections, poor growth, diarrhea and male infertility, result from the
   effects of CF on other parts of the body.

   CF is one of the most common fatal inherited diseases. It is most
   prevalent among Europeans and Ashkenazi Jews; one in twenty-two people
   of European descent carries one gene for CF, making it the most common
   genetic disease among them. Individuals with cystic fibrosis can be
   diagnosed prior to birth by genetic testing or in early childhood by a
   sweat test. There is no cure for CF, and most individuals with cystic
   fibrosis die young — many in their 20s and 30s from lung failure.
   Ultimately, lung transplantation is often necessary as CF worsens.

   CF is caused by a mutation in a gene called the cystic fibrosis
   transmembrane conductance regulator (CFTR). The product of this gene
   helps create sweat, digestive juices, and mucus. Although most people
   without CF have two working copies of the CFTR gene, only one is needed
   to prevent cystic fibrosis. CF develops when neither gene works
   normally. Therefore, CF is considered an autosomal recessive disease.
   The name cystic fibrosis refers to the characteristic scarring (
   fibrosis) and cyst formation within the pancreas, first recognized in
   the 1930s.

Symptoms and signs

   The symptoms of cystic fibrosis depend on the age of an individual, the
   extent the disease affects specific organs, prior therapy, and the
   types of infections experienced. Cystic fibrosis affects the entire
   body and impacts growth, breathing, digestion, and reproduction. The
   newborn period may be marked by poor weight gain and intestinal
   blockage caused by thick feces. Other symptoms of CF appear during the
   remainder of childhood and early adulthood. These include continued
   problems with growth, the onset of lung disease, and increasing
   difficulties with poor absorption of vitamins and nutrients by the
   gastrointestinal tract. In addition, difficulties with fertility may
   become apparent when reproduction is attempted.

Lung and sinus disease

   Lung disease results from clogging of airways due to inflammation.
   Inflammation and infection cause injury to the lungs and structural
   changes that lead to a variety of symptoms. In the early stages,
   incessant coughing, copious phlegm production, and decreased ability to
   exercise are common. Many of these symptoms occur when bacteria that
   normally inhabit the thick mucus grow out of control and cause
   pneumonia. In later stages of CF, changes in the architecture of the
   lung further exacerbate chronic difficulties in breathing.
   Aspergillus fumigatus - A common fungus which can lead to worsening
   lung disease in people with CF.
   Enlarge
   Aspergillus fumigatus - A common fungus which can lead to worsening
   lung disease in people with CF.

   Other symptoms include coughing up blood, changes in the major airways
   in the lungs ( bronchiectasis), high blood pressure in the lung (
   pulmonary hypertension), heart failure, difficulties getting enough
   oxygen to the body, and respiratory failure requiring support with
   breathing masks such as bilevel positive airway pressure machines or
   ventilators. In addition to typical bacterial infections, people with
   CF more commonly develop other types of lung disease. Among these is
   allergic bronchopulmonary aspergillosis, in which the body's response
   to the common fungus Aspergillus fumigatus causes worsening of
   breathing problems. Another is infection with mycobacterium avium
   complex (MAC), a group of bacteria related to tuberculosis which can
   cause further lung damage and does not respond to common antibiotics.

   Mucus in the paranasal sinuses is equally thick and may also cause
   blockage of the sinus passages, leading to infection. This may cause
   facial pain, fever, nasal drainage, and headaches. Individuals with CF
   may develop overgrowth of the nasal tissue ( nasal polyps) due to
   inflammation from chronic sinus infections These polyps can block the
   nasal passages and increase breathing difficulties.

Gastrointestinal, liver and pancreatic disease

   Prior to prenatal and newborn screening, cystic fibrosis was often
   diagnosed when a newborn infant failed to pass feces ( meconium).
   Meconium may completely block the intestines and cause serious illness.
   This condition, called meconium ileus, occurs in 10% of newborns with
   CF. In addition, protrusion of internal rectal membranes ( rectal
   prolapse) is more common in CF because of increased fecal volume,
   malnutrition, and increased intra–abdominal pressure due to coughing.

   The thick mucus seen in the lung has its counterpart in thickened
   secretions from the pancreas, an organ responsible for providing
   digestive juices which help break down food. These secretions block the
   movement of the digestive enzymes into the gut and result in
   irreversible damage to the pancreas, often with painful inflammation (
   pancreatitis). The lack of digestive enzymes leads to difficulty
   absorbing nutrients with their subsequent excretion in the feces, a
   disorder known as malabsorption. Malabsorption leads to malnutrition
   and poor growth and development because of calorie loss. Individuals
   with CF also have difficulties absorbing the fat-soluble vitamins A, D,
   E, and K. In addition to the pancreas problems, people with cystic
   fibrosis experience more heartburn, intestinal blockage by
   intussusception, and constipation. Older individuals with CF may also
   develop distal intestinal obstruction syndrome when thickened feces
   cause intestinal blockage.

   Thickened secretions also may cause liver problems in patients with CF.
   Bile secreted by the liver to aid in digestion may block the bile
   ducts, leading to liver damage. Over time, this can lead to cirrhosis,
   in which the liver fails to clean the blood of toxins and does not make
   important proteins such as those responsible for blood clotting.

Endocrine disease and growth

   Clubbing - Patients with CF often have enlargement of their fingers, as
   shown here.
   Enlarge
   Clubbing - Patients with CF often have enlargement of their fingers, as
   shown here.

   The pancreas contains the islets of Langerhans, which are responsible
   for making insulin, a hormone that helps regulate blood glucose. Damage
   of the pancreas can lead to loss of the islet cells, leading to
   diabetes. Vitamin D is involved in calcium and phosphorus regulation.
   Poor uptake of vitamin D from the diet because of malabsorption leads
   to the bone disease osteoporosis in which weakened bones are more
   susceptible to fractures. In addition, people with CF often develop
   clubbing of their fingers and toes due to the effects of chronic
   illness and low oxygen on their bones.

   Poor growth is a hallmark of CF. Children with CF typically do not gain
   weight or height at the same rate as their peers and occasionally are
   not diagnosed until investigation is initiated for poor growth. The
   causes of growth failure are multi–factorial and include chronic lung
   infection, poor absorption of nutrients through the gastrointestinal
   tract, and increased metabolic demand due to chronic illness.

Infertility

   Infertility affects both men and women. At least 97 percent of men with
   cystic fibrosis are infertile. These men make normal sperm but are
   missing the tube ( vas deferens) which connects the testes to the
   ejaculatory ducts of the penis. Many men found to have congenital
   absence of the vas deferens during evaluation for infertility have a
   mild, previously undiagnosed form of CF. Twenty percent of women with
   CF are infertile as a result of thickened cervical mucus, which
   interferes with the passage of sperm. In severe cases, malnutrition
   disrupts ovulation and causes amenorrhea.

Diagnosis and monitoring

   Cystic fibrosis may be diagnosed by newborn screening, sweat testing,
   or genetic testing. As of 2006 in the United States, ten percent of
   cases are diagnosed shortly after birth as part of newborn screening
   programs. The newborn screen identifies increased amounts of the enzyme
   trypsin. However, most states and countries do not screen for CF
   routinely at birth. Therefore, most individuals are diagnosed after
   symptoms prompt an evaluation for cystic fibrosis. The most commonly
   used form of testing is the sweat test. Sweat testing involves
   application of a medication that stimulates sweating ( pilocarpine) to
   one electrode of an apparatus and running electric current to a
   separate electrode on the skin. This process, called iontophoresis,
   causes sweating; the sweat is then collected on filter paper or in a
   capillary tube and analyzed for abnormal amounts of sodium and
   chloride. People with CF have increased amounts of sodium and chloride
   in their sweat. CF can also be diagnosed by identification of mutations
   in the CFTR gene.

   A multitude of tests is used to identify complications of CF and to
   monitor disease progression. X-rays and CAT scans are used to examine
   the lungs for signs of damage or infection. Examination of the sputum
   under a microscope is used to identify which bacteria are causing
   infection so that effective antibiotics can be given. Pulmonary
   function tests measure how well the lungs are functioning, and are used
   to measure the need for and response to antibiotic therapy. Blood tests
   can identify liver problems, vitamin deficiencies, and the onset of
   diabetes. DEXA scans can screen for osteoporosis and testing for fecal
   elastase can help diagnose insufficient digestive enzymes.

Prenatal diagnosis

   Couples who are pregnant or who are planning a pregnancy can themselves
   be tested for CFTR gene mutations to determine the likelihood that
   their child will be born with cystic fibrosis. Testing is typically
   performed first on one or both parents and, if the risk of CF is found
   to be high, testing on the fetus can then be performed. Because
   prenatal diagnosis does not allow for better or different treatment of
   children with CF, the main reason for testing is to offer abortion if
   the fetus is found to have CF. Cystic fibrosis testing is offered to
   many couples in the US. The American College of Obstetricians and
   Gynecologists recommends testing for couples who have a personal or
   close family history of CF as well as couples at high risk because of
   their ethnicity.

   Because development of CF in the fetus requires each parent to pass on
   a mutated copy of the CFTR gene and because CF testing is expensive,
   testing is often performed on just one parent initially. If that parent
   is found to be a carrier of a CFTR gene mutation, the other parent is
   then tested to calculate the risk that their children will have CF. CF
   can result from more than a thousand different mutations and, as of
   2006, it is not possible to test for each one. Testing analyzes the
   blood for the most common mutations such as ΔF508 — most commercially
   available tests look for 32 or fewer different mutations. If a family
   has a known uncommon mutation, specific screening for that mutation can
   be performed. Because not all known mutations are found on current
   tests, a negative screen does not guarantee that a child will not have
   CF. In addition, because the mutations tested are necessarily those
   most common in the highest risk groups, testing in lower risk
   ethnicities is less successful because the mutations commonly seen in
   these groups are less common in the general population.

   Couples who are at high risk for having a child with CF will often opt
   to perform further testing before or during pregnancy. In vitro
   fertilization with preimplantation genetic diagnosis offers the
   possibility to examine the embryo prior to its placement into the
   uterus. The test, performed 3 days after fertilization, looks for the
   presence of abnormal CF genes. If two mutated CFTR genes are
   identified, the embryo is excluded from embryo transfer and an embryo
   with at least one normal gene is implanted.

   During pregnancy, testing can be performed on the placenta ( chorionic
   villus sampling) or the fluid around the fetus ( amniocentesis).
   However, chorionic villus sampling has a risk of fetal death of 1 in
   100 and amniocentesis of 1 in 200, so the benefits must be determined
   to outweigh these risks prior to going forward with testing.
   Alternatively, some couples choose to undergo third party reproduction
   with egg or sperm donors.

Pathophysiology

   Cystic fibrosis occurs when there is a mutation in the CFTR gene. The
   protein created by this gene is anchored to the outer membrane of cells
   in the sweat glands, lung, pancreas, and other affected organs. The
   protein spans this membrane and acts as a channel connecting the inner
   part of the cell ( cytoplasm) to the surrounding fluid. This channel is
   primarily responsible for controlling the movement of chloride from
   outside the cell into the cell. When the CFTR protein does not work,
   chloride is trapped outside the cell. Because chloride is negatively
   charged, positively charged ions also cannot cross into the cell
   because they are affected by the electrical attraction of the chloride
   ions. Sodium is the most common ion in the extracellular space and the
   combination of sodium and chloride creates the salt which is lost in
   high amounts in the sweat of individuals with CF. This lost salt forms
   the basis for the sweat test.

   How this malfunction of cells in cystic fibrosis causes the clinical
   manifestations of CF is not well understood. One theory suggests that
   the lack of chloride absorption through the CFTR protein leads to the
   accumulation of nutrient–rich mucus in the lungs which allows bacteria
   to hide from the body's immune system. Another theory proposes that the
   CFTR protein failure leads to a paradoxical increase in sodium and
   chloride uptake, which, by leading to increased water reabsorption,
   creates dehydrated and thick mucus. Yet another theory focuses on
   abnormal chloride movement out of the cell, which also leads to
   dehydration of mucus, pancreatic secretions, biliary secretions, etc.
   These theories all support the observation that the majority of the
   damage in CF is due to blockage of the narrow passages of affected
   organs with thickened secretions. These blockages lead to remodeling
   and infection in the lung, damage by accumulated digestive enzymes in
   the pancreas, blockage of the intestines by thick feces, etc.

The role of chronic infection in lung disease

   The lungs of individuals with cystic fibrosis are colonized and
   infected by bacteria from an early age. These bacteria, which often
   spread amongst individuals with CF, thrive in the altered mucus, which
   collects in the small airways of the lungs. This mucus encourages the
   development of bacterial microenvironments ( biofilms) that are
   difficult for immune cells (and antibiotics) to penetrate. The lungs
   respond to repeated damage by thick secretions and chronic infections
   by gradually remodeling the lower airways ( bronchiectasis), making
   infection even more difficult to eradicate.

   Over time, both the types of bacteria and their individual
   characteristics change in individuals with CF. Initially, common
   bacteria such as Staphylococcus aureus and Hemophilus influenzae
   colonize and infect the lungs. Eventually, however, Pseudomonas
   aeruginosa (and sometimes Burkholderia cepacia) dominates. Once within
   the lungs, these bacteria adapt to the environment and develop
   resistance to commonly used antibiotics. Pseudomonas can develop
   special characteristics which allows the formation of large colonies —
   these strains are known as "mucoid" Pseudomonas and are rarely seen in
   people who do not have CF.

   One way in which infection has spread is by passage between different
   individuals with CF. In the past, people with CF often participated in
   summer "CF Camps" and other recreational gatherings. Hospitals grouped
   patients with CF into common areas and routine equipment (such as
   nebulizers) was not sterilized between individual patients. This led to
   transmission of more dangerous strains of bacteria among groups of
   patients. As a result, individuals with CF are routinely isolated from
   one another in the health care setting and health care providers are
   encouraged to wear gowns and gloves when examining patients with CF in
   order to limit the spread of virulent bacterial strains. Often,
   patients with particularly damaging bacteria will attend clinics on
   different days and in different buildings than those without these
   infections.

Molecular biology

   CFTR protein - Molecular structure of the CFTR protein
   Enlarge
   CFTR protein - Molecular structure of the CFTR protein

   The CFTR gene is found at the q31.2 locus of chromosome 7, is 180,000
   base pairs long, and creates a protein which is 1,480 amino acids long.
   The most common mutation, ΔF508 is a deletion (Δ) of three nucleotides
   that results in a loss of the amino acid phenylalanine (F) at the 508th
   (508) position on the protein. This mutation accounts for seventy
   percent of CF worldwide and ninety percent of cases in the United
   States. There are over 1,000 other mutations which can produce CF,
   however. In Caucasian populations, the frequency of mutations is as
   follows:
   Mutation Frequency
            worldwide
   ΔF508    66.0%
   G542X    2.4%
   G551D    1.6%
   N1303K   1.3%
   W1282X   1.2%

   There are several mechanisms by which these mutations cause problems
   with the CFTR protein. ΔF508, for instance, creates a protein which
   does not fold normally and is degraded by the cell. Several mutations
   which are common in the Ashkenazi Jewish population result in proteins
   that are too short because production is ended prematurely. Less common
   mutations produce proteins that do not use energy normally, do not
   allow chloride to cross the membrane appropriately, or are degraded at
   a faster rate than normal. Mutations may also lead to fewer copies of
   the CFTR protein being produced.
   The location of the CFTR gene on chromosome 7
   Enlarge
   The location of the CFTR gene on chromosome 7

   Structurally, CFTR is a type of gene known as an ABC gene. Its protein
   possesses two ATP-hydrolyzing domains which allows the protein to use
   energy in the form of ATP. It also contains two domains comprised of 6
   alpha helices apiece which allow the protein to cross the cell
   membrane. A regulatory binding site on the protein allows activation by
   phosphorylation, mainly by cAMP-dependent protein kinase. The carboxyl
   terminal of the protein is anchored to the cytoskeleton by a PDZ domain
   interaction.

Treatment

   A typical breathing treatment for cystic fibrosis, using a mask
   nebulizer and the ThAIRapy Vest
   Enlarge
   A typical breathing treatment for cystic fibrosis, using a mask
   nebulizer and the ThAIRapy Vest

   The most consistent aspect of therapy in cystic fibrosis is limiting
   and treating the lung damage caused by thick mucus and infection with
   the goal of maintaining quality of life. Intravenous, inhaled, and oral
   antibiotics are used to treat chronic and acute infections. Mechanical
   devices and inhalational medications are used to alter and clear the
   thickened mucus. Other aspects of CF therapy involve treatment of
   diabetes with insulin, pancreatic disease with enzyme replacement, and
   infertility with advanced reproductive techniques. In addition,
   therapies such as transplantation and gene therapy aim to cure some of
   the effects of cystic fibrosis.

Antibiotics to treat lung disease

   Antibiotics are given whenever pneumonia is suspected or there has been
   a decline in lung function. Antibiotics are often chosen based on
   information about prior infections. Many bacteria common in cystic
   fibrosis are resistant to multiple antibiotics and require weeks of
   treatment with intravenous antibiotics such as vancomycin, tobramycin,
   meropenem, ciprofloxacin, and piperacillin. This prolonged therapy
   often necessitates hospitalization and insertion of a more permanent IV
   such as a PICC line or Port-a-Cath. Inhaled therapy with antibiotics
   such as tobramycin and colistin is often given for months at a time in
   order to improve lung function by impeding the growth of colonized
   bacteria. Oral antibiotics such as ciprofloxacin or azithromycin are
   sometimes given to help prevent infection or to control ongoing
   infection. Some individuals spend years between hospitalizations for
   antibiotics, while others require several antibiotic treatments each
   year.

   Several common antibiotics such as tobramycin and vancomycin can cause
   hearing loss or kidney problems with long-term use. In order to prevent
   these side effects, the amount of antibiotics in the blood are
   routinely measured and adjusted accordingly.

Other methods to treat lung disease

   Several mechanical techniques are used to dislodge sputum and encourage
   its expectoration. In the hospital setting, physical therapy is
   utilized; a therapist pounds an individual's chest with his or her
   hands several times a day. Devices that recreate this percussive
   therapy include the ThAIRapy Vest and the intrapulmonary percussive
   ventilator (IPV). These are portable and adapted for home use. Aerobic
   exercise is of great benefit to people with cystic fibrosis. Not only
   does exercise increase sputum clearance, but it improves cardiovascular
   and overall health.

   Aerosolized medications which help loosen secretions include dornase
   alfa and hypertonic saline. Dornase is a recombinant human
   deoxyribonuclease which breaks down DNA in the sputum, thus decreasing
   its viscosity. N-Acetylcysteine may also decrease sputum viscosity, but
   research and experience have shown its benefits to be minimal.
   Albuterol and ipratropium bromide are inhaled to increase the size of
   the small airways by relaxing the surrounding muscles.

   As lung disease worsens, breathing support from machines may become
   necessary. Individuals with CF may need to wear special masks at night
   that help push air into their lungs. These machines, known as bilevel
   positive airway pressure (BiPAP) ventilators, help prevent low blood
   oxygen levels during sleep. BiPAP may also be used during physical
   therapy to improve sputum clearance. During severe illness, people with
   CF may need to have a tube placed in their throats and their breathing
   supported by a ventilator.

Treatment of other aspects of CF

   Intracytoplasmic sperm injection is used to provide fertility for men
   with cystic fibrosis.
   Enlarge
   Intracytoplasmic sperm injection is used to provide fertility for men
   with cystic fibrosis.

   Newborns with meconium ileus typically require surgery while adults
   with distal intestinal obstruction syndrome typically do not. Treatment
   of pancreatic insufficiency by replacement of missing digestive enzymes
   allows the gut to properly absorb nutrients and vitamins that would
   otherwise be lost in the feces. Even so, most individuals with CF take
   additional amounts of vitamins A, D, E, and K and eat high Calorie
   meals. The diabetes common in CF is typically treated with insulin
   injections. Development of osteoporosis can be prevented by increased
   intake of vitamin D and calcium and can be treated by bisphosphonates.
   Poor growth may be avoided by insertion of a feeding tube for
   increasing calories through supplemental feeds or by administration of
   injected growth hormone.

   Sinus infections are treated by prolonged courses of antibiotics. The
   development of nasal polyps or other chronic changes within the nasal
   passages may severely limit airflow through the nose. Sinus surgery is
   often used to alleviate nasal obstruction and to limit further
   infections. Nasal steroids such as fluticasone are used to decrease
   nasal inflammation. Female infertility may be overcome by assisted
   reproduction technology, particularly embryo transfer techniques. Male
   infertility may be overcome with intracytoplasmic sperm injection.
   Third party reproduction is also a possibility for women with CF.

Transplantation and gene therapy

   Lung transplantation often becomes necessary for individuals with
   cystic fibrosis as lung function and exercise tolerance declines.
   Although single lung transplantation is possible in other diseases,
   individuals with CF must have both lungs replaced because the remaining
   lung would contain bacteria that could infect the transplanted lung. A
   pancreatic or liver transplant may be performed at the same time in
   order to alleviate liver disease and/or diabetes. Lung transplantation
   is considered when lung function approaches a point where it threatens
   survival or requires assistance from mechanical devices.

   Gene therapy holds promise as a potential avenue to cure cystic
   fibrosis. Gene therapy attempts to place a normal copy of the CFTR gene
   into affected cells. Studies have shown that to prevent the lung
   manifestations of cystic fibrosis, only 5–10% the normal amount of CFTR
   gene expression is needed. Many approaches have been theorized and
   several clinical trials have been initiated but, as of 2006, many
   hurdles still exist before gene therapy can be successful.

Epidemiology

   CF is inherited in an autosomal recessive fashion.
   Enlarge
   CF is inherited in an autosomal recessive fashion.

   Cystic fibrosis is the most common life-limiting autosomal recessive
   disease among people of European heritage. In the United States,
   approximately 30,000 individuals have CF; most are diagnosed by six
   months of age. Canada has approximately 3,000 citizens with CF.
   Approximately 1 in every 25 people of European descent and 1 in every
   29 people of Ashkenazi Jewish descent is a carrier of a cystic fibrosis
   mutation. Although CF is less common in these groups, approximately 1
   in every 46 Hispanics, 1 in every 65 Africans and 1 in every 90 Asians
   carry at least one abnormal CFTR gene.

   Cystic fibrosis is diagnosed in males and females equally. For unclear
   reasons, males tend to have a longer life expectancy than females. Life
   expectancy for people with CF depends largely upon access to health
   care. In 1959, the median age of survival of children with cystic
   fibrosis was 6 months. In the United States, the life expectancy for
   infants born in 2006 with CF is 36.8 years, based upon data compiled by
   the Cystic Fibrosis Foundation. Similarly, in much of the western world
   people with CF live to a similar age. However, the life expectancy in
   underdeveloped countries is much less — the majority of individuals
   with CF do not live past the age of ten.

   The Cystic Fibrosis Foundation also compiles lifestyle information
   about American adults with CF. In 2004, the foundation reported that
   91% had graduated high school and 54% had at least some college
   education. Employment data revealed 12.6% of adults were disabled and
   9.9% were unemployed. Marital information showed that 59% of adults
   were single and 36% were married or living with a partner. In 2004, 191
   American women with CF were pregnant.

Theories about the prevalence of CF

   The ΔF508 mutation is estimated to be up to 52,000 years old. Numerous
   hypotheses have been advanced as to why such a lethal mutation has
   persisted and spread in the human population. Other common autosomal
   recessive diseases such as sickle cell anaemia have been found to
   protect carriers from other diseases, a concept known as heterozygote
   advantage. With the discovery that cholera toxin requires normal host
   CFTR proteins to function properly, it was hypothesized that carriers
   of mutant CFTR genes benefited from resistance to cholera and other
   causes of diarrhea. Further studies have not confirmed this hypothesis.

   Normal CFTR proteins are also essential for the entry of Salmonella
   typhi into cells, suggesting that carriers of mutant CFTR genes might
   be resistant to typhoid fever. No in vivo study has yet confirmed this.
   In both cases, the low level of cystic fibrosis outside of Europe, in
   places where both cholera and typhoid fever are endemic, is not
   immediately explicable.

History

   National Library of Medicine picture of Dorothy Hansine Andersen.
   Andersen first described cystic fibrosis of the pancreas.
   Enlarge
   National Library of Medicine picture of Dorothy Hansine Andersen.
   Andersen first described cystic fibrosis of the pancreas.

   Although the entire clinical spectrum of CF was not recognized until
   the 1930s, certain aspects of CF were identified much earlier. Indeed,
   literature from Germany and Switzerland in the 1700s warned "Wehe dem
   Kind, das beim Kuß auf die Stirn salzig schmekt, er ist verhext und
   muss bald sterben" which translates to "Woe is the child who tastes
   salty from a kiss on the brow, for he is cursed, and soon must die,"
   recognizing the association between the salt loss in CF and illness.
   Carl von Rokitansky described a case of fetal death with meconium
   peritonitis, a complication of meconium ileus associated with cystic
   fibrosis. Meconium ileus was first described in 1905 by Karl
   Landsteiner. In 1936, Guido Fanconi published a paper describing a
   connection between celiac disease, cystic fibrosis of the pancreas, and
   bronchiectasis.

   In 1938, Dorothy Hansine Andersen published an article titled "Cystic
   fibrosis of the pancreas and its relation to celiac disease: a clinical
   and pathological study" in the American Journal of Diseases of
   Children. In her paper, she described the characteristic cystic
   fibrosis of the pancreas correlated it with the lung and intestinal
   disease prominent in CF. She also first hypothesized that CF was a
   recessive disease and first used pancreatic enzyme replacement to treat
   affected children. In 1952, Paul di Sant' Agnese discovered
   abnormalities in sweat electrolytes; the sweat test was developed and
   improved over the next decade.

   In 1988, the first mutation for CF, ΔF508, was discovered by Francis
   Collins, Lap-Chee Tsui and John R. Riordan on the seventh chromosome.
   Research has subsequently found over 1000 different mutations that
   cause CF. Lap-Chee Tsui led a team of researchers at the Hospital for
   Sick Children in Toronto that discovered the gene responsible for CF in
   1989. Cystic fibrosis represents the first genetic disorder elucidated
   strictly by the process of reverse genetics. Because mutations in the
   CFTR gene are typically small, classical genetics techniques were not
   able to accurately pinpoint the mutated gene. Using protein markers,
   gene linkage studies were able to map the mutation to chromosome 7.
   Chromosome walking and jumping techniques were then used to identify
   and sequence the gene.

   CF is also widely known as "65 Roses." The phrase came into being when
   it was used by a young boy who had overheard his mother speaking of his
   illness. He later informed her that he knew she was working to help
   with "sixty-five roses". The term has since been used as a symbol by
   organizations and families of cystic fibrosis victims.

   Retrieved from " http://en.wikipedia.org/wiki/Cystic_fibrosis"
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   with only minor checks and changes (see www.wikipedia.org for details
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