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Cystic fibrosis |
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Types |
The classical type of cystic fibrosis (CF) manifests mainly as a disorder in the functioning of
certain body organs, particularly the lungs and pancreas, resulting in progressive failure of these organs.
Recently, with the discovery of the gene for CF, it has become clear that some of the mutations in
this gene can cause a milder clinical picture than that of classical CF, and it has become
apparent that clinical conditions that were not associated with CF in the past are in fact due to
this disease. These include the following in particular:
- Congenital bilateral absence of the vas deferens (male reproductive ducts) - CBAVD.
- Chronic bronchitis of older age.
- Recurrent pancreatitis.
It must be emphasized that the fact that these "non-classical" clinical presentations have been
found in association with the gene for CF does not mean that these affected individuals should
be regarded as CF patients.
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Clinical signs |
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Cystic fibrosis is a hereditary disease that mainly affects lung and
pancreatic function.
The secretions of the respiratory tract are viscous and cannot be
properly expelled.
Patients therefore suffer from respiratory difficulties and recurrent
infections of the respiratory system. From a few months of age the body weight is low
due to difficulties in digesting and absorbing food.
Patients need constant medical supervision, including constant respiratory
physiotherapy which assists in the draining of secretions from the respiratory tract.
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Furthermore, they need multiple drugs to assist them in the digestion of food and for
combating respiratory infections.
Until fairly recently, cystic fibrosis patients had a short life expectancy, and most of them
did not survive to adolescence. Nowadays, however, because of improved medical care, the life
span of these patients has increased significantly, although they still have a significant mortality,
mainly in the third and fourth decades.
The diagnostic test for CF is a sweat test - the sweat of patients with classical CF has a high
concentration of sodium and chloride ions (over 60 meq/liter). However, in infants up to
the age of 6 months, who do not have a perspiration mechanism, the test is unreliable.
The molecular genetic test can then help.
In the non-classical types, the levels of the sodium and chloride ions in the sweat are not
always high, and they can be normal or borderline.
Because the routine molecular test performed in Israel does not always identify the mutations
causing the "non-classical" types, there is sometimes diagnostic difficulty.
In these cases, electrical conduction tests in nasal mucosa cells can sometimes be used in cases
where there is a high clinical suspicion and there are respiratory signs of the disease.
This test is helpful in some cases.
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Inheritance pattern |
Autosomal recessive.
When both parents are carriers, the child will only be affected if he or she inherits two abnormal
genes - one from the mother and one from the father.
The severity of the classical disease does not differ much in the cases caused by the classic
mutations, and in these cases there is a combination of 2 moderately severe to severe mutations.
In the non-classical types, at least in one of the two abnormal genes the mutation is mild to very mild.
The severity of the respiratory disorder varies markedly according to the combination of mutations.
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Example of an Inheritance Pattern for Cystic Fibrosis
The image shows how Cystic fibrosis genes are inherited.
A person inherits two copies of the CFTR gene—one from each parent.
If each parent has a normal CFTR gene and a faulty CFTR gene, each child has a 25 percent
chance of inheriting two normal genes; a 50 percent chance of inheriting one normal gene
and one faulty gene; and a 25 percent chance of inheriting two faulty genes.
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Penetrance |
In the classical type, the disease is fully expressed. Expression is partial in the non-classical types.
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Associated features that can be demonstrated in tests performed during pregnancy |
In a significant number of cases of classical CF there is obstruction of the fetus's intestines
during intrauterine life due to excessive viscosity of the fetal feces (meconium).
This obstruction manifests as hyperechogenic intestines on ultrasound scan.
In the amniotic fluid, a decreased level of enzymes secreted by the intestines can be
detected - this is also due to the meconium obstruction.
The two tests are not diagnostic, i.e. even if they are positive, they do not necessarily
prove that the fetus has CF, unless mutations in the gene are found in a DNA test.
Ultrasound testing or amniotic fluid enzyme testing, if found to be normal, indicate a
lower risk for CF, but do not categorically exclude it.
In all these cases it is important to refer the couple for genetic counseling, to which
they should bring all data, including the results of other tests performed during the pregnancy
such as alpha-fetoprotein, nuchal translucency, etc.
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What is the risk of recurrence in a subsequent pregnancy? |
For a couple who has already had an affected child, the risk is 25% in every subsequent pregnancy.
This also applies to a couple where both partners have been found to be carriers of classical CF mutations.
When only one parent carries the abnormal gene, there is no risk that any of their offspring will have the disease;
however, in such families there is a 50% chance that the infant will be a carrier, but he himself
will be healthy, like the carrier parent.
The risk for more distant relatives depends on the degree of relationship between the relatives and
the affected individuals, the ethnic groups of their partners, affected relatives of partners,
consanguinity between the parents, if present, etc., and is established within genetic counseling.
In cases where one parent carries a "mild" mutation and the other a classical CF mutation the
risk is 25% in every pregnancy of having an affected child with the non-classical types of CF
described above - the risk level is established for each individual couple within genetic counseling.
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Molecular genetic information |
The gene for the disease
CFTR.
Location
Chromosome 7.
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Genetic testing |
Diagnostic testing
A direct test can be performed to identify the mutation in the gene by testing for the common mutations.
See: Testing the disease-causing gene for mutations that are common in a specific ethnic group - autosomal recessive diseases.
Carrier testing
Mutations in the gene causing cystic fibrosis exist in all ethnic groups.
The carrier rate varies between one in twenty in the healthy population of some ethnic groups to one in
a hundred in others. Not only is the frequency different in different ethnic groups, but the mutation
itself is also different.
Among the Jewish population, for example, hospital laboratories are capable of identifying more
than 90% of CF carriers in Jews of Ashkenazi, Turkish, Libyan and Tunisian origin, but only
about 50% - 85% in Jews of other ethnic groups.
Each ethnic group has its own specific set of mutations for which testing is recommended as part of
population screening. Among Caucasians in the USA, 90 mutations are tested which cover more than 90% of
the carriers.
In view of this, it is very important to ascertain the ethnic origins of the couple, and it is
advisable to examine first the partner with the greater chance that the mutation will be identified.
For example, if only one of the partners is of Ashkenazi Jewish origin, it is recommended that he or
she be examined first. In some ethnic groups, for example in people of Iraqi, Indian, Yemeni,
Afghani or Kurdish origin, it is not currently possible to test for carrier status with accuracy.
Carrier testing is also limited in Arabs and in people from the Far East.
It is important to emphasize that the disease exists in these ethnic groups (although less
frequently than in Caucasians), but the mutations have not yet been fully identified.
Carrier status testing in relatives of CF patients
It is important that relatives of CF patients clarify which mutations are present in the
patient or parents in their family in order to ascertain that they are included in the battery of
mutations routinely tested for - otherwise it will be necessary to expand the list of mutations
tested for and/or examine the partner. This will be discussed in genetic counseling.
Expansion of the battery of mutations tested
It is possible to expand the battery of mutations tested for - there are laboratories that test
for 90 or even more mutations - however the contribution of these additional mutations for the purpose
of detecting carriers is small. It is also possible to test for some of the mild mutations that
cause the non-classical types of CF as described above. However, these mutations are not
recommended for inclusion in the screening tests, and are hence not included in the regular battery,
because of their mild manifestation that does not impair quality of life in most cases.
See also:
Introduction to cystic fibrosis,
Gaucher disease, Canavan disease, familial dysautonomia, Bloom syndrome and Fanconi anemia.
Fetal testing
Same as the diagnostic test.
Prenatal diagnosis can also be offered to each couple who has had an affected child.
The best way is after identifying the mutations in the parents, but if these are not found, indirect
linkage analysis can be performed. See: Indirect testing for
genetic markers in a family that has one or more patients - when there is only one gene that can cause the disease - autosomal recessive diseases
Preimplantation diagnosis (before the embryonic cells implant in the uterine wall) can also be offered
for this disease - this is performed in special centers, mainly overseas, and in special cases this can
be considered within genetic counseling.
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What is Cystic Fibrosis?
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