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:
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.
- Congenital bilateral absence of the vas deferens (male reproductive ducts) - CBAVD.
- Chronic bronchitis of older age.
- Recurrent pancreatitis.
Cystic fibrosis is a hereditary disease that mainly affects lung and pancreatic
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.
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.
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.
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.
In the classical type, the disease is fully expressed. Expression is partial in
the non-classical types.
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.
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.
Molecular genetic information
The gene for the disease
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
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.
What is Cystic Fibrosis?