Cystic Fibrosis

Question

Dear experts,
a sweat test has been done with my 6-month-old son. The values were above 60. The test searched for 27 mutations, but nothing was found. What does this mean exactly? He is in Russia for the moment, but he will come to Belgium in October.

Answer

Dear questioner,

Thank you for this interesting question. This website only answers general questions about cystic fibrosis. We understand that you are worried about your son. We recommend you to see a specialized pediatrician, who can do a complete diagnostic examination.

You describe a situation with an abnormal sweat test and no mutations in the primary screen for mutations in the CF-gene. Three questions must be answered:

1. Could this abnormal sweat test may be a mistake?
The first question is whether the sweat test was performed correctly: was the standard method (Gibson and Cook, pilocarpine ionotophoresis) used? Is the value you mention the chloride content? Was there sufficient sweat available for analysis? It is recommended to confirm an abnormal result with a second sweat test performed in an experienced laboratory. The results of the test must be interpreted correctly (sufficient sweat?, correct use of normal values?). For more information you can have a look in the category diagnostic tests on this website.

2. Does this child have symptoms of cystic fibrosis?
First, it is important to know the symptoms of the child. If those are typical CF symptoms, and the sweat test is clearly abnormal (sweat chloride above 60 mEq/l with the classic method of measurement), the diagnosis of cystic fibrosis can be confirmed. Increased sweat chloride can rarely be a consequence of other diseases, such as severe malnutrition or dehydration, adrenal insufficiency, eczema or rare metabolic disorders. In practice, those diseases are not difficult to distinguish from cystic fibrosis.
If the symptoms are not typical for CF and the sweat test is abnormal, the sweat test certainly needs to be repeated, and other diseases must be excluded.

3. Is the genetic screening test appropriate for the origin of the child?
Genetic analysis can support the diagnosis of cystic fibrosis since cystic fibrosis is indeed caused by mutations in the CFTR-gene. Each individual has two CFTR-genes, one inherited from the father and the other from the mother. There are more than 1.800 known mutations in the CFTR-gene that can cause CF. The first test only detects the most frequent mutations of the CFTR-gene. Which mutations are “frequent” depends on the population group to which the patient belongs. For example, some mutations are frequent in almost all populations (F508del), and other mutations are rather specific for specific population groups (e.g. W1282X in Israel). With the first test only a limited number of mutations are searched for, which might represent only 50 to slightly more than 90 % of the mutations in that genetic background. Given the fact that each person has two CFTR genes, this first test will show in the best case 81% of the patients with two CF mutations, 18% with 1 mutation and 1% with no mutation. In the worst case only 25 % of the patients will be found to have two mutations, 50% with one mutation and 25% with no mutation.
If the analyzed mutation panel is not adapted to the origin of the patient, it is not uncommon to find only 1 or none mutation. A full analysis of the CFTR gene (sequencing) is more sensitive since it will detect nearly every defect in the gene. However, this test is expensive and not available everywhere. Even in rare cases this extensive genetic research does not result in a diagnosis and more specialized tests such as nasal potential measurement or potential measurement on an intestinal biopsy are needed. Read more about this in the category “diagnosis and diagnostics”.

You realize now, that many factors are important to come to a confirmed diagnosis of cystic fibrosis. We recommend you to discuss this with your specialized pediatrician.

Regards,
Porf. K. de Boeck

26.09.2013