Intron 8 7t/7t Exon 13 D727y

Question

Dear Sir or Madam,

My 10-year-old daughter (CF) was tested in 2009 because she often had abdominal pain with diarrhea and also respiratory infections and bronchitis.

Our pediatrician sent us to the CF outpatient department of the University Hospital Leipzig [Germany]. A sweat test was done which was positive [pathological] with a value of 77 mmol. Since the value was increased the test was repeated: the result was 77 mmol again. A further test was done, this time the result was even 102 mmol. For the doctors at the University Hospital it was evident, thus, that my daughter has CF. After an internal change of the treating doctor, the new doctor wanted to do a genetic test for further clarification. The result, however, was negative. Since all symptoms indicated that she had CF, the doctors decided to have a complete sequencing done (Hannover laboratory); this was also negative.

In fact, two mutations were found (Intron 8 – 7t/7t and D727y im Exon 13) but researchers have not found out so far if something relevant for the disease happens in the exon.

At the beginning, the X-ray of the lungs was conspicuous. Partly, the creatinine value was strongly increased and the bile acid value was too high. Kidneys are a bit enlarged. She also has fructose and sorbitol intolerance.
All diseases that could cause a false-positive test were excluded. A double-sided chloride testing was also negative (29 mmol) [normal].
I was told that the reason for the earlier positive sweat test results was the underweight of my daughter. Meanwhile she is 135 cm tall and weighs about 22-23 kgs, i.e. still underweight.

Now, I learned that there are also forms of CF without any detectable mutations. I simply would like to know if my child has CF or not. Such a situation is very unsettling for a mother. I hope you can give me your opinion about the whole situation that would help me to get a clearer picture. First of all, I would like to know why the sweat tests were positive.

Best regards

Answer

Hello,

[In the original German answer the expert repeated the question in form of a report.]

Understandably, the overall situation is unsettling you very much and you would like to know how the different results of the sweat tests can be explained. On the other hand, you would also like to know if your child is actually healthy or may be suffering from CF.
What the different results of the sweat tests are concerned it can be said that very likely two different methods were used. It can be assumed that the last double testing was a stimulation of the sweat secretion by using Pilocarpin iontophoresis and that the measurement of the chloride value was performed with a chloridometer. This method is the international standard for a sweat test.

It can only be assumed that the method used for the first tests was different; probably the so called measurement of sweat conductivity was done. This method is simpler on the laboratory scale but it is not recognized on an international level since false test values are frequent.

Your daughter’s clinical data that we know of could match CF but they could also be explained in another way; you do NOT report, e.g., about the pancreatic function of your daughter and thus I assume that this function is normal. The body weight of your daughter is about 5 kgs less than the ideal weight (referring to her height). This means that your daughter is very slim but I would not call her underweight.

If CF can be ruled out based on the results of the tests listed below, then you should consult a pediatric gastroenterologist so that you and him/her together can find an explanation for your daughter’s moderate weight development.

Based upon the current knowledge, the result of the molecular genetic test does not provide a clarification of the situation.

For the sake of absolute clarity a cell-physiological test method (nPD = nasal potential difference test or ICM = intestinal current measurement) should be performed that clarifies if the result which is typical CF will be detected for your daughter or if the result proves that your child is healthy. These two test methods are only performed in few reference centers. The treating doctor of your CF center can give you further details. [Please note that the original question and answer come from the German platform of ECORN-CF so that the answer is valid for Germany]

I hope to have been helpful with the answer (…).

Best regards,
Dr. H.-G. Posselt
[and input given by Dr. Frauke Stanke]

07.07.2015