Can one sibling have an atypical CF and one sibling a classical one?

Question

Dear ladies and gentlemen,
we have 2 sons, the older one is 2.5 years old, the younger one is 5 months old. Our older son has a massive failure to thrive, he weighs with his 2.5 years only 9 kg. As he is a former prenatal baby with a half-side paresis, the physicians thought the reason for this were there. Otherwise the boy has no symptoms of CF. The pediatrician however, wanted to rule it out via sweat test and this showed once a slight positive result (in a CF Center). Afterwards we went to a recheck in the nearer regional hospital. Which kind of testing they used, I do not know, at least we were told, that the values of salt were so low, that CF could be ruled out. I was content with the result and got pregnant again. We had a change of the physician of our older son and we were told that diagnostics with a slight positive and a negative sweat test were not correct and our son had to be tested now again. This time again in a CF Center. A sweat test had been done via Makroprodukt.
Amount of sweat 43 mikrolitre. The result was 30 mmol/l chloride. Therefore the borderline value of normal. The physician said, another sweat test would have to be done. However, our first born would have only an atypical CF at least, due to the low values, that has not such a bad course of the illness.
However it is like this, that our younger son, in contrast to the older brother, is very suspicious for CF. Has breathing sounds since the age of one week, whereby I cannot hear if it comes from the nose or the lungs. Cramping abdominal pain, whereby the whole body is cramping. Permanent diarrhae. He weighs with 5 months only 6 kg, in spite of his great appetite. However no pneumonias. Now my question:
Can it be that the youngest son has a severe form of CF while his brother has only at slight form at least? Both boys have genetically identical parents. After 1.5 years of diagnostic procedures I would be thankful for any help, especially as we would like to have other children.
Many thanks for your help.

Answer

I would like to answer in 2 paragraphs:

1. Can it be, that one sibling has a severe form of CF while the other sibling has a light, atypical one?
2. What does this mean (and the diagnostic wrong tracks) for the family planning?

I separate the answers in purpose, as you have to approach with these question to two different specialists: for the diagnostic question (1) you have to turn to a pediatrician, for the question about family planning (2) you have to turn to a human geneticist.

To 1.: The short answer is: yes. CF is a hereditary disease, that is known for the very many different genetic impairments that could be underlying and create very many different courses of the illness. If you talk at a CF congress with enough CF specialists from the centers, you will always find physicians who report seldom and artypical forms. It does not help you that this or that is very rare in the overall group of CF patients - because your children are a special case on their own.

I assume, that the CF physicians from the center that you consulted, decided "no typical CF" due to the overall clinical picture. However I am worried about the following: "[...] has breathing sounds since the age of one week whereby I cannot hear if it comes from the nose or the lungs. [...]" Because there are so many possible reasons for complaints of the airways and the intestinal tract in the first year of life and at toddlers age you are not intended to find it out yourself, rather let a pediatrician do an auscultation with the stethoscope.
I recommend here the second college, whom you mentioned: "We had a change of the physician of our older son and we were told that diagnostics with a slight positive and a negative sweat test were not correct and our son had to be tested now again. " as this is really true.
Besides the sweat test, however, there are other diagnostic measures - however a pediatrician should decide, which measures are now in the first line in your case. Notes about this: CFTR-genetic testing (see 2) and if necessary besides a sweat test further analysis o the CFTR-function, if possibly to recognize a non-functioning CFTR-gen. For the age of your children there comes only the ex-vivo measurement of the so-called ion flows in rectal biopsies (short term ICM diagnostic) into question, that are available in Germany in the centers in Berlin, Bochum, Gießen, Hannover and Heidelberg.
I hope that you live in Germany near a pediatrician. Especially if there is a failure to thrive and the diagnosis of CF is still suspected, you should not take acute signs of the illness alone on your shoulders - please consult always a pediatrician. Like it already happened, he will again test for CF if there is the suspicion, as it is not unlikely, that a sweat test cannot exclude the illness. The other way round it is easier, however is also not free of mistakes, therefore:
a pathological sweat test is mostly a reliable sign for CF and with this the physician would have known it for sure. With the “not so severe, only borderline” sweat test, that is however not unambiguous, either, it becomes clear that you have made another sweat test with your son as it was recommended to you – and now, you have not a secure diagnosis either, which is unsatisfactory for you yourself as well as for the pediatrician. Concerning the difficulties in finding a diagnose, you are sitting all in the same boat - however the pediatrician is skilled to know this (and hopefully can communicate it in the talk with the parents).
To 2.: Here I recommend a specialist for human genetics and can of course give your some information before. CF is a hereditary disease, if the copy of the CF gene from the mother AND from the father is defective. In other words: father and mother of the child inherit one defective CF gene each (this gene is called CFTR) to the child. Therefore the parents are healthy (have only ONE defective genetic copy of CFTR), the child can only be ill, if 2 defective CFTR genes come together. There are many genetic impairments in the CFTR gene, however in the majority of cases the human geneticist can identify those impairments via genetic testing. For this he needs some blood or another source of DNA, like e.g. a swab from the oral mucosa of the whole family (father, mother, both children). After the genetic testing the human geneticist can do a genetic counseling, and tell you how high the risk is to get a child with CF with a new pregnancy. Please contact your gynecologist who can for sure make a contact to such a specialist.
With my best wishes for the health of the two little patients,
Frauke Stanke

19.07.2015