R553x/IVS8-5T-TG12 mutations

Question

Hello,

my 5-year-old daughter was diagnosed with cystic fibrosis two weeks ago.

Sweat test was negative, but the paediatrician ordered a gene test, which showed that she has the R553x/IVS8-5T-TG12 mutations. This is supposed to be an atypical cystic fibrosis. What does that mean, and how does this influence the progression?

In addition, my daughter was diagnosed with Alpha 1-antitrypsin deficiency four weeks ago. Two weeks after that, the same laboratory diagnosed the rare genetic type MM. – This means she is healthy. After that came the CF diagnosis, again from the same laboratory.


My daughter rarely is phlegmy, only when she has an infection. She does not have any digestive problems or failure to thrive. She is 115 cm tall and weighs 19.5 kg.

Should we inquire further? Can this diagnosis really be true?

Many thanks.
Kind regards.
C.M.

Answer

Hello,

apart from the classic progression of cystic fibrosis (CF), also called mucoviscidosis, which is caused by a deficiency of the chloride channels in the epithelia cells, there are mild symptoms as well which are defined as CF-related disorder or as atypical CF. Your daughter’s combination of the R553X and TG12T5 mutations is indeed consistent with the diagnosis of an atypical CF or a CF-related disease, provided that both mutations are located on different chromosomes, i.e., one on a maternal and one a paternal chromosome. The R553X mutation is associated with classic CF and causes the functional deficiency in the chloride channel. The TG12T5 mutation, on the other hand, causes only part of the genetic products (the chloride channels) to lose their function. The other part remains functional, so that the symptoms are milder (relative to the fraction of functional genetic products) than with the classic form of the disease, where there is no functioning genetic product present at all.

In patients with the TG12T5 mutation, the percentage of functional chloride channels varies from patient to patient and from tissue to tissue and cannot be predicted on the basis of a gene test. Your daughter’s negative sweat test shows that there are functioning chloride channels present, and the function of the chloride channels in the intestinal tract seems to be so good that there are no digestive problems or any failure to thrive. The chloride channel function seems to be somewhat reduced in the respiratory tracts, though, so that phlegm is building up during infections. It would be possible to do a specific examination (a so-called transcriptional analysis) of the nasal epithelia cells, which one can obtain with a special small brush, in order to roughly determine the amount of functional products. However, this would only reflect the situation in the nasal epithelium and not in the lung tissue and would therefore only be of diagnostic, but not of prognostic value.

Diagnosis of atypical CF or of a CF-related disease means:
1. Progression is a lot milder than with classic CF.
2. Knowing the correct diagnosis, symptoms can immediately be treated adequately so that your child can gain the greatest possible benefit from receiving the right therapy early on.

In addition, genetic testing of the parents is recommended in order to verify that both mutations are located on a maternal and a paternal chromosome, respectively. If both parents are identified as carriers, further children run a 25% risk of bearing two CFTR mutations. The parents’ siblings also run a risk of carrying CF, so that a genetic assessment would be indicated for them as well. Children who are completely healthy and are not judicious yet, on the other hand, should not be tested for carrier status; this should only be done as soon as they can decide for themselves whether they want a genetic assessment or not.

I hope my explanations have answered your question to your satisfaction.

Kind regards

Prof. Sabina Gallati

06.09.2010