Mutations p.G542X p.R1162X -- Progression

Question

Our daugther is two years old. She was diagnosed at eight weeks due to increased trypsin (newborn screening). So far she has been healthy. :-)

Lung: pap smears always ok, no cough, no mucus obstruction. Pancreatic enzymes: ca. 100-150 mg of pancreatin for children daily.

Does the mild progression fit her genotype? Do you think one can already predict now that there is a certain chance our daughter’s disease will remain limited to the pancreas? If not – at which age could one give a prognosis about that?

Kind regards and many thanks in advance.

Answer

Dear questioner,

I will start with the short answers to your questions:

1. mild progression due to G542X/R1162X – quite possible. 2. prognosis about a limitation to the pancreas: not at all. – 3. prognosis based on the CFTR mutation genotype: not possible according to the current state of research.

The detailed explanations of this:

Generally, Cystic Fibrosis is a multi-organ disease – this means that it affects all organs that the defective CFTR gene develops (that is, digestive tract and respiratory system). [Translator’s comment: literal translation of the German answer would have been “…all organs that develop the defective CFTR gene” – assumed this to be incorrect and changed the translation accordingly.] It is correct that, depending on the inherited mutations, it is possible to draw conclusions about the average progression of the disease in a group of patients with the same CFTR mutations; however, this does not necessarily mean that this is true for the individual progression of a particular patient (i.e., your daughter). In a current statement issued by an international CF expert group, it says that… “far-reaching connections between mutation type and realization of the disease are useful for epidemiological research, but the CFTR genotype does not predict the progression of the disease with individual persons. Using the CFTR genotype as the basis for predictions of the prognosis for a patient at the time of diagnosis is therefore not recommended…” (for the sake of completeness, this is the source: Journal of Cystic Fibrosis 7(3):179-196; 2008). The reason for this lack of predictive power for the individual person lies in all the different factors that play a role apart from the CFTR mutation in influencing the progression of CF (environmental factors, other inherited features, and particularly important: doctor and therapeutic management of the disease) – according to current assessment, these “non-CFTR factors” are more significant for the progression of the disease than just the CFTR mutation type (hence the answer to 3.: prognosis based on the CFTR mutation genotype: not possible according to the current state of research).

I am really sorry that, based on the G542X/R1162X mutation, I cannot provide a reassuring prognosis about your daughter’s future concerning the probability of progression, not even with increasing age of the patient.
I assume you received the information that R1162X causes a mild progression of the respiratory disease. This might go as far back as to the work of Mr. Pignatti from Italy from 1992 (i.e., already 17 years ago), who described nine patients who all carry R1162X on both chromosomes (i.e., R1162X/R1162X as a mutation genotype). For this group of nine patients, Mr. Pignatti considers the respiratory disease “mild to moderate” (hence the answer to 2. prognosis about a limitation to the pancreas: not at all; unfortunately, “mild to moderate” also means having CF). This answers your question “does the mild progression fit her genotype” at least in part – the Italian patients described here carry the R1162X mutation on both chromosomes, your daughter carries it on one (hence the answer to 1. mild progression due to G542X/R1162X – quite possible, but I want to add that a mild progression is certainly also an outcome of your efforts about the well-being of your daughter and the early therapy of the disease).

Best regards,
Frauke Stanke

20.10.2009