uncertain cystic fibrosis diagnosis

Question

I have a daughter of 11 years old, diagnosed with cystic fibrosis, 3 years ago(the first sweat test was 68 and the second one 62). Tests were performed ​​after the third episode of pancreatitis (she does not have respiratory symptoms). The genetic test revealed heterozygous genotype for IVS8-5T allele (intron 8 poly-T-TG: 5t_11TG/7T-11TG) with specification from Germany that this polymorphism usually is not associated with clinical manifestation of cystic fibrosis. In 2011 she had another pancreatitis. The sweat test performed after that revealed a value of 42 mmol / l ; after this test, the diagnosis of cystic fibrosis was excluded. She had a colangio-RM and was diagnosed with pancreas divisum.
What do you think about the first diagnosis- cystic fibrosis- (genetic test was done for only 37 mutations)? Could she be only carrier of the disease and pancreatitis to be attributed to pancreas divisum ?
She does not take anymore Pulmozyme.

Answer

Hello,

In general, in your daughter`s case, the pancreas divisum may be the cause of recurrent pancreatitis. However the situation needs to be made more concrete: you report that the genetic test revealed heterozygous genotype for IVS8-5T allele (intron 8 poly-T-TG: 5T-11TG/7T-11TG), so besides this polymorphism it seems to be that no other CF-mutation has been found (about 37 mutations have been tested for). CF is a so-called autosomal-recessive disease, that means, a person suffers only from it if CFTR-genes on both chromosomes (one inherited from the father and one from the mother) carry a respective mutation. If there is no mutation on one CFTR-gene and a CF-causing mutation on the other, the person is a “healthy carrier” and does not suffer from CF. If there is a mutation on both CFTR-genes, the clinical picture is dominated according to the “milder” mutation. So in the case of your daughter, if one could be 100% sure that there was only this polymorphism and on the other CFTR-gene there was no other CFTR- mutation, she would be a healthy carrier, sweat tests would be normal and the pancreatitis would not be related to CF.

However, things are not as easy. There is a possibility, that the genetic test, which searched for about 37 mutations, did not detect an underlying CFTR-mutation on the other gene. Even if, in the worst case, your daughter carries on the other chromosome a mutation, that causes the “typical form” of CF, her clinical picture would be determined by the found milder mutation, the IVS8-5T allele (5T-11TG). This is a so-called splicing mutation and the clinical picture (phenotype) depends on the amount of correctly produced protein. In general, one cannot predict the phenotype just according to the genotype, as many other epigenetic and environmental factors play a role here. One can only try to picture a rough direction. The here mentioned polymorphism (assumed that there is a second, CFTR-mutation on the other chromosome) is highly unlikely to cause disease, in males with congenital bilateral absence of the vas deferens it can sometimes be found, and it cannot be excluded that it may lead to other forms of CFTR-related disorders, such as chronic pancreatitis, even if it is more likely, that it does not cause any symptoms at all.

In this context, the sweat test values are a bit striking to me. Concerning a sweat test, it is very important that it is performed in a experienced center, which uses the so-called pilocarpine ionotophoresis to measure the chloride concentration of the sweat. If this has been done, values 60mmol/l are positive. So the first two test have been positive, the last one borderline, if the test has been performed as described. So these results tend more in the direction of a kind of CFTR-related disorder, making a “healthy carrier state” more improbable.

So to clarify the situation, a repeated sweat test would help if the former ones were not according to guidelines or in an experienced center. Extended genetic analysis with a lager mutation panel or sequencing of the gene would also help to find out if there is a CFTR-related disorder underlying here. Testing of the fecal elastase, lung function, microbiological sputum testing and X-ray help to find out if there is any lung disease or how the pancreatic function is. Testing of the nasal potential difference would also help to make a diagnosis, is however not available everywhere.

If one comes to the conclusion, that the pancreatitis is not only due to the Pancreas divisum but also due to underlying mutations in the CFTR-gene, it is important to monitor the pancreatic function and the lung function of your daughter regularly in a CF center, to be able to react to any worsening promptly. Even if she is not suffering from CF and it is unlikely that the CFTR-related disorder will cause any lung disease at all, one is on the safe side.

Best regards,

Prof. Dr. Pop and Dr. Daniela d'Alquen

23.12.2011