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Potential cystic fibrosis

Me and my husband are cf carriers. I have the DF508del mutation and my husband the R117C. We have a two years old daugter with a mild cf and a five and a half years old son with the DF508del mutation. Some doctors and genetists say that my son is simply a carrier, even though he has two sweat tests at 69 and 55. Our cf doctor believes my son is a patient too even though only one of our gene mutations has identified. Please tell me if this is possible. I strongly believe that my son is ok but i have doughts because of the disagreement of the doctors opinions. I notice that my son's health is excellent. He is now 18 Kgr and 107cm and he had an intussusception at three.
Thank you for your question. The fact that your son had intussusceptions at the age of 3, along with borderline positive sweat tests would suggest, and quite strongly so, that he should be considered to have cystic fibrosis (CF).

Very often a diagnosis of CF is established without having identified any known culprit mutations (i.e. diagnosis made on the basis of sweat testing in conjunction with typical clinical findings). These rarer CF mutations are initially often not allocated to a specific class of mutation on CF Mutation databases. Furthermore, by virtue of being rare, it can also be challenging to be precise with regard to phenotype, or severity of disease, that the mutation renders in any given individual. In addition, the impact that any given CF mutation has on severity of disease is often determined by the combination of CF mutations, rather than any one mutation in isolation.[1]

The relationship between genotype and phenotype in cystic fibrosis is not always clear.[2] However, and in general, individuals who are compound heterozygous for a severe CF mutation (such as F508del), along with the R117C mutation, tend to have a milder phenotype, or a milder severity of disease.[3] The function of the cystic fibrosis transmembrane regulator (CFTR), a protein which we know is dysfunctional in CF, tends to retain a degree of function in individuals who harbour the R117C mutation. This, at least in part, explains why these individuals have milder disease.

Unfortunately because of the variable impact that R117C has on the amount of functioning CFTR, it can be challenging to predict clinical outcome precisely. Interestingly, the North American Cystic Fibrosis Foundation Consensus Panel has proposed that R117C should only be considered to have the ability to cause CF when associated, or what is known as “in cis”, with an additional mutation known as IVS8-5T.[4] It therefore would be of particular interest to know if your son also has this particular mutation. This would be able to provide further guidance as to the likely future outcome for your son.

Finally it is also important to keep in mind that there is a high variability in phenotype within identical CFTR genotypes.[5] As a definite modifier genes remains to be identified we support consensus statements advising that clinicians should not use genotype alone to predict clinical outcomes at the time of diagnosis.[6]

How can the situation be clarified now? Either one could try to clarify the genetics further and/or the clinical situation in order to find out, if your son is a “healthy carrier” or suffers from some kind of CF or CF-related disorder. Concerning the genetics, one has to make sure, that the result, that your son did not inherit the R117C mutation from the father is reliable. In case of doubt the test could be repeated and/or it could be tested for further CF mutations (using either a larger mutation panel or doing a complete gene sequencing) in order to be sure, that an until now undetected mutation plays a role here. If this should not lead to any conclusive result (some mutations are not described until now and cannot be detected by any test), one can only use the clinical information to clarify the situation furhter.

The sweat test is an important diagnostic tool: the results however, are only reliable if this test has been performed in an experienced center according to international guidelines, using a so-called pilocarpine ionotophoresis to measure the chloride concentration in the sweat. If the sweat chloride concentration is less than 40mmol/l, the test is negative. Concentrations greater than or equal to 60mmol/l are considered consistent with the diagnosis of CF. If the result is borderline (40-59mmol/l), the test should be repeated; if the result is still borderline, other measures to clarify the clinical situation are an option, such as measurement of the potential difference of the nasal or rectal mucosa, analysis of the pancreatic function (stool fat, pancreatic elastase in the stool), microbiological investigation of airway secretions, and x-ray of the lungs.
All these results together will help to lighten the clinical status of your son and will help to find a decision if a regular follow-up in a CF-center will be necessary.

Regards Dr Comer and Dr. D. d'Alquen

Reference List

1. Comer DM, Ennis M, McDowell C, Beattie D, Rendall J, Hall V, Elborn JS. Clinical phenotype of cystic fibrosis patients with the G551D mutation. QJM 2009; 102: 793-798.
2. Kerem E, Kerem B. Genotype-phenotype correlations in cystic fibrosis. Pediatr Pulmonol 1996; 22: 387-395.
3. Massie RJ, Poplawski N, Wilcken B, Goldblatt J, Byrnes C, Robertson C. Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C. Eur Respir J 2001; 17: 1195-1200.
4. Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. Cystic Fibrosis Foundation Consensus Panel. J Pediatr 1998; 132: 589-595.
5. Loubieres Y, Grenet D, Simon-Bouy B, Medioni J, Landais P, Ferec C, Stern M. Association between genetically determined pancreatic status and lung disease in adult cystic fibrosis patients. Chest 2002; 121: 73-80.
6. Castellani C, Cuppens H, Macek M, Jr., Cassiman JJ, Kerem E, Durie P, Tullis E, Assael BM, Bombieri C, Brown A, Casals T, Claustres M, Cutting GR, Dequeker E, Dodge J, Doull I, Farrell P, Ferec C, Girodon E, Johannesson M, Kerem B, Knowles M, Munck A, Pignatti PF, Radojkovic D, Rizzotti P, Schwarz M, Stuhrmann M, Tzetis M, Zielenski J, Elborn JS. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros 2008; 7: 179-196.

The answer is edited by: David Comer