Sustainability of pancreatic sufficiency in case of compound heterozygous mutation F508del/R347P

Question

Hello

My daughter is currently pancreatic sufficient since birth. I guess that when the patient is compound heterozygous (mutations deltaF508 and R347P) the mildest mutation gets over the other one
Will it remain so, or do studies / statistics and knowledge on the R347P mutation phenotype show that over time the pancreas may no longer assume its exocrine function? (I do not mean risk of diabetes).
Thank you in advance for your reply
Cordially

Answer

Hello,
The implementation of systematic newborn screening for cystic fibrosis has resulted in a diagnosis of a larger number of mild symptomatic forms associated with a compound heterozygous mutation. Actually, the mildest mutation largely determines the symptomatology (phenotype) since it allows the synthesis and the transport to the cell membrane of an amount of a functional CFTR protein. This ability of the pancreas to secrete enough enzymes to provide a suitable digestion of food including fat is very common in patients with class IV or V mutation.
This is the case of mutations where the amino-acid arginine (R) at position 347 of CFTR was replaced by another amino-acid, Histidine (R347H), Lysine (R347L) or Proline (R347P) .
Consulting the Cystic Fibrosis French Registry can find 18 compound heterozygous F508del/R347P patients as your daughter. Among them, 7 are pancreatic sufficient, 11 are pancreatic insufficient including 3 who became respectively at 1, 3 and 6 years.
While undoubtedly the compound heterozygous genotype F508del/R347P is associated with a most often mild phenotype, there is to date no clue to predict either the sustainability of the pancreatic sufficiency or the respiratory changes. Consequently, regular visits at CF center are recommended at suitable frequency. Note also that a French study is running. Its objectives are to assess the long-term evolution, to try to differenciate typical CF from other CFTR Related Disorders, to assign a different diagnosis wording to the different forms even though crossing from one form to another one remains possible, and finally to set up an adjusted monitoring protocol. Feel free to ask your CF doctor for further information on this study.
With my best greetings

Gilles RAULT, MD with aknowlegments to Claude FEREC, MD, PhD
Nortwestern France CF Network and Gil Bellis, Institut National d’Etudes Démographiques and French CF Registry

References:
J Inherit Metab Dis. 2007 Aug;30(4):613. Epub 2007 Jul 12.
Neonatal screening of cystic fibrosis: diagnostic problems with CFTR mild mutations.
Roussey M, Le Bihannic A, Scotet V, Audrezet MP, Blayau M, Dagorne M, David V, Deneuville E, Giniès JL, Laurans M, Moisan-Petit V, Rault G, Vigneron P, Férec C

20.06.2011