QOTW – “Can someone be a carrier for HAE and not express any symptoms?”

Sep 28, 2015

Dr. C:We would like to thank Janet Long from the HAEA for forwarding this question. I believe that this topic is of considerable interest for HAE patients and their families. The answer to our readers question is of course is a bit complicated. Dr Z and I have previously discussed the inheritance patterns of HAE in our June 29th ‘Question of the Week’ that can be found archived in the notes section of our Facebook page. The specific question as to whether someone can be a ‘carrier without symptoms’ is a slightly different focus. The likelihood of this is quite different depending on the category of HAE as well as factors such as estrogen exposure, which may influence disease expression. Marc, would you like to share your thoughts on this?

Dr. R:The answer to this is “yes”, but the likelihood of this occurring strongly depends on the type of HAE. In Type 1 and 2 HAE, which are due to C1INH deficiency, this phenomenon occurs very rarely. The largest study looking at this was by Agostoni and Cicaridi in Italy back in the 1990s. They studied 80 families and 226 individuals diagnosed with C1INH deficiency by lab testing and found that 5 percent reported no angioedema symptoms. Now we don’t know if those individuals might go on to have angioedema episodes at some point in the future, but it suggests that it’s possible, but rare, to have low C1INH level/function and no clear symptoms. However, the vast majority of the time, C1INH deficiency causes at least some level of recurrent swelling episodes. HAE with normal C1INH (Type III) is clearly different from Type 1 and 2 in a number of ways. First of all, it is not due to C1INH deficiency and so we currently don’t have good ways to define the condition biochemically with blood tests. That said, in the cases where a Factor XII mutation is found (a minority of cases worldwide), we can trace this mutation in families and it’s clear that asymptomatic carriers exist. This is most often seen in males that carry the Factor XII mutation but usually have no swelling symptoms. We call this a variably penetrant mutation so the symptoms are not expressed in every affected person. Our understanding of HAE with normal C1INH will hopefully improve in the near future as more research is conducted, so we can better understand the expression and inheritance patterns.

Dr. C:Very interesting. Bruce what are your thoughts regarding the possibility of being a ‘silent carrier’ for HAE ?

Dr. Z:I certainly agree with Marc’s comments. For type I and type II HAE, the rare asymptomatic family members can still be correctly diagnosed by simple laboratory testing. I would like to emphasize that I think all direct family members of a patient with type I or type II HAE should be tested for the disease. The lower penetrance seen in HAE-nl-C1INH makes it more likely that there are silent carriers. We can screen for the factor XII mutation in patients with HAE-nl-C1INH, giving us a similar (although somewhat more difficult) means to test family members. The lack of a test for HAE-nl-C1INH without a factor XII mutation makes it impossible at the current time to identify silent carriers.

Dr. C:Thank you, Bruce and Marc. We hope that continued progress in disease recognition and testing will help with defining the ‘carrier’ question in the future. We look forward to our next ‘Question of the Week’.

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