‘If a child has tested negative (ages 5-10) should they be retested? If so, how much after the first testing?’

Oct 26, 2015

Dr. C: As many of you heard at the HAEA patient summit this is ‘The Year of the Youth’—here is another of the ‘unanswered questions’ from the meeting. It is critical to have children tested for HAE if there is an affected parent. Families can then establish an effective treatment plan to ‘be prepared’. We have discussed some of the testing in our July 6th QOTW which we have posted in the notes section. For type I HAE this would involve checking a C4 level and C1 inhibitor protein level while for type II HAE it would involve checking a C4 level and C1 inhibitor functional level. It is important that samples be handled properly in particular for the C1 inhibitor functional testing; the chromogenic assay is the most accurate, but is subject to falsely low values if the sample is not processed correctly. These studies should be reliable after the age of one. If done correctly there is actually no need for a repeat but patients and physicians may want to check ‘one more time’ just to be sure. At this juncture for the HAE with normal C1 inhibitor I would recommend checking for the factor XII mutation if that is positive for the parent. As many of our readers know we do not have other testing which provides a marker for this type of HAE at present. There are many encouraging developments however so ‘stay tuned’. Marc and Bruce what are your thoughts?

Dr. R: I agree that laboratory testing for C1INH deficiency is generally quite reliable after 1 year of age. So testing done in this specific case should be accurate. There are certain situations where one might consider repeat testing after normal results if a child is showing symptoms strongly suggestive of HAE, particularly if there is a family history of C1INH deficiency. There are also some specific nuances to C1INH functional testing. One of the assays used may rarely misclassify function as ‘low’ or ‘normal’ – essentially the test is wrong a very small percentage of the time. So for families with Type II HAE (normal C1INH levels but low C1INH function) or when the overall lab result profile (C4, C1INH level, C1INH function) is conflicting, a repeat round of testing may be important. However these circumstances arise due to issues with the laboratory tests themselves, NOT due to changes in the child’s C1INH protein levels or function. Those C1INH levels are pretty much set and stable by age 1. If retesting is performed, it’s generally advisable to wait a month between tests.

Dr. Z: I’d like to stress two points. First, that a normal C4 level does not exclude the possibility of HAE type I or II. There can be so much variation in normal C4 levels that one occasionally does see normal C4 between attacks. Second as mentioned by Sandra and Marc, the C1 inhibitor testing required can be tricky for type II HAE where the protein level is not helpful and the “usual” test can occasionally give a falsely normal result. So, the full answer really depends on what testing had been done previously.

Dr. C: But assuming that the child had previously had the C1 inhibitor tested appropriately (protein level for type I or chromogenic assay for type II), could you envision a scenario in which the correct diagnosis could be missed?

Dr. Z: You’re playing with me! But, I enjoy thinking about this type of question. You’re correct in that there are theoretical reasons to believe that there could be SERPING1 mutations that cause HAE (that is the C1 inhibitor fails to inactivate plasma kallikrein or factor XII) but do not result in abnormalities in C1 inhibitor levels or function (because it does inactivate C1). While such a mutation has not yet been found, the converse (a mutation that results in abnormal C1 inhibitor function but does not result in angioedema because the inhibitor does inactivate plasma kallikrein and factor XII normally) has in fact been found. This possibility has led to some suggestions that we change how C1 inhibitor function is measured, using an assay for inhibition of the contact system rather than the complement system.

Dr. C: Very interesting…Thank you, Bruce and Marc. We hope that this clarifies the current approach for testing in childhood for our readers. We look forward to our next ‘Question of the Week’.

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