Q:

12/27/2013
I have a healthy 10 year-old boy with reported viral induced urticaria 6 months ago (normal cbc with diff, ALT, TSH, and ESR). He presents to me now with 2 episodes of idiopathic lip angioedema in the past 3 months, both lasting 24-48hr. No family history of HAE. He was asymptomatic when the following labs were drawn: C4 slightly low at 13 (ref range 15-50); low C1q 97 (ref range 109-242); normal C3 and normal C1 esterase level and function (not done at National Jewish lab). I would appreciate your thoughts regarding additional work-up and management.

A:

Thank you for your inquiry.

The "short answer" to your question is that I believe this young boy has idiopathic urticaria and angioedema. The other possibility is of course a spontaneous mutation in C1 esterase inhibitor ushering in the onset of C1 esterase inhibitor deficiency syndrome. In addition, since you performed a C1q which was also low, acquired C1 inhibitor deficiency syndrome is a possibility, but far less likely in someone his age.

The reason that I feel that he does not have a C1 esterase inhibitor deficiency syndrome is based on the fact that he has a normal functional level of C1 esterase, and in both forms of the inhibitor deficiency syndrome, the C1 esterase functional level should be low. The only evidence for a C1 esterase inhibitor deficiency is actually his C4, but as you can see from the abstract copied below, there are two separate genes that control the synthesis of C4. These are highly homologous. Within each of these genes there can be duplications, deletions, or inactivating mutations. The frequency of these makes the interpretation of a low serum complement difficult. In fact, a decreased concentration of C4 is relatively common, occurring in up to 2% of the population. Based on the frequency of the occurrence of low C4 levels, I doubt that the low C4 is of any significance.

If my assumption is correct, and this child does have chronic idiopathic urticaria and angioedema, the low C1 level is of no clinical significance, and could possibly be a lab error.

With these thoughts in mind, there are two options available to you:

1. Simply accept the most likely possibility which is that this child has idiopathic urticaria and angioedema, and treat according to this diagnosis. If such is the case, as in most instances of this condition, symptoms will resolve over time.

2. Repeat the C1q, C4, and C1 inhibitor at the National Jewish Laboratory. This would be done primarily to make sure that there was an accurate determination of all of these values, most importantly the C1q.

I would personally be comfortable at this time with Option 1, and repeating the studies if he did poorly. However, you may receive different opinions in this regard, and that is why I suggested the repeat assays. The rationale for these repeat assays to be performed at National Jewish has been expressed on our website on a number of occasions by Dr. Bruce Zuraw, who is an internationally recognized expert in C1 esterase inhibitor deficiency syndromes. You can access his comments in this regard by going to our Ask the Expert website and typing "Zuraw" into the search box. The most recent entry was posted on 10/28/2013, and relates to a question similar to yours. It is entitled "Recurrent episodes of angioedema in a 12 year-old with a family history of hereditary angioedema and contradictory lab data." The answer cites the fact that the chromogenic assay available through the National Jewish Complement Laboratory is the preferred test in such situations.

Thank you again for your inquiry and we hope this response is helpful to you.

G J O'Neill, et al, Two HLA-linked loci controlling the fourth component of human complement
PNAS October 1, 1978 vol. 75 no. 10 5165-5169
Abstract
An electrophoretic polymorphism of the fourth component of human complement (C4) is described. Three patterns of bands of C4 were observed in EDTA plasma from a panel of unrelated blood donors and family members by using the technique of immunofixation electrophoresis. These patterns consisted of four fast-moving anodal bands (F), four slow-moving cathodal bands (S), or a combination of both the F and S bands (FS). The C4 patterns of bands were observed in EDTA plasma and not in serum. Family studies showed that this polymorphism of C4 did not segregate with HLA histocompatibility genes in a fashion governed by two codominant alleles at a single genetic locus. The family data are in agreement with the hypothesis that two different genetic loci control the electrophoretic patterns of C4. One locus controls the presence (F) or absence (f0) of the four anodal (F) bands and the other controls the presence (S) or absence (s0) of the four cathodal (S) bands. The C4F and C4S loci are both closely linked to HLA-B.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology