Indications for testing include clinical suspicion or positive family history [
8,
19,
20,
22,
29‐
31]. Testing under one year of age may not be reliable and should be confirmed after age one (false negative and false positive tests may occur unless using genetic typing) [
8,
19,
20,
29‐
31]. If clinical suspicion of C1-INH deficiency, we recommend screening with C4, (C4 is normal between swelling events in only 2% of cases; [
19,
31]), C1 inhibitor antigenic protein and C1 inhibitor function, if available. However, a
normal C4 particularly during an edema attack should make one question the diagnosis of HAE (there is no indication for screening CH50 nor C3) [
6,
8,
10,
19,
22,
29,
31]. If serum C4 and C1-INH antigenic proteins are both low (below manufacturer's normal range) and AAE not suspected, then the diagnosis is compatible with
HAE-C1INH-Type I (Type I HAE) (suggest repeat testing once to confirm). If AAE is possible such as with no family history and later onset of symptoms (age over 40), then serum C1q antigenic protein testing is suggested. If low C1q, the diagnosis is compatible with
AAE (C1q antigenic protein is reduced in 75% of AAE but usually normal in HAE; [
10]). If C4 is normal or low and C1-INH antigenic protein normal but clinical suspicion is strong, HAE is
NOT ruled out and C1-INH functional assay should be obtained (in a laboratory skilled in functional C1-INH assay with careful sample drawing, handling, shipping, and interpreting results) [
8,
18,
19,
28,
29,
34]. If C1-INH functional activity is low with normal or elevated C1-INH antigenic protein and normal C1q, this is compatible with
HAE-C1INH-Type II (Type II HAE) (tests should be repeated at least once to confirm the diagnosis; sample mishandling is common) [
8,
18,
19,
28,
29,
34]. If C4 antigenic protein and C1-INH functional assays are both normal, this rules out Types I and II HAE but does not rule out
type III HAE (HAE-FXII and HAE-Unknown) (normal C1-INH protein and function occurring mainly in women; some with mutations in the coagulation factor XII gene or other unidentified defects; [
11,
13,
19,
25,
35] nor
medication-related angioedema (e.g. ACE-I-related Angioedema; [
10,
19,
22]). If C4 and C1-INH protein are normal, we suggest repeating these during an acute attack [
19,
28]. Genetic testing is usually not necessary to confirm the diagnosis of HAE-C1INH types I and II particularly if positive family history (autosomal dominant with approximately 25% representing de novo mutations) [
8,
19,
29,
31]. However, genetic testing is occasionally helpful in confirming HAE-C1INH (particularly before one year of age and cord blood; [
8]) and may contribute to investigation of type III HAE [
8,
11,
13,
19,
25]. Although C4 and C1-INH protein antigen are routine laboratory tests, C1-INH functional assays are specialized laboratory tests and should only be done in reference laboratories with careful attention to sample handling for complement [
8,
11,
13,
17,
19,
28,
29,
34]. C1-INH functional assays may use chromogenic or C1s binding ELISA assays. Both distinguish between normal and abnormal but the C1s ELISA assay performance may be poor if manufacturer's normal range (> 67%) is used. The reference laboratory should determine normal range locally with receiver operator characteristic (ROC) analysis, since higher cutoff (84%) may give better discrimination [
34].