Clinical characteristics and real-life diagnostic approaches in all Danish children with hereditary angioedema

Abstract

BackgroundWith a potentially early onset, hereditary angioedema (HAE) requires special knowledge also in infancy and early childhood. In children from families with HAE, the diagnosis should be confirmed or refuted early, which can be difficult. Studies of childhood HAE and the diagnostic approaches are limited. Our aim was to investigate the entire Danish cohort of children with HAE and non-HAE children of HAE patients for diagnostic approaches and clinical characteristics.ResultsWe included 41 children: 22 with HAE and 19 non-HAE. Of the HAE children, 14 were symptomatic—median age at onset was 4 [1–11] years. The first attack was peripheral in 8/14 children and abdominal in 6/14 children, i.e. no one had their first attacks in the upper airways. Most children had less than one attack per month. All of the symptomatic children had been treated with tranexamic acid and/or C1 inhibitor concentrate. Unlike in other countries, androgens were not used in our pediatric cohort. Home therapy with C1 inhibitor concentrate was established in 9 cases: 6 children were trained in self-administration and 3 children were treated by parents. Of the children, 10 had been diagnosed by symptoms, including 3 without family history—median age of diagnosis among these children was 5.35 [2–13.2] years. In 31 children, HAE was diagnosed or refuted before symptoms by blood samples. In 23 of these children, complement values were investigated, and in 9 cases genetic testing was added to the complement measurements. In 8 children recently investigated, genetic testing was first choice. Cord blood was used for complement measurements in 9 children and for genetic testing in 4 children. Results of complement measurements were equivocal in several cases, especially in the cord blood samples, and the sensitivity of low complement C4 for the diagnosis of HAE was 75%.ConclusionsWe investigated clinical characteristics in all Danish children with HAE. The rate of home therapy was high and androgens had been avoided. Complement values were often equivocal, especially in cord blood samples. Consequently, we have changed diagnostic practice to early genetic testing in children where the family mutation is known.

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

“…The assessment of complement in peripheral venous blood (serum/plasma) in children lacks reference values. However, with exceptions, in HAE 1/2 aged <1 year, C1‐INH antigenic level and/or functional activity are low . The measurement of C4, however, was found not to be useful for diagnosing of HAE‐1/2 in children below the age of 12 months, as C4 levels are frequently low in healthy infants .…”

“…However, with exceptions, in HAE 1/2 aged <1 year, C1‐INH antigenic level and/or functional activity are low . The measurement of C4, however, was found not to be useful for diagnosing of HAE‐1/2 in children below the age of 12 months, as C4 levels are frequently low in healthy infants . Genetic testing increases the diagnostic reliability in children and may be helpful in cases in which biochemical measurements are inconclusive and the genetic mutation of the parent is known .…”

“…The measurement of C4, however, was found not to be useful for diagnosing of HAE‐1/2 in children below the age of 12 months, as C4 levels are frequently low in healthy infants . Genetic testing increases the diagnostic reliability in children and may be helpful in cases in which biochemical measurements are inconclusive and the genetic mutation of the parent is known . All early complement testing performed in offspring of HAE‐1/2 patients should be repeated after the age of 1 year …”

“…Genetic testing increases the diagnostic reliability in children and may be helpful in cases in which biochemical measurements are inconclusive and the genetic mutation of the parent is known . All early complement testing performed in offspring of HAE‐1/2 patients should be repeated after the age of 1 year …”

Updates on hereditary angioedema in pediatrics

“…30,34 A chromogenic functional C1-INH assay appears to be superior to the ELISA-based C1-INH functional assay. 35 The measurement of C4, however, was found not to be useful for diagnosing of HAE-type I/II in infants below the age of 12 month, as C4 levels are frequently low in healthy infants 36,37 , thus should be repeated after the age of 1 year. [36][37][38] Abnormal results should be confirmed by repeating once to exclude ex vivo degradation of the sample or laboratory error.…”