Department of Dermatology, University Medical Center, Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany.
CSL Behring GmbH, Marburg, Germany.
Orphanet J Rare Dis. 2020 Oct 15;15(1):289. doi: 10.1186/s13023-020-01570-x.
Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) (HAEnCI) is associated with skin swellings, abdominal attacks, and the risk of asphyxia due to upper airway obstruction. Several different gene mutations linked to the HAE phenotype have been identified. Our aim was to qualitatively assess and describe the clinical differentiators of these genetically identified HAEnCI types. To achieve this, we performed a systematic literature review of patients with angioedema symptoms and a genetically confirmed diagnosis of an HAEnCI type.
A systematic literature search, conducted in March 2020, returned 132 records, 43 of which describe patients with symptoms of angioedema and a genetically confirmed diagnosis of an HAEnCI type. Overall, this included 602 patient cases from 220 families. HAEnCI with a mutation in the coagulation factor XII gene (F12) (HAE-FXII) was diagnosed in 446 patients from 185 families (male:female ratio = 1:10). Estrogens (oral contraceptives, hormonal replacement therapy, and pregnancy) negatively impacted the course of disease in most female patients (252 of 277). Asphyxia occurred in 2 of 446 patients. On-demand and/or long-term prophylaxis treatment included C1-INH concentrates, icatibant, progestins, and tranexamic acid. HAEnCI with a specific mutation in the plasminogen gene (HAE-PLG) was diagnosed in 146 patients from 33 families (male:female ratio = 1:3). Estrogens had a negative influence on the course of disease in the minority of female patients (14 of 62). Tongue swelling was an important clinical feature. Asphyxia occurred in 3 of 146 patients. On-demand treatment with icatibant and C1-INH concentrate and long-term prophylaxis with progestins and tranexamic acid were effective. HAEnCI with a specific mutation in the angiopoietin-1 gene (HAE-ANGPT1) was diagnosed in 4 patients from 1 family and HAEnCI with a specific mutation in the kininogen-1 gene (HAE-KNG1) in 6 patients from 1 family.
A number of clinical differentiators for the different types of HAEnCI have been identified which may support clinicians to narrow down the correct diagnosis of HAEnCI prior to genetic testing and thereby guide appropriate treatment and management decisions. However, confirmation of the causative gene mutation by genetic testing will always be required.
具有正常 C1 抑制剂（C1-INH）的遗传性血管性水肿（HAE）（HAEnCI）与皮肤肿胀、腹部发作以及因上呼吸道阻塞导致窒息的风险有关。已经确定了与 HAE 表型相关的几种不同的基因突变。我们的目的是定性评估和描述这些经基因鉴定的 HAEnCI 类型的临床差异。为此，我们对具有血管性水肿症状和经基因证实的 HAEnCI 类型诊断的患者进行了系统的文献复习。
2020 年 3 月进行的系统文献检索返回了 132 条记录，其中 43 条描述了具有血管性水肿症状和经基因证实的 HAEnCI 类型诊断的患者。总体而言，这包括来自 220 个家庭的 602 例患者病例。在来自 185 个家庭的 446 名患者中诊断出凝血因子 XII 基因突变（F12）（HAE-FXII）所致的 HAEnCI（男：女比例=1：10）。大多数女性患者（277 例中的 252 例）在接受雌激素（口服避孕药、激素替代疗法和妊娠）治疗后，病情会恶化。446 例患者中有 2 例发生窒息。按需和/或长期预防治疗包括 C1-INH 浓缩物、艾替班特、孕激素和氨甲环酸。在来自 33 个家庭的 146 名患者中诊断出纤溶酶原基因突变（HAE-PLG）所致的 HAEnCI（男：女比例=1：3）。少数女性患者（62 例中的 14 例）在接受雌激素治疗后病情会恶化。舌肿胀是一个重要的临床特征。在 146 例患者中有 3 例发生窒息。按需给予艾替班特和 C1-INH 浓缩物以及长期给予孕激素和氨甲环酸预防治疗有效。在来自 1 个家庭的 4 名患者中诊断出血管生成素-1 基因突变（HAE-ANGPT1）所致的 HAEnCI，在来自 1 个家庭的 6 名患者中诊断出激肽原-1 基因突变（HAE-KNG1）所致的 HAEnCI。
已经确定了不同类型的 HAEnCI 的一些临床差异，这有助于临床医生在进行基因检测之前缩小 HAEnCI 的正确诊断范围，从而指导适当的治疗和管理决策。然而，始终需要通过基因检测确认致病基因突变。
