Binkley K E, Davis A
Division of Clinical Immunology and Allergy, St Michael's Hospital, University of Toronto, Toront, Canada.
J Allergy Clin Immunol. 2000 Sep;106(3):546-50. doi: 10.1067/mai.2000.108106.
Two genetic forms of hereditary angioedema (HAE) are currently recognized. Both are transmitted in an autosomal dominant manner and are characterized by recurrent episodes of localized angioedema. Involvement of the gut leads to episodes of severe abdominal pain, and laryngeal involvement can lead to airway obstruction and even death. One type results from heterozygosity for a nonexpressed C1 inhibitor allele, and the other results from heterozygosity for a nonfunctional C1 inhibitor allele.
This report identifies a third type of HAE, with a unique estrogen-dependent phenotype.
Detailed medical histories were obtained from family members, and a pedigree was constructed to ascertain the mode of inheritance. Determination of serum complement factors, C1 inhibitor protein, C1 inhibitor function, coagulation factor XII, plasma prekallikrein, high molecular weight kininogen, and selected DNA sequences were performed in affected members by using standard assays.
Episodes of angioedema were clinically indistinguishable from those associated with previously described forms of HAE; however, these occurred only during pregnancy or the use of exogenous estrogens. Patients were otherwise asymptomatic, except for one patient who had acetyl salicylic acid/nonsteroidal anti-inflammatory drug-related angioedema later in life. History was available for members spanning 4 generations, and affected individuals were identified in 3 generations. Of 46 family members, phenotype could be determined in 13 members. Seven were affected, and 6 were not. One male of undetermined phenotype was an obligate carrier. The unique estrogen-dependent nature of the phenotype means that the status of several members in the third and fourth generation remains unknown. The disorder appears to be transmitted in an autosomal dominant fashion, although other modes of inheritance cannot be excluded entirely. C1 inhibitor protein, C1 inhibitor function, C2, C4, C1q, coagulation factor XII, prekallikrein, and high molecular kininogen were normal in 3 affected family members during asymptomatic periods. DNA sequencing revealed no abnormality in 3 patients in the coding region of the gene encoding C1 inhibitor or in the 5' flanking regions of the genes encoding C1 inhibitor and factor XII.
This family appears to have a novel form of inherited angioedema that does not result from C1 inhibitor deficiency or dysfunction. The phenotype is uniquely estrogen dependent. Implications for diagnosis and treatment are discussed. Further studies are required to define the exact nature of the genetic abnormality involved.
目前已确认遗传性血管性水肿（HAE）有两种遗传形式。两者均以常染色体显性方式遗传，其特征为局部血管性水肿反复发作。肠道受累会导致严重腹痛发作，喉部受累可导致气道阻塞甚至死亡。一种类型是由于未表达的C1抑制因子等位基因杂合性所致，另一种类型是由于无功能的C1抑制因子等位基因杂合性所致。
本报告鉴定出第三种类型的HAE，具有独特的雌激素依赖性表型。
从家庭成员处获取详细的病史，并构建家系图谱以确定遗传方式。通过标准检测方法对受累成员进行血清补体因子、C1抑制因子蛋白、C1抑制因子功能、凝血因子XII、血浆前激肽释放酶、高分子量激肽原及选定DNA序列的测定。
血管性水肿发作在临床上与先前描述的HAE形式相关发作无法区分；然而，这些发作仅在妊娠期间或使用外源性雌激素时出现。除一名患者在晚年出现阿司匹林/非甾体抗炎药相关血管性水肿外，患者在其他情况下无症状。有4代成员的病史资料，3代中有受累个体。在46名家庭成员中，可确定13名成员的表型。7名受累，6名未受累。一名表型未确定的男性为必然携带者。该表型独特的雌激素依赖性意味着第三代和第四代中几名成员的状况仍不清楚。尽管不能完全排除其他遗传方式，但该疾病似乎以常染色体显性方式遗传。3名受累家庭成员在无症状期时，C1抑制因子蛋白、C1抑制因子功能、C2、C4、C1q、凝血因子XII、前激肽释放酶和高分子量激肽原均正常。DNA测序显示，3名患者编码C1抑制因子的基因编码区及编码C1抑制因子和因子XII的基因5'侧翼区均无异常。
该家族似乎有一种新型遗传性血管性水肿，并非由C1抑制因子缺乏或功能障碍引起。其表型具有独特的雌激素依赖性。讨论了对诊断和治疗的影响。需要进一步研究以确定所涉及的基因异常的确切性质。
