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Hereditary Angioedema Types

Hereditary angioedema (HAE) is a genetic disease characterized by the development of vasogenic edema, in which an accumulation of extravascular fluid in diverse tissues is caused by a non-inflammatory, non-allergic process. HAE is estimated to affect between 1 in 10,000 and 1 in 150,000 people. Clinical features include swelling of sudden onset around the eyes, face, and extremities; abdominal pain (caused by bowel edema); and laryngeal edema resulting in vocal hoarseness, difficulty breathing, and rarely death.¹ HAE crisis does not respond to corticosteroids, antihistamines, or adrenalin and normally resolves spontaneously within 12 to 72 hours. Several types of HAE have been identified. In type 1, which accounts for most of the cases, C1-esterase inhibitor protein (C1-INH) is deficient or absent as a result of reduced synthesis. In type 2, C1-INH levels are normal or increased, but the protein is abnormal and dysfunctional. In 2000, another subtype of HAE, type 3, was identified, in which C1-INH is quantitatively and qualitatively normal. Clinically, type 3 HAE is indistinguishable from the other types.²

Hereditary Angioedema With C1-Esterase Inhibitor Deficiency/Dysfunction

Type 1

Type 1 HAE is caused by mutations in the genes that code for C1-INH protease, which belongs to the serine superfamily of proteins. Mutations in the serine protease inhibitor G1 gene (SERPING1) account for most cases of HAE.³ A variety of mutations in this gene are associated with type 1 HAE, including missense, nonsense, frameshift, deletion, and insertion. These cause truncated or misfolded C1-INH to form that cannot be released properly.⁴

Type 1 is an autosomal-dominant condition that frequently manifests in childhood, seldom appears before the age of 1 year, and generally worsens during puberty.⁴

Maintaining a high index of suspicion is the most critical step in diagnosing HAE with C1-INH deficiency. Repeated episodes of cutaneous angioedema (asymmetric, nonpruritic, disfiguring, and nonpitting) in the absence of urticaria, severe abdominal symptoms (pain and swelling), or both may prompt the clinician to suspect a diagnosis of HAE.⁴

Laboratory testing shows low levels of complement component 4 (C4) and C1-INH. C1-INH function can be deficient or normal.^5,6

Type 2

Type 2 accounts for approximately 15% of cases. Patients have normal or increased levels of nonfunctional C1-INH.⁶ SERPING1 mutations associated with this type of HAE consist of residues at or near the active site on the reactive mobile loop, which result in a secreted but dysfunctional mutant C1-INH protein. The SERPING1 gene is involved in the regulation of the complement cascade as it encodes a highly glycosylated plasma protein. Mutations in the SERPING1 gene can lead to disruption of protein function. Therefore, the C1-INH antigen level in plasma is normal or even raised in type 2 HAE, but protein function is reduced.³ The main features of type 2 HAE are a C1-INH-like phenotype, the absence of erythema marginatum, infrequent cutaneous hemorrhage, and possibly disease-free intervals longer than those in type 1.⁴ Laboratory testing reveals deficient C4 and C1-INH function, although C1-INH levels are within normal range.⁵

Hereditary Angioedema With Normal C1-Esterase Inhibitor Levels: Type 3

In type 3 HAE, C1-INH is quantitatively and qualitatively normal, although attacks of angioedema are identical to those in types 1 and 2. The mechanism underlying this condition is not entirely understood.⁶

The inheritance pattern is autosomal dominant with incomplete penetrance. Men may be silent carriers of the disease. Most patients have an alteration in the F12 gene, and these cases are frequently associated with increased levels of estrogen (eg, pregnancy, administration of exogenous estrogens).⁴ In addition to mutations in F12, pathogenic mutations in plasminogen (PLG), angiopoietin 1 (ANGPT1), Kininogen 1 (KNG1), Myoferlin (MYOF), or heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6) may serve as diagnostic biomarkers in individuals with unexplained angioedema, and therefore a molecular-level assay can be used to diagnose HAE with normal C1-INH (nC1-INH HAE).¹ Mutational analysis to understand the genetic basis of nC1-INH HAE facilitates the diagnosis.¹ In this rare type of HAE, C4 and C1-INH levels and C1-INH function are normal.⁵

References

Santacroce R, D’Andrea G, Maffione AB, Margaglione M, d’Apolito M. The genetics of hereditary angioedema: a review. J Clin Med. 2021;10(9):2023. doi:10.3390/jcm10092023
Miranda AR, Ue AP, Sabbag DV, Furlani Wde J, Souza PK, Rotta O. Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review. An Bras Dermatol. 2013;88(4):578-584. doi:10.1590/abd1806-4841.20131818
Abdulkarim A, Craig TJ. Hereditary angioedema. StatPearls [Internet]. Updated May 4, 2022.
Busse PJ, Christiansen SC. Hereditary angioedema. N Engl J Med. 2020;382(12):1136-1148. doi:10.1056/NEJMra1808012
Jindal AK, Bishnoi A, Dogra S. Hereditary angioedema: diagnostic algorithm and current treatment concepts. Indian Dermatol Online J. 2021;12(6):796-804. doi:10.4103/idoj.idoj_398_21
Abuzakouk M, AlMahmeed N, Memisoglu E, McManus M, Alrakawi A. Hereditary angioedema type II: first presentation in adulthood with recurrent severe abdominal pain. Case Reports Immunol. 2018;2018:7435870. doi:10.1155/2018/7435870

Reviewed by Debjyoti Talukdar, MD, on 6/27/2022.

Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.

Hereditary Angioedema (HAE)