High Estrogen States in Hereditary Angioedema: a Spectrum

Kulkarni, Maansi; Travers, Jeffrey B.; Rohan, Craig A.

doi:10.1007/s12016-021-08863-4

Cited by 11 publications

(14 citation statements)

References 23 publications

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“…The study sample included eight males (19.5%) and 33 females (80.5%). The protective role of male hormones and the well-known influence of estrogens as one of the main triggers of HAE attacks could explain this sexual disbalance ( 50 – 52 ). The patients were aged between four and 72 years (mean: 36.8 ± 16.9 years) and a positive family history for HAE attacks was reported for 23 (56.1%) of them.…”

Section: Resultsmentioning

confidence: 99%

A catalog of the genetic causes of hereditary angioedema in the Canary Islands (Spain)

Mendoza-Alvarez

Tosco-Herrera²,

Muñoz-Barrera³

et al. 2022

Front. Immunol.

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Hereditary angioedema (HAE) is a rare disease where known causes involve C1 inhibitor dysfunction or dysregulation of the kinin cascade. The updated HAE management guidelines recommend performing genetic tests to reach a precise diagnosis. Unfortunately, genetic tests are still uncommon in the diagnosis routine. Here, we characterized for the first time the genetic causes of HAE in affected families from the Canary Islands (Spain). Whole-exome sequencing data was obtained from 41 affected patients and unaffected relatives from 29 unrelated families identified in the archipelago. The Hereditary Angioedema Database Annotation (HADA) tool was used for pathogenicity classification and causal variant prioritization among the genes known to cause HAE. Manual reclassification of prioritized variants was used in those families lacking known causal variants. We detected a total of eight different variants causing HAE in this patient series, affecting essentially SERPING1 and F12 genes, one of them being a novel SERPING1 variant (c.686-12A>G) with a predicted splicing effect which was reclassified as likely pathogenic in one family. Altogether, the diagnostic yield by assessing previously reported causal genes and considering variant reclassifications according to the American College of Medical Genetics guidelines reached 66.7% (95% Confidence Interval [CI]: 30.1-91.0) in families with more than one affected member and 10.0% (95% CI: 1.8-33.1) among cases without family information for the disease. Despite the genetic causes of many patients remain to be identified, our results reinforce the need of genetic tests as first-tier diagnostic tool in this disease, as recommended by the international WAO/EAACI guidelines for the management of HAE.

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Section: Resultsmentioning

confidence: 99%

A catalog of the genetic causes of hereditary angioedema in the Canary Islands (Spain)

Mendoza-Alvarez

Tosco-Herrera²,

Muñoz-Barrera³

et al. 2022

Front. Immunol.

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“…Many cases of HAE nC1-INH have been shown to have a mutation in factor XII [ 10 ]. However, in this case, testing for this specific mutation came back negative.…”

Section: Discussionmentioning

confidence: 99%

“…HAE nC1-INH has long been thought to have an estrogen-related component in addition to genetic mutations. High estrogen states, such as contraceptives and pregnancy, have been linked with increased severity and frequency of flares in HAE [ 10 - 11 ]. Increased estrogen has also been shown to exacerbate the disease process in 91% of female patients with HAE nC1-INH with a factor XII mutation [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Hereditary Angioedema with Normal C1 Esterase Inhibitor Refractory to Long-Term Prophylaxis: A Case Report

Cobb¹,

Bernabe²

2023

Cureus

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Hereditary angioedema (HAE) was classically thought to be related to a deficiency in the C1 esterase inhibitor (C1-INH). However, HAE with a normal C1 esterase inhibitor (HAE nC1-INH) is a rare disease that has been recently characterized. In this case, we describe a woman with a 21-year history of angioedema who, in the last two years, has experienced severe exacerbations that led to the formal diagnosis of HAE nC1-INH. The patient has been treated with current HAE long-term prophylaxis (LTP) and on-demand therapies but is still experiencing severe, frequent attacks. Our case describes the timeline of this patient's presentation and provides valuable insight into the presentation and management of HAE nC1-INH.

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“…In patients with HAE type 1 and 2, the influence of estrogen on attack frequency and severity has been described extensively. 44 Previously suggested mechanisms for this observation are the increase of FXII levels, decrease of C1-inhibitor levels, induction of the release of nitric oxide and impairment of the functionality of angiotensin converting enzyme. 44 45 The specific characteristics of HAE-FXII suggest the influence of estrogen on FXII might be an important factor in the development of angioedema.…”

Section: Pathophysiologymentioning

confidence: 99%

“…44 Previously suggested mechanisms for this observation are the increase of FXII levels, decrease of C1-inhibitor levels, induction of the release of nitric oxide and impairment of the functionality of angiotensin converting enzyme. 44 45 The specific characteristics of HAE-FXII suggest the influence of estrogen on FXII might be an important factor in the development of angioedema. Another noteworthy difference in the clinical presentation of patients with HAE-FXII is the absence of erythema marginatum as a prodromal symptom.…”

Section: Pathophysiologymentioning

confidence: 99%

Hereditary Angioedema: The Clinical Picture of Excessive Contact Activation

Petersen

Fijen

Levi

et al. 2022

Semin Thromb Hemost

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Hereditary angioedema is a rare, genetic disorder characterized by painful, debilitating and potentially life-threatening angioedema attacks in subcutaneous and submucosal tissue. While usually unpredictable, attacks can be provoked by a variety of triggers including physical injury and certain medication and are often preceded by prodromal symptoms. Hereditary angioedema has a profound influence on the patients' lives. The fundamental cause of hereditary angioedema in almost all patients is a mutation in the SERPING1 gene leading to a deficiency in C1-inhibitor. Subsequently, the contact activation cascade and kallikrein-kinin pathway are insufficiently inhibited, resulting in excessive bradykinin production triggering vascular leakage. While C1-inhibitor is an important regulator of the intrinsic coagulation pathway, fibrinolytic system and complement cascade, patients do not have an increased risk of coagulopathy, autoimmune conditions or immunodeficiency disorders. Hereditary angioedema is diagnosed based on C1-inhibitor level and function. Genetic analysis is only required in rare cases where hereditary angioedema with normal C1-inhibitor is found. In recent years, new, highly specific therapies have greatly improved disease control and angioedema-related quality of life. This article reviews the clinical picture of hereditary angioedema, the underlying pathophysiology, diagnostic process and currently available as well as investigational therapeutic options.

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High Estrogen States in Hereditary Angioedema: a Spectrum

Cited by 11 publications

References 23 publications

A catalog of the genetic causes of hereditary angioedema in the Canary Islands (Spain)

A catalog of the genetic causes of hereditary angioedema in the Canary Islands (Spain)

Hereditary Angioedema with Normal C1 Esterase Inhibitor Refractory to Long-Term Prophylaxis: A Case Report

Hereditary Angioedema: The Clinical Picture of Excessive Contact Activation

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