Management of hereditary angioedema with normal C1Inh - A series of 163 French patients

Q: Which genes are most frequently associated with hereditary angioedema with normal C1Inh in this study?

The two most frequent pathogenic variants are in the FXII and PLG genes.

Q: What differences in symptoms and triggers were observed between HAE-FXII and HAE-PLG?

HAE-FXII showed much higher estrogen dependence and a predominance of symptomatic women, while HAE-PLG involved different clinical sensitivity patterns and oral (tongue) localization mentioned in the conclusion.

Q: How effective were icatibant and other treatments for the different variant groups?

Icatibant was needed by most HAE-PLG patients with reported high efficacy, while HAE-FXII patients commonly received treatments such as icatibant and C1Inh concentrate. The study also reports complete asymptomatic outcomes with lanadelumab in HAE-FXII.

Sep 30, 2026

Uploaded by Maya Linwood

Hereditary angioedema with normal C1Inh is a genetically mediated condition, most commonly linked to pathogenic variants in FXII and PLG. A French Reference Centre for Angioedema (CREAK) used a national retrospective design to evaluate therapeutic management for all identified patients. Among 287 cases, symptomatic disease varied by variant, including strong estrogen sensitivity in HAE-FXII and consistent responsiveness in HAE-PLG, with variant-specific prophylactic needs and outcomes. The study concludes that therapies for C1Inh-deficiency forms can be effective and safe, and highlights contraceptive considerations.

LanguageEnglish

CategoryHealthcare

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Pages6

Reading Time15 min

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Abstract

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Bocquet etal. Orphanet Journal of Rare Diseases (2026) 21:5 [https://doi.org/10.1186/s13023-025-04155-8](https://doi.org/10.1186/s13023-025-04155-8) Orphanet Journal of Rare Diseases RESEARCH Open Access Management of hereditary angioedema with normal C1Inh: a series of 163 French patients Alexis Bocquet 1, Laurence Bouillet 1,14*, Gael le Hardy 1,2, Isabelle Boccon-Gibod 1, Alban Deroux 1, Mélanie Arnaud 1, Fabien Pelletier3, Aurélie Du Thanh4, Nicolas Ozanne5, Guillaume Armengol6, Pierre Yves Jeandel7, Laurent Sailler8, Marie Caroline Taquet9, David Launay 10,11,12, Olivier Fain 13 and Delphine Gobert 13 Abstract Background The diagnosis of hereditary angioedema with a normal C1Inh was genetic. The two most frequent pathogenic variants are found in the FXII and PLG genes. Their management is similar to that of HAE patients with C1Inh deficiency but without evidence-based medicine. Objective The French Reference Centre for Angioedema (CREAK) Our center identified all patients with HAE with a normal C1Inh to evaluate their therapeutic management. Methods This was a national retrospective study conducted in our center the CREAK network. Results A total of 287 patients were identified with an F12 pathogenic variant (133 families), 38 with PLG (12 families) and one patient with KNG1 . Among these patients, 111 patients with HAE-FXII and 19 patients with HAE-PLG were symptomatic. More women than men were symptomatic (86 . 3% vs. 30. 8%, respectively) (p < 0,0001) . The mean age at first attack was 24 ± 12 years. 49% of patients with HAE-FXII were estrogen dependent (vs. 0% HAE-PLG, p < 0,01) . 91% of patients with HAE-PLG needed to receive at least one attack of icatibant with 100% efficacy. 67% of patients with HAE-FXII were treated at least once: 56% with icatibant and 54% with C1Inh concentrate (during pregnancy) . 12,6% of patients with HAE-FXII and 47,4% of patients with HAE-PLG required long-term prophylactic treatment: 66,7% of patients HAE-PLG who were taking tranexamic acid were attack-free (vs. 37,5 3% of HAE-FXII patients) . 100% of patients with HAE-FXII treated with lanadel umab were completely asymptomatic (vs. 25% of patients with HAE-PLG) . Conclusion HAE patients with a normal C1inh have specific clinical features, including a later age at first attack than HAE patients with a normal C1inh, high sensitivity to estrogens of HAE-FXII and the location of the HAE-PLG on the tongue. The treatments used for HAE patients with C1Inh deficiency appear to be effective and safe. Low-dose progestin-only pills are good contraceptive options. Highlights • Hereditary angioedema (HAE) with normal C1Inh are very rare and seem to have different clinical characteristics to those of HAE with C1Inh deficiency. *Correspondence: Laurence Bouillet [l bouillet@chu-grenoble.fr](l bouillet@chu-grenoble.fr) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/l](http://creativecommons.org/l)icenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ([http://creativecommons.org/publicdomain/zero/1.0/](http://creativecommons.org/publicdomain/ze

FAQs

Which genes are most frequently associated with hereditary angioedema with normal C1Inh in this study?

The two most frequent pathogenic variants are in the FXII and PLG genes.

What differences in symptoms and triggers were observed between HAE-FXII and HAE-PLG?

HAE-FXII showed much higher estrogen dependence and a predominance of symptomatic women, while HAE-PLG involved different clinical sensitivity patterns and oral (tongue) localization mentioned in the conclusion.

How effective were icatibant and other treatments for the different variant groups?

Icatibant was needed by most HAE-PLG patients with reported high efficacy, while HAE-FXII patients commonly received treatments such as icatibant and C1Inh concentrate. The study also reports complete asymptomatic outcomes with lanadelumab in HAE-FXII.

Sep 30, 2026

Uploaded by Maya Linwood