Homozygosity for a factor <scp>XII</scp> mutation in one female and one male patient with hereditary angio‐oedema

Background 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. Results 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. Conclusions 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.

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“…Individuals with homozygous genotype of Thr328Lys mutations have been described and appear to have a more severe phenotype [34].…”

Section: Inheritance Gender Penetrance Transmissionmentioning

confidence: 99%

Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence

Bork

Machnig

Wulff

et al. 2020

Orphanet J Rare Dis

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“…Mutations in the F12 gene are mainly heterozygous. There has just been one report of 2 Brazilian patients from unrelated families who had a p.Thr309Lys mutation in homozygosity 59 .…”

Section: Mutations In the F12 Genementioning

confidence: 99%

The genetics of hereditary angioedema: A review

Piñero-Saavedra¹,

González-Quevedo²

2017

J Rare Dis Res Treat

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“…Limited information exists to date as to how p.Thr328Lys or wild type gene dosages modify the phenotype in HAE-FXII patients. Data from two Brazilian HAE-FXII patients (symptomatic male and female) bearing the p.Thr328Lys variant in homozygous state who manifested more severe HAE phenotypes suggest that it is indeed a hypermorphic variant ( Grumach et al, 2016 ).…”

Section: Introductionmentioning

confidence: 97%

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

et al. 2020

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Background Hereditary angioedema due to the Thr328Lys variant in the coagulation factor XII (HAE-FXII) affects mainly women in whom the symptomatology is dependent on high estrogen levels. Clinical variability and incomplete penetrance are challenging features that hinder the diagnosis and management of HAE-FXII. The c.-4T>C Kozak polymorphism is the only common variation accounting for FXII plasma levels and was previously shown to modify the course of HAE due to C1-Inhibitor deficiency. Objectives To assess the influence of the c.-4T>C polymorphism on disease expression in 39 Spanish HAE-FXII index patients. Methods The c.-4T>C polymorphism was sequenced by the standard Sanger method, and HAE severity was calculated according to the score by Cumming et al. (2003) The activation of the contact system was quantified by the kallikrein-like activity of plasma in chromogenic assays upon activation with high-molecular-weight dextran sulfate. Results The c.-4CC genotype was overrepresented in the studied cohort: 82% were CC-homozygous (expected frequency = 59%) and 18% were CT-heterozygous (expected frequency = 39%) ( p = 0.001). Patients with a c.-4CC genotype exhibited higher kallikrein-like activity (0.9659 ± 0.1136) than those with a c.-4TC genotype (0.7645 ± 0.1235) ( p = 0.024) or healthy donors. Moreover, the polymorphism influenced HAE-FXII severity score (c.-4CC = 4.43 ± 2.28 vs c.-4TC = 2.0 ± 1.15; p = 0.006) but not the degree of estrogen dependence or time until remission. Conclusion The c.-4T>C polymorphism is overrepresented in a Spanish HAE-FXII cohort and significantly influences the degree of contact system activation and the clinical severity of the disease.

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Homozygosity for a factor XII mutation in one female and one male patient with hereditary angio‐oedema

Cited by 14 publications

References 22 publications

Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence

Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence

The genetics of hereditary angioedema: A review

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

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