Adenaeuer, Anke; Barco, Stefano; Trinchero, Alice; Krutmann, Sarah; Nazir, Hanan Fawzy; Ambaglio, Chiara; Rocco, Vincenzo; Pancione, Ylenia; Tomao, Luigi; Ruiz-Sáez, Arlette; Echenagucia, Marion; Alesci, Sonja; Sollfrank, Stefanie; Ezigbo, Eyiuche D; Häuser, Friederike; Lackner, Karl J; Lämmle, Bernhard; Rossmann, Heidi (2023). Severe high-molecular-weight kininogen deficiency: clinical characteristics, deficiency-causing KNG1 variants, and estimated prevalence. Journal of thrombosis and haemostasis, 21(2), pp. 237-254. Wiley-Blackwell 10.1016/j.jtha.2022.11.011
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BACKGROUND
Severe high-molecular-weight kininogen (HK) deficiency is a poorly studied autosomal recessive contact system defect caused by pathogenic, biallelic KNG1 variants.
AIM
We performed the first comprehensive analysis of diagnostic, clinical, genetic, and epidemiological aspects of HK deficiency.
METHODS
We collected clinical information and blood samples from a newly detected HK-deficient individual and from published cases identified by a systematic literature review. Activity and antigen levels of coagulation factors were determined. Genetic analyses of KNG1 and KLKB1 were performed by Sanger sequencing. The frequency of HK deficiency was estimated considering truncating KNG1 variants from GnomAD.
RESULTS
We identified 48 cases of severe HK deficiency (41 families), of these 47 have been previously published (n = 19 from gray literature). We genotyped 3 cases and critically appraised 10 studies with genetic data. Ten HK deficiency-causing variants (one new) were identified. All of them were truncating mutations, whereas the only known HK amino acid substitution with a relevant phenotype instead causes hereditary angioedema. Conservative estimates suggest an overall prevalence of severe HK deficiency of approximately one case per 8 million population, slightly higher in Africans. Individuals with HK deficiency appeared asymptomatic and had decreased levels of prekallikrein and factor XI, which could lead to misdiagnosis.
CONCLUSION
HK deficiency is a rare condition with only few known pathogenic variants. It has an apparently good prognosis but is prone to misdiagnosis. Our understanding of its clinical implications is still limited, and an international prekallikrein and HK deficiency registry is being established to fill this knowledge gap.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory |
UniBE Contributor: |
Lämmle, Bernhard |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1538-7836 |
Publisher: |
Wiley-Blackwell |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
27 Jan 2023 12:54 |
Last Modified: |
14 Feb 2023 00:16 |
Publisher DOI: |
10.1016/j.jtha.2022.11.011 |
PubMed ID: |
36700498 |
Uncontrolled Keywords: |
blood coagulation disorders diagnosis epidemiology high-molecular-weight kallikrein-kinin system kininogen partial thromboplastin time |
BORIS DOI: |
10.48350/177969 |
URI: |
https://boris.unibe.ch/id/eprint/177969 |
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