TREX-1-Related Disease Associated with the Presence of Cryofibrinogenemia
Cryofibrinogenemia is a rare cryopathy presenting as acrocyanosis following exposure to cold. Familial presentation has been described but the underlying molecular cause remained undetermined.
Forty (40) members from a large family with an initial diagnosis of familial cryofibrinogenemia were interviewed and examined to determine affected status and collect DNA. Exome sequencing was performed on three affected individuals from distinct branches of the pedigree.
Seventeen (17) family members reported a history of acrocyanosis with cold exposure. None reported symptoms were suggestive of lupus. Exome sequencing of three subjects identified the heterozygous mutation D18N in the TREX1 gene which was then confirmed by Sanger sequencing in all affected as well as 2 unaffected family members. The mutation is already being associated with familial chilblain lupus erythematosus (CHLE), and a systematic review of literature was undertaken to compare reports of familial CHLE and cryofibrinogenemia. Both entities were found to share highly similar clinical presentations suggesting they are part of a same syndrome in which cryofibrinogenemia and lupus manifestations have variable penetrance.
Familial cryofibrinogenemia without lupus should be added to the spectrum of TREX1-related disease.
KeywordsCryofibrinogenemia Cryofibrinogen TREX1 Chilblain Lupus Genetics Familial Acrocyanosis Auto-inflammatory Auto-inflammation
Chilblain lupus erythematosus
Collagen 7 alpha
Interferon regulatory factor 3
STING-associated vasculopathy with onset in infancy
Three-prime repair exonuclease 1
Ubiquitin-specific peptidase 19
The authors wish to thank the families for their participation in this study.
Dr. Bégin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Cossette, Bégin.
Acquisition of data: Paradis, Des Roches, Leclerc, Meloche, Gravel, Cadieux-Dion, Cossette, Bégin.
Analysis and interpretation of data: Cadieux-Dion, Paradis, Bégin.
Drafting of the manuscript: Cadieux-Dion, Paradis, Bégin.
Critical revision of the manuscript for important intellectual content: All.
Administrative, technical, or material support: Meloche, Gravel.
Study supervision: Cossette, Bégin.
Compliance with Ethical Standards
This project was approved by the research ethics committee of the Centre Hospitalier de l’Université de Montreal. The participants received no financial compensation.
Conflict of Interest
The authors declare that they have no conflict of interest.
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