Journal of Clinical Immunology

, Volume 39, Issue 1, pp 118–125 | Cite as

TREX-1-Related Disease Associated with the Presence of Cryofibrinogenemia

  • C. Paradis
  • M. Cadieux-Dion
  • C. Meloche
  • M. Gravel
  • J. Paradis
  • A. Des Roches
  • G. Leclerc
  • P. Cossette
  • P. BeginEmail author
Original Article



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.


Cryofibrinogenemia Cryofibrinogen TREX1 Chilblain Lupus Genetics Familial Acrocyanosis Auto-inflammatory Auto-inflammation 



Aicardi-Goutières syndrome




Chilblain lupus erythematosus


Collagen 7 alpha


Interferon regulatory factor 3


Lupus erythematosus


Mucin 6


STING-associated vasculopathy with onset in infancy


Single-stranded DNA


Three-prime repair exonuclease 1


Ubiquitin-specific peptidase 19



The authors wish to thank the families for their participation in this study.

Authors’ Contributions

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.


  1. 1.
    Moiseev S, Luqmani R, Novikov P, Shevtsova T. Cryofibrinogenaemia-a neglected disease. Rheumatology (Oxford). 2017;56(9):1445–51.Google Scholar
  2. 2.
    Saadoun D, Elalamy I, Ghillani-Dalbin P, Sene D, Delluc A, Cacoub P. Cryofibrinogenemia: new insights into clinical and pathogenic features. Am J Med. 2009;122(12):1128–35.CrossRefGoogle Scholar
  3. 3.
    McKee PA, Kalbfleisch JM, Bird RM. Incidence and significance of cryofibrinogenemia. J Lab Clin Med J Lab Clin Med. 1963;61:203–10.Google Scholar
  4. 4.
    Blain H, Cacoub P, Musset L, Costedoat-Chalumeau N, Silberstein C, Chosidow O, et al. Cryofibrinogenaemia: a study of 49 patients. Clin Exp Immunol. 2000;120(2):253–60.CrossRefGoogle Scholar
  5. 5.
    Belizna CC, Tron F, Joly P, Godin M, Hamidou M, Lévesque H. Outcome of essential cryofibrinogenaemia in a series of 61 patients. Rheumatology (Oxford). 2008;47(2):205–7.CrossRefGoogle Scholar
  6. 6.
    van Geest AJ, et al. Familial primary cryofibrinogenemia. J Eur Acad Dermatol Venereol. 1999;12(1):47–50.CrossRefGoogle Scholar
  7. 7.
    Wulffraat N, et al. Familial presence of primary cryofibrinogenaemia, a report of three cases. Br J Rheumatol. 1996;35(1):102–4.CrossRefGoogle Scholar
  8. 8.
    Lee-Kirsch MA, Chowdhury D, Harvey S, Gong M, Senenko L, Engel K, et al. A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med (Berl). 2007;85(5):531–7.CrossRefGoogle Scholar
  9. 9.
    Rice GI, Rodero MP, Crow YJ. Human disease phenotypes associated with mutations in TREX1. J Clin Immunol. 2015;35(3):235–43.CrossRefGoogle Scholar
  10. 10.
    Sugiura K, Takeichi T, Kono M, Ito Y, Ogawa Y, Muro Y, et al. Severe chilblain lupus is associated with heterozygous missense mutations of catalytic amino acids or their adjacent mutations in the exonuclease domains of 3′-repair exonuclease 1. J Invest Dermatol. 2012;132(12):2855–7.CrossRefGoogle Scholar
  11. 11.
    Tungler V, et al. Inherited or de novo mutation affecting aspartate 18 of TREX1 results in either familial chilblain lupus or Aicardi-Goutieres syndrome. Br J Dermatol. 2012;167(1):212–4.CrossRefGoogle Scholar
  12. 12.
    Abe J, Izawa K, Nishikomori R, Awaya T, Kawai T, Yasumi T, et al. Heterozygous TREX1 p.Asp18Asn mutation can cause variable neurological symptoms in a family with Aicardi-Goutieres syndrome/familial chilblain lupus. Rheumatology (Oxford). 2013;52(2):406–8.CrossRefGoogle Scholar
  13. 13.
    Gunther C, et al. Systemic involvement in TREX1-associated familial chilblain lupus. J Am Acad Dermatol. 2013;69(4):e179–81.CrossRefGoogle Scholar
  14. 14.
    Yamashiro K, Tanaka R, Li Y, Mikasa M, Hattori N. A TREX1 mutation causing cerebral vasculopathy in a patient with familial chilblain lupus. J Neurol. 2013;260(10):2653–5.CrossRefGoogle Scholar
  15. 15.
    Gunther C, et al. Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3′ repair exonuclease 1 (TREX1). JAMA Dermatol. 2015;151(4):426–31.CrossRefGoogle Scholar
  16. 16.
    Kisla Ekinci RM, Balci S, Bisgin A, Altintas DU, Yilmaz M. A homozygote TREX1 mutation in two siblings with different phenotypes: chilblains and cerebral vasculitis. Eur J Med Genet. 2017;60(12):690–4.CrossRefGoogle Scholar
  17. 17.
    Lolin Y, Razis PA, O’Gorman P, Hjelm M, Wierzbicki AS. Transient nephrotic syndrome after anaesthesia resulting from a familial cryofibrinogen precipitating at 35 degrees C. J Med Genet. 1989;26(10):631–6.CrossRefGoogle Scholar
  18. 18.
    Grieves JL, Fye JM, Harvey S, Grayson JM, Hollis T, Perrino FW. Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease. Proc Natl Acad Sci U S A. 2015;112(16):5117–22.CrossRefGoogle Scholar
  19. 19.
    Volkman HE, Stetson DB. The enemy within: endogenous retroelements and autoimmune disease. Nat Immunol. 2014;15(5):415–22.CrossRefGoogle Scholar
  20. 20.
    de Silva U, Choudhury S, Bailey SL, Harvey S, Perrino FW, Hollis T. The crystal structure of TREX1 explains the 3′ nucleotide specificity and reveals a polyproline II helix for protein partnering. J Biol Chem. 2007;282(14):10537–43.CrossRefGoogle Scholar
  21. 21.
    Fye JM, Orebaugh CD, Coffin SR, Hollis T, Perrino FW. Dominant mutation of the TREX1 exonuclease gene in lupus and Aicardi-Goutieres syndrome. J Biol Chem. 2011;286(37):32373–82.CrossRefGoogle Scholar
  22. 22.
    Aicardi J, Goutieres F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 1984;15(1):49–54.CrossRefGoogle Scholar
  23. 23.
    Haaxma CA, Crow YJ, van Steensel MAM, Lammens MMY, Rice GI, Verbeek MM, et al. A de novo p.Asp18Asn mutation in TREX1 in a patient with Aicardi-Goutieres syndrome. Am J Med Genet A. 2010;152A(10):2612–7.CrossRefGoogle Scholar
  24. 24.
    Hedrich CM, Fiebig B, Hauck FH, Sallmann S, Hahn G, Pfeiffer C, et al. Chilblain lupus erythematosus-a review of literature. Clin Rheumatol. 2008;27(10):1341.CrossRefGoogle Scholar
  25. 25.
    Toribara NW, Roberton AM, Ho SB, Kuo WL, Gum E, Hicks JW, et al. Human gastric mucin. Identification of a unique species by expression cloning. J Biol Chem. 1993;268(8):5879–85.Google Scholar
  26. 26.
    Kara Eroglu F, et al. STING-associated vasculopathy with onset in infancy: new clinical findings and mutation in three Turkish children. Pediatr Rheumatol Online J. 2015;13(supp 1):O85.CrossRefGoogle Scholar
  27. 27.
    Michaud M, Pourrat J. Cryofibrinogenemia. J Clin Rheumatol. 2013;19(3):142–8.CrossRefGoogle Scholar
  28. 28.
    de Vries PS, Chasman DI, Sabater-Lleal M, Chen MH, Huffman JE, Steri M, et al. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. Hum Mol Genet. 2016;25(2):358–70.CrossRefGoogle Scholar
  29. 29.
    Dang N, Murrell DF. Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa. Exp Dermatol. 2008;17(7):553–68.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.CHUM Research CenterUniversité de MontréalMontrealCanada
  2. 2.Center for Pediatric Genomic MedicineChildren’s Mercy HospitalKansas CityUSA
  3. 3.Department of MedicineCentre Hospitalier de l’Université de MontréalMontrealCanada
  4. 4.Department of PediatricsCentre Hospitalier Universitaire Ste-JustineMontréalCanada
  5. 5.Department of MedicineChicoutimi HospitalSaguenayCanada

Personalised recommendations