Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3' repair exonuclease 1 (TREX1)

JAMA Dermatol. 2015 Apr;151(4):426-31. doi: 10.1001/jamadermatol.2014.3438.


Importance: Familial chilblain lupus is a rare, autosomal dominant form of lupus erythematosus characterized by cold-induced inflammatory lesions at acral locations presenting in early childhood. Familial chilblain lupus is usually caused by a mutation in TREX1 (3' repair exonuclease 1).

Observations: We report on a family with dominant chilblain lupus segregating a novel TREX1 mutation (c.585C>G; H195Q) within the highly conserved exonuclease (Exo) III domain. Affected family members experienced cold-induced chilblain lesions of varying degrees, ranging from bluish-red infiltrations to mutilating necrotic ulcerations. In addition, all patients showed signs of systemic disease, such as arthritis, lymphopenia, or antinuclear antibodies. An increased expression of myxovirus resistance protein A in the skin and induction of interferon-stimulated genes in peripheral blood cells demonstrated activation of type I interferon.

Conclusions and relevance: This case further implicates type I interferon-dependent innate immune activation in the pathogenesis of TREX1-associated familial chilblain lupus. Unlike previously reported TREX1 mutations, which affect the Exo I or Exo II domains, the mutation presented here alters the Exo III domain, suggesting a particular role of mutations within the catalytic Exo domains in the pathogenesis of familial chilblain lupus. The high prevalence of extracutaneous manifestations, along with activation of type I interferon, underlines the systemic nature of familial chilblain lupus.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Chilblains / genetics*
  • Chilblains / physiopathology
  • Child
  • Exodeoxyribonucleases / genetics*
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Lupus Erythematosus, Cutaneous / genetics*
  • Lupus Erythematosus, Cutaneous / physiopathology
  • Male
  • Mutation
  • Phosphoproteins / genetics*


  • Phosphoproteins
  • Exodeoxyribonucleases
  • exodeoxyribonuclease II
  • three prime repair exonuclease 1

Supplementary concepts

  • Chilblain lupus 1