Familial Chilblain Lupus Due to a Novel Mutation in the Exonuclease III Domain of 3′ Repair Exonuclease 1 (TREX1)

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.

Familial chilblain lupus is a rare, autosomal dominant form of lupus erythematosus that typically presents in early childhood.¹ The clinical findings include cold-induced, bluish-red infiltrates on acral surfaces, which are painful and tend to ulcerate. The disease is caused by heterozygous mutations in TREX1 (3′ repair exonuclease 1) (OMIM *606609); to date, 7 familial cases have been reported (Table).^1-9 In addition, a mutation in SAMHD1 (SAM domain and HD domain–containing protein 1), a deoxynucleotide-degrading phosphohydrolase, has been described¹⁰ in a single family. The major intracellular 3′-5′ DNA exonuclease (Exo), TREX1 cleaves single-stranded DNA.¹¹ Biallelic mutations in both genes cause the inflammatory encephalopathy Aicardi-Goutières syndrome, which is characterized by increased levels of interferon (IFN) alfa in cerebrospinal fluid and signs of systemic autoimmunity including chilblain lesions, antinuclear antibodies, and arthritis.¹² Activation of type I IFN initiated in nonhematopoietic cells was shown¹³ to be essential in the pathogenesis of the autoimmune phenotype in TREX1-deficient mice. Indeed, upregulation of IFN-stimulated genes (ISGs) was also demonstrated in patients with Aicardi-Goutières syndrome and familial chilblain lupus.^14,15 The induction of type I IFN has been attributed to innate immune recognition of cytosolic DNA accumulating in TREX1-deficient cells. This unmetabolized intracellular DNA activates innate DNA sensors, leading to type I IFN induction that fosters the development of autoimmunity.^13,16

We report on a family with dominant chilblain lupus in 3 generations segregating a novel mutation in the Exo III domain of TREX1 (Figure 1). The index patient (I-1), who was in his 70s, had experienced cold-induced livoid infiltrates, blister formation, and painful ulcerations on his fingers, toes, ears, and nose since early childhood. He presented with destructive scars on his ears and fingers along with onychodystrophia and reduction deformities of both fifth fingers and nail loss on the left side (Figure 2A and B). He also reported recurrent arthritis of the knees, elbows, shoulders, and ankle joints that started in early adulthood. A radiograph of the patient’s hands revealed reduced bone calcification without osteolysis or erosion as well as anomalies of the fifth fingers with loss of the end phalanx on the left side. Histologic examination of lesional skin from the finger showed a lymphohistiocytic perivascular dermal inflammatory infiltrate. On direct immunofluorescence, broad granular depositions of C3 and IgM at the basement membrane zone were noted (Figure 2C). Similar, albeit less prominent, changes were detectable in nonlesional, sun-protected skin from the abdomen consistent with lupus erythematosus. His laboratory test findings were remarkable for mild thrombocytopenia (platelets, 136 × 10³/µL [reference range, 150-400 × 10³/µL]; conversion to ×10⁹/L is 1:1), lymphocytopenia (lymphocytes, 1230/µL [reference range, 1500-4000/µL]; to convert to ×10⁹/L, multiply by 0.001), and antinuclear antibodies at a low titer (1:160) in a few nuclear and cytoplasmic dot patterns. Other laboratory test findings, including erythrocyte sedimentation rate, complement levels, rheumatic factor, and liver and kidney function tests, as well as antibodies to extractable nuclear antigens, double-stranded DNA, and cyclic citrullinated peptide, were unremarkable. In addition, he had arterial hypertension and coronary artery disease. For those diagnoses he received aspirin, 100 mg/d. The cutaneous manifestations were not influenced by this treatment. He received antibiotics during severe inflammation and local wound care, but he was never given specific treatment for the disease manifestations.

The son (II-2) of the index patient reported cold-induced erythematous lesions at acral locations as well as arthralgia of the large joints and finger joints since childhood. Except for mild lymphopenia (lymphocytes, 1330/µL), his laboratory findings, including autoantibody screening, were within the reference ranges. He benefited from hydroxychloroquine treatment and protection of his hands and feet by heated gloves and insoles during the winter. Arthralgia and cutaneous lesions improved remarkably, reaching nearly complete remission for years.

The above man’s (II-2) daughter (III-2), who was younger than 10 years, was also affected and presented with cold-induced painful erythematous swellings of her fingers and toes (Figure 2H). She had not yet developed ulcerations.

The daughter (II-3) of the index patient, who was in her 40s, reported sensitivity to cold on her fingers and toes and arthralgia of the knees since early childhood. She experienced recurrent bursitis of the knee and arthritis of her large joints and finger joints during adolescence. At that time she developed infiltrates and ulcerations of her fingers (Figure 2D), nose, and ears during the winter season. The results of histologic evaluation of the lesions was consistent with lupus erythematosus and showed a perivascular lymphohistiocytic infiltrate with few neutrophils (Figure 2F), discrete hydropic changes of the basement membrane zone, and scarce mucin deposition in the dermis. The expression of the IFN-induced myxovirus resistance protein A was strongly increased (Figure 2G). The patient also reported recurrent erythematous erosions of the hard palate (Figure 2E). Her laboratory findings were remarkable for thrombocytopenia (platelets, 108 × 10³/µL), lymphopenia (lymphocytes, 800/µL), antinuclear antibodies (1:160, with a fine granular pattern) and anti-RA-33 antibodies consistent with arthritis. The results of other laboratory tests, including antibodies to extractable nuclear antigens, double-stranded DNA, and cyclic citrullinated peptide, as well as rheumatic factor, were unremarkable. For treatment of arthritis, the patient required systemic administration of leflunomide, prednisone, and celecoxib. Her arthritis and fatigue improved. There was also improvement of cutaneous infiltrates during prednisone treatment. However, during low-dose prednisone therapy (5 mg/d) the cold-induced chilblain lupus lesions still occurred.

In line with the observed systemic involvement of chilblain lupus, we detected an enhanced expression of ISGs in peripheral blood cells from patients I-1 and II-3 in comparison with healthy individuals serving as controls indicating type I IFN activation (Figure 3A) (eAppendix and eTable in the Supplement). Sequencing of the TREX1 gene revealed a heterozygous missense mutation (c.585C>G; H195Q) in all affected family members that was absent in nonaffected family members (Figure 3B-D). This sequence change was not listed in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP/) and was not detected in more than 1000 control individuals.¹⁷ The mutation affects a highly conserved histidine residue within the Exo III domain of the TREX1 enzyme (Figure 3C and D).

We report on a family with autosomal dominant familial chilblain lupus caused by a novel mutation in the Exo III domain of the DNase TREX1. To our knowledge, only 7 other families with TREX1-associated familial chilblain lupus have been reported (Table).^1-9 Five of those 7 families carry a missense mutation (D18N) in the first Exo domain (Table). In a Bangladeshi family a frameshift mutation in the second Exo domain (c.375dupT; G126fs) was identified,⁴ and a Japanese family also carried a missense mutation (P132A) within Exo II⁶ (Figure 3D). These findings suggest a particular role of mutations affecting the catalytic Exo domains of TREX1 in the pathogenesis of familial chilblain lupus.

Biallelic mutations in TREX1 cause Aicardi-Goutières syndrome, an inflammatory leukoencephalopathy that features signs of systemic autoimmunity.¹³ Heterozygous de novo mutations affecting Exo I of TREX1 have been described in 2 patients with Aicardi-Goutières syndrome^5,18 as well as in 1 member of a large family with familial chilblain lupus,⁷ suggesting a dominant negative effect under certain as-yet unknown circumstances.

Overall, the clinical presentation of the patients in different affected families is similar. In all families the first symptoms occurred in early childhood and were characterized by cold-induced chilblain lesions on acral locations that tend to ulcerate, leading to scar formation or mutilation (Table). These symptoms are in contrast to most cases of sporadic chilblain lupus, which mainly affect young adolescent women. The partial amputation of the fifth finger that occurred most likely owing to severe inflammation was not only seen in our patient, it was reported in other patients with familial chilblain lupus.^1,2,4,5,9

However, the expression of the phenotype may vary among the members of an individual family.^4,7 In the family described in the present report, the index patient experienced recurrent chilblain lesions and extensive scarring persisting during adulthood, whereas his son reported cold-induced infiltrates and ulcerations in childhood that declined in severity as he aged. This difference might be explained partially by the systemic anti-inflammatory treatment along with cold protection applied only for the son. The daughter of the index patient experienced severe arthritis requiring continuous anti-inflammatory medication. This joint involvement was accompanied by thrombocytopenia or lymphopenia and antinuclear antibodies. Signs of systemic disease involving the joints and hematologic system have been observed^8,15 in other families with familial chilblain lupus (Table). Cerebral vasculopathy leading to hemiparesis was reported in one case.⁹ To our knowledge, none of the patients with familial chilblain lupus has developed kidney or other severe internal organ involvement. The systemic symptoms were restricted to joint and hematologic involvement (Table). This is in contrast to patients with heterozygous mutations in TREX1 and systemic lupus erythematosus who have developed nephritis.¹⁷ Understanding these phenotypic differences requires further studies in a larger number of patients. Mutations in patients with familial chilblain lupus affect the catalytic center of TREX1, whereas those with systemic lupus erythematosus can harbor mutations that disturb the localization of the enzyme,¹⁷ suggesting a role of the type of mutation on phenotypic outcome.

Patients with systemic lupus erythematosus exhibit increased expression of ISGs in their blood. In line with previous observations¹⁵ we detected an upregulation of ISGs in the blood of 2 affected members of the family in the present report, supporting a pathogenic role of type I IFN in familial chilblain lupus. Furthermore, the high prevalence of systemic clinical manifestations in this family suggests that TREX1-associated familial chilblain lupus is a systemic disease with prominent cutaneous involvement.

Our findings identify a novel missense mutation in the Exo III domain of TREX1 causing autosomal dominant familial chilblain lupus. In addition to cold-induced chilblain lupus lesions, which can lead to scarring and mutilation, patients frequently display signs of systemic involvement and type I IFN upregulation, demonstrating a systemic effect of the TREX1 mutation in familial chilblain lupus.

Accepted for Publication: August 26, 2014.

Corresponding Author: Claudia Günther, MD, Department of Dermatology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany (claudia.guenther@uniklinikum-dresden.de).

Published Online: December 17, 2014. doi:10.1001/jamadermatol.2014.3438.

Author Contributions: Drs Günther and Lee-Kirsch had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Günther.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Günther, Berndt, Wolf.

Critical revision of the manuscript for important intellectual content: Günther, Lee-Kirsch.

Statistical analysis: Günther, Berndt, Wolf.

Obtained funding: Günther, Lee-Kirsch.

Administrative, technical, or material support: Günther.

Study supervision: Günther.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by grants from the Deutsche Forschungsgemeinschaft (LE 1074/3-1 and LE 1074/4-1 [Dr Lee-Kirsch] and GU 1212/1-1 and GU 1212/1-2 [Dr Günther]) and the Friede Springer Stiftung (Dr Lee-Kirsch).

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We are indebted to the patients for their participation in the study. Nick Zimmermann and Peggy Binkenstein (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden) provided excellent technical assistance. They received no financial compensation for their services.