Chilblain Lupus 1

A number sign (#) is used with this entry because of evidence that chilblain lupus-1 (CHBL1) is caused by heterozygous mutation in the TREX1 gene (606609) on chromosome 3p21.

Description

Chilblain lupus is a cutaneous form of systemic lupus erythematosus (SLE; 152700) characterized by the appearance of painful bluish-red papular or nodular lesions of the skin in acral locations (including the dorsal aspects of fingers and toes, heels, nose, cheeks, ears, and, in some cases, knees) precipitated by cold and wet exposure (summary by Lee-Kirsch et al., 2006).

Genetic Heterogeneity of Chilblain Lupus

See also CHBL2 (614415), caused by mutation in the SAMHD1 gene (606754) on chromosome 20q11.

Mutations in the TREX1 and SAMHD1 genes also cause Aicardi-Goutieres syndrome (AGS1, 225750 and AGS5, 612952, respectively).

Clinical Features

Chilblain lupus, a rare cutaneous form of systemic lupus erythematosus (152700), was first described by Jonathan Hutchinson (1888). Lee-Kirsch et al. (2006) described a large nonconsanguineous German family with 18 members over 5 generations affected with chilblain lupus. Affected individuals presented with painful bluish-red papular or nodular lesions of the skin in acral locations (including the dorsal aspects of fingers and toes, heels, nose, cheeks, ears, and, in some cases, knees) precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade. Sometimes a plaque-like appearance was noted, and ulceration was commonly seen. Although deep ulceration led to necrotic destruction of the distal interphalangeal joint of the left fifth finger in the index patient at age 15 years, the lesions usually healed without scars, occasionally leaving atrophic skin and pigmentary changes. The onset of the skin lesions was in early childhood, and, in most patients, the lesions tended to improve during summer. Mucous membranes and nails were not affected, although subungual lesions were sometimes seen. There was no associated Raynaud phenomenon (see 179600) or photosensitivity. There was no evidence of associated disease of any internal organ (including the CNS), immune deficiency, or malignancy. Arthralgias affected mainly large joints, such as knees and shoulders. There was no increased susceptibility to infection. Histologic findings included a deep inflammatory infiltrate with perivascular distribution and granular deposits of immunoglobulins and complement along the basement membrane. Some affected individuals showed antinuclear antibodies or immune complex formation, whereas cryoglobulins or cold agglutinins were absent. The family study suggested a highly penetrant trait with autosomal dominant inheritance. Chilblain lupus occurs predominantly in adult women and has only rarely been described in children. Before the report of Lee-Kirsch et al. (2006) there had been only one report of familial chilblain lupus, in 2 brothers (Weston and Morelli, 2000).

Rice et al. (2007) reported a nonconsanguineous Bangladeshi family in which 2 brothers and a sister were affected; the father had been similarly affected throughout his life but was unavailable for study. The onset of the disorder in this family was in early childhood. The patients presented with painful bluish-red swelling of the skin affecting mainly the fingers, toes, ears, helices, and, occasionally, the nose. The lesions were induced by cold temperatures and were significantly worse in the winter months. The lesions could ulcerate; the father and 2 sons were affected. In the affected males, the ulcerations led to a loss of ear cartilage and destruction of the proximal interphalangeal joints and distal toes. Ulcerative lesions healed but left areas of atrophic and hypopigmented skin. Antinuclear antibodies were intermittently raised, and 1 patient exhibited persistently elevated erythrocyte-sedimentation rate.

Mapping

By single-nucleotide polymorphism (SNP)-based genomewide linkage analysis in the family described by them, Lee-Kirsch et al. (2006) mapped a locus for chilblain lupus to 3p. Haplotype analysis refined the locus to a 13.8-cM interval on chromosome 3p21-p14, flanked by markers rs704920 and D3S1300, with a lod score of 5.04.

Other Features

The locus to which Lee-Kirsch et al. (2006) established linkage of the isolated CHBL phenotype partially overlaps that for type 1 Aicardi-Goutieres syndrome (225750). Children affected with Aicardi-Goutieres syndrome suffer from progressive microcephaly and severe cerebral dysfunction associated with calcification of basal ganglia, chronic lymphocytosis, and elevated interferon-alpha (see 147660) in the spinal fluid. Some patients have chilblain-like lesions that resemble those found in the family reported by Lee-Kirsch et al. (2006), although unaffected parents of children with this autosomal recessive disorder do not show any cutaneous findings. Aicardi-Goutieres syndrome has been suggested to be a form of systemic lupus erythematosus because of the findings of hypocomplementemia and antinuclear autoantibodies in addition to lupus-like skin lesions in some patients. Therefore, Lee-Kirsch et al. (2006) suggested that chilblain lupus and Aicardi-Goutieres syndrome may be allelic phenotypes representing different spectrums of the same disease.

In a large study of the clinical and molecular phenotype of Aicardi-Goutieres syndrome, Rice et al. (2007) discussed and illustrated chilblain lesions in patients with that disorder in patients from 127 pedigrees. Chilblain lesions were reported in 43% of patients and were associated with mutations in all 4 Aicardi-Goutieres syndrome causative genes: TREX1 (606609), RNASEH2A (606034), RNASEH2B (610326), and RNASEH2C (610330). The lesions were usually situated on the feet but sometimes also affected the hands and outer rim of the ears. Many parents reported a direct relationship with cold temperatures, with considerable worsening of the lesions during winter months.

Molecular Genetics

Rice et al. (2007) described a heterozygous mutation in the TREX1 gene (606609.0005) in affected members of a family with chilblain lupus.

In affected members of the large 5-generation German family with chilblain lupus previously described by Lee-Kirsch et al. (2006), Lee-Kirsch et al. (2007) identified heterozygosity for a missense mutation in the TREX1 gene (D18N; 606609.0007).

In a 16-year-old girl with relatively mild Aicardi-Goutieres syndrome (225750), who was negative for mutation in other known AGS genes, Haaxma et al. (2010) identified heterozygosity for the same D18N mutation in the TREX1 gene that had previously been found in the German family with chilblain lupus by Lee Kirsch et al. (2007). Haaxma et al. (2010) had no explanation for how the same mutation might cause such distinct phenotypes.

History

For a review of the career and clinical observations of Hutchinson, who first described chilblain lupus, see McKusick (1952, 2005).