Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p

Abstract

Systemic lupus erythematosus is a prototypic autoimmune disease. Apart from rare monogenic deficiencies of complement factors, where lupuslike disease may occur in association with other autoimmune diseases or high susceptibility to bacterial infections, its etiology is multifactorial in nature. Cutaneous findings are a hallmark of the disease and manifest either alone or in association with internal-organ disease. We describe a novel genodermatosis characterized by painful bluish-red inflammatory papular or nodular lesions in acral locations such as fingers, toes, nose, cheeks, and ears. The lesions sometimes appear plaquelike and tend to ulcerate. Manifestation usually begins in early childhood and is precipitated by cold and wet exposure. Apart from arthralgias, there is no evidence for internal-organ disease or an increased susceptibility to infection. Histological findings include a deep inflammatory infiltrate with perivascular distribution and granular deposits of immunoglobulins and complement along the basement membrane. Some affected individuals show antinuclear antibodies or immune complex formation, whereas cryoglobulins or cold agglutinins are absent. Thus, the findings are consistent with chilblain lupus, a rare form of cutaneous lupus erythematosus. Investigation of a large German kindred with 18 affected members suggests a highly penetrant trait with autosomal dominant inheritance. By single-nucleotide-polymorphism-based genomewide linkage analysis, the locus was mapped to chromosome 3p. Haplotype analysis defined the locus to a 13.8-cM interval with a LOD score of 5.04. This is the first description of a monogenic form of cutaneous lupus erythematosus. Identification of the gene responsible for familial chilblain lupus may shed light on the pathogenesis of common forms of connective-tissue disease such as systemic lupus erythematosus.

Figure  1.

Pedigree of the family with chilblain lupus. The arrow indicates the index patient. The asterisks (*) indicate family members included in the genomewide linkage analysis.

Figure  2.

Cutaneous findings. A, Hands of proband (V1) at 6 years of age and his mother (IV2) at 30 years of age, showing multiple ulcerating nodular lesions over dorsal aspects of fingers and knuckles. B, Dorsal feet and left heel with purpuric appearance of individual IV2. C, Left ear of individual V11 at 3 years of age, with ulcerating lesion. D, Face and hands of individual V1 at 8 years of age. The erythematous plaquelike lesions over cheeks, nose, and chin resemble butterfly rash. E, Fingers showing fresh lesions, which appear as bluish-red, indurated, and tender papules.

Figure  3.

Histology of lesional skin biopsy from proband V1. A, Hematoxylin-eosin staining (magnification 1:100) showing lamellar orthohyperkeratosis and regions of hydropic degeneration of the stratum basale as well as single-cell necrosis. Inflammatory infiltrates with perivascular and periadnexial distribution and interface dermatitis can be seen. B, Alcian blue staining (magnification 1:40) showing increased deposits of mucin throughout entire stratum reticulare. C, Direct immune fluorescence (magnification 1:100) showing broad granular deposits of C3 along basement membrane zone. A similar pattern was also seen with staining for IgM or IgA.

Figure  4.

Graphic summary of linkage analysis. A, Parametric linkage results identifying a single locus on chromosome 3p. B, Relative position of markers and refined physical interval for chilblain lupus, on the basis of haplotype analysis and genotyping of additional microsatellite markers. Key recombinant markers are marked in bold. AGS1 = Aicardi-Goutières syndrome, type 1.