Scleroderma, Familial Progressive
Description
Systemic sclerosis is a clinically heterogeneous connective tissue disorder characterized by immune activation, vascular damage, and fibrosis of the skin and major internal organs. Clinical and experimental data suggest that the disorder is multifactorial, involving both genetic and environmental factors (Fonseca et al., 2007).
Gabrielli et al. (2009) provided a detailed review of scleroderma, including clinical manifestations and pathophysiology.
See also Reynolds syndrome (613471), which shares some clinical features with scleroderma and CREST syndrome.
Clinical FeaturesGreger (1975) described 3 males, including father and son, with progressive systemic scleroderma (systemic sclerosis) in an inbred triracial isolate of southern Maryland, known as the Brandywine group. A sister of the aforementioned son had rheumatoid arthritis. The father and son had similar skin changes, sclerodactyly, Raynaud phenomenon, gastrointestinal involvement, and pulmonary symptoms.
Sheldon et al. (1981) described a kindred in which 3 sibs had scleroderma and 2 others had Raynaud phenomenon. The father died at age 43, having had, over the previous 20 years, 'flexion deformity of the fingers, cold intolerance, cyanosis, and pallor of the fingers with sores described as bone felons requiring lancing several times.' Sheldon et al. (1981) found reports of 19 instances of familial occurrence of scleroderma.
Black et al. (1983) found in scleroderma due to vinyl chloride the same relationship to HLA types B8 and DR3 and the same anticentromere and other antibodies as in idiopathic scleroderma.
CREST Syndrome
Winterbauer (1964) defined and named the CRST syndrome (calcinosis, Raynaud syndrome, sclerodactyly, telangiectasia), a variant of scleroderma, when he was a Johns Hopkins medical student. (The CRST syndrome simulates hereditary telangiectasia; see 187300.) The initialism CRST was expanded to the acronym CREST by Shulman's group (Frayha et al., 1973; Velayos et al., 1979), also at Johns Hopkins, who added esophageal involvement to the cardinal manifestations. (The same group (Stevens et al., 1964) had pointed out a correlation between Raynaud phenomenon and aperistalsis of the esophagus in connective tissue disorders. They proposed that the connection may indicate that the esophageal abnormality is due to autonomic dysfunction rather than sclerosis. Stevens (1984) suggested that if this is the case, E of CREST may stand for 'epiphenomenon.') The disorder had been called Thibierge-Weissenbach syndrome. Thibierge and Weissenbach (1911) described 'subcutaneous calcareous concretions and scleroderma' in a single patient and found 8 other similar cases in the literature. Although telangiectases were not noted in the summaries of the earlier reported cases or in their discussion and certainly were not conceived by them as an integral part of the syndrome, the authors commented that 'there exists also in our patient a third type of skin lesion, namely telangiectases, remarkably prominent on the face, neck and thorax.' Frayha et al. (1977) described the CRST syndrome in mother and daughter. McColl and Buchanan (1994) described the CREST syndrome in 2 sisters of 1 family and a grandmother and grandson in a second family.
Biochemical FeaturesIn a study of chemokine expression in fibroblasts from patients with systemic sclerosis and controls, Galindo et al. (2001) found that systemic sclerosis fibroblasts displayed increased constitutive expression of monocyte chemotactic protein-1 (MCP1; 158105) mRNA and protein and showed a blunted response to oxidative stress. In systemic sclerosis skin sections, expression of MCP1 was detected in fibroblasts, keratinocytes, and mononuclear cells, whereas it was undetectable in normal skin.
Using in situ hybridization and immunohistochemistry studies for MCP1 on skin biopsy specimens, Distler et al. (2001) found that MCP1 was expressed by fibroblasts, keratinocytes, and perivascular infiltrates throughout the skin, in involved as well as uninvolved areas, from 10 of 11 systemic sclerosis patients, whereas no expression of MCP1 was found in healthy controls. Stimulation with platelet-derived growth factor (PDGF; see 173430) resulted in a significant increase in MCP1 mRNA and protein. The chemotactic activity of peripheral blood mononuclear cells in systemic sclerosis fibroblast supernatants decreased when MCP1-blocking antibodies were added. No effect of recombinant MCP1 on the synthesis of type I collagen (see 120150) was observed. Distler et al. (2001) suggested that MCP1 may contribute to the initiation of inflammatory infiltrates in systemic sclerosis, possibly in response to stimulation by PDGF.
Using dermal fibroblasts from patients with systemic sclerosis and controls and from type 1 tight-skin (Tsk1) mice, Ong et al. (2003) demonstrated overexpression of the chemokine CCL7 (158106) in early-stage systemic sclerosis and neonatal Tsk1 skin. Pro-alpha-2(I) collagen (120160) promoter-reporter gene constructs were activated by CCL7 in transgenic mice and in transient transfection assays. The authors concluded that CCL7 may operate as a profibrotic mediator in addition to promoting an inflammatory cellular response, and may be an important early member of the cytokine cascade driving the pathogenesis of systemic sclerosis.
Svegliati Baroni et al. (2006) presented evidence showing that stimulatory autoantibodies to PDGFR (173410) are a specific hallmark of scleroderma. These antibodies appeared to trigger an intracellular loop that involves Ras (190020), ERK1 (601795)/ERK2 (176948), and reactive oxygen species (ROS) and that leads to increased type I collagen (120150) expression. The authors suggested that the biologic activity of PDGFR antibodies on fibroblasts has a causal role in the pathogenesis of the disease. Tan (2006) suggested that the profibrotic phenotype of fibroblasts in patients with scleroderma is maintained by at least 3 mechanisms involving TGFB1 (190180), PDGFR, and the RAS-ERK1/ERK2-ROS cascade.
Using proteome analysis, van Bon et al. (2014) identified increased levels of CXCL4 (173460) in skin and plasma plasmacytoid dendritic cells from patients with systemic sclerosis. The study included 779 patients from 5 independent cohorts. The levels of CXLC4 in patients with systemic sclerosis was significantly higher than in controls or compared to patients with systemic lupus erythematosus, ankylosing spondylitis, or liver fibrosis. CXLC4 levels were particularly increased in patients with early diffuse disease. In sclerosis patients, circulating CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro cellular studies showed that CXCL4 downregulated expression of transcription factor FLI1 (193067) and induced secretion of interferon I via toll-like receptors. In mice, infusion of CXCL4 induced the expression of inflammatory markers, promoted the infiltration of inflammatory cells in the skin, and resulted in increased skin thickening. Van Bon et al. (2014) suggested that CXCL4 is a biomarker for fibrosis and pulmonary arterial hypertension in systemic sclerosis, and may be useful in early diagnosis and risk assessment. The findings also implicated a central role for plasmacytoid dendritic cells in the pathogenesis of the disease.
PathogenesisMakino et al. (2013) found that the microRNA LET7A1 (605386) was downregulated in both systemic and localized human scleroderma in vivo and in vitro compared with normal or keloid skin. Inhibition of LET7A1 expression in human or mouse skin fibroblasts affected expression of type I collagen. Serum levels of LET7A1 were reduced in scleroderma patients, particularly those with the localized form. Intermittent overexpression of Let7a1 in mouse skin by intraperitoneal injection improved skin fibrosis in a mouse model of scleroderma. Makino et al. (2013) proposed that LET7A1 has a negative effect on type I collagen expression in normal fibroblasts, but that downregulation of LET7A1 by TGFB stimulation contributes to type I collagen overexpression in scleroderma fibroblasts.
In scleroderma, patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene (614258). As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, Joseph et al. (2014) hypothesized that the 'foreign' antigens in this autoimmune disease are encoded by somatically mutated genes in the patients' incipient cancers. Studying cancers from scleroderma patients, Joseph et al. (2014) found genetic alterations of the POLR3A locus in 6 of 8 patients with antibodies to RPC1, but not in 8 patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. Joseph et al. (2014) concluded that these results offered insight into the pathogenesis of scleroderma and provided support for the idea that acquired immunity helps to control naturally occurring cancers.
CytogeneticsRittner et al. (1988) found increased chromosomal breakage rate (ICBR) in 27 of 28 patients with systemic sclerosis; 5 patients with CREST syndrome, 4 with incomplete CREST, 1 with overlapping syndrome, and 18 with progressive systemic sclerosis were studied. In addition to the patients, about half of their first-degree relatives showed increased chromosomal breakage rate, segregating as a dominant marker in 9 families. In the 6 informative of the 9 families, the ICBR trait showed close linkage with HLA (maximum lod = 5.5 at theta = 0). ICBR was predominantly observed in linkage disequilibrium with HLA haplotype A1, Cw7, B8, C4AQ0B1, DR3, which is frequently observed in autoimmune diseases.
In a 67-year-old male patient with the CREST variant of systemic sclerosis and in his 34-year-old daughter, Schmid et al. (1989) found a supernumerary chromosome in over half of metaphases. The microchromosome consisted of constitutive heterochromatin and contained nuclear antigens reacting with specific antikinetochore antibodies. Furthermore, it showed a close association with the centromere of normal chromosomes. Kinetochore-specific autoantibodies are demonstrable in the sera of over 90% of CREST patients (Fritzler and Kinsella, 1980; Moroi et al., 1980; Tan et al., 1980). The daughter, who inherited the microchromosome from her father, was clinically healthy, and none of 15 other CREST patients was found to have a supernumerary microchromosome.
Using FISH, Invernizzi et al. (2005) assessed the presence of monosomy X in women with systemic sclerosis (SSC) or autoimmune thyroid disease (AITD; see 140300) and age-matched healthy women. The rate of monosomy X increased with age in all 3 groups, but it was significantly higher for women with SSC or AITD. Monosomy X was more frequent in peripheral T and B lymphocytes than in other blood cell populations, and there was no evidence of male fetal microchimerism. Invernizzi et al. (2005) proposed that chromosome instability is common in women with these autoimmune diseases and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance in autoimmune disease.
MappingAssociation with the FBN1 Gene on Chromosome 15q21.1
Tan et al. (1998) reported a candidate gene approach to the study of systemic sclerosis in a population of Choctaw Native Americans in which there was evidence of a possible founder effect. Microsatellite alleles on human 15q and 2q, homologous to the murine tight skin-1 (tsk1) and tsk2 loci, respectively, were analyzed in Choctaw cases and race-matched normal controls for possible disease association. Genotyping first-degree relatives of the cases identified potential disease haplotypes, and haplotype frequencies were obtained by expectation-maximization and maximum-likelihood estimation methods. Simultaneously, the ancestral origins of contemporary Choctaw systemic sclerosis cases were ascertained using census and historical records. A multilocus 2-cM haplotype was identified on 15q that showed significantly increased frequency in systemic sclerosis cases compared with controls. The haplotype contained 2 intragenic markers for the fibrillin-1 (FBN1; 134797) gene. Genealogic studies demonstrated that the systemic sclerosis cases were distantly related, and their ancestry could be traced back to 5 founding families in the mid-18th century. The probability that the systemic sclerosis cases share this haplotype due to familial aggregation effects alone was calculated and found to be very low. No evidence for a microsatellite allele disturbance on chromosome 2q in a region homologous to tsk2 or the region containing the interleukin-1 family of genes was found.
Zhou et al. (2003) performed a genomewide microsatellite screen using 400 markers in 20 Choctaw patients with systemic sclerosis and 76 ethnically matched controls. Twelve markers showed highly significant and 5 showed significant association with the disorder. Along with some potentially novel systemic sclerosis loci (1p32-p31, 7q35, 8q24.12, 19p13.2, 22q13.1, and Xq21-q23), 4 loci (6p22.3, 15q21.1, 5q31-q33, and 20q12) had previously been linked to the disorder. Several markers were located within the same candidate regions reported for other autoimmune diseases.
Tan et al. (2001) sequenced all 69 known FBN1 exons to ascertain the presence of changes that might show associations with systemic sclerosis in Choctaw and Japanese patients and controls. They identified 5 SNPs in FBN1: SNP1 in the 5-prime untranslated region, SNP2 in exon 15, SNP3 in intron 17, SNP4 in exon 27, and SNP5 in intron 27. Only SNP1 (T-to-C) demonstrated an association with systemic sclerosis in the Choctaw. They found 11 FBN1 SNP haplotypes in the Choctaw population, 2 of which were found only in the systemic sclerosis patients. These same FBN1 SNP haplotypes were associated with systemic sclerosis in the Japanese. The data were considered consistent with the hypothesis that FBN1 or a nearby gene on chromosome 15q is involved in systemic sclerosis susceptibility in the Choctaw and the Japanese.
In further studies in the Choctaw, Tan et al. (2003) concluded that polymorphisms in the THBS1 (188060) gene at 15q15, the FGF7 gene (148180) at 15q15-q21.1, the FUR gene (136950) at 15q25-q26, and the MFAP1 gene (600215) at 15q15-q12 cannot account for the high prevalence of systemic sclerosis in the Oklahoma Choctaw. These data, together with reports showing functional abnormalities in fibrillin-1 protein in systemic sclerosis fibroblasts (Wallis et al., 2001) and disease-specific autoimmune responses directed against fibrillin-1 in systemic sclerosis (Tan et al. (1999, 2000)), support the notion that FBN1 is the most likely candidate gene on the chromosome 15 haplotype previously associated with systemic sclerosis in the Choctaw.
Association with the CTGF Gene on Chromosome 6q23
In a study involving 1,000 subjects in 2 groups, Fonseca et al. (2007) found that a polymorphism (G-945C) in the promoter of the connective tissue growth factor (CTGF; 121009) gene on chromosome 6q23 was associated with susceptibility to systemic sclerosis. The GG genotype was significantly more common in patients with systemic sclerosis than in control subjects, with an odds ratio for the combined group of 2.2 (95% confidence interval, 1.5 to 3.2; P less than 0.001 for trend). Analysis of the combined group of patients with systemic sclerosis showed a significant association between homozygosity for the G allele and the presence of antitopoisomerase I antibodies (odds ratio, 3.3; 95% confidence interval, 2.0 to 5.6; P less than 0.001) and fibrosing alveolitis (odds ratio, 3.1; 95% confidence interval, 1.9 to 5.0; P less than 0.001). Fonseca et al. (2007) observed that the substitution of cytosine for guanine created a binding site of the transcriptional regulators Sp1 and Sp3. The C allele has high affinity for Sp3 and is associated with severely reduced transcriptional activity. A chromatin immunoprecipitation assay showed a marked shift in the ratio of Sp1 to Sp3 binding at this region, demonstrating functional relevance in vivo. Fonseca et al. (2007) concluded that the G-945C substitution represses CTGF transcription, and the -945G allele is significantly associated with susceptibility to systemic sclerosis.
Association with the STAT4 Gene on Chromosome 2q32.2-q32.3
Rueda et al. (2009) observed that the T allele of rs7574865 of the STAT4 gene (600558) was significantly associated with susceptibility to limited cutaneous systemic sclerosis (LCSSC) (p = 1.9 x 10(-5); odds ratio, 1.61), but not with diffuse cutaneous systemic sclerosis (DCSSC) in a Spanish case-control study of 242 LCSSC patients, 90 DSSSC patients, and 1,296 controls A dosage effect was observed with the TT genotype increased in LCSSC patients compared with controls (p = 1.02 x 10(-7); odds ratio, 3.34). Combined metaanalysis of the Spanish cohort and 5 independent cohorts of European ancestry showed a strong risk effect for the rs7574865 T allele and LCSSC susceptibility (pooled odds ratio, 1.54; p less than 0.0001).
Molecular GeneticsSee 142460 for discussion of a possible association between susceptibility to systemic sclerosis and variation in the SDC2 gene.
Animal ModelGreen et al. (1976) described a new mouse mutant, 'tight-skin' (Tsk). Heterozygotes had tight skin with marked hyperplasia of subcutaneous loose connective tissue. Increased growth of cartilage and bone was a feature different from the human mutation. Tendons were small with hyperplasia of the sheaths. Homozygotes die in utero. Growth hormone was normal. The authors speculated that the mutation may cause defective cell receptors with high affinity for a somatomedin-like factor promoting growth of connective tissue. Muryoi et al. (1991) showed that Tsk mice spontaneously produce anti-topoisomerase I antibodies, which are characteristically found only in patients with progressive systemic sclerosis but not in patients with the CREST syndrome, a systemic sclerosis-related disorder. The autoantibodies produced in the tight-skin mouse are encoded primarily by heavy-chain variable genes from the J558 family. Kasturi et al. (1994) showed that the J558 genes encoding these antibodies are not derived from a selected germline gene(s) or a single subfamily but rather from genes belonging to diverse J558 subfamilies. All the results strongly suggested that the establishment of the autoimmune repertoire is mediated by V(H)-gene-dependent selection of B cells, though the contribution of an antigen-mediated selection mechanism could not be ruled out.
The Tsk locus maps to a region on chromosome 2 that includes a segment that is syntenic with human chromosome 15 (Doute and Clark, 1994). Since the microfibrillar glycoprotein gene, fibrillin-1 (FBN1; 134797), is located on human 15q, it became a candidate for the Tsk mutation in the mouse. Siracusa et al. (1996) demonstrated that the Tsk chromosome harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame Fbn1 transcript. The findings provided possible explanations for the phenotypic features of Tsk/+ mice and the lethality of Tsk/Tsk embryos.