Centromeric association of a microchromosome

Summary A supernumerary microchromosome measuring 0.5–1 m found in over half of the metaphases of a CREST scleroderma patient and his daughter has been characterized by various cytogenetic techniques. The microchromosome consisted of constitutive heterochromatin and contained nuclear antigens reacting with specific anti-kinetochore antibodies. The most remarkable property of the microchromosome was its non-random position: it was closely associated with the centromere of any of the normal chromosomes in the majority of the metaphases. Furthermore, an inordinately high rate of Y chromosome aneuploidy was found in the CREST scleroderma patient. The origin and structure of the microchromosome, its possible connection with the CREST variant of scleroderma, and the phenomenon of centromeric association are discussed.     

The kinetochore is part of the metaphase chromosome scaffold

We used antisera from patients with the CREST syndrome of scleroderma (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) to show that an antigenic component of the kinetochore present in metaphase chromosomes is also present in nonhistone chromosome scaffolds isolated following extensive digestion of the DNA and extraction of the bulk of chromosomal protein. All sera from 12 scleroderma CREST patients previously shown by immunofluorescence microscopy to have circulating antikinetochore antibodies recognise a protein of Mr 77,000 (CREST-77) in an immunoblotting assay. 9 of the 12 sera also recognise an antigen of Mr 110,000 (CREST-110). These proteins are present in isolated chromosomes and nonhistone scaffolds derived from them by two different procedures. Sera of five scleroderma CREST patients who are antikinetochore negative (by immunofluorescence) bind to neither protein in immunoblots. These data suggest that CREST-77 (and possibly CREST-110) is a component of the human kinetochore, and that the kinetochore is an integral part of the mitotic chromosome scaffolding.     

Effect of oxidants and antioxidants on chromosomal breakage in Fanconi anemia lymphocytes

Summary Peripheral blood lymphocytes from eight Fanconi anemia (FA) patients, 14 FA heterozygotes, and nine normal subjects have been tested for their susceptibility to chromosomal breakage induction by diepoxybutane (DEB) and by two peroxides. In addition, the effect of five antioxidants was investigated in standard cultures and in cultures stressed either with DEB or with butylhydroperoxide (BHP) or with hydrogen peroxide (H₂O₂). DEB, BHP, and H₂O₂ dramatically increased the chromosomal breakage levels in homozygous and heterozygous FA cells. A partial correction of chromosomal instability was obtained by treating the patients' lymphocytes with antioxidants. A protective effect was also noted in the DEB or peroxide-stressed lymphocytes of patients and heterozygotes, grown in the presence of antioxidants.     

Cytoprotective effect of honey against chromosomal breakage in fanconi anemia patients in vitro

BACKGROUND:

Natural honey is widely used all over the world as a complementary and alternative medicine in various disorders including Fanconi anemia (FA). FA is a rare genetic chromosomal instability syndrome caused by impairment of DNA repair and reactive oxygen species (ROS) imbalance. This disease is also related to bone marrow failure and cancer. The aim of this study was to evaluate the cytoprotective effect of honey on mitomycin C (MMC-) induced chromosomal damage in peripheral lymphocytes from FA patients.

MATERIALS AND METHODS:

Treatment of these complications with alkylation agents MMC may enhance chromosomal breakage. We have evaluated the effect of honey on MMC- induced chromosomal breakage in FA blood cells using chromosomal breakage assay. The basal chromosomal breakage count was higher among FA patients than healthy subjects.

RESULTS:

The addition of MMC alone gave a significantly higher of chromosomal breakage in FA patients than control group (P < 0.0001). Pre- treatment with honey significantly inhibited breakage induced by MMC in FA patients by its antioxidant effect.

CONCLUSION:

Honey can prevent MMC- induced chromosomal breakage by its antioxidant effect.     

A linkage study of hereditary ataxias and related disorders

Genetic markers controlled by 21 genetic systems were studied in 13 families containing members suffering from various hereditary disorders involving ataxia. Classical cerebellar ataxia was present in four, Friedreich ataxia in two, hereditary spastic paraplegia in four, and the Charcot-Marie-Tooth syndrome in three families. In each family, every available member above the lowest age at onset observed in that family, was subjected to a thorough clinical investigation and blood was sampled for investigation of genetic markers.The families with cerebellar ataxia and with Charcot-Marie-Tooth syndrome contained enough informative relatives to allow a formal linkage study using the lodscore method. Three of the pedigress with cerebellar ataxia gave evidence of linkage between the disease and the HLA system with a combined lodscore of 2.128 at a recombination fraction of 0.05 for both sexes combined. The recombination fraction was considerably higher in females than in males, although the difference between the two sexes was not statistically significant.Negative lodscores were obtained for the remaining family with cerebellar ataxia, which might be due to the fact that this family only provided information on recombination in females. However, the clinical features in this family differed from those in the other three families by a significantly higher frequency of dementia and pyramidal tract lesions. Based on these observations and on contradictory results in the literature concerning linkage between cerebellar ataxia and HLA, we suggest that there are two forms of cerebellar ataxia: One (CA¹) linked to HLA with symptoms restricted to lesions in the cerebellum and spinocerebellar system and another (CA²) not linked to HLA with symptoms from more wide-spread lesions of the CNS.None of the other genetic markers (except perhaps GLO) showed linkage to the cerebellar ataxias. Negative lodscores throughout with all 21 genetic markers were found in the families with Charcot-Marie-Tooth syndrome.There was no evidence for linkage between HLA on the one hand and Friedreich ataxia or hereditary spastic paraplegia on the other.List of Abbreviations HA Hereditary ataxias - HLA Major histocompatibility system - CA Cerebellar ataxia - FA Friedreich ataxia - HSP Hereditary spastic paraplegia - CMT Charcot-Marie-Tooth syndrome - MS Multiple sclerosis - Hp Haptoglobin - Gc Group-specific component - PGM Phosphoglucomutase, locus 1 - SP (AcP) Acid phosphatase - AK Adenylatekinase - PGD 6-phosphogluconatedehydrogenase - ADA Adenosinedeaminase - GPT Glutamate pyruvat transaminase - GT Galaktose-1-phosphat uridylyltransferase - EsP Carboxylesterase D - GLO Glyoxylase I This study was aided by grants from Warwara Larsen's Foundation, the Danish Multiple Sclerosis Society and the Medical Research Council     

Hereditary cerebellar ataxia and genetic linkage with HLA

Summary Five families with at least three generations of members affected with autosomal dominant spinocerebellar ataxia (SCA) were studied. HLA typing was carried out and the coded HLA haplotypes were used to calculate the likelihood of linkage using the LIPED computer program. The combined lod scores from these five families does not, by itself, support linkage. Negative lod scores were observed in all five families, however, when pooled with the previously published data significant lod scores were obtained [Z=3.343 (=0.20) and +4.286 (=0.30)]. In four families, affected members had clinical features consistent with autosomal dommant cerebellar ataxia (ADCA) type I while in the fifth, ADCA type II was suggested. Clinical heterogeneity within ADCA raises doubts about the significance of summed lod scores. In view of the previous reports probably two genetically heterogeneous types of ADCA exist — HLA linked and nonlinked.     

Quasi-linkage: a confounding factor in linkage analysis of complex diseases?

Human linkage analysis is based on the assumption that unlinked genomic loci, particularly loci located on non-homologous chromosomes, segregate independently during meiosis. An exception to this rule is the phenomenon of quasi-linkage (QL) that describes the non-random segregation of non-homologous chromosomes, which can undermine the basic concept of linkage. Molecular mechanisms of QL are not clear; however, observations in mice and plants suggest a possible affinity between non-homologous chromosomal regions containing repetitive or like sequences. QL has not been investigated in humans. As QL may generate false linkages in genome scans of complex diseases, we sought to determine whether genomic loci detected in such genome scans exhibit QL. A number of individual markers showing linkage to schizophrenia, asthma, multiple sclerosis, inflammatory bowel disease and type-1 diabetes were tested for QL in a pairwise linkage analysis against all other markers exhibiting evidence for linkage in each specific study. The Marshfield genotype dataset of eight CEPH families was used for this purpose. The best QL lod scores generated from the analysis were within the range of the lukewarm lod scores reported in the majority of linkage studies for complex disorders. In addition, we performed a genome-wide QL analysis on the Marshfield family database which detected eight QL lod scores >6. The replication of the best Marshfield QL scores was performed using the deCODE families and although none of the eight pairs demonstrated independent evidence for QL, three pairs generated maximal lod scores of 0.11, 0.3, and 1.51. In conclusion, although complex disease relevant markers did not produce high QL lod scores, the general phenomenon of QL in humans cannot be excluded and potentially can be a confounding factor in genetic studies of complex traits.     

Ataxia-telangiectasia: Linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome

Summary Ataxia-telangiectasia (A-T) is a progressive autosomal recessive disease featuring neurodegeneration, immunodeficiency, chromosomal instability, radiation sensitivity and a highly increased proneness to cancer. A-T is ethnically widespread and genetically heterogeneous, as indicated by the existence of four complementation groups in this disease. Several A-T-like genetic diseases share various clinical and cellular characteristics with A-T. By using linkage analysis to study North American and Turkish A-O families, the ATA (A-T, complementation group A) gene has been mapped to chromosome 11q23. A number of Israeli Arab A-T patients coming from large, highly inbred families were assigned to group A In one of these families, an additional autosomal recessive disease was identified, characterized by ataxia, hypotonia, microcephaly and bilateral congenital cataracts. In two patients with this syndrome, normal levels of serum immunoglobulins and alpha-fetoprotein, chromosomal stability in peripheral blood lymphocytes and skin fibroblasts, and normal cellular response to treatments with X-rays and the radiomimetic drug neocarzinostatin indicated that this disease does not share, with A-T, any additional features other than ataxia. These tests also showed that another patient in this family, who is also mentally retarded, is affected with both disorders. This conclusion was further supported by linkage analysis with 11q23 markers. Lod scores between A-O and these markers, cumulated over three large Arab families, were significant and confirmed the localization of the ATA gene to aq23. However, another Druze family unassigned to a specific complementation group, showed several recombinants between A-T and the same markers, leaving the localization of the A-T gene in this family open.     

Marfan syndrome: exclusion of genetic linkage to five genes coding for connective tissue components in the long arm of chromosome 2

Summary Marfan syndrome represents a heterogeneous connective tissue disease, the symptoms arising in several tissues and organs. The defective gene(s) behind this autosomal dominant condition has not been found despite considerable research. The main targets of the research have been the genes coding for connective tissue components. Several of the candidate genes suspected to be defective in Marfan syndrome are located on the long arm of chromosome 2. These genes include a cluster of two genes coding for fibrillar collagens COL3A1 and COL5A2, and a third member of the collagen gene family: COL6A3. Furthermore, genes for elastin (ELN) and fibronectin (FN) are also located in this area of chromosome 2. We studied this chromosomal area using restriction fragment length polymorphism (RFLP) linkage analysis in five Finnish Marfan families with affected members in three generations. In two point linkage analyses, Lod scores of –3.192 ( = 0.1) to COL3A1, –1.683 ( = 0) to COL6A3 and –2.664 ( = 0.01) to FN were obtained, whereas the linkage analysis between elastin and the disease was non-informative (Lod score 0.444, = 0). With the multipoint linkage analysis that permits simultaneous examination of several loci and more efficient use of family data, we obtained an exclusion of all these loci as the site of the mutation leading to Marfan syndrome in these families.     

Identification of a family of human centromere proteins using autoimmune sera from patients with scleroderma

We have examined preimmune serum samples from a patient who progressively developed the symptoms of scleroderma CREST over a period of several years. During this period, anti-centromere antibodies (recognized by indirect immunofluorescence) appeared in the serum. Concomitant with the appearance of the anti-centromere antibodies, antibody species recognizing three chromosomal antigens in immunoblots of SDS polyacrylamide gels appeared in the patient's serum. These antigens migrate with electrophoretic mobilities corresponding to M_r=17, 80, and 140 kilodaltons (kd). Affinity-eluted antibody fractions recognizing the antigens have been prepared from sera of three other patients. Indirect immunofluorescence labeling of mitotic cells using these antibody fractions demonstrates that the antigens are centromere components. We designate them CENP (CENtromere Protein) — A (17kd), CENP-B (80kd), and CENP-C (140kd). The three CENP antigens share antigenic determinants. Immunoblotting experiments show that these patients make antibody species recognizing at least three distinct epitopes on CENP-B and two on CENP-C. Sera from different patients contain different mixtures of the antibody species.     

Fractionation and initial characterization of the kinetochore from mammalian metaphase chromosomes

We have partially isolated the kinetochore and associated centromeric structures from mammalian metaphase chromosomes. Human autoantibodies from scleroderma CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) patients were used as immunofluorescent probes to monitor fractionation. The procedure includes digestion of total chromosomal DNA with micrococcal nuclease, dehistonization with heparin, and dissociation of the remaining material with detergent and urea. We used a density gradient (metrizamide) to obtain an enriched fraction of stained material (kinetochore). When examined by electron microscopy, the kinetochore fraction is seen to contain numerous small immunoperoxidase-positive masses which are morphologically similar to the centromere/kinetochore region of intact metaphase chromosomes. The particulate fraction that contains kinetochore components represents less than 5% of total chromosomal proteins and contains less than 1% of total DNA. Two polypeptides of 18 and 80 kD were identified as kinetochore antigens by immunoblotting with CREST antiserum. In this paper we discuss the distribution of these kinetochore polypeptides with the associated centromeric chromatin.     

Linkage analysis with RFLPs in families with androgen resistance syndromes: evidence for close linkage between the androgen receptor locus and the DXS1 segment

Summary Three families with androgen resistance syndromes — two with testicular feminization and one with Reifenstein syndrome — have been studied for linkage analysis. Using three cloned DNA sequences from the centromere region and the proximal long arm of the X chromosome (p8, pDP34, and S9, which define respectively the chromosomal segments DXS1, DXYS1, and DXS17), we found no recombination between the DXS1 locus and the mutant genes in the three families. Assuming that these disorders are the result of allelic mutations at the same locus for the androgen receptor, we can conclude that there is a close linkage between DXS1 and the androgen receptor locus, with a maximum lod score =3.5 at a recombination fraction =0.0 using the LIPED program (Ott 1974).     

Reducing selection bias in case-control studies from rare disease registries

Background

Cockayne syndrome is a rare autosomal recessive neurodegenerative disease characterized by low-to-normal birth weight; growth failure; brain dysmyelination with calcium deposits, cutaneous photosensitivity; pigmentary retinopathy, cataract, and sensorineural hearing loss. To the best of our knowledge, cholestatic liver disease was not previously reported in these patients.

Aim

To highlight the presence of cholestasis and liver dysfunction in this group of patients and to suggest modified criteria for clinical diagnosis.

Methods

The study included nine patients with Cockayne from four different families (five males and four females) in which Cockayne was suspected clinically. In all patients chromosomal breakage studies revealed mild (45%) to moderate (60%) increase in frequency of chromatid and chromosome gaps and breaks versus 25% in normal controls. Diagnosis was confirmed by DNA repair assay.

Results

During routine follow up of these patients, seven of them had evident liver affection ranging from mild elevation in liver enzymes to cholestatic liver disease and liver cell failure. The attacks were recurrent in two patients and were sometimes preceded by infection. The attack may lead to deterioration of neurological and/or liver condition. It may end in liver cell failure that either recovers completely or may lead to death.

Conclusions

liver disease could be considered common in Egyptian patients with Cockayne with the cholestatic form being the most evident. The syndrome should be included in the list of causes of cholestatic liver disease. Chromosomal breakage study and positive family history should be included as major criteria for clinical diagnosis of Cockayne especially in a population like ours where consanguineous marriage is very high and molecular testing and UV sensitivity tests are considered unaffordable.     

Association of 5'-untranslated region of the Fibrillin-1 gene with Japanese scleroderma

Excessive production of extracellular matrix (ECM) constituents is a hallmark scleroderma or systemic sclerosis (SSc). Fibrillin-1, a major component of microfibrils in the ECM, may play a role in the pathogenesis of SSc. The TSK1 mouse model of SSc bears an in-frame duplication of the Fibrillin-1 gene (FBN1) which results in a larger than normal protein that is more susceptible to proteolysis. Metabolic labeling studies of Fibrillin-1 in human SSc dermal fibroblasts demonstrated that while normal amounts of Fibrillin-1 are synthesized, the protein itself appears to be unstable. Moreover, autoantibodies specific for Fibrillin-1 have been demonstrated in serum from SSc patients and TSK1 mice. In particular, a high frequency of anti-Fibrillin-1 was observed in Japanese patients with diffuse and limited scleroderma or CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) syndrome. Genetic studies in a Native American population with high prevalence of using microsatellite marker showed strong association between FBN1 haplotypes and SSc. Subsequently, studies of FBN1 single nucleotide polymorphisms (SNPs) demonstrated that certain FBN1 haplotypes were associated with SSc in both Native American and Japanese patients with limited scleroderma. Thus, FBN1 was sequenced in 22 Japanese SSc patients to ascertain the presence of any relevant mutations or SNPs. Sequence analysis revealed eight coding and 14 non-coding SNPs and other polymorphisms. Among them, a CT insertion in the 5'-untranslated region of exon A had a significant negative association with disease.     

"Scleroderma linearis: hemiatrophia faciei progressiva (Parry-Romberg syndrom) without any changes in CNS and linear scleroderma "en coup de sabre" with CNS tumor

Background

Hemifacial atrophy (Parry-Romberg syndrome) is a relatively rare disease. The etiology of the disease is not clear. Some authors postulate its relation with limited scleroderma linearis. Linear scleroderma "en coup de sabre" is characterized by clinical presence of most commonly one-sided linear syndrome. In a number of patients, neurological affection is the medium of the disease. The treatment of both scleroderma varieties is similar to the treatment of limited systemic sclerosis.

Case presentation

We present two cases of a disease: a case of a 49-year-old woman with a typical image of hemifacial atrophy, without any changes of the nervous system and a case of a 33-year-old patient with an "en coup de sabre" scleroderma and with CNS tumor.

Conclusion

We described typical cases of a rare diseases, hemifacial atrophy and "en coup de sabre" scleroderma. In the patient diagnosed with Parry-Romberg syndrome, with Borrelia burgdoferi infection and with minor neurological symptoms, despite a four-year case history, there was a lack of proper diagnosis and treatment. In the second patient only skin changes without any neurological symptoms could be observed and only a precise neurological diagnosis revealed the presence of CNS tumor.     

Cytochalasin induces abnormal anaphase in crane-fly spermatocytes and causes altered distribution of actin and centromeric antigens

Inhibition of cytokinesis by cytochalasins without an effect on karyokinesis has been demonstrated in several types of cells. We report here that treating crane-fly spermatocytes with cytochalasins at concentrations (10 M CE, 100 M CD, and 200 CB) in excess of that needed to inhibit cell division induces one or more half-bivalents to lag at anaphase during the first meiotic division. The behavior of the laggards is similar to that of maloriented half-bivalents. Following treatment at these concentrations, probing with rhodamine-phalloidin or bodipy-phallacidin reveals loss of filamentous actin from the poles and its appearance in the spindle, predominantly in regions where centromeres and kinetochores are normally found. When either N350 anti-actin monoclonal antibody or rhodamine DNase I was used to probe for actin in cytochalasin-treated cells, a similar redistribution of actin was observed. CD and CE treatments alter the pattern of fluorescence at centromere/kinetochore regions after staining with scleroderma CREST serum: CREST-positive structures become broader, with spikes extending from them toward the pole; in addition, some strands of CREST fluorescence appear that are apparently extraneous, and not associated with chromosomes. Probes for actin yield staining patterns in centromere/kinetochore regions that match closely the cytochalasin-altered pattern of CREST staining. Our finding of actin in the vicinity of kinetochores under conditions that result in abnormal chromosome behavior raises numerous questions about the possible role(s) of actin in meiosis, particularly in chromosome orientation.Abbreviations CREST calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia by W.C. Earnshaw     

Epitope analysis of chromo antigen and clinical features in a subset of patients with anti-centromere antibodies

Heterochromatin protein 1 (HP1) is one of the nonhistone chromosomal components tightly associated with the pericentromeric heterochromatic region in Drosophila. The human homologue of HP1 is recognized by a subpopulation of anti-centromere antibodies (ACA). Such autoantibodies recognize a group of several nuclear proteins with Mr of 23–25 kDa and have been termed anti-chromo antibodies (AChA) because an evolutionarily conserved N-terminal half called the chromo domain of HP1 is the epitope. In this study, 84 ACA sera were examined by immunoblotting with recombinant 25-kDa chromo protein (p25). The p25 antigen was expressed as a glutathione S-transferase-fusion protein in E. coli and purified with glutathione-sepharose. Except for one serum specimen, AChA-positive sera reacted with the N-terminus (a.a 16–106) and/or the C-terminus (a.a. 83–191) of p25. Autoimmune response against the N-terminus of p25 in 33 patients was significantly associated with systemic lupus erythematosus and significantly related to leukopenia, thrombocytopenia and elevated erythrocyte sedimentation rate; C-terminal reactivity in 30 patients was significantly associated with primary Sjogren's syndrome and related to leukopenia. The internal 64-amino acid stretch (a.a. 43–106) with DNA-binding activity was not autoantigenic. p25 has two separate homologous regions to Drosophila HP1 at the N- and C-termini; the chromo domain and the chromo shadow domain. Patients with autoimmune responses against these conserved domains might form a clinical subset of patients positive for ACA.Abbreviations ACA anti-centromere antibodies - AChA anti-chromo antibodies - CENP centromere protein - DM dermatomyositis - ESR erythrocyte sedimentation rate - GST glutathione S-transferase - HP1 heterochromatin protein 1 - p25 25-kDa chromo protein - SLE systemic lupus erythematosus - SS Sjogren's syndrome - SSc systemic sclerosis - WBC white blood cell     

Chromosome segregation from cell hybrids. VI. Centromeres of both parental chromosome sets stain with antikinetochore antibody

Antikinetochore antibodies obtained from serum of patients with the CREST syndrome of scleroderma were used to test the hypothesis that there are differences in protein binding to retained- and segregant-set centromeres in Chinese hamster--human hybrids. This hypothesis is not supported since identical staining of the two types of kinetochores was observed with CREST antibody.     

Aminolevulinate dehydratase (E.C. 4.2.1.24): Linkage analysis

Summary Linkage data on aminolevulinate dehydratase (ALADH, E.C. 4.2.1.24) and a series of other human genetic markers are presented. One hundred and two families (25 of them being informative) from southwestern Germany were tested. Close linkage (=0.05) between ALADH and the following markers could be excluded: Rh, PGM₁, Fy, ACP1, MNSs, HLA, Bf, GLO, PGM₃, Jk, Pi, PGP, K, GPT. There is some evidence of possible linkage with HPA.     

Early systemic sclerosis: marker autoantibodies and videocapillaroscopy patterns are each associated with distinct clinical,functional and cellular activation markers

Introduction

Early systemic sclerosis (SSc) is characterized by Raynaud''s phenomenon together with scleroderma marker autoantibodies and/or a scleroderma pattern at capillaroscopy and no other distinctive feature of SSc. Patients presenting with marker autoantibodies plus a capillaroscopic scleroderma pattern seem to evolve into definite SSc more frequently than patients with either feature. Whether early SSc patients with only marker autoantibodies or capillaroscopic positivity differ in any aspect at presentation is unclear.

Methods

Seventy-one consecutive early SSc patients were investigated for preclinical cardiopulmonary alterations. Out of these, 44 patients and 25 controls affected by osteoarthritis or primary fibromyalgia syndrome were also investigated for serum markers of fibroblast (carboxyterminal propeptide of collagen I), endothelial (soluble E-selectin) and T-cell (soluble IL-2 receptor alpha) activation.

Results

Thirty-two of the 71 patients (45.1%) had both a marker autoantibody and a capillaroscopic scleroderma pattern (subset 1), 16 patients (22.5%) had only a marker autoantibody (subset 2), and 23 patients (32.4%) had only a capillaroscopic scleroderma pattern (subset 3). Patients with marker autoantibodies (n = 48, 67.6%) had a higher prevalence of impaired diffusing lung capacity for carbon monoxide (P = 0.0217) and increased serum levels of carboxyterminal propeptide of collagen I (P = 0.0037), regardless of capillaroscopic alterations. Patients with a capillaroscopic scleroderma pattern (n = 55, 77.5%) had a higher prevalence of puffy fingers (P = 0.0001) and increased serum levels of soluble E-selectin (P = 0.0003) regardless of marker autoantibodies.

Conclusion

These results suggest that the autoantibody and microvascular patterns in early SSc may each be related to different clinical-preclinical features and circulating activation markers at presentation. Longitudinal studies are warranted to investigate whether these subsets undergo a different disease course over time.