Familial occurrence of scleroderma

In the above article Iranzo et al. reported on three siblings with cutaneous involvement of atrophoderma Passini–Pierini type, i.e. a distinct subset of morphoea. The familial occurrence of both systemic scleroderma (SSc) and localized (cutaneous) scleroderma is of special interest as the genetic aetiopathogenesis is uncertain and the relationship between systemic and localized disease is not entirely clear. Very few studies having convincing documentation were based on large cohorts of probands and first-degree relatives (parent–child, siblings) and controls.1–6 An important role of genetics in the aetiopathogenesis of scleroderma is supported by a cluster of SSc cases in Choctaw Native Americans in Oklahoma,7 significant familial occurrence in highly inbred Brandywine tri-racial mixture of the American Indians, black people and Caucasians,8 and in three large US cohorts.6 The familial links with other connective tissue diseases, frequent occurrence of antinuclear antibodies in relatives,1,3 as well as twin studies showing a low concordance rate in monozygotic twins, similar to that in other autoimmune diseases, suggest a definite but relatively weak genetic component.7,9 The major contributions appear to have environmental factors and/or acquired genetic changes.10 As the family members also share common environmental exposure, the genetic factors and environmental hazards are not infrequently interrelated and overlapping.11 This is best shown in two male siblings concordant for silica-induced SS-A antinuclear antibodies (ANA) and DRw52 haplotypes. However, the non-affected sibling also showed concordance for haplotype and silica exposure.12 Of special interest in this respect is the occurrence of SSc in a husband and his wife exposed to silica, who developed the disease within a 3-year period.13 Since that time several studies have confirmed the occurrence of topoisomerase I antibodies and SSc in non-related individuals, particularly in miners.14,15 It is conceivable that environmental factors are responsible for relatively rare and rather atypical cases of SSc in males. A different set of HLA D alleles, in combination with exogenous hazards, could be involved in the induction of SSc-specific antitopoisomerase I antibodies and susceptibility to the disease.15 In general, a genetic link has been established between HLA DRB1 and DQB1 alleles and SSc-specific antibodies,16,17 such that the SSc subsets are defined by these antibodies.18 The recognition of immunodominant epitopes on DNA topoisomerase I by topoisomerase I positive sera is, however, heterogeneous, and also influenced by ethnic background.19 Thus, the disease expression of SSc is related not only to genetic and environmental factors, but also ethnic factors. It is of note that in ANA-positive first-degree relatives of SSc patients, antitopoisomerase I SSc-specific antibodies have not been detected,1,2 which favours their specificity for SSc. Familial SSc is very rare. The absence of a common haplotype for familial scleroderma and discordance in monozygotic twins do not favour a strong genetic contribution to scleroderma aetiology. A recent Australian study validates SSc affecting first-degree relatives in 31 reported families, including 19 horizontal transmissions (siblings) and 12 vertical transmissions (parent–child). The absolute risk for first-degree family members was found to be low (approximately 1%).5 Another recent study of US cohorts showed 2–3% prevalence of SSc in first-degree family members vs. 11–17% in patients with Raynaud’s phenomenon and 7% in patients with systemic lupus erythematosus.6 Although the clustering of familial cases in SSc is infrequent, their incidence appears to be underestimated, probably due to under-reporting. Genetic contribution does not appear to play an important part in the aetiopathogenesis of localized (cutaneous) scleroderma, although there are several reports on single familial cases.20 No significant HLA associations have been demonstrated, except for a weak association with HLA DR2 A3 and B7 antigens.21 However some genetic factors may predispose to rare cases of cutaneous scleroderma.22 The absence of pedigree information and unknown environmental influences in most studies do not permit evaluation of the risk factor for the first-degree family members. Iranzo et al. report on three siblings with very superficial, hyperpigmented, non-indurated, long-lasting plaques with identical haplotype A1, B8 and DR3 in two, providing support for possible genetic influences in morphoea. The cutaneous involvement in their cases has all the characteristics of Passini–Pierini atrophoderma, which appears to be a distinct subset of morphoea. Morphoea shows greater heterogeneity than SSc both in clinical presentation and pathogenesis because diverse causative factors have been implicated, e.g. tryptophan metabolism abnormalities, borreliosis in several north and central European countries, etc.23 Although localized scleroderma differs from SSc (absence of significant internal involvement, immunological abnormalities, and Raynaud’s phenomenon, as well as by more benign course with frequent spontaneous resolution), the sclerotic cutaneous changes are very similar in their clinical and histological presentation. A possible development of morphoea, generalized morphoea or SSc in the graft-versus-host-reaction after organ transplantation indicates their similar pathogenic mechanisms. The transition of localized forms into systemic disease are exceedingly rare, but the appearance of ANA (usually of unidentified specificity) in linear scleroderma and generalized morphoea suggest some immune activation, and the coexistence of localized scleroderma with SSc or other CTD has been seen in first-degree relatives. Genetic contributions are probably more difficult to establish in morphoea than in SSc because the genetic markers in SSc were found associated with autoantibody profiles, and no specific antibodies were demonstrated in localized disease. Such studies, as reported on three siblings, should be performed in large cohorts and in different types of localized scleroderma, both in children and adults. There is evident misinformation concerning the rare occurrence of localized scleroderma24 as these cases are mostly in the care of dermatologists, whereas the epidemiological studies were performed in general by rheumatologists. In conclusion, the unclear genetic and environmental influences in the pathogenesis of localized scleroderma will be clarified only through studies on large cohorts of patients and their families by epidemiologists in conjunction with dermatologists and paediatricians.