Objective: To investigate the relative contribution of the major histocompatibility (MHC) gene complex in the etiopathogenesis of familial scleroderma and/or its variants, in 5 Australian families, each with 2 affected members.
Methods: Affected individuals and consenting first degree relatives were examined and had blood collected for histocompatibility leukocyte (HLA) class I, class II antigen, and complement C4 typing. An antinuclear (ANA) profile screen on each family member was performed.
Results: Family 1, had 2 affected siblings (scleroderma, CREST), each anticentromere positive (> 1/640 titer), with identical HLA haplotypes. A brother, who was HLA identical to his affected sisters was clinically normal and ANA negative. In Family 2, there were no HLA haplotype similarities between the 2 sisters affected with diffuse scleroderma. Both were ANA positive (> 1/640). A 3rd sister was HLA identical to the proband but was clinically normal and ANA negative. In Family 3, affected siblings (CREST, morphea) had identical HLA haplotypes. In Family 4, both mother (CREST) and one of her 2 daughters (scleroderma) had anticentromere antibodies (1/2560). The unaffected daughter, not sharing either of her sister's haplotypes, was normal and ANA negative. In Family 5, 2 sisters (CREST, CREST) were HLA identical.
Conclusion: A female predominance in familial scleroderma was observed. There was no common HLA haplotype between different families affected with scleroderma or its disease variants. Within families (except in one case, where the possibility of crossover exists or a question of paternity) affected siblings shared both HLA haplotypes. The development of disease was not totally accounted for by HLA genes, since family members with the same HLA haplotypes as the proband, were not affected. It appears that genes within the MHC complex are required but are not sufficient for the development of systemic sclerosis.