OBJECTIVE To determine whether HLA and autoimmunity contribute to the pathogenesis of Blau syndrome (familial granulomatous arthritis, uveitis, and rash) and evaluate whether this condition is related to sarcoidosis. DESIGN Large family survey. SETTING General community, Green Bay, Wis, and two tertiary care medical centers in Philadelphia, Pa. PARTICIPANTS Thirty-six family members and spouses from a large kindred with Blau syndrome. SELECTION PROCEDURES Volunteer and convenience sample. INTERVENTIONS None. MEASUREMENTS AND RESULTS Ten affected and many unaffected subjects were personally examined. Medical records and previous biopsy reports and specimens, when available, were reviewed. Two affected subjects had skin biopsies performed and three affected adult subjects were tested with Kveim skin-test reagent. Serologic and genomic class I and class II HLA typing was performed on 27 affected and unaffected subjects. All 13 living affected subjects and the one obligate carrier had the following assays performed; antinuclear antibody titer, rheumatoid factor, serum angiotensin converting enzyme level, quantitative immunoglobulins of the IgG, IgM, and IgA classes, and clinical chemistry profiles. Several had complete blood cell counts and erythrocyte sedimentation rates performed. Four affected subjects, one possibly affected subject, and one obligate carrier were newly identified. Flexion contractures of the fingers and toes (camptodactyly) were found, for the first time, to be a phenotype characteristic. Earlier onset and worsening of symptoms in succeeding generations (anticipation) were observed. Sixteen HLA haplotypes were identified. No conclusive evidence for linkage between these haplotypes and phenotype expression could be demonstrated. All 13 affected subjects, however, carried the DR2 (DR beta 1*1501) and/or DR4 (DR beta 1*0401) allele. There was no evidence of hypercalcemia, hypergammaglobulinemia M, rheumatoid factor production, or abnormal blood cell counts. Two affected subjects had low-titer antinuclear antibody screening tests, five had mild to moderately elevated IgG and/or IgA levels, two had raised serum angiotensin converting enzyme levels, and three had mild elevation of the erythrocyte sedimentation rate. All three subjects tested with Kveim skin-test reagent showed no reactivity by visual inspection. Both subjects who had had skin biopsies performed had evidence of granulomatous inflammation. CONCLUSIONS This family's illness is distinct from both classic and early-onset sarcoidosis. There is minimal evidence for autoimmunity and systemic inflammation. Camptodactyly should be added to the list of syndrome-defining characteristics. Although HLA haplotypes do not appear to segregate with affected subjects, HLA-DR2 and HLA-DR4 subtypes may play a permissive role in phenotype expression. This family represents a unique opportunity to define the molecular mechanisms involved in the initiation of arthritis and uveitis in humans. Genetic linkage studies to determine the chromosomal location of the Blau syndrome gene are in progress.