ANALYSIS OF A LARGE KINDRED WITH BLAU SYNDROME FOR HLA, AUTOIMMUNITY,AND SARCOIDOSIS

Objective.-To determine whether HLA and autoimmunity contribute to the pathogenesis of Blau syndrome (familial granulomatous arthritis, uvei tis, and rash) and evaluate whether this condition is related to sarco idosis. 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 kindr ed with Blau syndrome. Selection Procedures.-Volunteer and convenience sample. Interventions.-None. Measurements and Results.-Ten affected a nd many unaffected subjects were personally examined. Medical records and previous biopsy reports and specimens, when available, were review ed. Two affected subjects had skin biopsies performed and three affect ed adult subjects were tested with Kveim skin-test reagent. Serologic and genomic class I and class II HLA typing was performed on 27 affect ed and unaffected subjects. All 13 living affected subjects and the on e obligate carrier had the following-assays performed; antinuclear ant ibody titer, rheumatoid factor, serum angiotensin converting enzyme le vel, quantitative immunoglobulins of the IgG, IgM, and IgA classes, an d 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 id entified. Flexion contractures of the fingers and toes (camptodactyly) were found, for the first time, to be a phenotype characteristic. Ear lier onset and worsening of symptoms in succeeding generations (antici pation) were observed. Sixteen HLA haplotypes were identified. No conc lusive evidence for linkage between these haplotypes and phenotype exp ression could be demonstrated. All 13 affected subjects, however, carr ied the DR2 (DRbeta11501) and/or DR4 (DRbeta1*0401) allele. There was no evidence of hypercalcemia, hypergammaglobulinemia M, rheumatoid fa ctor production, or abnormal blood cell counts. Two affected subjects had low-titer antinuclear antibody screening tests, five had mild to m oderately elevated IgG and/or IgA levels, two had raised serum angiote nsin converting enzyme levels, and three had mild elevation of the ery throcyte 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 inf lammation. Conclusions.-This family's illness is distinct from both cl assic and early-onset sarcoidosis. There is minimal evidence for autoi mmunity and systemic inflammation. Camptodactyly should be added to th e list of syndrome-defining characteristics. Although HLA haplotypes d o not appear to segregate with affected subjects, HLA-DR2 and HLA-DR4 subtypes may play a permissive role in phenotype expression. This fami ly 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 syn drome gene are in progress.