Analysis of a large kindred with Blau syndrome for HLA, autoimmunity, and sarcoidosis
S. A. Raphael, E. B. Blau, W. H. Zhang and S. H. Hsu
Department of Pediatrics, Temple University School of Medicine, Philadelphia, PA.
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.
