Developmental Disorders of the Lymphatics

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Wednesday, January 31, 2007

Blau Syndrome

Blau syndrome--a chronic granulomatous, genetic disease

Ugeskr Laeger. 2006 Oct 16;168(42):3612-4.

Milman N,
Byg KE.
H:S Rigshospitalet, Hjertecentret, Medicinsk Afdeling B, Afsnit for Lungetransplantation, Kobenhavn O.

Blau syndrome is a rare hereditary granulomatous disease presenting in patients of young age with exanthema, granulomatous arthritis and uveitis. Genetic analysis has shown an autosomal dominant inheritance and a number of specific mutations on chromosome 16q in codon 334, of which the most predominant are R334W and R334Q. Blau syndrome exists in Caucasian, Asian and Afro-American families, and de novo mutations have been reported. The estimated minimum incidence in Denmark is 0.05 per 100,000 person-years. Blau syndrome has pathological, clinical and therapeutic features in common with sarcoidosis but rarely involves the lungs or other parenchymatous organs. Discrimination between Blau syndrome and early-onset sarcoidosis should rely on chromosome analysis.

PMID: 17069723 [PubMed - indexed for MEDLINE]

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Paratuberculosis in Blau Syndrome tissues

Dow CT.

University of Wisconsin, Madison, Wisconsin, USA

Blau syndrome is familial, juvenile, systemic granulomatosis with primary clinical findings of uveitis, arthritis, and dermatitis. Although rare, Blau syndrome shares aspects of the more common diseases sarcoidosis and Crohn's disease. The clinical findings of Blau syndrome are similar to those of juvenile sarcoidosis and mutations of Blau syndrome are on the same chromosome 16 gene that confers susceptibility to Crohn's disease, CARD15. The product of this gene is a component of the innate immune system involved in bacterial pathogen surveillance. Mycobacterium avium subsp. paratuberculosis (MAP) has been implicated as a causative agent of sarcoidosis and Crohn's disease. The presence of MAP in Blau syndrome tissue was postulated and archival tissues of individuals with Blau syndrome were acquired to test for the DNA of MAP. Six tissues of five patients representing three kindred were tested. The tissues were granulomatous lesions of skin, synovium, liver and kidney. Paratuberculosis was detected in all tissues. Its presence in these multi-system disease tissues expands the argument for the disease-causing role of MAP beyond the gut and positions MAP for consideration as a “superantigen”.


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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.


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.

Archives of Pediatrics

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