| #186580 | ||||||||||||||||||||||||||||||||||||||||||||||||
| BLAU SYNDROME | ||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||
| GRANULOMATOSIS, FAMILIAL JUVENILE SYSTEMIC ARTHROCUTANEOUVEAL GRANULOMATOSIS; ACUG JABS SYNDROME GRANULOMATOUS INFLAMMATORY ARTHRITIS, DERMATITIS, AND UVEITIS, FAMILIAL GRANULOMATOSIS, FAMILIAL, BLAU TYPE | ||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | ||||||||||||||||||||||||||||||||||||||||||||||||
| SYNOVITIS, GRANULOMATOUS, WITH UVEITIS AND CRANIAL NEUROPATHIES, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because Blau syndrome is caused by mutations in the NOD2/CARD15 gene (605956). Blau syndrome shows phenotypic overlap with early-onset sarcoidosis (609464), which is also caused by mutations in the CARD15 gene. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||
| Blau (1985) reported a large 4-generation family in which 11 members had a variable constellation of granulomatous arthritis, iritis, and skin rash. Ten had arthritis, 2 had skin, eye, and joint involvement, 1 had skin and joint disease, and 1 had iritis only. The disease was transmitted as an autosomal dominant trait. The major long-term problems were iritis and joint contractures. The disorder was distinguished from that described by Rotenstein et al. (1982) (see 108050) by the absence of fever, hypertension, and large vessel vasculitis. Jabs et al. (1985) reported a family in which 4 individuals had a syndrome of granulomatous synovitis and nongranulomatous uveitis. The proband, his brother, their father, and the decreased paternal grandmother were affected. Disease onset was in childhood. All patients had symmetric, boggy polysynovitis of the hands and wrists, resulting in nearly identical boutonniere deformities. Synovectomy specimens in the proband and his brother showed granulomatous inflammation with giant cells. Recurrent, nongranulomatous, acute iridocyclitis with visual impairment occurred in the proband, brother, and father. Hand radiographs showed no erosions or joint destruction despite more than 20 years of disease. In addition, the proband had corticosteroid-responsive hearing loss, and another patient had a transient sixth nerve palsy, which Jabs et al. (1985) referred to as 'cranial neuropathies.' Pastores et al. (1989) described a mother and 2 daughters with uveitis and symmetric polyarthritis. Both daughters also had cysts over the wrist and ankle joints and an intermittent generalized erythematous papular rash, which on histopathologic examination was found to represent noncaseating granulomatous infiltration. Response to intermittent, low-dose steroid therapy was dramatic. Pastores et al. (1989, 1990) thought the disorder was distinct from that reported by Jabs et al. (1985) because there was no cranial neuropathy and because Jabs' cases had no cysts. The authors also thought it was distinct from the disorder reported by Rotenstein et al. (1982), but they thought it was the same as the disorder reported by Blau (1985); indeed, they referred to it as 'Blau syndrome.' In a follow-up of the family reported by Blau (1985), Raphael (1993) found flexion contractures of the fingers and toes (camptodactyly) as a phenotypic characteristic. Raphael (1993) was impressed with earlier onset and worsening of symptoms in succeeding generations, i.e., anticipation. Raphael et al. (1993) concluded that the illness in the original family was distinct from classic sarcoidosis (181000). All 3 subjects tested with Kveim skin-test reagent showed no reactivity by visual inspection; however, both subjects who had had skin biopsies performed had evidence of granulomatous inflammation. No specific HLA association could be demonstrated. Saini and Rose (1996) described a family with Blau syndrome in whom liver granulomata were found in one member of the family in whom liver biopsy was performed. A mother and 2 sons of mixed Caucasian and black ancestry were described. Camptodactyly-like contractures of the proximal interphalangeal joints was noted. The authors postulated a relationship to early-onset sarcoidosis (609464), which is an allelic disorder (Kanazawa et al,. 2005). In a large affected family, Tromp et al. (1996) based diagnosis of Blau syndrome was based on any one or combination of the following: (1) persistent inflammation of any joint or tendon or both, characterized by marked edema and giant cyst formation or biopsy-proved granulomatous joint inflammation or both; (2) ophthalmologist-diagnosed anterior- or posterior-tract uveitis, or both, in one or both eyes at any age, in the absence of trauma or any other identifiable cause; and (3) persistent rash characterized by biopsy-proved granulomatous inflammation. Color photographs of striking arthritic, retinal, and cutaneous lesions were provided. The retinal view showed multifocal chorioretinal lesions, several pigmented scars, and marked perivascular sheathing. Manouvrier-Hanu et al. (1998) described what they considered to be the sixth family with this disorder. Affected individuals were monozygotic twin brothers, the son of one and the daughter of the other. Latkany et al. (2002) reviewed the ophthalmologic findings in 16 patients with juvenile systemic granulomatosis from 8 families examined at 6 academic medical centers. Of the 16 patients, 15 had evidence of panuveitis with multifocal choroiditis. One patient had only an anterior uveitis. One patient each had ischemic optic neuropathy, presumably due to small vessel vasculopathy, and retinal vasculopathy. Ocular complications were common, including cataract in 11, glaucoma in 6, band keratopathy in 6, cystoid macular edema in 6, and optic disc edema in 6. All 16 patients had polyarthritis, and at least 9 had skin rash. Often patients were misdiagnosed initially as having either juvenile rheumatoid arthritis or sarcoidosis. Latkany et al. (2002) concluded that patients with a diagnosis of juvenile rheumatoid arthritis but having a family history of the disorder and multifocal choroiditis should be suspected of having familial juvenile systemic granulomatosis. Dhondt et al. (2008) reported a patient with Blau syndrome who had large recalcitrant leg ulcers. Biopsies of 1 of the ulcers showed granulomas. Molecular analysis identified a heterozygous mutation in the CARD15 gene (605956.0006). There was no family history of the disorder. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Inheritance | ||||||||||||||||||||||||||||||||||||||||||||||||
| Alonso et al. (2003) described a new kindred consisting of a mother and 3 affected children that demonstrated autosomal dominant inheritance and anticipation. The patients had classic findings including cutaneous and joint involvement with camptodactyly. Only the mother and daughter had chronic uveitis. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||
| In an extended family in which 16 members were affected with Blau syndrome, Tromp et al. (1996) demonstrated linkage to DNA markers in the 16p12-q21 interval. With 2-point analysis, the marker D16S298 gave a maximum lod score of 3.75 at theta = 0.04. Most affected patients were examined by one of the authors, S. Raphael. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||
| Because mutations in the NOD2/CARD15 gene had been found in Crohn disease (266600), a disorder characterized by episodic intestinal inflammation with epithelioid granulomas, and because CARD15 is expressed predominantly in monocytes, a cell type that can differentiate into giant and epithelioid cells aggregating in granuloma formations, Miceli-Richard et al. (2001) did a mutation screen of 4 families with Blau syndrome and identified 3 different missense mutations in the CARD15 gene (605956.0004-605956.0006). One of the families had been reported by Manouvrier-Hanu et al. (1998). | ||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | ||||||||||||||||||||||||||||||||||||||||||||||||
| Goyal et al. (2007) reported an unusual case of a 12-year-old girl who presented with persistent focal seizures and MRI signal abnormalities. Brain biopsies showed marked dural granulomatous inflammation with focal extension into the brain parenchyma. Studies for systemic sarcoidosis were negative. Treatment with infliximab, a TNF-alpha inhibitor, resulted in clinical improvement. Family history revealed a paternal uncle and grandfather with Crohn disease, and molecular analysis identified 3 missense mutations in the NOD2 gene in the proband. | ||||||||||||||||||||||||||||||||||||||||||||||||
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