Also known as:
- Sarcoidosis Early-Onset
- EOS Granulomatosis
- Familial Juvenile Systemic Arthrocutaneouveal Granulomatosis
- ACUG Jabs Syndrome
- Granulomatous Inflammatory Arthritis
Blau syndrome is characterized by the triad of granulomatous arthritis, uveitis, and dermatitis. First described in 1985, it was considered to be distinct from sarcoidosis due to the early age of onset and autosomal dominant inheritance pattern. Published reports of sporadic cases of children with ‘early-onset sarcoidosis’ (EOS) with granulomatous involvement of different organs, primarily affecting joints, eyes, and skin, were suspected to represent the same disorder because the patients’ characteristics were nearly identical. Subsequently, identical NOD2 mutations were identified in patients with Blau syndrome as well as in patients diagnosed with EOS, confirming earlier suspicions that they represented the same disease (summary by Borzutzky et al., 2010). Unlike older children diagnosed with sarcoidosis, these patients have no apparent pulmonary involvement; however, the disease is progressive and may result in severe complications such as blindness and/or joint destruction (Shetty and Gedalia, 1998).
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 deceased 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.
Ukae et al. (1994) studied a Japanese girl who presented at age 3.3 years with brown 3- to 5-mm scaly papules on her trunk and extremities. At age 4, the skin lesions were unchanged, and she developed painless swelling of her right knee joint; over the next month, painless nonerythematous joint swelling eventually involved both wrists, knees, and ankles. Ophthalmologic examination revealed bilateral mild uveitis of the posterior globe. She had no lymph node swelling and no cardiopulmonary or neurologic findings. Skin biopsy showed noncaseating granuloma, which the authors noted was consistent with a diagnosis of sarcoidosis. She was treated with aspirin alone, and at 5.3 years of age, she had mild uveitis, but the joint swelling and skin lesions had improved, and she did not exhibit pulmonary involvement. Ukae et al. (1994) designated the patient’s disease ‘preschool sarcoidosis.’
Saini and Rose (1996) described a family with Blau syndrome in which 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.
In a large affected family, Tromp et al. (1996) based the diagnosis of Blau syndrome 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 Blau syndrome. 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. Patients were often 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 with a family history of the disorder and multifocal choroiditis should be suspected of having familial juvenile systemic granulomatosis.
Dhondt et al. (2008) reported a 63-year-old man with Blau syndrome who had severe camptodactyly and bilateral large recalcitrant leg ulcers. Biopsies of 1 of the ulcers showed granulomas. There was no family history of the disorder.
Borzutzky et al. (2010) reported a 9-month-old Caucasian boy who presented at 2 weeks of age with intermittent fevers, feeding intolerance, failure to thrive, migratory rash, and nontender subcutaneous nodules. Evaluation at 9 months of age showed systemic inflammation and disseminated granulomatous disease, including the triad of granulomatous arthritis, uveitis, and dermatitis. Esophageal biopsy showed nonnecrotizing granulomata in the lamina propria. The authors stated that this was the first report of gastrointestinal tract granulomas in this disorder.
The transmission pattern of Blau syndrome in the family reported by Blau (1985) was consistent with autosomal dominant inheritance.
Alonso et al. (2003) described a kindred in which a mother and 3 of her children with Blau syndrome 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.
In an extended family in which 16 members had 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.
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).
In a 27-year-old Japanese man with systemic granulomatous disease, in whom lack of a family history of the disease led to a diagnosis of ‘early-onset sarcoidosis’ rather than Blau syndrome, Kanazawa et al. (2004) identified 1 of the same CARD15 mutations (R334W; 605056.0006) that had previously been detected in Blau syndrome.
Kanazawa et al. (2005) retrospectively collected Japanese ‘early-onset sarcoidosis’ cases in search of CARD15 mutations. Among 10 EOS cases, missense mutations were identified in 9: 4 patients, including a patient originally reported by Sakurai et al. (1997) and the 27-year-old man previously studied by Kanazawa et al. (2004), were heterozygous for the R334W mutation that had been reported in patients diagnosed with Blau syndrome; and 4 patients, including a 32-year-old woman originally diagnosed with ‘ocular sarcoidosis’ by Shimomura et al. (1982), carried different novel missense mutations (see, e.g., 605956.0008). In addition, a 16-year-old girl who was reported by Ukae et al. (1994) to have ‘preschool sarcoidosis’ was found to have 2 missense mutations (D382E, 605956.0009 and A612T, 605956.0010). (The pathogenicity of the A612T variant was later called into question.) All of these variants of CARD15 showed increased basal NFKB activity. Kanazawa et al. (2005) concluded that most patients given a diagnosis of early-onset sarcoidosis or Blau syndrome share a common genetic etiology of CARD15 mutations that cause constitutive NFKB activation, and noted that this supported the long-standing hypothesis that sporadic cases of EOS and familial cases of Blau syndrome represent different types of the same juvenile systemic granulomatosis syndrome.
In a 63-year-old man who exhibited features of Blau syndrome and also had severe camptodactyly and recalcitrant leg ulcers, Dhondt et al. (2008) sequenced the candidate gene NOD2 and identified heterozygosity for the R334W mutation.
In a 9-month-old Caucasian boy with Blau syndrome, who also exhibited gastrointestinal granulomas, Borzutzky et al. (2010) identified heterozygosity for the IVS8+158 variant (605056.0007) in the NOD2 gene.
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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