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Arthrocutaneouveal granulomatosis/Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous recurrent uveitis, dermatitis, and symmetric arthritis. The gene responsible for BS has been identified in the caspase recruitment domain gene CARD15/NOD2. In the majority of patients, the disease is characterized by early-onset, usually before 3-4years of age. The manifestations at disease onset are usually represented by articular and cutaneous involvement signs, generally followed later by ocular manifestations which are often the most relevant morbidity of BS.
Blau Syndrome is an autosomal dominant genetic inflammatory disorder which affects the skin, eyes, and joints. It is caused by a mutation in the NOD2 (CARD15) gene. Symptoms usually begin before the age of 4, and the disease manifests as early-onset cutaneous sarcoidosis, granulomatous arthritis, and uveitis.
Blau syndrome which is also known as familial or pediatric granulomatous arthritis or early-onset sarcoidosis (EOS), is a granulomatous disease with an autosomal dominant inheritance pattern. The typical sites that are affected are skin, including a maculopapular skin rash, joints, with polyarticular granulomatous arthritis, and eyes, with granulomatous uveitis. In severe cases, the granulomatous inflammation can disseminate to liver, lung and kidney. Diagnosis is made by a combination of medical history, histologic evidence of (non-caseating) granulomas at the site of inflammation and genetic testing for mutations in the NOD2/CARD15 gene.
The NOD2 protein is part of the NOD family of proteins. These proteins form intracellular pattern recognition molecules that recognize danger signals such as toxins, bacteria or viruses and are an important part of innate immunity. NOD2 specifically recognizes muramyl dipeptide that is part of the bacterial cell wall peptidoglycan. When activated NOD2 leads to NF-kappa beta release, which in turn promotes apoptosis.
NOD2 mutations in Blau syndrome affect the nucleotide-binding domain of the protein. This leads to a gain of function that is now independent of muramyl dipeptide concentration, resulting in excessive NF kappa beta activation. Interestingly, susceptibility to Crohn’s disease has also been associated with mutations in NOD2, which shares some phenotypic similarities with Blau such as multisystem granulomatous inflammation. Polymorphisms associated with Crohn’s effect a different region of the NOD2 gene.
Recently, Mycobacterium avium ss. paratuberculosis (MAP) DNA has been identified in affected tissues from Blau patients. This organism has been implicated in the pathogenesis of Crohn’s and has also been found in patients with sarcoidosis. It is possible that NOD2 mutations in Blau could allow the persistence of MAP, leading to aberrant inflammation.
Causes of Blau Syndrome
The elucidation that the gene defect in BS involves the CARD15/NOD2 gene has stimulated many investigators, to define how this gene operates as part of the innate immune system, that responds to bacterial polysaccharides, such as muramyl dipeptide, to induce signaling pathways that induce cytokine responses and protect the organism. In BS the genetic defect seems to lead to overexpression, and poor control of the inflammatory response leading to widespread granulomatous, inflammation and tissue damage.[rx][rx]
Symptoms of Blau Syndrome
- Arthritis typically affects peripheral joints mainly wrists, knees, ankles, and proximal interphalangeal (PIP) joints of the hands.
- Tenosynovitis is equally a characteristic feature; tendon sheaths appear enlarged on examination; most often the extensor tendons of the wrist, the pes anserinus, peroneal and flexor tibialis tendon sheaths are affected.
- Lymphocyte subpopulations, microcytic anemia (HB = 8.2 g/dl; MCV = 59.4 fl),
- Anisocytosis and anisochromia on the manual blood smear, a slightly elevated level of C-reactive protein (9.28 mg/l), the lowered concentration of iron without other iron irregularities,
- Deficiency of class M and G3 immunoglobulins, and vitamin D3 deficiency.
- Symmetrical knee and ankle arthritis without erosive and destructive changes in the joints.
- Tenosynovitis and synovitis were excluded.
- Eczematous dermatitis decreased,
- Multiple subcutaneous nodules emerged on both upper and lower limbs, as well as on the torso;
- The skin lesions responded well to the escalation of the glucocorticoid dose.
- Recurrent diarrhea and concomitant abdominal pain
- Features included fever, sialadenitis,
- Erythema nodosum,
- Leukocytoclastic vasculitis,
- Transient neuropathies,
- Granulomatous glomerular and interstitial nephritis, interstitial lung disease,
- Arterial hypertension, pericarditis,
- Pulmonary embolism,
- Hepatic granulomas, splenic involvement, and chronic renal failure.
- Dermatitis in the form of a dark red, slightly scaly, maculopapular, or eczematoid-like or lichenoid-like rash may occur frequently in the first year of life.[rx ,rx]
- Dermatitis is often symmetric, on the trunk and/or extremities and is usually intermittent with spontaneous resolution,
- Other described cutaneous findings are represented by erythema nodosum, leukocytoclastic vasculitis, bilateral leg ulcers, ichthyosis Vulgaris and pityriasis lichenoides.[rx] ,[rx], [rx]
- Granulomatous uveitis is a frequent manifestation (70–80%), often bilateral and with a chronic recurrent course.[rx ,rx]
- Ocular granulomatosis is often referred to as the blurred vision, painful and red eyes, floaters and photophobia. [rx]
- Ocular involvement can potentially evolve into moderate or severe visual loss, thus representing in many patients the most severe manifestation of these diseases.[rx ,rx]
- It can also affect all the ocular segments, with iridocyclitis, band keratopathy with inflammatory precipitates and vitrinite.[rx ,rx]
- Involvement of the posterior ocular segment with chorioretinitis, vasculitis, macular oedema with retinal detachment, and optic neuritis has been described in several cases.[rx]
- Cataracts, inflammatory glaucoma, peripheral synechiae, increased intraocular pressure and optic atrophy can represent uveitis complications.[rx]
Diagnosis of Blau Syndrome
On physical examination,
- Numerous 1- to 2-mm, red-brown to pinkish-tan, flat-topped papules covered much of the face, trunk, and extremities. Individual lesions were closely grouped in oval clusters and linear arrays, with the confluence on the face.
- The upper part of the chest knees, elbows, palms, and soles was relatively spared. No oral mucosal or conjunctival lesions were evident. No joint tenderness or swelling, lymphadenopathy, or hepatosplenomegaly was found.
The following laboratory tests produced normal results
- Complete blood cell count – chemistry panel, serum calcium level, hepatic function panel, erythrocyte sedimentation rate, and urinalysis.
- Blood test – blood tests are important to exclude other diseases that can be associated with granulomatous inflammation (such as immune deficiency or Crohn’s disease). They are also important to see the extent of the inflammation and to evaluate the involvement of other organs (such as the kidney or liver).
- The serum angiotensin-converting enzyme – level was 159 U/L (reference range, 13-100 U/L). A tuberculin skin test result was negative
- Chest radiography results – were normal, and ultrasonography of the wrists, elbows, and knees revealed no synovial thickening or effusions.
- Abdominal ultrasound scan (USS) – documented enlargement of the liver (30 mm below the right costal arch) and spleen (length 118 mm, with age-specific reference range up to 95 mm), with normal echogenicity of both organs.
- Peripheral lymph node USS – revealed the presence of suspicious (hypoechogenic, up to 20 mm in diameter, without a marked sinus) supraclavicular, infraclavicular and axillary lymph nodes.
- Histopathological examination – of one of the left supraclavicular lymph nodes showed reactive changes with neutrophilic infiltration.
- Examination of the skin biopsy – specimen demonstrated the presence of multiple granulomas composed of giant cells and epithelial cells at the border of the skin and subcutaneous tissue, raising suspicion of sarcoidosis or erythema annulare.
- Clinical suspicion – It is relevant to consider Blau syndrome when a child presents a combination of symptoms (joint, skin, eye) out of the typical clinical triad. A detailed investigation into the family history should be considered because this disease is very rare and inherited in an autosomal dominant manner.
- Demonstration of granulomas – to make the diagnosis of Blau syndrome/EOS, the presence of typical granulomas in the affected tissue is essential. Granulomas can be seen on a biopsy of a skin lesion or of an inflamed joint. Other causes of granulomatous inflammation (such as tuberculosis, immune deficiency or other inflammatory diseases such as some vasculitides) need to be excluded by thorough clinical examination and blood tests, imaging, and other tests.
- Genetic analysis – in the last couple of years, it has been possible to perform a genetic analysis of patients to ascertain the presence of mutations that are thought to be responsible for the development of Blau syndrome/EOS.
- Advanced Skin biopsy – a skin biopsy involves the removal of a tiny piece of tissue from the skin and it is very easy to perform. If the skin biopsy shows granulomas, the diagnosis of Blau syndrome is made after the exclusion of all other diseases that are associated with granuloma formation.
- The Genetic Testing Registry (GTR) – provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
- Genetic test – the only test that unambiguously confirms the diagnosis of Blau syndrome is a genetic test that shows the presence of a mutation in the NOD2 gene.
Treatment of Blau Syndrome
Treatment options should be guided by which organs are affected. Empiric experience has guided therapeutic choices as there have been no clinical trials owing to the rarity of Blau syndrome.
- Consider no treatment as a rash may spontaneously resolve.
- Superpotent (Class 1) or potent (class 2) topical corticosteroids may aid resolution of rash, although relapse may occur when discontinuing treatment.
- Azithromycin (orally) 10mg/kg 3 times weekly was described as efficacious in one case report.
Arthritis and Occular Manifestations
- NSAIDs may help with low-level joint inflammation.
- Low-dose systemic corticosteroids (0.5mg/kg per day) with occasional up-titration of dose for flares has been the mainstay of treatment described historically.
- Methotrexate has been used as a steroid-sparing agent.
- Thalidomide at an initial dose of 2mg/kg has been used successfully in two children with refractory ocular disease.
- Infliximab (5mg/kg IV infusion every 6 to 8 weeks) has been used in refractory cases.
- Anakinra (100mg s.c.) once daily has been used in one patient with success, although another report of two patients showed no improvement.
- High-dose corticosteroids – have been shown to be efficacious when administered in concomitance with BS and EOS acute flares, as well as low-dose corticosteroids that are generally used during the quiescent stage.[rx ,rx]
- Concomitant use of immunosuppressants – (methotrexate, or azathioprine, or mycophenolate mofetil) has been shown to be effective.[rx ,rx ,rx]
- Further, the anti-TNF-α agent – adalimumab, in combination with corticosteroids and/or methotrexate, has recently been shown to induce remission in case of refractory arthrocutaneous, ocular and systemic involvement.[rx]
- Treatment with another anti-TNF-α drug – infliximab, has led to successful outcomes, also as monotherapy.[rx ,rx,rx]
- Cyclosporine – (3 mg/kg/day) and intravenous human immunoglobulins at a supplementation dose (0.4 g/kg/month) were added to the therapeutic protocol.
- If local treatment fails – oral prednisolone alone or in combination with MTX, azathioprine and mycophenolate mofetil, can be introduced.
- High-dose prednisolone – can be used during attacks and low dose in more stable periods (10). Also, TNF-α inhibitors, such as infliximab and adalimumab, are used in BS/EOS (10, 11). Interleukin (IL)-1β receptor antagonists, such as anakinra and canakinumab, have been used with variable clinical outcome.
- In cases with severe uveitis – canakinumab may be useful. In our case infliximab in combination with MTX induced remission for 8 months. However, when the MTX dose was decreased, symptoms reoccurred. Adalimumab improved uveitis and arthritis, but not a cutaneous eruption.
- Anecdotal evidence supports – the use of steroids immunomodulation with TNF-α inhibitors and possibly other immunomodulatory therapies, such as thalidomide, methotrexate, and anti-IL-1 therapy, in the treatment of Blau syndrome.