Blue syndrome D71

Autosomal-dominantly inherited, autoimmunologic systemic disease (mutations in NOD2/CARD15 gene; 18q12) with 3 main clinical symptoms:

• granulomatous arthritis
• lichenoid granulomatous dermatitis
• refractory uveitis (ADU).

This disease is more frequently observed in African-American children. In a Danish registry the annual incidence was estimated to be 1:1,670,000 per year for children < 5 years. The prevalence is about 1:1,000,000.

The syndrome is caused by a mutation in the NOD2 gene (CARD15 gene). Normally, this gene codes for the NOD2 receptor. Blue syndrome is associated with Crohn's disease, which also involves mutations in the CARD15 gene.

Symmetrical arthritis (with serous synovitis and tendosynovitis) manifests on the wrists, ankles, knees and sometimes on the elbows. Camptodactyly due to hypertrophic tendosynovitis is often described in advanced disease. A severe disability usually does not occur before the age of 40-50 years.

Further characteristic features are a creeping granulomatous iridocyclitis and a posterior uveitis with possible destructive panuveitis. In addition, iris nodules, focal synechia, cataracts, glaucoma and lumpy deposits surrounding the cornea may occur. A significant loss of vision occurs in 20-30% of those affected.

A papular exanthema (face, trunk, upper extremity) is found before the 4th LJ. Disseminated lichen-nitidus-like skin changes can also be found.

Also: recurrent fever, systemic and pulmonary hypertension, granulomatous vasculitis of the large vessels and granulomatous inflammation of the liver, kidneys and lungs.

Non-cheesy epitheloid cellular granulomas of the skin, which are very reminiscent of sarcoidosis.

The diagnosis is largely based on the detection of the non-caseating granulomatous inflammation with epithelioid cells and multinucleated giant cells in the skin (histological changes are similar to those of sarcoidosis) -, synovial or conjunctival biopsies and on mutation detection in the NOD2 gene (0.5 - 2 ml EDTA blood - normal mail - after isolation of the patient's genomic DNA, exon 4 of the CARD15/NOD2 gene is amplified by polymerase chain reaction and completely sequenced).

Polyarthritis, systemic juvenile idiopathic arthritis, granulomatous inflammation in primary immunodeficiency, systemic granulomatous vasculitis. Exclusion of chronic infections (mycobacterioses, mycotic infections).

Dermatitis, perioral granulomatous of childhood (no familiarity, otherwise largely identical clinical picture).

Glucocorticoids with moderate to low dosage (7.5-15mg prednisolone).

Supplemental: body weight-adapted methotrexate 1x/week.

Alternative: Biologicals: Monoclonal anti-TNF antibody agents (Infliximab and Adalimumab).

BS is a chronic and progressive disease with a variable and often unpredictable course. In cases with a greater number of symptoms, life expectancy may be reduced. The prognosis of uveitis is unfavorable.

The blue syndrome is named after the American pediatrician Edward Bernard Blau.

The term blue syndrome refers to a disorder with both familial and sporadic occurrence (the sporadic occurrence, however, is called "early onset sarcoidosis - EOS - or early onset sarcoidosis ").

In contrast to sarcoidosis, there is no lung infection.

1. Arvesen KB et al (2017) Diagnosis and Treatment of Blue Syndrome/Early-onset Sarcoidosis, on Autoinflammatory Granulomatous Disease, in an Infant. Acta Derm Venereol 97:126-127.
2. Caso F et al (2015) Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease. RMD Open 20:e000097.
3. Kim W et al (2016) A familial case of blue syndrome caused by a novel NOD2 genetic mutation. Korean J Pediatr 59(Suppl 1):S5-S9.
4. Li C et al (2017) Gene mutations and clinical phenotypes in Chinese children with blue syndrome. Sci China Life Sci 60:758-762.
5. Rose CD (2017) Blau Syndrome: A Systemic Granulomatous Disease of Cutaneous Onset and Phenotypic Complexity. Pediatric Dermatol 34:216-218.
6. Wouters CH et al (2014) Blue syndrome, the prototypic auto-inflammatory granulomatous disease. Pediatric Rheumatol Online J 12:33.
7. Zeybek C et al (2015) A new mutation in blue syndrome. Case Rep Rheumatol:463959.