Blau syndrome
Synonyms and keywords: Pediatric Granulomatous Arthritis (PGA), Juvenile Systemic Granulomatosis, Early Onset Sarcoidosis, Jabs Syndrome, NOD2-associated disease-Blau

# Overview
Blau syndrome is characterized by the triad of early-onset symmetric polyarticular synovitis, skin rash, and eye involvement with recurrent anterior uveitis.

# Historical Perspective
- Blau syndrome was first discovered by Dr. Edward B. Blau, in 1985 following observation of a four-generation family with a variety of symptoms including granulomatous arthritis, iritis, and skin rash.
- Jabs Syndrome was introduced in the same year (1985) by Dr. A. Douglas Jabs following visiting patients with polyarthritis, uveitis, and cranial neuropathy.
- In 2001, NOD2 mutations were first implicated in the pathogenesis of Blau syndrome.

# Classification
- There is no established system for the classification of Blau syndrome.

# Pathophysiology
- The exact pathogenesis of Blau syndrome is not fully understood. However, it is caused by a NATCH domain of the NOD2 / CARD15 gene.
- The disease is inherited in an autosomal dominant mode.
- This gene encodes a protein involving in the immune system.
- NOD2 mutation leads to over activation of NF-kB which may explain an exaggerated inflammatory response observed in these patients.

# Causes
- Blau syndrome may be caused by a mutation in the NOD2 gene.

# Differentiating Blau syndrome from Other Diseases
- Blau syndrome must be differentiated from other diseases that cause arthritis, skin rash, and ophthalmological involvement, such as Neonatal onset multisystem inflammatory disease (NOMID), cryopyrin-associated periodic syndrome (CAPS), and familial mediterranean fever.
- For more information on the differential diagnosis of Blau syndrome please click here.

# Epidemiology and Demographics
- The prevalence of Blau syndrome has been reported less than 0.1 per 100,000 individuals worldwide.
- Blau syndrome commonly affects individuals younger than 4 years of age.
- There is no racial predilection to Blau syndrome.
- Blau syndrome affects men and women equally.

# Risk Factors
- There are no established risk factors for Blau syndrome.

# Screening
- There is insufficient evidence to recommend routine screening for Blau syndrome.

# Natural History, Complications, and Prognosis
- If left untreated, patients with Blau syndrome may progress to develop blindness, vasculitis, and joint deformities.
- Other possible complications include arterial hypertension, pulmonary embolism, and arthritis.
- Prognosis is generally poor if left untreated.

# Diagnosis

## Diagnostic Study of Choice
- There are no established criteria for the diagnosis of Blau syndrome. However, it usually manifests with a triad consist of symmetric early-onset of polyarticular synovitis, skin rash, and eye involvement with recurrent anterior uveitis.
- It is notable that some patients may present with signs/symptoms other than the aforementioned, which make the clinical diagnosis more challenging. Therefore, the genetic analysis is the diagnostic study of choice for Blau syndrome.

## History and Symptoms
- Blau syndrome first presents with a scaly rash often by 4 months of age. Fever, arthritis, abdominal pain, and other symptoms may present later by 4 years of age.
- Rash spread follows a cephalocaudal order. It first appears on the face and then affects the trunk.
- Arthritis usually affects wrists, knees, and ankles and tends to be symmetrical and chronic.

## Physical Examination
- Common physical examination findings of Blau syndrome include fever, scaly rash, and arthritis.
- Other possible findings include cranial nerve involvement, lymphadenopathy, hepatosplenomegaly, uveitis, conjunctivitis, cataracts, and panniculitis

## Laboratory Findings
- Common laboratory findings of Blau syndrome include elevated acute phase reactant levels, hypercalcemia and hypercalciuria, elevated angiotensin converting enzyme (ACE) level, elevated immunoglobulins, leukopenia and eosinophilia, hematuria, proteinuria, pyuria, and Abnormal liver function tests.

## Electrocardiogram
- There are no ECG findings associated with Blau syndrome. However, pericarditis may be one of the possible complication of Blau syndrome.
- For more information on ECG finding of pericarditis please click here

## X-ray
- There are no x-ray findings associated with Blau syndrome. However, an x-ray may be helpful in the evaluation of arthritis associated with Blau syndrome, which may indicate findings such as camptodactyly (flexion contracture in PIP joints), carpal dysplasia with carpal crowding (changes in shape and position affecting bones in the proximal carpal row), abnormal distal radial epiphysis with a biconcave articular surface (prominent bony ridge is in contact with the scapholunate joint), abnormal shape of the distal ulna (plump ulna) as well as a short ulna, and/or abnormal shape of the second metacarpal bone (long small diaphysis).

## Echocardiography or Ultrasound
- There are no echocardiography findings associated with Blau syndrome. However, pericarditis may be one of the possible complication of Blau syndrome.
- For more information on echocardiography finding of pericarditis please click here

## CT scan
- CT scan findings may be helpful in the diagnosis of conditions associated with Blau syndrome. It may indicate findings associated with pneumonitis such as:
Mild upper mediastinal adenopathy
Several small areas of ground glass opacity
- Mild upper mediastinal adenopathy
- Several small areas of ground glass opacity

## MRI
- There are no MRI findings associated with Blau syndrome.

## Other Imaging Findings
- There are no other imaging findings associated with Blau syndrome.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with Blau syndrome.

# Treatment

## Medical Therapy
- There is no treatment for Blau syndrome; the mainstay of therapy is supportive care.
- Treatment options for mild clinical phenotype include:
Topical steroid drops
NSAIDs
Methotrexate
- Topical steroid drops
- NSAIDs
- Methotrexate
- Treatment options for severe clinical phenotype include:
Systemic corticosteroids
Systemic immune suppression with biologic agents
Biologic agents targeting TNF and IL-1 are especially beneficial in refractory uveitis.
- Systemic corticosteroids
- Systemic immune suppression with biologic agents
Biologic agents targeting TNF and IL-1 are especially beneficial in refractory uveitis.
- Biologic agents targeting TNF and IL-1 are especially beneficial in refractory uveitis.

## Surgery
- Surgical intervention is not recommended for the management of Blau syndrome.

## Primary Prevention
- There are no established measures for the primary prevention of Blau syndrome.

## Secondary Prevention
- There are no established measures for the secondary prevention of Blau syndrome.