Blau syndrome
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2]
Synonyms and keywords: Pediatric Granulomatous Arthritis (PGA), Juvenile Systemic Granulomatosis, Early Onset Sarcoidosis, Jabs Syndrome, NOD2-associated disease-Blau
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Overview
Blau syndrome is characterized by
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.[1]
- Jabs Syndrome was introduced in the same year (1985) by Dr. A. Douglas Jabs following visiting patients with polyarthritis, uveitis, and cranial neuropathy.[2]
- In 2001, NOD2 mutations were first implicated in the pathogenesis of Blau syndrome.[3]
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.[3]
- The disease is inherited in an autosomal dominant mode.
- This gene encodes a protein involving in the immune system.[4]
- NOD2 mutation leads to overactivation of NF-kB which may explain an exaggerated inflammatory response observed in these patients.
Causes
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.[5]
- 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.[6][7][8].
- Other possible complications include:
- 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:[9]
- Early-onset of polyarticular synovitis
- Skin rash
- 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.[6]
- 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
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- Common physical examination findings of Blau syndrome include fever, scaly rash, and arthritis.[6]
- Other possible findings include:
Laboratory Findings
- Common laboratory findings of Blau syndrome include:[7]
- Elevated acute phase reactant levels
- Hypercalcemia and hypercalciuria
- Elevated angiotensin converting enzyme (ACE) level
- Elevated immunoglobulins
- Leukopenia and eosinophilia
- Hematuria, proteinuria, pyuria
- 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.[6]
- 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 the following findings:[10]
- 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
- 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.[6]
- 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:[6]
- 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.[11]
- Treatment options for mild clinical phenotype include:
- 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.[12]
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.
References
- ↑ Blau, Edward B. (1985). "Familial granulomatous arthritis, iritis, and rash". The Journal of Pediatrics. 107 (5): 689–693. doi:10.1016/S0022-3476(85)80394-2. ISSN 0022-3476.
- ↑ Jabs, Douglas A.; Houk, J.Lawrence; Bias, Wilma B.; Arnett, Frank C. (1985). "Familial granulomatous synovitis, uveitis, and cranial neuropathies". The American Journal of Medicine. 78 (5): 801–804. doi:10.1016/0002-9343(85)90286-4. ISSN 0002-9343.
- ↑ 3.0 3.1 3.2 Miceli-Richard, Corinne; Lesage, Suzanne; Rybojad, Michel; Prieur, Anne-Marie; Manouvrier-Hanu, Sylvie; Häfner, Renate; Chamaillard, Mathias; Zouali, Habib; Thomas, Gilles; Hugot, Jean-Pierre (2001). "CARD15 mutations in Blau syndrome". Nature Genetics. 29 (1): 19–20. doi:10.1038/ng720. ISSN 1061-4036.
- ↑ Ogura, Yasunori; Inohara, Naohiro; Benito, Adalberto; Chen, Felicia F.; Yamaoka, Shoji; Núñez, Gabriel (2001). "Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κB". Journal of Biological Chemistry. 276 (7): 4812–4818. doi:10.1074/jbc.M008072200. ISSN 0021-9258.
- ↑ Yi Yong, Cee; Mukhtyar, Chetan; Armon, Kate (2018). "65. Blau syndrome treated with sequential biologics". Rheumatology Advances in Practice. 2 (suppl_1). doi:10.1093/rap/rky034.028. ISSN 2514-1775.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Rosé, Carlos D.; Aróstegui, Juan I.; Martin, Tammy M.; Espada, Graciela; Scalzi, Lisabeth; Yagüe, Jordi; Rosenbaum, James T.; Modesto, Consuelo; Cristina Arnal, Maria; Merino, Rosa; García-Consuegra, Julia; Carballo Silva, María Antonia; Wouters, Carine H. (2009). "NOD2-Associated pediatric granulomatous arthritis, an expanding phenotype: Study of an international registry and a national cohort in spain". Arthritis & Rheumatism. 60 (6): 1797–1803. doi:10.1002/art.24533. ISSN 0004-3591.
- ↑ 7.0 7.1 Glass DA, Maender J, Metry D (December 2009). "Two pediatric cases of Blau syndrome". Dermatol. Online J. 15 (12): 5. PMID 20040255.
- ↑ Khubchandani, Raju P.; Hasija, Rachana; Touitou, Isabelle; Khemani, Chetna; Wouters, Carine H.; Rose, Carlos D. (2012). "Blau Arteritis Resembling Takayasu Disease with a Novel NOD2 Mutation". The Journal of Rheumatology. 39 (9): 1888–1892. doi:10.3899/jrheum.120156. ISSN 0315-162X.
- ↑ Imayoshi, Miyoko; Ogata, Yoshiyasu; Yamamoto, Shuichi (2018). "A Case of Sporadic Blau Syndrome with an Uncommon Clinical Course". Case Reports in Rheumatology. 2018: 1–5. doi:10.1155/2018/6292308. ISSN 2090-6889.
- ↑ Rose, C. D.; Pans, S.; Casteels, I.; Anton, J.; Bader-Meunier, B.; Brissaud, P.; Cimaz, R.; Espada, G.; Fernandez-Martin, J.; Hachulla, E.; Harjacek, M.; Khubchandani, R.; Mackensen, F.; Merino, R.; Naranjo, A.; Oliveira-Knupp, S.; Pajot, C.; Russo, R.; Thomee, C.; Vastert, S.; Wulffraat, N.; Arostegui, J. I.; Foley, K. P.; Bertin, J.; Wouters, C. H. (2014). "Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes". Rheumatology. 54 (6): 1008–1016. doi:10.1093/rheumatology/keu437. ISSN 1462-0324.
- ↑ DeSouza, Philip J.; Shah, Rajiv (2019). "Characterization of Blau syndrome panuveitis with wide-field fluorescein angiography". American Journal of Ophthalmology Case Reports. 14: 92–94. doi:10.1016/j.ajoc.2019.03.006. ISSN 2451-9936.
- ↑ Rose, Carlos D.; Martin, Tammy M.; Wouters, Carine H. (2011). "Blau syndrome revisited". Current Opinion in Rheumatology. 23 (5): 411–418. doi:10.1097/BOR.0b013e328349c430. ISSN 1040-8711.