Blau syndrome is an

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

dominant genetic inflammatory disorder which affects the skin, eyes, and joints. It is caused by a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

in the ''NOD2'' (''CARD15'') gene. Symptoms usually begin before the age of four, and the disease manifests as early onset cutaneous

sarcoidosis Sarcoidosis (also known as ''Besnier-Boeck-Schaumann disease'') is a disease involving abnormal collections of inflammatory cells that form lumps known as granulomata. The disease usually begins in the lungs, skin, or lymph nodes. Less commonly af ...

, granulomatous arthritis, and

uveitis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and ...

Presentation

Cause

The elucidation that the gene defect in Blau syndrome involves the ''CARD15''/''NOD2'' gene has stimulated many investigators to define how this gene operates as part of the innate immune system. The innate immune system recognizes

pathogen-associated molecular patterns Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...

, including bacterial polysaccharides such as

muramyl dipeptide Muramyl dipeptide is constituent of both Gram-positive and Gram-negative bacteria composed of N-acetylmuramic acid linked by its lactic acid moiety to the N-terminus of an L-alanine D- isoglutamine dipeptide. It can be recognized by the immune s ...

, via its

pattern recognition receptors Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...

, such as NOD2, to induce signaling pathways that activate cytokine responses and protect the organism. In Blau syndrome, the genetic defect seems to lead to overactivation and poor control of the inflammatory response leading to widespread granulomatous inflammation and tissue damage.

Diagnosis

Treatment

Treatment has included the usual anti-inflammatory drugs such as adrenal

glucocorticoids Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

, anti-metabolites and also biological agents such as anti-TNF and

infliximab Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...

all with varying degrees of success.

History

In 1981, Malleson et al. reported a family that had autosomal dominant synovitis, camptodactyly, and iridocyclitis. One member died of granulomatous arteritis of the heart and aorta. In 1982, Rotenstein reported a family with granulomatous arteritis, rash, iritis, and arthritis transmitted as an autosomal dominant trait over three generations. In 1985, Edward Blau, a pediatrician in Marshfield, Wisconsin, reported a family that over four generations had

granuloma A granuloma is an aggregation of macrophages that forms in response to chronic inflammation. This occurs when the immune system attempts to isolate foreign substances that it is otherwise unable to eliminate. Such substances include infectious ...

tous inflammation of the skin, eyes and joints. The condition was transmitted as an autosomal dominant trait. In the same year Jabs et al. reported a family that over two generations had granulomatous synovitis, uveitis and cranial neuropathies. The condition was transmitted in an autosomal dominant fashion. Then in 1990 Pastores et al. reported a kindred with a phenotype very similar to what Blau described and suggested that the condition be called Blau syndrome. They also pointed out the similarities in the families noted above to Blau syndrome but also pointed out the significant differences in the phenotypes. In 1996 Tromp et al. conducted a

genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...

wide search using affected and non affected members of the original family. A marker, D16S298, gave a maximum logarithm of odds score of 3.75 and put the Blau syndrome susceptibility locus within the 16p12-q21 interval. Hugot et al. found a susceptibility locus for Crohn disease, a granulomatous inflammation of the bowel, on chromosome 16 close to the locus for BS. Based on the above information Blau suggested in 1998 that the genetic defect in Blau syndrome and Crohn Disease might be the same or similar. Finally in 2001 Miceli-Richard et al. found the defect in Blau syndrome to be in the nucleotide-binding domain of CARD15/NOD2. They commented in their article that mutations in CARD15 had also been found in

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...

. Confirmation of the defect in Blau syndrome being in the ''CARD15'' gene was made by Wang et al. in 2002 using the Blau syndrome family and others. With that information the diagnosis of Blau syndrome was not only determined by phenotype but by genotype. Early onset

is Blau syndrome without a family history, Blau syndrome has been diagnosed in patients who have not only the classic triad but granuloma in multiple organs.

References

* Wouters CH, Maes A, Foley KP, Bertin J, and Rose CD: Blau Syndrome, the prototypic auto-inflammatory granulomatous disease. ''Pediatric Rheumatology'' 2014;12:33. . . . * Blau EB : Familial Granulomatous Arthritis, Iritis, and Rash. ''The Journal of Pediatrics'' 1985; 107: 689-693. . . * Jabs DA, Houk JL, Bias WB, and Arnett FC: Familial Granulomatous Synovitis, Uveitis, and Cranial Neuropathies. ''The American Journal of Medicine'' 1985; 78: 801–804. . . * Malleson P, Schaller JG, Dega F, Cassidy SB, and Pagon RA : Familial Arthritis and Camplodactyly. ''Arthritis and Rheumatism'' 1981; 24: 1199–1204. . . * Rotenstein D, Gibbas DL, Majmudar B, and Chastain EA: Familial Granulomatous Arteritis with Polyarthritis of Juvenile Onset. ''The New England Journal of Medicine'' 1982; 306: 85–90. . . * Pastores GM, Michels VV, Stickler GB, Su WP, Nelson AM, and Bovenmyer DA: Autosomal dominant granulomatous arthritis, uveitis, skin rash, and synovial cysts. ''The Journal of Pediatrics'' 1990; 117: 403–408. . . * Tromp G, Kuivaniemi H, Raphael S, et al.: Genetic Linkage of Familial Granulomatous Inflammatory Arthritis, Skin Rash, and Uveitis to Chromosome 16. ''The American Journal of Human Genetics'' 1996; 59: 1097-1107. . . * Hugot JP, Chamaillard M, Zouali H, et al.: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. ''Nature'' 2001; 411:599-603. . . * Blau EB : Autosomal dominant granulomatous disease of childhood: The naming of things. ''The Journal of Pediatrics'' 1998; 133: 322–323. . . * Miceli-Richard C, Lesage S, Rybojad M, Prieur A-M, Manouvrier-Hanu S, Häfner R, Chamaillard M, Zouali H, Thomas G, and Hugot J-P: ''CARD15'' mutations in Blau syndrome. ''Nature Genetics'' 2001; 29: 19-20. . . * Wang X, Kuivaniemi H, Bonavita G, Mutkus L, Mau U, Blau E, Inohara N, Nunez G, Tromp G, and Williams CJ: ''CARD15'' Mutations in Familial Granulomatous Syndromes: A Study of the Original Blau Syndrome Kindred and Other Families with Large-Vessel Arteritis and Cranial Neuropathy. ''Arthritis and Rheumatism'' 2002; 46: 3041-3045. . . * Caso F, Galozzi P, Costa L, Sfriso P, Cantarini L, and Punzi L; Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease. ''RMD Open'' 2015; 1: e000097. . . .

External links

{{Medical resources , DiseasesDB = 32725 , ICD10 = , ICD9 = , ICDO = , OMIM = 186580 , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = , Orphanet = 90340
Blau Syndrome in Orpha website
Autoinflammatory syndromes Genodermatoses