| Blau syndrome | |
|---|---|
| Other names | Arthrocutaneouveal granulomatosis [1] |
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| Coarse facial features in a boy with Blau syndrome | |
| Specialty | Dermatology |
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. [2] Symptoms usually begin before the age of four, and the disease manifests as early onset cutaneous sarcoidosis, granulomatous arthritis, and uveitis.
Blau syndrome classically presents in early childhood as a triad of granulomatous dermatitis, arthritis, and uveitis. Arthritis typically affects peripheral joints mainly wrists, knees, ankles, and proximal interphalangeal (PIP) joints of the hands. Tenosynovitis is another 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. Skin rash is typically the first symptom to appear, usually in the first year of life. The most frequent appearance is that of an erythematous maculo-micropapular fine scaly rash on the trunk and extremities. Uveitis presents as an insidious granulomatous iridocyclitis with posterior uveitis in 60–80% of patients. [3]
The discovery that the gene defect in Blau syndrome involves the CARD15/NOD2 gene has sparked investigation into its function as part of the innate immune system. The innate immune system recognizes pathogen-associated molecular patterns, including bacterial polysaccharides such as muramyl dipeptide, via its pattern recognition receptors, 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. [4] [5]
The diagnosis of Blau syndrome is made by the presentation of classical clinical features and can be confirmed by genetic testing and biopsy. Laboratory and imaging studies can be supportive but are usually not diagnostic. [6]
Treatment has included anti-inflammatory drugs such as adrenal glucocorticoids, anti-metabolites, and biological agents such as anti-TNF and infliximab all with varying degrees of success.[ citation needed ]
In 1981, Malleson et al. reported a family that had autosomal dominant synovitis, camptodactyly, and iridocyclitis. [7] 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. [8]
In 1985, Edward Blau, a pediatrician in Marshfield, Wisconsin, reported a family that over four generations had granulomatous 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. [9] The condition was transmitted in an autosomal dominant fashion.[ citation needed ]
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. [10]
In 1996 Tromp et al. conducted a genome 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. 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. [9] With that information the diagnosis of Blau syndrome was not only determined by phenotype but by genotype. Early onset sarcoidosis 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.[ citation needed ]
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, fever, abdominal distension, and weight loss. Complications outside of the gastrointestinal tract may include anemia, skin rashes, arthritis, inflammation of the eye, and fatigue. The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum. Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer.
Sarcoidosis 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 affected are the eyes, liver, heart, and brain, though any organ can be affected. The signs and symptoms depend on the organ involved. Often, no, or only mild, symptoms are seen. When it affects the lungs, wheezing, coughing, shortness of breath, or chest pain may occur. Some may have Löfgren syndrome with fever, large lymph nodes, arthritis, and a rash known as erythema nodosum.
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 includes the iris, ciliary body, and choroid. Uveitis is described anatomically, by the part of the eye affected, as anterior, intermediate or posterior, or panuveitic if all parts are involved. Anterior uveitis (iridocyclitis) is the most common, with the incidence of uveitis overall affecting approximately 1:4500, most commonly those between the ages of 20-60. Symptoms include eye pain, eye redness, floaters and blurred vision, and ophthalmic examination may show dilated ciliary blood vessels and the presence of cells in the anterior chamber. Uveitis may arise spontaneously, have a genetic component, or be associated with an autoimmune disease or infection. While the eye is a relatively protected environment, its immune mechanisms may be overcome resulting in inflammation and tissue destruction associated with T-cell activation.
Melkersson–Rosenthal syndrome is a rare neurological disorder characterized by recurring facial paralysis, swelling of the face and lips and the development of folds and furrows in the tongue. Onset is in childhood or early adolescence. After recurrent attacks, swelling may persist and increase, eventually becoming permanent. The lip may become hard, cracked, and fissured with a reddish-brown discoloration. The cause of Melkersson–Rosenthal syndrome is unknown, but there may be a genetic predisposition. It has been noted to be especially prevalent among certain ethnic groups in Bolivia. It can be symptomatic of Crohn's disease or sarcoidosis. Approximately 400 cases have been reported worldwide.
Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.
Fever of unknown origin (FUO) refers to a condition in which the patient has an elevated temperature (fever) but, despite investigations by a physician, no explanation is found.
TNF receptor associated periodic syndrome (TRAPS) is a periodic fever syndrome associated with mutations in a receptor for the molecule tumor necrosis factor (TNF) that is inheritable in an autosomal dominant manner. Individuals with TRAPS have episodic symptoms such as recurrent high fevers, rash, abdominal pain, joint/muscle aches and puffy eyes.
Neonatal-onset multisystem inflammatory disease is a rare genetic periodic fever syndrome which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Symptoms include skin rashes, severe arthritis, and chronic meningitis leading to neurologic damage. It is one of the cryopyrin-associated periodic syndromes.
Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. [1].
Orofacial granulomatosis (OFG) is a condition characterized by persistent enlargement of the soft tissues of the mouth, lips and the area around the mouth on the face, causing in most cases extreme pain. The mechanism of the enlargement is granulomatous inflammation. The underlying cause of the condition is not completely understood, and there is disagreement as to how it relates to Crohn's disease and sarcoidosis.
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also known as caspase recruitment domain-containing protein 15 (CARD15) or inflammatory bowel disease protein 1 (IBD1), is a protein that in humans is encoded by the NOD2 gene located on chromosome 16. NOD2 plays an important role in the immune system. It recognizes bacterial molecules (peptidoglycans) and stimulates an immune reaction.
Anti-Saccharomyces cerevisiae antibodies (ASCAs) are antibodies against antigens presented by the cell wall of the yeast Saccharomyces cerevisiae. These antibodies are directed against oligomannose sequences α-1,3 Man n. ASCAs and perinuclear antineutrophil cytoplasmic antibodies (pANCAs) are the two most useful and often discriminating biomarkers for colitis. ASCA tends to recognize Crohn's disease more frequently, whereas pANCA tend to recognize ulcerative colitis.
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare condition (1:1,000,000), in which the bones have lesions, inflammation, and pain. It is called multifocal because it can appear in different parts of the body, primarily bones, and osteomyelitis because it is very similar to that disease, although CRMO appears to be without any infection.
The nucleotide-binding oligomerization domain-like receptors, or NOD-like receptors (NLRs), are intracellular sensors of pathogen-associated molecular patterns (PAMPs) that enter the cell via phagocytosis or pores, and damage-associated molecular patterns (DAMPs) that are associated with cell stress. They are types of pattern recognition receptors (PRRs), and play key roles in the regulation of innate immune response. NLRs can cooperate with toll-like receptors (TLRs) and regulate inflammatory and apoptotic response.
PAPA syndrome is a rare genetic disorder characterised by its effects on skin and joints. The acronym PAPA stands for pyogenic arthritis, pyoderma gangrenosum and acne.
Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome, the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway, and keratoendotheliitis fugax hereditaria in which the autoinflammatory symptoms affect only the anterior segment of the eye.
Hagemoser–Weinstein–Bresnick syndrome is an autosomal dominant genetic disorder first described by Hagemoser et al. in 1989. It is characterized by optic atrophy followed shortly by loss of hearing and peripheral neuropathy. Onset of the disease occurred in early childhood, as opposed to the later onset of similar diseases. Optic atrophy occurs in the first year and the following symptoms show up before thirteen years. A possible autosomal recessive form of this disease was described in 1970 by Iwashita et al.
Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. They are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.
Familial episodic pain syndrome, also known simply as FEPS, is a group of rare genetic peripheral neuropathies which are characterized by recurrent random episodes of intense pain which occur most often in the upper or lower parts of the body occurring in several members of the same family. They are often triggered by cold temperatures, physical exercise, fatigue, etc. It may or may not get better with age.
This article incorporates textfrom this source, which is available under the CC BY 4.0 license. PMC 4136643. doi : 10.1186/1546-0096-12-33 
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