Auto-inflammatory disorders

# Overview
Auto-inflammatory disorders are characterized by spontaneous inflammation, due to the over activation of innate immunity, which occur without any predisposing infections or autoimmunity disorders. These disorders can be broadly classified into type types; hereditary and acquired. Auto-inflammatory disorders which are related to primary immunodeficiency diseases belong to the hereditary type. Although immunodeficiency and auto-inflammation are separate entities, situations can occur when both inflammation and infections coexist. Hence, it is important to rule out infections when diagnosing auto-inflammatory disorders in immunodeficiency.

# Classification

# Familial Mediterranean Fever
- Autosomal recessive (AR) transmission.
- It is caused by mutation in the pyrin gene (MEFV) on chromosome 16.
- Patients present with recurrent fever and attacks of peritonitis.
- Attacks are self-limiting, and require analgesia and non-steroidal anti-inflammatory drugs (such as diclofenac)
- Colchicine has also proved useful in reducing painful attacks.
For more information about familial mediterranean fever, click here.

# Mevalonate kinase deficiency (Hyper IgD syndrome)
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the gene encoding mevalonate kinase (MVK) on chromosome 12.
- Patients present with cervical adenopathy, headache, arthralgia and diarrhea.
- Laboratory findings include leukocytosis with high IgD levels.
For more information about mevalonate kinase deficiency, click here.

# TNF receptor-associated periodic syndrome
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the tumor necrosis factor receptor-1 gene (TNFRSF1A) on chromosome 12.
- Patients present with recurrent attacks of fever, abdominal pain, tender skin lesions, and myalgia.
- Etanercept has proven successful as treatment in a case of a young Danish child.

# Familial Cold Auto-Inflammatory Syndrome
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the NLRP3 gene on chromosome 1.
- Patients present with maculopapular rash, fever, chills and arthralgias after exposure to cold temperature.
For more information about familial cold auto-inflammatory syndrome, click here.

# Muckle-Wells Syndrome
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the NLRP3 gene on chromosome 1.
- Patients present with skin rashes, arthralgias, and fever along with sensorineural deafness and renal amyloidosis.
For more information about Muckle-Wells syndrome, click here.

# Neonatal onset multisystem inflammatory disease
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the NLRP3 gene on chromosome 1.
- Patients present with skin rashes, severe arthritis and chronic meningitis.
- Treatment with the IL1R antagonist anakinra has shown marked improvement in a number of patients.
For more information about neonatal onset multisystem inflammatory disease, click here.

# PLAID (PLCg2 associated antibody deficiency and immune dysregulation)
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the PLCG2 gene on chromosome 16.
- Patients present with recurrent blistering skin lesions, arthralgia, eye inflammation, enterocolitis, cellulitis, and recurrent sinopulmonary infections.

# NLRP1 deficiency
- Autosomal recessive (AR) transmission.
- It is caused by heterozygous or homozygous mutation in the NLRP1 gene on chromosome 17.
- Patients present with skin dyskeratosis, fever, arthritis and autoimmunity.

# A20 halpoinsufficiency
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the TNFAIP3 gene on chromosome 6.
- Patients present with mucosal ulcers, particularly in the oral and genital areas, in addition to uveitis and arthritis.

# Candle syndrome
- Autosomal recessive (AR) transmission.
- It is caused by homozygous mutation in the PSMB8 gene on chromosome 6.
- Patients present with erythematous plaques on the face and extremities, recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly and basal ganglia calcifications.

# COPA defect
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the COPA gene on chromosome 1.
- Patients present with interstitial lung disease and inflammatory arthritis.

# NLRC4-MAS (Macrophage activating syndrome)
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the NLRC4 gene on chromosome 2.
- Patients present with severe enterocolitis and episodes of severe auto-inflammation.

# Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia and hypercalprotectinemia
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the PSTPIP1 gene on chromosome 15.
- Patients present with pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne.

# Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)
- Majeed syndrome (MJDS) is caused by homozygous mutation in the LPIN2 gene on chromosome 18.
- Patients present with chronic, recurrent multifocal osteomyelitis (CRMO) and transfusion-dependant anemia.

# DIRA (Deficiency of the interleukin 1 receptor antagonist)
- Autosomal recessive (AR) transmission.
- It is caused by homozygous mutation in the IL1RN gene on chromosome 2.
- Patients present with sterile multifocal osteomyelitis, periostitis, and pustulosis.

# Cherubism
- Autosomal dominant (AD) tranmission.
- It is caused by heterozygous mutation in the SH3BP2 gene on chromosome 4.
- Patients present with bone degeneration in the mandible and maxilla and often in the anterior ends of the ribs.
For more information about cherubism, click here.

# Blau syndrome
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the NOD2/CARD15 gene on chromosome 16.
- Patients present with granulomatous arthritis, iritis, skin rash and flexion contractures of the fingers and toes.
For more information about Blau syndrome, click here.

# CAMPS (CARD14 mediated psoriasis)
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the CARD14 gene on chromosome 17.
- Patients present with psoriasis.

# DITRA (Deficiency of IL-36 receptor anatagonist)
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the IL36RN gene on chromosome 2.
- Patients present with episodes of high-grade fever, generalized rash, and disseminated pustules.

# ADAM17 deficiency
- Autosomal recessive (AR) transmission.
- It is caused by homozygous mutation in the ADAM17 gene on chromosome 2.
- Patients may develop neonatal skin lesions like perioral and anal erythema, and a generalized pustular rash that may develop into psoriasiform erythroderma. Skin infections with Staphylococcus aureus causing otitis externa  and recurrent blepharitis might also occur. Patients may also present with early-onset malabsorptive diarrhea and broken, wiry hair.

# SLC29A3 mutation
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the SLC29A3 gene (Solute carrier family 29 (nucleoside transporter), member 3) on chromosome 10.
- Patients present with hyperpigmentation, hypertrichosis, and histiocytosis lymphadenopathy.

# Otulipenia
- Autosomal recessive (AR) transmission.
- It is caused by homozygous mutation in the OTULIN gene on chromosome 5.
- Patients present with panniculitis, recurrent fevers, diarrhea, failure to thrive, and painful swollen joints. Neutrophilia and lipodystrophy are also sometimes present.

# AP1S3 deficiency
- Also known as adaptor-related protein complex 1, sigma-3 subunit deficiency.
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the AP1S3 gene on chromosome 2.
- Patients present with pustular psoriasis.

# Aicardi-Goutieres syndrome
- Aicardi-Goutieres syndrome can have different inheritance patterns:
Mutations in the ADAR, TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1 genes have an autosomal recessive (AR) pattern. Mutations in the IFIH1 gene and certain severe mutations in the TREX1 or ADAR have an autosomal dominant (AD) pattern.
- Mutations in the ADAR, TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1 genes have an autosomal recessive (AR) pattern. Mutations in the IFIH1 gene and certain severe mutations in the TREX1 or ADAR have an autosomal dominant (AD) pattern.
- Patients present with encephalopathy, cerebral atrophy, thrombocytopenia, elevated hepatic enzymes, and chronic cerebrospinal fluid lymphocytosis.
For more information about Aicardi-Goutieres syndrome, click here.

# Spondyloenchondro-dysplasia with immune dysregulation
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the ACP5 gene on chromosome 19.
- Patients present with short stature, arthralgia/arthritis, lupus nephritis, hypocomplementemia, and positive autoantibodies, including antinuclear and anti-dsDNA antibodies.
- Hemolytic anemia, thrombocytopenia  and skeletal dysplasias are also some other characteristic features of this disease.

# STING-associated vasculopathy-infantile onset
- Autosomal dominant (AD) transmission.
- It is caused by heterozygous mutation in the STING gene (TMEM173) on chromosome 5.
- It is an auto-inflammatory vasculopathy which can cause severe skin lesions resulting in ulceration and necrosis.
- Some patients also have interstitial lung disease.

# Adenosine deaminase 2 deficiency
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the CECR1 gene on chromosome 22.
- Patients present with recurrent ischemic stroke leading to neurologic dysfunction, recurrent fever, myalgias, and livedo reticularis.
- Some patients also develop hypertension, aneurysms, or ischemic necrosis of the digits.

# XL reticulate pigmentary disorder
- X-linked recessive (XLR) transmission.
- It is caused by hemizygous or heterozygous mutation in the POLA1 gene on chromosome Xp22.
- Patients may develop recurrent pneumonias, bronchiectasis, chronic diarrhea, diffuse skin hyperpigmentation with a distinctive reticulate pattern, corneal inflammation, enterocolitis, and recurrent urethral strictures. Males also have a characteristic facies (frontally upswept hair and flared eyebrows).

# USP18 deficiency
- Also known as uniquitin-specific protease 18.
- Autosomal recessive (AR) transmission.
- It is caused by homozygous or compound heterozygous mutation in the USP18 gene on chromosome 22.
- Patients may develop intracranial hemorrhage, brain malformations, liver dysfunction, thrombocytopenia, respiratory insufficiency and seizures.