What are the other Names for this Condition? (Also known as/Synonyms)

• POMP-Associated Autoinflammation and Dysregulation Disease
• PRAAS2 (Proteasome-Associated Autoinflammatory Syndrome 2)
• Proteasome-Related Autoinflammatory Syndrome 2 (PRAS2)

What is Proteasome-Associated Autoinflammatory Syndrome 2? (Definition/Background Information)

• Proteasome-Associated Autoinflammatory Syndrome 2 (PRAAS2) is a rare autoinflammatory genetic syndrome, one of the PRAAS family of syndromes, which are numbered 1-5. The disorder presents in infancy (congenital manifestation) and is characterized by recurrent episodes of fever, skin rash, joint inflammation, and variable immunodeficiency
• Proteasome-Associated Autoinflammatory Syndrome 2 is caused by mutations in the POMP gene (that encodes a molecule necessary for the proper assembly of proteasome). It is believed to be inherited in an autosomal recessive manner. However, there are no known risk factors for PRAAS2; none of the few cases reported have had a second affected child
• Proteasome-Associated Autoinflammatory Syndrome 2 is typically diagnosed based on a combination of clinical examination, genetic testing, and blood tests to measure the levels of inflammatory markers
• The treatment for Proteasome-Associated Autoinflammatory Syndrome 2 is typically symptomatic and supportive and may include medications, such as non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, to reduce inflammation and prevent recurrent episodes
• The prognosis of Proteasome-Associated Autoinflammatory Syndrome 2 is generally poor. Severe cases of PRAAS2 may result in complications that include recurrent infections, joint pain, immunodeficiency, and chronic inflammation 

Who gets Proteasome-Associated Autoinflammatory Syndrome 2? (Age and Sex Distribution)

• Proteasome-Associated Autoinflammatory Syndrome 2 is a rare disorder with congenital manifestation; the onset of signs and symptoms occur in infancy
• It affects both males and females
• With the limited number of cases, no information is presently available on worldwide distribution and racial/ethnic groups at risk for the disorder

What are the Risk Factors for Proteasome-Associated Autoinflammatory Syndrome 2? (Predisposing Factors)

• The risk factors for Proteasome-Associated Autoinflammatory Syndrome 2 may include having a parent with the disorder. Although, presently, a positive family history of the disorder is yet to be reported

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Proteasome-Associated Autoinflammatory Syndrome 2? (Etiology)

Proteasome-Associated Autoinflammatory Syndrome 2 (PRAAS2) is a genetic disorder caused by mutations in the POMP gene and is reported to be inherited in an autosomal dominant pattern.

• The POMP gene, known as the PRAAS gene, encodes a molecular chaperone essential for proper proteasome (protein complexes) assembly
• Abnormal functioning of the proteasome causes recurrent inflammation, immunodeficiency, a characteristic rash, and other chronic symptoms

PRAAS2 is a very rare disorder that may be caused by a new and spontaneous mutation. Some reports list it as having an autosomal dominant inheritance pattern, but the PRAAS family of syndromes (1-5) show variable genetics.

Autosomal dominant mode of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Proteasome-Associated Autoinflammatory Syndrome 2?

The signs and symptoms of Proteasome-Associated Autoinflammatory Syndrome 2 include:

• Recurrent episodes of fever
• Growth retardation
• Facial edema
• Periorbital edema and swelling, with violaceous eyelids
• Skin rash with many neutrophils
• Joint inflammation
• Enlarged lymph nodes
• Brachydactyly and clinodactyly (finger abnormalities)
• Recurrent bacterial and viral infections

Elevated inflammatory markers, hypergammaglobulinemia, and autoantibodies seen in autoimmune diseases.

How is Proteasome-Associated Autoinflammatory Syndrome 2 Diagnosed?

Proteasome-Associated Autoinflammatory Syndrome 2 is typically diagnosed based on a combination of the following:

• Clinical examination and assessment of presenting signs and symptoms
• Evaluation of family history of the condition
• Blood tests to measure the levels of inflammatory markers
• Blood tests for mutations in the POMP gene

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Proteasome-Associated Autoinflammatory Syndrome 2?

Complications of Proteasome-Associated Autoinflammatory Syndrome 2 may include 

• Failure to thrive
• Severe neutrophilic dermatitis
• Autoimmunity, as reflected in classical autoimmune antibodies
• Variable immunodeficiency, with severe and frequent infections
• Chronic inflammation

How is Proteasome-Associated Autoinflammatory Syndrome 2 Treated?

Treatment for Proteasome-Associated Autoinflammatory Syndrome 2 is typically symptomatic and supportive and may include medications to reduce inflammation and prevent recurrent episodes such as through:

• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Corticosteroids
• Antibiotics for infections
• Stem cell transplantation

How can Proteasome-Associated Autoinflammatory Syndrome 2 be Prevented?

Presently, it is not possible to prevent Proteasome-Associated Autoinflammatory Syndrome 2 as the cause is a genetic mutation. 

• Genetic counseling and testing may be recommended for individuals with a family history of the disorder and couples planning to have children
• However, early diagnosis and appropriate treatment can help manage the symptoms and prevent complications

What is the Prognosis of Proteasome-Associated Autoinflammatory Syndrome 2? (Outcomes/Resolutions)

The prognosis of Proteasome-Associated Autoinflammatory Syndrome 2 (PRAAS2) may depend on its severity and treatment response.

• It is not possible to determine a prognosis for PRAAS2 based only on a few cases
• As of 2019, only three unrelated patients have been reported. The low number of cases has not permitted a reproducible treatment protocol too

Additional and Relevant Useful Information for Proteasome-Associated Autoinflammatory Syndrome 2:

The PRAAS name Stands for PRoteasome Associated Autoinflammatory Syndrome. Currently, five different mutations have been detected, with mostly similar but somewhat varied clinical manifestations. Besides having different complex names, they are also referred to as PRAAS 1, PRAAS2, PRAAS3, PRAAS4, and PRAAS5.

The POMP gene responsible for PRAAS2 is also abnormal in another autoinflammatory disease, keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK).