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

• CANDLE/PRAAS3
• Digenic Proteasome-Associated Autoinflammatory Syndrome 3
• PRAAS3 (Proteasome-Associated Autoinflammatory Syndrome 3)

What is Proteasome-Associated Autoinflammatory Syndrome 3? (Definition/Background Information)

• Proteasome-Associated Autoinflammatory Syndrome 3 (PRAAS3) is an extremely rare autoinflammatory genetic syndrome, one of the PRAAS family of syndromes, which are numbered 1-5. Presently, only three cases of PRAAS3 are reported
• It is an inherited disorder that presents in infancy (congenital manifestation), with recurrent fevers, a nodular rash, and panniculitis resulting in fat dystrophy, muscle inflammation, enlarged lymph nodes, and generalized inflammation
• Proteasome-Associated Autoinflammatory Syndrome 3 is caused by mutations in the PSMB4 gene and/or the PSMB9 gene (that encodes a molecule necessary for the proper function of proteasome). It is inherited in an autosomal recessive manner. Thus, the risk factor for PRAAS3 includes a positive family history of the disorder
• Proteasome-Associated Autoinflammatory Syndrome 3 may be diagnosed based on a combination of clinical examination, blood tests, imaging studies, and genetic tests to measure defects in the PSMB4/PSMB9 gene
• The treatment is typically symptomatic and supportive and may include physical and speech therapy. Due to only three cases being identified so far, the prognosis of Proteasome-Associated Autoinflammatory Syndrome 3 is indeterminate

Who gets Proteasome-Associated Autoinflammatory Syndrome 3? (Age and Sex Distribution)

• Proteasome-Associated Autoinflammatory Syndrome 3 is an extremely rare disorder that has been reported in three patients, two of whom belong to a single family
• Both females and males have been affected
• 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 3? (Predisposing Factors)

The risk factors for Proteasome-Associated Autoinflammatory Syndrome 3 (PRAAS3) include:

• Having a family history of the disorder
• Inheriting two copies of the mutated PSMB4/PSMB9 gene, one from each parent, to develop the disorder
• PRAAS3 may be more frequent in consanguineous pairings (closely related to each other), where the mother and father share significant genetic similarities

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 3? (Etiology)

Proteasome-Associated Autoinflammatory Syndrome 3 (PRAAS3) is caused by mutations in the PSMB4 and/or PSMB9 gene, which encodes a molecule necessary for the function of a proteasome (protein complexes).

• These mutations lead to abnormal functioning of the proteasome, which causes recurrent generalized inflammation, panniculitis, characteristic rashes, and other autoinflammatory symptoms
• From the reported few cases, it is observed that PRAAS3 is inherited in an autosomal recessive pattern. The parents will not have any clinical manifestations and may remain unaffected
• Type 1 Interferon-induced gene patterns are seen

Currently, only three cases of PRAAS3 have been reported.

• In the first two patients reported, a mutation in the PSMB4 gene was found, inherited in an autosomal recessive pattern
• An unrelated patient was the second reported case. This patient had inherited a mutated PSMB4 gene from one unaffected parent and a mutation in the PSMB9 gene from the other unaffected parent. This is termed digenic transmission. In essence, it is inherited as an autosomal recessive pattern caused by two separate but very closely related genes

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Proteasome-Associated Autoinflammatory Syndrome 3?

The signs and symptoms of Proteasome-Associated Autoinflammatory Syndrome 3 may include:

• Recurrent episodes of fever
• Limb edema
• Purple eyelids
• Panniculitis (fat inflammation)
• Mild motor and speech delays
• Enlargement of liver and spleen (hepatosplenomegaly)
• Enlarged lymph nodes
• Lipodystrophy (atrophy or hypertrophy of fat)
• Myositis atrophy and joint contractures
• Some patients have intracranial calcifications
• Elevated inflammatory markers and elevated type 1 interferon response is observed
• Lymphopenia
• Metabolic syndrome

Variable features include joint contractures, anemia, thrombocytopenia, autoantibodies, and hypergammaglobulinemia. One patient had recurrent ear infections, sinusitis, and bronchiolitis obliterans organizing pneumonia (BOOP) of the lungs.

How is Proteasome-Associated Autoinflammatory Syndrome 3 Diagnosed?

Proteasome-Associated Autoinflammatory Syndrome 3 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, as needed
• Imaging studies, as needed
• Genetic testing for alterations in the PSMB4 and/or PSMB9 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 3?

Complications of Proteasome-Associated Autoinflammatory Syndrome 3 may include the following:

• Growth retardation and slow development
• Mobility problems from muscle atrophy and joint contractures
• Splenomegaly, which can lead to low platelets and increased risk of bleeding
• Sequelae of metabolic syndrome
• Chronic lung disease

How is Proteasome-Associated Autoinflammatory Syndrome 3 Treated?

Treatment for Proteasome-Associated Autoinflammatory Syndrome 3 may be symptomatic and supportive and may include:

• Speech therapy
• Physical therapy
• Corticosteroids and methotrexate have not been effective in treating the disorder

How can Proteasome-Associated Autoinflammatory Syndrome 3 be Prevented?

Presently, it is not possible to prevent Proteasome-Associated Autoinflammatory Syndrome 3 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 3? (Outcomes/Resolutions)

• The prognosis of Proteasome-Associated Autoinflammatory Syndrome 3 (PRAAS3) may depend on its severity and treatment response
• It is not possible to determine a prognosis for PRAAS3 based on the three reported cases

Additional and Relevant Useful Information for Proteasome-Associated Autoinflammatory Syndrome 3:

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.