Proteasome-associated autoinflammatory syndrome (ORPHA:324977)
A rare, autosomal recessive autoinflammatory disorder characterized by early-onset erythematous popular/nodular skin eruptions, recurrent fever, possible joint contractures, lipodystrophy, erythematous inflammatory skin changes, joint and muscle involvement (joint contractures, arthralgia, muscle weakness), and hepatosplenomegaly.
Epidemiology
To date less than 50 cases have been reported in the scientific and medical literature; the distribution is worldwide.
Clinical description
The disease presents as spectrum with onset ranging from the neonatal period to childhood, with the majority of reported cases occurring in infancy. The principal manifestations are of pernio-like and/or erythematous lesions and periodic fever. Lesions can be annular, nodular or maculopapular involving the hands and feet or periorbital regions, and may be associated with seasonal variation. Variable skin manifestations include heliotrope-like rash on eyelids, nodular episcleritis, ear and nose chondritis, plantar hyperkeratosis, hyperhidrosis of hands and feet. Lipodystrophy is first noted in the face and upper limbs, giving a characteristic thin and angular facial appearance, and may become generalized to include the abdomen and lower limbs. Lipodystrophy is progressive and irreversible. Joint contractures affect mainly the hands and feet at first but can later spread to other joints and can cause pain and joint deformities. Fingers may appear long and clubbed. Arthralgia without arthritis may be noted. Hepatosplenomegaly is frequently reported and delayed physical development (low height and weight) is possible. Other less common manifestations include conjunctivitis, short stature, and attacks of aseptic meningitis, seizures, microcytic anemia.
Etiology
The disease is due to loss of function variants in the gene PSMB8 (6p21.3) encoding the beta5i subunit of immunoproteasome. In all reported Japanese patients, the disease is due to the homozygous c.602G>T (p.Gly201Val) variant. The immunoproteasome is involved in proteolysis and maintenance of cell homeostasis. If proteolysis is disrupted, this can lead to an increase in interferon (IFN) signaling and cell stress. This dysregulation of the IFN pathway is thought to be responsible for the manifestations seen in this disease. Some cases remain to be genetically determined, indicating the possibility of other disease-causing genes.
Diagnostic methods
Diagnosis is based on clinical presentation and family history and confirmed by genetic testing. In Japan, clinical diagnosis is established on presentation of five or more major clinical characteristics (autosomal recessive heritability, skin rash, periodic fever, nodular erythema, lipodystrophy ranging from localized to near generalized, muscular atrophy, elongated clubbed fingers or joint contractures, hepato-splenomegaly, or calcification in the basal ganglia). Histopathologic examination of skin biopsy reveals focal mononuclear cell infiltration with vasculopathy. Laboratory findings include constantly elevated serum C-reactive protein (CRP) levels and hyper-gamma-globulinemia. Autoantibody titers increase as the disease progresses in some but remain negative in others. Molecular genetic testing can identify disease causing variants, confirming diagnosis.
Differential diagnosis
Differential diagnoses include cryopyrin-associated periodic syndrome, mucopolysaccharidosis, familial partial lipodystrophy, systemic lupus erythematosus, lupus erythematosus panniculitis, dermatomyositis, Sjögren syndrome, inclusion body myositis, Aicardi-Goutières syndrome, and Weber-Christian disease.
Genetic counseling
The pattern of inheritance is autosomal recessive and genetic counseling should be offered to affected families. Where both parents are unaffected carriers, there is a 25% risk of transmission to offspring at each pregnancy.
Management and treatment
There is no effective therapeutic regimen. Fever and skin lesions respond well to systemic steroid administration but usually reoccur after tapering. Biologics (notably tocilizumab and baricitinib) have been used to varying effect; however, randomized controlled trials are lacking. These treatments are all ineffective in halting lipodystrophy progression.
Prognosis
Life expectancy can be compromised, with death often the result of multi-organ inflammation. Quality of life is largely affected as patients suffer from reduced activity, fever, pain and repeated episodes of severe inflammation.

                            Last update: 
                            November 2020


                            - Expert reviewer(s): 
                            Dr Abhimanyu GARG