Proteasome-associated autoinflammatory syndrome 2 M35.-

Proteasome-associated autoinflammatory syndrome 2 is an autosomal dominant disorder caused by a heterozygous mutation in the POMP gene on chromosome 13q12.

See also CANDLE syndrome (=Proteasome-Associated Autoinflammatory Syndrome 1)

Detectable heterozygous frameshift mutations in the POMP gene. Mutations in POMP resulted in impaired proteasome assembly with decreased 20S proteasome levels, decreased proteasome subunit incorporation, and increased proteasomal precursor complexes. Overall proteasome activity is decreased.

This may lead to aggregation of ubiquitin-modified proteins and result in activation of the unfolded protein response. The consequence may be a severalfold higher expression of interferon-inducible type I genes in hematopoietic as well as in non-hematopoietic cells (compared to healthy individuals).

Early childhood.

Affected individuals develop severe inflammatory, sometimes scarring neutrophilic dermatitis, autoimmunity, and variable immunodeficiency (Poli M C et al 2018). Symptoms present in the first few weeks of life. Patients suffer from recurrent viral and bacterial infections (including Pneumocystis jiroveci), especially of the respiratory tract, and episodic fever. Disseminated mycobacterial disease has also been reported sporadically. Other features may include cyclic thrombocytopenia and seizures.

High total T cell count with low CD8+ T cells and high CD4+ T cells. Functional studies show impaired cytokine production by T cells. B cell counts are low. Patients tend to have increased production of autoantibodies, including antinuclear antibodies and those against beta-2-glycoprotein.

Skin biopsies show neutrophilic infiltration consistent with neutrophilic dermatosis. Evidence of thrombotic vasculopathy with vascular fibrinoid necrosis may also be present.

Some patients showed a good response to rituximab. Hematopoietic stem cell transplantation is a potential option (Verhoeven D et al. 2021).

Megarbane et al (2002) reported on a boy of unrelated Palestinian parents who presented shortly after birth with recurrent fevers associated with painful joints and periorbital edema, followed by weakness. He also exhibited delayed development and started walking at the age of 4 years but had normal thinking at the age of 10 years. He had subcutaneous nodules that showed leukocytoclastic vasculitis and chronic lymphadenitis on biopsy.

Other features included short stature, poor overall growth, brachydactyly, large interphalangeal joints, clinodactyly, flat feet, and dysmorphic features such as a large nasal bridge, inverted lower lip, and bifid uvula. Laboratory tests showed an elevated C-reactive protein.

The results suggest an autoinflammatory syndrome.

1. Brehm A et al (2016) Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest 125: 4196-4211
2. Megarbane A et al (2002) An unknown autoinflammatory syndrome associated with short stature and dysmorphic features in a young boy. J Rheum 29: 1084-1087.
3. Poli M C et al.(2018) Heterozygous truncating variants in POMP escape nonsense-mediated decay and cause a unique immune dysregulatory syndrome. Am J Hum Genet 102: 1126-1142.
4. Verhoeven D et al (2021) Hematopoietic stem cell transplantation in a patient with proteasome-associated autoinflammatory syndrome (PRAAS). J Allergy Clin Immunol S0091:6749(21)01244-6.