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Conditions

Proteasome-associated autoinflammatory syndromes

Proteasome-associated autoinflammatory syndromes (also called chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature, or CANDLE, syndrome) are a rare group of genetically heterogenous autoinflammatory conditions characterised by early onset progressive lipodystrophy, neutrophilic skin disease and systemic inflammation.

Overview

Proteasome-associated autoinflammatory syndromes (PRAAS) are also called CANDLE syndrome, which stands for chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature. The syndromes encompass a group of genetic autoinflammatory conditions caused by variants in genes coding for proteins that form the immunoproteasome, a key cellular structure required for protein degradation.

Clinical features

PRAAS presents with a classic triad of symptoms:

  1. Chronic atypical neutrophilic dermatosis:
    • persistent, sterile, annular lesions;
    • swollen eyelids; and
    • skin biopsy showing predominant neutrophil infiltrate.
  2. Lipodystrophy:
    • widespread and progressive;
    • peripheral loss of subcutaneous fat, particularly affecting the face and extremities; and
    • relative preservation or even increased fat deposition in the abdomen.
  3. Systemic inflammation:
    • early onset episodic fevers unresponsive to antipyretics;
    • failure to thrive;
    • inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) above 100 mg/L or >100 mm/hr respectively;
    • markedly elevated ferritin >1000 ng/ml;
    • anaemia; and
    • raised expression of selected interferon target genes as measured by type I interferon signature assay (check local availability).

Some cases have been associated with more atypical clinical features, including:

  • neurodevelopmental delay;
  • severe combined immunodeficiency with immune dysregulation;
  • primary pulmonary hypertension; and
  • cytopaenias.

Genomics

PRAAS are caused by biallelic, loss-of-function variants in genes encoding subunits of the immunoproteasome. The majority of cases are caused by pathogenic variants in PSMB8, which encodes β5i, the major catalytic subunit. The other confirmed cause is biallelic pathogenic variants in PSMB4, which present with a similar clinical phenotype. Single case reports have also been described in patients with pathogenic variants in PSMB9, PSMB10, PSMA3 and POMP.

In patients with PRAAS, pathogenic genetic variants impact on the function of an immunoproteasome subunit to derail normal protein degradation and cause accumulation of misfolded proteins. This causes excessive inflammasome activation, leading to release of the pro-inflammatory cytokines IL-1β and IL-18. Cytokines recruit more inflammatory cells, which cause damage in tissues – particularly those with high cell turnover, such as skin and blood cells.

PSMB8 variants account for the majority of genetic causes of CANDLE syndrome and appear to cause a more pronounced and progressive disease course. Both missense and protein-truncating variants may lead to reduced or absent function of the immunoproteasome. There is no clear genotype:phenotype correlation and heterozygous carriers do not appear to be affected.

Digenic inheritance has been described in relation to the PRAAS in PSMB8, PSMB4, PSMA3 and PSMB9 genes, which code for immunoproteasome subunits. Recently, monoallelic dominant negative variants in PSMB8 have been described in patients with symptoms of PRAAS, but further reports are required for confirmation.

Diagnosis

A diagnosis of PRAAS may be made in patients presenting with suggestive clinical features, as listed above, alongside molecular confirmation of biallelic pathogenic variants in PSMB8, PSMB4 and PSMB9. Digenic inheritance may occur, where monoallelic pathogenic variants in two separate immunoproteasome genes are sufficient to cause PRAAS.

Laboratory and imaging tests can help support the diagnosis:

  • elevated inflammatory markers (CRP, ESR, ferritin) during episodic flares;
  • raised serum amyloid A; and
  • absent signs of infection during episodic flares such as repeated sterile skin/blood cultures

For information about testing, see ‘Child with a suspected autoinflammatory condition‘.

PRAAS may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to autoinflammatory or specialist rheumatology services. Please refer to the local pathway for your region for this condition.

Inheritance and genetic counselling

Autosomal recessive inheritance is the predominant inheritance type described in PRAAS. A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate.

  • If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
    • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
    • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
    • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

Careful counselling will be required for those families in which other forms of inheritance are suspected. Dominant negative PRAAS is an autosomal dominant condition.

  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
  • Incomplete penetrance can occur (that is, not everyone who has the variant develops the disease).

In cases of digenic inheritance:

  • individuals have variants in two different proteasome genes, with each parent typically carrying a heterozygous variant in one of the genes involved; and
  • the risk of recurrence in future pregnancies depends on whether both parents are confirmed carriers for each respective gene.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

Inflammasomopathies such as PRAAS are rare, complex conditions and are best managed by a multidisciplinary autoinflammatory and/or specialist rheumatology service. Treatment is aimed at controlling inflammation and preventing complications, such as growth failure and amyloidosis.

The key treatment is IL-1 inhibitors for patients with a confirmed genetic diagnosis. Early diagnosis is required for good outcomes. Lipodystrophy is generally not reversible with treatment. Treatments include:

  • canakinumab: an anti-IL-1β monoclonal antibody;
  • anakinra: recombinant IL-1 receptor antagonist; and
  • rilonacept: an IL-1 fusion protein that binds IL-1.

Mild or intermittent inflammatory symptoms may be treated with steroid-sparing agents, such as non-steroidal anti-inflammatory agents or corticosteroids.

PRAAS may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 08/12/2025
  • Next review due: 08/12/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay