CANDLE syndrome

Overview

CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) is a very rare autoinflammatory disorder that presents in early infancy. It is characterized by recurrent fevers, distinctive skin rashes, swollen liver and spleen, lipodystrophy (loss of fat tissue), joint inflammation, and delayed physical development. CANDLE is a type of interferonopathy, meaning it involves abnormal regulation of type I interferons, a group of proteins involved in the body’s immune response. It is a lifelong and progressive condition, requiring specialized care and immune modulation.

Causes

CANDLE syndrome is caused by mutations in the PSMB8 gene, which encodes a subunit of the immunoproteasome—a protein complex responsible for breaking down damaged or unneeded proteins within cells. Defective proteasome function leads to the accumulation of abnormal proteins and a persistent inflammatory response. This results in excessive production of type I interferons, contributing to the chronic inflammation seen in CANDLE. The condition follows an autosomal recessive inheritance pattern, meaning a child must inherit one defective gene from each parent to develop the syndrome.

Symptoms

Symptoms of CANDLE syndrome typically begin in the first months of life and may include:

• Recurrent fevers – often daily or near-daily high temperatures without infection

• Skin rashes – persistent or episodic, including red or purple plaques, nodules, and pustules, mainly on the face and limbs

• Lipodystrophy – progressive loss of fat tissue, particularly in the face and upper body

• Hepatosplenomegaly – enlargement of the liver and spleen

• Muscle weakness and joint inflammation

• Delayed growth and physical development

• Anemia and other blood abnormalities

• Facial swelling or periorbital edema

• Failure to thrive in infancy

Over time, children with CANDLE syndrome may develop chronic fatigue, reduced mobility, and systemic inflammation affecting multiple organs.

Diagnosis

Diagnosing CANDLE syndrome involves a combination of clinical evaluation, laboratory testing, and genetic analysis. Key diagnostic steps include:

• Clinical history and physical examination – looking for hallmark signs such as early-onset fevers, skin lesions, and lipodystrophy

• Blood tests – showing elevated inflammatory markers (e.g., CRP, ESR), anemia, and elevated liver enzymes

• Skin biopsy – revealing neutrophilic dermatosis (inflammation involving neutrophils in the skin)

• Immunologic testing – elevated type I interferon signature in blood

• Genetic testing – confirmation of mutations in the PSMB8 gene or other proteasome subunit genes

Given the rarity and complexity of CANDLE syndrome, diagnosis is often made at specialized centers or through research protocols.

Treatment

There is no definitive cure for CANDLE syndrome, but treatment focuses on controlling inflammation and improving quality of life. Management strategies include:

• Glucocorticoids (steroids) – often used to reduce inflammation, though long-term use has side effects

• Immunosuppressive agents – such as methotrexate or cyclosporine, though responses are variable

• Biologic therapies – drugs targeting inflammatory pathways, including:

  • JAK inhibitors (e.g., baricitinib) – block the JAK-STAT pathway involved in interferon signaling

  • Anti-IL-1 or anti-IL-6 agents – may offer benefit in selected cases

• Supportive care – includes physical therapy, nutritional support, and treatment for anemia or infections

• Monitoring and regular follow-up – with rheumatologists, dermatologists, immunologists, and other specialists

Prognosis

The prognosis for individuals with CANDLE syndrome varies depending on the severity of symptoms and response to treatment. While the condition is chronic and progressive, newer therapies, particularly JAK inhibitors, have shown promise in reducing inflammation and improving daily functioning. Without treatment, ongoing inflammation can lead to growth delays, organ damage, and significant disability. Early diagnosis, multidisciplinary care, and targeted therapy are essential for improving outcomes and preserving quality of life in affected individuals.