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

• CANDLE Syndrome
• Nakajo-Nishimura Syndrome (NNS)
• Proteasome-Associated Autoinflammatory Syndrome (PRAAS)

What is Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome? (Definition/Background Information)

• Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome (or CANDLE Syndrome) is a rare genetic disorder characterized by recurrent skin rashes, inflammation of the eyes and joints, as well as lipodystrophy, and elevated body temperatures. This autoinflammatory disorder is mainly observed in young children
• The disorder is caused by a genetic mutation in the PSMB8 gene that leads to abnormal inflammatory activity in the body and is generally inherited in an autosomal recessive manner. Studies have shown that other genes can also be involved. Having a family history of Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome can increase one’s risk of developing the same
• The diagnosis is made by a pediatric specialist based on the presenting signs and symptoms, physical examination, laboratory test results, and genetic testing. A treatment for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome may include medications, biologic therapy, and physical therapy for muscle weakness and joint stiffness
• The prognosis for individuals with CANDLE Syndrome varies on a case-by-case basis and depends on its severity and treatment effectiveness. With early diagnosis and treatment, most symptoms can be managed, and long-term joint damage and other complications avoided. Currently, it is not possible to prevent the disorder

Who gets Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome? (Age and Sex Distribution)

• Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature is an extremely rare disorder that manifests at birth (congenital presentation)
• The signs and symptoms are usually observed in infants before age 1. In some rare cases, it can also be noted during adulthood
• CANDLE Syndrome is more common in females than males; however, currently, only a handful of cases are reported in the medical literature
• The ethnicity predilection is undetermined so far. Cases have been reported among Caucasians, Hispanics, Jewish, and Japanese individuals. A few cases have been noted in Bangladeshi families, and one case has been reported from the country of South Africa

What are the Risk Factors for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome? (Predisposing Factors)

The main risk factor for developing Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE) include:

• A positive family history of the disorder
• Children born to consanguineous parents may bear an increased risk of developing CANDLE Syndrome
• Genetic mutation in the PSMB8, PSMB4, PSMB9, PSMA3, or POMP genes

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 Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome? (Etiology)

Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE) Syndrome is caused by genetic mutations in the PSMB8 gene.

• This gene codes for an immunoproteasome, known as proteasome subunit beta, type 8, which is involved in the maintenance of cellular homeostasis
• Mutation(s) in the PSMB8 gene may lead to dysregulation of the interferon pathway, causing the characteristic symptoms of the disorder
• Some patients show defects in related genes such as PSMB4, PSMB9, PSMA3, and POMP genes
• The inheritance pattern of CANDLE Syndrome is autosomal recessive

Autosomal recessive mode of 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 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 Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome?

The signs and symptoms of Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE) may vary from one individual to another and can be mild or severe. These may include:

• Recurrent skin rashes: The rashes are often seen in a round pattern (annular)
• Inflammation of the eyes, with conjunctivitis, keratitis, and periorbital edema
• Inflammatory arthritis of the joints; bone pain and muscle weakness
• Lipodystrophy, which is the loss of fat tissue under the skin
• Elevated body temperature (fever)
• Fatigue
• Weight loss
• Diarrhea with disease flares
• Facial abnormalities

How is Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Diagnosed Syndrome?

Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature is diagnosed by a pediatric rheumatologist or pediatrician based on the following:

• Clinical examination and family medical history evaluation
• Assessment of the presenting signs and symptoms
• Laboratory tests, including complete blood count (CBC) test, erythrocyte sedimentation rate (ESR) test, alanine transaminase blood test, etc.
• Imaging studies
• Genetic testing

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 Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome?

The complications of Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature may include:

• Joint damage
• Clubbing of the fingers
• Microcytic anemia
• Skeletal muscle atrophy
• Growth delays (short stature)
• Failure to thrive (low height and weight)
• Chronic pain
• Enlarged liver or spleen, which can lead to a noticeably enlarged abdomen
• Inflammation of fat leading to a local absence of the fat layer between the skin and underlying structures such as muscle, bone, or internal organs
• In some cases, the skin rashes can cause scarring and be disfiguring
• Cardiomyopathy with an enlarged heart, cardiac arrhythmias, and congestive heart failure
• Abnormal heart function can lead to cardiac arrest
• Meningitis
• Increased risk of falls and injury if seizures are present
• Poor quality of life

Multiorgan failure can be a serious condition and result in fatalities.

How is Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome Treated?

There is no cure for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. The treatment options may include: 

• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Corticosteroids
• Immunosuppressants
• Biologic therapy
• Physical therapy to help with muscle weakness and joint stiffness

How can Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome be Prevented?

Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature is a genetic disorder that cannot be prevented

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations is recommended.

What is the Prognosis of Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome? (Outcomes/Resolutions)

The prognosis for individuals with Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature varies depending on the disorder's severity and the treatment's effectiveness.

• Individuals with mild conditions have a better prognosis than those with severe symptoms and complications
• With early diagnosis and treatment, most individuals are able to manage their symptoms and prevent long-term complications
• The lipodystrophy in affected individuals is progressive and cannot be reversed
• Severe inflammation of multiple organs may lead to reduced lifespan

Additional and Relevant Useful Information for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome:

The following link is a useful resource for further information on rare diseases and disorders:

https://www.dovemed.com/diseases-conditions/rare-disorders/