Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature
Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE) is a rare autoinflammatory disease that belongs to the proteasome associated autoinflammatory syndromes. Patients with this disease suffer from recurrent episodes with fever, swollen purplish eyelids, skin lesions for several days/weeks leaving bruise-like lesions, muscle atrophy, progressive lipodystrophy, arthralgia and joint contractures.
Disease onset is in the first two weeks to six months after birth. During childhood, symptoms consist of recurrent fever and attacks of red ring-shaped skin plaques, that can last for several days to a few weeks and that leave purplish lesions. Characteristic symptoms in the face are swollen eyelids with a purple colour and swollen lips.
Lipodystrophy (decrease in fatty tissue)) often appears later in childhood and is present in all patients (especially in the face and upper extremities) and is often associated with decreased growth.
Arthralgia (joint pain) without arthritis (joint inflammation) is noted in most patients and severe joint contractures (restriction of movement in the joints) develop over time. Other, less common symptoms include conjunctivitis, nodular episcleritis, inflammation of the deep tissues of ear and nose, and attacks of aseptic meningitis (non-infectious meningitis). Lipodystrophy is progressive (gets progressively worse) and is irreversible.
CANDLE is a rare disease. Currently, about 60 cases are known in the literature, but it is likely that there are other, un-diagnosed cases. When a child is born with a mutated gene (error in the DNA) that causes CANDLE (PSMB8 gene mutation), he or she will develop this disease. Because of this mutation, the proteasomes do not work as well. Normally, these proteasomes recycle the waste products of cells. When this gene does not work properly, there is a build-up of these protein waste products in the cells of the body. This also causes an induction of interferon genes, which subsequently appears to cause an inflammatory response.
It is inherited as an autosomal recessive disease (which means that it is not linked to gender and that neither parent needs to show symptoms of the disease). This type of transmission means that to develop CANDLE, an individual must have inherited two mutated genes, one from the mother and the other from the father. Hence, both parents are usually carriers of the gene, but not patients (a carrier has only one mutated copy but not the disease). Parents who have a child with CANDLE have a 25% risk that a second child will have CANDLE as well. Antenatal diagnosis is possible.
How is the diagnosis made?
First, there has to be a suspicion of CANDLE based on the child’s symptoms. CANDLE can only be proven by genetic analysis. The diagnosis of CANDLE is confirmed if the patient carries two mutations, one from each parent.
As yet, there is no effective treatment for CANDLE syndrome. High doses of steroids (1-2 mg/kg/day) have been shown to improve some symptoms, including skin eruptions, fever and joint pain, but these manifestations often return. Tumor necrosis factor alpha (TNF-alpha) inhibitors provide temporary improvement in some patients, but cause worsening of the disease in others. The immunosuppressive drug tocilizumab, has shown minimal efficacy. Experimental studies with the use of JAK-kinase inhibitors are ongoing.
CANDLE is a life-long disease. It is not possible to cure it completely because it is a hereditary disease. All children with this disorder are seriously ill, but the symptoms and severity are not the same in all children. Even within one family, not all children with this disorder suffer from the disease to the same degree. The quality of life is affected, as patients suffer from decreased activity, fever, pain, and repeated episodes of severe inflammation. Life expectancy may be reduced. If better medication is found, it may be possible to better control the disease in the future.