CANDLE is an acronym standing for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature (1–3). CANDLE syndrome is an autoinflammatory disease (AID) characterized by the appearance of recurrent fever in the first months of life, along with characteristic skin lesions, lipodystrophy, and manifestations of multisystem inflammation. Mutations in different genes encoding protein subunits of the proteasome–immunoproteasome system are the cause of CANDLE syndrome.

CANDLE syndrome was described in 2010 by Torrelo et al. (1). They reported on four children collected in two centers in Madrid and Chicago, two of whom were siblings, who showed striking skin lesions which on histopathology displayed an infiltration of immature, myeloid, mononuclear cells, resembling leukemia cutis. Because in many parts of the skin biopsies there was some maturation into polymorphonuclears and karyorrhexis, a type of yet undescribed “neutrophilic dermatosis” was suspected. The skin lesions had appeared very early in infancy, in attacks that occurred after common triggers (especially cold and viral infections), but some degree of skin involvement was present all the time. Furthermore, the patients had recurrent, almost daily, fevers or temperature elevations below 38.3°C, also since very early in life. The disease seemed to cause some general growth delay, and after more than 10 years of follow-up most patients looked wasted, with a striking loss of fat. With all these features, the chronic eruption with skin neutrophilic and mononuclear immature infiltration, the fevers and the lipodystrophy, an acronym was coined. The dermatological aspects were emphasized in this description, because they had been the most constant features, but it was recorded that the patients had suffered unexplained inflammatory attacks in many different organs of the body, such as the central nervous system (CNS), cartilage, joints, testes, and many others. One of the patients died of an attack of “carditis,” but autopsy was not performed.

Also, in 2010, Garg et al. (4) reported three adult patients with a disease they named JMP (Joint Contractures, Muscle atrophy, microcytic anemia, and Panniculitis-induced lipodystrophy syndrome). The authors emphasized the lipodystrophic features that were related to panniculitis, and the joint features, but did not mention on the skin manifestations of the disease. However, they anticipated that their patients would suffer a disease of the innate immune system.

A similar constellation of signs had been reported in the Japanese literature. It had been reported by Nakajo in 1939 and Nishimura in 1950, under the names “secondary hypertrophic osteoperiostosis with pernio,” a syndrome with nodular erythema, elongated and thickened fingers, and emaciation, and “hereditary lipomuscular atrophy with joint contracture, skin eruptions and hyper-γ-globulinemia” (5). An eponym for the syndrome was proposed by the Japanese authors as “Nakajo–Nishimura syndrome.” Overall, patients described started in early infancy with a pernio-like rash, periodic high fever, nodular erythema-like eruptions, and myositis. Lipoatrophy and joint contractures occurred progressively in life, mainly on the upper part of the body, leading to a very characteristic facial appearance.

After the description of CANDLE and JMP, and the appearance of new cases from Japan, a number of cases from different parts of the world were published. It was later disclosed that most patients described under these descriptions had homozygous or compound heterozygous mutations in the gene PSMB8, encoding the subunit β5i of the immunoproteasome (2, 6–8). However, some patients with CANDLE syndrome did not bear mutations in PSMB8 (2). Further genetic studies disclosed that some patients have homozygous and compound heterozygous mutations in other subunits of the proteasome–immunoproteasome, as well as digenic heterozygous mutations in two different genes encoding subunits (9). Finally, mutations in the proteasome maturation protein (POMP) gene have also been reported in a patient of Lebanese origin that had been reported by Mégarbané et al. (9, 10) in 2002 under the name “unknown autoinflammatory syndrome associated with short stature and dysmorphic features.”

Several terms have been proposed to encompass the three denominations, such as PRAAS (proteasome-associated autoinflammatory syndrome) (11) or ALDD (autoinflammation, lipodystrophy, and dermatitis) (12). However, all of them represent the same entity, and it seems that the most accepted nomenclature is CANDLE syndrome. The general appearance of consumption in the patients, like a burntout candle, emphasizes the name of the syndrome.

Overall, proteasome–immunoproteasome dysfuntion causes a continuous state of inflammation with exacerbations in CANDLE syndrome. Proteasome–immunoproteasome dysfunction leads to constitutional hypersecretion of type 1 Interferons (IFNs), which by several mechanisms will lead to accumulation of waste proteins within the cells (13). Thus, further proteasome–immunoproteasome activity is required, which cannot be achieved. Accumulation of waste proteins within the cell causes cellular stress, which in turn stimulates type 1 IFN, and finally closes the circle of inflammation. Common triggers, such as cold, physical or psychical stress, banal infections or others cause stimulation of type 1 IFN secretion, and thus provoke severe inflammatory attacks that can occur in any organ of the body.

The first gene mutations detected in patients with CANDLE syndrome were located in the gene PSMB8 (proteasome subunit, beta-type, 8) in chromosome 6p21.32, encoding for the β5i (i = inducible) subunit of the immunoproteasome (2, 6–8). Mutations in PSMB8 were responsible for CANDLE, JMP, and Nakajo–Nishimura syndromes. However, mutations in other genes, encoding other proteasome–immunoproteasome subunits or the regulatory protein POMP, were later discovered in patients with CANDLE syndrome, thus expanding the CANDLE genotype (9). All mutations were located in highly conserved sites in vertebrates and were thus predicted to be pathogenetic. It was proven that CANDLE syndrome is a disease of proteasome–immunoproteasome dysfunction, which could be inherited as a recessive homozygous, compound heterozygous or digenic trait, or less commonly in a dominant fashion (9). The following mutations have been so far identified in patients with CANDLE (9):

PSMB4 mutations. The gene PSMB4 (proteasome subunit, beta-type, 4), located in chromosome 1q21, encodes for the β7 subunit of the proteasome. It seems to be important for proteasome assembly and stabilization.

The c.-9G>A mutation originates a β7 subunit protein with lower expression than that of wild type, which is therefore less incorporated into proteasome complexes than the wild-type counterpart. It is also possible that this mutant β7 subunit also impairs propeptide cleavage of the β5i subunit. A deletion of three aminoacids in β7, p.D212-V214, affects the N terminus of an α-helix forming an intramolecular hydrogen-bonding network that stabilizes its C-terminal extension. The C-terminal extension is essential for proteasome assembly (29). Two other mutations affect the C-terminal extension: (1) the c.44insG insertion, which causes a frameshift mutation (p.P16Sfs*45) and leads to non-expression of the mutant allele; and (2) the missense p.Y222X, which causes the loss of the C-terminal extension of the β7 subunit; although β7 subunit is expressed, it fails to incorporate into the 20S or 26S proteasome complexes.

Finally, the deletion causing the p.D212_V214del mutant of β7 leads to a poor maturation of the β7 subunit. Although the mutant protein is detected in proteasome assembly intermediates, it is poorly incorporated into 20S or 26S proteasomes.

Patients with CANDLE have shown variable combinations of these mutations (9). Most frequently, patients are homozygous or compound heterozygous for PSMB8 mutations, but others are compound heterozygous for PSMB4, or are heterozygous for combinations such as PSMA3/PSMB8, PSMB9/PSMB4, or PSMB8/PSMB4. In the latter situation, a digenic inheritance is suggested causing additive proteasome defects. Patients with digenic inheritance have variable proteolytic defects. For example, a combination of PSMB8/PSMA3 causes impairment in all three proteolytic activities, somewhat similar to patients’ compound heterozygous for PSMB4 in whom proteasome assembly is severely impaired. Patients with combined PSMB9/PSMB4 mutations have reduced caspase-like activity, which is conferred by subunit β1i. Finally, patients with double PSMB8 mutations experience a severe decrease in chemotrypsin-like activity.

As is the case with other AIDs, laboratory findings are not very striking (1, 3, 32). The most common features are elevation of acute phase reactants (ESR, CRP, and thrombocytosis) and a chronic, hypochromic anemia. Liver enzymes are usually moderately elevated, but this may be caused by lipodystrophy itself; also, increased triglyceride levels can occur in relation to metabolic disturbance by lipodystrophy. Less frequently, elevated muscle enzymes (CPK and aldolase) reveal chronic muscle involvement (1). Studies for autoimmunity and autoantibodies are usually negative, but some patients show increased levels of antinuclear antibodies. Serum levels of immunoglobulins are regularly normal. Bone marrow and lymph node biopsies have been unconspicuous, revealing only reactive changes.

Other laboratory and imaging anomalies are seen during acute inflammatory attacks; these are dependent on the organs affected by inflammation.

The diagnosis of CANDLE is suspected by the early onset of fevers, skin lesions, and lipodystrophy. A skin biopsy with immunohistochemistry studies can be characteristic enough to permit an accurate diagnosis. The genetic study of the genes involved establishes a confirmation diagnosis.

Other AIDs may share some features with CANDLE syndrome, including NOMID syndrome, TRAPS, or hyper-IgD syndrome. Lipodystrophy in CANDLE syndrome is a very characteristic feature of the disease, but other causes of loss of fat must be considered, including generalized congenital lipodystrophy, partial familial lipodystrophy, leprechaunism, or acquired partial lipodystrophy of Barraquer–Simons. Aicardi–Goutières syndrome and other type 1 interferonopathies (such as SAVI syndrome, familial chilblain lupus, or C1q deficiency) may show features similar to CANDLE syndrome (28, 40, 41). Sweet syndrome in infants may present with violaceous ring lesions reminiscent of CANDLE syndrome, and histology may be misleading in some cases. Fat loss and skin lesions are clinical manifestations of a recently described autoinflammatory syndrome named otulipenia, due to loss-of-function mutations in OTULIN, encoding a deubiquitinase that cleaves Met1-linked chains (42).

CANDLE patients have a variable outcome. Some patients have had a lethal course due to acute attacks of inflammation in important organs of the body. In other patients, a long survival is possible, with variable degrees of disability (1, 3, 4).

Regular clinical follow-up is mandatory. A protocol has not been established, but attention must be paid to identify inflammatory attacks as early as possible. Regular skin, eye, and joint exams are recommended. Endocrinologist consultation is mandatory for diet and metabolic control because of lipodystrophy. Basic laboratory follow-up must include CBC (with special attention to anemia, leukocytosis with increased neutrophil count, and thrombocytosis), ESR, CRP, serum liver enzymes, muscle enzymes, and metabolic profile (including glucose, triglyceride, and cholesterol levels). Ultrasound may be helpful in detecting enlarged liver, spleen, or lymph nodes. Specific tests for organ involvement must be considered in patients with abnormal clinical examination.

So far, no individual treatment has been consistently effective in CANDLE syndrome. Oral corticosteroids and methotrexate can provide some improvement. Methotrexate can be considered the first line therapy. NSAIDs may provide partial control of fevers. Dapsone or colchicine has been ineffective. Cyclosporine, azathioprine, or intravenous immunoglobulins have achieved minimal improvements, if any. Anti-TNF drugs such as etanercept have not been helpful and have even been the cause of disease exacerbations (1). Acute attacks may need systemic corticosteroids as well as organ-specific therapy.

A compassionate use treatment protocol has been started for CANDLE syndrome with the selective JAK1/2 kinase inhibitor baricitinib. Oral baricitinib was used in patients who failed to achieve control or required high doses of corticosteroids. Eight patients treated with this drug showed clinical and analytical improvement (43), but these results still await confirmation.

Finally, physical therapy to prevent joint contractures and specific organ therapy must be provided.

CANDLE syndrome is an AID due to gene mutations leading to protesome–immunoproteasome dysfunction. CANDLE syndrome can be diagnosed very early in life because the skin signs and their histopathology are very characteristic. Genetic confirmation is necessary. Early therapy to prevent disabling manifestations is desirable, but still no agent has been truly effective. Prevention and treatment of acute inflammatory attacks will permit longer life expectancy in these patients.

There is one single author for this article. The manuscript has been completely written by AT.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.