Candle syndrome E88.1

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 26.12.2023

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CANDLE Syndromes; Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature; Japanese autoinflammatory syndrome with lipodystrophy; JASL; JMP syndrome; Nakajo-Nishimura Syndrome

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In Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, as both Nakajo (1939) and Nishimura et al. (1950) contributed to the original description of the phenotype.

Nakajo-Nishimura syndrome is a hereditary disorder affecting many parts of the body and has been described only in the Japanese population.

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CANDLE syndrome (CANDLE is the acronym for "chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature") is a very rare autoinflammatory syndrome inherited in an autosomal recessive manner, which manifests in early childhood with anular erythematous skin lesions, panniculitis-induced lipodystrophy, arthritis, joint contractures, and recurrent fevers (Torrelo A et al. 2010). Some patients develop calcifications of the basal ganglia or antinuclear antibodies (see case reports below).

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CANDLE is a very rare disease. To date, <100 cases have been described in the literature.

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CANDLE is caused by homozygous mutations in the PSMB8 (proteasome subunit beta 8) gene (177046) on chromosome 6p21. PSMB8 encodes a subunit of the proteasome and is involved in the processing of MHC class I epitopes in antigen-presenting cells.

Mutations in the encoded protein lead to variable defects in the catalytic activity of the proteasome-immunoproteasome (Brehm A et al. 2015; Liu Y et al. 2012). The end result is a persistently elevated production of type 1 interferons, which can be significantly increased by trivial triggers such as the common cold, stress or viral infections.

Digenic forms of PRAAS1 can be caused by a heterozygous mutation in the PSMB8 gene and a heterozygous mutation in either the PSMA3 gene (176843) on chromosome 14q23 or the PSMB4 gene (602177) on chromosome 1q21.

Summary: The results indicate that a malfunction of the immunoproteasome (see proteasome below) can lead to an autoinflammatory disease.

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Sickness onset between two weeks and six months after birth.

Clinical features
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Clinical symptoms are recurrent fever, annular erythema (with neutrophilia) which can last from several days to several weeks. Also Pernnio-like symptoms. Furthermore, persistent purple eyelid edema and edema of the lips.

Progressive peripheral lipodystrophy occurs mainly on the face and upper limbs. Facial lipodystrophy gives patients a unique and distinctive phenotype.

Lipodystrophy is irreversible and is often accompanied by growth disturbances of varying severity. Other symptoms include arthralgias, sometimes significant joint deformities, blepharitis, nodular episcleritis, chondritis of the ear and nasal cartilage and episodes of aseptic meningitis.

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In the blood, a type I interferon signature with constitutive "signal transducers and activators of transcription" (STAT1) phosphorylation can be detected.

Internal therapy
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Trials with TNF-alpha antagonists have led to a temporary improvement in some patients, but in other patients they have induced relapse activities. Tocilizumab (imunosuppressive drug) showed only limited efficacy. The effects of tofacitinib and the JAK inhibitor baricitinib remain to be seen.

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CANDLE is a life-long disease with fluctuating disease activity.

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CANDLE syndrome is classified as a type 1 interferonopathy. These represent a group of rare, genetically and phenotypically heterogeneous disease patterns caused by a dysfunction of the innate immune system (Crow YJ 2011). With the exception of multifactorial SLE, these are very rare diseases. Pathogenetically, type 1 interferonopathies are based on disturbances in metabolism and immunological recognition of intracellular nucleic acids.

Case report(s)
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Kitamura et al (2011) presented three Japanese patients with CANDle-including those reported by Tanaka et al (1993). The patients presented with recurrent high fever with nodular erythema from 1 month to 3 years of age and began to develop partial lipodystrophy from 6 to 12 years of age. Lipodystrophy was particularly prominent on the face, fingers, and upper limbs. Other features included muscle weakness, deformities of the hands, and frostbite of the hands. Laboratory tests revealed an increase in serum C-reactive protein, IgG, and IgA. Autoantibodies were absent.

Arima et al (2011) reported 7 patients with this condition. Clinical features included narrow facial shape, partial lipomuscular atrophy. All suffered from Pernio-like heliotropic exanthema accompanied by periodic fever and joint contractures. All had signs of chronic inflammation with elevated ESR and hypergammaglobulinemia. Most had microcytic anemia, hepatosplenomegaly, and basal ganglia calcification. More variable features included hyperhidrosis and short stature; only 1 patient had low IQ. About half of the patients had various autoantibodies.

Garg et al (2010) reported a Portuguese man and 2 Mexican siblings with marked generalized lipodystrophy, progeria-like appearance, severe joint contractures of the elbows, hands, fingers, feet, and toes. The lipodystrophy began in childhood after nodular skin lesions appeared (biopsy: panniculitis). All patients were small in stature and had muscle wasting and weakness. Other features included dry, sclerosed skin, hepatosplenomegaly, microcytic anemia, and hypergammaglobulinemia. HDL cholesterol levels decreased. The Mexican siblings both had seizures, but neither patient was mentally retarded. Continued significantly elevated serum levels of IL6 (147620) and gamma interferon (IFNG; 147570). IL8 (146930) was elevated in one pat.

Torrelo et al. (2010) reported four patients, including two siblings, with recurrent fever in infancy, anular erythematous plaques (grnaulomatous dermatitis with neutrophilia., persistent purple eyelid swelling, reduced growth, partial lipodystrophy, hepatomegaly, and arthralgias. Laboratory tests: ESR, C-reactive protein elevated, further: hypochromic anemia, intermittently elevated liver enzymes, hypertriglyceridemia, thrombocytosis, basal ganglia calcifications. Torrelo et al (2010) proposed the acronym chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Liu et al (2012) identified a homozygous mutation in the PSMB8 gene (T75M; 177046.0001) in all pat.

Digenic mode of inheritance: Brehm et al. (2015) reported two brothers of Irish descent (family 5) with digenic inheritance. The patients carried a heterozygous nonsense mutation in the PSMB4 gene (Y222X; 602177.0001) on one allele and a missense mutation in the PSMB8 gene (K105Q; 177046.0005) on the other allele. Initial skin lesions (annular plaques, purple eyelids, hyperpigmented patches, scars) in the first 3 to 4 weeks of life with fever and anemia. Other features included poor overall growth, lymphadenopathy, hepatosplenomegaly, myositis, arthritis/arthralgias, recurrent infections, joint contractures, and lipodystrophy. Laboratory tests revealed elevated acute phase reactants, microcytic anemia and lymphopenia, basal ganglia calcifications. One patient had autoantibodies.

Brehm et al (2015) also reported two other unrelated patients (patients 2 and 3) with digenic CANDLE syndrome. Both patients had a heterozygous missense mutation in the PRMB8 gene (T75M; 177046.0001) and a heterozygous mutation in the PSMA3 gene (176843.0001 and 176843.0002, respectively). Patients experienced symptoms in the first months of life. Features were quite variable but included periorbital erythema and edema, purplish eyelids, fever, skin lesions, myositis, arthralgia, joint contractures, increased acute phase reactants, lymphadenopathy, lipodystrophy, and overall poor growth. Laboratory studies revealed thrombocytopenia, hypochromic anemia, lymphopenia, autoantibodies, lipid abnormalities, abnormal liver enzymes, elevated acute-phase reactants, and hypergammaglobulinemia.

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  1. Agarwal AK et al (2010) PSMB8 encoding the beta-5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet 87: 866-872.
  2. Arima K et al (2011) Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Nat Acad Sci 108: 14914-14919.
  3. Brehm A et al. (2015) Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. Journal of Clinical Investigation. American Society for Clinical Investigation 125: 4196-4211.
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  10. Kitamura A et al (2011) A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest 121: 4150-4160.
  11. Liu Y et al. (2012) Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum 64: 895-907.
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Last updated on: 26.12.2023