CANDLE syndrome

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CANDLE syndrome
Autosomal recessive - en.svg
CANDLE syndrome is inherited via autosomal recessive manner

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is an autosomal recessive disorder that presents itself via various autoinflammatory responses throughout the body, multiple types of skin lesions, and recurrent long-term fever symptoms. [1] The current known cause for the disorder is a mutation in the PSMB8 gene or mutations in other closely related genes. [1] The syndrome was first named and classified in March 2010 after four patients were reviewed with similar symptoms. [2] There have been approximately 30 cases reported in the scientific literature as of 2015. [3]

Contents

Signs and symptoms

The symptoms of CANDLE syndrome can manifest themselves in a variety of different ways and combinations related to skin disorders, internal inflammatory responses, and fever-based conditions. The types of outwardly visible conditions involve facies not matching other known disorders, contracture of the joints, and skin lesions appearing across any part of the body. The multiple inflammatory developments include nonspecific lymphadenopathy, hepatosplenomegaly, and autoimmune hemolytic anemia. Other possible conditions are hypertriglyceridemia and lipodystrophy. [1]

Other novel mutations resulting in the syndrome have also involved the manifestation of other conditions, such as Sweet's syndrome and pericarditis. [4] Another case in 2015 showcased previously undescribed dental symptoms, such as microdontia and osteopenia of the jaw, along with a general case of diabetes mellitus. [3]

Causes

The most common known cause of the syndrome are mutations in the Proteasome Subunit, Beta Type, 8 (PSMB8) gene that codes for proteasomes that in turn break down other proteins. This occurs specifically when a mutation causes the homozygous recessive form to emerge. The mutated gene results in proteins not being degraded and oxidative proteins building up in cellular tissues, eventually leading to apoptosis, especially in muscle and fat cells. [3]

A study conducted by Brehm et al. in November 2015 discovered additional mutations that can cause CANDLE syndrome, including PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and the proteasome maturation protein (POMP), with 8 mutations in total between them. An additional unknown mutation type in the original PSMB8 gene was also noted. [5]

Diagnosis

Treatment

Unlike other autoinflammatory disorders, patients with CANDLE do not respond to IL-1 inhibition treatment in order to stop the autoinflammatory response altogether. This suggests that the condition also involves IFN dysregulation. [5]

History

The category that CANDLE syndrome is a part of, along with related disorders, falls under the banner of proteasome-associated autoinflammatory syndromes (PRAAS). The first one to be described was by Nakajo at Tohoku University in 1939, where he collected symptoms including skin lesions, clubbing of the fingers, and various thickening of heart walls. He termed the collective symptoms Nakajo-Nishimura syndrome (NKJO). Further symptoms were added onto the overall condition from work by Nishimura, with the overall symptoms being similar to CANDLE syndrome. [3] [6] A related syndrome was described by Garg et al. in 2010 and titled Joint contractures, Muscular Atrophy, Microcytic anemia, and Panniculitis-induced Lipodystrophy (JMP) syndrome. [3] [7]

The primary differences between the syndromes is the lack of fever in JMP syndrome and the lack of seizures in NKJO syndrome, both of which are present in CANDLE syndrome. [3] Though it has been proposed by Wang et al. that the different syndromes are actually just clinical phenotypic variations of the same syndrome based around different mutations of the PSMB8 gene. [8]

Related Research Articles

Lipodystrophy syndromes are a group of genetic or acquired disorders in which the body is unable to produce and maintain healthy fat tissue. The medical condition is characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy, is used when describing the loss of fat from one area. This condition is also characterized by a lack of circulating leptin which may lead to osteosclerosis. The absence of fat tissue is associated with insulin resistance, hypertriglyceridemia, non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome.

<span class="mw-page-title-main">Cockayne syndrome</span> Medical condition

Cockayne syndrome (CS), also called Neill-Dingwall syndrome, is a rare and fatal autosomal recessive neurodegenerative disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), eye disorders and premature aging. Failure to thrive and neurological disorders are criteria for diagnosis, while photosensitivity, hearing loss, eye abnormalities, and cavities are other very common features. Problems with any or all of the internal organs are possible. It is associated with a group of disorders called leukodystrophies, which are conditions characterized by degradation of neurological white matter. There are two primary types of Cockayne syndrome: Cockayne syndrome type A (CSA), arising from mutations in the ERCC8 gene, and Cockayne syndrome type B (CSB), resulting from mutations in the ERCC6 gene.

<span class="mw-page-title-main">Hartnup disease</span> Metabolic disorder

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<span class="mw-page-title-main">Hermansky–Pudlak syndrome</span> Medical condition

Heřmanský–Pudlák syndrome is an extremely rare autosomal recessive disorder which results in oculocutaneous albinism, bleeding problems due to a platelet abnormality, and storage of an abnormal fat-protein compound. It is thought to affect around 1 in 500,000 people worldwide, with a significantly higher occurrence in Puerto Ricans, with a prevalence of 1 in 1800. Many of the clinical research studies on the disease have been conducted in Puerto Rico.

<span class="mw-page-title-main">McLeod syndrome</span> Medical condition

McLeod syndrome is an X-linked recessive genetic disorder that may affect the blood, brain, peripheral nerves, muscle, and heart. It is caused by a variety of recessively inherited mutations in the XK gene on the X chromosome. The gene is responsible for producing the Kx protein, a secondary supportive protein for the Kell antigen on the red blood cell surface.

An immunoproteasome is a type of proteasome that degrades ubiquitin-labeled proteins found in the cytoplasm in cells exposed to oxidative stress and proinflammatory stimuli. In general, proteasomes consist of a regulatory and a catalytic part. Immunoproteasomes are induced by interferon gamma and oxidative stress, which in the cell triggers the transcription of three catalytic subunits that do not occur in the classical proteasome. Another possible variation of proteasome is the thymoproteasome, which is located in the thymus and folds to present peptides to naive T cells.

<span class="mw-page-title-main">PSMB8</span> Protein found in humans

Proteasome subunit beta type-8 as known as 20S proteasome subunit beta-5i is a protein that in humans is encoded by the PSMB8 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. The constitutive subunit beta1, beta2, and beta 5 can be replaced by their inducible counterparts beta1i, 2i, and 5i when cells are under the treatment of interferon-γ. The resulting proteasome complex becomes the so-called immunoproteasome. An essential function of the modified proteasome complex, the immunoproteasome, is the processing of numerous MHC class-I restricted T cell epitopes.

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Familial partial lipodystrophy, also known as Köbberling–Dunnigan syndrome, is a rare genetic metabolic condition characterized by the loss of subcutaneous fat.

<span class="mw-page-title-main">X-linked spinal muscular atrophy type 2</span> Medical condition

X-linked spinal muscular atrophy type 2, also known as arthrogryposis multiplex congenita X-linked type 1 (AMCX1), is a rare neurological disorder involving death of motor neurons in the anterior horn of spinal cord resulting in generalised muscle wasting (atrophy). The disease is caused by a mutation in UBA1 gene and is passed in an X-linked recessive manner by carrier mothers to affected sons.

<span class="mw-page-title-main">Nakajo syndrome</span> Medical condition

Nakajo syndrome, also called nodular erythema with digital changes, is a rare autosomal recessive congenital disorder first reported in 1939 by A. Nakajo in the offspring of consanguineous parents. The syndrome can be characterized by erythema, loss of body fat in the upper part of the body, and disproportionately large eyes, ears, nose, lips, and fingers.

<span class="mw-page-title-main">Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome</span> Medical condition

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome is a rare cutaneous condition characterized by ichthyosis and keratoderma.

<span class="mw-page-title-main">Majeed syndrome</span> Medical condition

Majeed syndrome is an inherited skin disorder characterized by chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia and a neutrophilic dermatosis. It is classified as an autoinflammatory bone disorder. The condition is found in people with two defective copies of the LPIN2 gene. LPIN2 encodes lipin-2 which is involved in lipid metabolism. The pathogenesis of this mutation with the clinical manifestations has not been elucidated.

Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are. The term progeroid syndrome does not necessarily imply progeria, which is a specific type of progeroid syndrome.

<span class="mw-page-title-main">H syndrome</span> Medical condition

H syndrome, also known as Histiocytosis-lymphadenopathy plus syndrome or PHID, is a rare genetic condition caused by mutations in the SLC29A3 gene which encode the human equilibrative nucleoside transporter (hENT3) protein.

VEXAS syndrome is an adult-onset autoinflammatory disease primarily affecting males, caused by a somatic mutation of the UBA1 gene in hematopoietic progenitor cells. The name VEXAS is an acronym deriving from the core features of disease:

Autoinflammatory diseases (AIDs) are a group of rare disorders caused by dysfunction of the innate immune system. These responses are characterized by periodic or chronic systemic inflammation, usually without the involvement of adaptive immunity.

References

  1. 1 2 3 Tüfekçi Ö, Bengoa Ş, Karapinar TH, Ataseven EB, İrken G, Ören H (May 2015). "CANDLE syndrome: a recently described autoinflammatory syndrome". Journal of Pediatric Hematology/Oncology . 37 (4). Lippincott Williams & Wilkins: 296–299. doi:10.1097/MPH.0000000000000212. PMID   25036278. S2CID   37875499.
  2. ↑ Torrelo A, Patel S, Colmenero I, Gurbindo D, Lendínez F, Hernández A, López-Robledillo JC, Dadban A, Requena L, Paller AS (March 2010). "Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome". Journal of the American Academy of Dermatology . 62 (3). Elsevier: 489–495. doi:10.1016/j.jaad.2009.04.046. PMID   20159315.
  3. 1 2 3 4 5 6 Roberts T, Stephen L, Scott C, di Pasquale T, Naser-eldin A, Chetty M, Shaik S, Lewandowski L, Beighton P (December 28, 2015). "CANDLE SYNDROME: Orodfacial manifestations and dental implications". Head & Face Medicine . 11 (38). BioMed Central: 38. doi: 10.1186/s13005-015-0095-4 . PMC   4693439 . PMID   26711936.
  4. ↑ Cavalcante MP, Brunelli JB, Miranda CC, Novak GV, Malle L, Aikawa NE, Jesus AA, Silva CA (May 2016). "CANDLE syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature-a rare case with a novel mutation". European Journal of Pediatrics . 175 (5). Springer Science+Business Media: 735–740. doi:10.1007/s00431-015-2668-4. PMID   26567544. S2CID   20175274.
  5. 1 2 Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q, Montealegre G, Biancotto A, Reinhardt A, Almeida de Jesus A, Pelletier M, Tsai WL, Remmers EF, Kardava L, Hill S, Kim H, Lachmann HJ, Megarbane A, Chae JJ, Brady J, Castillo RD, Brown D, Casano AV, Gao L, Chapelle D, Huang Y, Stone D, Chen Y, Sotzny F, Lee CC, Kastner DL, Torrelo A, Zlotogorski A, Moir S, Gadina M, McCoy P, Wesley R, Rother KI, Hildebrand PW, Brogan P, Krüger E, Aksentijevich I, Goldbach-Mansky R (November 2, 2015). "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production". Journal of Clinical Investigation . 125 (11). American Society for Clinical Investigation: 4196–4211. doi:10.1172/JCI81260. PMC   4639987 . PMID   26524591.
  6. ↑ Nakajo A (1939). "Secondary hypertrophic osteoperiostosis with pernio". Japanese Journal of Dermatology and Urology . 45. Japanese Dermatological Association: 77–86.
  7. ↑ Garg A, Hernandez MD, Sousa AB, Subramanyam L, Martínez de Villarreal L, dos Santos HG, Barboza O (September 2010). "An autosomal recessive syndrome of joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy". The Journal of Clinical Endocrinology and Metabolism . 95 (9). Endocrine Society: E58-63. doi:10.1210/jc.2010-0488. PMC   2936059 . PMID   20534754.
  8. ↑ Wang H, Das L, Tan Hung Tiong J, Vasanwala RF, Arkachaisri T (November 2014). "CANDLE syndrome: an extended clinical spectrum". Rheumatology . 53 (11). Oxford University Press: 2119–2120. doi: 10.1093/rheumatology/keu298 . PMID   25065002.
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