Chronic Atypical Neutrophilic Dermatosis Research Articles

PW02-024 - A case of candle syndrome treated with thalidomide

A new group of autoinflammatory diseases caused by immunoproteasome dysfunction has been recently reported. The mutation in the PSMB8 gene encoding immunoproteasome subunit β type 8 causes a number of clinical syndromes that described as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome and Nakajo-Nishimura syndrome (NNS).

P02-016 - A novel PSMB8 mutation causing candle syndrome

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a newly described autoinflammatory disease, which had been recently reported in 9 patients. It is characterized by onset during the first year of life of recurrent fevers, purpuric skin lesions, arthralgia, progressive lipodystrophy, hypochromic or normocytic anemia, delayed physical development and increased levels of acute phase reactants.

A case of proteasome-associated auto-inflammatory syndrome with compound heterozygous mutations

To the Editor: Proteasome-associated autoinflammatory syndrome (PRAAS) is caused by autosomal recessive mutations in the proteasome subunit β type 8 (PSMB8) gene. It includes Nakajo-Nishimura syndrome (NNS),1 Japanese autoinflammatory syndrome with lipodystrophy (JASL),2 joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome (JMP)3 and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE).4 Occasionally affected patients present with periodic fevers, rash, lipodystrophy, myositis, hyper-gamma-globulinemia and autoantibodies.

Autoinflammatory Diseases in Pediatrics

Autoinflammatory diseases (AIDs) are characterized by recurrent episodes of systemic and organ-specific inflammation. Many of these diseases share fever as a common presenting feature. Physicians need to consider AIDs in children with recurrent, unexplained fevers, when infectious and malignant causes have been discarded. This article discusses the differential diagnosis of recurrent fever in children, with a focus on AIDs. It discusses pharyngitis, and cervical adenitis and the monogenic autoinflammatory diseases that cause recurrent fevers including familial Mediterranean fever, hyper-immunoglobulin (Ig) D and periodic fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin associated periodic syndromes, deficiency of interleukin-36 receptor antagonist, Majeed syndrome, chronic atypical neutrophilic dermatosis with lipodystrophy and increased temperature syndrome, and deficiency of the interleukin-1 receptor antagonist. In addition, the granulomatous disorders, pyogenic sterile arthritis, pyoderma gangrenosum, and acne and Blau syndrome, will be discussed.

SP0155 New genes in autoinflammation ... provide new insights into disease pathogenesis beyond IL-1

The rapid discovery of the molecular basis of a growing number of autoinflammatory diseases presenting early in childhood with fever and systemic and sterile organ inflammation, is providing us with...

Abnormal neutrophils present in peripheral blood of Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE) syndrome patients. (P4173)

Abstract CANDLE syndrome (CS) is an autoinflammatory disease caused by autosomal recessive mutations in PSMB8. CANDLE involves dysregulation of the IFN signaling pathway and skin infiltrates of immature neutrophils and other cells. We investigated circulating neutrophils from patients with CS for changes in activation or homing markers and quantified the circulating low density granulocytes.. Compared with healthy donors (HD), or matched, paired unaffected parents (PP) carrying one copy of the mutated gene CS patients had increased proportions of immature CD10- neutrophils (7% in CS vs 2.6% in PP and vs 2.4% in HD). In addition, in CS, the reduced proportion of CD10+ mature neutrophils presented an activated phenotype based on expression of CD64 (8.6% vs 4.5% in PP vs 0.9% in HD). We illustrated changes in the maturation activation pattern of neutrophil by calculating the CD10+/CD10- ratio, and showed reduced ratio in CS patients, ratio=13.3 vs 40.1 in PP vs 44.4 in HD. We observed a reduction of CD62L and CD11b/CD18 expression on mature, and increased expression on the immature population. We observed higher circulating LDGs in PBMC fraction of CS (2%) compared to PP (1.1%) or HD (0.7%). The abnormal phenotype of circulating neutrophils, could explain the migration of immature neutrophils to inflammatory skin tissues; however, the overlap of this population with the increased circulating LDG population and their capacity to generate functional responses, remains still unclear.

Neonatal Sweet Syndrome: A Potential Marker of Serious Systemic Illness

Sweet syndrome is an inflammatory disease characterized by fever and painful erythematous plaques with a dermal neutrophilic infiltrate. It is most common in adults, where it is often parainflammatory or paraneoplastic, but is rare in children. We describe 3 cases of neonatal Sweet syndrome, including 1 patient who had myelodysplastic syndrome and immunodeficiency, the first report of a premalignancy underlying infantile Sweet syndrome. We reviewed the literature on patients presenting with neutrophilic dermatosis in the first 6 months of life. Of 20 cases, 6 had a probable viral etiology, 4 primary immunodeficiencies, 3 neonatal lupus syndrome, 1 gastrointestinal involvement, 1 HIV, and 5 probable genetic cases. Three of these had chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome, caused by mutations in the PSMB8 gene. Most children who presented within the first 6 weeks of life had either a serious underlying condition, such as primary immunodeficiency, or a genetic Sweet syndrome, with 2 fatalities among this latter group. The outcome of postinfective cases was good. Extracutaneous involvement was unusual, whereas postinflammatory scarring and cutis laxa occurred in a minority of patients. In conclusion, Sweet syndrome in the neonatal period often heralds a serious underlying disorder and requires thorough investigation.

Uncommon disorders in the spotlight

Uncommon disorders in the spotlight

Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome) is an autoinflammatory syndrome recently described in children. We undertook this study to investigate the clinical phenotype, genetic cause, and immune dysregulation in 9 CANDLE syndrome patients. Genomic DNA from all patients was screened for mutations in PSMB8 (proteasome subunit β type 8). Cytokine levels were measured in sera from 3 patients. Skin biopsy samples were evaluated by immunohistochemistry, and blood microarray profile and STAT-1 phosphorylation were assessed in 4 patients and 3 patients, respectively. One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A), suggesting a protein truncation; 4 patients were homozygous and 2 were heterozygous for a previously reported missense mutation (c.224C>T); and 1 patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the 4 patients with the same mutation, only 2 shared the same haplotype, indicating a mutational hot spot. PSMB8 mutation-positive and -negative patients expressed high levels of interferon-γ (IFNγ)-inducible protein 10. Levels of monocyte chemotactic protein 1, interleukin-6 (IL-6), and IL-1 receptor antagonist were moderately elevated. Microarray profiles and monocyte STAT-1 activation suggested a unique IFN signaling signature, unlike in other autoinflammatory disorders. CANDLE syndrome is caused by mutations in PSMB8, a gene recently reported to cause "JMP" syndrome (joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced childhood-onset lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8-associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target.

Comparative cytokine analysis across a spectrum of genetically and/or clinically defined auto-inflammatory syndromes

Background/purposeAuto-inflammatory diseases constitute a group of disorders that manifest systemic inflammation in the absence of infection, auto-antibodies or auto-reactive T cells. A specific genetic mutation is identified in some of...

Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome: A Case Report

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome is a recently described chronic inflammatory syndrome consisting of widespread annular violaceous skin lesions and multisystemic inflammatory manifestations. We report a 12½-year-old boy with a young-age onset of recurrent fevers, annular violaceous plaques, alopecia areata, lipodystrophy, low weight and height, deformed fingers, wide-spaced nipples, chronic anemia, and elevated acute phase reactants. An abdominal punch biopsy demonstrated dense perivascular and interstitial infiltrates in the dermis, composed mainly of mononuclear cells. This syndrome may represent a new autosomal recessive auto-inflammatory genodermatosis. Increased awareness may lead to the discovery of more cases, and clarify its pathogenesis.