Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome: a report of a novel mutation and review of the literature.
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ABSTRACT:
SUBMITTER: Kluk J
PROVIDER: S-EPMC4232891 | biostudies-literature | 2014 Jan
REPOSITORIES: biostudies-literature
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Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome: a report of a novel mutation and review of the literature.
Kluk J J Rustin M M Brogan P A PA Omoyinmi E E Rowczenio D M DM Willcocks L C LC Melly L L Lachmann H J HJ
The British journal of dermatology 20140101 1
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Project description:OBJECTIVE: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. METHODS:Genomic DNA from all patients was screened for mutations in PSMB8 (proteasome subunit ? 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. RESULTS: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-? (IFN?)-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. CONCLUSION: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.
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Project description:We have successfully generated induced pluripotent stem cells (iPSC) from dermal fibroblasts and peripheral blood mononuclear cells from patients with a homozygous missense mutation in the gene encoding PSMB8. Biallelic loss of function mutations in this gene are responsible for the PSMB8 deficiency termed Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). The iPSC carrying the homozygous PSMB8 gene mutation (c.224C > T, T75M) are phenotypically normal and have the capacity to differentiate toward the three germ layers. These iPSC have great potential to study the role of PMSB8 in the regulation of immune responses and other cellular pathways.
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Project description:In this article, we describe a case of neutrophilic dermatosis of the dorsal hands (NDDH) complicated with myelodysplastic syndrome and chronic active hepatitis C infection. NDDH was first suggested by Galaria et al in 2000. After comparing features of NDDH with Sweet syndrome in terms of encompassing clinical, laboratory, and histological characteristics, it can be concluded that "distributional or localized variant" of Sweet syndrome is classified as NDDH. Early diagnosis and treatment can improve prognosis. Systemic glucocorticoids are the mainstay of treatment.
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Project description:IntroductionNecrotizing neutrophilic dermatoses can clinically resemble necrotizing fasciitis and therefore pose a diagnostic and therapeutic challenge. Given their similar presentations, misdiagnosis and inappropriate or delayed treatments are possible.Presentation of caseWe discuss the case of a woman with acute myeloid leukemia who presented with fevers, chills, cough, and a leg wound. She underwent amputation of her lower extremity after she was presumed to have necrotizing fasciitis; however, symptoms persisted. She was ultimately diagnosed with and treated for necrotizing Sweet's syndrome with notable clinical improvement.DiscussionBoth, necrotizing neutrophilic dermatoses and necrotizing fasciitis, grossly affect the skin and are associated with rapidly progressing systemic features including fevers, chills, leukocytosis, and elevated inflammatory markers. Recent literature in dermatology addresses these similarities and the appropriate approach to management; however, it is critical that medical and surgical subspecialties have an understanding of necrotizing neutrophilic dermatoses and their clinical presentations, diagnostic approaches, as well as therapeutic interventions. Familiarity with this entity can mitigate the risk of misdiagnosis, morbidity, and mortality.ConclusionWith this report, we seek to review the features that are suggestive of and aid in the diagnosis of necrotizing neutrophilic dermatoses to help prevent significant and avoidable morbidity.
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Project description:ImportancePyoderma gangrenosum and necrotizing Sweet syndrome are diagnostically challenging variants of neutrophilic dermatosis that can clinically mimic the cutaneous and systemic features of necrotizing fasciitis. Improved characterization of these rare variants is needed, as improper diagnosis may lead to inappropriate or delayed treatment and the potential for morbidity.ObjectiveTo determine the characteristics of necrotizing neutrophilic dermatosis to improve diagnostic accuracy and distinguish from infection.Design, setting, and participantsA case series of patients with necrotizing neutrophilic dermatosis treated at 3 academic hospitals (University of California San Francisco, Oregon Health and Science University, and University of Minnesota) from January 1, 2015, to December 31, 2017, was performed along with a literature review of related articles published between January 1, 1980, and December 31, 2017. Data were obtained from medical records as well as Medline and Embase databases. All patients had signs resembling necrotizing infection and had a final diagnosis of pyoderma gangrenosum with systemic features or necrotizing Sweet syndrome. Patients were excluded if a diagnosis other than neutrophilic dermatosis was made, if key clinical information was missing, and if reported in a non-English language.Main outcomes and measuresDescription of key characteristics of necrotizing neutrophilic dermatosis.ResultsOverall, 54 patients with necrotizing neutrophilic dermatosis were included, of which 40 had pyoderma gangrenosum with systemic features and 14 had necrotizing Sweet syndrome. Of the 54 patients, 29 (54%) were male and 25 (46%) were female, with a mean (SD) age of 51 (19) years. Skin lesions commonly occurred on the lower (19 [35%]) and upper (13 [24%]) extremities and developed after a surgical procedure (22 [41%]) or skin trauma (10 [19%]). Shock was reported in 14 patients (26%), and leukemoid reaction was seen in 15 patients (28%). Of the patients with necrotizing neutrophilic dermatosis, 51 (94%) were initially misdiagnosed as necrotizing fasciitis and subsequently received inappropriate treatment. Debridement was performed in 42 patients (78%), with a mean (SD) of 2 (2 [range, 1-12]) debridements per patient. Four amputations (7%) were performed. Forty-nine patients (91%) received antibiotics when necrotizing neutrophilic dermatosis was misdiagnosed as an infection, and 50 patients (93%) received systemic corticosteroids; all patients responded to immunosuppressants.Conclusions and relevanceA complex spectrum of clinical findings of pyoderma gangrenosum and Sweet syndrome with prominent systemic inflammation exists that defines a new subset of neutrophilic dermatoses, termed necrotizing neutrophilic dermatoses; recognizing the difference between this variant and severe infection may prevent unnecessary surgical procedures and prolonged disease morbidity associated with a misdiagnosis and may expedite appropriate medical management.
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Project description:Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid neoplasms defined largely by morphologic criteria. The discovery of CSF3R mutations in aCML and CNL have prompted a more comprehensive genetic profiling of these disorders. These studies have revealed aCML to be a genetically more heterogeneous disease than CNL, however, several groups have reported that SETBP1 and ASXL1 mutations occur at a high frequency and carry prognostic value in both diseases. We also report a novel finding-our study reveals a high frequency of U2AF1 mutations at codon Q157 associated with CSF3R mutant myeloid neoplasms. Collectively, these findings will refine the WHO diagnostic criteria of aCML and CNL and help us understand the genetic lesions and dysregulated signaling pathways contributing to disease development. Novel therapies that emerge from these genetic findings will need to be investigated in the setting of a clinical trial to determine the safety and efficacy of targeting various oncogenic drivers, such as JAK1/2 inhibition in CSF3R-T618I-positive aCML and CNL. In summary, recent advances in the genetic characterization of CNL and aCML are instrumental toward the development of new lines of therapy for these rare leukemias that lack an established standard of care and are historically associated with a poor prognosis.
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Project description:Despite identification of causal genes for various lipodystrophy syndromes, the molecular basis of some peculiar lipodystrophies remains obscure. In an African-American pedigree with a novel autosomal dominant, atypical familial partial lipodystrophy (FPLD), we performed linkage analysis for candidate regions and whole-exome sequencing to identify the disease-causing mutation. Affected adults reported marked loss of fat from the extremities, with excess fat in the face and neck at age 13-15 years, and developed metabolic complications later. A heterozygous g.112837956C>T mutation on chromosome 10 (c.202C>T, p.Leu68Phe) affecting a highly conserved residue in adrenoceptor α 2A (ADRA2A) was found in all affected subjects but not in unaffected relatives. ADRA2A is the main presynaptic inhibitory feedback G protein-coupled receptor regulating norepinephrine release. Activation of ADRA2A inhibits cAMP production and reduces lipolysis in adipocytes. As compared with overexpression of a wild-type ADRA2A construct in human embryonic kidney-293 cells and differentiated 3T3-L1 adipocytes, the mutant ADRA2A produced more cAMP and glycerol, which were resistant to the effects of the α2-adrenergic receptor agonist clonidine and the α2-adrenergic receptor antagonist yohimbine, suggesting loss of function. We conclude that heterozygous p.Leu68Phe ADRA2A mutation causes a rare atypical FPLD, most likely by inducing excessive lipolysis in some adipose tissue depots.
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Project description:BackgroundThe molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms.MethodsTo identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies.ResultsWe identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib.ConclusionsMutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.).
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