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A novel Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to Familial Mediterranean Fever.

ABSTRACT: Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) is a recently described monogenic autoinflammatory disease. The causal p.S242R MEFV mutation disrupts a binding motif of the regulatory 14-3-3 proteins within pyrin. Here, we investigate a family with clinical features consistent with PAAND in whom the novel p.E244K MEFV mutation, located in the +2?site of the 14-3-3 binding motif in pyrin, has been found.Multiplex cytokine analyses were performed on p.E244K patient and control serum. Peripheral blood mononuclear cells were stimulated ex vivo with lipopolysaccharide (LPS). In vitro, inflammasome complex formation was evaluated by flow cytometry of Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) specks. Interleukin-1? (IL-1?) and IL-18 production was quantified by ELISA. The ability of the p.E244K pyrin mutation to interact with 14-3-3 was assessed by immunoprecipitation.PAAND p.E244K patient serum displayed a different cytokine profile compared with patients with Familial Mediterranean Fever (FMF). In overexpression models, p.E244K pyrin was associated with decreased 14-3-3 binding and increased ASC speck formation. THP-1 monocytes expressing PAAND pyrin mutations demonstrated spontaneous caspase-1-dependent IL-1? and IL-18 secretion, as well as cell death, which were significantly greater than those of wild-type and the FMF-associated mutation p.M694V.In PAAND, disruption of the +2?position of a 14-3-3 binding motif in pyrin results in its constitutive activation, with spontaneous production of IL-1? and IL-18, associated with inflammatory cell death. The altered serum cytokine profile may explain the different clinical features exhibited by PAAND patients compared with those with FMF.

SUBMITTER: Moghaddas F

PROVIDER: S-EPMC5687562 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A novel Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to Familial Mediterranean Fever.

Moghaddas Fiona F Llamas Rafael R De Nardo Dominic D Martinez-Banaclocha Helios H Martinez-Garcia Juan J JJ Mesa-Del-Castillo Pablo P Baker Paul J PJ Gargallo Vanessa V Mensa-Vilaro Anna A Canna Scott S Wicks Ian P IP Pelegrin Pablo P Arostegui Juan I JI Masters Seth L SL

Annals of the rheumatic diseases 20170823 12

<h4>Objective</h4>Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) is a recently described monogenic autoinflammatory disease. The causal p.S242R <i>MEFV</i> mutation disrupts a binding motif of the regulatory 14-3-3 proteins within pyrin. Here, we investigate a family with clinical features consistent with PAAND in whom the novel p.E244K <i>MEFV</i> mutation, located in the +2 site of the 14-3-3 binding motif in pyrin, has been found.<h4>Methods</h4>Multiplex cytokine anal ...[more]

PMID: 28835462

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Project description:ImportancePyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) is a monogenic autoinflammatory disorder with autosomal dominant inheritance and has been associated with monoallelic p.Ser242Arg and p.Glu244Lys variations in the MEFV gene. This dermatosis shares clinical features and pathogenesis with familial Mediterranean fever, although it is a clinically distinct entity.ObjectiveTo identify the genetic basis of PAAND in a consanguineous family with 2 affected children and to prescribe an effective genotype-guided treatment.Design, setting, and participantsThis case series study examined 2 siblings who presented with clinical features of PAAND. We sought the genetic basis of this disease with trio whole exome sequencing (trio-WES). Genome-wide homozygosity mapping provided additional evidence for causality of a sequence variant identified by trio-WES.Main outcomes and measuresAssociation of a biallelic MEFV variation with a new form of autosomal recessive PAAND was documented by genetic analysis. Response to treatment with colchicine and a low-dose steroid was assessed clinically and experimentally.ResultsTwo siblings, a girl (proband; age 5 years) and a boy (age 2.5 years) of Iranian-Azeri ancestry born to first-cousin consanguineous parents presented with clinical features of PAAND-recurrent episodes of maculopapular and pustular rash, gastrointestinal involvement resembling inflammatory bowel disease, and intussusception with generalized mesenteric lymphadenitis. A trio-WES test detected a previously unreported homozygous missense variation, p.Ser242Gly, in both patients' MEFV gene. Genome-wide homozygosity mapping revealed shared regions of homozygosity in the patients' DNA, including 1 on chromosome 16 harboring MEFV. Whole transcriptome sequencing by RNA-sequencing revealed that the variant MEFV transcript, among the inflammasome-associated transcripts, was most upregulated, and the cell-cell receptor interaction and innate immune system pathways were most positively enriched. Under the guidance of MEFV genotype, treatment with colchicine (1 mg/d) and low-dose prednisolone (2.5 mg every other day) was started, and the patients responded well.Conclusions and relevanceThis case series study demonstrated successful genotype-guided treatment with colchicine and low-dose prednisolone, a low-cost therapeutic option with minimal adverse effects, in patients with a novel form of autosomal recessive PAAND. This case report examines the genetic basis of PAAND in a consanguineous family with 2 affected children and seeks to prescribe an effective genotype-guided treatment.

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.

Project description:ImportanceVEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described severe adult-onset autoinflammatory disease that is associated with myeloid lineage-restricted ubiquitin-activating enzyme 1 (UBA1) somatic variations that primarily affect the skin (Sweet syndrome), cartilage, and bone marrow. Skin symptoms have been poorly described.ObjectiveTo better describe clinical and pathological skin manifestations and their pathophysiology in VEXAS syndrome.Design, setting, and participantsThis multicenter retrospective case series study of clinical and histological features of 8 patients with VEXAS syndrome and skin involvement was conducted in France from December 2007 to March 2021, with molecular data obtained from March to April 2022. Any UBA1 variations were detected by Sanger or next-generation sequencing that was performed on bone marrow and formalin-fixed paraffin-embedded tissue sections of skin lesion biopsies.ResultsAll 8 patients were men, and the median age at symptom onset was 65.5 years (interquartile range, 54-76 years). All patients had neutrophilic dermatosis skin lesions, including tender red or violaceous papules, sometimes edematous, without fever, arthralgia, recurrence or pathergy, inflammatory edematous papules on the neck and trunk (sometimes umbilicated), and firm erythematous purpuric or pigmented infiltrated plaques and nodules. Three patients had livedo racemosa. The infiltrates were perivascular and consisted of mature neutrophils with leukocytoclasia, which were admixed with myeloperoxidase-positive CD163-positive myeloid cells with indented nuclei and lymphoid cells in all cases. A sequencing analysis of paired bone marrow samples and skin lesion biopsies identified the same loss-of-function UBA1 variation in both samples for all patients.Conclusions and relevanceThis case series study describes the different clinical presentations of skin lesions found in VEXAS syndrome, which is characterized histologically by neutrophilic dermatosis. The findings suggested that the dermal infiltrates seen in VEXAS skin lesions are derived from the pathological myeloid clone. This suggests that using therapies that target the pathological clone may be effective in the long-term management of the disease.

Dataset Information

A novel Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to Familial Mediterranean Fever.

Publications

A novel Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to Familial Mediterranean Fever.

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