Generation of iPSCs from a Patient with the M694V Mutation in the MEFV Gene Associated with Familial Mediterranean Fever and Their Differentiation into Macrophages.

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder caused by inherited mutations in the MEFV (Mediterranean FeVer) gene, located on chromosome 16 (16p13.3) and encoding the pyrin protein. Despite the existing data on MEFV mutations, the exact mechanism of their effect on the development of the pathological processes leading to the spontaneous and recurrent autoinflammatory attacks observed in FMF, remains unclear. Induced pluripotent stem cells (iPSCs) are considered an important tool to study the molecular genetic mechanisms of various diseases due to their ability to differentiate into any cell type, including macrophages, which contribute to the development of FMF. In this study, we developed iPSCs from an Armenian patient with FMF carrying the M694V, p.(Met694Val) (c.2080A>G, rs61752717) pathogenic mutation in exon 10 of the MEFV gene. As a result of direct differentiation, macrophages expressing CD14 and CD45 surface markers were obtained. We found that the morphology of macrophages derived from iPSCs of a patient with the MEFV mutation significantly differed from that of macrophages derived from iPSCs of a healthy donor carrying the wild-type MEFV gene.

The significance of carrying MEFV variants in symptomatic and asymptomatic individuals.

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent attacks of fever, serositis (peritonitis, pleuritis, or synovitis), and erysipelas-like erythema. Genetic variants in the MEFV gene are associated with this disease. Familial Mediterranean fever is considered an autosomal recessive disease. However, in Middle Eastern countries, a third of the patients expressing FMF manifestations, carry a single mutation only. Moreover, some cases of pure dominant inheritance linked to specific single MEFV variants have also been described. This complex inheritance of MEFV-associated inflammatory diseases poses a serious challenge when interpreting the results of genetic testing in patients having recurrent fever syndromes. In addition, in certain situations, asymptomatic individuals may be incidentally found to carry MEFV variants. These cases pose the question of their exact diagnosis and whether they should be treated. Previous studies have focused on genetic results interpretations among symptomatic patients. In the current article, we would like to elaborate on the genetic interpretation in cases of symptomatic individuals suspected to have FMF and on asymptomatic individuals carrying MEFV variants. We aim to assist physicians unfamiliar with FMF to cope with genetic results interpretation when facing symptomatic and asymptomatic individuals carrying MEFV variants and suggest a management plan accordingly.

Associations of MEFV gene variants, IL-33, and sST2 with the risk of Henoch-Schönlein purpura in children.

Objective: Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children. HSP is a multifactorial inflammatory disease, but its pathogenesis is still unclear. The pathogenicity of familial Mediterranean fever gene (MEFV) variants in HSP remains controversial. The objective of this study was to evaluate relationships between MEFV variants and susceptibility to HSP and their associations with clinical outcomes. We also investigated levels of IL-33 and soluble suppression of tumorigenicity 2 (sST2) in children with HSP and their clinical significance. Methods: We selected 100 children with HSP as the case group. The control group consisted of 50 children who visited the hospital for physical health examinations. All subjects were screened for MEFV gene exon mutations, and levels of IL-33 and sST2 were measured. Results: The frequency of MEFV variants was significantly greater in HSP patients than in healthy controls. The variant with the highest frequency was E148Q. The frequency of the C allele of the MEFV variant E148Q was 32 % in HSP patients and 18 % in controls (P-adjust = 0.04). Patients with the MEFV E148Q variant had more frequent joint involvement and recurrent purpura and higher levels of IL-33 and C-reactive protein (CRP). Levels of IL-33 and sST2 in children with HSP were significantly higher than those in the control group, and the sST2/IL-33 ratio in children with HSP was unbalanced (P-adjust <0.05). Logistic regression analysis revealed the presence of E148Q and an unbalanced sST2/IL-33 ratio to be independent risk factors for HSP. Conclusion: The results of this study suggest that the MEFV variant E148Q is associated with HSP susceptibility in Chinese children and that carriers of the variant may have more severe clinical manifestations and greater inflammatory responses. E148Q and the sST2/IL-33 ratio may play important roles in the pathogenesis of HSP.

Recurrent Bouts of Fever and Transient Hydrosalpinx Manifested in a Female Carrying MEFV G304R Gene Variant: A Case Report.

Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease characterized by recurrent bouts of fever and serositis. Mediterranean Fever (MEFV) gene mutations may cause not just FMF but various serositis including arthritis, enterocolitis, aseptic meningitis, pulmonary disease, and pericarditis. In this report, we present a 44-year-old female carrying MEFV gene variant. She was admitted to our hospital with a high fever, right back pain during inspiration, and lower-left abdominal pain. Laboratory findings showed high inflammatory response. Computed tomography (CT) indicated pleurisy of the right lobe and inflammation of the left uterine appendage. Transvaginal sonography and magnetic resonance imaging (MRI) indicated hydrosalpinx of the left oviduct. The symptoms of recurrent fever and transient serositis suggested FMF, and abdominal pain was resolved after taking colchicine. Later, it turned out that she had MEFV gene mutation (exon2 G304R heterozygous). Although she did not meet the criteria of FMF, this is the first reported MEFV variant carrier with transient hydrosalpinx. Attacks in female patients with FMF are triggered by menstruation. Moreover, FMF and associated amyloidosis may cause both male and female infertility. Although male patients with FMF may present with acute scrotum, diagnostic criteria of FMF do not include inflammation of uterine appendages. Internal medicine physicians need to cooperate with gynecologists to diagnose female patients carrying MEFV gene variants.

A Case of Atypical Familial Mediterranean Fever With Pseudopolyposis-Like Mucosal Changes in the Ileum.

A 15-year-old male patient presented with recurrent fever. Three months prior, he experienced repeated fevers of 38°C, headaches, and malaise for three days. He experienced repeated fevers over 38°C for >72 hours two weeks prior to the current visit. A computed tomography scan showed enlarged lymph nodes around the ileum, suggesting familial Mediterranean fever (FMF) or inflammatory bowel disease. Endoscopic examination revealed a deformed Bauhin valve and inflammatory changes in the ileum, making inflammatory bowel disease unlikely. Thus, FMF was suspected, and after a thorough explanation, the patient was treated with colchicine, and his symptoms improved. Genetic testing revealed a mutation in the MEFV gene P369S-R408Q, and atypical FMF was diagnosed.

Evaluation of cardiac functions in children with familial Mediterranean fever.

OBJECTIVES: Familial Mediterranean fever is an autosomal recessive autoinflammatory inherited disease. We aimed to evaluate cardiac involvement in children with familial Mediterranean fever during the attack-free period. MATERIAL AND METHODS: The prospective study included 75 familial Mediterranean fever patients during the attack-free period and 50 healthy children. Cardiac evaluation was performed using electrocardiography, 24-hour ambulatory Holter monitoring, and conventional and tissue Doppler echocardiography. Aortic stiffness indices were calculated. RESULTS: There were no differences between the groups in age, height, sex, body mass index, and arterial blood pressure parameters (p > 0.05). QT and corrected QT dispersion parameters were similar in both groups (p > 0.05). The E wave velocity and the E/A ratio of the mitral and tricuspid valves decreased, and the A wave velocity of the tricuspid and mitral valve increased in familial Mediterranean fever by the Doppler echocardiography (p < 0.05). The myocardial contraction velocities (Sd), early relaxation velocity (Ed), and Ed/late relaxation velocity (Ad) of both ventricles were decreased in familial Mediterranean fever group, whereas the Ad of both ventricles and the interventricular septum was increased in familial Mediterranean fever group. Aortic strain and distensibility were decreased, and pressure strain elastic modules (Ep), pressure strain normalised (Ep*) by diastolic pressure, and aortic stiffness ß index were increased in familial Mediterranean fever patients (p < 0.05). When time domain heart rate variability parameters were evaluated, SDNN-i, RMSSD, and PNN50 significantly decreased in familial Mediterranean fever patients (p < 0.05), whereas SDNN and SDANN were similar in both groups (p > 0.05). CONCLUSION: Our findings showed that cardiac involvement could exist in familial Mediterranean fever patients, even during nonattack periods.

Heterozygous Pyrin (MEFV) E148Q allele carriers indicate a reduced glaucoma risk for Turkish population: a prospective clinical analysis.

PURPOSE: The MEFV gene encodes pyrin, a protein linked to increased severity of symptoms in Familial Mediterranean Fever (FMF). We consider that inflammation due to MEFV variants would increase eye inflammation and damage aqueous humor regulation. The present study is the first analysis investigating a MEFV (E148Q) variant as a marker protecting from glaucoma. METHODS: In this prospective clinical analyze, we performed detailed gene sequencing focusing on 22 specific regions of the pyrin (MEFV) gene. The study involved two distinct groups: individuals diagnosed with glaucoma (n = 200) and control subjects without glaucoma (n = 100). Both groups were carefully selected to exclude individuals with symptoms or a previous diagnosis of Familial Mediterranean Fever (FMF). The diagnosis of glaucoma for each participant was rigorously established through comprehensive direct ophthalmic examinations. RESULTS: A significant odds ratio for protection against glaucoma was found in carriers of the subclinical E148Q allele (OR:2.22; 95%CI: 1.098-4.485). No significant differences were found for other variants. One mutant E148Q-allele could decrease the probability of glaucoma development by approximately 68,9%. We observed no differences in the genotype frequency between glaucoma and healthy for the other MEFV gene variants. CONCLUSION: The pyrin variant of the MEFV gene resulting in a subclinical phenotype appears to reduce the incidence of glaucoma, and heterozygous pyrin (MEFV) E148Q allele carriers confer protection against glaucoma. It is important to consider the limitations arising from the relatively small number of studies conducted on this topic.

Predicting genetic risk factors for AA amyloidosis in Algerian patients with familial Mediterranean fever.

Renal amyloid-associated (AA) amyloidosis is a harmful complication of familial Mediterranean fever (FMF). Its occurrence involves polymorphisms and mutations in the Serum Amyloid A1 (SAA1) and Mediterranean Fever (MEFV) genes, respectively. In Algeria, the association between SAA1 variants and FMF-related amyloidosis was not investigated, hence the aim of this case-control study. It included 60 healthy controls and 60 unrelated FMF patients (39 with amyloidosis, and 21 without amyloidosis). All were genotyped for the SAA1 alleles (SAA1.1, SAA1.5, and SAA1.3), and a subset of them for the - 13 C/T polymorphism by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Comparisons between genotype and allele frequencies were performed using Chi-square and Fisher tests. The SAA1.1/1.1 genotype was predominant in amyloid FMF patients, compared to non-amyloid FMF patients (p = 0.001) and controls (p < 0.0001). SAA1.1/1.5 was higher in non-amyloid patients (p = 0.0069) and in controls (p = 0.0082) than in patients with amyloidosis. Bivariate logistic regression revealed an increased risk of AA amyloidosis with three genotypes, SAA1.1/1.1 [odds ratio 7.589 (OR); 95% confidence interval (CI): 2.130-27.041] (p = 0.0018), SAA1.1/1.3 [OR 5.700; 95% CI: 1.435-22.644] (p = 0.0134), and M694I/M694I [OR 4.6; 95% CI: 1.400-15.117] (p = 0.0119). The SAA1.1/1.5 genotype [OR 0.152; 95% CI: 0.040-0.587] (p = 0.0062) was protective against amyloidosis. In all groups, the - 13 C/C genotype predominated, and was not related to renal complication [OR 0.88; 95% CI: 0.07-10.43] (p = 0.915). In conclusion, in contrast to the - 13 C/T polymorphism, the SAA1.1/1.1, SAA1.1/1.3 and M694I/M694I genotypes may increase the risk of developing renal AA amyloidosis in the Algerian population.

Old paradigms and new concepts in familial Mediterranean fever (FMF): an update 2023.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent attacks of fever and polyserositis. Its first description as a new entity was published by Siegal in 1945. Colchicine has been the treatment of choice for this disease since 1972. Significant progress has been made over the years in understanding FMF's clinical features, diagnosis, mode of inheritance, pathogenesis and therapeutic approach. However, many old paradigms related to FMF have proven inaccurate, leading to the emergence of new concepts that provide more precise insights. The term 'FMF' is no longer appropriate as the disease is found beyond the Mediterranean basin. The concept of diagnosis based only upon clinical ground proved to be wrong. The paradigm that MEFV mutations in FMF lead to loss of function of the encoded peptide pyrin turned out to be a gain of function mutation. Finally, the concept that as a genetic disease FMF should be treated for life was found to be inaccurate for the subpopulation of the heterozygote patients. Thus, the breakthroughs of identifying the gene associated with the disease (MEFV) and the deciphering of its pathogenesis revolutionized our old paradigms and replaced them with new and more precise insights.

Characteristics and course of patients with AA amyloidosis: single centre experience with 174 patients from Turkey.

OBJECTIVES: This study aimed to evaluate the clinical, laboratory and genetic characteristics and outcomes of patients with AA amyloidosis. METHODS: Patients followed up in a tertiary referral centre in Turkey with the diagnosis of inflammatory rheumatic diseases and immunohistologically proven AA amyloidosis were included in the study and retrospectively analysed. RESULTS: Among 184 patients with the diagnosis of AA amyloidosis, 174 (83 female, 91 male) were included in the analysis. The most common cause of AA amyloidosis was FMF (78.7%), and 91% of FMF-AA amyloidosis patients were carrying the p.M694V variant (74.1% homozygous). AA amyloidosis was identified earlier in patients with homozygous or compound heterozygous MEFV exon 10 variants compared with the heterozygous patients (27, 30 and 41 years, respectively). Patients with an estimated glomerular filtration rate <60 ml/min at admission had a higher frequency of progression to end-stage renal disease (P < 0.001). The overall mortality rate was 15.3% and it increased gradually in association with the amyloid burden (10% in patients with renal, 15% in renal + gastrointestinal and 43% in those with additional cardiac involvement). Renal findings responded completely to treatment in 31% of the patients, a partial response was observed in 4%, a stable course in 23.6% and progression in 38.5%. Amyloid storm was identified in nine patients and was found to be associated with increased mortality within 1 year. CONCLUSION: FMF patients still constitute the majority of AA amyloidosis patients in Turkey. The MEFV genotype and associated inflammatory load may affect the age of onset of AA amyloidosis, and earlier diagnosis and stricter follow-up and treatment may delay progression of the disease.

Single Nucleotide Polymorphisms of the MEFV Gene E148Q Are Highly Associated With Disease Phenotype in Crohn's Disease.

BACKGROUND: Single nucleotide polymorphisms (SNPs) of the MEFV gene may modify inflammatory bowel disease (IBD) activity. The prevalence of MEFV gene SNPs in IBD patients and their involvement in IBD pathophysiology remains unclear. METHODS: We analyzed 12 MEFV gene SNPs in peripheral leukocytes of Japanese IBD patients (Crohn's disease [CD]: 69 patients, ulcerative colitis: 32 patients) by polymerase chain reaction using next-generation DNA sequencing and evaluated their prevalence and association with the disease characteristics. Inflammasome activity and mature interleukin (IL)-1ß and IL-18 production were evaluated in peripheral blood mononuclear cells obtained from CD patients stimulated with lipopolysaccharides and adenosine triphosphate, and compared between those with and without the E148Q SNP. COL1A1 and HSP47 gene expression was analyzed in CCD-18Co cells costimulated with IL-1ß and other inflammatory cytokines. RESULTS: The prevalence of MEFV gene SNPs in IBD patients was similar to that in the human gene database. E148Q was the most common SNP. Compared with CD patients without E148Q, those with E148Q had a significantly greater frequency of the stricture phenotype, and their peripheral blood mononuclear cells exhibited significantly higher IL-1ß and IL-18 levels and higher caspase-1 activity. IL-1ß and IL-17A synergistically increased COL1A1 and HSP47 gene expression. CONCLUSIONS: MEFV gene SNPs, including E148Q, modify the behavior of CD. IL-1ß and IL-18 are produced through enhanced caspase-1 activity in monocytes of CD patients with E148Q. IL-1ß promotes gene expression of fibrosis-related genes by cooperating with IL-17A in myofibroblasts. Therefore, E148Q might be a disease-modifying gene associated with the fibrostenosis phenotype in CD patients.

MEFV gene single nucleotide polymorphisms, including E148Q, modify the behavior of Crohn's disease to form stenosis. Interleukin-1ß is produced through enhanced caspase-1 activity in monocytes of Crohn's disease patients with E148Q, and promotes gene expression of fibrosis-related genes by cooperating with interleukin-17A in myofibroblasts.

Colchicine-resistant sacroiliitis in a Japanese patient with familial Mediterranean fever.

The articular involvement in patients with familial Mediterranean fever (FMF) represents a clinical characteristic of acute monoarthritis with pain and hydrarthrosis, which always resolves spontaneously. Colchicine prevents painful arthritis attacks in most FMF cases. Spondyloarthritis is rarely associated with Japanese patients with FMF. Here, we report a Japanese male patient with FMF-related axial joint involvement. A 43-year-old male Japanese patient who presented with recurrent febrile episodes with hip joint and back pain was referred to our hospital. He carried heterozygous variants in exon 2 (L110P/E148Q) of the MEFV gene. FMF was suspected, and oral administration of colchicine (1 mg/day) was initiated. Colchicine treatment improved his febrile attack with hip joint pain. He was diagnosed as having FMF based on the Tel-Hashomer diagnostic criteria for FMF since he fulfilled one major criterion (repeated febrile attack accompanied by hip joint pain) and one minor criterion (improvement with colchicine treatment). Although the human leucocyte antigen-B27 allele was not detected, sacroiliitis-related symptoms progressed despite the ongoing colchicine treatment. Salazosulphapyridine and methotrexate were administered in addition to colchicine; however, these treatments were not effective. Canakinumab treatment successfully resolved this unique aspect of sacroiliitis, and the patient was finally diagnosed with FMF-associated axial joint involvement.

French protocol for the diagnosis and management of familial Mediterranean fever.

Familial Mediterranean fever is the most common monogenic auto-inflammatory disease in the world. It mainly affects people originating from the Mediterranean region. The mutated gene is MEFV, which codes for pyrin. Transmission is autosomal recessive. Patients present with recurrent attacks of fever since childhood associated with abdominal and/or thoracic pain lasting an average of 2-3days and a biological inflammatory syndrome. Other symptoms include arthralgia or arthritis in large joints such as the knees and ankles, myalgia in the lower limbs and pseudo-erysipelas in the ankles. The most serious complication is inflammatory amyloidosis, which can lead to kidney failure. Treatment is based on colchicine, which helps to prevent flares and the onset of renal amyloidosis. This paper proposes national guidelines for the diagnosis, management and follow-up of familial Mediterranean fever in France, where we estimate there are between 5000 and 10,000 patients with the disease at all stages of life. The diagnosis is suspected on the basis of clinical and anamnestic factors and confirmed by genetic analysis. These guidelines also suggest a "treat-to-target" approach to disease management, particularly in case of suspected colchicine resistance - a very rare situation that should remain a diagnosis of elimination, especially after colchicine compliance has been verified. Two special situations are also addressed in these guidelines: kidney failure and pregnancy.

Effectiveness of Colchicine or Canakinumab in Japanese Patients with Familial Mediterranean Fever: A Single-Center Study.

Background: To investigate the clinical features of Japanese patients with Familial Mediterranean Fever (FMF), we evaluated the frequency of attacks, treatment responses, and adverse effects in 27 patients with FMF treated with colchicine or canakinumab in a real-world clinical setting. Methods: We retrospectively reviewed 27 Japanese patients with FMF treated at our institute between April 2012 and June 2023. All patients were diagnosed with FMF according to the Tel-Hashomer criteria. We performed genetic analyses of the MEFV gene using targeted next-generation sequencing. The clinical response was monitored through the number of attacks, and inflammatory markers were monitored through the C-reactive protein (CRP), and serum amyloid A (SAA) concentrations. Colchicine resistance was defined as the presence of at least one attack/month despite administration of the maximum tolerated dose of colchicine for at least 6 months, and C-reactive protein and serum amyloid A levels above the normal range between attacks. Results: A total of 27 patients diagnosed with FMF were enrolled in this study and the median follow-up period was 36.4 months. The median attack frequency was 1.0 (interquartile range: 0.33-1.0) every 3 months before treatment initiation. All the patients (n = 27) were treated with colchicine. Among the 27 patients, 20 (71.8%) showed a clinical response and 7 (25.9%) showed an incomplete response with sufficient doses of colchicine (n = 5) and non-sufficient doses (n = 2). Two patients on non-sufficient doses were unable to increase colchicine to the maximum dose due to diarrhea and liver dysfunction. All seven patients achieved a reduction in attack frequency after the initiation of canakinumab. No serious adverse events associated with canakinumab treatment were observed. In these seven patients with colchicine-resistant FMF (crFMF), the MEFV exon 10 variant was not detected, and the absence ratio of the MEFV variant was significantly higher compared to those without crFMF. Conclusions: Colchicine was effective in 71.8% (20/27) of Japanese patients with FMF; however, the remaining patients (7/27) had crFMF. Canakinumab effectively controlled febrile attacks in crFMF, even in the absence of pathogenic MEFV exon 10 variants.

Utility of a targeted next-generation sequencing-based genetic screening panel in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.

Objectives: This study aims to investigate a genetic panel in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and examine its performance for an accurate differential diagnosis. Patients and methods: Between January 2021 and January 2022, a total of 104 children with PFAPA syndrome (63 males, 41 females; mean age: 4.8±2.3 years; range, 1.2 to 8.9 years) were retrospectively analyzed. Next-generation sequencing test was performed using a custom QIAGEN- QIAseq™ Targeted DNA Panel which includes six genes namely ELANE, LPIN2, MEFV, MVK, NLRP3, and TNFRSF1A. Results: Of 104 patients, 38 (36.5%) had variants in the genetic panel. The most common variants were found in the MEFV gene (n=35, 33.6%), the most frequent genotype was E148Q heterozygosity (n=16). Four and two patients were eventually diagnosed with Familial Mediterranean fever (FMF) and hyperimmunoglobulin D syndrome (HIDS), since they had confirmative biallelic pathogenic in the MEFV and MVK genes, respectively. Conclusion: A genetic panel, including MEFV and MVK genes, may be useful in patients, clinically resembling PFAPA, since they may have HIDS or FMF, but lack typical features of the exact disease. Nonetheless, we believe that distinct genetic panels should be developed for different populations.

Frequency of Familial Mediterranean Fever Gene Mutation in Patients Presenting With Joint Pain and Diagnosed With Acute Rheumatic Fever.

Introduction Acute rheumatic fever (ARF) is a non-suppurative systemic inflammatory disease that manifests 1-5 weeks following a Group A beta-hemolytic streptococcal infection. On the other hand, familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized as an autosomal recessive disease, with affected individuals having pathogenic mutations in the Mediterranean fever gene (MEFV) gene located on the short arm of chromosome 16. FMF and ARF have overlapping symptoms and signs, and both disorders are common in Turkey. In ARF, the target organ is the heart, while in FMF, the target organ is the kidney; both organs can benefit from prophylactic measures. Our study aims to determine the frequency of the FMF gene mutation in patients with ARF in Turkey and detect any overlapping conditions. Method Patients who were diagnosed with a first-attack ARF between May 2015 and May 2018 were retrospectively screened. Patients who underwent MEFV gene analysis considering FMF in the differential diagnosis were included in the study. Results In this study, no statistical difference was found between the presence of MEFV gene mutations, carditis, high anti-streptolysin-O antibody (ASO) levels, and the groups with monoarthritis, polyarthritis, and polyarthralgia (p >0.05). Conclusions In conclusion, patients with ARF should be evaluated for FMF to avoid irreversible complications.

A case with febrile attacks and vasculopathy associated with ADA2 and MEFV pathogenic variants.

Deficiency of adenosine deaminase 2 (DADA2), caused by recessive mutations in the adenosine deaminase 2 (ADA2) gene, results in cutaneous or systemic vasculitis with variable clinical manifestations. There is only one other case in literature carrying both ADA2 and MEFV gene pathogenic variants. Here we report the second case that carries both ADA2 and MEFV pathogenic variants, presenting with characteristic phenotypes of both familial Mediterranean fever (FMF) and DADA2. A male patient, currently 29 years old, was initially diagnosed with FMF and developed livedo reticularis and nodular dermal lesions compatible with cutaneous polyarteritis nodosa (PAN) a year after diagnosis. His family history revealed a brother 2 years older than himself who was diagnosed with PAN and died at age 22 because of gut perforation secondary to acute mesenteric ischaemia. ADA2 gene mutation analysis on chromosome 22q11.1 was positive, and the patient responded to colchicine and infliximab.