Editors’
ChoiceCASE REPORT

Nagoya J. Med. Sci. 85. 195–203, 2023
doi:10.18999/nagjms.85.1.195

Myelodysplastic syndrome with trisomy 8 presenting periodic
fever and multiple MEFV gene variants outside exon 10:
a case reportNoriyuki Takahashi1,2, Ryo Hanajiri3, Masashi Suzuki4, Chise Anan5,
Atsushi Inagaki6,7, Dai Kishida8, Shohei Ozawa2, Sho Kohri2,
Nobuhide Kamiya9, Motoki Sato2 and Juichi Sato2
Department of Education for Community-Oriented Medicine, Nagoya University Graduate School of
Medicine, Nagoya, Japan2
Department of General Medicine, Nagoya University Hospital, Nagoya, Japan3
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
4
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
5
Department of Neurology, NTT West Tokai Hospital, Nagoya, Japan
6
Department of Hematology and Oncology, Nagoya City University West Medical Center, Nagoya, Japan
7
Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences,
Nagoya, Japan
8
Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine,
Matsumoto, Japan
9
Department of General Medicine, Meitoh Hospital, Nagoya, Japan
1

ABSTRACT
Myelodysplastic syndrome is associated with the development of autoinflammatory conditions, such asrecurrent fever, polymyalgia, arthralgia, and erythema. Trisomy 8 is a common chromosomal abnormality
in patients with myelodysplastic syndrome. Myelodysplastic syndrome with trisomy 8 involves autoinflammatory conditions, especially Behçet’s disease-like symptoms with intestinal mucosal damage. MEFV
variants, particularly those in exon 10, are pathogenic in familial Mediterranean fever, the most common
autoinflammatory disease, presenting typical symptoms such as periodic fever and pleuritis/pericarditis/
peritonitis. MEFV variants outside exon 10 are common in Japanese patients with familial Mediterranean
fever and are associated with atypical symptoms, including myalgia and erythema. MEFV variants inmyelodysplastic syndrome with trisomy 8 have rarely been investigated, although myelodysplastic syndrome
with trisomy 8 might develop autoinflammatory conditions similar to those in familial Mediterranean fever.
We encountered a 67-year-old man who had myelodysplastic syndrome with trisomy 8 and multiple MEFV
variants outside exon 10. He presented with periodic fever, as well as chest/abdominal pain, myalgia, anderythema, although the symptoms did not fulfill the diagnostic criteria of familial Mediterranean fever.
We discussed the possibility that these symptoms are modified by MEFV variants outside exon 10 inmyelodysplastic syndrome with trisomy 8.
Keywords: autoinflammatory disease, myelodysplastic syndrome, trisomy 8, MEFV gene
Abbreviations:
FMF: familial Mediterranean fever

Received: November 1, 2021; accepted: March 23, 2022
Corresponding Author: Noriyuki Takahashi, MD, PhD
Department of Education for Community-Oriented Medicine, Nagoya University Graduate School of
Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Tel: +81-52-744-2031, E-mail: nori1007@med.nagoya-u.ac.jp
195Noriyuki Takahashi et al

MDS: myelodysplastic syndrome
NF-kB: nuclear factor k-light-chain-enhancer of activated B cells
This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

INTRODUCTION
Studies have shown that cellular genetic abnormalities (eg, chromosomal abnormalities
and somatic variants) in patients with myelodysplastic syndrome (MDS) are associated with
autoinflammatory disease.1,2 Autoinflammatory disease is characterized by the dysregulationof innate immunity, in which myeloid lineage cells (ie, neutrophils) and monocyte lineage
cells (ie, macrophages) are important cellular players.1,2 The discovery of a novel adult-onset
autoinflammatory disease associated with MDS has indicated the importance of characterizing
the autoinflammatory disease in MDS cases.2,3 Among 134 patients with MDS, 61 (46.3%)
had an autoinflammatory condition, including recurrent fever, polymyalgia, arthralgia, arthritis,
erythema, and pleural effusion.1 Trisomy 8 is a common chromosomal abnormality in patientswith MDS, occurring in approximately 10% of cases.4 Trisomy 8 in patients with MDS causes
autoinflammatory conditions, especially Behçet’s disease-like symptoms (eg, fever, abdominal
pain, and ulcerative intestinal lesions).5-9 Only a few other inflammatory conditions are related to
MDS trisomy 8: pyoderma gangrenosum, Sweet’s syndrome, pulmonary alveolar proteinosis, andinflammatory arthritis.10 Although some reports have suggested that trisomy 8 in patients with
MDS leads to periodic fever and erythema nodosum without intestinal mucosal damage, thesecases are currently recognized as being within the category of Behçet’s disease-like symptoms.8,9Gain-of-function variants in pyrin, a product of the MEFV gene, cause familial Mediterranean
fever (FMF).11 FMF is the most common autoinflammatory disease, affecting 120,000 people
worldwide.11 The Tel-Hashomer criteria described by Livneh et al are widely used to diagnose
FMF.12 They include five major criteria and four minor criteria. The five major criteria are: 1)
peritonitis; 2) pleuritis or pericarditis; 3) monoarthritis; 4) fever alone; and 5) incomplete abdominal attacks differing from the typical attacks. The four minor criteria are: 1) and 2) incomplete
attacks differing from the typical attacks, involving the chest or joints, respectively; 3) exertionalleg pain; and 4) favorable response to colchicine. To diagnose FMF, one or more major criteria
or two or more minor criteria should be met. Typical symptoms of FMF, including pleuritis andperitonitis, are related to variants in exon 10 of the MEFV gene.13,14 Conversely, other MEFV
variants (outside exon 10), which are more common in Japanese individuals, produce atypicalsymptoms, including myalgia and erythema.13-15 Tanaka et al reported a patient with MDS who
had trisomy 8 and an MEFV variant (outside exon 10) that manifested as periodic fevers andintestinal Behçet’s disease-like symptoms.16 However, to the best of our knowledge, no reports
have been published describing MDS trisomy 8 presenting with periodic fever involving multiple
MEFV variants (outside exon 10) with a suspicion of autoinflammatory conditions other thanBehçet’s disease-like symptoms. Here, we describe a patient with MDS and trisomy 8 exhibiting
multiple MEFV variants outside exon 10, although his symptoms such as periodic fever, as well
as chest/abdominal pain, myalgia, and erythema, did not fulfill the diagnostic criteria of FMF.

CASE PRESENTATION
Our patient, a 67-year-old Japanese man with no family history of periodic fever, presented
to our hospital. At the age of 61 years, he had begun to experience fever “attacks” of 40°C at
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Trisomy 8 MDS with multiple MEFV variants

intervals of approximately 4 weeks; the duration of each attack was approximately 5–7 days.
Symptoms were right anterior chest pain, left posterior back pain, abdominal pain, upper- andlower-extremity myalgia, and bilateral leg erythema. He did not experience oral aphtha/uveitis/
genital ulcers. During each fever attack, thrombocytopenia and macrocytic anemia appeared(platelets 13.5×104/µL; hemoglobin 7.7 g/dL at admission), along with an elevated inflammatory
response (C-reactive protein of 22.34 mg/dL at admission); however, his symptoms consistently
resolved spontaneously (Table 1). Bone marrow examination revealed orthomorphic to partially

Table 1

Laboratory data upon hospital admission and serum cytokine analysis in a febrile period

Laboratory data on admission
Complete blood countWBC
7700/µL
Neutrophils
78.5%
Lymphocytes 14.4%
Atypical
1.0%
lymphocytes
Blasts0%
RBC
208×104/µL
Hemoglobin
7.7 g/dL
Hematocrit
23.9%
MCV
114.9 fL
Platelets
13.5×104/µL
Coagulation
PT-INR
1.01
APTT
30.3 seconds
Fibrinogen
637 mg/dL
D-dimer
0.67 µg/mL
Endocrine
TSH
1.6078 µU/mL
Free T3
2.03 pg/mL
Free T4
1.57 ng/dL
Urine
U-glucose(–)
U-protein(–)
U-occult blood (–)

Biochemistry
Total protein
7.9 g/dL
Albumin
3.3 g/dL
Glucose118 mg/dL
BUN
40.9 mg/dL
Creatinine
1.54 mg/dL
Na
134 mEq/L
K
3.9 mEq/L
Cl
94 mEq/L
AST
33 U/LALT
16 U/LLDH
362 U/L
g-GTP
20 U/LCK
516 U/L
CRP
22.34 mg/dL
Ferritin
2,318 ng/mL
Vitamin B12776 pg/mL
Folic acid10.0 ng/mL
sIL-2R
842.0 U/mL
MMP-3
89.8 ng/mL
HTLV-1 Ab
0.1 C.O.I
Immunologic test
Anti-Tg Ab
22.4 IU/mL
Anti-TPO Ab 33 IU/mL
ANA<×40
PR3-ANCA<1.0 U/mL
MPO-ANCA <1.0 U/mL

Immunologic test (continues)
IgG
1,833 mg/dL
IgA
287 mg/dL
IgM
98 mg/dL
Genetic analysis
Chromosomal 47, XY, +8
analysis[18 cells/(G-band)20 cells]
WT1 mRNA
170 copy/µg
RNA
HLA
A24, B7, B52,
DR1, DR15
MEFV gene

E148Q (exon 2),
heterozygous
R202Q (exon 2),
heterozygous
S503C (exon 5),
heterozygous

Serum cytokine (febrile)
TNF-a3.46 pg/mL(NR 0.75–1.66
pg/mL)
IL-1b
194 pg/mL(NR <10 pg/mL)
IL-6

35.5 pg/mL(NR <4.0 pg/mL)

IL-18

720 pg/mL(No suggested
NR)

ALT: alanine aminotransferase
ANA: anti-nucleolar antigen
Anti-Tg Ab: anti-thyroglobulin antibody
Anti-TPO Ab: anti-thyroid peroxidase antibody
APTT: activated partial thromboplastin time
AST: aspartate aminotransferase
BUN: blood urea nitrogen
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Noriyuki Takahashi et al

CK: creatine kinase
Cl: chlorine
CRP: C-reactive protein
g-GTP: g-glutamyl transpeptidase
HLA: human leukocyte antigen
HTLV-1 Ab: human T-lymphotropic virus type 1 antibody
Ig: immunoglobulin
IL: interleukin
K: potassium
LDH: lactate dehydrogenase
MCV: mean corpuscular volume
MMP-3: matrix metalloprotease 3
MPO-ANCA: myeloperoxidase anti-neutrophil cytoplasmic antibodies
Na: sodium
NR: normal range
PR3-ANCA: proteinase 3 anti-neutrophil cytoplasmic antibodies
PT-INR: prothrombin time-international normalized ratio
RBC: red blood cellsIL-2R: serum interleukin-2 receptor
TNF-a: tumor necrosis factor-a
TSH: thyroid-stimulating hormone
WBC: white blood cell
WT1 mRNA: Wilms’ tumor 1 gene mRNA

Fig. 1 Bone marrow smear images
Low-power field shows orthomorphic to partially hyperplastic bone marrow with increased megakaryocytes(Panel A; scale bar = 100 µm). High-power fields show specific morphological abnormalities indicative of
myelodysplastic syndrome with hypo-segmented mature neutrophils (red arrows) (Panel B; scale bar = 10 µm)
and micro-megakaryocytes (green arrow) (Panel C; scale bar = 10 µm). Panels A–C depict Giemsa staining
results. Black arrows indicate trisomy 8 (Panel D).
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Trisomy 8 MDS with multiple MEFV variants

hyperplastic bone marrow with increased megakaryocytes and specific morphological abnormalities with hypo-segmented mature neutrophils and micro-megakaryocytes. Chromosomal analysis(G-band) revealed 47,XY,+8 in 18/20 cells. The patient was thus diagnosed with MDS-refractory
cytopenia with multi-lineage dysplasia (ie, MDS-RCMD) and trisomy 8 (Fig. 1). Two sets ofblood cultures were negative. Contrast-enhanced computed tomography and gallium-67 citratescintigraphy showed no obvious findings regarding the origin of the fever. Upper and lower
gastrointestinal endoscopy showed no malignant findings/ulcerative lesions. Enteroscopy was not
performed because bloody/black stools never appeared. Skin biopsies of erythema and purpura
on both legs showed no obvious vasculitis/neutrophilic infiltration. The patient exhibited gait
disturbance as well as dysarthria, which became worse. The patient’s general condition improved
during afebrile periods, although neurological symptoms, including impaired gait and dysarthria,
remained. There was muscle weakness in distal muscles but not in proximal muscles (eg, deltoid,
iliopsoas, and quadriceps). Needle electromyography showed no obvious myogenic findings; there
were no fibrillation potentials, positive sharp waves, or myogenic changes of motor unit potentials
in proximal muscles (tested in deltoid, biceps, and quadriceps). Elevated creatinine kinase atadmission was normalized without specific therapy. Head magnetic resonance imaging showedchronic cerebral ischemic changes, and spine magnetic resonance imaging showed osteoarthritis,
as well as cervical and lumbar spinal canal stenosis (C3/4-6/7, L3/4, L4/5). The patient did notexhibit findings suggestive of meningitis on cerebrospinal fluid examination.
At the time of determining the therapeutic plan, no evidence suggested the cause of the periodic fever, such as bacterial infection, solid malignancy, myositis, meningitis, vasculitis, Sweet’s
syndrome, Behçet’s disease, or tumor necrosis factor receptor-associated periodic syndrome (ie,TRAPS), except for MDS with trisomy 8. The symptoms of periodic fever, chest/abdominal/left

Fig. 2
BT: body temperature
CRP: C-reactive protein
mPSL: methylprednisolone
PCI: percutaneous coronary intervention
PSL: prednisolone
WBC: white blood cell
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Clinical course of this patient199

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Noriyuki Takahashi et alposterior back pain, upper- and lower-extremity myalgia, and bilateral leg erythema resembled
FMF. We investigated only all 10 exons of the MEFV gene in the affected patient, based onreports of known variants according to the Infevers database (http://fmf.igh.cnrs.fr/ISSAID/
infevers/).17 These investigations revealed the heterozygotic variants E148Q (exon 2), R202Q(exon 2), and S503C (exon 5) in the MEFV gene.
The patient began 15 mg of prednisolone daily followed by pulse treatment (1 g ofmethylprednisolone per day for 3 consecutive days) considering the inflammatory condition in
relation to MDS with trisomy 8, but his periodic fever did not disappear (Fig. 2). Then, we
considered the possibility that the symptoms were related to FMF. Colchicine was initiatedand corticosteroid treatment was gradually reduced, but the interval between the fever attacks
shortened to approximately once every 2 weeks. Canakinumab treatment did not help to resolve
the fever attacks and was therefore discontinued after 4 months. Currently, the patient continues
to experience periodic fever at intervals of 1–3 months, despite the oral administration of 10
mg of prednisolone daily. The patient underwent lung lobectomy of the upper right lobe foradenocarcinoma and percutaneous coronary intervention for acute myocardial infarction during
the follow-up period (at 19 and 42 months after the first visit to our hospital, respectively).

DISCUSSION
Our patient exhibited MDS with trisomy 8 and periodic fever complicated by chest/abdominal
pain, myalgia, and erythema, although there were no specific findings, including pleuritis,
peritonitis, arthritis, and vasculitis. Our patient was diagnosed with MDS-refractory cytopenia
with multi-lineage dysplasia at the time of diagnosis in accordance with the 2008 World HealthOrganization criteria.18 The symptoms of our patient resembled FMF, despite not fulfilling thecriteria for this condition. Our patient exhibited typical FMF symptoms such as chest pain andexertional leg pain, which are compatible with the Tel-Hashomer criteria. However, a periodof 5–7 febrile days was longer than that of typical attacks (lasting between 12 hours and 3days in the criteria), and he did not exhibit typical FMF findings (eg, pleuritis, peritonitis, andmonoarthritis) during periods of fever. Furthermore, a reduction in the frequency of fever attacks
was finally achieved not by colchicine, but by corticosteroid. The Tel-Hashomer criteria do notstrictly define a good response to colchicine, but the administration of this treatment is expected
to reduce fever attack frequency and symptom severity.11,12
The patient had multiple MEFV variants in exons 2 and 5. MEFV variants have been associatedwith diseases other than FMF, such as vasculitis including IgA vasculitis, polyarteritis nodosa,
Behçet’s disease, and juvenile rheumatoid arthritis, although the exon sites were not reported.19-21
MEFV variants in MDS were previously reported in Sweet’s disease and patients with intestinal
Behçet’s disease-like symptoms.16,22 These diseases were potential differential diagnoses of ourpatient. Although small bowel inflammation was not completely ruled out, none of these diseases
sufficiently explained the periodic fever condition and clinical findings of the patient.
MDS, trisomy 8, and multiple MEFV gene variants can be etiologically associated with theactivation of innate immunity. Nuclear factor kappa-light-chain-enhancer of activated B cells(NF-kB) is an important component of the innate immune response, and is also importantin the pathogenesis of autoinflammation.23,24 In MDS, the pathway through Toll-like receptors(TLRs), which activate NF-kB, is overactive.25 Trisomy 8 has the possibility of being involvedin the activation of NF-kB. A report suggests that trisomy 8 causes duplication of the IkB
kinase b gene.26 IkB kinase b is a protein that promotes apoptosis-resistant, proinflammatory,
and proliferative pathways through NF-kB.23,27 Pyrin, encoded by the MEFV gene, binds to andNagoya J. Med. Sci. 85. 195–203, 2023

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Trisomy 8 MDS with multiple MEFV variants

deregulates IkBa, which originally functions to inactivate the NF-kB pathway, and results in theactivation of NF-kB.23,28
The pathogenic significance of each MEFV variant in patients who have MDS with trisomy
8 is unclear because MEFV variants in MDS with trisomy 8 are rarely investigated in affectedpatients. Among the MEFV variants in FMF, E148Q and R202Q in exon 2 and S503C inexon 5 are assumed to have unknown or no pathogenicity.29,30 However, E148Q in exon 2, in
combination with non-exon 10 variants, may cause clinical manifestations of FMF (eg, periodic
fevers, abdominal pain, and arthralgia).31 The coexistence of E148Q and R202Q variants in exon
2 was also reported as a disease modifier in chronic myelogenous leukemia-associated Sweet’s
disease.32 Multiple reports have suggested a pathogenic role for S503C in exon 5.33-35 Therefore,
although it is still controversial whether MEFV variants are involved in its pathogenesis, they
may have a disease-modifying effect on the autoinflammatory pathology of MDS with trisomy 8.
This case report had several limitations. First, it was not determined whether the MEFV
variants that occurred in this patient were germinal or somatic. In FMF, MEFV gene variants
occur in the germline.2,11 Therefore, it is natural that the patient was born with multiple MEFV
variants but was asymptomatic and developed MDS trisomy 8 later in life. Conversely, Watad
et al reported that somatic variants in MDS are a risk factor for autoinflammatory diseases.1
A report also suggests that acquired MEFV variants occurred in patients with polycythemia
myelofibrosis.36 Thus, it is notable that the MEFV variants were caused by MDS along withtrisomy 8 in our reported case. Second, the cause of our patient’s neurological symptoms was
unclear. Gait disturbance and dysarthria might be explained as neurological symptoms, which
occur in approximately 14% of autoinflammatory diseases associated with MDS.1 Because ourpatient exhibited thyroid autoantibodies, his neurological symptoms may also have been related toan autoimmune mechanism associated with MDS.37 Furthermore, his chronic cerebral ischemia, as
well as his cervical and lumbar spinal canal stenosis, may have led to a worse overall condition
during periods of fever.

CONCLUSION
We encountered a patient who had MDS with trisomy 8 and exhibited multiple MEFV variants outside exon 10. However, the symptoms of the patient did not fulfill the Tel-Hashomer
criteria for diagnosing FMF. The findings in this case suggest that MDS with trisomy 8 may becomplicated by MEFV variants, which are related to the autoinflammatory pathogenesis.

ACKNOWLEDGEMENTS
We thank Ryan Chastain-Gross, PhD, and J. Ludovic Croxford, PhD, from Edanz (https://jp.edanz.com/ac) for editing drafts of this manuscript.

ETHICAL STATEMENT
This case report was approved by the university ethics review committee (approval number:
2018-0445), of which the first author was a former member. Written informed consent was
obtained from the patient for the publication of this report.

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CONFLICTS OF INTEREST STATEMENTNT reports that his current affiliated institution was established by donations from Aichi
Prefecture and Nagoya City, Japan, and that he has received grants and personal fees from
Novartis Pharma KK outside the submitted work.

FUNDING STATEMENT
Nothing to disclose.

REFERENCES
1

2

3
4
5
6

7

8

9

10
11
12
13
14
15

16

Watad A, Kacar M, Bragazzi NL, et al. Somatic mutations and the risk of undifferentiated autoinflammatory disease in MDS: an under-recognized but prognostically important complication. Front Immunol.
2021;12:610019. doi:10.3389/fimmu.2021.610019.
Oganesyan A, Hakobyan Y, Terrier B, Georgin-Lavialle S, Mekinian A. Looking beyond VEXAS: coexistenceof undifferentiated systemic autoinflammatory disease and myelodysplastic syndrome. Semin Hematol.
2021;58(4):247–253. doi:10.1053/j.seminhematol.2021.10.003.
Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383(27):2628–2638. doi:10.1056/NEJMoa2026834.
Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med. 2009;361(19):1872–1885. doi:10.1056/
NEJMra0902908.
Lin YC, Liang TH, Chang HN, Lin JS, Lin HY. Behçet disease associated with myelodysplastic syndrome.
J Clin Rheumatol. 2008;14(3):169–174. doi:10.1097/RHU.0b013e3181776bde.
Shen Y, Ma HF, Luo D, Cai JF, Zou J, Guan JL. High incidence of gastrointestinal ulceration andcytogenetic aberration of trisomy 8 as typical features of Behçet’s disease associated with myelodysplastic
syndrome: a series of 16 consecutive Chinese patients from the Shanghai Behçet’s disease database andcomparison with the literature. Biomed Res Int. 2018;2018:8535091. doi:10.1155/2018/8535091.
Wesner N, Drevon L, Guedon A, et al. Inflammatory disorders associated with trisomy 8-myelodysplastic
syndromes: French retrospective case-control study. Eur J Haematol. 2019;102(1):63–69. doi:10.1111/
ejh.13174.
Esatoglu SN, Hatemi G, Salihoglu A, Hatemi I, Soysal T, Celik AF. A reappraisal of the association between
Behçet’s disease, myelodysplastic syndrome and the presence of trisomy 8: a systematic literature review.
Clin Exp Rheumatol. 2015;33(6 Suppl 94):S145-S151.
Fujimura T, Yukawa N, Nakashima R, et al. Periodic fever and erythema nodosum associated with MDS
with trisomy 8: report of two cases and review of the literature. Mod Rheumatol. 2010;20(4):413–419.
doi:10.1007/s10165-010-0291-9.
Jachiet V, Fenaux P, Sevoyan A, et al. Inflammatory and immune disorders associated with myelodysplastic
syndromes. Hemato. 2021;2(2):329–346. doi:10.3390/hemato2020019.
Padeh S, Bilginer Y, Ozen S. Familial Mediterranean Fever. In: Hashkes PJ, Laxer RM, Simon A, eds.
Textbook of Autoinflammation. Switzerland: Springer Nature; 2019:chap 16. doi:10.1007/978-3-319-98605-0.
Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis
Rheum. 1997;40(10):1879–1885. doi:10.1002/art.1780401023.
Migita K, Uehara R, Nakamura Y, et al. Familial Mediterranean fever in Japan. Medicine (Baltimore).
2012;91(6):337–343. doi:10.1097/MD.0b013e318277cf75.
Migita K, Agematsu K, Yazaki M, et al. Familial Mediterranean fever: genotype-phenotype correlations inJapanese patients. Medicine (Baltimore). 2014;93(3):158–164. doi:10.1097/MD.0000000000000029.
Kishida D, Nakamura A, Yazaki M, Tsuchiya-Suzuki A, Matsuda M, Ikeda S. Genotype-phenotype
correlation in Japanese patients with familial Mediterranean fever: differences in genotype and clinicalfeatures between Japanese and Mediterranean populations. Arthritis Res Ther. 2014;16(5):439. doi:10.1186/
s13075-014-0439-7.
Tanaka N, Sakuraba H, Hiraga H, et al. Long-term maintenance of the mucosal healing induced by
azacitidine therapy in a patient with intestinal Behçet’s-like disease accompanied with myelodysplastic
syndrome involving trisomy 8. Immunol Med. 2019;42(3):135–141. doi:10.1080/25785826.2019.1687251.

Nagoya J. Med. Sci. 85. 195–203, 2023

202

doi:10.18999/nagjms.85.1.195

Trisomy 8 MDS with multiple MEFV variants

17

18

19
20
21
22
23
24

25
26
27
28

29
30

31

32
33
34
35
36

37

Sarrauste de Menthière C, Terriere S, Pugnère D, Ruiz M, Demaille J, Touitou I. INFEVERS: the registry for
FMF and hereditary inflammatory disorders mutations. Nucleic Acids Res. 2003;31(1):282–285. doi:10.1093/
nar/gkg031.
Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO)classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood.
2009;114(5):937–951. doi:10.1182/blood-2009-03-209262.
Abbara S, Grateau G, Ducharme-Bénard S, Saadoun D, Georgin-Lavialle S. Association of vasculitis andfamilial Mediterranean fever. Front Immunol. 2019;10:763. doi:10.3389/fimmu.2019.00763.
Touitou I, Magne X, Molinari N, et al. MEFV mutations in Behçet’s disease. Hum Mutat. 2000;16(3):271–
272. doi:10.1002/1098-1004(200009)16:3<271::AID-HUMU16>3.0.CO;2-A.
Ayaz NA, Ozen S, Bilginer Y, et al. MEFV mutations in systemic onset juvenile idiopathic arthritis.
Rheumatology (Oxford). 2009;48(1):23–25. doi:10.1093/rheumatology/ken409.
Jo T, Horio K, Migita K. Sweet’s syndrome in patients with MDS and MEFV mutations. N Engl J Med.
2015;372(7):686–688. doi:10.1056/NEJMc1412998.
Alberts B, Johnson A, Lewis J, et al. Chapter 15 Cell Signaling. In: Molecular Biology of the Cell. Sixth
ed. New York: Garland Science; 2017:813–888.
Lorente-Sorolla C, Netea MG, Ballestar E. Epigenetics in Autoinflammation. In: Hashkes PJ, Laxer RM,
Simon A, eds. Textbook of Autoinflammation. Switzerland: Springer Nature; 2019:chap 3. doi:10.1007/9783-319-98605-0.
Glenthøj A, Ørskov AD, Hansen JW, Hadrup SR, O’Connell C, Grønbæk K. Immune mechanisms inmyelodysplastic syndrome. Int J Mol Sci. 2016;17(6):944. doi:10.3390/ijms17060944.
Vander Pluym JH, O’Sullivan J, Andrew G, Bolduc FV. Genomic characterization of chromosome 8
pericentric trisomy. Clin Case Rep. 2015;3(7):570–577. doi:10.1002/ccr3.234.
Schmid JA, Birbach A. IkB kinase b (IKKb/IKK2/IKBKB) — A key molecule in signaling to the transcription
factor NF-kB. Cytokine Growth Factor Rev. 2008;19(2):157–165. doi:10.1016/j.cytogfr.2008.01.006.
Chae JJ, Wood G, Richard K, et al. The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kB through its N-terminal fragment. Blood. 2008;112(5):1794–1803. doi:10.1182/
blood-2008-01-134932.
Fujikura K. Global epidemiology of familial Mediterranean fever mutations using population exome
sequences. Mol Genet Genom Med. 2015;3(4):272–282. doi:10.1002/mgg3.140.
Bernot A, Da Silva C, Petit JL, et al. Non-founder mutations in the MEFV gene establish this gene as
the cause of familial Mediterranean fever (FMF). Hum Mol Genet. 1998;7(8):1317–1325. doi:10.1093/
hmg/7.8.1317.
Fujimoto K, Hidaka Y, Koga T, et al. MEFV E148Q variant is more associated with familial Mediterranean
fever when combined with other non-exon 10 MEFV variants in Japanese patients with recurrent fever.
Mod Rheumatol. 2021;31(6):1208–1214. doi:10.1080/14397595.2021.1880534.
Miyoshi T, Yamashita K, Ohno T, et al. Familial Mediterranean fever gene as a possible modifier of Sweet
syndrome with chronic myelogenous leukemia. Acta Haematol. 2008;120(1):57–62. doi:10.1159/000158578.
Sugie M, Ouchi T, Kishida D, Yasaki S. Atypical type of familial Mediterranean fever: an underdiagnosed
cause of chronic aseptic meningitis. Neurol Clin Neurosci. 2018;6(6):191–193. doi:10.1111/ncn3.12232.
Kimura K, Mizooka M, Migita K, et al. Five cases of familial Mediterranean fever in Japan: the relationshipwith MEFV mutations. Intern Med. 2018;57(16):2425–2429. doi:10.2169/internalmedicine.0057-17.
Sato T, Takezaki S, Goto T, et al. Atypical familial Mediterranean fever in a Japanese boy with heterozygous
MEFV p. Ser503Cys exon 5 variant. Case Rep Pediatr. 2021;2021:6650226. doi:10.1155/2021/6650226.
Shinar Y, Tohami T, Livneh A, et al. Acquired familial Mediterranean fever associated with a somatic
MEFV mutation in a patient with JAK2 associated post-polycythemia myelofibrosis. Orphanet J Rare Dis.
2015;10:86. doi:10.1186/s13023-015-0298-6.
Komrokji RS, Kulasekararaj A, Al Ali NH, et al. Autoimmune diseases and myelodysplastic syndromes.
Am J Hematol. 2016;91(5):E280-E283. doi:10.1002/ajh.24333.

References End

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