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Neuro-Sweet disease (NSD) is defined as Sweet disease with central nervous system (CNS) involvement. Also known as acute febrile neutrophilic dermatosis, NSD is characterised by painful erythematous plaques and multisystem neutrophilic infiltration.1
Familial Mediterranean fever (FMF), characterised by recurrent fever and serositis, is caused by mutations of the Mediterranean fever (MEFV) gene. FMF is rarely reported in patients with Sweet’s syndrome.2 In this report, we discuss three cases of possible NSD. Our findings indicate that some mutations in the MEFV gene may act as additional susceptibility factors in autoimmune inflammatory neurological diseases, including NSD.
Patients and methods
We conducted MEFV mutation analyses on genomic DNA samples from three patients diagnosed with possible NSD between 1 April 2014 and 31 October 2016. Patients were diagnosed with NSD in accordance with previously described criteria.1 In all patients, infection, malignancy and other autoimmune diseases were clinically excluded. All patients provided written informed consent to participate in this study. MEFV gene analyses were performed via PCR (see online supplementary file 1).
Supplementary file 1
A 62-year-old man presented with headache and difficulty understanding spoken language in June 2014, following which he experienced a generalised seizure and was transferred to our hospital. Dark-red, mottled erythema was observed on the surface of his skin. High levels of protein and interleukin (IL)-6 were observed in the cerebrospinal fluid (CSF). MRI revealed a tumefactive lesion in the left temporo-occipital region on T1, gadolinium-enhanced, fluid-attenuated inversion recovery (FLAIR) sequences (figure 1A,B). Brain biopsy of the lesion demonstrated perivascular inflammation (figure 1C), while skin biopsy revealed mild inflammation (figure 1D). Human leucocyte antigen (HLA) typing revealed serotypes of B54 and Cw1. Treatment with intravenous methylprednisolone (1 g/day, 5 days) was initiated following a diagnosis of possible NSD. The patient exhibited partial improvement in symptoms. Genetic analysis of MEFV revealed heterozygous R202Q in exon 2.
A 46-year-old man with a history of periodic aphthous stomatitis presented with high fever, nuchal stiffness and generalised seizure in April 2015. Laboratory analyses revealed an elevated serum C reactive protein level (150 mg/L) and neutrophilia (90%). CSF showed pleocytosis and high levels of protein and IL-6. MRI revealed lesions in the right subcortical region and brainstem (figure 1E,F). During hospitalisation, he developed a skin rash on his extremities (figure 1G), following which a skin biopsy was performed. Histopathological analysis of the erythematous plaque revealed perivascular dermatitis (figure 1H). His condition dramatically improved following treatment with intravenous methylprednisolone (1 g/day, 3 days). HLA typing results were positive for B54 and Cw1, and he was diagnosed with possible NSD. Genetic analysis of MEFV revealed E148Q and R202Q in exon 2.
In March 2016, a 51-year-old woman was referred to our hospital due to a 3-month history of pain and weakness in her right hand. At age 37, she had experienced an episode of recurrent genital ulcers; a skin biopsy had revealed perivascular dermatitis. Brain MRI revealed high-intensity lesions in the right thalamus, left basal ganglia and brainstem on FLAIR images (figure 1I, J). Nerve conduction studies revealed a reduction in motor and sensory nerve amplitudes in the right ulnar nerve. Following treatment with intravenous methylprednisolone (1 g/day, 3 days), she experienced a reduction in pain and partial improvement in grip strength. HLA typing results were positive for B54 and Cw1, and she was diagnosed with possible NSD. Genetic analysis of MEFV revealed heterozygous E84K in exon 1.
While the clinical characteristics of the three patients were diverse, all findings agreed with the characteristics of possible NSD (see online supplementary file 2). All patients exhibited brain and skin involvement, while none had presented with uveitis. Furthermore, all patients exhibited brainstem lesions on MRIs as well as skin biopsy findings indicative of perivascular dermatitis without necrotising vasculitis or thrombosis. Although follow-up MRI revealed little change in each patient, all three have remained stable without recurrence under treatment with oral prednisolone (started 0.5 mg/kg daily, tapered to 10 mg daily). Analyses of the MEFV gene revealed mutations in all patients.
Supplementary file 2
The present report is the first to discuss MEFV gene mutations in patients diagnosed with possible NSD. Our findings suggest an association between CNS inflammation and MEFV gene mutations.
Previous studies have indicated that FMF may also be associated with other autoimmune diseases, such as Behçet’s disease (BD).3 NSD and neuro-Behçet’s disease (NBD) overlap in clinical features and are sometimes difficult to differentiate.1 Indeed, the three patients of the present report exhibited some features common to both NSD and NBD. However, as all patients exhibited marked responsiveness to systemic glucocorticoid treatment and an absence of characteristic BD features (eg, uveitis, cutaneous vasculitis and HLA-B51), findings in each case suggested NSD. In particular, patients with NSD typically show higher frequency of HLA-B54 and Cw1 than B51 (63%, 89% and 25%, respectively).1 Dermatological features in our patients were atypical of NSD; therefore, MEFV gene mutations and positive HLA-B54 and Cw1 results support the diagnosis of NSD, even without typical pathological skin biopsy findings.
Although MEFV mutations in exon 10 mutations (M694I) are most common among Japanese patients with FMF, other mutations have been found, including P369S, P408Q, G304R, R202Q, E148Q, L110P and E84K.4 E148Q occurs frequently (23%) in the healthy Japanese population and therefore may be insufficient for inducing inflammatory symptoms without the influence of other factors.5 These alternative MEFV variants are thought to act as disease modifiers. Moreover, MEFV mutations in BD include M694V in exon 10 and E148Q in exon 2.3 Therefore, mutations in MEFV may play an important role in the onset of NSD, although further studies involving larger patient samples are required.
Similar to BD, NSD likely includes features of autoimmune diseases associated with both environmental and genetic factors. Colchicine has been used as a therapeutic option in NSD,1 as well as NBD and FMF. MEFV gene mutations should be evaluated in patients with suspected NSD because they may be risk factors for onset of NSD.
We are grateful to all patients for their participation; to Dr. Shunya Kawasaki and Dr. Chika Oka for assisting the care of the patients; to Editage (http://www.editage.jp) for English language editing.
Contributors HI contributed to the interpretation of findings, wrote the initial draft of the report, and revised and edited the manuscript. YI, AN and KM were involved in treatment planning, and revised and edited the manuscript. DK was involved in MEFV gene analysis and edited the manuscript. AS and HT were involved in treatment planning, and contributed to interpretation of the findings and critical revision of the manuscript.
Competing interests None declared.
Ethics approval The study was approved by the Ethics Committee of Mie University Hospital (approval number 1756).
Provenance and peer review Not commissioned; externally peer reviewed.
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