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Familial Mediterranean fever (FMF) is a recessively inherited disorder characterised by recurrent attacks of fever and serositis that usually begin in childhood, last for fewer than 3 days, and which can largely be prevented by colchicine prophylaxis. Identification of the gene associated with FMF, MEFV, has facilitated genotype:phenotype studies, and we report here on a patient with a little described exon 9 mutation associated with an atypical inflammatory syndrome.
A 56 year old white French woman presented with normochromic anaemia, haemoglobin 61 g/l, and recent onset fatigue and headaches. Extensive investigations including upper and lower gastrointestinal endoscopy, autoantibody screens, bone marrow examination, and whole body computed tomography proved normal. There was no family history of note or consanguinity.
Over the following 9 years her symptoms—comprising pyrexia, headache, and drenching night sweats—intensified, occurring about every fourth day and lasting for 24 hours. She required intermittent blood transfusions and her erythrocyte sedimentation rate remained markedly raised. Repeat bone marrow, echocardiogram, radiolabelled white cell scan, and computed tomographic imaging were normal. An investigation for infectious disease was non-diagnostic and a trial of prednisolone ineffective.
The possibility of atypical FMF was considered and was supported by complete resolution of symptoms after the introduction of colchicine 1 mg daily. Before treatment, her median serum amyloid A protein was 338 mg/l and C reactive protein 56 mg/l. Both markers were in the healthy range of <10 mg/l with colchicine (fig 1).
Sequencing of MEFV showed a single exon 9 mutation, encoding pyrin I591T; no mutations were found in exons 2, 3, 5, or 10. The TNFRSF1A gene, associated with TRAPS (tumour necrosis factor receptor associated periodic fever syndrome) was wild type. A reduction in colchicine to 0.5 mg/day led to recurrence of symptoms and acute phase response, which resolved when the dose was increased. She remains well and has a normal haemoglobin at 12 months’ follow up.
FMF is an inherited inflammatory disorder predominantly affecting people of the Mediterranean littoral, but which has been described in many populations.1 The gene associated with FMF, MEFV, was cloned in 1997 and comprises 10 exons.1 Forty eight mutations associated with FMF have been reported, just five of which are associated with 70–80% of cases.2 Although finding a mutation in each MEFV allele corroborates a diagnosis of FMF, the sensitivity and specificity of DNA analysis are hampered by reduced penetrance, and by the fact that only a single mutation can be identified in up to 20% of patients with classical FMF.3–5 This suggests that certain people may be especially susceptible to a single MEFV mutation, or that other as yet unidentified genes can contribute to the pathogenesis of the disease. The diagnosis of FMF therefore remains clinical, and the Tel Hashomer criteria are well validated for this purpose.6,7
Pyrin I591T was first reported in 2001 with no accompanying clinical data.8 A Spanish kindred was subsequently described, in which three siblings were compound heterozygotes for pyrin I591T and M694I, the latter a recognised variant causing FMF.9 Only one subject was symptomatic, and the contribution from I591T was therefore unclear. However, a pathogenic role for pyrin I591T in our patient is supported because she fulfilled diagnostic criteria for probable FMF, had attacks of characteristically short duration which responded to colchicine, and we only identified this mutation in one other case among our large referral practice, in a patient with classical FMF who had a second MEFV mutation, M694V. Furthermore, the absence of serositis and a late onset of symptoms have all been described in FMF.10
This case illustrates the usefulness of a therapeutic trial of colchicine monitored objectively by frequent acute phase protein measurements in patients with undiagnosed periodic fever syndromes. It also raises the possibility that a low threshold for analysing the FMF gene might disclose a wider spectrum of associated disease.
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