Colchicine-responsive chronic recurrent multifocal osteomyelitis with MEFV mutations: a variant of familial Mediterranean fever?

Sir, FMF is an autosomal recessive disease characterized by self-limited recurrent attacks of fever with serositis such as peritonitis, pleuritis and arthritis [1]. FMF is caused by mutations in the MEFV gene [2]. This gene had been considered to be responsible only for FMF in the past; however, recent reports show that the MEFV gene is associated with more than typical FMF and is linked to additional clinical presentations within the family of the autoinflammatory diseases [2–4]. Here, we describe a case of colchicine-responsive chronic recurrent multifocal osteomyelitis (CRMO) with MEFV gene mutations. A 14-year-old female was referred with fever of unknown origin persisting for 15 days. Physical examination was unremarkable. Laboratory findings showed normal white blood cell count (3.9 × 109/l), high levels of CRP (3.1 mg/dl), accelerated ESR (72 mm/h), normal levels of immunoglobulins and negative autoantibodies. Blood culture was negative. Unexpectedly, gallium (Ga) scintigraphy on Day 3 after admission demonstrated significant uptake in the bilateral proximal region of the tibia (Fig. 1A). Plain radiography showed no significant findings (Fig. 1D), but MRI demonstrated multifocal lesions whose intensity was low in T1-weighted condition and high in T2-weighted condition in bilateral tibia (Fig. 1E). Biopsy of the left tibia showed non-specific inflammatory changes and no malignant cells. The culture of bone marrow was negative. She had severe pain of the left heel on Day 21. MRI on Day 23 demonstrated multifocal lesions whose intensity was low in the T1-weighted condition and high in the T2-weighted condition in bilateral tarsal bones (Fig. 1F). Ga scintigraphy on Day 38 demonstrated significant uptake in left calcaneus and bilateral femur (Fig. 1B). From these findings, the diagnosis of multifocal recurrent osteomyelitis was made. No evidence of bone destruction or hyperostosis was observed at the time of diagnosis. High fever continued despite treatment with appropriate antibiotics and naproxen for 8 weeks. However, she was relieved dramatically from high fever soon after colchicine (2 mg/day) was started. Mutation analysis demonstrated the heterozygous mutation E148Q-P369S-R408Q in cis on one allele of the MEFV gene. But no mutation was found in the LPIN2 gene. Colchicine dose was gradually decreased to 0.5 mg/day and daily colchicine therapy (0.5 mg/day) relieved her from febrile attacks for 1 year, although she had one episode of osteomyelitis in the left fibula (Fig. 1C) when she ceased to take colchicine. (A–C) Ga scintigraphy: the image on Day 3 (A) showing significant uptake in the bilateral proximal region of tibia. Day 38 (B) showing significant uptake in the left calcaneus and bilateral femur. Nine months later (C) showing significant uptake in the left fibula. (D) A plain X-ray, frontal view, showed no significant findings including screlosis in the bilateral tibia. (E and F) MRI: the T1-weighted image on Day 3 (E) showing multiple lesions whose intensity was low in the bilateral tibia. The T2-weighted image on Day 23 (F) showing multiple lesions whose intensity was high in the bilateral tarsal bones. FMF is an autosomal recessive, inherited periodic inflammatory syndrome, characterized by self-limited recurrent attacks of fever with serositis such as peritonitis, pleuritis and arthritis [1]. The disease is common among people of eastern Mediterranean ancestry. The mainstay of treatment is cochicine, which is effective for both relieving symptoms and preventing secondary amyloidosis. The MEFV gene encodes a protein named pyrin, which is expressed in neutrophils and monocytes. The function of pyrin is still unknown and remains to be determined. The MEFV gene had been considered to be responsible only for FMF in the past. However, about one-third of patients with FMF have a single mutation on one allele. This finding suggests that FMF might be transferred as an autosomal dominant trait with partial penetration. Another possibility is that an additional, unidentified gene might be associated with the disease in these patients with single allele mutation. Recently, a case with heterozygous MEFV mutations and distinct clinical presentations not typical of FMF has been reported, with colchicine-responsive recurrent episodes of muscle pains [3]. These reports including our case show that the MEFV gene is associated with more than a single disease (FMF) and is linked to additional clinical presentations within the family of the autoinflammatory diseases [4, 5] and some rheumatic diseases such as systemic-onset juvenile idiopathic arthritis [6, 7]. Mutation analysis in our patient demonstrated the heterozygous mutation E148Q-P369S-R408Q. In the whole list of 187 sequence alterations reported in Infevers—an online database for autoinflammatory mutations available at http://fmf.igh.cnrs.fr/ISSAID/infevers [8], this mutation is reported to be associated with atypical clinical presentations of FMF. CRMO is an ill-defined inflammatory disease. In typical cases, multiple bone lesions with apparent bone destruction, hyperostosis and pustulosis of the skin are seen [9]. But there are variable clinical manifestations, which make differential diagnosis of CRMO often difficult. LPIN2 mutation is detectable in a syndrome form of CRMO known as Majeed syndrome [10], but for most cases the responsible gene is unknown. CRMO is unusual, or an unexpected manifestation of FMF and this is the first case of CRMO with MEFV mutations to our knowledge. To start the treatment with colchicines promptly, thereby relieving symptoms and preventing secondary amyloidosis, mutation analysis of MEFV gene should be performed in cases of CRMO. Disclosure statement: The authors have declared no conflicts of interest.