Introduction

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS, MIM 142680) is a dominantly inherited disorder characterised by recurrent episodes of sustained fever. Recently, McDermott et al. [4] identified mutations of TNF receptor 1 (TNFR1) gene ( TNFRSF1A) as a cause of this syndrome. As indicated in its old name of familial Hibernian fever, most reported patients with TRAPS are of northern European, especially Irish and/or Scottish, ancestry. So far, no confirmed case has been reported in an eastern Asian population. In this paper, we describe a case of TRAPS with a novel TNFRSF1A mutation in a Japanese family.

Case report

A 14-year-old Japanese girl was referred to our institution because of sustained fever of 2 weeks duration, dehydration and renal dysfunction. She had a history of periodic episodes of sustained fever beginning at age 2 months. Attacks were characterised by high fever (>39°C) accompanied by nausea, rash, shoulder pain and conjunctival injection. The episode lasted for 2 to 3 weeks and recurred at intervals of 2 months. After 8 years of age, a short course of intravenous hydrocortisone during attacks and low dose oral prednisolone (5–10 mg) between attacks had been administered by a general practitioner as he had an impression that steroids ameliorated the attacks. A grandfather, a great-grandmother and an uncle had the same episodes and her mother had similar but much milder symptoms (Fig. 1). On admission, she appeared emaciated and showed the signs of dehydration with 10% weight loss. No specific abnormal physical finding was noted. There was a strong acute phase response indicated by WBC count (46,570/µl), C-reactive protein (280 mg/l) and erythrocyte sedimentation rate (128 mm/h). Other laboratory investigations showed increased blood urea nitrogen (86 mg/dl) and creatinine (1.8 mg/dl), decreased serum and urinary sodium concentrations (121 mEq/l and <10 mEq/l, respectively) and normal serum immunoglobulin D concentration (3.7 mg/dl). She was initially diagnosed as having fever of unknown aetiology, hypotonic dehydration and resultant hypovolaemic renal dysfunction. As her past and family histories and her relatively good general condition strongly suggested that she was suffering from febrile attack of TRAPS, we treated her only with parenteral supplementation of fluid and electrolytes. Her temperature gradually decreased and she became completely afebrile 3 days after admission. Her body weight returned to the previous value within 5 days. Bacteriological examinations of blood, urine and throat swab, chest X-ray film on admission and gallium scanning after admission were not remarkable. Serum or plasma levels of cytokines and cytokine receptors were as follows: interleukin-6, 25.6 pg/ml; tumour necrosis factor-α (TNF-α) <5 pg/ml; interferon-γ <0.1 IU/ml; soluble TNF receptor 1 (sTNFR1), 3,280 pg/ml; sTNFR2, 9,620 pg/ml. Plasma sTNFR1 level measured by ELISA (Quantikine Human sTNFR1, R & D Systems Inc., Minneapolis, USA) 1 month after the febrile episode was 461 pg/ml (reference range: 484–1407 pg/ml). After informed consent was obtained from the patient and her parents, PCR sequencing of the TNFRSFIA gene which encodes TNFR1 was performed using the primer pairs described by McDermott et al. [4]. We found a novel missense mutation on one allele: TGC→AGC at codon 70 leading to an exchange of cysteine for serine (C70S, GenBank AY182755) (Fig. 1). As mutations causing substitution of the same cysteine residue (C70Y, C70R) have been reported in TRAPS families [2,6], we diagnosed the patient as having TRAPS. We performed genetic analysis of her family after informed consent was obtained and found the C70S mutation in her mother and sister but not in her father (Fig. 1). Her 48-year-old mother had been having very mild febrile attacks twice a year since childhood and the 17-year-old sister remained asymtomatic. Their plasma sTNFR1 levels were low: 357 pg/ml and 400 pg/ml in mother and sister, respectively. The patient’s subsequent febrile attacks were successfully alleviated by oral prednisolone.

Fig. 1
figure 1

a Pedigree of the family. Patient ( arrow) , deceased ( line through symbol), affected ( closed symbol), unaffected ( open symbol), mutation carrier without clinical symptoms ( open symbol around a black circle). N no mutation, NT no genetic analysis performed. b DNA sequence electrophoretogram of C70S mutation (TGC→AGC, indicated by arrow) in TNFRSF1A which was found in the patient. c DNA sequence of a healthy donor with normal pattern (TGC) at position 70

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Discussion

TRAPS is the second most common disease among hereditary periodic fever syndromes next to familial Mediterranean fever. To date, there have been more than 140 patients with TRAPS identified [3]. Although most of the reported families with TRAPS are of northern European ancestry including Irish, Scottish, Finnish, French and Dutch populations, families of other ethnic groups such as Jewish, Arab, and Puerto-Rican have also been described. Simon et al. [6] has reported a female case of Dutch-Indonesian descent with C70Y mutation. In this case, the authors stated that it was unclear whether the disease originated from the Dutch or Indonesian side of the family. The presented case is the first confirmed TRAPS patient in an eastern Asian population. This supports a concept that TRAPS is more common worldwide than previously appreciated [2].

TNFR1 is one of the two receptors for TNF-α, a multifunctional cytokine with pro-inflammatory, cytotoxic, cytokine-inducing and anti-viral activities. In its extracellular portion, TNFR1 has four cysteine-rich domains (CRDs), where six cysteine residues form three disulphide bonds. To date, 32 TRAPS-associated mutations of TNFRSF1A have been registered in the INFEVERS database (http://fmf.igh.cnrs.fr/infevers/) [5]. All these mutations reside in exons 2–4 encoding CRD1 and CRD2, except F112I corresponding to CRD3 and a splice-junction mutation in intron 3. The majority of the documented mutations are those with substitution of cysteine residues. We identified a novel mutation, C70S, in the presented family. Similar to the reported mutations of the same cysteine residue (C70R, C70Y), this mutation disrupts one of the three disulphide bonds in CRD2. It has been postulated that subsequent structural changes in the extracelluar domain of the protein leads to sustained activation of TNF-α-mediated pathway through impaired shedding of activated receptor and resultant decreased down-regulation of TNFR1 on the cell surface and diminished antagonistic activities of sTNFR1 in plasma [4].

It is notable that patient’s sister was asymptomatic and their mother showed mild symptoms. Both of them had the same mutation as the proband and showed decreased level of sTNFR1. McDermott et al. [4] reported significant differences in sTNFR1 levels between mutation carriers not experiencing attacks and normal individuals. These findings suggested that a decreased plasma level of sTNFR1 is directly related to genotype but is not the critical factor in the development of febrile attacks. In the C70Y mutation, two of the ten mutation-positive family members were asymptomatic, showing a penetrance of 80% [6]. Reduced penetrance described in some TRAPS mutations has been hypothetically explained by gene environment interactions, polymorphisms of background genes involved in TNF-α signalling pathways and varying thresholds for modifier protein function [1]. These factors may contribute to the discrepancy between genotype and phenotype in the presented family. In addition, as the onset age of TRAPS ranges from 2 weeks to 53 years of age [3], it is possible that the patient’s sister will develop symptoms later in life.

It is not uncommon for paediatricians to see children and young adults with recurrent fever of unknown origin. Our case indicated the need to include TRAPS in the differential diagnosis of such patients, even in ethnic groups in which no TRAPS case has been documented.