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Keywords:

  • autoinflammatory disorder;
  • intra-abdominal abscess;
  • TNFRSF1A;
  • TRAPS

Abstract.

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Case report
  5. Discussion
  6. Conflict of interest statement
  7. Acknowledgements
  8. References

Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disorder characterized by periodic attacks of fever and inflammation, due to mutations in the gene coding for the TNF type I receptor (TNFRSF1A). A 16-year-old patient with the diagnosis of TRAPS was admitted to hospital because of fever and abdominal pain. Initially, the symptoms were interpreted as manifestations of another TRAPS attack, but the patient's condition worsened, despite treatment with corticosteroids and antibiotics. A repeated computer tomography revealed an intra-abdominal abscess, which necessitated urgent surgical intervention. This case stresses the importance of differential diagnostic vigilance when dealing with patients with rare genetic diseases.


Introduction

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Case report
  5. Discussion
  6. Conflict of interest statement
  7. Acknowledgements
  8. References

The systemic autoinflammatory disorders are a group of syndromes characterized by periodically recurrent fever, peritonitis, pleurisy, pericarditis, arthritis and skin rash. A rise in serum acute phase protein levels is detected during the attack, but there is no antigen-specific T-cell activation or rise in serum autoantibody concentrations [1, 2]. At present, eight different diseases are included amongst the systemic autoinflammatory disorders: familial Mediterranean fever (FMF), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS), Blau syndrome, PAPA syndrome and the cryopyrin-associated periodic fever syndromes, which include Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) [3]. FMF and HIDS are inherited recessively in the autosome, whereas TRAPS, MWS/FCAS/NOMID (/CINCA), the Blau and PAPA syndromes are autosomally dominantly inherited [4].

The genetic defect in TRAPS was established in 1999 as missense mutations in the gene coding for the TNF-α type I receptor, TNFRSF1A, located on chromosome 12p [5]. The mutations are believed to alter the structure of TNFRSF1A so that its shedding from the cell membrane, in association with some mutations, becomes defective and as a consequence, not enough soluble receptor is available to bind TNF-α, resulting in an inappropriate inflammatory reaction. Recent data indicate that defective intra-cellular signalling also plays an important role in the pathogenesis of TRAPS [6, 7]. Typical symptoms of TRAPS attacks include high peaks of fever, abdominal pain, muscular and articular manifestations, periorbital oedema and conjunctivitis, and sometimes a migratory erythematous rash [4, 5]. The attacks may last from one or several days up to weeks [4, 5, 8]. Corticosteroids and the TNFRSF1B fusion protein etanercept are known to alleviate the inflammatory episodes [1, 9]. We have previously reported three novel TNFRSF1A mutations in Finnish families with dominantly inherited recurrent fever [5, 10–12]. Here we present a differential diagnostic problem in a TRAPS patient, in whom the cause of fever and abdominal pain proved to be an intra-abdominal abscess.

Case report

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Case report
  5. Discussion
  6. Conflict of interest statement
  7. Acknowledgements
  8. References

A 16-year-old female patient was diagnosed with TRAPS at the age of 14 [11]. She has suffered from recurring attacks of fever and abdominal pain once or twice a year since the age of 11. The attacks usually last from 1 to 3 weeks and the pain localizes to the right side of the lower abdomen. Nonsteroidal anti-inflammatory drugs and occasional courses of corticosteroids, at an initial dose of 30 mg prednisolone per day and tapering within 4–6 weeks by 5–10 mg a week have relieved the abdominal pain. Her mother and maternal grandfather have also had recurring attacks of fever and abdominal pain. Through sequence analysis performed on genomic DNA a missense mutation in exon 4 of the TNFRSF1A gene, resulting in an F112I amino acid substitution in the third extracellular domain, was identified in all three family members, as well as in two of the half-siblings of the patient's mother [11].

On 1 January 2003, the patient was taken to hospital because of high fever and abdominal pain. As opposed to earlier febrile attacks due to TRAPS, she was nauseous and had vomited. The pain was diffusely localized to her lower abdomen, and not to the right as during previous attacks. Clinical examination revealed muscle guarding suggesting peritoneal irritation. Findings on chest X-rays were normal, and X-rays of the abdomen revealed dilated bowels and fluid in the colon. Laboratory findings included a leucocytosis of 20.7 × 109 L−1 (normal 4.5–13 × 109 L−1) and a rise in the serum C-reactive protein (CRP) level of 55 mg L−1 (normal <10 mg L−1). Due to the patient's medical history, the symptoms were initially considered to be manifestations of her autoinflammatory disease. As the CRP level rose to 358 mg L−1 and the abdominal pain intensified, an enteric bacterial infection was considered probable, and intravenous cefuroxime and metronidazole treatment was commenced 3 days after admission. Despite the differential diagnostic option of a bacterial infection, an autoinflammatory reaction associated with TRAPS was not ruled out, and, consequently, treatment with intravenous methyl prednisolone 32 mg daily was commenced on the fifth day of hospitalization. The CRP level first decreased, but started to rise again 9 days after admission, reaching a level of 101 mg L−1. A computer tomography (CT) of the abdomen revealed no signs of perforation, and no abnormalities in the liver, spleen, kidneys or pancreas. An echocardiography was performed to rule out signs of valvular vegetations or pericarditis. As the symptoms grew worse and the CRP level continued to rise despite ongoing treatment with the above-mentioned intravenous antibiotics and corticosteroids, on the 13th day of hospitalization the patient was transferred to the Helsinki University Central Hospital for further examinations.

Upon arrival, a new CT of the abdomen was performed and close scrutiny revealed a collection of fluid in the lower abdomen indicating an intraperitoneal abscess (Fig. 1). The radiological findings in association with long-standing intestinal occlusion forced a decision of emergency laparotomy 4 days after admission. Laparotomy revealed a large abscess attached to the peritoneum in the lower abdomen. It proved to involve part of the terminal ileum, which had undergone necrosis. The abscess was drained and the necrotic bowel segment was resected. Decompression of the small intestine was performed and an ileostomy was created. After the operation the patient started to recover, her CRP level gradually declined, and she was discharged 18 days after the operation. Histological examination of the resected bowel segment showed a necrotic intestinal wall without signs of thrombosis or inflammation and there were no amyloid deposits. Subsequently, over a 2-year follow-up period, the patient has had three relatively mild TRAPS attacks but no severe abdominal symptoms.

image

Figure 1. Computer tomography of the abdomen. (a) The small intestine shows distended loops and air-fluid levels (arrows). The colon is empty (arrowheads). (b) A large triangular abscess with small air bubbles (arrow) and enhancement of its capsule (arrowheads) is revealed in the lower abdomen.

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Discussion

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Case report
  5. Discussion
  6. Conflict of interest statement
  7. Acknowledgements
  8. References

The attacks of TRAPS have a variable duration of 1–20 days [13] (Table 1), but frequently they last for more than 5 days, beginning with diffuse inflammatory symptoms that intensify during the first couple of days and continuing at maximum severity for 3 days or more [1]. The abdominal pain is described as severe, and is often associated with vomiting and constipation. The pain is usually diffusely localized to the lower abdomen, but lumbar pain associated with TRAPS attacks has also been described [13]. The symptoms have often led to laparotomy, upon which formation of adhesions between the bowels has been observed, and histological examination of the bowel has shown an infiltrate of mononuclear cells, indicating an inflammation of the serosa [1]. Other major symptoms in TRAPS include cramp-like myalgia, usually in a distinct group of muscles, as well as a migratory skin erythema. Scrotal and testicular involvement has also been reported [1]. The most common complication of TRAPS is the development of amyloidosis, having been reported in about 24% of patients with cysteine mutations and in 2% of patients with noncysteine mutations, at an average of 15% of all TRAPS families [1].

Table 1.  Hereditary syndromes manifesting themselves as periodically occurring abdominal pain and fever
Gene affected; chromosomal location; protein productDiseaseEthnic backgroundDuration of inflammatory attacksLocalization of abdominal painOther characteristic symptoms
  1. FMF, familial Mediterranean fever; HIDS, hyperimmunoglobulinaemia D with periodic fever syndrome; TRAPS, tumour necrosis factor receptor-associated periodic syndrome.

MEFV, 16p13.3; pyrin, marenostrinFMFCommon in populations of Mediterranean origin: Sephardic Jews, Armenians, Turks, Arabs12–72 hDiffusely locatedFever, erysipeloid erythema, pleuritis, pericarditis, myalgia, monoarthritis
MVK, 12q24; mevalonate kinaseHIDSMainly in European populations3–7 daysDiffusely locatedFever, maculopapular rash, cervical lymphadenopathy, polyarthritis
TNFRSF1A, 12p13; TNF receptor type I, TNFRSF1ATRAPSMost common in European populations, occurs also in other ethnic groupsOften more than 1 weekDiffusely locatedFever, pleuritis, migratory rash, myalgia, monoarthritis, conjunctivitis, periorbital oedema

In our patient with verified TRAPS heredity, the clinical features resembled those of previous febrile and inflammatory attacks, and the symptoms were thus initially attributed to TRAPS (Table 1). Indeed, upon admittance to the hospital, the patient's high fever and abdominal pain, as well as the high CRP level corresponded to her previous TRAPS attacks. The unusual severity and persistence of the symptoms, as well as the patient's deteriorating general condition were key factors in revealing an underlying cause other than TRAPS behind these symptoms.

The appearance of an abscess in a young patient, without predisposition to infections, requires some consideration. It has been shown that in systemic inflammatory reactions pro-inflammatory cytokines and nitric oxide cause dysfunction of intestinal epithelial cells and disrupt tight junctions between them [14]. The effect of TNF-α, on disrupting tight junctions in the intestinal epithelium [15] and on increasing tight junction permeability in intestinal epithelial cells, is mediated through activation of NF-κB [16]. An increase in intestinal permeability, caused by a rise in the intestinal intraluminal pressure, has also been reported in animal models of in vivo rabbit intestinal segments [17]. TRAPS is characterized by periodically occurring inflammation, believed to be due, in part, to inappropriately functioning TNFRSF1A and subsequent prolonged action of TNF-α. As the abnormal TNFRSF1A is inadequately cleaved from the cell surface, the intracellular protein cascade activated by TNF-α, upon binding to its transmembrane receptor, is kept activated for a prolonged period of time. It is tempting to speculate that the patient of this report would initially have had an attack of TRAPS, which caused an intestinal paralysis and an increase in intra-intestinal pressure. The subsequent increase in epithelial cell permeability and bacterial extravasation, possibly accelerated by the action of pro-inflammatory cytokines, may thereby have resulted in the formation of an intra-abdominal abscess.

Retrospectively, the diagnosis of an infectious process in the abdomen might have been attained earlier, had not the diagnosis of TRAPS been a misleading factor. Also, the systemic corticosteroid treatment, which had proved to alleviate the patient's recurrent TRAPS attacks, could have been potentially hazardous because of its ability to mask the symptoms of a bacterial infection. The case of this patient stresses the importance of differential diagnostic vigilance when dealing with patients with rare genetic diseases.

Acknowledgements

  1. Top of page
  2. Abstract.
  3. Introduction
  4. Case report
  5. Discussion
  6. Conflict of interest statement
  7. Acknowledgements
  8. References

This study was supported by grants from the Helsinki University Central Hospital Research Funds, the Finska Läkaresällskapet and the Finnish Medical Society Duodecim.

References

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  2. Abstract.
  3. Introduction
  4. Case report
  5. Discussion
  6. Conflict of interest statement
  7. Acknowledgements
  8. References
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