1Departments of Infectious Diseases and Immunology, Children's Hospital and 2Clinical Chemistry-Grosshadern, University of Munich, Germany and Departments of 3Diabetes and Metabolic Medicine and 4Immunology, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK
Correspondence to S. Stojanov, Department of Infectious Diseases and Immunology, Children's Hospital, University of Munich, Lindwurmstr. 4, 80337 Munich, Germany. E-mail: Silvia.Stojanov{at}med.uni-muenchen.de
SIR, The hereditary periodic fever syndromes are characterized by recurrent episodes of fever due to multisystemic inflammation. In the case of autosomal dominantly inherited tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), these attacks are associated with severe abdominal pain, localized myalgia, painful migratory erythematous skin rash, conjunctivitis and/or periorbital oedema. TRAPS is caused by sequence alterations in the TNFRSF1A gene, which encodes the 55-kDa TNF receptor [1].
Familial Mediterranean fever (FMF) is the most common autosomal recessively inherited periodic fever syndrome. Attacks of FMF are of 13 days duration and characterized by polyserositis (mainly peritonitis) and colchicine responsiveness [2]. FMF is caused by mutations in the MEFV gene, which encodes the protein pyrin/marenostrin [3]. E148Q is one of the five most common MEFV mutations and has a high allele frequency among healthy Chinese controls, being present on 15% of the alleles [4]. In combination with a second MEFV mutation, E148Q has an aggravating effect, while homozygosity or heterozygosity for this mutation is generally not associated with disease. Asymptomatic E148Q heterozygotes may, however, show a subclinical inflammatory syndrome with increased baseline erythrocyte sedimentation rate (ESR) and increased plasma levels of C-reactive protein (CRP) and serum amyloid A (SAA), reflecting chronic non-specific inflammation [4].
We report a 12-yr-old Chinese male patient presenting with recurrent episodes of fever up to 40°C since the age of 1 yr. These episodes were preceded by severe abdominal pain, lasting 23 weeks, and occurred at intervals of about 3 months. Since the age of 11 yr, the febrile attacks have shortened to about 4 days and symptom-free intervals have reduced to 24 weeks. Regularly associated symptoms included headache, pharyngitis and mild exudative tonsillitis, with occasional arthralgias, diarrhoea and non-specific rashes. Lymphadenopathy, splenomegaly, myalgia, conjunctivitis and periorbital oedema were absent. During attacks, a pronounced acute-phase response was observed, with leucocytosis (maximum 19.8 x 103/l), a high ESR (maximum 123/145 mm/h), CRP levels up to 26.4 mg/dl, and SAA values up to 116 mg/l. Elevated serum immunoglobulin (Ig) A (maximum 627 mg/dl) and IgM (maximum 277 mg/dl) were continuously present.
Colchicine treatment over 4 yr had no effect. The attacks disappeared completely within a few hours after a single dose of prednisone (2 mg/kg), given during the first day of the febrile episode. Non-steroidal anti-inflammatory agents also had a temporary effect in reducing high temperatures and arthralgias. The boy is thriving normally, and all other family members are healthy.
In view of the possibility of periodic fever, the TNFRSF1A and MEFV genes were screened for mutations after written informed consent for blood drawing and the genetic analyses were obtained from the patient's parents. Soluble tumour necrosis factor receptor superfamily member 1A (sTNFRSF1A) was measured in plasma samples of the asymptomatic boy and family members, and cellular TNFRSF1A expression and shedding analyses were performed by FACS (fluorescence-activated cell sorter), using monocytes from the patient and his healthy father [1]. The study was approved by the Ethics Committee of the Ludwig-Maximilians-University in Munich and was conducted according to the Helsinki Committee standards.
DNA sequence analysis revealed that the boy was a heterozygous carrier of a novel T145G transversion in exon 2 of the TNFRSF1A gene, leading to the replacement of tyrosine (TAT) by aspartic acid (GAT) at amino acid position 20 (Y20D; Fig. 1). This nucleotide substitution was not present in the genomic DNA of his parents and his two siblings. In addition, the proband and his asymptomatic father were heterozygous carriers of the MEFV E148Q variant. sTNFRSF1A concentrations were within the normal range in all family members. FACS analysis showed that shedding of TNFRSF1A receptor was entirely normal in monocytes of both the patient and his healthy father.
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The boy presented with the typically prolonged febrile episodes of TRAPS in combination with severe abdominal pain and, occasionally, arthralgia. This clinical picture is similar to that of a 49-yr-old woman carrying the TNFRSF1A Y20H mutation [5], but with certain differences regarding disease onset, skin lesions and the development of amyloidosis. Both individuals were unsuccessfully treated with colchicine, whereas glucocorticoids shortened the duration of their attacks.
Heterozygosity for MEFV E148Q may serve as a disease modifier, resulting in a more severe phenotype. The combination of a heterozygous MEFV mutation with a TNFRSF1A mutation has been described for the MEFV E148Q and V726A substitutions and for the TNFRSF1A R92Q variant; the latter is known to be a low-penetrance mutation [5].
Until now, the boy has not shown any clinical signs of amyloidosis, despite prolonged elevation of acute-phase reaction proteins and the presence of the proinflammatory E148Q mutation.
The authors have declared no conflicts of interest.
References