Correspondence

Hereditary Periodic Fever

N Engl J Med 2002; 346:1415-1416May 2, 2002

Article

To the Editor:

Several details in the review article on hereditary periodic fever (Dec. 13 issue)1 warrant clarification. The authors state that the frequency of the susceptibility gene for familial Mediterranean fever is 1 in 135 among Ashkenazi Jews, a figure derived from population studies performed before the gene (MEFV ) was cloned. Since the advent of DNA analysis, we and others have reported a frequency of 1 in 5 among Ashkenazi Jews.2-4 The discrepancy may be due in part to the high frequency of the E148Q mutation, which may be associated with mild disease or nonpenetrance. The authors also suggest that the dose of colchicine in adults with familial Mediterranean fever may be increased to 3 mg per day — a dosage that, in our experience, is tolerated in only a small minority of patients.

With regard to the tumor necrosis factor (TNF) receptor–associated periodic syndrome, the authors mention that the risk of amyloidosis is increased in patients with a family history of amyloidosis. We agree but would like to note that persons harboring cysteine mutations in the p55 TNF receptor have a higher risk of amyloidosis than do those with noncysteine mutations.5 Finally, we would like to add a word of caution regarding the efficacy of etanercept in preventing amyloidosis in the TNF-receptor–associated periodic syndrome. Recently, new-onset nephrotic proteinuria developed in a patient with the C52F mutation who had been described in our original report on the TNF-receptor–associated periodic syndrome and who had been taking etanercept for more than two years, with dramatic improvement in symptoms. Her renal-biopsy specimen (Figure 1Figure 1Glomerular Amyloid Deposition in a Renal-Biopsy Specimen (Congo Red, ×400).) contained substantial amyloid deposits.

Keith M. Hull, M.D., Ph.D.
Daniel L. Kastner, M.D., Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892
hullk@mail.nih.gov

James E. Balow, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892

5 References

1. 1

   Drenth JPH, van der Meer JWM. Hereditary periodic fever. N Engl J Med 2001;345:1748-1757
   Full Text | Web of Science | Medline

2. 2

   Aksentijevich I, Torosyan Y, Samuels J, et al. Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. Am J Hum Genet 1999;64:949-962
   CrossRef | Web of Science | Medline

3. 3

   Stoffman N, Magal N, Shohat T, et al. Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. Eur J Hum Genet 2000;8:307-310
   CrossRef | Web of Science | Medline

4. 4

   Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R. Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 2001;9:634-637
   CrossRef | Web of Science | Medline

5. 5

   Aksentijevich I, Galon J, Soares M, et al. The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet 2001;69:301-314[Erratum, Am J Hum Genet 2001;69:1160.]
   CrossRef | Web of Science | Medline

To the Editor:

In their excellent review of hereditary periodic fever, Drenth and van der Meer state that monoarthritis of the knee, ankle, or wrist joints is the sole manifestation of an attack of familial Mediterranean fever in 75 percent of patients. The source of this information is probably the seminal article on this disease, published by Israeli investigators.1 Although it may be true that arthralgia and arthritis occur in nearly 75 percent of North African Jews with familial Mediterranean fever, rheumatologic manifestations of familial Mediterranean fever are distinctly uncommon among patients seen in the United States. In my own experience of providing care or consultation for numerous patients with familial Mediterranean fever in this country, I have been able to evoke a history of arthritis in fewer than 10 percent of them. Even in these patients, the arthritis is usually oligoarticular rather than monoarticular. Although the difference in the frequency of arthritis in the United States may be related to the fact that fewer Americans (whether Jewish or non-Jewish) than North African Jews have the M694V mutation in MEFV, it is likely that other factors, some of which may be environmental, play a part. In any event, it would be unfortunate if physicians were to lower their suspicion of familial Mediterranean fever in patients with periodic bouts of fever and abdominal pain if a history of monoarthritis cannot be elicited.

Stephen E. Goldfinger, M.D.
Massachusetts General Hospital, Boston, MA 02114
sgoldfinger@partners.org

1 References

1. 1

   Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med 1967;43:227-253
   CrossRef | Web of Science | Medline

To the Editor:

Drenth and van der Meer dismiss the value of measuring urinary mevalonate in establishing a diagnosis of the hyper-IgD syndrome caused by mevalonate kinase deficiency. In our experience, however, routine gas chromatography–mass spectroscopy is usually sufficiently sensitive to detect transient 50-to-200-fold elevations in the urinary mevalonate level, which typically peaks on the second or third day of fever in patients with the hyper-IgD syndrome.1 Moreover, we have found that the level of urinary mevalonate, when measured by isotope-dilution gas chromatography–mass spectroscopy, is diagnostically high (typically at least 5 to 10 times the upper limit of normal) at all times in patients with this syndrome. Similarly, Frenkel and colleagues2 recently reported the detection of increased urinary mevalonate levels during febrile crises in nine of nine children with mutation-positive hyper-IgD syndrome.

The existence of patients who have periodic fever, elevated urinary mevalonate levels, and mutations in MVK (the gene encoding mevalonate kinase) but who have normal serum IgD levels, including one in our recent experience, underscores the value of measuring urinary mevalonate, irrespective of the serum IgD level.

Richard I. Kelley, M.D., Ph.D.
Kennedy Krieger Institute, Baltimore, MD 21205
kelle_ri@jhuvms.hcf.jhu.edu

Kazuki Takada, M.D.
Ivona Aksentijevich, M.D.
National Institute of Arthritis and Musculoskeletal, and Skin Diseases, Bethesda, MD 20892

2 References

1. 1

   Kelley RI. Inborn errors of cholesterol biosynthesis. Adv Pediatr 2000;47:1-53
   Medline

2. 2

   Frenkel J, Houten SM, Waterham HR, et al. Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinemia D. Rheumatology (Oxford) 2001;40:579-584
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Hull and colleagues note that colchicine at a daily dosage of 3 mg may be poorly tolerated. Although we do not disagree, dosages higher than 2 mg per day are usually given for uncontrolled attacks of familial Mediterranean fever and only for a short period, to prevent acute colchicine toxicity.1 Furthermore, dosages that are higher than usual may be needed in patients who have limited absorption of the drug. Their observation of the development of (presumably amyloid A–type) nephropathic amyloidosis in a patient with the TNF-receptor–associated periodic syndrome during treatment with etanercept is very disturbing. It is hypothesized that in this type of reactive systemic amyloidosis, amyloid A fibrils stem from circulating, acute-phase protein serum amyloid A.2 Theoretically, etanercept treatment decreases serum amyloid A levels, leading to interruption of the amyloidogenesis. Of course, it can be speculated that amyloid deposits were already present in their patient and that the clinical picture developed later. On the other hand, it is possible that despite clinical remission, residual inflammation persisted and triggered the formation of amyloid.

Kelley and colleagues advocate the measurement of urinary mevalonate in patients with periodic fever to detect the hyper-IgD syndrome. As noted, the variability of urine mevalonate excretion in the hyper-IgD syndrome is large, and the amount secreted during remission is in most instances too low to be detected by routine gas chromatography–mass spectroscopy. As pointed out, the sensitivity of isotope-dilution gas chromatography–mass spectroscopy is higher, but this technique is not universally available. Furthermore, we have noted that urinary mevalonate excretion can be detected in patients with febrile disorders other than the hyper-IgD syndrome, possibly compromising the diagnostic potential of this measurement.

Goldfinger estimates that fewer than 10 percent of patients with familial Mediterranean fever in the United States have arthritic attacks, in contrast to the 75 percent reported elsewhere.3 To interpret these figures correctly, we have to consider that the occurrence of unilateral monoarticular arthritis is age-dependent: the frequency of arthritic attacks decreases and the frequency of pleuroperitoneal attack increases with increasing age.4 Furthermore, environmental factors probably play a part. For example, arthritis occurs in 44 percent of Armenian patients living in Yerevan, as compared with 34 percent of those residing in the United States.5

Joost P.H. Drenth, M.D., Ph.D.
Jos W.M. van der Meer, M.D., Ph.D.
University Hospital St. Radboud, 6500 HB Nijmegen, the Netherlands
joostphdrenth@cs.com

5 References

1. 1

   Ben-Chetrit E, Levy M. Colchicine: 1998 update. Semin Arthritis Rheum 1998;28:48-59
   CrossRef | Web of Science | Medline

2. 2

   Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 2001;358:24-29
   CrossRef | Web of Science | Medline

3. 3

   Majeed HA, Rawashdeh M. The clinical patterns of arthritis in children with familial Mediterranean fever. QJM 1997;90:37-43
   Medline

4. 4

   Barakat MH, Karnik AM, Majeed HA, el-Sobki NI, Fenech FF. Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs: a study of 175 patients and review of the literature. Q J Med 1986;60:837-847
   Web of Science | Medline

5. 5

   Mimouni A, Magal N, Stoffman N, et al. Familial Mediterranean fever: effects of genotype and ethnicity on inflammatory attacks and amyloidosis. Pediatrics 2000;105:1150-1150 abstract.
   CrossRef | Web of Science

Citing Articles (11)

Citing Articles

1. 1

   Juan I. Aróstegui. (2011) Hereditary systemic autoinflammatory diseases. Reumatolog ía Cl ínica (English Edition) 7:1, 45-50
   CrossRef

2. 2

   Karyl Barron, Balu Athreya, Daniel Kastner. 2011. PERIODIC FEVER SYNDROMES AND OTHER INHERITED AUTOINFLAMMATORY DISEASES. , 642-660.
   CrossRef

3. 3

   Petra Lehmann, Bernd Salzberger, Peter Haerle, Ivona Aksentijevich, Daniel Kastner, Juergen Schoelmerich, Stephanie Rosenfeld, Ulf Mueller-Ladner. (2010) Variable intrafamilial expressivity of the rare tumor necrosis factor-receptor associated periodic syndrome-associated mutation I170N that affects the TNFR1A cleavage site. Modern Rheumatology 20:3, 311-315
   CrossRef

4. 4

   Adriana A. Jesus, João B. Oliveira, Ivona Aksentijevich, Erika Fujihira, Magda M. S. Carneiro-Sampaio, Alberto J. S. Duarte, Clovis A. A. Silva. (2008) TNF receptor-associated periodic syndrome (TRAPS): Description of a novel TNFRSF1A mutation and response to etanercept. European Journal of Pediatrics 167:12, 1421-1425
   CrossRef

5. 5

   Juan I. Aróstegui, Jordi Yagüe. (2007) Enfermedades autoinflamatorias sistémicas hereditarias. Síndromes hereditarios de fiebre periódica. Medicina Clínica 129:7, 267-277
   CrossRef

6. 6

   C. Huemer, M. Huemer. (2006) Genetische Fiebersyndrome. Zeitschrift für Rheumatologie 65:7, 595-603
   CrossRef

7. 7

   Leigh D. Church, Sarah M. Churchman, Philip N. Hawkins, Michael F. McDermott. (2006) Hereditary auto-inflammatory disorders and biologics. Springer Seminars in Immunopathology 27:4, 494-508
   CrossRef

8. 8

   Silvia Stojanov, Daniel L Kastner. (2005) Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Current Opinion in Rheumatology 17:5, 586-599
   CrossRef

9. 9

   Keith M. Hull, Nitza Shoham, Jae Jin Chae, Ivona Aksentijevich, Daniel L. Kastner. (2003) The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations. Current Opinion in Rheumatology 15:1, 61-69
   CrossRef

10. 10

    Michael F McDermott. (2002) Genetic clues to understanding periodic fevers, and possible therapies. Trends in Molecular Medicine 8:12, 550-554
    CrossRef

11. 11

    KEITH M. HULL, ELIZABETH DREWE, IVONA AKSENTIJEVICH, HARJOT K. SINGH, KONDI WONG, ELIZABETH M. MCDERMOTT, JANE DEAN, RICHARD J. POWELL, DANIEL L. KASTNER. (2002) The TNF Receptor-Associated Periodic Syndrome (TRAPS). Medicine 81:5, 349-368
    CrossRef