Correspondence

Familial Mediterranean Fever Gene

N Engl J Med 1998; 338:992-993April 2, 1998

Article

To the Editor:

Babior and Matzner (Nov. 20 issue)1 state that the recently identified familial Mediterranean fever (FMF) gene2,3 can be used to establish the diagnosis of this disease. However, the penetrance of the four described mutations is not known, and patients with pyrin, or marenostrin, mutations affecting only a single allele will remain a diagnostic challenge, as illustrated by the following case report.

Recurrent fever, abdominal pain, and pleural effusions developed in a 27-year-old Armenian man. Plasma C-reactive protein concentrations exceeded 100 mg per liter during the attacks but on other occasions were normal (<10 mg per liter). The results of numerous investigations were nondiagnostic, and the patient's symptoms responded partially to colchicine therapy. DNA analysis revealed that he was heterozygous for the Met694Val (“Med”)2 FMF mutation. However, continued fever, pleurisy, and radiographic changes suggested a diagnosis of pulmonary tuberculosis, which was confirmed bacteriologically. The patient's entire clinical course could be explained on the basis of tuberculosis infection and reactivation, whereas the clinical significance of his FMF mutation remains unclear.

Familial Mediterranean fever is an autosomal recessive disease carried by one in seven Armenians.4 The four described mutations in the pyrin gene occur in only 85 percent of carriers of familial Mediterranean fever chromosomes,2 and therefore, there may be other unidentified mutations or other factors able to promote the expression of the disease in patients with mutations affecting a single allele. Alternatively, some mutations may be dominant. These points are highlighted by the case of another patient of ours with long-standing classic familial Mediterranean fever in whom we have also identified a Met694Val mutation in only a single allele.

It is possible that features of the disease can develop in carriers of familial Mediterranean fever under certain circumstances. The absence of any identifiable mutation makes the diagnosis of familial Mediterranean fever unlikely, but the clinical significance of pyrin mutations affecting only a single allele is not yet clear.

Alison H. Holmes, M.D.
David R. Booth, Ph.D.
Philip N. Hawkins, F.R.C.P.
Hammersmith Hospital, London W12 0NN, United Kingdom

4 References

1. 1

   Babior BM, Matzner Y. The familial Mediterranean fever gene -- cloned at last. N Engl J Med 1997;337:1548-1549
   Full Text | Web of Science | Medline

2. 2

   The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17:25-31
   CrossRef | Web of Science | Medline

3. 3

   Balow JE Jr, Shelton DA, Orsborn A, et al. A high-resolution genetic map of the familial Mediterranean fever candidate region allows identification of haplotype-sharing among ethnic groups. Genomics 1997;44:280-291
   CrossRef | Web of Science | Medline

4. 4

   Rogers DB, Shohat M, Petersen GM, et al. Familial Mediterranean fever in Armenians: autosomal recessive inheritance with high gene frequency. Am J Med Genet 1989;34:168-172
   CrossRef | Web of Science | Medline

Citing Articles (7)

Citing Articles

1. 1

   Dina Marek-Yagel, Yackov Berkun, Shai Padeh, Almogit Abu, Haike Reznik-Wolf, Avi Livneh, Mordechai Pras, Elon Pras. (2009) Clinical disease among patients heterozygous for familial mediterranean fever. Arthritis & Rheumatism 60:6, 1862-1866
   CrossRef

2. 2

   Dimitrios Zonios, Clio P. Mavragani, Stavros Giaglis, Konstatinos Ritis. (2007) A novel mutation of the familial Mediterranean fever gene in a Greek family related to a non-classical, variably expressed FMF phenotype. Rheumatology International 28:2, 167-169
   CrossRef

3. 3

   Levon Yepiskoposyan, Ashot Harutyunyan. (2007) Population genetics of familial Mediterranean fever: a review. European Journal of Human Genetics 15:9, 911-916
   CrossRef

4. 4

   Merav Lidar, Mordechai Pras, Pnina Langevitz, Avi Livneh. (2002) Thoracic and lung involvement in familial Mediterranean fever (FMF). Clinics in Chest Medicine 23:2, 505-511
   CrossRef

5. 5

   Sabine Deckers, Etienne Delgrange, Michel Hoebeke, Karine Dahan, Julian Donckier. (1999) Non-Mediterranean periodic fever. The Lancet 353:9150, 382
   CrossRef

6. 6

   Jonathan Samuels, Ivona Aksentijevich, Yelizaveta Torosyan, Michael Centola, Zuoming Deng, Raman Sood, Daniel L. Kastner. (1998) Familial Mediterranean Fever at the Millennium. Medicine 77:4, 268-297
   CrossRef

7. 7

   Xavier Bosch, Mónica Pomares. (1998) Familial Mediterranean fever. The Lancet 351:9116, 1658
   CrossRef