American Journal of Medical Genetics 44:179-182 (1992)

Twin Studies in Familial Mediterranean Fever M. Shohat, A. Livneh, D. Zemer, M. Pras, and E. Sohar The Heller Institute of Medical Research, Sheba Medical Center, Tel Hashomer (A.L., DZ.,M.P., E.S.), and Department of Medical Genetics, Felsenstein Medical Research Center, Children Hospital, Beilinson Medical Center, Petah Tikva (M.S.).,Tel Auiv University Medical School, Israel Familial Mediterranean fever (FMF) is a genetic disease characterized by recurrent short episodes of fever, accompanied by peritonitis, pleuritis, or arthritis. The disease is almost completely ethnically restricted to patients of Mediterranean d e s c e n t s e p h a r d i c Jews, Armenians, Anatolian ’hrks, and Arabs. Although many family studies have been performed, no twin study has been reported as yet. We studied 21 di- and monozygotic twin sets, identified among the 1,943 FMF patients in our registry. Full concordance was observed in all the 10 monozygotic twin sets. In the 11 dizygotic twins, concordance for FMF disease was found in only 3 pairs. Variability in the clinical manifestations and degree of severity have been noted within twins. These findings provide definitive evidence for the genetic cause of FMF. They also support the single gene autosomal recessive model, and provide support for the contention that the lower observed than expected incidence found in FMF is due to genetically affected but clinically undiagnosed patients. 0 1992 Wiley-Liss, Inc.

KEY WORDS twins, penetrance, expressivity INTRODUCTION Familial Mediterranean fever (FMF) is a genetic disorder characterized by recurrent short attacks of fever accompanied by peritonitis, pleuritis, or arthritis and insidious development of amyloidosis, leading to terminal renal failure [Siegel, 1945; Mamou and Cattan, 1952; Heller et al., 1958,1961; Sohar et al., 1961,1967; Schwabe and Peters, 1974; Eliakim et al., 19811. There is no reliable specific biochemical test and diagnosis is

Received for publication November 13, 1991; revision received February 18, 1992. Address reprint requests to Mordechai Shohat, M.D., Director, Medical Genetics, Beilinson Medical Center, 49100 Petah Tikva, Israel.

0 1992 Wiley-Liss, Inc.

based entirely on clinical criteria [Sohar et al., 19671. Patients whose attacks are less intense or patients who are phenotype I1 (present with amyloidosisprior t o FMF attacks), may remain undiagnosed. The genetic cause of FMF was suspected on the basis of familial aggregation [Siegel, 1945; Mamou and Cattan, 1952; Heller et al., 1958; Sohar et al., 1961, 1967; Schwabe and Peters, 1974; Khachadurian and Armenian, 1974; Naffah et al., 1975; Rogers et al., 19891 and markedly increased frequency among those of Mediterranean descentsephardic Jews, Armenians, Anatolian lhrks, and Arabs [Siegel, 1945; Heller et al., 1958; Schwabe and Peters, 1974; Eliakim et al., 19811. However,neither familial aggregationnor differences in genetic frequency among ethnic groups definitely Drove a genetic cause, and studies to separate common genetic from common environmental factors, such as twins, spouse, and adoption studies have not been undertaken in FMF. In addition, most segregation analyses, although suggesting autosomal recessive transmission, have always found a significant lower “observed”than “expected number of patients [Sohar et al., 1961; Khachadurian and Armenian, 1974;Naffah et al., 1975; Rogers et al., 19891. This finding may be due to incomplete penetrance or to underdiagnosis of clinically affected patients. This paper reports a study of a cohort of twins with FMF in order to evaluate this issue. PATIENTS AND METHODS Twins with FMF were selected for this study from a total of 1,943 patients on the roster of the National Center for FMF at the Tel Hashomer Hospital. This clinic is the referral center for all FMF patients in Israel and it is assumed that at least one member of most FMF families living in Israel is being followed there. Twenty-onepairs of twins, all of them SephardicJews, were identified in whom one or both were diagnosed as having FMF, based on the criteria of Sohar et al. [1967]. All pairs were then reexamined individually in the clinic by the same investigator. Complete medical history was recorded, including pregnancy, delivery, birth weight, perinatal complications, age-at-onset of FMF, types of FMF attacks, age at the initiation of prophylactic colchicine treatment, and response of the attacks to the drug, presence of amyloidosis,and existence of other diseases. Physical examination for twin identity was

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one episode of peritonitis and 2 episodes of pleuritis, during one of which he was hospitalized. In pair 5 , one twin had severe attacks of peritonitis and arthritis for which he had been treated with 2 mg per day colchicine. The second twin had a few attacks of abdominal pain. None of the M Z twins showed clinical signs of amyloidosis. Greater discrepancies occurred in the age of onset. In 7 of the 13twin pairs, age of onset was the same RESULTS or very close for both twins of each pair. In the other 6 Ofthe 21 pairs of twins, 10 were monozygotic (MZ, 12 sets, age of onset differed among each pair between 4 and males, 8 females), and 11 dizygotic (DZ, 8 males, 14 14 years (mean: 10 years). females). Single chorionic membranes occurred in twin pairs 8 and 9. Nonidentity was determined by either DISCUSSION DNA studies (pair 131, or significant dissimilarities in This study demonstrates full concordance for FMF in height, eye color, or sex difference. Tables I and I1 depict the clinical information col- all 10 sets of MZ twins and 3 of the 11 DZ twin pairs. lected. Except for one MZ pair of twins (pair 71, all were These findings confirm that FMF is a genetic disorder over age 10years and most of them over 20. While only 3 with autosomal recessive transmission [Sohar et al., pairs of DZ twins were concordant for FMF, full concor- 1961; Rogers et al., 19891. In any population, the rate of dance was found in all 10 MZ twin pairs. Of the 13 twin twins is around 1230, two-thirds of them DZ. Therefore, sets in which both twins were affected, in 11pairs symp- 16 FMF patients followed up a t the clinic should have toms and types of attacks were identical or very similar been one of a pair of DZ twins. The somewhat reduced in both twins (Tables I, 11).Marked variability in the ascertainment of this type of twins may be due to the clinical manifestations within 2 MZ twin pairs has been fact that no attention was paid t o this detail when family observed (pairs 4 and 5). In each pair, one of the twins history was originally obtained prior to this study. Inwas not diagnosed as affected prior to this study. In pair deed, several DZ twin sets (pairs 11,14,17,18,19,and 20) 4, one twin had recurrent attacks of pleuritis with high were identified prospectively as such only during this fever since he was 10, while his brother reported only study. The segregation ratio among the DZ twins in this

completed in all cases. Except for twin pairs 7-9, who refused to provide blood samples, a blood test for identity by DNA fingerprinting techniques [Jeffreys et al., 19851 was performed in all the twin sets who did not have major dissimilarities (more than 10 cm difference in height, sex differences, completely different hairleye color, etc.).

TABLE I. Summary of Clinical Findings in 10 Monozygotic Twin-Pairs Twin set

Agelsex

Age onset

a b

41lM

34 23

a b

20n7

10 6

a b

22/F

6 6

+ + + + +

a b

35lM

10 34

+

a b

35lF

a

34lM

5 5

a b

4/M

2

a b

16lF

3 3

a b 10 a b

i81M

10 10

81M

3 4

1 2

3 4 .

5 10

20

6 b

7

2

8

9

Per

+

+ + +

+ + + + + + +

Type of attacks" Art Pleu Fev

+ + + +

+ + + + + +

+

DNA

+ + + + +

DNA

+

Notes

DNA DNA Undiagnosed DNA Undiagnosed

+

+

+ + + +

Identity by

+

DNA

+ + +

Clinical

+

Clinical

Single chorion

+

Clinical

Single chorion

+ +

DNA

+

+

"Fev,attacks of fever only; Per, attacks of fever with peritonitis; Art, attacks of fever with arthritis; Pleu, attacks of fever with pleuritis.

Twin Studies in FMF

181

TABLE 11. Summary of Clinical Findings in 11 Dizygotic Twin-Pairs Twin set 11 a

Agelsex

Age onset

351F lSblF

-

40lM 40lM

19

a

391M 39lM

24 10

b 12

a

b 13 b 14

2

-

a

251F

b 15

25lF

11 11

a

441M 44IM

40

a

33/F 33lF

20 14

a

111M lllF

-

301F 301F

15

b 16 b 17 b 18 a

-

1

-

Per

+ +

+ +

+

Clinical

+ + + +

DNA Clinical Clinical

+

+

+ + +

+

+

+ +

+

+

Clinical

+

+

Clinical

181F

9

18lF

-

26lF

a b 21

19

-

+

26lM

a

39/F 39lF

17 17

+

Notes

Clinical

+ +

a

b

+ + +

Nonidentitv bv

+

b 20

+

+ + + +

+ +

b 19

Type of attacka __ Art Pleu Fev

+

Clinical Clinical Clinical Clinical

Separate placenta

a Fev, attacks of fever only; Per, attacks of fever with peritonitis; Art, attacks of fever with arthritis; Pleu, attacks of fever with pleuritis. Died at age 16 of amyloidosis.

study is therefore between 0.27 and 0.19, consistent with autosomal recessive inheritance. Full concordance for FMF in the MZ twins was observed in this study, suggesting that underdiagnosis of afflicted patients rather than incomplete penetrance is mainly responsible for a lower than expected segregation ratio for recessive transmission. Indeed, marked variability in age of onset was found in 6 pairs. Marked variability in clinical manifestations was found in only 2 MZ twins, in that one of each pair was not diagnosed as an FMF patient prior to this study. Therefore, the reduced penetrance reported in segregation analyses may be explained by the extreme clinical variability, and thus an unaffected relative in previous studies may be affected if carefully examined. Sibs of FMF patients should be examined periodically, especially for proteinuria. This might help in preventing amyloidosis, which may develop in patients without attacks (phenotype 11) [Sohar et al., 19671. Since no specific biochemical test is available for FMF and in the light of the present study, which appears to show close to 100%genetic penetrance but a t the same time extreme variation is expression, mapping of the FMF gene is eagerly awaited to better identify patients.

ACKNOWLEDGMENTS “his study was supported by Grant #88-0098/1from the US-Israel National Science Foundation (BSF),Jerusalem, Israel. REFERENCES Eliakim M, Levy M, Ehrenfeld M (1981):“Recurrent Polyserositis (Familial Mediterranean Fever, Periodic Disease).” Amsterdam: ElsevierNorth Holland Biomedical Press, p. 1-207. Heller H, Sohar E, Gafni J, Heller J (1961):Amyloidosis in familial Mediterranean fever. Arch Intern Med 107:539-550. Heller H, Sohar E, Sherf L (1958):Familial Mediterranean fever. Arch Intern Med 10250-71. Jeffreys AJ, Wilson V, Thein SL (1985):Hypervariable minisatellite regions in human DNA. Nature 314:67-73. Khachadurian AK, Armenian HK (1974):Familial paroxysmal polyserositis (familial Mediterranean fever) incidence of amyloidosis and mode of inheritance. BD:OAS X(4):62-66. Mamou H,Cattan R (1952):La maladie p6riodique (sur 14 cas personnels dont 8 compliquks de nephropathies). Semaine HBp Paris 28:1062-1070. Naffah J, Bitar E, Nasr W, Khouri K (1975):Etude g6n6tique de la polyserite pazoxystique familiale, a propos de 72 cas. Nouv Resse Med 4:1031-1037.

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Rogers DB, Shohat M, Petersen GM, Bickal J, Congleton J, Schwabe A, Rotter JI (1989): Familial Mediterranean fever in Armenians: autosoma1 recessive inheritance with high gene frequency. Am J Med Genet 34:168-172. Schwabe AD, Peters RS (1974):Familial Mediterranean fever in Armenians: Analysis of 100 cases. Medicine 53:53-46.

Siege1 S (1945):Benign paroxysmal peritonitis. Ann Intern Med 23:l-21. Sohar E, Gafni J, Pras M, Heller H (1967):Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43:227-253. Sohar E, b a s M, Heller J, Heller H (1961):Genetics of familial Mediterranean fever. Arch Intern Med 107:529-538.

Twin studies in familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a genetic disease characterized by recurrent short episodes of fever, accompanied by peritonitis, pleuritis, or ...
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