liefs, and prior screening behavior among blacks and whites report-ing for prostate cancer screening. Urology. 1995;46:346 –351.

14. McCoy CB, Anwyl RS, Metsch LR, et al. Prostate cancer in Florida.Knowledge, attitudes, practices, and beliefs. Cancer Pract. 1995;3:88 –93.

15. Mainous AG, Hagen MD. Public awareness of prostate cancer andthe prostate-specific antigen test. Cancer Pract. 1994;2:217–221.

16. Zemencuk JK, Hayward RA, Skarupski KA, Katz SJ. Patients’ de-sires and expectations for medical care: a challenge to improvingpatient satisfaction. Am J Med Qual. 1999;14:21–27.

17. Zemencuk JK, Feightner JW, Hayward RA, et al. Patients’ desiresand expectations for medical care in primary care clinics. J GenIntern Med. 1998;13:273–276.

18. American Cancer Society. Cancer Facts and Figures. Atlanta, Ga:American Cancer Society; 1998.

19. American College of Physicians. Clinical guideline: part III. Screen-ing for prostate cancer. Ann Intern Med. 1997;126:480 – 484.

From the Center for Practice Management and Outcomes Research (JKZ,RAH), Ann Arbor VA Medical Center Health Services Research and De-velopment Field Program, the Departments of Internal Medicine andHealth Management and Policy (RAH, SJK), and the Consortium forHealth Outcomes, Innovation and Cost-Effectiveness Studies (CHOICES)(SJK), The University of Michigan, Ann Arbor, Michigan.

Supported by the Research and Education Foundation of the AmericanMedical Association and by the V.A. Center for Practice Management andOutcomes Research. Dr. Katz was a Robert Wood Johnson Generalist Fac-ulty Scholar at the time of this study. The opinions herein are those of theauthors and not necessarily those of the Robert Wood Johnson Foundationor the Department of Veterans Affairs.

Correspondence should be addressed to Judith K. Zemencuk, MA, Vet-erans Affairs’ Center for Practice Management and Outcomes Research,PO Box 130170, Ann Arbor, Michigan 48113-0170.

Manuscript submitted May 10, 2000, and accepted in revised formNovember 6, 2000.

Familial Periodic Feverand Amyloidosis Due to aNew Mutation in theTNFRSF1A GeneAnna Simon, MD, Catherine Dode, PhD,Jos W. M. van der Meer, MD, PhD,Joost P. H. Drenth, MD, PhD

Establishing a diagnosis in patients with recurrentepisodes of fever is often very difficult (1,2). Theepisodes of fever and signs of inflammation may

lead to a considerable morbidity, and to notable frustra-tion in patients and doctors as extensive diagnostic at-tempts often fail to reveal the cause. However, after rulingout infectious causes for the febrile attacks, one shouldconsider syndromal causes of periodic fever. At leastthree separate periodic fever syndromes have been recog-

nized: hyper-immunoglobulin (Ig)D and periodic feversyndrome (HIDS, MIM260920), the tumor necrosisfactor (TNF)-receptor associated periodic syndrome(TRAPS, MIM142680), and the best known and mostprevalent syndrome, familial Mediterranean fever (FMF,MIM249100). The identification of causative genes foreach of them (3–7) has greatly advanced diagnostic pos-sibilities and has implications for treatment as well.

We present the following observation as an example ofa typical familial case of periodic fever and amyloidosis.With the use of molecular tools we were able to make adefinitive diagnosis of TRAPS.

CASE REPORT

A 61-year old woman of Dutch-Indonesian ancestry wasreferred because of recurrent episodes of high fever andproteinuria. She had her first attack of fever as a 9-year-old child in Indonesia. At that time no elaborate diagnos-tic procedures were performed, and the recurrent feverwas attributed to attacks of malaria. She moved to theNetherlands at the age of 21 years, and shortly thereaftershe was admitted to a hospital because of a 3-week-longattack of fever, which subsided spontaneously. No perti-nent diagnosis could be made. From that time onward,the fever episodes occurred approximately twice a yearand generally lasted up to 3 weeks. Usually, a short courseof steroids was administered because the impression ex-isted that this ameliorated the attacks. Apart from fever,generalized myalgia, and fatigue during the attacks she

Figure 1. A. Family tree, index patient indicated by arrow. Linethrough a symbol 5 deceased; f 5 affected, e 5 unaffected,

5 carrier of mutation without clinical symptoms. B. DNAsequence electrospherogram of C70Y mutation (TGC3 TAC,indicated by arrow) in the gene for the type 1 TNF-receptor,which is found in the affected members of this family. C. DNAsequence of a healthy person with normal pattern (TGC) atposition 70.

Familial Periodic Fever and Amyloidosis Due to a New Mutation/Simon et al

March 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 313

had no specific symptoms. During each of her three (un-complicated) pregnancies she was free from symptoms,but after each delivery she experienced a severe febrilebout. Attacks could further be provoked by emotionaland physical stress. She gave a positive family history. Hersister, who died at age 47 due to breast carcinoma, hadexperienced similar febrile attacks during life. Three ofher sister’s six children and three of her sister’s five grand-sons were also affected (Figure 1). Symptoms and perti-nent laboratory results of our patient and four affectedrelatives are summarized in Table 1. There are notenough data available to determine definitely which ofthe parents of our patient transmitted the disease to theiroffspring. It is also unclear whether the disease originatedfrom the Dutch or Indonesian side of the family.

Our patient noticed an increase in the frequency of thefever attacks after reaching menopause to about 4 or 5times each year. In the following years she developed re-nal failure, despite colchicine treatment. Both rectal andrenal biopsies showed evidence of type AA amyloidosis.Since 1997 she has been dependent on intermittent he-modialysis. Most remarkably, the decrease of renal func-tion coincided with a cessation of fever episodes, andsince 1996 she has been free from attacks (Figure 2)

The autosomal dominant inheritance, the long dura-tion of attacks, and the (partial) response to steroids re-minded us of TRAPS. After sequencing the TNFRSF1Agene, which codes for the p55 TNF-receptor, the incrim-inated molecule in TRAPS (8), we discovered a novel mis-sense mutation in our patient: cystine replaces tyrosine atposition 70 of the amino acid sequence of the protein(C70Y, Figure 1). The C70Y mutation has been found in10 of 17 tested family members, 2 of whom remainasymptomatic up to this day, which suggests a penetranceof 80%. With the exception of our patient (II:1), the af-fected family members had low concentrations of solubleTNFRSF1A in their blood (Table 1) as measured by en-zyme-linked immunosorbent assay (9).

DISCUSSION

The acronym TRAPS was recently suggested by McDer-mott et al (3) to be used for a group of autosomal domi-nantly inherited periodic fever syndromes previouslyknown by several names (eg, familial Hibernian fever,familial periodic fever). Patients experience recurrent at-tacks of fever accompanied by abdominal pain, myalgia,skin lesions, and conjunctivitis. Nephropathic reactiveamyloidosis of the AA type has been reported in 4 patientsup till now (10,11). The attacks occur in varying fre-quency and generally last 2 to 3 weeks. Laboratory exam-ination reveals acute phase response. The autosomal Tab

le1.

Clin

ical

Feat

ure

san

dLa

bora

tory

Res

ult

sof

Aff

ecte

dFa

mily

Mem

bers

Indi

vidu

al

Age

(Yrs

)A

ttac

ksSy

mpt

oms

and

Sign

s

C-r

eact

ive

Pro

tein

(mg/

L)

Labo

rato

ryR

esu

lts

Cu

rren

tO

nse

tLe

ngt

h(D

ays)

Freq

uen

cyM

yalg

iaA

bdom

inal

Pai

nP

leu

ral

Pai

nR

ash

Red

Eye

sIn

guin

alH

ern

ia

Seru

mA

myl

oid

AP

rote

in(m

g/L)

Solu

ble

TN

FRSF

1A

(ng/

mL)

Solu

ble

TN

FRp7

5(n

g/m

L)

II:1

*61

921

†Y

esN

oN

oN

oN

oN

A2.

70.

910

.522

.0II

I:4

458

141x

/yr

Yes

Yes

Yes

Yes

Yes

NA

152.

50.

813.

23IV

:120

514

1x/y

rY

esY

esN

oY

esY

esN

o8

3.2

0.66

3.28

IV:2

180

141x

/yr

Yes

Yes

Yes

Yes

Yes

Yes

285.

91.

003.

80IV

:315

221

1-2x

/yr

No

Yes

Yes

Yes

Yes

No

105

110.

693.

15

Indi

vidu

alis

gen

erat

ion

and

nu

mbe

rfr

omfa

mily

tree

(Fig

ure

1).

*Pro

ban

dan

dm

ain

subj

ect

ofth

iscl

inic

alob

serv

atio

n.

†V

aryi

ng

freq

uen

cydu

rin

glif

e,n

own

oat

tack

san

ymor

e,se

ete

xtfo

rde

tails

.C

-rea

ctiv

epr

otei

n(n

orm

al,

2.7

mg/

L)‡

Mea

sure

din

seru

m;s

eru

mam

yloi

dA

prot

ein

(nor

mal

,4.

2m

g/L)

‡M

easu

red

inse

rum

;sT

NFR

5so

lubl

eT

NF-

rece

ptor

con

cen

trat

ion

sin

plas

ma;

p55

5ty

pe1

(mea

n5

1.50

ng/

mL)

;p75

5ty

pe2

(mea

n5

2.51

ng/

mL)

.All

labo

rato

rym

easu

rem

ents

wer

edo

ne

from

sam

ples

take

nin

the

atta

ck-f

ree

inte

rval

.

Familial Periodic Fever and Amyloidosis Due to a New Mutation/Simon et al

314 March 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110

dominant inheritance pattern is one of the main charac-teristics that distinguishes TRAPS from the two othermain periodic fever syndromes, familial Mediterraneanfever and hyperimmunoglobulinemia D and periodic fe-ver syndrome, both being autosomal recessive.

The gene responsible for TRAPS is located on the shortarm of chromosome 12 (12,13) and encodes for the typeI receptor of TNF (TNFRSF1A) (3). The TNFRSF1A pro-tein is a cell membrane coupled receptor expressed on alarge variety of cells. TNF has many effects, includinginduction of cytokine secretion, increased expression ofadhesion molecules on leukocytes and endothelial cells,activation of leukocytes, fever, and cachexia. Activationof the receptor also leads to a specific negative feedbackmechanism called shedding: the receptor is cleaved by aprotease, by which the extracellular part of the receptor isreleased in a soluble form into the extracellular space,where it can act as a competitive inhibitor of TNFRSF1A.Mutations in this gene lead to a structural change in theextracellular part of the receptor and it has been suggestedthat this impairs shedding of the receptor (3). Followingthis hypothesis, the autoinflammatory phenotype ofTRAPS results from an impaired downregulation ofmembrane-bound TNFRSF1A, and decreased formationof soluble TNFRSF1A (3). As a consequence, a trivial trig-ger leads to an uncontrolled inflammatory response.

Until recently, no adequate treatment for TRAPS wasavailable and attacks were treated symptomatically byoral steroids and colchicine with varying results. After thediscovery of the molecular defect, the administration ofrecombinant soluble TNF receptors became a logicaltherapeutic step. Indeed, in selected patients it seemsbeneficial with a decrease in frequency of attacks (14). Wedid not treat our patient with recombinant soluble TNFreceptors because she did not have any further attacks orevidence of acute phase response. As soluble TNF recep-tors are cleared from the body by the kidneys, we ex-

pected high concentrations in our patient because of co-existing renal failure. This was confirmed: plasma con-centrations of soluble TNF receptor were clearly elevated(Table 1). As shown in Figure 2 the cessation of feverepisodes in our patient coincided with the deteriorationof her renal function. A relation between these two obser-vations could be explained by the increase in concentra-tion of soluble TNFRSF1A, which could protect her fromfurther attacks of fever.

ACKNOWLEDGMENTSWe would like to thank Johanna van der Ven-Jongekrijg for hertechnical assistance.

REFERENCES1. Knockaert DC, Vanneste LJ, Bobbaers HJ. Recurrent or episodic

fever of unknown origin. Review of 45 cases and survey of the lit-erature. Medicine (Baltimore). 1993;72:184 –196.

2. De Kleijn EM, Vandenbroucke JP, Van der Meer JW. Fever of un-known origin (FUO). I. A prospective multicenter study of 167patients with FUO, using fixed epidemiologic entry criteria. TheNetherlands FUO Study Group. Medicine (Baltimore). 1997;76:392– 400.

3. McDermott MF, Aksentijevich I, Galon J, et al. Germline mutationsin the extracellular domains of the 55 kDa TNF receptor, TNFR1,define a family of dominantly inherited autoinflammatory syn-dromes. Cell. 1999;97:133–144.

4. Drenth JP, Cuisset L, Grateau G, et al. Mutations in the gene en-coding mevalonate kinase cause hyper-IgD and periodic fever syn-drome. Nat Genetics. 1999;22:178 –181.

5. Houten SM, Kuis W, Duran M, et al. Mutations in MVK, encodingmevalonate kinase, cause hyperimmunoglobulinaemia D, and pe-riodic fever syndrome. Nat Genetics 1999;22:175–177.

6. The International FMF Consortium. Ancient missense mutationsin a new member of the RoRet gene family are likely to cause famil-ial Mediterranean fever. Cell. 1997;90:797– 807.

7. The French FMF Consortium. A candidate gene for familial Medi-terranean fever. Nat Genetics. 1997;17:25–31.

8. Dode C, Papo T, Fieschi C, et al. A novel missense mutation (C30S)in the gene encoding tumor necrosis factor receptor 1 linked toautosomal dominant recurrent fever with localized myositis in aFrench family. Arthritis Rheum. 2000;43:1535–1542.

9. Drenth JPH, Van Deuren M, Van der Ven-Jongekrijg J, et al. Cyto-kine activation during attacks of the hyperimmunoglobulinemia Dand periodic fever syndrome. Blood. 1995;85:3586 –3593.

10. McDermott EM, Smillie DM, Powell RJ. Clinical spectrum of fa-milial Hibernian fever: a 14-year follow-up study of the index caseand extended family. Mayo Clin Proc. 1997;72:806 – 817.

11. Zaks N, Kastner DL. Clinical syndromes resembling familial Med-iterranean fever. In: Sohar E, Gafni J, Pras M, eds. Familial Medi-terranean Fever. London and Tel Aviv: Freund; 1997:211–215.

12. Mulley J, Saar K, Hewitt G, et al. Gene localization for an autosomaldominant familial periodic fever to 12p13. Am J Hum Genetics.1998;62:884 – 889.

13. McDermott MF, Ogunkolade BW, McDermott EM, et al. Linkageof familial Hibernian fever to chromosome 12p13. Am J Hum Ge-netics. 1998;62:1446 –1461.

14. Galon J, Aksentijevich I, McDermott MF, et al. TNFRSF1A muta-

Figure 2. Calculated creatinine clearance as a measure of renalfunction in relation to occurrence and cessation of fever attacks.The last fever attack occurred in November 1995.

Familial Periodic Fever and Amyloidosis Due to a New Mutation/Simon et al

March 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110 315

tions, and autoinflamatory syndromes. Curr Opin Immunol. 2000;12:479 – 486.

From the Department of General Internal Medicine (AS, JWMVDM,JPHD), UMC St. Radboud, Nijmegen, The Netherlands; and Laboratoirede Biochimie et de Genetique Moleculaire Humaine (CD), Universite ParisV, Institut Cochin de Genetique Moleculaire, and Hopital Cochin, Assis-tance Publique-Hopitaux de Paris, Paris, France.

Supported by le Program Hospitalier de Recherche Clinique (1997). Dr.Simon is a recipient of a Dutch organization for Scientific Research Fellow-ship for Clinical Investigators (KWO nr. 920 – 03–116).

Correspondence should be addressed to Anna Simon, MD, Departmentof General Internal Medicine, 541, UMC St. Radboud, PO Box 9101, 6500HB Nijmegen, The Netherlands.

Manuscript submitted July 14, 2000, and accepted in revised form Oc-tober 27, 2000.

Familial Periodic Fever and Amyloidosis Due to a New Mutation/Simon et al

316 March 2001 THE AMERICAN JOURNAL OF MEDICINEt Volume 110