What is Familial Mediterranean Fever?

Summary
Disease characteristics.   Familial Mediterranean fever (FMF) type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms vary among patients, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication. FMF type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.

Diagnosis/testing.   The diagnosis of FMF is suspected in individuals with recurrent episodes of fever associated with abdominal pain (peritonitis) and/or pleuritic pain and/or arthritis (ankle/knee) usually lasting two to three days. Blood tests reveal a high erythrocyte sedimentation rate, leukocytosis, and a high fibrinogen level. Molecular genetic testing of the MEFV gene (chromosomal locus 16p13.3) usually confirms the diagnosis. Molecular genetic testing is also used for carrier detection.

Management.   Patients who are homozygotes for the mutation M694V or compound heterozygotes for M694V and another disease-causing allele benefit from treatment with colchicine as soon as the diagnosis is confirmed. Colchicine prevents both the inflammatory attacks and the deposition of amyloid.

Genetic counseling.  FMF is inherited in an autosomal recessive manner. In general, both parents of a proband are considered to be obligate carriers. However, in populations with a high carrier rate and/or a high rate of consanguineous marriages, it is possible that affected children may be born to an affected individual and a carrier, or even to two affected individuals. Thus, it is appropriate to consider molecular genetic testing of the parents of the proband. If both parents are heterozygotes, the risk to sibs of being affected is 25%. Prenatal testing is possible if both MEFV mutations in a family are known.

--------------------------------------------------------------------------------

Diagnosis
The diagnosis of familial Mediterranean fever (FMF) is suspected in individuals with recurrent episodes of fever associated with abdominal pain (peritonitis) and/or pleuritic pain and/or arthritis (ankle/knee) usually lasting two to three days. Blood tests reveal a high erythrocyte sedimentation rate (ESR), leukocytosis, and a high fibrinogen level. Molecular genetic testing of the MEFV gene (chromosomal locus 16p13.3) usually confirms the diagnosis.

Clinical Diagnosis
The features taken into consideration when a diagnosis of FMF is suspected:

• Recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis
• Favorable response to continuous colchicine treatment
• Recurrent erysipelas-like erythema
• Repeated laparotomies for "acute abdomen" with no pathology found
• Amyloidosis of the AA type that characteristically develops after 15 years of age in untreated individuals, even those who do not have a history of recurrent inflammatory attacks
• FMF in a first-degree relative
• At-risk ethnic group
• Testing

During the inflammatory attack, the following typically occur:

• High erythrocyte sedimentation rate (ESR)
• Leukocytosis
• High fibrinogen level
• Molecular Genetic Testing
• Gene.   MEFV is the only gene currently known to be associated with familial Mediterranean fever.

Seventeen mutations have been identified, of which 11 are in exon 10, three in exon 2, two in exon 3, and one in exon 5. These mutations account for most of the disease-causing mutations in the population at risk for FMF (Armenian; Turkish; Arab; North African, Iraqi, and Ashkenazi Jewish; and a few other Mediterranean populations.) A small proportion of patients with FMF have mutations that are not detectable by current mutation analyses or only a single mutation detectable by mutation analysis.

Uses of testing

• Confirmatory diagnostic testing
• Predictive testing
• Carrier testing
• Prenatal diagnosis
• Test methods

Mutation analysis.  Testing for known MEFV mutations is available on a clinical basis. The mutations included in testing panels vary across laboratories. The detection rate of mutation analysis is dependent on the mutations included in the testing panel and the ethnicity of the patient.

Sequence analysis of exon 10.  Sequence analysis of exon 10 is available on a clinical basis. Most of the known MEFV mutations are in exon 10; however, there is also one relatively common mutation (E148Q) in exon 2.

Direct DNA.  Molecular genetic testing to identify MEFV mutations in patients with atypical clinical presentations is available on a research basis.

Table 1. Molecular Genetic Testing Used in Familial Mediterranean Fever  Test Method Mutations Detected Mutation Detection Rate for Both Mutations  Test Availability
Mutation analysis:

Mutation panels may include mutations in exon 10 (M680I, V726A, M694V, M694I, K695R, A744S, R761H, 692delI, A653H, A408G), exon 2 (E148Q, G167A, T267I), exon 3 (P369S), and exon 5 (F479L) Armenian: 90% 

Clinical:

Turkish: 90%
Arab: 70%
North African Jewish: 95%
Iraqi Jewish: 80%
Ashkenazi Jewish: 90%

Sequence analysis Mutations in exon 10 30-50%
Direct DNA MEFV mutations for the detection of mutations outside exon 10 Another 30-40% Research

Linkage analysis.  Linkage analysis is available on a clinical basis and may be an option for carrier testing for families in which both MEFV mutations have not been identified. Samples from multiple family members, including a sample from at least one affected individual, are necessary to perform linkage analysis. The accuracy of linkage analysis is dependent on 1) the informativeness of genetic markers in the patient's family and 2) the accuracy of the clinical diagnosis of FMF in the affected family member.

Genetically Related Disorders: No other phenotypes have been associated with mutations in the MEFV gene.

Clinical Description
Familial Mediterranean fever is divided into types 1 and 2. Type 1 is characterized by recurrent short episodes of inflammation and serositis including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis and meningitis. The symptoms vary among patients, sometimes even among members of the same family. Amyloidosis, which can lead to renal failure, is the most severe complication. Type 2 is characterized by amyloidosis as the first clinical manifestation of FMF in an otherwise asymptomatic individual.

1. Recurrent fever.  Recurrent fever during early childhood may be the only manifestation of FMF.

2. Abdominal attacks.   Experienced by 90% of patients, abdominal attacks start with the sudden onset of fever and pain affecting the entire abdomen. Physical examination reveals board-like rigidity of the abdominal muscles, rebound tenderness, abdominal distension, and loss of peristaltic sounds. Radiographs reveal multiple small air-fluid levels in the small bowel. The diagnosis of "acute abdomen" usually results in laparotomy, but if not, the signs and symptoms resolve without sequelae over 24-48 hours.

3. Articular attacks.  Experienced by about 75% of patients, articular attacks occur suddenly, and may be precipitated by minor trauma or effort, such as prolonged walking. The three characteristic features are 1) a very high fever in the first 24 hours, 2) involvement of one of the large joints of the leg (knee, ankle, or hip), and 3) gradual resolution of the signs and symptoms after peaking in 24-48 hours, leaving no sequelae. Often a sterile synovial effusion is present. Around 5% of patients have protracted arthritic attacks, which may persist for more than a month. These attacks are commonly in the hip or knee, but may occur in other joints, such as the ankle, shoulder, temporomandibular joint, or sternoclavicular joint. The joint remains swollen and painful, clinically resembling chronic monoarthritis, which subsides spontaneously only after several weeks or months. Severe damage to the joint can result, and permanent deformity may require joint replacement.

4. Pleural attacks.  Experienced by about 45% of patients, pleural attacks are the sudden onset of an acute, one-sided febrile pleuritis, which resolves rapidly. The patient complains of painful breathing, and breath sounds are diminished on the affected side. Radiographs may reveal a small exudate in the costophrenic angle. Attacks resolve within 48 hours.

5. Pericarditis.  Pericarditis is a rare occurrence. Patients have retrosternal pain. Electrocardiogram (ECG) shows an elevated ST segment. Radiographs may reveal transient enlargement of the cardiac silhouette, and echocardiography may show evidence of pericardial effusion.

5. Amyloidosis.  Type AA amyloidosis commonly occurs in untreated individuals, especially in Jews of North African origin. Patients have persistent, heavy proteinuria leading to nephrotic syndrome and progressive nephropathy leading to end stage renal disease (ESRD). Patients who are otherwise asymptomatic can develop renal amyloidosis as the first and only manifestation of FMF. With increased longevity of patients with renal failure through dialysis and/or renal transplantation, amyloid deposits are being found in other organs as well. The prevalence of amyloidosis varies by ethnicity. In untreated individuals, amyloidosis can occur in 60% of patients of Turkish heritage and in up to 75% of North African Jews.

6. Rarer manifestations of FMF attacks:

Protracted febrile myalgia.   This is a severe debilitating myalgia with prolonged low-grade fever, increased erythrocyte sedimentation rate (about 100), leukocytosis, and hyperglobulinemia. It usually lasts 6-8 weeks and responds to treatment with prednisone.

Erysipelas-like erythema.   This is characterized by fever, and hot, tender, swollen, sharply bordered red lesions that are typically 10-35 cm2 in area and occur mainly on the legs, between the ankle and the knee, or on the dorsum of the foot. The lesions usually last one to two days. Isolated short-lived elevation of temperature lasting a few hours can occur without any pain or inflammation.

Vasculitides.   These are rare and include Henoch-Schnölein purpura and polyarteritis nodosa.

Genotype-Phenotype Correlations
A significant association has been found between the mutation M694V, which is found in more than 90% of Jewish patients of North African origin, and the development of amyloidosis, especially in those patients who are homozygous for this mutation. Some studies have found that this mutation is also associated with a generally more severe form of the disease, but other studies have failed to confirm this. Amyloidosis occurs less frequently in the presence of mutations other than M694V.

The mutation E148Q, which is the predominant mutation in Ashkenazi and Iraqi Jews, Armenians, and Turks, has been found to be associated with a generally mild form of FMF, and many individuals, who are either homozygotes for this mutation or compound heterozygotes for this mutation and a mutation other than M694V, are asymptomatic. Such individuals also have a low risk - if any - for developing amyloidosis. The possible exception is those individuals who are compound heterozygotes for the mutations E148Q/M694V; such patients may be clinically affected and also at risk of developing amyloidosis.

Prevalence
This disease predominantly affects populations living in the Mediterranean region, especially North African Jews, Armenians, Turks, and Arabs. The carrier rate for FMF has been calculated to be as high as 1:3-1:7 in North African Jews, Iraqi Jews, Armenians, and Turks. Although mutation analysis has confirmed the carrier frequency to be as high as 1:5 in Ashkenazi Jews, the predominant mutation is for a mild form of FMF and thus, the prevalence of the disease in this ethnic group is not high.

Differential Diagnosis
For those patients who present with recurrent fever, differential diagnosis includes:

• PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, and Adenopathy syndrome)
• HIDS (HyperImmunoglobulinemia D and periodic fever Syndrome) (autosomal recessive) is characterized by recurrent attacks of fever, abdominal pain, and arthralgia, and is caused by a mutation in the mevalonate kinase gene. A subgroup of HIDS is caused by another gene as yet unknown.
• TRAPS (TNF Receptor-Associated Periodic Syndrome) (TNF = tumor necrosis factor) is caused by a mutation in the TNFRSF1A gene. This mutation results in decreased serum levels of soluble TNF receptor leading to inflammation due to unopposed TNF-alpha action. The disease is characterized by attacks of fever, sterile peritonitis, arthralgia, myalgia, skin rash, and conjunctivitis. Transmission is by autosomal dominant inheritance. Some patients develop amyloidosis. Treatment with recombinant TNF-receptor analogues is promising.
• FPF (Familial Periodic Fever) (autosomal dominant). The gene for this condition has also been mapped to chromosome 12p13. For information about laboratory testing for familial periodic fever, see .
• ELA-related neutropenia, which includes congenital neutropenia and cyclic neutropenia.

The differential diagnosis of renal amyloidosis is Muckle-Wells syndrome and familial cold urticaria, which are probably allelic disorders caused by a mutation in the CIAS1 gene. These diseases are transmitted by autosomal dominant inheritance and are characterized by urticaria, deafness, and renal amyloidosis.

For those patients who present with abdominal pain, acute abdomen from any cause needs to be considered. These include acute appendicitis, perforated ulcer, intestinal obstruction, acute pyelitis, acute pancreatitis, cholecystitis, diverticulitis, and in females, various gynecological conditions such as ectopic pregnancy, acute or chronic salpingitis, torsion of ovarian cyst, bilateral pyosalpinx, and endometriosis.

For those patients presenting with joint pains, the differential diagnosis includes acute rheumatoid arthritis, rheumatic fever, septic arthritis, and collagen disease.

Patients presenting with pleuritic pain may be diagnosed as having pleurisy or pulmonary embolism.

For patients presenting with amyloidosis, transthyretin-related amyloidosis needs to be considered.

Management
Affected individuals

Patients who are homozygotes for the mutation M694V or compound heterozygotes for M694V and another disease-causing allele should be treated with colchicine as soon as the diagnosis is confirmed, since this drug prevents both the inflammatory attacks and the deposition of amyloid. It is given orally, 1-2 mg per day in adults. Such patients should receive colchicine for life.
Patients who do not have the M694V mutation and who are only mildly affected (those with infrequent inflammatory attacks) should either be treated with colchicine or monitored every six months for the presence of proteinuria.
Continuous treatment with colchicine appears to be less indicated for individuals who are homozygotes or compound heterozygotes for the mutation E148Q; colchicine should only be given to these patients if they develop severe inflammatory episodes and/or proteinuria due to amyloidosis.
Surveillance of at-risk family members.  Once a patient has been diagnosed as having FMF and the mutations identified, it is important to offer molecular genetic testing to all first degree relatives and other family members whether or not they have symptoms. This is especially important when the allele M694V is present because of the possibility that other affected family members may not have inflammatory attacks but nevertheless remain at risk for amyloidosis (FMF type 2). Family members who are found to be homozygous for this mutation, or compound heterozygous for this and another mutation, should undergo lifelong colchicine treatment, even when asymptomatic.

Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal or cultural issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance
Familial Mediterranean fever is inherited in an autosomal recessive manner.

Risk to Family Members
Parents of a proband.  The parents are obligate heterozygotes and, therefore, carry a single copy of a disease-causing mutation. Heterozygotes are asymptomatic. In general, both parents are considered to be obligate carriers. However, in populations with a high carrier rate, and with a high rate of consanguineous marriages, it is possible that affected children may be born to an affected individual and a carrier, or even to two affected individuals. Thus, it is appropriate to consider molecular genetic testing of the parents of the proband.

Sibs of a proband
At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being unaffected, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
Heterozygotes are asymptomatic.
Offspring of a proband.  All of the offspring inherit one MEFV gene mutation. In populations with a high carrier rate and a high rate of consanguineous marriages, it is possible that the partner of the proband may be affected or a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's partner.

Other family members of a proband.  The sibs of obligate heterozygotes have a 50% chance of being heterozygotes.

Carrier testing.  Carrier testing is available on a clinical basis once the mutation(s) has/have been identified in the proband.

Related Genetic Counseling Issues
Since treatment for FMF is readily available, easy to administer, and effective, the testing and possible treatment of asymptomatic at-risk family members is warranted.

Family planning.  Determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing are best done before pregnancy whenever possible.

DNA banking.  DNA banking is the storage of DNA that has been extracted from white blood cells for possible future use. Because it is likely that testing methodologies and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA. DNA banking is particularly important if the sensitivity of currently available testing is less than 100%. See DNA Banking.

Prenatal Testing
Prenatal diagnosis for pregnancies at 25% risk is possible. DNA extracted from fetal cells obtained by amniocentesis at 16-18 weeks' gestation* or chorionic villus sampling (CVS) at about 10-12 weeks' gestation is analyzed. Both disease-causing alleles of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Other issues to consider.  Prenatal diagnosis of a treatable condition associated with a good prognosis with early treatment may be controversial if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider this to be the choice of the parents, careful discussion and examination of these issues is appropriate.

* Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular Genetics
Table 2. Molecular Genetics of Familial Mediterranean Fever  Gene Locus Product Genomic Databases
MEFV  16p13 Pyrin (marenostrin)      

Normal allelic variants: See mutations.
Pathologic allelic variants: 17 mutations have been identified.
Normal gene product: The normal gene is a member of a family of nuclear factors homologous to the Ro52 autoantigen. It encodes a 3.7 Kb transcript that is expressed exclusively in granulocytes, white blood cells important in the immune response. The protein encoded by this gene has been called pyrin by the International FMF Consortium, and marenostrin by the French FMF Consortium. It contains 781 amino acids, and its normal function is probably to assist in keeping inflammation under control by deactivating the immune response. Without this "brake," an inappropriate full-blown inflammatory reaction of the serosal membranes occurs - an attack of FMF.
Abnormal gene product: The abnormal alleles code for a less active pyrin protein due to a single amino acid change.
Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.


NCBI Genes and Disease Webpage
www.ncbi.nlm.nih.gov/disease/FMF.html

References
 Articles on Familial Mediterranean Fever

Literature Cited
Aksentijevich I, Galon J, Soares M, Mansfield E, Hull K, Oh HH, Goldbach-Mansky R, Dean J, Athreya B, Reginato AJ, Henrickson M, Pons-Estel B, O'Shea JJ, Kastner DL (2001) 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 69:301-14 [Medline]


Aksentijevich I, Torosyan Y, Samuels J, Centola M, Pras E, Chae JJ, Oddoux C, Wood G, Azzaro MP, Palumbo G, Giustolisi R, Pras M, Ostrer H, Kastner DL (1999) 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 [see comments]. Am J Hum Genet 64:949-62 [Medline]


Bernot A, da Silva C, Petit JL, Cruaud C, Caloustian C, Castet V, Ahmed-Arab M, Dross C, Dupont M, Cattan D, Smaoui N, Dode C, Pecheux C, Nedelec B, Medaxian J, Rozenbaum M, Rosner I, Delpech M, Grateau G, Demaille J, Weissenbach J, Touitou I (1998) Non-founder mutations in the MEFV gene establish this gene as the cause of familial Mediterranean fever (FMF). Hum Mol Genet 7:1317-25 [Medline]


Booth DR, Gillmore JD, Booth SE, Pepys MB, Hawkins PN (1998) Pyrin/marenostrin mutations in familial Mediterranean fever. QJM 91:603-6 [Medline]

Daniels M, Shohat T, Brenner-Ullman A, Shohat M (1995) Familial Mediterranean fever: high gene frequency among the non- Ashkenazic and Ashkenazic Jewish populations in Israel. Am J Med Genet 55:311-4 [Medline]


French FMF Consortium (1997) A candidate gene for familial Mediterranean fever. Nat Genet 17:25-31 [Medline]


Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R (2001) Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 9:634-7 [Medline]


Kone Paut I, Dubuc M, Sportouch J, Minodier P, Garnier JM, Touitou I (2000) Phenotype-genotype correlation in 91 patients with familial Mediterranean fever reveals a high frequency of cutaneomucous features. Rheumatology (Oxford) 39:1275-9 [Medline]


Langevitz P, Livneh A, Padeh S, Zaks N, Shinar Y, Zemer D, Pras E, Pras M (1999) Familial Mediterranean fever: new aspects and prospects at the end of the millennium. IMAJ 1:31-6

Livneh A, Langevitz P, Shinar Y, Zaks N, Kastner DL, Pras M, Pras E (1999) MEFV mutation analysis in patients suffering from amyloidosis of familial Mediterranean fever. Amyloid 6:1-6 [Medline]


Pras E, Aksentijevich I, Gruberg L, Balow JE Jr, Prosen L, Dean M, Steinberg AD, Pras M, Kastner DL (1992) Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 326:1509-13 [Medline]


Pras E, Langewitz P, Livneh A, Zemer D, Migdal A, Padeh S, Lubetzky A, Aksentijevich I, Centola M, Zaks N, Deng Z, Sood R, Kastner DL, Pras M (1997) Genotype/phenotype correlation in familial Mediterranean fever (a preliminary report). In: Sohar E, Gafni J, Pras M (eds) Familial Mediterranean Fever. Freund Publishing House, Tel Aviv, pp 260-4


Pras M (1998) Familial Mediterranean fever: from the clinical syndrome to the cloning of the pyrin gene [editorial]. Scand J Rheumatol 27:92-7 [Medline]


Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R, Kastner DL (1998) Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore) 77:268-97 [Medline]

Shinar Y, Livneh A, Langevitz P, Zaks N, Aksentijevich I, Koziol DE, Kastner DL, Pras M, Pras E (2000) Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol 27:1703-7 [Medline]


Shohat M, Magal N, Shohat T, Chen X, Dagan T, Mimouni A, Danon Y, Lotan R, Ogur G, Sirin A, Schlezinger M, Halpern GJ, Schwabe A, Kastner D, Rotter JI, Fischel-Ghodsian N (1999) Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis. Eur J Hum Genet 7:287-92 [Medline]


Simon A, Cuisset L, Vincent MF, van Der Velde-Visser SD, Delpech M, van Der Meer JW, Drenth JP (2001) Molecular analysis of the mevalonate kinase gene in a cohort of patients with the hyper-igd and periodic fever syndrome: its application as a diagnostic tool. Ann Intern Med 135:338-43 [Medline]


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 43:227-53 [Medline]


Stoffman N, Magal N, Shohat T, Lotan R, Koman S, Oron A, Danon Y, Halpern GJ, Lifshitz Y, Shohat M (2000) Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. Eur J Hum Genet 8:307-10 [Medline]

International FMF Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797-807 [Medline]


Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J (1986) Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med 314:1001-5 [Medline]


Suggested Readings
Heller H, Sohar E, Gafni J, Heller J (1961) Amyloidosis in familial Mediterranean fever. An independent genetically determined characteristic. Arch Intern Med 107:539-50


Author Information
Mordechai Shohat, MD 
Director, Department of Medical Genetics
Rabin Medical Center
Petah Tikva
Professor, Pediatrics and Genetics
Sackler School of Medicine
Tel Aviv

Professor Mordechai Shohat, MD has been involved with research into familial Mediterranean fever, including the molecular analysis of the MEFV gene and phenotype-genotype correlation studies, for over ten years.

Contact GeneTests
Copyright© 1997-2003, All Rights Reserved
University of Washington, Seattle
Terms of Use
 

--------------------------------------------------------------------------------
Funding Support:
National Institutes of Health
Health Resources and Services Administration
US Department of Energy
 Technical Support:
University of Washington
Seattle, Washington
 Administrative Support:
University of Washington School of Medicine
Seattle, Washington