Familial Mediterranean Fever and Related Disorders: Genetics and Disease Characteristics

An Exploratory Study of the Genetics, Pathophysiology, and Natural History of Autoinflammatory Diseases

This study is designed to explore the genetics and pathophysiology of diseases presenting with intermittent fever, including familial Mediterranean fever, TRAPS, hyper-IgD syndrome, and related diseases.

The following individuals may be eligible for this natural history study: 1) patients with known or suspected familial Mediterranean fever, TRAPS, hyper-IgD syndrome or related disorders; 2) relatives of these patients; 3) healthy, normal volunteers 7 years of age or older.

Patients will undergo a medical and family history, physical examination, blood and urine tests. Additional tests and procedures may include the following:

1. X-rays
2. Consultations with specialists
3. DNA sample collection (blood or saliva sample) for genetic studies. These might include studies of specific genes, or more complete sequencing of the genome.
4. Additional blood samples a maximum of 1 pint (450 ml) during a 6-week period for studies of white cell adhesion (stickiness)
5. Leukapheresis for collecting larger amounts of white cells for study. For this procedure, whole blood is collected through a needle in an arm vein. The blood flows through a machine that separates it into its components. The white cells are removed and the rest of the blood is returned to the body through another needle in the other arm.

Patients may be followed approximately every 6 months to monitor symptoms, adjust medicine dosages, and undergo routine blood and urine tests. They will receive genetic counseling by the study team on the risk of having affected children and be advised of treatment options.

Participating relatives will undergo a medical and family history, possibly with a review of medical records, physical examination, blood and urine tests. Additional procedures may include a 24-hour urine collection, X-rays, and consultations with medical specialists. A DNA sample (blood or saliva) will also be collected for genetic studies. Additional blood samples of no more than 550 mL during an 8-week period may be requested for studies of white cell adhesion (stickiness).

Relatives who have familial Mediterranean fever, TRAPS, or hyper-IgD syndrome will receive the same follow-up and counseling as described for patients above.

Normal volunteers and patients with gout will have a brief health interview and check of vital signs (blood pressure and pulse) and will provide a blood sample (up to 90 ml, or 6 tablespoons). Additional blood samples of no more than 1 pint over a 6-week period may be requested in the future.

Study Overview

• Status: Recruiting
• Conditions: Fever; Genetic Diseases; Familial Mediterranean Fever (FMF); Autoinflammation; Periodic Fever; ROSAH; ALPK1

Detailed Description

Study Description

This is an exploratory natural history protocol that will enroll patients with known or as yet undiagnosed disorders of inflammation. Blood, saliva, or buccal samples will be collected for genetic analysis, blood samples will be obtained for immunologic and other functional studies, a small number of subjects may undergo skin biopsy, leukapheresis, or bone marrow aspiration and biopsy, and some patients will be provided standard medical care follow up, with retrospective analysis of the clinical data gathered during follow up.

Objectives

Primary Objective: To discover the genetic basis of human disorders of inflammation.

Secondary Objective: To enumerate immunologic features and genotype-phenotype associations in specific inflammatory diseases.

Tertiary Objectives: To describe the clinical features of poorly characterized or newly defined disorders of inflammation, through the retrospective chart review of standard medical practice follow up and through the enrollment of selected subjects in separate, disease-specific protocols.

Endpoints

Primary Endpoints: The discovery of rare, high-penetrance genetic variants and common, low-penetrance genetic variants conferring susceptibility to inflammatory disease; the discovery of structural genomic variants (insertions, deletions, inversions, translocations, etc.) that cause human inflammatory disease; the discovery of common, low-penetrance germline variants that confer susceptibility to human inflammatory disease; and the discovery of somatic mutations that give rise to human inflammatory disease.

Secondary Endpoint: The description of immune cell populations, inflammatory mediators, gene expression profiling, epigenetic features, and ex vivo functional assays of leukocytes from subjects with specific inflammatory diseases.

Tertiary Endpoints: Given the wide range of inflammatory diseases, the endpoints will be formulated for specific conditions based on the clinical features of that condition.

• Study Type: Observational
• Enrollment (Estimated): 5000

Contacts and Locations

• Study Contact: Name: Benjamin D Solomon, M.D.; Phone Number: (301) 402-8824; Email: solomonb@mail.nih.gov
• Study Contact Backup: Name: Amanda K Ombrello, M.D.; Phone Number: (301) 827-4258; Email: ombrelloak@mail.nih.gov

Study Locations

• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Completed
      • Childrens National Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Completed
      • Johns Hopkins University
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov
    • Bethesda, Maryland, United States, 20301
      • Completed
      • Walter Reed National Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • Not yet recruiting
      • University of Pittsburgh
      • Contact: Daniella Schwartz; Phone Number: 412-648-1587; Email: Daniella.Schwartz@pitt.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients with autoinflammatory disorders and unaffected family members, and healthy volunteers.

Description

• INCLUSION CRITERIA:

There are three populations that will be included in this study: subjects with known or suspected autoinflammatory diseases, family members of subjects with known or suspected autoinflammatory diseases, and healthy controls. Persons interested in participation may be given a screening questionnaire to determine eligibility. Questions in the screening questionnaire are important to help us determine if subjects have known autoinflammatory diseases, or if there is a high clinical suspicion of autoinflammatory disease.

In order to be eligible to participate in this study as a subject with known or suspected autoinflammatory disease, an individual must meet all of the following criteria:

1. Stated willingness to participate in study procedures (which at the very least includes providing a mail-in sample for genetic analysis);
2. Regardless of gender, at least one month of age;
3. A medical history that, in the expert opinion of the study team, is consistent with the possibility of autoinflammatory disease; and
4. Ability of the subject, parents (in the case of children), or Legally Authorized Representative to understand and the willingness to sign a written informed consent document.

In order to be eligible to participate in this study as a family member of a subject with known or suspected autoinflammatory disease, an individual must meet all of the following criteria:

1. Stated willingness to participate in study procedures (which at the very least includes providing a mail-in sample for genetic analysis);
2. Regardless of gender, at least one month of age;
3. Relationship, either by blood or marriage, to an individual enrolled or about to be enrolled in the study with known or suspected autoinflammatory disease;
4. Likelihood, in the expert opinion of the study team, that analysis of a sample from the individual would advance genetic or functional analysis of the affected relative's possible autoinflammatory condition; and
5. Ability of the subject, parents (in the case of children), or Legally Authorized Representative to understand and the willingness to sign a written informed consent document.

In order to be eligible to participate in this study as a healthy volunteer, an individual must meet all of the following criteria:

1. Stated willingness to participate in study procedures for healthy volunteers;
2. Regardless of gender, at least one year old, and not pregnant (by history of a missed menstrual period);
3. Likelihood, in the expert opinion of the study team, that a sample from the individual would advance the functional analysis of an autoinflammatory condition under study; and
4. Ability of the subject or parents (in the case of children) to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

For any of the three categories of subjects, an individual will be excluded from participation in this study if he or she has a medical condition that would, in the opinion of the investigators, confuse the interpretation of the study.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Healthy Volunteers
Affected; Patients with auto-inflammatory disorders
Family Members; Family members of patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genetic linkage in autoinflammatory dise	discovery of genetic associations to autoinflammatory disorders	annually

Collaborators and Investigators

• Sponsor: National Human Genome Research Institute (NHGRI)
• Collaborators: Merck Sharp & Dohme LLC; Duke University; University of Massachusetts, Worcester
• Investigators: Principal Investigator: Benjamin D Solomon, M.D., National Human Genome Research Institute (NHGRI)

Publications and helpful links

General Publications

• Aksentijevich I, Kastner DL. Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol. 2011 Jul 5;7(8):469-78. doi: 10.1038/nrrheum.2011.94.
• Bulua AC, Mogul DB, Aksentijevich I, Singh H, He DY, Muenz LR, Ward MM, Yarboro CH, Kastner DL, Siegel RM, Hull KM. Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study. Arthritis Rheum. 2012 Mar;64(3):908-13. doi: 10.1002/art.33416.
• Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A, Park G, Barron KS, Weisman MH, Pashinian N, Reiff AO, Samuels J, Wright DA, Kastner DL, Lovell DJ. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012 Oct 16;157(8):533-41. doi: 10.7326/0003-4819-157-8-201210160-00003.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 1994

Study Registration Dates

• First Submitted: November 3, 1999
• First Submitted That Met QC Criteria: November 3, 1999
• First Posted (Estimated): November 4, 1999

Study Record Updates

• Last Update Posted (Actual): June 5, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: May 20, 2026

More Information

Terms related to this study

• Keywords: Genetics; Autoinflammation; Alpha-Kinase 1; Periodic Fever; Familial Mediterranean; Retinal Dystrophy; Optic Nerve Edema; Splenomegaly; Anhidrosis; HEADACHE
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Pathological Conditions, Anatomical; Eye Diseases; Skin Diseases; Sweat Gland Diseases; Skin Diseases, Genetic; Retinal Diseases; Body Temperature Changes; Retinal Degeneration; Hypertrophy; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Signs and Symptoms; Headache; Genetic Diseases, Inborn; Fever; Retinal Dystrophies; Familial Mediterranean Fever; Hereditary Autoinflammatory Diseases; Splenomegaly; Hypohidrosis
• Other Study ID Numbers: 940105; 94-HG-0105

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual genomic sequencing data and corresponding phenotype data will be deposited in dbGaP as part of the study's Genomic Data Sharing Plan. Non-genomic and/or phenotypic individual data will not be deposited in shared databases for broad research use.
• IPD Sharing Time Frame: Genomic Sharing Plan in effect since 2018 with genomic data deposited to dbGaP for broad availability within six months of final data analysis of each genomic sequence. No end date of data availability through dbGaP.
• IPD Sharing Access Criteria: Genomic sequences will be deposited to dbGaP following final sequence analysis and available for broad use, as determined by dbGaP usage committee.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No