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

The following individuals may be eligible for this study: 1) patients 5 years of age and older with known or suspected familial Mediterranean fever, TRAPS, hyper-IgD syndrome or related disorders; 2) relatives of these patients; 3) healthy, normal volunteers 18 years of age or older; and 4) healthy patients with gout 18 years of age or older who are taking colchicine.

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 sample or cells obtained from a brushing of the inside of the cheek) for genetic studies, if this has not already been done.

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.

6. Bone marrow aspiration to study white cells early in their development. This procedure will be requested of only a few patients. An area of skin on the back is numbed, a needle is inserted into a pelvic bone, and a small amount of bone marrow is withdrawn.

Patients will be followed approximately every 6 months to monitor symptoms, adjust medicine levels, and undergo routine blood and urine tests. They will receive genetic counseling 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 cheek swabbing) will also be collected for genetic studies. Additional blood samples of no more than 1 pint during a 6-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.

Condition
Periodic Disease

The purpose of this protocol is to study the genetics and pathophysiology of familial Mediterranean fever (FMF) and other related diseases. FMF is a recessively inherited condition characterized by episodes of fever and serositis or synovitis; some patients also develop systemic amyloidosis. Our laboratory has identified the FMF gene and several disease-related mutations. The FMF gene encodes a novel protein called pyrin that is the prototype of a family of molecules involved in the regulation of apoptosis (cell-death) and inflammation. The precise biochemical mechanism by which these proteins function, and by which mutations cause disease, is still unknown.

There are a number of other conditions, sometimes referred to as autoinflammatory syndromes because of the lack of high-titer autoantibodies or antigen-specific T-cells, that are also characterized by episodic inflammation. Six are caused by recently-discovered mutations in four other genes: the TNF-receptor associated periodic syndrome (TRAPS) is caused by mutations in one of the receptors for tumor necrosis factor (TNF); the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is caused by mutations in the gene encoding mevolonate kinase; Muckle-Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS), and neonatal onset multisystem inflammatory disease (NOMID) are caused by mutations in the gene encoding cryopyrin, a member of the aforementioned pyrin family of proteins; and the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) is caused by mutations in PSTPIP1, a protein that binds pyrin. In addition, there are patients with episodic fevers and/or inflammation who do not have identifiable mutations in any of these genes. Some of these latter cases appear to cluster in families, while others are sporadic.

The goals of this protocol are: 1) to gather and evaluate clinical data on selected patients with FMF and related conditions, so as to characterize more thoroughly the clinical features and natural history of patients with recognized disorders as well as those with as yet undefined autoinflammatory conditions; 2) to identify mutations, both in known autoinflammatory genes and in other genes, that lead to syndromes of periodic inflammation, and to study possible correlations between specific genetic mutations and disease manifestations; and 3) to undertake functional, biochemical, and molecular studies of leukocytes from patients with both known and as yet poorly defined autoinflammatory conditions.

Patients will undergo screening history, physical examination, and clinical laboratory evaluation, usually in the outpatient department. Imaging studies and skin or muscle biopsies may be performed when clinically indicated. Where appropriate, we will ask probands to obtain permission from family members to be contacted. We will collect blood samples from consenting affected individuals and, in some cases, unaffected family members, extract DNA, and perform molecular genetic analyses. For cellular and biochemical studies we will obtain blood samples from patients, selected unaffected family members, and unrelated controls. In some cases adult patients may be asked to interrupt treatment temporarily to obtain additional blood samples. We may also ask a small number of adult patients to undergo leukapheresis and/or bone marrow aspiration for research purposes.

Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

INCLUSION CRITERIA:
Individuals referred to the NIH with a possible diagnosis of FMF, TRAPS, HIDS, MWS, FCAS, PAPA, PFAPA, or other unexplained febrile illnesses.
Individuals over 1 year of age may be seen for initial evaluation, genetic studies, and research blood specimens, or may send blood or buccal samples for genetic testing only.
We place the following age restrictions on other studies:
Leukapheresis will only be performed on individuals over the age of 18 years;
Brief interruption of ongoing therapy for research blood sampling will only be proposed to individuals over the age of 18 years;
Research bone marrow aspirations and biopsies will only be performed on individuals over the age of 18 years.
Family members of individuals: Individuals over 1 year of age may be seen for initial evaluations, genetic studies, or research blood specimens, or may send blood or buccal samples for genetic testing only. Unaffected family members will not be asked to undergo leukapheresis, interruption of ongoing therapy, or bone marrow aspirations and biopsies.
Controls for cellular, biochemical, or molecular assays: All these individuals will be required to be over the age of 18, not pregnant, and otherwise in good health.
EXCLUSION CRITERIA
Inability to provide informed consent or, in the case of minors, unavailability of a parent or guardian.
Presence of any medical condition that would, in the opinion of the investigators confuse the interpretation of the study.

Maryland
      National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  940105; 94-AR-0105
Record last reviewed:  March 3, 2004
Last Updated:  March 3, 2004
Record first received:  November 3, 1999
ClinicalTrials.gov Identifier:  NCT00001373
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-11-08