Familial Mediterranean Fever and Related Disorders: Genetics and Disease Characteristics



Status:Recruiting
Conditions:Infectious Disease
Therapuetic Areas:Immunology / Infectious Diseases
Healthy:No
Age Range:Any
Updated:4/6/2019
Start Date:March 10, 1994
Contact:Amanda K Ombrello, M.D.
Email:ombrelloak@mail.nih.gov
Phone:(301) 827-4258

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Genetics and Pathophysiology of Autoinflammatory Disorders.

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 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....

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 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. Seven are caused by mutations in five 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 mevalonate kinase; Muckle-Wells
syndrome (MWS), 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; deficiency of the
interleukin-1 receptor antagonist (DIRA) is caused by mutations in the gene that codes for
the interleukin-1 receptor antagonist, a protein that helps to regulate levels of the
inflammatory cytokine, interleukin-1; 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 other procedures 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 and possibly salivary 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.

- INCLUSION CRITERIA:

1. Individuals referred to the NIH with a possible diagnosis of FMF, TRAPS, HIDS,
MWS, FCAS, NOMID, DIRA, PAPA, PFAPA, or other unexplained febrile or inflammatory
illnesses. Individuals may be seen for initial evaluation, genetic studies, and
research blood specimens, or may send blood, buccal, or saliva samples for
genetic testing only. However, we place the following age restrictions on other
studies:

1. Leukapheresis will only be performed on individuals over the age of 18
years;

2. Brief interruption of ongoing therapy for research blood sampling will only
be proposed to individuals over the age of 18 years;

3. Research bone marrow aspirations and biopsies will only be performed on
affected individuals over the age of 12 without sedation.

2. Family members of individuals included under item 1: may be seen for initial
evaluations, genetic studies, or research blood specimens, or may send blood,
buccal, or saliva samples for genetic testing only. Unaffected family members
will not be asked to undergo leukapheresis, interruption of ongoing therapy, or
bone marrow biopsies.

3. Controls for cellular, molecular, biochemical assays and genetic studies:
Individuals who undergo phlebotomy specifically to provide a random control
specimen will be required to be over the age of 7 years and not pregnant.
Individuals providing a control specimen who are already undergoing phlebotomy
for other reasons must be greater than 1 year of age and not pregnant.

EXCLUSION CRITERIA:

1. In the case of adults, inability to provide informed consent and unavailability of a
legally authorized representative (LAR) to provide surrogate consent.

2. In the case of minors, unavailability of a parent or guardian.

3. Presence of any medical condition that would, in the opinion of the investigators,
confuse the interpretation of the study.
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