Familial Mediterranean Fever and Related Disorders: Genetics and Disease Characteristics

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.