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Genetics and Pathophysiology of Familial Mediterranean Fever and Related Disorders

Open (Enrolling)
Periodic Disease

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Trial Information

Genetics and Pathophysiology of Familial Mediterranean Fever and Related Disorders

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

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 and possibly saliva 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.

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 or saliva samples for
genetic testing only. However, we place the following age restrictions on other

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

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
individuals over the age of 18 years.

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 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.

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.


1. Inability to provide informed consent or, in the case of minors, unavailability of a
parent or guardian.

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

Type of Study:


Study Design:


Principal Investigator

Daniel L Kastner, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Human Genome Research Institute (NHGRI)


United States: Federal Government

Study ID:




Start Date:

March 1994

Completion Date:

Related Keywords:

  • Periodic Disease
  • Familial Mediterranean Fever
  • Genetics
  • Familial
  • Fever
  • Mediterranean
  • Hyper IgD Sydrome (HIDS) / Mevalonate kinase deficiency
  • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
  • Muckle-Wells syndrome
  • Familial cold autoinflammatory syndrome (FCAS)
  • Neonatal onset multisystem inflammatory disease (NOMID)
  • Brucellosis
  • Familial Mediterranean Fever
  • Hereditary Autoinflammatory Diseases



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892