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$Unique_ID{BRK03431}
$Pretitle{}
$Title{Agammaglobulinemias, Primary}
$Subject{Agammaglobulinemias, Primary Antibody Deficiency Immunoglobulin
Gammaglobulin X-linked Agammaglobulinemia (Bruton's Agammaglobulinemia Common)
Agammaglobulinemia Growth Hormone Autosomal Recessive Agammaglobulinemia
Infantile Agammaglobulinemia  Lymphoproliferative Syndrome (Duncan's Disease)
Common, Variable, Unclassifiable Immunodeficiency Transient
Hypogammaglobulinemia of Infancy Selective IgA Selective of IgG Subclass
Immunodeficiency Hyper-IgM (Hyper IgM Janeway I Dysgammaglobulinemia)
Selective IgM Selective of IgG Subclasses Kappa Light Chain Secretory
Component (Secretory IgA) Specific Antibody Normal Immunoglobulins Thymic
Hypoplasia (DiGeorge) Chronic Mucocutaneous Candidiasis Cellular
Immunodeficiency Purine Nucleoside Phosphorylase Acquired Immunodeficiency
(AIDS) Severe Combined Immunodeficiency (SCID) X-linked Recessive Severe
Combined Immunodeficiency Autosomal Recessive Severe Combined Immunodeficiency
Severe Combined Immunodeficiency Adenosine Deaminase Hypogammaglobulinemia,
Late-Onset Immunoglobulin Idiopathic Immunoglobulin Variable Onset
Immunoglobulin Dysgammaglobulinemia Antibody near normal Immunoglobulins
Anti-Epstein-Barr Virus Nuclear Antigen (EBNA) Antibody Acquired
Immunodeficiency  (AIDS) Ataxia Telangiectasia DiGeorge  Nezelof  Severe
Combined Immunodeficiency Wiskott-Aldrich  IgA (General)}
$Volume{}
$Log{}

Copyright (C) 1986, 1987, 1988, 1989, 1993 National Organization for Rare
Disorders, Inc.

73:
Agammaglobulinemias, Primary

** IMPORTANT **
It is possible that the main title of the article (Agammaglobulinemias,
Primary) is not the name you expected.  Please check the SYNONYMS listing to
find the alternate name and disorder subdivisions covered by this article.

Synonyms

     Antibody Deficiency
     Immunoglobulin Deficiency
     Gammaglobulin Deficiency

DISORDER SUBDIVISIONS:

     X-linked Agammaglobulinemia (Bruton's Agammaglobulinemia Common)
     X-Linked Agammaglobulinemia with Growth Hormone Deficiency
     Autosomal Recessive Agammaglobulinemia

PRIMARY AGAMMAGLOBULINEMIAS THAT INVOLVE B CELL DEFICIENCY DISORDERS:

     X-Linked Infantile Agammaglobulinemia
     X-Linked Lymphoproliferative Syndrome (Duncan's Disease)
     Common, Variable, Unclassifiable Immunodeficiency
     Transient Hypogammaglobulinemia of Infancy
     Selective IgA Deficiency
     Selective Deficiency of IgG Subclass
     Immunodeficiency with Hyper-IgM (Hyper IgM Syndrome and Janeway I
     Dysgammaglobulinemia)
     Selective IgM Deficiency
     Selective Deficiency of IgG Subclasses
     Kappa Light Chain Deficiency
     Secretory Component Deficiency (Secretory IgA Deficiency)
     Specific Antibody Deficiency with Normal Immunoglobulins

PRIMARY AGAMMAGLOBULINEMIAS THAT INVOLVE T CELL DEFICIENCY DISORDERS:

     Thymic Hypoplasia (DiGeorge Syndrome)
     Chronic Mucocutaneous Candidiasis
     Cellular Immunodeficiency with Purine Nucleoside Phosphorylase Deficiency
     Acquired Immunodeficiency Syndrome (AIDS)

COMBINED B CELL AND T CELL DEFICIENCY DISORDERS:

     Severe Combined Immunodeficiency (SCID)
     X-linked Recessive Severe Combined Immunodeficiency
     Autosomal Recessive Severe Combined Immunodeficiency
     Severe Combined Immunodeficiency with Adenosine Deaminase Deficiency

OTHER PRIMARY AGAMMAGLOBULINEMIAS:

     Hypogammaglobulinemia, Late-Onset Immunoglobulin Deficiency, Idiopathic
     Immunoglobulin Deficiency and Variable Onset Immunoglobulin Deficiency
     Dysgammaglobulinemia
     Antibody Deficiency with near normal Immunoglobulins
     Anti-Epstein-Barr Virus Nuclear Antigen (EBNA) Antibody Deficiency

Information on the following diseases can be found in the Related
Disorders section of this report:

     Acquired Immunodeficiency Syndrome (AIDS)
     Ataxia Telangiectasia
     DiGeorge Syndrome
     Nezelof Syndrome
     Severe Combined Immunodeficiency
     Wiskott-Aldrich Syndrome
     IgA Deficiency (General)

General Discussion

** REMINDER **
The Information contained in the Rare Disease Database is provided for
educational purposes only.  It should not be used for diagnostic or treatment
purposes.  If you wish to obtain more information about this disorder, please
contact your personal physician and/or the agencies listed in the "Resources"
section of this report.


Primary Agammaglobulinemias are a group of inherited immune deficiencies
characterized by insufficient antibodies.  Antibodies are composed of certain
proteins (immunoglobulins) that are essential to the immune system.  They are
produced by specialized cells (i.e., B lymphocytes) that circulate in the
lymphatic fluid and blood.  Antibodies fight off bacteria, viruses, and other
foreign substances that threaten the body.  Agammaglobulinemias are also
characterized by the abnormal function of specialized white blood cells
called B lymphocytes.  The B lymphocytes are supposed to search out and
identify bacteria, viruses, or other foreign substances in the body.  T
lymphocytes, also known as the "killer cells," assist B lymphocytes to
respond to infection and other antigens.  However, in some forms of Primary
Agammaglobulinemias neither the B nor the T lymphocytes function normally.

There are three types of Primary Agammaglobulinemias:  X-linked
Agammaglobulinemia (XLA), X-linked Agammaglobulinemia with growth hormone
deficiency, and autosomal recessive Agammaglobulinemia.  All of these
disorders are characterized by a weakened immune system that must be enhanced
by gammaglobulin in order to fight infections.

Symptoms

The most frequent symptoms of Primary Agammaglobulinemia are usually repeated
bacterial infections resulting from failures in specific immune responses
because of defects in T and B lymphocytes.  These lymphocytes are responsible
for the production of antibodies.  Autoimmune disorders also occur more
frequently than normal in people with Primary Agammaglobulinemia.  The
bacteria, Giardia lamblia, is a frequent cause of chronic inflammation of the
intestines and diarrhea in patients with all forms of Primary
Agammaglobulinemia.

Infections may begin to occur in males with X-linked Primary
Agammaglobulinemia (also known as Bruton agammaglobulinemia) late in the
first year of life, only after the IgG antibodies from the mother have been
depleted.  These children typically have recurrent pus filled areas of
infection on the skin.  Repeated infections may also occur in the middle ear
and respiratory tract (upper and lower).  Most of the infections in people
with X-Linked Primary Agammaglobulinemia are bacterial, but persistent viral
and parasitic infections can occur as well.

Infections by enteroviruses and the poliomyelitis virus may result in
unusually severe illness in children with Primary Agammaglobulinemia.
Echovirus infection can cause a group of symptoms that closely resembles
Dermatomyositis.  These symptoms may include muscle weakness, often in the
hip and shoulder areas, and difficulty swallowing.  Areas of patchy, reddish
skin may appear around the eyes, knuckles and elbows and occasionally on the
knees and ankles.  (For more information on this disorder, choose
"Dermatomyositis" as your search term in the Rare Disease Database.)

Infections caused by Mycoplasma bacteria can lead to severe arthritis
including joint swelling and pain, in children with Primary
Agammaglobulinemia.  Hemophilus influenzae is the most common mucous-
producing infection (pyogenic) that occurs in people with X-Linked Primary
Agammaglobulinemia.  Children may also have repeated infections with
pneumococci, streptococci, and staphylococci bacteria, and infrequently
pseudomonas infection.

People with X-Linked Agammaglobulinemia have abnormally low levels of
IgA, IgG, and IgM antibodies circulating in their blood.  Specialized white
blood cells (neutrophils) are impaired in their ability to destroy bacteria,
viruses, or other invading organisms (microbes).  This occurs because
neutrophils require antibodies from the immune system to begin to destroy
invading bacteria (opsonization).  The levels of circulating neutrophils in
children with Primary Agammaglobulinemia may be persistently low, or may wax
and wane (cyclic, transient neutropenia) in people with these disorders.  The
number of B lymphocytes and parts of the cell that they produce (plasma cell
progeny) are typically reduced by 100-fold or more in children with X-Linked
Primary Agammaglobulinemia.  X-Linked Agammaglobulinemia patients are usually
without tonsils, which are composed mostly of B lymphocytes.  (For more
information, choose "Neutropenia" as your search term in the Rare Disease
Database.)

A single family has been described by researchers to have X-linked
Agammaglobulinemia with growth hormone deficiency.  The boys in this family
have reduced or undetectable numbers of B lymphocytes and may also have a
deficiency in all the immune factors (panhypogammaglobulinemia) but with
substantial amounts of IgA and IgM and normal T lymphocytes.  Researchers are
unable to explain why growth hormone coexists with X-Linked
Agammaglobulinemia in this family.

Familial Primary Agammaglobulinemia also occurs in females, suggesting
that one form of the disorder may be inherited as an autosomal genetic trait.

Causes

X-Linked Agammaglobulinemia (B lymphocyte defect) is inherited as an X-linked
recessive genetic trait.  Human traits, including the classic genetic
diseases, are the product of the interaction of two genes, one received from
the father and one from the mother.  X-linked recessive disorders are
conditions which are coded on the X chromosome.  Females have two X
chromosomes, but males have one X chromosome and one Y chromosome.
Therefore, in females, disease traits on the X chromosome can be masked by
the normal gene on the other X chromosome.  Since males only have one X
chromosome, if they inherit a gene for a disease present on the X, it will be
expressed.  Men with X-linked disorders transmit the gene to all their
daughters, who are carriers, but never to their sons.  Women who are carriers
of an X-linked disorder have a fifty percent risk of transmitting the carrier
condition to their daughters, and a fifty percent risk of transmitting the
disease to their sons.

One very rare form of Primary Agammaglobulinemia is inherited as an
autosomal recessive genetic trait.  This form of the disease may occur in
brothers and in males whose sisters have children with X-Linked
Agammaglobulinemia.  In recessive disorders, the condition does not appear
unless a person inherits the same defective gene for the same trait from each
parent.  If one receives one normal gene and one gene for the disease, the
person will be a carrier for the disease, but usually will not show symptoms.
The risk of transmitting the disease to the children of a couple, both of
whom are carriers for a recessive disorder, is twenty-five percent.  Fifty
percent of their children will be carriers, but healthy as described above.
Twenty-five percent of their children will receive both normal genes, one
from each parent, and will be genetically normal.

Affected Population

Primary Agammaglobulinemia is a rare disorder that occurs almost exclusively
in males although some females have been affected by certain types of this
disorder.

Related Disorders

Symptoms of the following disorders can be similar to those of Primary
Agammaglobulinemias.  Comparisons may be useful for a differential diagnosis:

Acquired Immune Deficiency Syndrome (AIDS) is an immunosuppressive
disorder caused by infection with the human immunodeficiency virus (HIV).
The immune deficiency is a result of a viral infection and the destruction of
specific T cells.  Initially HIV infection is characterized by a period
without symptoms.  This may be followed by the development of swollen lymph
nodes (lymphadenopathy).  Eventually most people with Acquired Immune
Deficiency Syndrome experience a progression of symptoms that occur as a
result of a compromised immune system.  However, AIDS is a contagious disease
whereas Primary Agammaglobulinemias are not transmitted from person to person
except through hereditary.  (For more information on this disorder, choose
"AIDS" as your search term in the Rare Disease Database.)

Ataxia Telangiectasia is a severe, rare, inherited neurological disorder
characterized by the progressive loss of motor coordination in the arms,
legs, and head (cerebellar ataxia).  Some cases of this disorder are
associated with immunodeficiencies (IgA or IgE).  Mental development may be
normal in the early stages of the disease, but progressive dementia may
occur.  This disease usually begins in infancy but may not be apparent until
the child is school age.   Classic red spots or telangiectasia appear in the
eyes, and later on the face and roof of the mouth.  (For more information on
this disorder, choose "Ataxia Telangiectasia" as your search term in the Rare
Disease Database.)

DiGeorge Syndrome is a very rare immune deficiency that results from
developmental defects in the thymus and parathyroid glands.  This disorder is
characterized by seizures during the first few days of life due to the
abnormal function of the parathyroid gland.  Inability to fight off frequent
infections from viruses, fungi, and other bacteria is characteristic of this
disorder.  Children with DiGeorge Syndrome frequently have chronic nasal
infections, diarrhea, oral candidiasis, and Pneumocystis pneumonia.  (For
more information on this disorder, choose "DiGeorge" as your search term in
the Rare Disease Database.)

Nezelof Syndrome is a rare immune deficiency disorder characterized by
the impairment of cellular immunity against infections.  Symptoms of this
disorder may include frequent and severe infections from birth including oral
candidiasis, diarrhea, skin infections, septicemia, urinary tract infections,
measles, pulmonary infections, and vaccinia.  Typically a child with this
disorder may be mentally retarded and have a progressive loss of muscle
tissue.  (For more information on this disorder, choose "Nezelof" as your
search term in the Rare Disease Database.)

Severe Combined Immunodeficiency (SCID) is a group of rare, congenital
disorders characterized by little or no immune response.  A person with this
disorder is susceptible to recurring infections with bacteria, viruses,
fungi, and other infectious agents.  If untreated, this disorder may result
in frequent, severe infections, growth retardation, and can be life-
threatening.  Other symptoms of this disorder may include weight loss,
weakness, infections of the middle ear, and skin infections.  (For more
information on this disorder, choose "Severe Combined Immunodeficiency" as
your search term in the Rare Disease Database.)

Wiskott-Aldrich Syndrome is a rare X-Linked inherited disorder of
childhood characterized by immunodeficiency that results in recurrent skin
rashes (eczema) and abnormally low levels of circulating platelets in the
blood (thrombocytopenia).  Symptoms of this disorder may include excessive
bleeding from circumcision or minor trauma.  Bleeding, which can be severe,
may also occur in the intestines or stomach.  Skin rashes that are red
(petechiae) are typically present.  (For more information on this disorder,
choose "Wiskott-Aldrich" as your search term in the Rare Disease Database.)

IgA Deficiency is an antibody deficiency that is related to Primary
Agammaglobulinemia and is characterized by low levels of IgA in the blood in
the presence of normal or increased levels of IgG and IgM.  IgA Deficiency is
the most common primary immunodeficiency.  Other deficiencies of
immunoglobulin isotopes are IgM deficiency and IgG subclass deficiencies.

Therapies:  Standard

The administration of intravenous gammaglobulin replacement therapy is the
standard treatment for Primary Agammaglobulinemia.  The optimal dose for a
person with X-Linked Agammaglobulinemia must be determined by a physician.
The dosage is generally at least 300 mg/kg of body weight per month.  It is
used to treat most of the Agammaglobulinemias including Common Variable
Immunodeficiency and X-Linked Agammaglobulinemia.  Gammaglobulin may also be
of value in transient hypogammaglobulinemia of infancy although there is risk
that the body will delay production of immune factors in some infants.  Fresh
frozen blood plasma may also be used in some cases.

Selective IgA deficiency is more difficult to treat.  Gammaglobulins and
fresh or frozen plasma must be avoided because of the risk of life
threatening shock (anaphylaxis) due to the presence of antibodies to IgA in
the blood or plasma.  If blood transfusions are necessary, only multiple
washed red blood cells or blood products from other IgA deficient individuals
should be used.

Antibiotics are prescribed for people with Primary Agammaglobulinemia
when bacterial infections occur.  Some patients are treated with antibiotics
to prevent getting infections (prophylactically).  All people who are
immunodeficient should be protected as much as possible from exposure to
infectious diseases.  Corticosteroids or any drug that depresses the immune
system (immunosuppressant drugs) should be avoided as much as possible, as
well as physical activities such as rough contact sports that risk damage to
the spleen.

In people with immunodeficiency with elevated IgM, there is a tendency to
bleed excessively associated with abnormally low levels of circulating
platelets in the blood (thrombocytopenia).  This may complicate any surgical
procedure.

Genetic counseling will be of benefit for people with Primary
Agammaglobulinemias and their families.  Prenatal testing is being developed
to detect these disorders before birth, particularly in the developing fetus
of mothers who already have a child with X-Linked Primary Agammaglobulinemia.
More studies are needed before this testing is widely available.  Other
treatment is symptomatic and supportive.

Therapies:  Investigational

Research on genetic defects and their causes is ongoing.  The National
Institutes of Health (NIH) is sponsoring the Human Genome Project that is
aimed at mapping every gene in the human body and learning why they sometimes
malfunction.  It is hoped that this new knowledge will lead to prevention and
treatment of genetic disorders in the future.

This disease entry is based upon medical information available through
June 1993.  Since NORD's resources are limited, it is not possible to keep
every entry in the Rare Disease Database completely current and accurate.
Please check with the agencies listed in the Resources section for the most
current information about this disorder.

Resources

For more information on Primary Agammaglobulinemias, please contact:

     National Organization for Rare Disorders (NORD)
     P.O. Box 8923
     New Fairfield, CT  06812-1783
     [phone]

     Immune Deficiency Foundation
     3565 Ellicott Mill Drive, Unit B2
     Ellicott City, MD 21043
     [phone]
     [phone]

     NIH/National Institute of Allergy and Infectious Diseases (NIAID)
     9000 Rockville Pike
     Bethesda, MD  20892
     [phone]

     Centers for Disease Control (CDC)
     1600 Clifton Road, NE
     Atlanta, GA  30333
     [phone]

For Genetic Information and Genetic Counseling Referrals:

     March of Dimes Birth Defects Foundation
     1275 Mamaroneck Avenue
     White Plains, NY 10605
     [phone]

     Alliance of Genetic Support Groups
     35 Wisconsin Circle, Suite 440
     Chevy Chase, MD  20815
     (800) 336-GENE
     [phone]

References

MENDELIAN INHERITANCE IN MAN, 10th Ed.:  Victor A. McKusick, Editor:  Johns
Hopkins University Press, 1992.  Pp. 1200, 1773-77.

THE METABOLIC BASIS OF INHERITED DISEASE, 6th Ed.:  Charles R. Scriver, et
al., Editors; McGraw Hill, 1989.  Pp. 2689-90.

CECIL TEXTBOOK OF MEDICINE, 19th Ed.:  James B. Wyngaarden, and Lloyd H.
Smith, Jr., Editors; W.B. Saunders Co., 1990.  Pp. 1446-53.

THE MERCK MANUAL, 16th Ed.:  Robert Berkow Ed.; Merck Research
Laboratories, 1992.  Pp. 303-315.

HEMATOLOGY, 4th Ed,:  William J. Williams, et al,; Editors; McGraw-Hill,
Inc., 1990.  Pp. 970-71.

BIRTH DEFECTS ENCYCLOPEDIA, Mary Louise Buyse, M.D., Editor-In-Chief;
Blackwell Scientific Publications, 1990.  Pp. 947-962.

IMMUNODEFICIENCY.  R.H. Buckley; J Allergy Clin Immunol (Dec 1983; 72(6))
Pp. 627-41.

MOLECULAR ANALYSIS OF X-LINKED AGAMMAGLOBULINEMIA WITH GROWTH HORMONE
DEFICIENCY.  M.E. Conley; J Pediatr (Sept 1991; 119(3)).  Pp. 392-397.

HOME TREATMENT OF HYPOGAMMAGLOBULINAEMIA WITH SUBCUTANEOUS GAMMAGLOBULIN
BY RAPID INFUSION.  A. Gardulf; Lancet (July 1991; 338(8760)).  Pp. 162-6.

PRIMARY HYPOGAMMAGLOBULINEMIA:  A SURVEY OF CLINICAL MANIFESTATIONS AND
COMPLICATIONS.  R.A. Hermaszewshi; Q J Med (Jan 1986; 86(1)).  Pp. 31-42.

CARRIER DETECTION AND PRENATAL DIAGNOSIS OF X-LINKED AGAMMAGLOBULINEMIA.
O. Journet; Am J Med Genet (July 1992; 15(43)).  Pp. 885-87.

X-LINKED AGAMMAGLOBULINEMIA.  E. Timmers; Clin Immunol Immunopathol (Nov
1991; 61(2 Pt 2)).  Pp. S83-93.

CLINICAL USE OF IMMUNE SERUM GLOBULIN AS REPLACEMENT THERAPY IN PATIENTS
WITH PRIMARY IMMUNODEFICIENCY SYNDROMES.  S.A. Schwartz; Clin Rev Allergy
(Spring-Summer 1992; 10(1-2)).  Pp. 1-12.