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IDF PATIENT/FAMILY HANDBOOK | CHAPTER VIII
The X-Linked Hyper IgM Syndrome
Patients with the Hyper IgM Syndrome have an inability to switch
their antibody (immunoglobulin) production from IgM to IgG, IgA,
and IgE. As a result, patients have decreased levels of IgG and IgA
and normal or elevated levels of IgM. A number of different genetic
defects can cause the Hyper IgM Syndrome. The most common
form is inherited as an X-chromosome linked trait and affects only
boys. Most of the other forms are inherited as autosomal recessive
traits and affect both girls and boys.
 Definition of Hyper IgM Syndrome:
Patients with Hyper IgM (HIM) syndrome have
an inability to switch production of antibodies
of the IgM type to antibodies of the IgG, IgA, or
IgE type. As a result, patients with this primary
immunodeficiency disease have decreased levels
of serum IgG and IgA and normal or elevated
levels of IgM. B-lymphocytes can produce
IgM antibodies on their own, but they require
interactive help from T-lymphocytes in order to
switch antibody production from IgM to IgG, IgA
and IgE. The hyper IgM syndrome results from a
variety of genetic defects that affect this interaction
between T-lymphocytes and B-lymphocytes.
The most common form of hyper IgM syndrome
results from a defect or deficiency of a protein that is
found on the surface of activated T-lymphocytes.
The affected protein is called "CD40 ligand"
because it binds to a protein on B-lymphocytes
called CD40. CD40 ligand is made by a gene
on the X-chromosome. Therefore, this primary
immunodeficiency disease is inherited as an
X-linked recessive trait and usually found only
in boys. As a consequence of their deficiency in
CD40 ligand, affected patients' T-lymphocytes are
unable to instruct B-lymphocytes to switch their
production of immunoglobulins from IgM to IgG,
IgA and IgE. In addition, CD40 ligand is important
for other T-lymphocyte functions, and therefore,
patients with X-linked hyper IgM syndrome (XHIM)
also have a defect in some of the protective
functions of their T-lymphocytes.
Other forms of HIM syndrome are inherited as
autosomal recessive traits (see chapter titled
Inheritance) and have been observed in females
and males. The molecular bases for some of the
other forms of HIM have been discovered.
These
forms of HIM syndrome result from defects in
the genes that are involved in the CD40 signaling
pathway. Genetic defects in CD40 are very rare
and have been described in few families. The
resulting disease is almost identical to XHIM
because although the CD40 ligand is present on
T-lymphocytes, the CD40 found on B-lymphocytes
and other cells of the immune system is either not
present or does not function normally. Two other
genes (AID and UNG) have been identified that
are necessary for B-lymphocytes to switch their
antibody production from IgM to IgG, IgA or IgE.
Defects in both of these genes have been found
in patients with HIM syndrome. Since the function
of these genes is limited to antibody switching,
the other T-lymphocyte functions of CD40 ligand
are not affected, and these patients are less likely
to have infections caused by organisms that are
controlled by T-cells.
Finally, a defect in another X-linked gene that
is necessary for the activation of the signaling
molecule NF-κB has been identified in a form
of HIM that is associated with a skin condition
called ectodermal dysplasia. Patients have
immunodeficiency with sparse hair and conical
teeth among other abnormalities. NF-κB is
activated by CD40 and is necessary for the
signaling pathway that results in antibody
switching. NF-κB is also activated by other
signaling pathways that are important in fighting
infections. Therefore, these affected boys are
susceptible to a variety of serious infections.
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Clinical Presentation of Hyper IgM Syndrome:
Most patients with Hyper IgM (HIM) syndrome
develop clinical symptoms during their first or
second year of life. The most common problem
is an increased susceptibility to infection including
recurrent upper and lower respiratory tract
infections. The most frequent infective agents
are bacteria. A variety of other microorganisms
can also cause serious infections. For example,
Pneumocystis jiroveci (carinii) pneumonia, an
opportunistic infection, is relatively common during
the first year of life and its presence may be the
first clue that the child has the X-linked form of
HIM syndrome (XHIM). Lung infections may also
be caused by viruses such as Cytomegalovirus
and fungi such as Cryptococcus. Gastrointestinal
complaints, most commonly diarrhea and
malabsorption, have also been reported in
some patients. One of the major organisms
causing gastrointestinal symptoms in XHIM is
Cryptosporidium that may cause sclerosing
cholangitis, a severe disease of the liver.
Approximately half of the patients with XHIM
syndrome develop neutropenia (low white blood
cell count), either transiently or persistently. The
cause of the neutropenia is unknown, although
most patients respond to treatment with the
colony stimulating factor, G-CSF. Neutropenia
is often associated with oral ulcers, proctitis
(inflammation and ulceration of the rectum) and
skin infections. Enlargement of the lymph nodes
is seen more frequently in patients with autosomal
recessive HIM syndrome than in most of the other
primary immunodeficiency diseases.
As a result, patients often have enlarged tonsils,
a big spleen and liver, and enlarged lymph
nodes. Autoimmune disorders may also occur in
patients with HIM syndrome. Their manifestations
may include chronic arthritis, low platelet
counts (thrombocytopenia), hemolytic anemia,
hypothyroidism, and kidney disease.
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Diagnosis of Hyper IgM Syndrome:
The diagnosis of X-linked Hyper IgM (XHIM)
syndrome should be considered in any boy
presenting with hypogammaglobulinemia,
characterized by low or absent IgG and IgA and
normal or elevated IgM levels. Failure to express
CD40 ligand on activated T-cells is a characteristic
finding. However, some patients with other
forms of immunodeficiency may have a markedly
depressed expression of CD40 ligand while their
CD40 ligand gene is perfectly normal. Therefore,
the final diagnosis of XHIM syndrome depends on
the identification of a mutation affecting the CD40
ligand gene. This type of DNA analysis can be
done in several specialized laboratories.
The autosomal recessive forms of HIM can be
suspected if a patient has the characteristics of
XHIM but is either a female patient and/or has a
normal CD40 ligand gene with normal expression
on activated T-lymphocytes.
Ectodermal Dysplasia with Immunodeficiency,
another X-linked form of HIM, can be suspected
in a patient who has features of ectodermal
dysplasia (e.g. sparse hair and conical teeth) and
recurrent infections, normal or elevated IgM and
low IgG, IgA and IgE.
The diagnosis of the different forms of autosomal
recessive HIM or of Ectodermal Dysplasia with
Immunodeficiency can be confirmed by mutation
analysis of the genes known to cause these disorders.
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Inheritance of Hyper IgM Syndrome:
X-linked Hyper IgM (XHIM) and Ectodermal
Dysplasia with Immunodeficiency are inherited
as X-linked recessive disorders. As a result, only
boys are affected. See chapter titled Inheritance
for more complete information on how X-linked
recessive disorders are passed on from generation
to generation. Since these are inherited diseases,
transmitted as an X-linked recessive trait, there
may be brothers or maternal uncles (mother's
brothers) who have similar clinical findings. As in
other X-linked disorders, there also may be no
other affected members of the family.
Since the autosomal recessive forms of HIM require
that the gene on both chromosomes be affected,
they are less frequent than the X-linked conditions.
If the precise mutation in the affected gene is
known in a given family, it is possible to make a
prenatal diagnosis or test family members to see if
they are carriers of the mutation.
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Treatment of Hyper IgM Syndrome:
Patients with Hyper IgM (HIM) syndrome have a
severe deficiency in IgG. Regular treatment with
immunoglobulin replacement therapy every 3 to
4 weeks is effective in decreasing the number
of infections (see chapter titled Specific Medical
Therapy). The immunoglobulin replaces the
missing IgG and often results in a reduction
or normalization of the serum IgM level. Since
patients with the XHIM syndrome also have a
marked susceptibility to Pneumocystis jiroveci
(carinii) pneumonia, many physicians feel it is
important to initiate prophylactic or preventative
treatment for Pneumocystis jiroveci pneumonia
by starting affected infants on trimethoprimsulfamethoxazole
(Bactrim, Septra) prophylaxis
as soon as the diagnosis of XHIM syndrome is
made. Sometimes, neutropenia may improve
during treatment with IVIG. Patients with persistent
neutropenia may also respond to granulocyte
colony stimulating factor (G-CSF) therapy.
However, G-CSF treatment is only necessary
in selected patients and long-term treatment
with G-CSF is usually not recommended. Boys
with HIM, similar to other patients with primary
immunodeficiency diseases, should not receive
live virus vaccines since there is a remote
possibility that the vaccine strain of the virus may
cause disease. It is also important to reduce the
possibility of drinking water that is contaminated
with Cryptosporidium because exposure to this
organism may cause severe gastrointestinal
symptoms and chronic liver disease. The family
should be proactive and contact the authorities
responsible for the local water supply and ask if
the water is safe and tested for Cryptosporidium.
Patients with XHIM syndrome have defects in
T-lymphocyte function in addition to their antibody
deficiency, and patients with Ectodermal Dysplasia
with Immunodeficiency also have defects in
other aspects of their immune system. Treatment
with immunoglobulin may not fully protect these
patients against all infections. In recent years,
bone marrow transplantation or cord blood stem
cell transplantation have been advocated (see
chapter titled Specific Medical Therapy). More
than a dozen patients with XHIM have received
an HLA identical sibling bone marrow transplant
with excellent success. Thus, a permanent cure
for this disorder is possible. Cord blood stem cell
transplants, fully or partially matched, have also
been successfully performed, resulting in complete
immune reconstitution. Matched unrelated donor
(MUD) transplants are nearly as successful as
matched sibling transplants. Since patients
with the XHIM syndrome may have strong T-cell
responses against organ transplants, including
bone marrow transplants, immunosuppressive
drugs or low dose irradiation are usually required.
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Expectation for the Hyper IgM Syndrome Patient:
Although patients with the X-linked
Hyper IgM syndrome have defects in both the production of IgG and IgM and some
aspects of their T-lymphocyte function, a number of effective therapies exist
which allow these children to grow into happy and successful adults.
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