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Hyper IgM Syndromes
Hyper IgM Syndromes
Hyper IgM Syndromes
rarediseases.org/rare-diseases/hyper-igm-syndrome/
HIGM
IHIS
immunodeficiency with hyper IgM syndrome
General Discussion
Summary
Hyper IgM syndromes are a group of rare disorders in which the immune system does
not function properly. They are classified as rare primary immunodeficiency disorders,
which are a group of disorders characterized by irregularities in the cell development
and/or cell maturation process of the immune system. The immune system is divided
into several components, the combined actions of which are responsible for defending
the body against different infectious agents. The T cell system is responsible for
fighting yeast and fungi, several viruses, and some bacteria. The B cell system fights
infection caused by other viruses and bacteria. It does so by secreting immune factors
called antibodies (also known as immunoglobulins) into the fluid portion of the blood
(serum) and body secretions (e.g., saliva). There are five classes of immunoglobulins
known as IgA, IgD, IgE, IgG, and IgM. Antibodies can directly kill microorganisms or
coat them so they are more easily destroyed by white blood cells (leukocytes).
Hyper IgM syndromes are caused by very rare, one-in-a-million, and potentially life-
threatening genetic mutations that severely compromise the immune system and
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resulting in the individual’s inability to produce antibodies. Patients with hyper IgM
are at significant risk for opportunistic and repeated infections. In addition, the defect
in the immune system results in a decreased ability to identify and fight cancer cells as
well as an inability to produce a response to pathogens. Some individuals with hyper-
IgM syndrome have abnormally high levels of immunoglobulin IgM in the fluid portion
of the blood, which led to the term “hyper IgM” syndrome. However, researchers have
determined that many affected individuals have normal levels of IgM. Affected
individuals may have normal to high IgM, but cannot produce adequate levels of
immunoglobulins IgG, IgA, and IgE because they cannot switch from the production of
IgM to these other immunoglobulin classes. Because these other immunoglobulins are
deficient, affected individuals are susceptible to recurrent episodes of certain pus-
producing (pyogenic) bacterial infections. The gastrointestinal system is often involved
causing recurrent, prolonged (protracted) diarrhea.
Approximately 70% of people with hyper IgM syndrome inherit the disorder in an X-
linked recessive pattern. This is called X-linked hyper IgM syndrome or XHIM and is
the most common type. Because it is X-linked, the disorder predominately affects
males. Less often, affected individuals inherit the disorder in an autosomal recessive
pattern. There are at least four types of autosomal recessive hyper IgM syndrome;
these forms affect men and women equally. They are known as hyper IgM syndromes
type 2, 3, 4, and 5.
The signs and symptoms of hyper IgM syndromes can vary from one person to
another. This is true even among members of the same family. Affected individuals are
more susceptible to developing various infections and cannot fight off infections well
once they occur. Without treatment, these disorders can become life-threatening
during childhood or adolescence. The initial symptoms of hyper IgM syndrome usually
develop in the first or second year of life.
Other findings associated with X-linked hyper-IgM syndrome, some of which may
become apparent at as early as six to nine months of age, may include chronic diarrhea
that, in some people, may lead to impaired absorption of nutrients by the intestinal
tract (malabsorption). Affected infants with intestinal malabsorption may fail to grow
and gain weight at the expected rate (failure to thrive). Infants and children may also
develop widespread warty growths (verruca vulgaris) on the skin and/or skin rashes
consisting of discolored spots (macules) and small elevated areas (papules) on the face,
the scalp, and the bending surfaces of certain joints.
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(thrombocytopenia) may result in increased susceptibility to bruising, the appearance
of small purplish spots (petechiae) on the skin, and/or abnormal bleeding into various
tissues of the body.
Other autoimmune complications that can develop in people with X-liked hyper IgM
syndrome include arthritis, impairment function of the thyroid (hypothyroidism),
inflammatory bowel disease, and kidney disease.
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HYPER IGM SYNDROME TYPE 4
Affected individuals have developed infections of the sinuses and lungs
(sinopulmonary infections), widespread infection of the blood (sepsis), inflammation
and infection of the lymph nodes (lymphadenitis), and infection and inflammation of
bone (osteomyelitis). Osteomyelitis can cause fever, chills, sweating, bone pain, and
swelling and limited movement of nearby joints. Generally, individuals develop
similar, but generally milder symptoms than individuals with hyper IgM syndrome
type 2. Most affected individuals do not develop opportunistic infections.
Causes
Hyper IgM syndromes are caused by variations (mutations) in specific genes. Genes
provide instructions for creating proteins that play a critical role in many functions of
the body. When a mutation of a gene occurs, the protein product may be faulty,
inefficient, absent, or overproduced. Depending upon the functions of the particular
protein, this can affect many organ systems of the body. X-linked hyper IgM syndrome
is caused by a variation in the CD40LG gene. Hyper IgM syndrome type 2 is caused by
a variation in the AICDA (also called AID) gene. Hyper IgM syndrome type 3 is caused
by a variation in the CD40 gene. The genetic cause of hyper IgM syndrome type 4 is
unknown. Hyper IgM syndrome type 5 is caused by a variation in the UNG gene.
The CD40LG gene responsible for X-linked hyper-IgM syndrome is located on the long
arm (q) of chromosome X (Xq26). This gene creates (encodes) a specialized protein
called CD40 ligand. Because of the variation in the CD40LG gene, the body does not
produce enough CD40 ligand, or produces an abnormal form of the protein. Affected
individuals lack functional levels of this protein. In affected individuals, the B cell
immune response is deficient as a result of a T cell defect. The first response of the B
cell system to an invader (antigen) is normally the production of immunoglobulin M
(IgM) antibodies. Antigens are those substances, such as microorganisms, toxins, or
other foreign substances, that may trigger production of particular antibodies as part
of an immune response. The other classes of immunoglobulins (IgG, IgA, and IgE),
each of which has its own defensive duties to perform, are then produced sequentially
(in a process called “class switching”) in the normal progression of an immune
response.
Two “steps” or signals are necessary for the B cell system to switch from the production
and secretion of IgM to the production and secretion of IgG, IgA, and IgE. Certain
immune response proteins (e.g., interleukin-2, interleukin-4, etc.) produced by T cells
must bind to their “companion” interleukin receptors on B cells, which signal B cells to
switch from producing IgM to producing IgA, IgE, and IgM. In addition, a certain
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molecule (CD40) found on the surface of particular B cells must interact with a
companion binding protein (CD40 ligand) on the surface of certain activated T cells.
Because T cells of individuals with X-linked hyper-IgM syndrome cannot create or
synthesize the CD40 ligand, the sequential production of immunoglobulins G, A, and E
(i.e., “class-switching” signaling) is inhibited, which, in turn, results in the
susceptibility of affected individuals to many infectious disorders.
The CD40 gene responsible for hyper IgM syndrome type 3 is located on chromosome
20. This gene encodes CD40, which is a protein receptor. Receptors are found on the
surface of certain cells and interact with other proteins such as CD40 ligand. The
altered CD40 gene does not produce enough functional CD40 receptor protein, which
prevents the binding of CD40 ligand. CD40 ligand has a role in other functions of T
cells, such as cytotoxic T cells that identify and eliminate other cells that are damaged,
stressed, or infected. Other cell types in the immune system also express CD40
including dendritic cells, monocytes, and macrophages.
Hyper IgM syndromes type 2 is caused by a variation in the AID gene. This gene is also
called AICDA. Hyper IgM syndrome type 5 is caused by a variation in the UNG gene.
These genes produce enzymes, activation-induced cytidine deaminase for type 2 and
uracil nucleoside glycosylase for type 5, that are essential for the process of somatic
hypermutation. Unlike X-linked hyper IgM syndrome or hyper IgM syndrome type 3,
which affect both the T cell and B cell systems, these two forms of the disorder only
affect the B cell system.
INHERITANCE PATTERNS
Genetic diseases are determined by the combination of genes for a particular trait that
are on the chromosomes received from the father and the mother. X-linked hyper IgM
syndrome is caused by an altered gene on the X chromosome and is inherited in an X-
linked recessive pattern.
Females have two X chromosomes in their cells, but one of the X chromosomes is
“turned off” or inactivated during development, a process termed “lyonization,” and all
of the genes on that chromosome are inactivated. Lyonization is a random process, and
varies from tissue to tissue; within tissues it can also vary from cell to cell. Females
who have a disease gene present on one X chromosome are carriers of that disorder.
As the result of the lyonization process, most carrier females have about 50% of the
normal X and 50% of the mutant X expressed in each tissue, and usually do not display
symptoms of the disorder. Because of the randomness of the lyonization process,
exceptions to this rule exist, particularly if the inactivation of one copy of the X
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chromosome is significantly “skewed” in favor of one of the copies. If the normal copy
prevails, then female carriers can be and remain completely asymptomatic. If the
mutant copy prevails, then carrier females can develop symptoms of the disorder.
Affected Populations
X-liked hyper IgM syndrome is estimated to affect about 2 in 1,000,000 newborn boys.
The autosomal recessive forms of hyper IgM syndrome are extremely rare. Hyper IgM
syndrome type 2 is estimated to affect fewer than 1 in 1,000,000 people in the general
population. The other forms of hyper IgM syndrome have only been described in the
medical literature in a very small number of people. Because rare disorders often go
undiagnosed, determining their true frequency in the general population is difficult.
The X-linked form predominately affects males; the autosomal recessive forms affect
both males and females. X-linked hyper IgM syndrome accounts for about 70% of
people with this disorder.
Related Disorders
Symptoms of the following disorders can be similar to those of hyper IgM syndromes.
Comparisons may be useful for a differential diagnosis.
There are conditions that are not genetic that cause elevated levels of IgM. These are
referred to as acquired forms because they are “acquired” at some point during life and
not present at birth. These conditions include congenital rubella syndrome, in which
newborns are ill because the mother is infected with measles (rubella) and certain
cancers (malignancies) such as multiple myeloma or lymphoma. These conditions are
not inherited genetic forms of immunodeficiency and do not fall under the families of
diseases known as hyper IgM syndromes.
There are several, rare genetic disorders that are associated with an ability of the body
to change from creating IgM to creating other immunoglobulin classes. These
disorders are sometimes classified as forms of hyper IgM syndrome. They are
extremely rare and include PMS2 deficiency, phosphoinositide 3-kinase (PI3K)
deficiency, mutator S homolog 6 (MSH6) deficiency, and deficiency in INO80
chromatin remodeling complex. Other disorders that can have elevated IgM levels
include common variable immunodeficiency (CVID), Nijmegen syndrome, and ataxia
telangiectasia. NORD has reports on some of these disorders (For more information,
choose the exact disorder name as your search term in the Rare Disease Database.)
Diagnosis
Most times an exam called flow cytometry is used. This is a technology that can analyze
the physical and chemical characteristics of particles in a fluid. Flow cytometry of the
peripheral blood means that the peripheral blood (the blood that is circulating through
the body) is studied through a machine called a flow cytometer. The flow cytometer
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will be able to tell the number and percentage of cells in the blood sample. It can also
determine the size, shape and unique characteristics of cells such as biomarkers on the
cells’ surfaces including the number of B cells in various stages of development. A key
reason to order flow cytometry is to show absent or decreased expression of CD40
ligand protein on the surface of T cells or decreased ability to T cells to bind CD40,
which is indicative of X-linked hyper IgM syndrome. Hyper IgM syndrome type 3 can
be indicated when assessing the expression of the CD40 receptor on B cells and a type
of white blood cell call monocytes.
Standard Therapies
Treatment
The treatment of hyper IgM syndromes is directed toward the specific symptoms that
are apparent in each individual. Treatment may require the coordinated efforts of a
team of specialists. Pediatricians, physicians who specialize in the diagnosis and
treatment of immune system disorders (immunologists), specialize in the diagnosis
and treatment of blood disorders (hematologists), infectious diseases specialists, and
other healthcare professionals may need to systematically and comprehensively plan
treatment. Genetic counseling is recommended for affected individuals and their
families. Psychosocial support for the entire family is essential as well.
Individuals with all forms of hyper IgM syndrome are treated with regular
immunoglobulin replacement therapy. This can be administered by direct infusion
into the vein in an arm (intravenously) or just below the surface of the skin
(subcutaneously). These infusions contain antibodies (IgG) obtained from the fluid
portion of the blood (plasma) from donors. This will restore the immunoglobulin levels
to normal. This therapy can be very helpful for all forms of IgM. It markedly reduces
the frequency of bacterial infections and reduces the likelihood of developing lymphoid
hyperplasia.
Immunoglobulin replacement therapy does not help with opportunistic infections that
are seen in X-linked hyper IgM syndrome or hyper IgM syndrome type 3. In addition
to immunoglobulin replacement therapy, individuals with these forms of the disorder
will receive preventive (prophylactic) therapy with antibiotic medications such as
trimethoprim-cotrimoxazole, a combination of antibiotics against specific bacterial
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infections such as Pneumocystis jirovecii, which causes pneumonia. Antibiotic
medications, nitazoxanide and azithromycin, have been used to treat active
Cryptosporidium infection.
Hyper IgM syndrome types 2, 4, and 5 can often be treated with immunoglobulin
replacement therapy alone. However, sometimes prophylactic antibiotic therapy will
be recommended for individuals who develop chronic complications such as
bronchiectasis or recurrent sinus infections.
Affected individuals with chronic neutropenia have been treated with granulocyte-
colony stimulating factor. This drug stimulates the production of neutrophils. When
autoimmune disorders occur, they are treated as with people who do not have hyper
IgM syndrome and develop an autoimmune disorder.
The only curative therapy for hyper IgM syndrome is an allogeneic hematopoietic stem
cell transplant. This therapy is generally considered for individuals with X-linked hyper
IgM syndrome or hyper IgM syndrome type 3. Hematopoietic stem cells are specialized
cells found in the bone marrow (the soft spongy material found in long bones). These
blood stem cells grow and eventually develop into one of the three main types of blood
cells– red blood cells, white blood cells or platelets. A transplant is done to replace the
bone marrow (and consequently the whole blood system) of an affected individual
with marrow from a person who does not have a particular disorder. The healthy cells
produced by the new marrow contain sufficient levels of white blood cells and produce
the proper levels of immunoglobulins (antibodies). The procedure is expensive and
carries the risk of serious complications including graft-versus-host disease and other
long-term and late effects.
LIFESTYLE CHANGES
Individuals with hyper IgM syndromes will be advised to make certain lifestyle
changes including only drinking water that has been boiled or filtered through a
reverse osmosis process. Swimming in lakes or communal pools should be avoided.
Some medical sources recommend that young children avoid daycare and preschool
because children there are often sick, avoid contact with farm animals, and minimize
contact with kittens and puppies.
Investigational Therapies
Gene therapy is also being studied as another approach to therapy for individuals with
hyper IgM syndrome. In gene therapy, the defective gene present in a patient is
replaced with a normal gene to enable the production of the active enzyme and prevent
the development and progression of the disease in question. Given the permanent
transfer of the normal gene, which is able to produce active enzyme at all sites of
disease, this form of therapy is theoretically most likely to lead to a “cure.” However, at
this time, there remain some technical difficulties to resolve before gene therapy can
be advocated as a viable alternative approach.
For information about clinical trials being conducted at the NIH Clinical Center in
Bethesda, MD, contact the NIH Patient Recruitment Office:
Some current clinical trials also are posted on the following page on the NORD
website:
https://rarediseases.org/for-patients-and-families/information-resources/info-
clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
Other Organizations
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American Autoimmune & Related Diseases Association, Inc.
22100 Gratiot Ave.
Eastpointe, MI 48021
Phone: (586) 776-3900
Toll-free: (888) 852-3456
Email: [email protected]
Website: http://www.aarda.org/
Center for International Blood and Marrow Transplant Research
Froedtert and the Medical College of Wisconsin Clinical Cancer Center
9200 W. Wisconsin Avenue
Milwaukee, WI 53226
Phone: (414) 805-0700
Email: [email protected]
Website: http://www.cibmtr.org/
European Society for Immunodeficiencies
c/o Kenes International ,
Olga Coschina 7, rue François-Versonnex
Geneva 6, CP 6053 1207 Switzerland
Phone: 41229069163
Email: [email protected]
Website: http://www.esid.org
Genetic and Rare Diseases (GARD) Information Center
PO Box 8126
Gaithersburg, MD 20898-8126
Phone: (301) 251-4925
Toll-free: (888) 205-2311
Website: http://rarediseases.info.nih.gov/GARD/
International Patient Organization for Primary Immunodeficiencies
Firside Main Road
Downderry
Cornwall, PL11 3LE United Kingdom
Phone: 441503250668
Email: [email protected]
Website: http://www.ipopi.org/
Jeffrey Modell Foundation
780 Third Avenue
New York, NY 10017 USA
Phone: (212) 819-0200
Toll-free: (866) 469-6474
Email: [email protected]
Website: http://www.info4pi.org
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National Bone Marrow Transplant Link
20411 W. 12 Mile Rd
Suite 108
Southfield, MI 48076
Phone: (248) 358-1886
Toll-free: (800) 546-5268
Email: [email protected]
Website: http://www.nbmtlink.org
National Neutropenia Network
P.O. Box 1693
Brighton, MI 48116 USA
Phone: (877) 326-7117
Email: [email protected]
Website: http://www.neutropenianet.org
Neutropenia Support Association, Inc.
971 Corydon Avenue
P.O. Box 243
Manitoba, R3M 3S7 Canada
Phone: (204) 489-8454
Toll-free: (800) 663-8876
Email: [email protected]
Website: http://www.neutropenia.ca
NIH/National Heart, Lung and Blood Institute
P.O. Box 30105
Bethesda, MD 20892-0105
Phone: (301) 592-8573
Email: [email protected]
Website: http://www.nhlbi.nih.gov/
NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
Information Clearinghouse
One AMS Circle
Bethesda, MD 20892-3675 USA
Phone: (301) 495-4484
Toll-free: (877) 226-4267
Email: [email protected]
Website: http://www.niams.nih.gov/
References
JOURNAL ARTICLES
De la Morena MT, Leonard D, Torgenson TR, et al. Long-term outcomes of 176
patients with X-linked hyper IgM syndrome treated with or without hematopoietic cell
transplantation. J Allergy Clin Immunol. 2017;139:1282-1292.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374029/
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Clinical phenotypes of hyper IgM syndromes. J Allergy Clin Immunol Pract.
2016;4:1023-1036. https://www.ncbi.nlm.nih.gov/pubmed/27836054
Leven EA, Maffucci P, Ochs HD, et al. Hyper IgM syndrome: a report from the
USIDNET registry. J Clin Immunol. 2016;36:490-501.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039943/
Ochs HD. Patients with abnormal IgM levels: assessment, clinical interpretation, and
treatment. Ann Allergy Asthma Immunol. 2008;100:509-511.
https://www.ncbi.nlm.nih.gov/pubmed/18517086
Etzioni A, Ochs HD. The hyper IgM syndrome – an evolving story. Pediatr Res.
2004;56:519-525. https://www.nature.com/articles/pr2004508.pdf
INTERNET
Johnson J, Filipovich AH, Zhang K. X-Linked Hyper IgM Syndrome. 2007 May 31
[Updated 2013 Jan 24]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors.
GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-
2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1402/ Accessed
December 10, 2018.
Genetics Home Reference. X-linked hyper IgM syndrome. April 2013. Available at:
https://ghr.nlm.nih.gov/condition/x-linked-hyper-igm-syndrome Accessed
September 21, 2018.
Genetics and Rare Diseases Information Center. Immunodeficiency with hyper IgM
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type 1. August 1, 2013. Available at:
https://rarediseases.info.nih.gov/diseases/73/immunodeficiency-with-hyper-igm-
type-1 Accessed September 21, 2018.
Years Published
2018
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