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Last updated: December 13, 2018
Years published: 2018
NORD gratefully acknowledges Maite de la Morena, MD, Seattle Childrenโs Hospital, David Hagin, MD, PhD, Tel-Aviv Sourasky Medical Center, and Akiva Zablocki, MPH, President, Hyper IgM Foundation, for assistance in the preparation of this report.
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 resulting in the individualโs 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 โhyper IgMโ 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.
X-LINKED HYPER IGM SYNDROME
Affected individuals are susceptible to recurrent episodes of certain pus-producing (pyogenic) bacterial infections that may affect the upper and lower respiratory tract including the sinuses (sinusitis) and/or the lungs (pneumonitis or pneumonia); the middle ear (otitis media); the external ear canal (otitis externa); the membrane that lines the eyelids and the white portions (sclera) of the eyes (conjunctivitis); the skin (pyoderma); and/or other areas. These infections usually begin during infancy, often in the first year or two of life.
Affected individuals may also be unusually susceptible to โopportunisticโ infections. The term โopportunisticโ infection refers either to infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems or to widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. Pneumocystis carinii, a microorganism to which individuals with X-linked hyper IgM syndrome are particularly susceptible, causes a form of pneumonia characterized by fever, cough, abnormally rapid breathing (tachypnea), and/or a bluish discoloration (cyanosis) of the skin and mucous membranes. Affected individuals may also be susceptible to Histoplasma capsulatum, a fungus whose spores, when inhaled, may produce histoplasmosis, an infection characterized by fever; cough; a general feeling of ill health (malaise); and/or irregularities of the lymph nodes (lymphadenopathy). Chronic inflammation and swelling of the sinuses (sinusitis) and thickening, widening, and scarring of the small airway tubes of the lungs due to chronic inflammation and infection (bronchiectasis) are common.
In addition, parasitic Cryptosporidium is sometimes found in the intestinal tract of affected individuals, causing persistent diarrhea. Cryptosporidium may also be associated with degenerative disease of the liver (cirrhosis) and inflammation, thickening and scarring of the bile ducts (sclerosing cholangitis). The bile ducts are the passages that carry bile from the liver. These conditions can be associated with abdominal pain, fever, chills, and/or persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice). Some individuals may experience liver disease because of infection with cytomegalovirus.
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.
Individuals with X-linked hyper-IgM syndrome may also be prone to developing autoimmune disorders, especially those affecting certain elements of the blood. The term โautoimmuneโ refers to conditions in which the bodyโs natural defenses against invading microorganisms mistakenly attack healthy tissue. Affected individuals may experience recurrent (cyclic) or persistent (chronic), often severe neutropenia, a condition in which there is an abnormal decrease in the number of certain white blood cells (neutrophils). Neutrophils play a major role in detecting, destroying, and removing invading bacteria from the blood (phagocytosis). An abnormal decrease in neutrophils (neutropenia) is often associated with fever, inflammation of the gums (gingivitis), and/or inflammation and/or ulceration of the mucous membranes of the mouth (stomatitis). In some people, neutropenia may also result in weight loss and/or susceptibility to other infections. Other autoimmune disorders that can develop include hemolytic anemia, a condition resulting from autoimmune destruction of red blood cells, and/or thrombocytopenic purpura, a condition characterized by abnormally low levels of circulating blood platelets. Platelets are specialized blood cells that help prevent and stop bleeding. Decreased levels of circulating blood platelets (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.
In approximately 10-15% of affected individuals, neurological symptoms can develop because of infection of the central nervous system.
In addition, affected individuals may be more prone to developing certain forms of cancer than the general population. Cancers associated with this disorder have included leukemias (a cancer of the blood), those occurring in the gastrointestinal tract (colon and liver), including cancer of the bile ducts (cholangiocarcinoma) and the most common type of liver cancer (hepatocarcinoma); and neuroectodermal tumors of the gastrointestinal tract and the pancreas.
HYPER IGM SYNDROME TYPE 2
This form of hyper IgM syndrome is also known as activation-induced cytidine deaminase (AID) deficiency. The signs and symptoms are similar to those seen in individuals with X-linked hyper IgM syndrome. Affected individuals often develop bacterial infections, especially those of the sinuses and lungs (sinopulmonary infections). These infections usually begin very early in life. Chronic inflammation and swelling of the sinuses (sinusitis) and thickening, widening, and scarring of the small airway tubes of the lungs due to chronic inflammation and infection (bronchiectasis) are common. Gastrointestinal infections often due to Giardia lamblia or viruses are also common. Abnormal enlargement of the spleen (splenomegaly) and the lymph nodes (lymphadenopathy) because of an increase in the number of white blood cells within lymph nodes (lymphoid hyperplasia) are also common. The tonsils may become abnormally large and require surgical removal. Autoimmune conditions, such as autoimmune cytopenia as described, are more common in hyper IgM syndrome type 2 than the X-linked form. Low levels of red cells (anemia) and platelets (thrombocytopenia) are most common. Other autoimmune conditions can develop including inflammation of the liver (hepatitis), and in rare cases, inflammatory bowel syndrome and arthritis. Unlike X-linked hyper IgM syndrome, individuals with hyper IgM syndrome type 2 usually do not develop opportunistic infections. Generally, IgM levels in the blood are much higher than in the X-linked form. Some affected individuals have a mild disease that can go undiagnosed into the teen-aged years or 20s.
HYPER IGM SYNDROME TYPE 3
This form of hyper IgM syndrome is also known as hyper IgM syndrome due to CD40 deficiency. This form of the disorder causes signs and symptoms that are virtually indistinguishable from X-linked hyper IgM syndrome described above.
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.
HYPER IGM SYNDROME TYPE 5
This form is also known as uracil-DNA-glycosylase deficiency. Affected individuals develop signs and symptoms that are similar to those seen in hyper IgM syndrome type 2 including a susceptibility to bacterial infections and lymphoid hyperplasia, and a lack of opportunistic infections.
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 โclass switchingโ) in the normal progression of an immune response.
Two โstepsโ 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 โcompanionโ interleukin receptors on B cells, which signal B cells to switch from producing IgM to producing IgA, IgE, and IgM. In addition, a certain 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., โclass-switchingโ 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.
Another normal process in the โswitchingโ of B cell production of IgM to the production other immunoglobins is called somatic hypermutation. During this process, frequent mutations occur in immunoglobulin genes. These mutations occur in response to an infectious agent and help B cells create specific antibodies that can target specific infectious or foreign materials in the body. Somatic hypermutation may also be affected in individuals with hyper IgM syndrome.
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 โturned offโ or inactivated during development, a process termed โlyonization,โ 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 chromosome is significantly โskewedโ 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.
Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be carriers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female carrier of an X-linked disorder has a 50% chance with each pregnancy of having a carrier daughter, a 50% chance of having a non-carrier daughter, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son.
Hyper IgM types 2, 3, 4 and 5 are inherited in an autosomal recessive pattern. Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual 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 for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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.
A diagnosis of hyper IgM syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, a variety of specialized tests, including laboratory testing that can detect a pattern of immune system defects.
Clinical Testing and Workup
Blood tests will be ordered to determine the status of immunoglobulins in the blood, including normal or high levels of IgM and low levels of other immunoglobulin classes. Low levels of red and white blood cells or platelets can also be detected when autoimmune cytopenia is present.
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 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 cellsโ 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.
If possible, molecular genetic testing should then be recommended to confirm a diagnosis. Molecular genetic testing can detect variations (mutations) in specific genes known to cause hyper IgM syndromes. These tests are the preferred diagnostic methods for hyper IgM syndromes, and although performed by specialized laboratories, these tests are becoming more available and more easily performed. X-linked hyper IgM syndrome and hyper IgM syndrome type 3 are mostly diagnosed by genetic testing. Hyper IgM syndromes type 2 and 5 are usually confirmed through genetic testing. Because the underlying genetic defect for hyper IgM syndrome type 4 is unknown, there is no test to confirm a diagnosis.
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 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 cellsโ 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.
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 โcure.โ However, at this time, there remain some technical difficulties to resolve before gene therapy can be advocated as a viable alternative approach.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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/
Clinical phenotypes of hyper IgM syndromes. J Allergy Clin Immunol Pract. 2016;4:1023-1036. https://www.ncbi.nlm.nih.gov/pubmed/27836054
Durandy A, Kracker S. Immunoglobulin class-switch recombination deficiencies. Arthritis Res Ther. 2012;14:218. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580555/
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/
Davies EG, Thrasher AJ. Update on the hyper immunoglobulin M syndromes. Br J Haematol. 2010;149:167-180. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855828/
Kracker S, Gardes P, Mazerolles F, Durandy A. Immunoglobulin class switch recombination deficiencies. Clin Immunol. 2010;135:193-203. https://www.ncbi.nlm.nih.gov/pubmed?term=20167540
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 โ 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. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1402/ Accessed December 10, 2018.
Notarangelo L. Hyperimmunoglobulin syndromes. UpToDate, Inc. 2018 Jul 18. Available at: https://www.uptodate.com/contents/hyperimmunoglobulin-m-syndromes Accessed September 18, 2018.
Fernandez J. Hyper-IgM syndrome. Merck Manual Online Consumer Version website. June 2018. Available at: https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/hyper-igm-syndrome Accessed September 21, 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 type 1. August 1, 2013. Available at: https://rarediseases.info.nih.gov/diseases/73/immunodeficiency-with-hyper-igm-type-1 Accessed September 21, 2018.
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