Hyper-IgM Syndrome (HIM) is a rare genetic (primary) immunodeficiency disorder that is typically inherited as an X-linked recessive genetic trait. Symptoms and physical findings associated with the disorder usually become apparent in the first or second year of life. Hyper-IgM Syndrome may be characterized by recurrent pus-producing (pyogenic) bacterial infections of the upper and lower respiratory tract including the sinuses (sinusitis) and/or the lungs (pneumonitis or pneumonia); the middle ear (otitis media); the membrane that lines the eyelids and the white portions (sclera) of the eyes (conjunctivitis); the skin (pyoderma); and/or, in some cases, other areas. Individuals with Hyper-IgM Syndrome are also susceptible to "opportunistic" infections, i.e., infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems (non-immunocompromised) or widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. In individuals with Hyper-IgM Syndrome, such opportunistic infections may include those caused by Pneumocystis carinii, a microorganism that causes a form of pneumonia, or Cryptosporidium, a single-celled parasite (protozoa) that can cause infections of the intestinal tract. In addition, individuals with Hyper-IgM Syndrome are prone to certain autoimmune disorders affecting particular elements of the blood, such as neutropenia, a condition in which there is an abnormal decrease of certain white blood cells (neutrophils). Additional physical findings often associated with the disorder may include enlargement (hypertrophy) of the tonsils, enlargement of the liver and spleen (hepatosplenomegaly), chronic diarrhea and impaired absorption of nutrients by the intestinal tract (malabsorption), and/or other symptoms.
The range and severity of symptoms and physical features associated with this disorder may vary from case to case. Because approximately 70 percent of reported cases of Hyper-IgM Syndrome are inherited as an X-linked recessive genetic trait, the vast majority of affected individuals are male. However, some cases of autosomal recessive and autosomal dominant genetic inheritance have been reported. In addition, a rare acquired form of the disorder has been described in the medical literature.
The symptoms and physical findings associated with Hyper-IgM Syndrome (HIM), a rare genetic (primary) immunodeficiency disorder, typically become apparent during the first or second year of life. Such symptoms and physical findings may include recurrent pus-producing (pyogenic) bacterial infections; opportunistic infections; chronic diarrhea, impaired absorption of nutrients by the intestinal tract (malabsorption), and failure to grow and gain weight at the expected rate (failure to thrive); autoimmune diseases affecting certain elements of the blood; abnormalities involving the lymph nodes and lymph vessels; and/or physical characteristics associated with or secondary to such irregularities. The range and severity of such symptoms and physical findings may vary greatly from case to case.
Hyper-IgM Syndrome is considered a rare primary immunodeficiency disorder, one of 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 against different infectious agents (i.e., invading microscopic life-forms [microorganisms]). The T cell system (cell-mediated immune response) is responsible for fighting yeast and fungi, several viruses, and some bacteria. The B cell system (humoral immune response) 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 (Ig) 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. (The white blood cells [leukocytes] are part of the body’s system of defenses, playing an essential role in protecting against infection as well as fighting infection once it occurs.) In addition, antibodies are produced following vaccination, providing protection from infectious diseases like polio, measles, and tetanus.
Many individuals with Hyper-IgM Syndrome have abnormally high levels of immunoglobulin IgM in the fluid portion of the blood (thus the term “Hyper IgM”). However, because these same individuals may be incapable of producing adequate levels of the immunoglobulins IgG, IgA, and IgE, they 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.
Affected individuals may also be unusually susceptible to “opportunistic” infections. The term “opportunistic” 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 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). In addition, parasitic Cryptosporidium is sometimes found in the intestinal tract of affected individuals, causing persistent diarrhea. Cryptorsporidium may also be associated with degenerative disease of the liver (cirrhosis) and inflammation of the bile ducts (cholangitis) with resulting abdominal pain, fever, chills, and/or persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice).
Individuals with Hyper-IgM Syndrome may also be prone to developing autoimmune disorders affecting certain elements of the blood. The term “autoimmune” refers to conditions in which the body’s natural defenses against invading microorganisms mistakenly attack healthy tissue. Individuals with Hyper-IgM Syndrome 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 cases, neutropenia may also result in weight loss, enlargement of the spleen (splenomegaly), and/or susceptibility to other infections. Other autoimmune disorders associated with Hyper-IgM Syndrome may 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 findings associated with Hyper-IgM Syndrome, some of which may become apparent at as early as six to nine months of age, may include abnormal enlargement (hypertrophy) of the tonsils and/or lymph nodes, enlargement of the liver and spleen (hepatosplenomegaly), and/or chronic diarrhea that, in some cases, 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 with Hyper-IgM Syndrome may also develop widespread wart-like 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 (flexor surfaces [e.g., in front of the elbows, behind the knees]).
Males with X-linked Hyper-IgM Syndrome are more likely to develop opportunistic infections and/or autoimmune disorders such as neutropenia than individuals with other forms of the disorder (i.e., autosomal recessive form, autosomal dominant form, or acquired form). In addition, some individuals with Hyper-IgM Syndrome, particularly males with X-linked recessive genetic inheritance, may be more prone to developing certain forms of cancer than the general population. In such cases, the cancer usually affects the lymphatic system (e.g., Hodgkin’s or non-Hodgkin’s lymphoma), often in the gastrointestinal tract and the liver.
Approximately 70 percent of reported cases of Hyper-IgM Syndrome are inherited as an X-linked recessive genetic trait. In general, 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 that are coded on the X chromosome. Females have two X chromosomes, while males have one X chromosome and one Y chromosome. In females, disease traits on the X chromosome can be masked by the normal gene on the second 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 50 percent risk of transmitting the carrier condition to their daughters, and a 50 percent risk of transmitting the disease to their sons. Thus, in summary, when Hyper-IgM Syndrome is inherited as an X-linked recessive trait, the disorder is usually fully expressed in males only.
The gene responsible for X-Linked Hyper-IgM Syndrome (HIGM1) is located on the long arm (q) of chromosome X (Xq26). Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into many bands that are numbered. For example, “chromosome Xq26” refers to band 26 on the long arm of chromosome X.
In individuals with X-linked Hyper-IgM Syndrome, the B cell or humoral 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. 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., “class-switching” signaling) is inhibited, which, in turn, results in the susceptibility of affected individuals to many infectious disorders.
The gene responsible for X-Linked Hyper-IgM Syndrome encodes the CD40 ligand. Researchers have determined that several different genetic changes (mutations) and deletions have been present in the CD40 ligand gene in affected individuals.
In some cases, Hyper-IgM Syndrome is inherited as an autosomal recessive or autosomal dominant genetic trait. Although defects in B cell CD40 signaling (see above) have also been demonstrated in individuals with autosomal Hyper-IgM Syndrome, the gene or genes responsible for the variant form of the disorder are currently unknown.
Researchers have also described rare cases of an acquired form of the disorder that appears to be associated with exposure to the anticonvulsant drug, phenytoin, or with Congenital Rubella Syndrome, which is caused by a maternal viral infection also known as German measles (rubella). In Congenital Rubella Syndrome, affected infants may experience a variety of symptoms and physical abnormalities (e.g., deafness, congenital heart disease, hepatosplenomegaly, mental retardation, etc.) due to the mother’s infection with rubella during early or mid pregnancy (i.e., up to four months gestation).
Individuals with autosomal recessive or dominant inheritance or with the acquired form of Hyper-IgM Syndrome may be either male or female.
Hyper-IgM Syndrome is a very rare disorder that, when inherited as an X-linked recessive trait, is usually fully expressed in males only. In cases of autosomal recessive or autosomal dominant inheritance or in acquired cases, males and females are affected in equal numbers. Approximately 70 percent of reported cases are X-linked.
Because the gene responsible for X-linked Hyper-IgM Syndrome has been identified, precise genetic testing may be possible. In some cases, for example, X-Linked Hyper-IgM Syndrome may be diagnosed before birth (prenatally) as early as the tenth to eleventh week of pregnancy if the specific genetic mutation carried by the affected family is known. However, although genetic testing to aid in accurate diagnosis and carrier determination is possible, such testing may only be available through research laboratories with a special interest in this disease.
Therefore, in most cases, Hyper-IgM Syndrome is diagnosed within the first few years of life, based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, and a pattern of immune system defects found through laboratory testing. In many cases, certain findings suggestive of the disorder, particularly upper and lower respiratory tract infections (especially if Pneumocystis carinii infection is involved), persistent diarrhea, and enlargement of the tonsils, lymph nodes, spleen, and/or liver, may be evident at as early as six to nine months of age. In addition, because immunoglobulin G, which is passed to the fetus from the mother through the placenta, protects the infant from numerous infections for only approximately six months, an affected child may begin to exhibit recurrent, persistent, and often severe bacterial infections after this time period.
Confirming a variety of immunologic abnormalities may play an essential role in establishing a diagnosis. For example, specialized tests may reveal the inability of CD40 to bind to the CD40 ligand on certain activated T cells of affected males, confirming the diagnosis of X-linked Hyper-IgM Syndrome. The same test performed on female carriers of X-Linked Hyper-IgM Syndrome will demonstrate binding in approximately half of these specialized T cells. (Female carriers do not exhibit the syndrome or its associated symptoms because they have enough T cell CD40 ligand available to achieve "class-switching" signaling and, thus, an effective immunoglobulin response.. In addition, studies conducted on the liquid portion of the blood (serum) may show elevated levels of immunoglobulin M (IgM) and, in some cases, immunoglobulin D (IgD), while levels of IgG may be extremely low and IgA and IgE may be undetectable. Also, in males with X-Linked Hyper-IgM Syndrome, while immunization will produce specific IgM antibodies, antibodies of the other immunoglobulin classes will not be produced. Other specialized testing may reveal that, in some cases, the lymph nodes lack germinal centers, the area in the center of the lymph nodes that form antibodies.
The treatment of Hyper-IgM Syndrome requires the coordinated efforts of a team of specialists who may need to systematically and comprehensively plan an affected child's treatment. Such specialists may include pediatricians; specialists in the functioning of the immune system (immunologists); physicians specializing in blood disorders (hematologists), the lungs (pulmonologists), and/or the digestive tract (gastroenterologists); and/or other health care specialists.
Treatments that have been shown to help prevent the recurrent infections associated with Hyper-IgM Syndrome (prophylactic therapy) include the administration of antibiotic medication and/or infusions with antibodies (immunoglobulins) obtained from plasma, the fluid portion of the blood (intravenous gammaglobulin). In addition, although steroid therapy is often effective in the treatment of neutropenia, autoimmune disorders in children with Hyper-IgM Syndrome may present a difficult treatment dilemma since the use of steroid medications often suppresses an already weak immune system. In some cases, non-steroidal anti-inflammatory drugs may be helpful in controlling the autoimmune-like symptoms while avoiding the use of corticosteroids.
As in the case of individuals affected with other primary immunodeficiency disorders, children with Hyper-IgM Syndrome should not be given live virus vaccines since there is the remote possibility that the vaccine strains of virus may cause disease in these children as a result of their defective immune systems. However, other, unaffected members of the household where an affected individual resides should be immunized to help prevent them from bringing home a potentially dangerous infection to the individual with Hyper-IgM Syndrome.
The Food and Drug Administration (FDA) recommends that individuals with weakened immune systems such as those with primary immunodeficiency disorders should exercise caution when consuming certain fruit and vegetable juices. The FDA recommends that such individuals should drink only pasteurized versions of these juices, since unpasteurized juices may contain harmful bacteria that could cause overwhelming infectious illnesses.
Genetic counseling will be of benefit for affected children and their family members. Other treatment is symptomatic and supportive.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., immune deficiency, autoimmune disorders affecting certain elements of the blood, etc.].)
Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:3889.
Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:967-68.
Fuleihan RL. The hyper IgM syndrome. Curr Allergy Asthma Rep. 2001;1:445-50.
Fuleihan RL Hyper IgM syndrome: the other side of the coin. Curr Opin Pediatr. 2001;13:528-32.
Ferrari S, et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci USA. 2001;98:12614-19.
Revy P, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. 2000;102:565-75.
Durandy A, et al. Abnormal CD40-mediated activation pathway in B lymphocytes from patients with hyper-IgM syndrome and normal CD40 ligand expression. J Immunol. 1997;158:2576-84.
Hayward AR, et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol. 1997;158:977-83.
Levy J, et al. The clinical spectrum of X-linked hyper IgM syndrome. J Pediatr. 1997;131:47-54.
Notarangelo LD, et al. CD40lbase: a database of CD40l gene mutations causing X-linked hyper-IgM syndrome. Immunol Today. 1996;17:511-16.
Razanajaona D, et al. Somatic mutations in human IG variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome. J Immunol. 1996;157:1492-98.
Rosen FS, et al. The primary immunodeficiencies. N Engl J Med. 1995;333:431-40.
Thomas C, et al. Brief report: correction of X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation. N Engl J Med. 1995;333:426-29.
Chu YW, et al. Somatic mutation of human immunoglobulin V genes in the X-linked hyper IgM syndrome. J Clin Invest. 1995;95:1389-93.
Hirasawa A, et al. An adult diagnosed as hyper-IgM immunodeficiency syndrome. Intern Med. 1995;34:640-42.
Saiki O, et al. Signaling through CD40 rescues IgE but not IgG or IgA secretion in X-linked immunodeficiency with hyper-IgM. J Clin Invest. 1995;95:510-14.
Facchetti F, et al. Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells. J Immunol. 1995;154:6624-33.
Iwata M, et al. Neutropenia in patient with X-linked hyper-IgM syndrome. Rinsho Ketsueki. 1995;36:1223-29.
Conley ME, et al. Hyper IgM syndrome associated with defective CD40-mediated B cell activation. J Clin Invest. 1994;94:1404-09. Comment in: J Clin Invest. 1994;94:1349.
Banatvala N, et al. Hypogammaglobulinaemia associated with normal or increased IgM (the hyper IgM syndrome): a case series review. Arch Dis Child. 1994;71:150-52.
Wang WC, et al. Successful treatment of neutropenia in the hyper-immunoglobulin m syndrome with granulocyte colony-stimulating factor. Am J Pediatr Hematol Oncol. 1994;16:160-63.
Korthauer U, et al. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993;361:539-41. Comment in: Nature. 1993;361:494.
Callard RE, et al. CD40 ligand and its role in X-linked hyper-IgM syndrome. Immunol Today. 1993;14:559-64.
Allen RC, et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993;259:990-3. Comment in: Science. 1993;259:896-97.
Notarangelo LD, et al. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev. 1992;3:101-21.
Iwakiri R, et al. A familial case of hyper-IgM immunodeficiency. Acta Haematol. 1992;88:50-54.
Mayer ML, et al. Evidence for a defect in “switch” T cells in patients with immunodeficiency and hyperimmunoglobulinemia. N Engl J Med. 1986;314:409-13.
Levitt D, et al. Hyper IgM immunodeficiency. A primary dysfunction of B lymphocyte isotype switching. J Clin Invest. 1983;72:1650-57.
FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:308230; Last Update: 4/16/02. Entry Number 308230. Entry No:605258; Last Update:4/15/02. Entry No:606843; Last Update:4/15/02.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100