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Hyper-IgM syndrome type 1(HIGM; IHIS; XHIM; HIGM1; IMD3)

MedGen UID:
96019
Concept ID:
C0398689
Disease or Syndrome
Synonyms: Hyper IgM immunodeficiency, X-linked; Hyper-IgM Immunodeficiency Syndrome, Type 1; Immunodeficiency with hyper IgM type 1; X-linked hyper-IgM syndrome
SNOMED CT: X-linked hyper-IgM syndrome (403835002); X-linked with hyper-IgM immunodeficiency (403835002); X-linked hyper-immunoglobulin M syndrome (403835002)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): CD40LG (Xq26.3)
 
Monarch Initiative: MONDO:0010626
OMIM®: 308230
Orphanet: ORPHA101088

Disease characteristics

Excerpted from the GeneReview: X-Linked Hyper IgM Syndrome
X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE with normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal, but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells. Defective oxidative burst of both neutrophils and macrophages has been reported. The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years. HIGM1 usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with failure to thrive. Neutropenia is common; thrombocytopenia and anemia are less commonly seen. Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as well as increased risk for neoplasms have been reported as medical complications of this disorder. Significant neurologic complications, often the result of a CNS infection, are seen in 5%-15% of affected males. Liver disease, a serious complication of HIGM1 once observed in more than 80% of affected males by age 20 years, may be decreasing with adequate screening and treatment of Cryptosporidium infection. [from GeneReviews]
Authors:
Clinton P Dunn  |  M Teresa de la Morena   view full author information

Additional descriptions

From OMIM
HIGM is a rare immunodeficiency characterized by normal or elevated serum IgM levels associated with markedly decreased IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections and an increased susceptibility to opportunistic infections. Patients with X-linked HIGM also tend to have neutropenia, as well as a high rate of gastrointestinal and central nervous system infections, often resulting in severe liver disease and/or neurodegeneration (summary by Levy et al., 1997). Genetic Heterogeneity of Immunodeficiency with Hyper-IgM Other forms of HIGM include HIGM2 (605258), which results from mutation in the AICDA gene (605257), HIGM3 (606843), which results from mutation in the CD40 gene (109535), and HIGM5 (608106), which results from mutation in the UNG gene (191525). See also HIGM4 (608184).  http://www.omim.org/entry/308230
From MedlinePlus Genetics
X-linked hyper IgM syndrome is a condition that affects the immune system and occurs almost exclusively in males. People with this disorder have abnormal levels of proteins called antibodies or immunoglobulins. Antibodies help protect the body against infection by attaching to specific foreign particles and germs, marking them for destruction. There are several classes of antibodies, and each one has a different function in the immune system. Although the name of this condition implies that affected individuals always have high levels of immunoglobulin M (IgM), some people have normal levels of this antibody. People with X-linked hyper IgM syndrome have low levels of three other classes of antibodies: immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE). The lack of certain antibody classes makes it difficult for people with this disorder to fight off infections.

Individuals with X-linked hyper IgM syndrome begin to develop frequent infections in infancy and early childhood. Common infections include pneumonia, sinus infections (sinusitis), and ear infections (otitis). Infections often cause these children to have chronic diarrhea and they fail to gain weight and grow at the expected rate (failure to thrive). Some people with X-linked hyper IgM syndrome have low levels of white blood cells called neutrophils (neutropenia). Affected individuals may develop autoimmune disorders, neurologic complications from brain and spinal cord (central nervous system) infections, liver disease, and gastrointestinal tumors. They also have an increased risk of lymphoma, which is a cancer of immune system cells.

The severity of X-linked hyper IgM syndrome varies among affected individuals, even among members of the same family. Without treatment, this condition can result in death during childhood or adolescence.  https://medlineplus.gov/genetics/condition/x-linked-hyper-igm-syndrome

Clinical features

From HPO
Ankle clonus
MedGen UID:
68672
Concept ID:
C0238651
Finding
Clonus is an involuntary tendon reflex that causes repeated flexion and extension of the foot. Ankle clonus is tested by rapidly flexing the foot upward.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatitis
MedGen UID:
5515
Concept ID:
C0019158
Disease or Syndrome
Inflammation of the liver.
Chronic hepatitis
MedGen UID:
9223
Concept ID:
C0019189
Disease or Syndrome
Hepatitis that lasts for more than six months.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Hemolytic anemia
MedGen UID:
1916
Concept ID:
C0002878
Disease or Syndrome
A type of anemia caused by premature destruction of red blood cells (hemolysis).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Hypoxemia
MedGen UID:
152145
Concept ID:
C0700292
Finding
An abnormally low level of blood oxygen.
Recurrent lower respiratory tract infections
MedGen UID:
756211
Concept ID:
C3163798
Disease or Syndrome
An increased susceptibility to lower respiratory tract infections as manifested by a history of recurrent lower respiratory tract infections.
Sclerosing cholangitis
MedGen UID:
3036
Concept ID:
C0008313
Disease or Syndrome
Cholangitis associated with evident ductal fibrosis that develops as a consequence of long-standing bile duct inflammatory, obstruction, or ischemic injury; it can be obliterative or nonobliterative.
Dysgammaglobulinemia
MedGen UID:
41679
Concept ID:
C0013374
Disease or Syndrome
Selective deficiency of one or more, but not all, classes of immunoglobulins.
Immunodeficiency
MedGen UID:
7034
Concept ID:
C0021051
Disease or Syndrome
Failure of the immune system to protect the body adequately from infection, due to the absence or insufficiency of some component process or substance.
Meningitis
MedGen UID:
6298
Concept ID:
C0025289
Disease or Syndrome
Inflammation of the meninges.
Sepsis
MedGen UID:
48626
Concept ID:
C0036690
Disease or Syndrome
Systemic inflammatory response to infection.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Stomatitis
MedGen UID:
52511
Concept ID:
C0038362
Disease or Syndrome
Stomatitis is an inflammation of the mucous membranes of any of the structures in the mouth.
Decreased circulating IgA concentration
MedGen UID:
57934
Concept ID:
C0162538
Disease or Syndrome
Decreased levels of immunoglobulin A (IgA).
Increased circulating IgA concentration
MedGen UID:
66800
Concept ID:
C0239984
Finding
An abnormally increased level of immunoglobulin A in blood.
Enlarged tonsils
MedGen UID:
78800
Concept ID:
C0272386
Disease or Syndrome
Increase in size of the tonsils, small collections of lymphoid tissue facing into the aerodigestive tract on either side of the back part of the throat.
Enteroviral encephalitis
MedGen UID:
572543
Concept ID:
C0338401
Disease or Syndrome
Inflammation of the brain related to infection by an enterovirus.
Decreased circulating IgE concentration
MedGen UID:
1714318
Concept ID:
C0853668
Finding
An abnormally decreased level of immunoglobulin E (IgE) in blood.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Increased circulating IgM level
MedGen UID:
333454
Concept ID:
C1839972
Finding
An abnormally increased level of immunoglobulin M in blood.
Impaired Ig class switch recombination
MedGen UID:
374953
Concept ID:
C1842528
Finding
An impairment of the class-switch recombination process that normally leads B lymphocytes to produce IgG, IgA, or IgE.
Recurrent bacterial infections
MedGen UID:
334943
Concept ID:
C1844383
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.
Decreased T cell activation
MedGen UID:
339550
Concept ID:
C1846550
Finding
Decreased or impaired activation of T cells in response to a mitogen, cytokine, chemokine, cellular ligand, or an antigen for which it is specific.
Absence of lymph node germinal center
MedGen UID:
376112
Concept ID:
C1847383
Finding
Absence of germinal centers in lymph nodes. Germinal centers are the parts of lymph nodes in which B lymphocytes proliferate, differentiate, mutate through somatic hypermutation and class switch during antibody responses.
Chronic oral candidiasis
MedGen UID:
870166
Concept ID:
C4024599
Disease or Syndrome
Chronic accumulation and overgrowth of the fungus Candida albicans on the mucous membranes of the mouth, generally manifested as associated with creamy white lesions on the tongue or inner cheeks, occasionally spreading to the gums, tonsils, palate or oropharynx.
Impaired memory B cell generation
MedGen UID:
871195
Concept ID:
C4025672
Cell or Molecular Dysfunction
Impaired production of memory cells, the B cells that persist for years or an entire lifetime and which confer rapid and enhanced response to secondary challenge.
Abnormal circulating IgM concentration
MedGen UID:
1688699
Concept ID:
C5139423
Finding
An abnormal deviation from normal levels of IgM immunoglobulin in blood.
Decreased circulating IgG concentration
MedGen UID:
1720114
Concept ID:
C5234937
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.
Pneumocystis carinii pneumonia
MedGen UID:
994080
Concept ID:
CN315554
Finding
Pneumocystis carinii pneumonia is an opportunistic infection that occurs in immunosuppressed populations.
Gingivitis
MedGen UID:
4895
Concept ID:
C0017574
Disease or Syndrome
Inflammation of the gingiva.
Oral ulcer
MedGen UID:
57699
Concept ID:
C0149745
Disease or Syndrome
Erosion of the mucous mebrane of the mouth with local excavation of the surface, resulting from the sloughing of inflammatory necrotic tissue.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHyper-IgM syndrome type 1
Follow this link to review classifications for Hyper-IgM syndrome type 1 in Orphanet.

Professional guidelines

PubMed

Huang S, Niu Y, Li J, Gao M, Zhang Y, Yan J, Ma S, Gao X, Gao Y
J Assist Reprod Genet 2020 Aug;37(8):2025-2031. Epub 2020 Jun 5 doi: 10.1007/s10815-020-01846-y. PMID: 32500460Free PMC Article
França TT, Barreiros LA, Al-Ramadi BK, Ochs HD, Cabral-Marques O, Condino-Neto A
Expert Rev Clin Immunol 2019 May;15(5):529-540. Epub 2019 Feb 18 doi: 10.1080/1744666X.2019.1573674. PMID: 30681380
Ochs HD
Ann Allergy Asthma Immunol 2008 May;100(5):509-11. doi: 10.1016/S1081-1206(10)60479-6. PMID: 18517086

Recent clinical studies

Etiology

Tang WJ, An YF, Dai RX, Wang QH, Jiang LP, Tang XM, Yang XQ, Yu J, Tu WW, Zhao XD
Hum Immunol 2014 Jul;75(7):633-40. Epub 2014 Apr 24 doi: 10.1016/j.humimm.2014.04.014. PMID: 24768948
Wolska-Kusnierz B, Bajer A, Caccio S, Heropolitanska-Pliszka E, Bernatowska E, Socha P, van Dongen J, Bednarska M, Paziewska A, Sinski E
J Pediatr Gastroenterol Nutr 2007 Oct;45(4):458-64. doi: 10.1097/MPG.0b013e318054b09b. PMID: 18030213
Tomizawa D, Imai K, Ito S, Kajiwara M, Minegishi Y, Nagasawa M, Morio T, Nonoyama S, Mizutani S
Am J Hematol 2004 May;76(1):33-9. doi: 10.1002/ajh.20044. PMID: 15114594

Diagnosis

Tang WJ, An YF, Dai RX, Wang QH, Jiang LP, Tang XM, Yang XQ, Yu J, Tu WW, Zhao XD
Hum Immunol 2014 Jul;75(7):633-40. Epub 2014 Apr 24 doi: 10.1016/j.humimm.2014.04.014. PMID: 24768948
Fremerey C, Wiebe B, Feyen O, Lenski C, Pohlmann U, Ehlen M, Schofer O, Meindl A, Niehues T, Bartmann P
Klin Padiatr 2009 Sep;221(5):302-4. Epub 2009 Aug 25 doi: 10.1055/s-0029-1192041. PMID: 19707993
Wolska-Kusnierz B, Bajer A, Caccio S, Heropolitanska-Pliszka E, Bernatowska E, Socha P, van Dongen J, Bednarska M, Paziewska A, Sinski E
J Pediatr Gastroenterol Nutr 2007 Oct;45(4):458-64. doi: 10.1097/MPG.0b013e318054b09b. PMID: 18030213

Therapy

Wolska-Kusnierz B, Bajer A, Caccio S, Heropolitanska-Pliszka E, Bernatowska E, Socha P, van Dongen J, Bednarska M, Paziewska A, Sinski E
J Pediatr Gastroenterol Nutr 2007 Oct;45(4):458-64. doi: 10.1097/MPG.0b013e318054b09b. PMID: 18030213

Prognosis

Takada YK, Shimoda M, Maverakis E, Felding BH, Cheng RH, Takada Y
J Biol Chem 2021 Jan-Jun;296:100399. Epub 2021 Feb 9 doi: 10.1016/j.jbc.2021.100399. PMID: 33571526Free PMC Article
Takada YK, Yu J, Shimoda M, Takada Y
J Immunol 2019 Sep 1;203(5):1383-1391. Epub 2019 Jul 22 doi: 10.4049/jimmunol.1801630. PMID: 31331973
Fremerey C, Wiebe B, Feyen O, Lenski C, Pohlmann U, Ehlen M, Schofer O, Meindl A, Niehues T, Bartmann P
Klin Padiatr 2009 Sep;221(5):302-4. Epub 2009 Aug 25 doi: 10.1055/s-0029-1192041. PMID: 19707993
Imai K, Shimadzu M, Kubota T, Morio T, Matsunaga T, Park YD, Yoshioka A, Nonoyama S
Biochim Biophys Acta 2006 Mar;1762(3):335-40. Epub 2005 Oct 28 doi: 10.1016/j.bbadis.2005.10.003. PMID: 16311023
Tomizawa D, Imai K, Ito S, Kajiwara M, Minegishi Y, Nagasawa M, Morio T, Nonoyama S, Mizutani S
Am J Hematol 2004 May;76(1):33-9. doi: 10.1002/ajh.20044. PMID: 15114594

Clinical prediction guides

Takada YK, Shimoda M, Maverakis E, Felding BH, Cheng RH, Takada Y
J Biol Chem 2021 Jan-Jun;296:100399. Epub 2021 Feb 9 doi: 10.1016/j.jbc.2021.100399. PMID: 33571526Free PMC Article
Takada YK, Yu J, Shimoda M, Takada Y
J Immunol 2019 Sep 1;203(5):1383-1391. Epub 2019 Jul 22 doi: 10.4049/jimmunol.1801630. PMID: 31331973
Tang WJ, An YF, Dai RX, Wang QH, Jiang LP, Tang XM, Yang XQ, Yu J, Tu WW, Zhao XD
Hum Immunol 2014 Jul;75(7):633-40. Epub 2014 Apr 24 doi: 10.1016/j.humimm.2014.04.014. PMID: 24768948
Wolska-Kusnierz B, Bajer A, Caccio S, Heropolitanska-Pliszka E, Bernatowska E, Socha P, van Dongen J, Bednarska M, Paziewska A, Sinski E
J Pediatr Gastroenterol Nutr 2007 Oct;45(4):458-64. doi: 10.1097/MPG.0b013e318054b09b. PMID: 18030213

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