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Immunodeficiency with hyper IgM type 1(HIGM1)

MedGen UID:
96019
Concept ID:
C0398689
Disease or Syndrome
Synonyms: HIGM1; Hyper IgM immunodeficiency, X-linked; Hyper IgM syndrome; Hyper IgM syndrome 1; Hyper-IgM Immunodeficiency Syndrome, Type 1; X-Linked Hyper IgM Syndrome
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Sources: HPO, OMIM, 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.
X-linked recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: X-linked hyper-IgM syndrome (403835002); X-linked with hyper-IgM immunodeficiency (403835002); X-linked hyper-immunoglobulin M syndrome (403835002); X-linked hyperimmunoglobulin M syndrome (234536003); CD40 - Cluster of differentiation ligand deficiency (234536003)
 
Gene (location): CD40LG (Xq26.3)
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 and IgA and normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal, but NK- and T-cell cytotoxicity are frequently impaired. Antigen-specific responses may be decreased or absent. 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, and recurrent or protracted diarrhea associated with failure to thrive. Neutropenia, thrombocytopenia, and anemia are common. Autoimmune and/or inflammatory disorders, such as sclerosing cholangitis, have been reported. Significant neurologic complications, often the result of a CNS infection, are seen in 10%-15% of affected males. Liver disease, including primary cirrhosis and carcinomas (bile duct carcinomas, hepatocellular carcinomas, adenocarcinomas of the liver and gall bladder), and tumors of the gastrointestinal tract (carcinoid of the pancreas, glucagonoma of the pancreas) are common life-threatening complications in adolescents and young adults with HIGM1. Affected males are also at an increased risk for lymphoma, particularly Hodgkin's disease associated with Epstein-Barr virus infection. [from GeneReviews]
Authors:
Judith Johnson  |  Alexandra H Filipovich  |  Kejian Zhang   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 GHR
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://ghr.nlm.nih.gov/condition/x-linked-hyper-igm-syndrome

Clinical features

Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Diarrhea means that you have loose, watery stools more than three times in one day. You may also have cramps, bloating, nausea and an urgent need to have a bowel movement. . Causes of diarrhea include bacteria, viruses or parasites, certain medicines, food intolerances and diseases that affect the stomach, small intestine or colon. In many cases, no cause can be found. . Although usually not harmful, diarrhea can become dangerous or signal a more serious problem. You should talk to your doctor if you have a strong pain in your abdomen or rectum, a fever, blood in your stools, severe diarrhea for more than three days or symptoms of dehydration. If your child has diarrhea, do not hesitate to call the doctor for advice. Diarrhea can be dangerous in children. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Sign or Symptom
Enlargement of the liver.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.
Immunodeficiency
MedGen UID:
7034
Concept ID:
C0021051
Disease or Syndrome
Syndromes in which there is a deficiency or defect in the mechanisms of immunity, either cellular or humoral.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral 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.
Decreased T cell activation
MedGen UID:
339550
Concept ID:
C1846550
Finding
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.
Recurrent bacterial infections
MedGen UID:
893153
Concept ID:
C4020846
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.
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.
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.
Decreased T cell activation
MedGen UID:
339550
Concept ID:
C1846550
Finding
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVImmunodeficiency with hyper IgM type 1
Follow this link to review classifications for Immunodeficiency with hyper IgM type 1 in Orphanet.

Recent clinical studies

Etiology

Al-Saud B, Al-Mousa H, Al-Ahmari A, Al-Ghonaium A, Ayas M, Alhissi S, Al-Muhsen S, Al-Seraihy A, Arnaout R, Al-Dhekri H, Hawwari A
Pediatr Transplant 2015 Sep;19(6):634-9. Epub 2015 Jun 13 doi: 10.1111/petr.12538. PMID: 26073206
Liu PN, Li H, Li Q, Yin ZW, Zhou CY, Jiang MY, Guo X
Asian Pac J Allergy Immunol 2014 Sep;32(3):270-4. doi: 10.12932/AP0365.32.3.2014. PMID: 25268346
Wang LL, Zhou W, Zhao W, Tian ZQ, Wang WF, Wang XF, Chen TX
J Immunol Res 2014;2014:683160. Epub 2014 Aug 20 doi: 10.1155/2014/683160. PMID: 25215306Free PMC Article
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
Jain A, Kovacs JA, Nelson DL, Migueles SA, Pittaluga S, Fanslow W, Fan X, Wong DW, Massey J, Hornung R, Brown MR, Spinner JJ, Liu S, Davey V, Hill HA, Ochs H, Fleisher TA
Blood 2011 Oct 6;118(14):3811-7. Epub 2011 Aug 12 doi: 10.1182/blood-2011-04-351254. PMID: 21841160Free PMC Article

Diagnosis

Al-Saud B, Al-Mousa H, Al-Ahmari A, Al-Ghonaium A, Ayas M, Alhissi S, Al-Muhsen S, Al-Seraihy A, Arnaout R, Al-Dhekri H, Hawwari A
Pediatr Transplant 2015 Sep;19(6):634-9. Epub 2015 Jun 13 doi: 10.1111/petr.12538. PMID: 26073206
Wang LL, Zhou W, Zhao W, Tian ZQ, Wang WF, Wang XF, Chen TX
J Immunol Res 2014;2014:683160. Epub 2014 Aug 20 doi: 10.1155/2014/683160. PMID: 25215306Free PMC Article
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
Caratão N, Cortesão CS, Reis PH, Freitas RF, Jacob CM, Pastorino AC, Carneiro-Sampaio M, Barreto VM
Clin Immunol 2013 Aug;148(2):279-86. Epub 2013 Jun 7 doi: 10.1016/j.clim.2013.05.017. PMID: 23803409
Silva R, Da Costa JT
Eur Ann Allergy Clin Immunol 2010 Oct;42(5):194-6. PMID: 21192628

Therapy

Wang LL, Zhou W, Zhao W, Tian ZQ, Wang WF, Wang XF, Chen TX
J Immunol Res 2014;2014:683160. Epub 2014 Aug 20 doi: 10.1155/2014/683160. PMID: 25215306Free PMC Article
Fan X, Upadhyaya B, Wu L, Koh C, Santín-Durán M, Pittaluga S, Uzel G, Kleiner D, Williams E, Ma CA, Bodansky A, Oliveira JB, Edmonds P, Hornung R, Wong DW, Fayer R, Fleisher T, Heller T, Prussin C, Jain A
Clin Immunol 2012 May;143(2):152-61. Epub 2012 Feb 7 doi: 10.1016/j.clim.2012.01.014. PMID: 22459705Free PMC Article
Jain A, Kovacs JA, Nelson DL, Migueles SA, Pittaluga S, Fanslow W, Fan X, Wong DW, Massey J, Hornung R, Brown MR, Spinner JJ, Liu S, Davey V, Hill HA, Ochs H, Fleisher TA
Blood 2011 Oct 6;118(14):3811-7. Epub 2011 Aug 12 doi: 10.1182/blood-2011-04-351254. PMID: 21841160Free PMC Article
Silva R, Da Costa JT
Eur Ann Allergy Clin Immunol 2010 Oct;42(5):194-6. PMID: 21192628
Aschermann Z, Gomori E, Kovacs GG, Pal E, Simon G, Komoly S, Marodi L, Illes Z
Arch Neurol 2007 Feb;64(2):273-6. doi: 10.1001/archneur.64.2.273. PMID: 17296845

Prognosis

Al-Saud B, Al-Mousa H, Al-Ahmari A, Al-Ghonaium A, Ayas M, Alhissi S, Al-Muhsen S, Al-Seraihy A, Arnaout R, Al-Dhekri H, Hawwari A
Pediatr Transplant 2015 Sep;19(6):634-9. Epub 2015 Jun 13 doi: 10.1111/petr.12538. PMID: 26073206
Tsai HY, Yu HH, Chien YH, Chu KH, Lau YL, Lee JH, Wang LC, Chiang BL, Yang YH
J Microbiol Immunol Infect 2015 Feb;48(1):113-8. Epub 2012 Sep 24 doi: 10.1016/j.jmii.2012.07.004. PMID: 23010537
Wang LL, Zhou W, Zhao W, Tian ZQ, Wang WF, Wang XF, Chen TX
J Immunol Res 2014;2014:683160. Epub 2014 Aug 20 doi: 10.1155/2014/683160. PMID: 25215306Free PMC Article
Jain A, Kovacs JA, Nelson DL, Migueles SA, Pittaluga S, Fanslow W, Fan X, Wong DW, Massey J, Hornung R, Brown MR, Spinner JJ, Liu S, Davey V, Hill HA, Ochs H, Fleisher TA
Blood 2011 Oct 6;118(14):3811-7. Epub 2011 Aug 12 doi: 10.1182/blood-2011-04-351254. PMID: 21841160Free PMC Article
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

Clinical prediction guides

Lopez-Saucedo C, Bernal-Reynaga R, Zayas-Jahuey J, Galindo-Gomez S, Shibayama M, Garcia-Galvez C, Estrada-Parra S, Estrada-Garcia T
Biomed Res Int 2015;2015:679850. Epub 2015 May 3 doi: 10.1155/2015/679850. PMID: 26064940Free PMC Article
Tsai HY, Yu HH, Chien YH, Chu KH, Lau YL, Lee JH, Wang LC, Chiang BL, Yang YH
J Microbiol Immunol Infect 2015 Feb;48(1):113-8. Epub 2012 Sep 24 doi: 10.1016/j.jmii.2012.07.004. PMID: 23010537
Wang LL, Zhou W, Zhao W, Tian ZQ, Wang WF, Wang XF, Chen TX
J Immunol Res 2014;2014:683160. Epub 2014 Aug 20 doi: 10.1155/2014/683160. PMID: 25215306Free PMC Article
Madkaikar M, Gupta M, Chavan S, Italia K, Desai M, Merchant R, Radhakrishnan N, Ghosh K
Blood Cells Mol Dis 2014 Sep;53(3):99-104. Epub 2014 Jun 11 doi: 10.1016/j.bcmd.2014.05.008. PMID: 24929972
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

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