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Hyper-IgM syndrome type 3(HIGM3)

MedGen UID:
328419
•Concept ID:
C1720957
•
Disease or Syndrome
Synonyms: Hyper-IgM Immunodeficiency Syndrome, Type 3; Immunodeficiency with hyper IgM type 3
 
Gene (location): CD40 (20q13.12)
 
Monarch Initiative: MONDO:0011735
OMIM®: 606843
Orphanet: ORPHA101090

Definition

Type 3 immunodeficiency with hyper-IgM (HIGM3), first described in humans by Ferrari et al. (2001), is characterized by hypogammaglobulinemia with normal or elevated levels of IgM. For a general phenotypic description and a discussion of genetic heterogeneity of immunodeficiency with hyper-IgM, see HIGM1 (308230). [from OMIM]

Clinical features

From HPO
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.
See: Feature record | Search on this feature
Decreased circulating IgA concentration
MedGen UID:
57934
•Concept ID:
C0162538
•
Disease or Syndrome
Decreased levels of immunoglobulin A (IgA).
See: Feature record | Search on this feature
Decreased circulating IgE concentration
MedGen UID:
1714318
•Concept ID:
C0853668
•
Finding
An abnormally decreased level of immunoglobulin E (IgE) in blood.
See: Feature record | Search on this feature
Neutropenia
MedGen UID:
163121
•Concept ID:
C0853697
•
Finding
An abnormally low number of neutrophils in the peripheral blood.
See: Feature record | Search on this feature
Increased circulating IgM level
MedGen UID:
333454
•Concept ID:
C1839972
•
Finding
An abnormally increased level of immunoglobulin M in blood.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
Recurrent bacterial infections
MedGen UID:
334943
•Concept ID:
C1844383
•
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
Decreased circulating IgG concentration
MedGen UID:
1720114
•Concept ID:
C5234937
•
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.
See: Feature record | Search on this feature

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHyper-IgM syndrome type 3
Follow this link to review classifications for Hyper-IgM syndrome type 3 in Orphanet.

Professional guidelines

PubMed

Low Rates of Poliovirus Antibodies in Primary Immunodeficiency Patients on Regular Intravenous Immunoglobulin Treatment.
Costa-Carvalho BT, Sullivan KE, Fontes PM, Aimé-Nobre F, Gonzales IGS, Lima ES, Granato C, de Moraes-Pinto MI
J Clin Immunol 2018 Jul;38(5):628-634. Epub 2018 Jul 14 doi: 10.1007/s10875-018-0531-x. PMID: 30006913

Recent clinical studies

Etiology

AA Amyloidosis Secondary to Primary Immune Deficiency: About 40 Cases Including 2 New French Cases and a Systematic Literature Review.
Delplanque M, Galicier L, Oziol E, Ducharme-Bénard S, Oksenhendler E, Buob D, Grateau G, Boutboul D, Georgin-Lavialle S
J Allergy Clin Immunol Pract 2021 Feb;9(2):745-752.e1. Epub 2020 Sep 30 doi: 10.1016/j.jaip.2020.09.023. PMID: 33007500
Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand.
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
Study of patients with Hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature.
Karaca NE, Durandy A, Gulez N, Aksu G, Kutukculer N
Eur J Pediatr 2011 Aug;170(8):1039-47. Epub 2011 Jan 28 doi: 10.1007/s00431-011-1400-2. PMID: 21274562
Clinical and molecular characterization of X-linked hyper-IgM syndrome patients in China.
An Y, Xiao J, Jiang L, Yang X, Yu J, Zhao X
Scand J Immunol 2010 Jul;72(1):50-6. doi: 10.1111/j.1365-3083.2010.02406.x. PMID: 20591076
Hematopoietic cell transplantation for correction of primary immunodeficiencies.
Filipovich A
Bone Marrow Transplant 2008 Aug;42 Suppl 1:S49-S52. doi: 10.1038/bmt.2008.121. PMID: 18724301

Diagnosis

Inflammatory aortitis in a patient with type 2 hyper IgM syndrome.
Staels F, Betrains A, Willemsen M, Corvelyn A, Tousseyn T, Dierickx D, Humblet-Baron S, Liston A, Vanderschueren S, Schrijvers R
Rheumatology (Oxford) 2021 Mar 2;60(3):e87-e89. doi: 10.1093/rheumatology/keaa573. PMID: 32940674
X-linked hyper IgM syndrome: clinical, immunological and molecular features in patients from India.
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
Acute eosinophilic pneumonia occurring in a dedicator of cytokinesis 8 (DOCK8) deficient patient.
Tsuge I, Ito K, Ohye T, Kando N, Kondo Y, Nakajima Y, Inuo C, Kurahashi H, Urisu A
Pediatr Pulmonol 2014 Mar;49(3):E52-5. Epub 2013 Sep 18 doi: 10.1002/ppul.22814. PMID: 24106060
Index of suspicion. Case 1: Daily fevers, rash, myalgia, arthralgia, and hepatomegaly in a teen-age girl. Case 2: Subcutaneous nodules and arthritis in an 11-year-old boy. Case 3: Fever, fatigue, cervical lymphadenopathy, and hepatosplenomegaly in a 3-year-old boy.
Weaver M, Mauriello C, Galperina K, Gaur S, Moorthy LN, Evans M, Ratanasen M, Li ST
Pediatr Rev 2013 Mar;34(3):137-42. doi: 10.1542/pir.34-3-137. PMID: 23457201
Assessment and clinical interpretation of reduced IgG values.
Agarwal S, Cunningham-Rundles C
Ann Allergy Asthma Immunol 2007 Sep;99(3):281-3. doi: 10.1016/S1081-1206(10)60665-5. PMID: 17910333Free PMC Article

Therapy

Inflammatory aortitis in a patient with type 2 hyper IgM syndrome.
Staels F, Betrains A, Willemsen M, Corvelyn A, Tousseyn T, Dierickx D, Humblet-Baron S, Liston A, Vanderschueren S, Schrijvers R
Rheumatology (Oxford) 2021 Mar 2;60(3):e87-e89. doi: 10.1093/rheumatology/keaa573. PMID: 32940674
X-Linked Hyper IgM Syndrome Manifesting as Recurrent Pneumocystis jirovecii Pneumonia: A Case Report.
Huang SH, Meng XY, Bai ZJ, Li Y, Wu SY
J Trop Pediatr 2020 Dec 1;66(6):648-654. doi: 10.1093/tropej/fmaa023. PMID: 32388558
Low Rates of Poliovirus Antibodies in Primary Immunodeficiency Patients on Regular Intravenous Immunoglobulin Treatment.
Costa-Carvalho BT, Sullivan KE, Fontes PM, Aimé-Nobre F, Gonzales IGS, Lima ES, Granato C, de Moraes-Pinto MI
J Clin Immunol 2018 Jul;38(5):628-634. Epub 2018 Jul 14 doi: 10.1007/s10875-018-0531-x. PMID: 30006913
Hematopoietic Stem Cell Transplantation for CD40 Ligand Deficiency: Single Institution Experience.
Allewelt H, Martin PL, Szabolcs P, Chao N, Buckley R, Parikh S
Pediatr Blood Cancer 2015 Dec;62(12):2216-22. Epub 2015 Aug 20 doi: 10.1002/pbc.25711. PMID: 26291959
Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand.
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

Prognosis

AA Amyloidosis Secondary to Primary Immune Deficiency: About 40 Cases Including 2 New French Cases and a Systematic Literature Review.
Delplanque M, Galicier L, Oziol E, Ducharme-Bénard S, Oksenhendler E, Buob D, Grateau G, Boutboul D, Georgin-Lavialle S
J Allergy Clin Immunol Pract 2021 Feb;9(2):745-752.e1. Epub 2020 Sep 30 doi: 10.1016/j.jaip.2020.09.023. PMID: 33007500
Hematopoietic Stem Cell Transplantation for CD40 Ligand Deficiency: Single Institution Experience.
Allewelt H, Martin PL, Szabolcs P, Chao N, Buckley R, Parikh S
Pediatr Blood Cancer 2015 Dec;62(12):2216-22. Epub 2015 Aug 20 doi: 10.1002/pbc.25711. PMID: 26291959
Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand.
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
Study of patients with Hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature.
Karaca NE, Durandy A, Gulez N, Aksu G, Kutukculer N
Eur J Pediatr 2011 Aug;170(8):1039-47. Epub 2011 Jan 28 doi: 10.1007/s00431-011-1400-2. PMID: 21274562
Female hyper IgM syndrome type 1 with a chromosomal translocation disrupting CD40LG.
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

Clinical prediction guides

Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India.
Rawat A, Tyagi R, Chaudhary H, Pandiarajan V, Jindal AK, Suri D, Gupta A, Sharma M, Arora K, Bal A, Madaan P, Saini L, Sahu JK, Ogura Y, Kato T, Imai K, Nonoyama S, Singh S
Sci Rep 2022 Mar 8;12(1):4036. doi: 10.1038/s41598-022-08019-0. PMID: 35260754Free PMC Article
Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome.
Hubbard N, Hagin D, Sommer K, Song Y, Khan I, Clough C, Ochs HD, Rawlings DJ, Scharenberg AM, Torgerson TR
Blood 2016 May 26;127(21):2513-22. Epub 2016 Feb 22 doi: 10.1182/blood-2015-11-683235. PMID: 26903548
X-linked hyper IgM syndrome: clinical, immunological and molecular features in patients from India.
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
Hyper-immunoglobulin M syndrome type 3 with normal CD40 cell surface expression.
Karaca NE, Forveille M, Aksu G, Durandy A, Kutukculer N
Scand J Immunol 2012 Jul;76(1):21-5. doi: 10.1111/j.1365-3083.2012.02697.x. PMID: 22443339
Study of patients with Hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature.
Karaca NE, Durandy A, Gulez N, Aksu G, Kutukculer N
Eur J Pediatr 2011 Aug;170(8):1039-47. Epub 2011 Jan 28 doi: 10.1007/s00431-011-1400-2. PMID: 21274562

Recent systematic reviews

AA Amyloidosis Secondary to Primary Immune Deficiency: About 40 Cases Including 2 New French Cases and a Systematic Literature Review.
Delplanque M, Galicier L, Oziol E, Ducharme-Bénard S, Oksenhendler E, Buob D, Grateau G, Boutboul D, Georgin-Lavialle S
J Allergy Clin Immunol Pract 2021 Feb;9(2):745-752.e1. Epub 2020 Sep 30 doi: 10.1016/j.jaip.2020.09.023. PMID: 33007500

Supplemental Content

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      Clinical tests in GTR
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    • OMIM(Genes)
      OMIM records containing genes associated with phenotypes registered in MedGen
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