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Increased circulating IgG level

MedGen UID:
347032
Concept ID:
C1858977
Finding
Synonym: Increased levels of IgG
 
HPO: HP:0003237

Definition

An abnormally increased level of immunoglobulin G in blood. [from HPO]

Conditions with this feature

Autoimmune lymphoproliferative syndrome type 1
MedGen UID:
231300
Concept ID:
C1328840
Disease or Syndrome
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Immunodeficiency 25
MedGen UID:
346666
Concept ID:
C1857798
Disease or Syndrome
Any severe combined immunodeficiency in which the cause of the disease is a mutation in the CD247 gene.
Autoimmune lymphoproliferative syndrome type 2A
MedGen UID:
349065
Concept ID:
C1858968
Disease or Syndrome
Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age. Autoimmune disease, mostly directed toward blood cells. Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma. In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in FAS), non-malignant lymphoproliferation typically manifests in the first years of life, inexplicably waxes and wanes, and then often decreases without treatment in the second decade of life; in many affected individuals, however, neither splenomegaly nor the overall expansion of lymphocyte subsets in peripheral blood decreases. Although autoimmunity is often not present at the time of diagnosis or at the time of the most extensive lymphoproliferation, autoantibodies can be detected before autoimmune disease manifests clinically. In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in FAS, severe lymphoproliferation occurs before, at, or shortly after birth, and usually results in death at an early age. ALPS-sFAS, resulting from somatic FAS pathogenic variants in selected cell populations, notably the alpha/beta double-negative T cells (a/ß-DNT cells), appears to be similar to ALPS-FAS resulting from heterozygous germline pathogenic variants in FAS, although lower incidence of splenectomy and lower lymphocyte counts have been reported in ALPS-sFAS and no cases of lymphoma have yet been published.
Immunodeficiency 27A
MedGen UID:
860386
Concept ID:
C4011949
Disease or Syndrome
Immunodeficiency-27A (IMD27A) results from autosomal recessive (AR) IFNGR1 deficiency. Patients with complete IFNGR1 deficiency have a severe clinical phenotype characterized by early and often fatal mycobacterial infections. The disorder can thus be categorized as a form of mendelian susceptibility to mycobacterial disease (MSMD). Bacillus Calmette-Guerin (BCG) and environmental mycobacteria are the most frequent pathogens, and infection typically begins before the age of 3 years. Plasma from patients with complete AR IFNGR1 deficiency usually contains large amounts of IFNG (147570), and their cells do not respond to IFNG in vitro. In contrast, cells from patients with partial AR IFNGR1 deficiency, which is caused by a specific mutation in IFNGR1, retain residual responses to high IFNG concentrations. Patients with partial AR IFNGR1 deficiency are susceptible to BCG and environmental mycobacteria, but they have a milder clinical disease and better prognosis than patients with complete AR IFNGR1 deficiency. The clinical features of children with complete AR IFNGR1 deficiency are usually more severe than those in individuals with AD IFNGR1 deficiency (IMD27B), and mycobacterial infection often occurs earlier (mean age of 1.3 years vs 13.4 years), with patients having shorter mean disease-free survival. Salmonellosis is present in about 5% of patients with AR or AD IFNGR1 deficiency, and other infections have been reported in single patients (review by Al-Muhsen and Casanova, 2008).
Immunodeficiency 23
MedGen UID:
862808
Concept ID:
C4014371
Disease or Syndrome
IMD23 is an autosomal recessive primary immunodeficiency syndrome characterized by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity (summary by Bjorksten and Lundmark, 1976 and Zhang et al., 2014).
STING-associated vasculopathy with onset in infancy
MedGen UID:
863159
Concept ID:
C4014722
Disease or Syndrome
STING-associated vasculopathy with onset in infancy is an autoinflammatory vasculopathy causing severe skin lesions, particularly affecting the face, ears, nose, and digits, and resulting in ulceration, eschar formation, necrosis, and, in some cases, amputation. Many patients have interstitial lung disease. Tissue biopsy and laboratory findings show a hyperinflammatory state, with evidence of increased beta-interferon (IFNB1; 147640) signaling (summary by Liu et al., 2014).
Autoinflammation with arthritis and dyskeratosis
MedGen UID:
1380109
Concept ID:
C4479278
Disease or Syndrome
Autoinflammation with arthritis and dyskeratosis (AIADK) is characterized by recurrent fever, widespread skin dyskeratosis, arthritis, elevated biologic markers of inflammation, and mild autoimmunity with a high transitional B-cell level (summary by Grandemange et al., 2016).
Combined immunodeficiency due to DOCK8 deficiency
MedGen UID:
1648410
Concept ID:
C4722305
Disease or Syndrome
Hyper-IgE syndrome-2 with recurrent infections (HIES2) is an autosomal recessive immunologic disorder characterized by recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. It is distinguished from autosomal dominant HIES1 (147060) by the lack of connective tissue and skeletal involvement (Renner et al., 2004). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see 147060. See also TYK2 deficiency (611521), a clinically distinct disease entity that includes characteristic features of both autosomal recessive HIES2 and mendelian susceptibility to mycobacterial disease (MSMD; 209950) (Minegishi et al., 2006).
Proteasome-associated autoinflammatory syndrome 1
MedGen UID:
1648310
Concept ID:
C4746851
Disease or Syndrome
Proteasome-associated autoinflammatory syndrome-1 (PRAAS1) is an autosomal recessive disorder characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011). This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions. Genetic Heterogeneity of Proteasome-Associated Autoinflammatory Syndrome See also PRAAS2 (618048), caused by mutation in the POMP gene (613386) on chromosome 13q12; PRAAS3 (617591), caused by mutation in the PSMB4 gene (602177) on chromosome 1q21; PRAAS4 (619183), caused by mutation in the PSMG2 gene (609702) on chromosome 18p11; PRAAS5 (619175), caused by mutation in the PSMB10 gene (176847) on chromosome 16q22; and PRAAS6 (620796), caused by mutation in the PSMB9 gene (177045) on chromosome 6p21.
Proteasome-associated autoinflammatory syndrome 2
MedGen UID:
1648482
Concept ID:
C4747989
Disease or Syndrome
Proteasome-associated autoinflammatory syndrome-2 (PRAAS2) is an autosomal dominant disorder with onset in early infancy. Affected individuals develop severe inflammatory neutrophilic dermatitis, autoimmunity, and variable immunodeficiency (summary by Poli et al., 2018). For a discussion of genetic heterogeneity of PRAAS, see PRAAS1 (256040).
Inflammatory bowel disease, immunodeficiency, and encephalopathy
MedGen UID:
1648434
Concept ID:
C4748708
Disease or Syndrome
A rare genetic disease characterized by infantile onset of severe inflammatory bowel disease manifesting with bloody diarrhea and failure to thrive, and central nervous system disease with global developmental delay and regression, impaired speech, hypotonia, hyperreflexia, and epilepsy. Brain imaging shows global cerebral atrophy, thin corpus callosum, delayed myelination, and posterior leukoencephalopathy. Cases with recurrent infections and impaired T-cell responses to stimulation, as well as decreased T-cell subsets, have been reported.
Immunodeficiency 63 with lymphoproliferation and autoimmunity
MedGen UID:
1682943
Concept ID:
C5193126
Disease or Syndrome
Immunodeficiency-63 with lymphoproliferation and autoimmunity (IMD63) is an autosomal recessive disorder characterized by immune dysregulation. Affected individuals present in infancy with features of both abnormal activation of certain immune signaling pathways, resulting in lymphoid proliferation, dermatitis, enteropathy, and hypergammaglobulinemia, as well as features of immunodeficiency, such as recurrent infections and increased susceptibility to viral infections, especially CMV. Laboratory studies show increased NK cells that show impaired differentiation, as well as abnormal T cell populations or responses. Some patients may die in childhood; hematopoietic bone marrow transplantation is curative (summary by Zhang et al., 2019).
Immunodeficiency 64
MedGen UID:
1684716
Concept ID:
C5231402
Disease or Syndrome
Immunodeficiency-64 with lymphoproliferation (IMD64) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show variably decreased numbers of T cells, with lesser deficiencies of B and NK cells. There is impaired T-cell proliferation and activation; functional defects in B cells and NK cells may also be observed. Patients have increased susceptibility to EBV infection and may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity (summary by Salzer et al., 2016, Mao et al., 2018, and Winter et al., 2018).
Immunodeficiency 72 with autoinflammation
MedGen UID:
1749856
Concept ID:
C5436540
Disease or Syndrome
Immunodeficiency-72 with autoinflammation and lymphoproliferation (IMD72) is an autosomal recessive immunologic disorder characterized by onset of recurrent infections or systemic inflammation in the first year of life. Affected individuals develop bacterial and viral infections that can be severe, including bacteremia, recurrent pneumonia, and meningitis, consistent with an immunodeficiency. There is also an autoimmune and hyperinflammatory aspect to the disorder, manifest as atopy or allergies, hepatosplenomegaly, and lymphoproliferation, including hemophagocytic lymphohistiocytosis (HLH). Immunologic workup shows variable abnormalities, including low or high Ig subsets, increased B cells, irregular T-cell activation and cytokine response, impaired immune synapse formation, and defective cellular migration. At the cellular level, these defects are related to abnormal F-actin polymerization and altered intracellular signaling (summary by Cook et al., 2020).
Immunodeficiency 78 with autoimmunity and developmental delay
MedGen UID:
1785772
Concept ID:
C5543159
Disease or Syndrome
Immunodeficiency-78 with autoimmunity and developmental delay (IMD78) is an autosomal recessive systemic disorder characterized by onset of symptoms in early childhood. Affected individuals present with features of immune deficiency, such as recurrent sinopulmonary or skin infections, as well as autoimmunity, including autoimmune cytopenias, hemolytic anemia, and thrombocytopenia. Autoimmune hepatitis or thyroid disease and central nervous system vasculitis with stroke may also occur. There is increased susceptibility to bacterial, viral, and fungal infections. Laboratory studies show lymphopenia with advanced differentiation and premature senescence of CD8+ T cells and B cells; some patients may have hypergammaglobulinemia. The findings indicate immune dysregulation. Patients also have global developmental delay with speech delay and variable intellectual disability. Many patients die prematurely, but successful hematopoietic bone marrow transplant may be curative (summary by Lu et al., 2014 and Atallah et al., 2021).
VISS syndrome
MedGen UID:
1794165
Concept ID:
C5561955
Disease or Syndrome
VISS syndrome is a generalized connective tissue disorder characterized by early-onset thoracic aortic aneurysm and other connective tissue findings, such as aneurysm and tortuosity of other arteries, joint hypermobility, skin laxity, and hernias, as well as craniofacial dysmorphic features, structural cardiac defects, skeletal anomalies, and motor developmental delay (Van Gucht et al., 2021). Immune dysregulation has been observed in some patients (Ziegler et al., 2021).
Immunodeficiency 89 and autoimmunity
MedGen UID:
1794237
Concept ID:
C5562027
Disease or Syndrome
Immunodeficiency-89 and autoimmunity (IMD89) is an autosomal recessive immune disorder characterized by adult onset of recurrent infections, allergies, microcytic anemia, and Crohn disease (see 266600) (Yang et al., 2020).

Professional guidelines

PubMed

Sloan EE, Kmetova K, NaveenKumar SK, Kluge L, Chong E, Hoy CK, Yalavarthi S, Sarosh C, Baisch J, Walters L, Nassi L, Fuller J, Turnier JL, Pascual V, Wright TB, Madison JA, Knight JS, Zia A, Zuo Y
Clin Immunol 2024 Apr;261:109926. Epub 2024 Feb 13 doi: 10.1016/j.clim.2024.109926. PMID: 38355030
Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, Fischler B, Gupte G, Hierro L, Indolfi G, Jahnel J, Smets F, Verkade HJ, Hadžić N
J Pediatr Gastroenterol Nutr 2018 Feb;66(2):345-360. doi: 10.1097/MPG.0000000000001801. PMID: 29356770
Kado R, Sanders G, McCune WJ
Curr Opin Rheumatol 2016 May;28(3):251-8. doi: 10.1097/BOR.0000000000000272. PMID: 27027812

Recent clinical studies

Etiology

Borysenko A, Timokhina T, Kononova O
Georgian Med News 2021 Oct;(319):22-27. PMID: 34749317
Xiao N, He X, Niu H, Yu H, Cui N, Li H, Yan L, Shao Z, Xing L, Wang H
J Immunol Res 2021;2021:4302515. Epub 2021 Sep 30 doi: 10.1155/2021/4302515. PMID: 34631897Free PMC Article
Oniszczuk J, Beldi-Ferchiou A, Audureau E, Azzaoui I, Molinier-Frenkel V, Frontera V, Karras A, Moktefi A, Pillebout E, Zaidan M, El Karoui K, Delfau-Larue MH, Hénique C, Ollero M, Sahali D, Mahévas M, Audard V
Nephrol Dial Transplant 2021 Mar 29;36(4):609-617. doi: 10.1093/ndt/gfaa279. PMID: 33241414
Tao J, Song D, Liu XL, Yu F, Zhao MH
Clin Immunol 2020 Aug;217:108514. Epub 2020 Jun 18 doi: 10.1016/j.clim.2020.108514. PMID: 32565324
Shilova N, Huflejt ME, Vuskovic M, Obukhova P, Navakouski M, Khasbiullina N, Pazynina G, Galanina O, Bazhenov A, Bovin N
Top Curr Chem 2015;366:169-81. doi: 10.1007/128_2013_469. PMID: 24037491

Diagnosis

Aranda CJ, Gonzalez-Kozlova E, Saunders SP, Fernandes-Braga W, Ota M, Narayanan S, He JS, Del Duca E, Swaroop B, Gnjatic S, Shattner G, Reibman J, Soter NA, Guttman-Yassky E, Curotto de Lafaille MA
Allergy 2023 Mar;78(3):752-766. Epub 2022 Dec 19 doi: 10.1111/all.15601. PMID: 36445014Free PMC Article
Freitag TL, Podojil JR, Pearson RM, Fokta FJ, Sahl C, Messing M, Andersson LC, Leskinen K, Saavalainen P, Hoover LI, Huang K, Phippard D, Maleki S, King NJC, Shea LD, Miller SD, Meri SK, Getts DR
Gastroenterology 2020 May;158(6):1667-1681.e12. Epub 2020 Feb 4 doi: 10.1053/j.gastro.2020.01.045. PMID: 32032584Free PMC Article
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J Pediatr Gastroenterol Nutr 2018 Feb;66(2):345-360. doi: 10.1097/MPG.0000000000001801. PMID: 29356770
Culver EL, Chapman RW
Nat Rev Gastroenterol Hepatol 2016 Oct;13(10):601-12. Epub 2016 Sep 14 doi: 10.1038/nrgastro.2016.132. PMID: 27625195
Shilova N, Huflejt ME, Vuskovic M, Obukhova P, Navakouski M, Khasbiullina N, Pazynina G, Galanina O, Bazhenov A, Bovin N
Top Curr Chem 2015;366:169-81. doi: 10.1007/128_2013_469. PMID: 24037491

Therapy

Freitag TL, Podojil JR, Pearson RM, Fokta FJ, Sahl C, Messing M, Andersson LC, Leskinen K, Saavalainen P, Hoover LI, Huang K, Phippard D, Maleki S, King NJC, Shea LD, Miller SD, Meri SK, Getts DR
Gastroenterology 2020 May;158(6):1667-1681.e12. Epub 2020 Feb 4 doi: 10.1053/j.gastro.2020.01.045. PMID: 32032584Free PMC Article
Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, Fischler B, Gupte G, Hierro L, Indolfi G, Jahnel J, Smets F, Verkade HJ, Hadžić N
J Pediatr Gastroenterol Nutr 2018 Feb;66(2):345-360. doi: 10.1097/MPG.0000000000001801. PMID: 29356770
Culver EL, Chapman RW
Nat Rev Gastroenterol Hepatol 2016 Oct;13(10):601-12. Epub 2016 Sep 14 doi: 10.1038/nrgastro.2016.132. PMID: 27625195
Kaplan AP
Chem Immunol Allergy 2014;100:140-7. Epub 2014 May 22 doi: 10.1159/000358619. PMID: 24925394
Cohen AJ, Kessler CM
Baillieres Clin Haematol 1996 Jun;9(2):331-54. doi: 10.1016/s0950-3536(96)80067-9. PMID: 8800509

Prognosis

Martín F, Blanco-Suárez M, Zambrano P, Cáceres O, Almirall M, Alegre-Martín J, Lobo B, González-Castro AM, Santos J, Domingo JC, Jurek J, Castro-Marrero J
Front Immunol 2023;14:1253121. Epub 2023 Sep 7 doi: 10.3389/fimmu.2023.1253121. PMID: 37744357Free PMC Article
Borysenko A, Timokhina T, Kononova O
Georgian Med News 2021 Oct;(319):22-27. PMID: 34749317
Heeringa JJ, McKenzie CI, Varese N, Hew M, Bakx ATCM, Aui PM, Rolland JM, O'Hehir RE, van Zelm MC
Allergy 2020 May;75(5):1121-1132. Epub 2019 Nov 4 doi: 10.1111/all.14073. PMID: 31587307Free PMC Article
Kado R, Sanders G, McCune WJ
Curr Opin Rheumatol 2016 May;28(3):251-8. doi: 10.1097/BOR.0000000000000272. PMID: 27027812
Cohen AJ, Kessler CM
Baillieres Clin Haematol 1996 Jun;9(2):331-54. doi: 10.1016/s0950-3536(96)80067-9. PMID: 8800509

Clinical prediction guides

Martín F, Blanco-Suárez M, Zambrano P, Cáceres O, Almirall M, Alegre-Martín J, Lobo B, González-Castro AM, Santos J, Domingo JC, Jurek J, Castro-Marrero J
Front Immunol 2023;14:1253121. Epub 2023 Sep 7 doi: 10.3389/fimmu.2023.1253121. PMID: 37744357Free PMC Article
Borysenko A, Timokhina T, Kononova O
Georgian Med News 2021 Oct;(319):22-27. PMID: 34749317
Chen B, Qin C, Chen M, Yu HH, Tao R, Chu YH, Bu BT, Tian DS
Front Immunol 2021;12:650782. Epub 2021 Jul 21 doi: 10.3389/fimmu.2021.650782. PMID: 34367127Free PMC Article
Heeringa JJ, McKenzie CI, Varese N, Hew M, Bakx ATCM, Aui PM, Rolland JM, O'Hehir RE, van Zelm MC
Allergy 2020 May;75(5):1121-1132. Epub 2019 Nov 4 doi: 10.1111/all.14073. PMID: 31587307Free PMC Article
Shilova N, Huflejt ME, Vuskovic M, Obukhova P, Navakouski M, Khasbiullina N, Pazynina G, Galanina O, Bazhenov A, Bovin N
Top Curr Chem 2015;366:169-81. doi: 10.1007/128_2013_469. PMID: 24037491

Recent systematic reviews

Al-Awadhi S, Raynaud M, Louis K, Bouquegneau A, Taupin JL, Aubert O, Loupy A, Lefaucheur C
Front Immunol 2023;14:1265796. Epub 2023 Oct 2 doi: 10.3389/fimmu.2023.1265796. PMID: 37849755Free PMC Article
Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, Fischler B, Gupte G, Hierro L, Indolfi G, Jahnel J, Smets F, Verkade HJ, Hadžić N
J Pediatr Gastroenterol Nutr 2018 Feb;66(2):345-360. doi: 10.1097/MPG.0000000000001801. PMID: 29356770
Baccarelli A, Mocarelli P, Patterson DG Jr, Bonzini M, Pesatori AC, Caporaso N, Landi MT
Environ Health Perspect 2002 Dec;110(12):1169-73. doi: 10.1289/ehp.021101169. PMID: 12460794Free PMC Article

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