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Immunodeficiency 36(IMD36)

MedGen UID:
863371
Concept ID:
C4014934
Disease or Syndrome
Synonyms: IMD36; IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION
 
Gene (location): PIK3R1 (5q13.1)
 
Monarch Initiative: MONDO:0014453
OMIM®: 616005

Disease characteristics

Excerpted from the GeneReview: Activated PI3K Delta Syndrome
Activated PI3K delta syndrome (APDS) is characterized by a spectrum of clinical manifestations involving the immune system leading to increased susceptibility to infections (e.g., otitis media, sinusitis, bronchitis, and pneumonia), autoimmune/autoinflammatory manifestations including autoimmune cytopenias, gastrointestinal manifestations resembling Crohn-like colitis, intussusception, and lymphoproliferation (e.g., lymphadenopathy, hepatosplenomegaly, and nodular lymphoid hyperplasia), and an increased risk of developing B-cell lymphomas and other malignancies. Short stature, growth delays, and neurodevelopmental delays are also reported. APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1. The key clinical differences between APDS1 and APDS2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2. [from GeneReviews]
Authors:
Keith Sacco  |  Gulbu Uzel   view full author information

Additional descriptions

From OMIM
Immunodeficiency-36 with lymphoproliferation (IMD36) is an autosomal dominant primary immunodeficiency with a highly heterogeneous clinical phenotype, characterized primarily by recurrent respiratory tract infections, lymphoproliferation, and antibody deficiency. Other features include growth retardation, mild neurodevelopmental delay, and autoimmunity. The major complication is development of B-cell lymphoma (Elkaim et al., 2016).  http://www.omim.org/entry/616005
From MedlinePlus Genetics
Some people with activated PI3K-delta syndrome develop autoimmunity, which occurs when the body attacks its own tissues and organs by mistake.

There are two types of activated PI3K-delta syndrome, each with different genetic causes.

Another possible feature of activated PI3K-delta syndrome is abnormal clumping of white blood cells. These clumps can lead to enlarged lymph nodes (lymphadenopathy) or an enlarged spleen (splenomegaly). The white blood cells can also build up to form solid masses (nodular lymphoid hyperplasia), usually in the moist lining of the airways or intestines. While nodular lymphoid hyperplasia is not cancerous (benign), activated PI3K-delta syndrome increases the risk of developing forms of blood cancer called Hodgkin lymphoma and non-Hodgkin lymphoma.

Most commonly, people with activated PI3K-delta syndrome develop recurrent infections that begin in childhood, particularly in the lungs, sinuses, and ears. Over time, recurrent respiratory tract infections can lead to a condition called bronchiectasis, which damages the passages leading from the windpipe to the lungs (bronchi) and can cause breathing problems. People with activated PI3K-delta syndrome may also have chronic active viral infections, such as Epstein-Barr virus, herpes simplex virus, or cytomegalovirus infections.

Activated PI3K-delta syndrome (also known as APDS) is a disorder that impairs the immune system. Individuals with this condition often have low numbers of white blood cells (lymphopenia), particularly B cells and T cells. Normally, these cells recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. The severity of activated PI3K-delta syndrome varies widely. Some people may have multiple, severe infections while others show mild symptoms to none at all.  https://medlineplus.gov/genetics/condition/activated-pi3k-delta-syndrome

Clinical features

From HPO
B-cell chronic lymphocytic leukemia
MedGen UID:
44120
Concept ID:
C0023434
Neoplastic Process
Chronic lymphocytic leukemia (CLL) is a common neoplasia of B lymphocytes in which these cells progressively accumulate in the bone marrow, blood, and lymphoid tissues. The clinical evolution of the disorder is heterogeneous, with some patients having indolent disease and others having aggressive disease and short survival (summary by Quesada et al., 2012). Genetic Heterogeneity of Susceptibility to Chronic Lymphocytic Leukemia Susceptibility loci have been mapped to chromosomes 11p11 (CLLS1; 609630) and 13q14 (CLLS2; 109543) by genomewide linkage analysis and translocation studies, respectively. Susceptibility mapping to chromosome 9q34 (CLLS3; 612557) is associated with downregulation of the DAPK1 gene (600831). Genomewide association studies have identified susceptibility loci on chromosomes 6p25.3 (CLLS4; 612558) and 11q24.1 (CLLS5; 612559).
B-cell lymphoma
MedGen UID:
86953
Concept ID:
C0079731
Neoplastic Process
A type of lymphoma that originates in B-cells.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Chronic diarrhea
MedGen UID:
96036
Concept ID:
C0401151
Finding
The presence of chronic diarrhea, which is usually taken to mean diarrhea that has persisted for over 4 weeks.
Neurodevelopmental delay
MedGen UID:
868344
Concept ID:
C4022738
Finding
Neurodevelopmental delay (NDD) refers to delays in the maturation of the brain and central nervous system; infants and young children with NDD may experience delays in the development of one or more skills including gross motor abilities, fine-motor coordination, language abilities and ability to solve increasingly complex problems.
Bronchiectasis
MedGen UID:
14234
Concept ID:
C0006267
Disease or Syndrome
Persistent abnormal dilatation of the bronchi owing to localized and irreversible destruction and widening of the large airways.
Recurrent upper respiratory tract infections
MedGen UID:
154380
Concept ID:
C0581381
Disease or Syndrome
An increased susceptibility to upper respiratory tract infections as manifested by a history of recurrent upper respiratory tract infections (running ears - otitis, sinusitis, pharyngitis, tonsillitis).
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.
Autoimmunity
MedGen UID:
2136
Concept ID:
C0004368
Pathologic Function
The occurrence of an immune reaction against the organism's own cells or tissues.
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.
Lymphopenia
MedGen UID:
7418
Concept ID:
C0024312
Disease or Syndrome
A reduced number of lymphocytes in the blood.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Decreased circulating IgA concentration
MedGen UID:
57934
Concept ID:
C0162538
Disease or Syndrome
Decreased levels of immunoglobulin A (IgA).
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.
Increased circulating IgM level
MedGen UID:
333454
Concept ID:
C1839972
Finding
An abnormally increased level of immunoglobulin M in blood.
Recurrent bacterial infections
MedGen UID:
334943
Concept ID:
C1844383
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.
B lymphocytopenia
MedGen UID:
340780
Concept ID:
C1855067
Finding
An abnormal decrease from the normal count of B cells.
Persistent EBV viremia
MedGen UID:
767466
Concept ID:
C3554552
Finding
Persistent presence of Epstein-Barr virus in the blood.
Increased proportion of transitional B cells
MedGen UID:
892766
Concept ID:
C4072920
Finding
An elevation in the normal proportion of transitional B cells (CD19+/CD38high/IgMhigh) in circulation relative to the total number of B cells. B cells originate from precursors in the bone marrow, and the first cells which migrate to the peripheral blood have been classified as transitional B cells.
Persistent CMV viremia
MedGen UID:
1696514
Concept ID:
C5139221
Finding
Lasting (uncontrolled) presence of cytomegalovirus in the blood circulation.
Decreased proportion of naive CD8 T cells
MedGen UID:
1694295
Concept ID:
C5139538
Finding
An abnormally reduced proportion of naive CD8 T cells relative to the total number of T cells.
Decreased proportion of naive CD4 T cells
MedGen UID:
1705154
Concept ID:
C5139539
Finding
An abnormally reduced proportion of naive CD4 T cells relative to the total number of T cells.
Decreased circulating IgG concentration
MedGen UID:
1720114
Concept ID:
C5234937
Finding
An abnormally decreased level of immunoglobulin G (IgG) in blood.

Professional guidelines

PubMed

McHale TC, Boulware DR, Kasibante J, Ssebambulidde K, Skipper CP, Abassi M
Clin Microbiol Rev 2023 Dec 20;36(4):e0015622. Epub 2023 Nov 28 doi: 10.1128/cmr.00156-22. PMID: 38014977Free PMC Article
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Pediatr Infect Dis J 2017 Dec;36(12):1205-1213. doi: 10.1097/INF.0000000000001763. PMID: 29140947

Recent clinical studies

Etiology

Kochanoff KD
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Zhang Q, Jing H, Su HC
J Clin Immunol 2016 Jul;36(5):441-9. Epub 2016 May 20 doi: 10.1007/s10875-016-0296-z. PMID: 27207373Free PMC Article
Rodríguez-Cortez VC, Del Pino-Molina L, Rodríguez-Ubreva J, López-Granados E, Ballestar E
J Clin Immunol 2016 May;36 Suppl 1:48-56. Epub 2016 Mar 17 doi: 10.1007/s10875-016-0267-4. PMID: 26984849
Piot P, Bartos M, Ghys PD, Walker N, Schwartländer B
Nature 2001 Apr 19;410(6831):968-73. doi: 10.1038/35073639. PMID: 11309626

Diagnosis

Levy A, Guidez S, Debiais C, Princet I, Bouyer S, Dindinaud E, Delwail V, Systchenko T, Moya N, Gruchet C, Sabirou F, Bobin A, Gardeney H, Nsiala L, Cailly L, Olivier G, Motard C, Fleck E, Corby A, Roul C, Denis G, Dieval C, Leleu X, Tomowiak C
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Allenspach E, Torgerson TR
J Clin Immunol 2016 May;36 Suppl 1:57-67. Epub 2016 May 23 doi: 10.1007/s10875-016-0294-1. PMID: 27210535
Zhang Q, Jing H, Su HC
J Clin Immunol 2016 Jul;36(5):441-9. Epub 2016 May 20 doi: 10.1007/s10875-016-0296-z. PMID: 27207373Free PMC Article
Fang M, Abolhassani H, Lim CK, Zhang J, Hammarström L
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Dosanjh A
Pediatr Rev 2015 Nov;36(11):489-94; quiz 495. doi: 10.1542/pir.36-11-489. PMID: 26527628

Therapy

Libera M, Caputo V, Laterza G, Moudoud L, Soggiu A, Bonizzi L, Diotti RA
J Immunol Res 2024;2024:2147912. Epub 2024 Apr 8 doi: 10.1155/2024/2147912. PMID: 38628675Free PMC Article
McHale TC, Boulware DR, Kasibante J, Ssebambulidde K, Skipper CP, Abassi M
Clin Microbiol Rev 2023 Dec 20;36(4):e0015622. Epub 2023 Nov 28 doi: 10.1128/cmr.00156-22. PMID: 38014977Free PMC Article
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Annu Rev Med 1985;36:241-61. doi: 10.1146/annurev.me.36.020185.001325. PMID: 3922284

Prognosis

Levy A, Guidez S, Debiais C, Princet I, Bouyer S, Dindinaud E, Delwail V, Systchenko T, Moya N, Gruchet C, Sabirou F, Bobin A, Gardeney H, Nsiala L, Cailly L, Olivier G, Motard C, Fleck E, Corby A, Roul C, Denis G, Dieval C, Leleu X, Tomowiak C
Leuk Lymphoma 2021 Nov;62(11):2665-2670. Epub 2021 Jun 4 doi: 10.1080/10428194.2021.1907379. PMID: 34085595
GBD 2017 HIV collaborators
Lancet HIV 2019 Dec;6(12):e831-e859. Epub 2019 Aug 19 doi: 10.1016/S2352-3018(19)30196-1. PMID: 31439534Free PMC Article
Torres M, Moayedi S
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Clinical prediction guides

Banday AZ, Nisar R, Patra PK, Kaur A, Sadanand R, Chaudhry C, Bukhari STA, Banday SZ, Bhattarai D, Notarangelo LD
J Clin Immunol 2023 Dec 22;44(1):17. doi: 10.1007/s10875-023-01633-1. PMID: 38129705Free PMC Article
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Clin Infect Dis 2021 Jun 15;72(12):2087-2094. doi: 10.1093/cid/ciaa382. PMID: 32270862Free PMC Article
Nanda A, Al-Herz W, Al-Sabah H, Al-Ajmi H
Am J Dermatopathol 2014 Oct;36(10):832-7. doi: 10.1097/DAD.0000000000000112. PMID: 25062261
Piot P, Bartos M, Ghys PD, Walker N, Schwartländer B
Nature 2001 Apr 19;410(6831):968-73. doi: 10.1038/35073639. PMID: 11309626

Recent systematic reviews

GBD 2019 Lip, Oral, and Pharyngeal Cancer Collaborators, Cunha ARD, Compton K, Xu R, Mishra R, Drangsholt MT, Antunes JLF, Kerr AR, Acheson AR, Lu D, Wallace LE, Kocarnik JM, Fu W, Dean FE, Pennini A, Henrikson HJ, Alam T, Ababneh E, Abd-Elsalam S, Abdoun M, Abidi H, Abubaker Ali H, Abu-Gharbieh E, Adane TD, Addo IY, Ahmad A, Ahmad S, Ahmed Rashid T, Akonde M, Al Hamad H, Alahdab F, Alimohamadi Y, Alipour V, Al-Maweri SA, Alsharif U, Ansari-Moghaddam A, Anwar SL, Anyasodor AE, Arabloo J, Aravkin AY, Aruleba RT, Asaad M, Ashraf T, Athari SS, Attia S, Azadnajafabad S, Azangou-Khyavy M, Badar M, Baghcheghi N, Banach M, Bardhan M, Barqawi HJ, Bashir NZ, Bashiri A, Benzian H, Bernabe E, Bhagat DS, Bhojaraja VS, Bjørge T, Bouaoud S, Braithwaite D, Briko NI, Calina D, Carreras G, Chakraborty PA, Chattu VK, Chaurasia A, Chen MX, Cho WCS, Chu DT, Chukwu IS, Chung E, Cruz-Martins N, Dadras O, Dai X, Dandona L, Dandona R, Daneshpajouhnejad P, Darvishi Cheshmeh Soltani R, Darwesh AM, Debela SA, Derbew Molla M, Dessalegn FN, Dianati-Nasab M, Digesa LE, Dixit SG, Dixit A, Djalalinia S, El Sayed I, El Tantawi M, Enyew DB, Erku DA, Ezzeddini R, Fagbamigbe AF, Falzone L, Fetensa G, Fukumoto T, Gaewkhiew P, Gallus S, Gebrehiwot M, Ghashghaee A, Gill PS, Golechha M, Goleij P, Gomez RS, Gorini G, Guimaraes ALS, Gupta B, Gupta S, Gupta VB, Gupta VK, Haj-Mirzaian A, Halboub ES, Halwani R, Hanif A, Hariyani N, Harorani M, Hasani H, Hassan AM, Hassanipour S, Hassen MB, Hay SI, Hayat K, Herrera-Serna BY, Holla R, Horita N, Hosseinzadeh M, Hussain S, Ilesanmi OS, Ilic IM, Ilic MD, Isola G, Jaiswal A, Jani CT, Javaheri T, Jayarajah U, Jayaram S, Joseph N, Kadashetti V, Kandaswamy E, Karanth SD, Karaye IM, Kauppila JH, Kaur H, Keykhaei M, Khader YS, Khajuria H, Khanali J, Khatib MN, Khayat Kashani HR, Khazeei Tabari MA, Kim MS, Kompani F, Koohestani HR, Kumar GA, Kurmi OP, La Vecchia C, Lal DK, Landires I, Lasrado S, Ledda C, Lee YH, Libra M, Lim SS, Listl S, Lopukhov PD, Mafi AR, Mahumud RA, Malik AA, Mathur MR, Maulud SQ, Meena JK, Mehrabi Nasab E, Mestrovic T, Mirfakhraie R, Misganaw A, Misra S, Mithra P, Mohammad Y, Mohammadi M, Mohammadi E, Mokdad AH, Moni MA, Moraga P, Morrison SD, Mozaffari HR, Mubarik S, Murray CJL, Nair TS, Narasimha Swamy S, Narayana AI, Nassereldine H, Natto ZS, Nayak BP, Negru SM, Nggada HA, Nouraei H, Nuñez-Samudio V, Oancea B, Olagunju AT, Omar Bali A, Padron-Monedero A, Padubidri JR, Pandey A, Pardhan S, Patel J, Pezzani R, Piracha ZZ, Rabiee N, Radhakrishnan V, Radhakrishnan RA, Rahmani AM, Rahmanian V, Rao CR, Rao SJ, Rath GK, Rawaf DL, Rawaf S, Rawassizadeh R, Razeghinia MS, Rezaei N, Rezaei N, Rezaei N, Rezapour A, Riad A, Roberts TJ, Romero-Rodríguez E, Roshandel G, S M, S N C, Saddik B, Saeb MR, Saeed U, Safaei M, Sahebazzamani M, Sahebkar A, Salek Farrokhi A, Samy AM, Santric-Milicevic MM, Sathian B, Satpathy M, Šekerija M, Senthilkumaran S, Seylani A, Shafaat O, Shahsavari HR, Shamsoddin E, Sharew MM, Sharifi-Rad J, Shetty JK, Shivakumar KM, Shobeiri P, Shorofi SA, Shrestha S, Siddappa Malleshappa SK, Singh P, Singh JA, Singh G, Sinha DN, Solomon Y, Suleman M, Suliankatchi Abdulkader R, Taheri Abkenar Y, Talaat IM, Tan KK, Tbakhi A, Thiyagarajan A, Tiyuri A, Tovani-Palone MR, Unnikrishnan B, Vo B, Volovat SR, Wang C, Westerman R, Wickramasinghe ND, Xiao H, Yu C, Yuce D, Yunusa I, Zadnik V, Zare I, Zhang ZJ, Zoladl M, Force LM, Hugo FN
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