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Immunodeficiency 33(IMD33)

MedGen UID:
370376
Concept ID:
C1970879
Disease or Syndrome
Synonyms: IMD33; Immunodeficiency without anhidrotic ectodermal dysplasia; Immunodeficiency, isolated; Immunodeficiency, pure
 
Gene (location): IKBKG (Xq28)
 
Monarch Initiative: MONDO:0010386
OMIM®: 300636

Definition

Immunodeficiency-33 (IMD33) is an X-linked recessive disorder that affects only males. It is characterized by early-onset severe infections, usually due to pneumococcus, H. influenzae, and atypical mycobacteria, although other organisms have also been detected. Immunologic investigations may show variable abnormalities or may be normal. Disturbances include dysgammaglobulinemia with hypogammaglobulinemia, decreased IgG2, aberrant levels of IgM and IgA, and decreased class-switched memory B cells. There is often poor, but variable, response to vaccination; in particular, most patients do not develop antibodies to certain polysaccharide vaccines, notably pneumococcus. Other immunologic abnormalities may include impaired NK cytotoxic function, impaired cytokine production upon stimulation with IL1B (147720) or TNFA (191160), low IL6 (147620), low IL12 (see 161561), and decreased IFNG (147570). Patients do not have overt abnormalities of T-cell proliferation, although signaling pathways, such as CD40LG (300386)/CD40 (109535), may be disturbed. There is heterogeneity in the immunologic phenotype, resulting in highly variable clinical courses, most likely due to the different effects of hypomorphic mutations. Treatment with antibiotics and IVIg is usually beneficial; hematopoietic stem cell transplantation may not be necessary, but can be effective. Features of hypohidrotic ectodermal dysplasia are generally not present, although some patients may have conical teeth or hypodontia (summary by Orange et al., 2004, Filipe-Santos et al., 2006, Salt et al., 2008, Heller et al., 2020). [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.
Increased circulating IgA level
MedGen UID:
66800
Concept ID:
C0239984
Finding
An abnormally increased level of immunoglobulin A in blood.
Decreased circulating total IgM
MedGen UID:
116095
Concept ID:
C0239989
Finding
An abnormally decreased level of immunoglobulin M (IgM) in blood.
Pneumocystosis
MedGen UID:
777048
Concept ID:
C1535939
Disease or Syndrome
An opportunistic disease caused by invasion of unicellular fungus Pneumocystis jirovecii. Transmission of P. jirovecii cysts takes place through the airborne route, and usually, its presence in lungs is asymptomatic. However, people with impaired immunity, especially those with CD4+ T cell count below 200/microliter, are still at risk of the development of Pneumocystis pneumonia due to P. jirovecii invasion. Symptoms induced by this disease are not specific
Recurrent bacterial infections
MedGen UID:
334943
Concept ID:
C1844383
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.
Disseminated nontuberculous mycobacterial infection
MedGen UID:
1687715
Concept ID:
C5139240
Disease or Syndrome
An infection with nontuberculous mycobacteria that affects multiple body sites. Such infections can occur in individuals with immune disease.
Partial congenital absence of teeth
MedGen UID:
43794
Concept ID:
C0020608
Congenital Abnormality
Tooth agenesis in some form is a common human anomaly that affects approximately 20% of the population. Although tooth agenesis is associated with numerous syndromes, several case reports describe nonsyndromic forms that are either sporadic or familial in nature, as reviewed by Gorlin et al. (1990). The incidence of familial tooth agenesis varies with each class of teeth. Most commonly affected are third molars (wisdom teeth), followed by either upper lateral incisors or lower second premolars; agenesis involving first and second molars is very rare. Also see 114600 and 302400. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). Faulty use of the terms, however, have confounded their use. The term 'partial anodontia' is obsolete (Salinas, 1978). Genetic Heterogeneity of Selective Tooth Agenesis Other forms of selective tooth agenesis include STHAG2 (602639), mapped to chromosome 16q12; STHAG3 (604625), caused by mutation in the PAX9 gene (167416) on chromosome 14q12; STHAG4 (150400), caused by mutation in the WNT10A gene (606268) on chromosome 2q35; STHAG5 (610926), mapped to chromosome 10q11; STHAG7 (616724), caused by mutation in the LRP6 gene (603507) on chromosome 12p13; STHAG8 (617073), caused by mutation in the WNT10B gene (601906) on chromosome 12q13; STHAG9 (617275), caused by mutation in the GREM2 gene (608832) on chromosome 1q43; STHAG10 (620173), caused by mutation in the TSPEAR gene (612920) on chromosome 21q22; and STHAGX1 (313500), caused by mutation in the EDA gene (300451) on chromosome Xq13. A type of selective tooth agenesis that was formerly designated STHAG6 has been incorporated into the dental anomalies and short stature syndrome (DASS; 601216). Of 34 unrelated patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) found that 56% (19 patients) had mutations in the WNT10A gene (STHAG4), whereas only 3% and 9% had mutations in the MSX1 (STHAG1) and PAX9 (STHAG3) genes, respectively. The authors concluded that WNT10A is a major gene in the etiology of isolated hypodontia. Genotype-Phenotype Correlations Yu et al. (2016) observed that the most frequently missing permanent teeth in WNT10B-associated oligodontia were the lateral incisors (83.3%), whereas premolars were missing only 51.4% of the time, which they noted was a pattern 'clearly different' from the oligodontia patterns resulting from WNT10A mutations. They also stated that the selective pattern in WNT10B mutants was different from that associated with mutations in other genes, such as MSX1, in which second premolars are missing, and PAX9, in which there is agenesis of molars.
Delayed eruption of teeth
MedGen UID:
68678
Concept ID:
C0239174
Finding
Delayed tooth eruption, which can be defined as tooth eruption more than 2 SD beyond the mean eruption age.
Conical tooth
MedGen UID:
82730
Concept ID:
C0266037
Congenital Abnormality
An abnormal conical form of the teeth, that is, a tooth whose sides converge or taper together incisally.

Professional guidelines

PubMed

McCluskey SM, Siedner MJ, Marconi VC
Infect Dis Clin North Am 2019 Sep;33(3):707-742. Epub 2019 Jun 27 doi: 10.1016/j.idc.2019.05.004. PMID: 31255384Free PMC Article
Alemu Belachew W, Naafs B
J Eur Acad Dermatol Venereol 2019 Jul;33(7):1205-1213. Epub 2019 Apr 3 doi: 10.1111/jdv.15569. PMID: 30945360
Maartens G, Celum C, Lewin SR
Lancet 2014 Jul 19;384(9939):258-71. Epub 2014 Jun 5 doi: 10.1016/S0140-6736(14)60164-1. PMID: 24907868

Recent clinical studies

Etiology

Leiding JW, Vogel TP, Santarlas VGJ, Mhaskar R, Smith MR, Carisey A, Vargas-Hernández A, Silva-Carmona M, Heeg M, Rensing-Ehl A, Neven B, Hadjadj J, Hambleton S, Ronan Leahy T, Meesilpavikai K, Cunningham-Rundles C, Dutmer CM, Sharapova SO, Taskinen M, Chua I, Hague R, Klemann C, Kostyuchenko L, Morio T, Thatayatikom A, Ozen A, Scherbina A, Bauer CS, Flanagan SE, Gambineri E, Giovannini-Chami L, Heimall J, Sullivan KE, Allenspach E, Romberg N, Deane SG, Prince BT, Rose MJ, Bohnsack J, Mousallem T, Jesudas R, Santos Vilela MMD, O'Sullivan M, Pachlopnik Schmid J, Průhová Š, Klocperk A, Rees M, Su H, Bahna S, Baris S, Bartnikas LM, Chang Berger A, Briggs TA, Brothers S, Bundy V, Chan AY, Chandrakasan S, Christiansen M, Cole T, Cook MC, Desai MM, Fischer U, Fulcher DA, Gallo S, Gauthier A, Gennery AR, Gonçalo Marques J, Gottrand F, Grimbacher B, Grunebaum E, Haapaniemi E, Hämäläinen S, Heiskanen K, Heiskanen-Kosma T, Hoffman HM, Gonzalez-Granado LI, Guerrerio AL, Kainulainen L, Kumar A, Lawrence MG, Levin C, Martelius T, Neth O, Olbrich P, Palma A, Patel NC, Pozos T, Preece K, Lugo Reyes SO, Russell MA, Schejter Y, Seroogy C, Sinclair J, Skevofilax E, Suan D, Suez D, Szabolcs P, Velasco H, Warnatz K, Walkovich K, Worth A; STAT3 GOF Working Group members, Seppänen MRJ, Torgerson TR, Sogkas G, Ehl S, Tangye SG, Cooper MA, Milner JD, Forbes Satter LR
J Allergy Clin Immunol 2023 Apr;151(4):1081-1095. Epub 2022 Oct 11 doi: 10.1016/j.jaci.2022.09.002. PMID: 36228738Free PMC Article
Tallar M, Routes J
Clin Perinatol 2020 Mar;47(1):77-86. Epub 2019 Sep 27 doi: 10.1016/j.clp.2019.09.004. PMID: 32000930
Patel SY, Carbone J, Jolles S
Front Immunol 2019;10:33. Epub 2019 Feb 8 doi: 10.3389/fimmu.2019.00033. PMID: 30800120Free PMC Article
Taylor GS, Long HM, Brooks JM, Rickinson AB, Hislop AD
Annu Rev Immunol 2015;33:787-821. Epub 2015 Feb 11 doi: 10.1146/annurev-immunol-032414-112326. PMID: 25706097
Schuman P, Sobel JD
Aust N Z J Obstet Gynaecol 1993 Nov;33(4):341-50. doi: 10.1111/j.1479-828x.1993.tb02106.x. PMID: 8179538

Diagnosis

Leiding JW, Vogel TP, Santarlas VGJ, Mhaskar R, Smith MR, Carisey A, Vargas-Hernández A, Silva-Carmona M, Heeg M, Rensing-Ehl A, Neven B, Hadjadj J, Hambleton S, Ronan Leahy T, Meesilpavikai K, Cunningham-Rundles C, Dutmer CM, Sharapova SO, Taskinen M, Chua I, Hague R, Klemann C, Kostyuchenko L, Morio T, Thatayatikom A, Ozen A, Scherbina A, Bauer CS, Flanagan SE, Gambineri E, Giovannini-Chami L, Heimall J, Sullivan KE, Allenspach E, Romberg N, Deane SG, Prince BT, Rose MJ, Bohnsack J, Mousallem T, Jesudas R, Santos Vilela MMD, O'Sullivan M, Pachlopnik Schmid J, Průhová Š, Klocperk A, Rees M, Su H, Bahna S, Baris S, Bartnikas LM, Chang Berger A, Briggs TA, Brothers S, Bundy V, Chan AY, Chandrakasan S, Christiansen M, Cole T, Cook MC, Desai MM, Fischer U, Fulcher DA, Gallo S, Gauthier A, Gennery AR, Gonçalo Marques J, Gottrand F, Grimbacher B, Grunebaum E, Haapaniemi E, Hämäläinen S, Heiskanen K, Heiskanen-Kosma T, Hoffman HM, Gonzalez-Granado LI, Guerrerio AL, Kainulainen L, Kumar A, Lawrence MG, Levin C, Martelius T, Neth O, Olbrich P, Palma A, Patel NC, Pozos T, Preece K, Lugo Reyes SO, Russell MA, Schejter Y, Seroogy C, Sinclair J, Skevofilax E, Suan D, Suez D, Szabolcs P, Velasco H, Warnatz K, Walkovich K, Worth A; STAT3 GOF Working Group members, Seppänen MRJ, Torgerson TR, Sogkas G, Ehl S, Tangye SG, Cooper MA, Milner JD, Forbes Satter LR
J Allergy Clin Immunol 2023 Apr;151(4):1081-1095. Epub 2022 Oct 11 doi: 10.1016/j.jaci.2022.09.002. PMID: 36228738Free PMC Article
Tallar M, Routes J
Clin Perinatol 2020 Mar;47(1):77-86. Epub 2019 Sep 27 doi: 10.1016/j.clp.2019.09.004. PMID: 32000930
Patel SY, Carbone J, Jolles S
Front Immunol 2019;10:33. Epub 2019 Feb 8 doi: 10.3389/fimmu.2019.00033. PMID: 30800120Free PMC Article
Taylor GS, Long HM, Brooks JM, Rickinson AB, Hislop AD
Annu Rev Immunol 2015;33:787-821. Epub 2015 Feb 11 doi: 10.1146/annurev-immunol-032414-112326. PMID: 25706097
Cohen MS, Shaw GM, McMichael AJ, Haynes BF
N Engl J Med 2011 May 19;364(20):1943-54. doi: 10.1056/NEJMra1011874. PMID: 21591946Free PMC Article

Therapy

Cuvelier GDE, Logan BR, Prockop SE, Buckley RH, Kuo CY, Griffith LM, Liu X, Yip A, Hershfield MS, Ayoub PG, Moore TB, Dorsey MJ, O'Reilly RJ, Kapoor N, Pai SY, Kapadia M, Ebens CL, Forbes Satter LR, Burroughs LM, Petrovic A, Chellapandian D, Heimall J, Shyr DC, Rayes A, Bednarski JJ, Chandra S, Chandrakasan S, Gillio AP, Madden L, Quigg TC, Caywood EH, Dávila Saldaña BJ, DeSantes K, Eissa H, Goldman FD, Rozmus J, Shah AJ, Vander Lugt MT, Thakar MS, Parrott RE, Martinez C, Leiding JW, Torgerson TR, Pulsipher MA, Notarangelo LD, Cowan MJ, Dvorak CC, Haddad E, Puck JM, Kohn DB
Blood 2022 Aug 18;140(7):685-705. doi: 10.1182/blood.2022016196. PMID: 35671392Free PMC Article
Adamian CMC, de Lima Mota MA, Martins AAF, Aragão MC, Carvalho MS, Meneses GC, Silva Júnior GBD, Leitão TDMJS, De Francesco Daher E
Int J STD AIDS 2022 May;33(6):544-553. Epub 2022 Mar 28 doi: 10.1177/09564624221076605. PMID: 35343333
Cadiñanos J, Montejano R, de Miguel Buckley R, Marcelo C, Arribas JR
Expert Opin Drug Saf 2021 Apr;20(4):397-409. Epub 2021 Feb 24 doi: 10.1080/14740338.2021.1887135. PMID: 33557651
Costiniuk CT, Jenabian MA
AIDS 2019 Dec 1;33(15):2273-2288. doi: 10.1097/QAD.0000000000002345. PMID: 31764093
Robins JM, Finkelstein DM
Biometrics 2000 Sep;56(3):779-88. doi: 10.1111/j.0006-341x.2000.00779.x. PMID: 10985216

Prognosis

Szczawinska-Poplonyk A, Schwartzmann E, Bukowska-Olech E, Biernat M, Gattner S, Korobacz T, Nowicki F, Wiczuk-Wiczewska M
Eur J Pediatr 2022 Apr;181(4):1371-1383. Epub 2021 Dec 23 doi: 10.1007/s00431-021-04287-6. PMID: 34939152Free PMC Article
Caka C, Cimen O, Kahyaoğlu P, Tezcan İ, Cagdas D
Pediatr Allergy Immunol 2021 Aug;32(6):1327-1334. Epub 2021 Mar 29 doi: 10.1111/pai.13497. PMID: 33706406
Facciolà A, Venanzi Rullo E, Ceccarelli M, D'Andrea F, Coco M, Micali C, Cacopardo B, Marino A, Cannavò SP, Di Rosa M, Condorelli F, Pellicanò GF, Guarneri C, Nunnari G
Dermatol Ther 2020 Jan;33(1):e13180. Epub 2019 Dec 9 doi: 10.1111/dth.13180. PMID: 31770477
Schuman P, Sobel JD
Aust N Z J Obstet Gynaecol 1993 Nov;33(4):341-50. doi: 10.1111/j.1479-828x.1993.tb02106.x. PMID: 8179538
Pomeroy C, Filice GA
Clin Infect Dis 1992 Apr;14(4):863-70. doi: 10.1093/clinids/14.4.863. PMID: 1576281

Clinical prediction guides

Leiding JW, Vogel TP, Santarlas VGJ, Mhaskar R, Smith MR, Carisey A, Vargas-Hernández A, Silva-Carmona M, Heeg M, Rensing-Ehl A, Neven B, Hadjadj J, Hambleton S, Ronan Leahy T, Meesilpavikai K, Cunningham-Rundles C, Dutmer CM, Sharapova SO, Taskinen M, Chua I, Hague R, Klemann C, Kostyuchenko L, Morio T, Thatayatikom A, Ozen A, Scherbina A, Bauer CS, Flanagan SE, Gambineri E, Giovannini-Chami L, Heimall J, Sullivan KE, Allenspach E, Romberg N, Deane SG, Prince BT, Rose MJ, Bohnsack J, Mousallem T, Jesudas R, Santos Vilela MMD, O'Sullivan M, Pachlopnik Schmid J, Průhová Š, Klocperk A, Rees M, Su H, Bahna S, Baris S, Bartnikas LM, Chang Berger A, Briggs TA, Brothers S, Bundy V, Chan AY, Chandrakasan S, Christiansen M, Cole T, Cook MC, Desai MM, Fischer U, Fulcher DA, Gallo S, Gauthier A, Gennery AR, Gonçalo Marques J, Gottrand F, Grimbacher B, Grunebaum E, Haapaniemi E, Hämäläinen S, Heiskanen K, Heiskanen-Kosma T, Hoffman HM, Gonzalez-Granado LI, Guerrerio AL, Kainulainen L, Kumar A, Lawrence MG, Levin C, Martelius T, Neth O, Olbrich P, Palma A, Patel NC, Pozos T, Preece K, Lugo Reyes SO, Russell MA, Schejter Y, Seroogy C, Sinclair J, Skevofilax E, Suan D, Suez D, Szabolcs P, Velasco H, Warnatz K, Walkovich K, Worth A; STAT3 GOF Working Group members, Seppänen MRJ, Torgerson TR, Sogkas G, Ehl S, Tangye SG, Cooper MA, Milner JD, Forbes Satter LR
J Allergy Clin Immunol 2023 Apr;151(4):1081-1095. Epub 2022 Oct 11 doi: 10.1016/j.jaci.2022.09.002. PMID: 36228738Free PMC Article
Cabañero-Navalon MD, Garcia-Bustos V, Nuñez-Beltran M, Císcar Fernández P, Mateu L, Solanich X, Carrillo-Linares JL, Robles-Marhuenda Á, Puchades-Gimeno F, Pelaez Ballesta A, López-Osle N, Torralba-Cabeza MÁ, Bielsa Masdeu AM, Diego Gil J, Tornador Gaya N, Pascual Castellanos G, Sánchez-Martínez R, Barragán-Casas JM, González-García A, Patier de la Peña JL, López-Wolf D, Mora Rufete A, Canovas Mora A, Forner Giner MJ, Moral Moral P
Front Immunol 2022;13:1033666. Epub 2022 Oct 28 doi: 10.3389/fimmu.2022.1033666. PMID: 36389743Free PMC Article
Haukoos JS, White DAE, Rowan SE, Lyle C, Gravitz S, Basham K, Godoy A, Kamis K, Hopkins E, Anderson E
AIDS Patient Care STDS 2021 Jun;35(6):211-219. doi: 10.1089/apc.2021.0012. PMID: 34097464Free PMC Article
Stiehm ER
Pediatr Res 1993 Jan;33(1 Suppl):S2-7; discussion S7-8. doi: 10.1203/00006450-199305001-00007. PMID: 8433870
Schuman P, Sobel JD
Aust N Z J Obstet Gynaecol 1993 Nov;33(4):341-50. doi: 10.1111/j.1479-828x.1993.tb02106.x. PMID: 8179538

Recent systematic reviews

Wu S, Wang J, Guo Q, Lan H, Sun Y, Ren M, Liu Y, Wang P, Wang L, Su R, Zhang J, Chen Y, Li G
Clin Microbiol Infect 2023 Aug;29(8):1000-1007. Epub 2023 Mar 13 doi: 10.1016/j.cmi.2023.03.002. PMID: 36921717
Clarke MA, Deshmukh AA, Suk R, Roberts J, Gilson R, Jay N, Stier EA, Wentzensen N
Int J Cancer 2022 Dec 1;151(11):1889-1901. Epub 2022 Aug 6 doi: 10.1002/ijc.34199. PMID: 35793241Free PMC Article
Saleh K, Michot JM, Camara-Clayette V, Vassetsky Y, Ribrag V
Curr Oncol Rep 2020 Mar 6;22(4):33. doi: 10.1007/s11912-020-0898-8. PMID: 32144513
Peebles K, Velloza J, Balkus JE, McClelland RS, Barnabas RV
Sex Transm Dis 2019 May;46(5):304-311. doi: 10.1097/OLQ.0000000000000972. PMID: 30624309
Liu AY, Nabel CS, Finkelman BS, Ruth JR, Kurzrock R, van Rhee F, Krymskaya VP, Kelleher D, Rubenstein AH, Fajgenbaum DC
Lancet Haematol 2016 Apr;3(4):e163-75. Epub 2016 Mar 17 doi: 10.1016/S2352-3026(16)00006-5. PMID: 27063975

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