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Immunodeficiency 72 with autoinflammation(IMD72)

MedGen UID:
1749856
Concept ID:
C5436540
Disease or Syndrome
Synonym: IMMUNODEFICIENCY 72 WITH AUTOINFLAMMATION AND LYMPHOPROLIFERATION
 
Gene (location): NCKAP1L (12q13.13-13.2)
 
Monarch Initiative: MONDO:0033551
OMIM®: 618982

Definition

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). [from OMIM]

Clinical features

From HPO
Clubbing of fingers
MedGen UID:
3129
Concept ID:
C0009080
Finding
Terminal broadening of the fingers (distal phalanges of the fingers).
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
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.
Molluscum contagiosum
MedGen UID:
10081
Concept ID:
C0026393
Disease or Syndrome
Molluscum contagiosum is a cutaneous viral infection that is commonly observed in both healthy and immunocompromised children. The infection is caused by a member of the Poxviridae family, the molluscum contagiosum virus. Molluscum contagiosum presents as single or multiple small white or flesh-colored papules that typically have a central umbilication. The central umbilication may be difficult to observe in young children and, instead, may bear an appearance similar to an acneiform eruption. The lesions vary in size (from 1 mm to 1 cm in diameter) and are painless, although a subset of patients report pruritus in the area of infection. On average, 11-20 papules appear on the body during the course of infection and generally remains a self-limiting disease. However, in immunosuppressed patients, molluscum contagiosum can be a severe infection with hundreds of lesions developing on the body. Extensive eruption is indicative of an advanced immunodeficiency state.
Increased circulating IgE concentration
MedGen UID:
116018
Concept ID:
C0236175
Finding
An abnormally increased overall level of immunoglobulin E in blood.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Herpes simplex encephalitis
MedGen UID:
75794
Concept ID:
C0276226
Disease or Syndrome
Infection of the brain parenchyma with herpes simplex virus, resulting in inflammation of the brain parenchyma with neurologic dysfunction.
Lymphadenopathy
MedGen UID:
96929
Concept ID:
C0497156
Disease or Syndrome
Enlargement (swelling) of a lymph node.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Increased B cell count
MedGen UID:
349067
Concept ID:
C1858972
Finding
An abnormal increase from the normal count of B cells.
Increased circulating IgG concentration
MedGen UID:
347032
Concept ID:
C1858977
Finding
An abnormally increased level of immunoglobulin G in blood.
Increased proportion of memory T cells
MedGen UID:
1695266
Concept ID:
C5139181
Finding
An abnormally elevated proportion of memory T cells compared to the total number of T cells in the blood.

Recent clinical studies

Etiology

Aykut A, Durmaz A, Karaca N, Gulez N, Genel F, Celmeli F, Cogurlu MT, Akcan M, Cicek D, Cipe FE, Kiykim A, Yıldıran A, Unluhizarci K, Kilic SS, Aksu G, Ardeniz O, Kutukculer N
Immunol Res 2024 Aug;72(4):714-726. Epub 2024 Apr 22 doi: 10.1007/s12026-024-09477-6. PMID: 38644452Free PMC Article
Sikking MA, Stroeks SLVM, Henkens MTHM, Raafs AG, Cossins B, van Deuren RC, Steehouwer M, Riksen NP, van den Wijngaard A, Brunner HG, Hoischen A, Verdonschot JAJ, Heymans SRB
JACC Heart Fail 2024 May;12(5):905-914. Epub 2023 Aug 25 doi: 10.1016/j.jchf.2023.06.037. PMID: 37638520
Jeyaratnam J, Simon A, Calvo I, Constantin T, Shcherbina A, Hofer M, Gattorno M, Martini A, Bader-Meunier B, Vastert B, Levy J, Dekker E, de Benedetti F, Frenkel J
Rheumatology (Oxford) 2022 May 5;61(5):2088-2094. doi: 10.1093/rheumatology/keab696. PMID: 34554243
Arts P, Simons A, AlZahrani MS, Yilmaz E, AlIdrissi E, van Aerde KJ, Alenezi N, AlGhamdi HA, AlJubab HA, Al-Hussaini AA, AlManjomi F, Alsaad AB, Alsaleem B, Andijani AA, Asery A, Ballourah W, Bleeker-Rovers CP, van Deuren M, van der Flier M, Gerkes EH, Gilissen C, Habazi MK, Hehir-Kwa JY, Henriet SS, Hoppenreijs EP, Hortillosa S, Kerkhofs CH, Keski-Filppula R, Lelieveld SH, Lone K, MacKenzie MA, Mensenkamp AR, Moilanen J, Nelen M, Ten Oever J, Potjewijd J, van Paassen P, Schuurs-Hoeijmakers JHM, Simon A, Stokowy T, van de Vorst M, Vreeburg M, Wagner A, van Well GTJ, Zafeiropoulou D, Zonneveld-Huijssoon E, Veltman JA, van Zelst-Stams WAG, Faqeih EA, van de Veerdonk FL, Netea MG, Hoischen A
Genome Med 2019 Jun 17;11(1):38. doi: 10.1186/s13073-019-0649-3. PMID: 31203817Free PMC Article
Piram M, Koné-Paut I, Lachmann HJ, Frenkel J, Ozen S, Kuemmerle-Deschner J, Stojanov S, Simon A, Finetti M, Sormani MP, Martini A, Gattorno M, Ruperto N; EUROFEVER, EUROTRAPS and the Paediatric Rheumatology International Trials Organisation (PRINTO) networks
Ann Rheum Dis 2014 Dec;73(12):2168-73. Epub 2013 Sep 11 doi: 10.1136/annrheumdis-2013-203666. PMID: 24026675Free PMC Article

Diagnosis

Aykut A, Durmaz A, Karaca N, Gulez N, Genel F, Celmeli F, Cogurlu MT, Akcan M, Cicek D, Cipe FE, Kiykim A, Yıldıran A, Unluhizarci K, Kilic SS, Aksu G, Ardeniz O, Kutukculer N
Immunol Res 2024 Aug;72(4):714-726. Epub 2024 Apr 22 doi: 10.1007/s12026-024-09477-6. PMID: 38644452Free PMC Article
Delafontaine S, Meyts I
Curr Opin Immunol 2021 Oct;72:331-339. Epub 2021 Sep 17 doi: 10.1016/j.coi.2021.08.004. PMID: 34543865
Arts P, Simons A, AlZahrani MS, Yilmaz E, AlIdrissi E, van Aerde KJ, Alenezi N, AlGhamdi HA, AlJubab HA, Al-Hussaini AA, AlManjomi F, Alsaad AB, Alsaleem B, Andijani AA, Asery A, Ballourah W, Bleeker-Rovers CP, van Deuren M, van der Flier M, Gerkes EH, Gilissen C, Habazi MK, Hehir-Kwa JY, Henriet SS, Hoppenreijs EP, Hortillosa S, Kerkhofs CH, Keski-Filppula R, Lelieveld SH, Lone K, MacKenzie MA, Mensenkamp AR, Moilanen J, Nelen M, Ten Oever J, Potjewijd J, van Paassen P, Schuurs-Hoeijmakers JHM, Simon A, Stokowy T, van de Vorst M, Vreeburg M, Wagner A, van Well GTJ, Zafeiropoulou D, Zonneveld-Huijssoon E, Veltman JA, van Zelst-Stams WAG, Faqeih EA, van de Veerdonk FL, Netea MG, Hoischen A
Genome Med 2019 Jun 17;11(1):38. doi: 10.1186/s13073-019-0649-3. PMID: 31203817Free PMC Article
Piram M, Koné-Paut I, Lachmann HJ, Frenkel J, Ozen S, Kuemmerle-Deschner J, Stojanov S, Simon A, Finetti M, Sormani MP, Martini A, Gattorno M, Ruperto N; EUROFEVER, EUROTRAPS and the Paediatric Rheumatology International Trials Organisation (PRINTO) networks
Ann Rheum Dis 2014 Dec;73(12):2168-73. Epub 2013 Sep 11 doi: 10.1136/annrheumdis-2013-203666. PMID: 24026675Free PMC Article

Therapy

Jeyaratnam J, Simon A, Calvo I, Constantin T, Shcherbina A, Hofer M, Gattorno M, Martini A, Bader-Meunier B, Vastert B, Levy J, Dekker E, de Benedetti F, Frenkel J
Rheumatology (Oxford) 2022 May 5;61(5):2088-2094. doi: 10.1093/rheumatology/keab696. PMID: 34554243
Güngör T, Teira P, Slatter M, Stussi G, Stepensky P, Moshous D, Vermont C, Ahmad I, Shaw PJ, Telles da Cunha JM, Schlegel PG, Hough R, Fasth A, Kentouche K, Gruhn B, Fernandes JF, Lachance S, Bredius R, Resnick IB, Belohradsky BH, Gennery A, Fischer A, Gaspar HB, Schanz U, Seger R, Rentsch K, Veys P, Haddad E, Albert MH, Hassan M; Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation
Lancet 2014 Feb 1;383(9915):436-48. Epub 2013 Oct 23 doi: 10.1016/S0140-6736(13)62069-3. PMID: 24161820

Prognosis

Sikking MA, Stroeks SLVM, Henkens MTHM, Raafs AG, Cossins B, van Deuren RC, Steehouwer M, Riksen NP, van den Wijngaard A, Brunner HG, Hoischen A, Verdonschot JAJ, Heymans SRB
JACC Heart Fail 2024 May;12(5):905-914. Epub 2023 Aug 25 doi: 10.1016/j.jchf.2023.06.037. PMID: 37638520

Clinical prediction guides

Sikking MA, Stroeks SLVM, Henkens MTHM, Raafs AG, Cossins B, van Deuren RC, Steehouwer M, Riksen NP, van den Wijngaard A, Brunner HG, Hoischen A, Verdonschot JAJ, Heymans SRB
JACC Heart Fail 2024 May;12(5):905-914. Epub 2023 Aug 25 doi: 10.1016/j.jchf.2023.06.037. PMID: 37638520
Jeyaratnam J, Simon A, Calvo I, Constantin T, Shcherbina A, Hofer M, Gattorno M, Martini A, Bader-Meunier B, Vastert B, Levy J, Dekker E, de Benedetti F, Frenkel J
Rheumatology (Oxford) 2022 May 5;61(5):2088-2094. doi: 10.1093/rheumatology/keab696. PMID: 34554243
Zinngrebe J, Walczak H
Trends Mol Med 2017 Apr;23(4):296-309. Epub 2017 Mar 18 doi: 10.1016/j.molmed.2017.02.003. PMID: 28325627
Piram M, Koné-Paut I, Lachmann HJ, Frenkel J, Ozen S, Kuemmerle-Deschner J, Stojanov S, Simon A, Finetti M, Sormani MP, Martini A, Gattorno M, Ruperto N; EUROFEVER, EUROTRAPS and the Paediatric Rheumatology International Trials Organisation (PRINTO) networks
Ann Rheum Dis 2014 Dec;73(12):2168-73. Epub 2013 Sep 11 doi: 10.1136/annrheumdis-2013-203666. PMID: 24026675Free PMC Article

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