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Agammaglobulinemia 4, autosomal recessive(AGM4)

MedGen UID:: 462102
•Concept ID:: C3150752
•: Disease or Syndrome

Synonyms:	AGAMMAGLOBULINEMIA, AUTOSOMAL RECESSIVE, DUE TO BLNK DEFECT; AGM4

Gene (location): Gene(s) directly associated with this condition or phenotype.	BLNK (10q24.1)

Monarch Initiative:	MONDO:0013289
OMIM®:	613502

Definition

Any autosomal agammaglobulinemia in which the cause of the disease is a mutation in the BLNK gene. [from MONDO]

Clinical features

From HPO

Protein-losing enteropathy

MedGen UID:: 19522
•Concept ID:: C0033680
•: Disease or Syndrome

Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is characterized by abdominal pain and diarrhea, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption. Some patients also exhibit bowel inflammation, recurrent infections associated with hypogammaglobulinemia, and/or angiopathic thromboembolic disease. Patient T lymphocytes show increased complement activation, causing surface deposition of complement and generating soluble C5a (Ozen et al., 2017).

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Recurrent pneumonia

MedGen UID:: 195802
•Concept ID:: C0694550
•: Disease or Syndrome

An increased susceptibility to pneumonia as manifested by a history of recurrent episodes of pneumonia.

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Agammaglobulinemia

MedGen UID:: 168
•Concept ID:: C0001768
•: Disease or Syndrome

A lasting absence of total IgG and total IgA and total IgM in the blood circulation, whereby at most trace quantities can be measured.

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Chronic sinusitis

MedGen UID:: 101751
•Concept ID:: C0149516
•: Disease or Syndrome

A chronic form of sinusitis.

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Decreased circulating IgA level

MedGen UID:: 57934
•Concept ID:: C0162538
•: Disease or Syndrome

Decreased levels of immunoglobulin A (IgA).

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Decreased circulating total IgM

MedGen UID:: 116095
•Concept ID:: C0239989
•: Finding

An abnormally decreased level of immunoglobulin M (IgM) in blood.

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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.

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Neutropenia

MedGen UID:: 163121
•Concept ID:: C0853697
•: Finding

An abnormally low number of neutrophils in the peripheral blood.

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Recurrent bacterial infections

MedGen UID:: 334943
•Concept ID:: C1844383
•: Finding

Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.

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Abnormal T cell morphology

MedGen UID:: 343416
•Concept ID:: C1855752
•: Finding

An abnormality of T cells.

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Decreased circulating IgG level

MedGen UID:: 1720114
•Concept ID:: C5234937
•: Finding

An abnormally decreased level of immunoglobulin G (IgG) in blood.

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Abnormality of the digestive system
- Protein-losing enteropathy
Abnormality of the immune system
Abnormality of the respiratory system
- Recurrent pneumonia

Professional guidelines

PubMed

Newborn Screening for Severe T and B Cell Lymphopenia Using TREC/KREC Detection: A Large-Scale Pilot Study of 202,908 Newborns.

Marakhonov AV, Efimova IY, Mukhina AA, Zinchenko RA, Balinova NV, Rodina Y, Pershin D, Ryzhkova OP, Orlova AA, Zabnenkova VV, Cherevatova TB, Beskorovainaya TS, Shchagina OA, Polyakov AV, Markova ZG, Minzhenkova ME, Shilova NV, Larin SS, Khadzhieva MB, Dudina ES, Kalinina EV, Mudaeva DA, Saydaeva DH, Matulevich SA, Belyashova EY, Yakubovskiy GI, Tebieva IS, Gabisova YV, Irinina NA, Nurgalieva LR, Saifullina EV, Belyaeva TI, Romanova OS, Voronin SV, Shcherbina A, Kutsev SI
J Clin Immunol 2024 Apr 5;44(4):93. doi: 10.1007/s10875-024-01691-z. PMID: 38578360

See all (1)

Recent clinical studies

Etiology

Newborn Screening for Severe T and B Cell Lymphopenia Using TREC/KREC Detection: A Large-Scale Pilot Study of 202,908 Newborns.

Evaluation of respiratory complications in patients with X-linked and autosomal recessive agammaglobulinemia.

Fekrvand S, Yazdani R, Olbrich P, Azizi G, Shirzadi R, Modaresi M, Sohani M, Delavari S, Kalantari A, Shariat M, Shafiei A, Lu N, Hassanpour G, Rahimi Hajiabadi M, Ashournia P, Razaghian A, Asgharyan M, Shahraki-Ghadimi Z, Rouhani R, Hoda Fallah F, Rezaei N, Abolhassani H, Aghamohammadi A
Pediatr Allergy Immunol 2020 May;31(4):405-417. Epub 2020 Mar 6 doi: 10.1111/pai.13228. PMID: 32058651

First report on the Moroccan registry of primary immunodeficiencies: 15 years of experience (1998-2012).

Bousfiha AA, Jeddane L, El Hafidi N, Benajiba N, Rada N, El Bakkouri J, Kili A, Benmiloud S, Benhsaien I, Faiz I, Maataoui O, Aadam Z, Aglaguel A, Baba LA, Jouhadi Z, Abilkassem R, Bouskraoui M, Hida M, Najib J, Alj HS, Ailal F; Moroccan Society for Primary Immunodeficiencies (MSPID)
J Clin Immunol 2014 May;34(4):459-68. Epub 2014 Mar 12 doi: 10.1007/s10875-014-0005-8. PMID: 24619622

Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations.

Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P, Coxon FP, Helfrich MH, Crockett JC, Mellis D, Vellodi A, Tezcan I, Notarangelo LD, Rogers MJ, Vezzoni P, Villa A, Frattini A
Am J Hum Genet 2008 Jul;83(1):64-76. doi: 10.1016/j.ajhg.2008.06.015. PMID: 18606301 Free PMC Article

Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome.

Lee WI, Torgerson TR, Schumacher MJ, Yel L, Zhu Q, Ochs HD
Blood 2005 Mar 1;105(5):1881-90. Epub 2004 Sep 9 doi: 10.1182/blood-2003-12-4420. PMID: 15358621

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Diagnosis

Clinical, Immunologic and Molecular Spectrum of Patients with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome: A Systematic Review.

Kiaee F, Zaki-Dizaji M, Hafezi N, Almasi-Hashiani A, Hamedifar H, Sabzevari A, Shirkani A, Zian Z, Jadidi-Niaragh F, Aghamahdi F, Goudarzvand M, Yazdani R, Abolhassani H, Aghamohammadi A, Azizi G
Endocr Metab Immune Disord Drug Targets 2021;21(4):664-672. doi: 10.2174/1871530320666200613204426. PMID: 32533820

Clinical Phenotypes and Immunological Characteristics of 18 Egyptian LRBA Deficiency Patients.

Meshaal S, El Hawary R, Adel R, Abd Elaziz D, Erfan A, Lotfy S, Hafez M, Hassan M, Johnson M, Rojas-Restrepo J, Gamez-Diaz L, Grimbacher B, Shoman W, Abdelmeguid Y, Boutros J, Galal N, El-Guindy N, Elmarsafy A
J Clin Immunol 2020 Aug;40(6):820-832. Epub 2020 Jun 6 doi: 10.1007/s10875-020-00799-2. PMID: 32506362

Evaluation of respiratory complications in patients with X-linked and autosomal recessive agammaglobulinemia.

Genetic Approaches for Definitive Diagnosis of Agammaglobulinemia in Consanguineous Families.

Ben-Ali M, Kechout N, Mekki N, Yang J, Chan KW, Barakat A, Aadam Z, Gamara J, Gargouri L, Largueche B, BelHadj-Hmida N, Nedri A, Ameur HB, Mellouli F, Boukari R, Bejaoui M, Bousfiha A, Ben-Mustapha I, Lau YL, Barbouche MR
J Clin Immunol 2020 Jan;40(1):96-104. Epub 2019 Nov 6 doi: 10.1007/s10875-019-00706-4. PMID: 31696364

ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome.

Cagdas D, Gur Cetinkaya P, Karaatmaca B, Esenboga S, Tan C, Yılmaz T, Gümüş E, Barış S, Kuşkonmaz B, Ozgur TT, Bali P, Santisteban I, Orhan D, Yüce A, Cetinkaya D, Boztug K, Hershfield M, Sanal O, Tezcan İ
J Clin Immunol 2018 May;38(4):484-493. Epub 2018 May 9 doi: 10.1007/s10875-018-0496-9. PMID: 29744787

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Therapy

Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation.

Nihira H, Izawa K, Ito M, Umebayashi H, Okano T, Kajikawa S, Nanishi E, Keino D, Murakami K, Isa-Nishitani M, Shiba T, Honda Y, Hijikata A, Yasu T, Kubota T, Hasegawa Y, Kawashima Y, Nakano N, Takada H, Ohga S, Heike T, Takita J, Ohara O, Takei S, Takahashi M, Kanegane H, Morio T, Iwaki-Egawa S, Sasahara Y, Nishikomori R, Yasumi T
J Allergy Clin Immunol 2021 Aug;148(2):550-562. Epub 2021 Jan 30 doi: 10.1016/j.jaci.2021.01.018. PMID: 33529688

Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency.

Cicalese MP, Ferrua F, Castagnaro L, Pajno R, Barzaghi F, Giannelli S, Dionisio F, Brigida I, Bonopane M, Casiraghi M, Tabucchi A, Carlucci F, Grunebaum E, Adeli M, Bredius RG, Puck JM, Stepensky P, Tezcan I, Rolfe K, De Boever E, Reinhardt RR, Appleby J, Ciceri F, Roncarolo MG, Aiuti A
Blood 2016 Jul 7;128(1):45-54. Epub 2016 Apr 29 doi: 10.1182/blood-2016-01-688226. PMID: 27129325 Free PMC Article

First report on the Moroccan registry of primary immunodeficiencies: 15 years of experience (1998-2012).

See all (3)

Prognosis

Newborn Screening for Severe T and B Cell Lymphopenia Using TREC/KREC Detection: A Large-Scale Pilot Study of 202,908 Newborns.

A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review.

Xue Y, Zhao Y, Wu B, Shu J, Yan D, Li D, Yu X, Cai C
Mol Genet Genomic Med 2023 Aug;11(8):e2197. Epub 2023 May 19 doi: 10.1002/mgg3.2197. PMID: 37204045 Free PMC Article

Clinical Phenotypes and Immunological Characteristics of 18 Egyptian LRBA Deficiency Patients.

Evaluation of respiratory complications in patients with X-linked and autosomal recessive agammaglobulinemia.

Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency.

See all (5)

Clinical prediction guides

A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review.

Xue Y, Zhao Y, Wu B, Shu J, Yan D, Li D, Yu X, Cai C
Mol Genet Genomic Med 2023 Aug;11(8):e2197. Epub 2023 May 19 doi: 10.1002/mgg3.2197. PMID: 37204045 Free PMC Article

Evaluation of respiratory complications in patients with X-linked and autosomal recessive agammaglobulinemia.

Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2.

Carmona-Rivera C, Khaznadar SS, Shwin KW, Irizarry-Caro JA, O'Neil LJ, Liu Y, Jacobson KA, Ombrello AK, Stone DL, Tsai WL, Kastner DL, Aksentijevich I, Kaplan MJ, Grayson PC
Blood 2019 Jul 25;134(4):395-406. Epub 2019 Apr 23 doi: 10.1182/blood.2018892752. PMID: 31015188 Free PMC Article

ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome.

First report on the Moroccan registry of primary immunodeficiencies: 15 years of experience (1998-2012).

See all (6)