The Many Faces of XMEN Disease, Report of Two Patients with Novel Mutations

Hoyos-Bachiloglu, Rodrigo; Concha, Sara; Sepúlveda, Pablo; Campos, R; Pérez-Mateluna, Guillermo; King, Alejandra; Zúñiga, Pamela

doi:10.1007/s10875-020-00746-1

Cited by 16 publications

(13 citation statements)

References 4 publications

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“…A total of 36 unique male patients have been reported [ 2 – 8 , 10 – 12 , 14 , 15 ]. Females with heterozygous MAGT1 mutations are healthy carriers with a pattern of X chromosome inactivation (XCI) skewed towards the normal allele in their hematopoietic cells [ 1 , 11 , 12 ].…”

Section: Epidemiology and Geneticsmentioning

confidence: 99%

“…Almost half of the patients have CD4 T cell lymphopenia, but life-threatening opportunistic infections are rare in the absence of concomitant immunosuppressive treatment[ 4 ]. An infant with severe pneumonia had Pneumocystis jirovecii and cytomegalovirus in the bronchoalveolar lavage[ 15 ]. Progressive multifocal leukoencephalopathy (PML) was reported in one XMEN patient during chemotherapy for an underlying lymphoma[ 5 ].…”

Section: Immunodeficiency and Immune Dysregulationmentioning

confidence: 99%

“…Condyloma accuminatum requiring surgical excision was reported in one young adult[ 4 ]. Varicella zoster virus (VZV) infection and herpes simplex virus (HSV) infections have also been reported[ 3 , 12 , 15 ]. Mild, sometimes transient, thrombocytopenia is a common hematological abnormality, even in patients with no splenomegaly and no history of autoimmune (AI) cytopenias[ 4 ].…”

Section: Immunodeficiency and Immune Dysregulationmentioning

confidence: 99%

“…A leukemoid reaction was reported in an EBV-naïve infant with no clonal lymphoproliferative disorder[ 4 ]. A significant hemorrhagic risk, usually disproportionate for the degree of thrombocytopenia and involving mucosal sites, has been identified in some patients[ 10 , 15 ]. This bleeding risk appears to be a relatively common and severe complication after allogenic bone marrow transplant (BMT) in XMEN, for which a precise mechanism has not been identified[ 10 ].…”

Section: Immunodeficiency and Immune Dysregulationmentioning

confidence: 99%

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An Update on XMEN Disease

Ravell

Chauvin

et al. 2020

J Clin Immunol

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“X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia” (XMEN) disease is an inborn error of glycosylation and immunity caused by loss of function mutations in the magnesium transporter 1 ( MAGT1 ) gene. It is a multisystem disease that strongly affects certain immune cells. MAGT1 is now confirmed as a non-catalytic subunit of the oligosaccharyltransferase complex and facilitates Asparagine (N)-linked glycosylation of specific substrates, making XMEN a congenital disorder of glycosylation manifesting as a combined immune deficiency. The clinical disease has variable expressivity and impaired glycosylation of key MAGT1-dependent glycoproteins in addition to Mg 2+ abnormalities can explain some of the immune manifestations. NKG2D, an activating receptor critical for cytotoxic function against EBV, is poorly glycosylated and invariably decreased on CD8 + T cells and natural killer (NK) cells from XMEN patients. It is the best biomarker of the disease. The characterization of EBV-naïve XMEN patients has clarified features of the genetic disease that were previously attributed to EBV infection. Extra-immune manifestations, including hepatic and neurological abnormalities have recently been reported. EBV-associated lymphomas remain the main cause of severe morbidity. Unfortunately, treatment options to address the underlying mechanism of disease remain limited and Mg 2+ supplementation has not proven successful. Here, we review the expanding clinical phenotype and recent advances in glycobiology that have increased our understanding of XMEN disease. We also propose updating XMEN to “ X -linked M AGT1 deficiency with increased susceptibility to E BV-infection and N -linked glycosylation defect” in light of these novel findings.

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Section: Epidemiology and Geneticsmentioning

confidence: 99%

Section: Immunodeficiency and Immune Dysregulationmentioning

confidence: 99%

Section: Immunodeficiency and Immune Dysregulationmentioning

confidence: 99%

Section: Immunodeficiency and Immune Dysregulationmentioning

confidence: 99%

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An Update on XMEN Disease

Ravell

Chauvin

et al. 2020

J Clin Immunol

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“…We here report an additional case of EBV+ EMZL associated with another form of primary immunodeficiency, XMEN disease. A total of 10 EBV+ lymphomas associated with XMEN disease were described, including 6 cases of classical Hodgkin lymphoma, 3 cases of diffuse large B-cell lymphoma, and 2 cases of Burkitt lymphoma ( 3 – 5 , 8 , 9 ). The present case of EBV+ EMZL expands the spectrum of EBV+ lymphomas in patients with XMEN disease.…”

Section: Discussionmentioning

confidence: 99%

Case Report: EBV-Positive Extra-Nodal Marginal Zone Lymphoma Associated With XMEN Disease Caused by a Novel Hemizygous Mutation in MAGT1

et al. 2021

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BackgroundX-linked immunodeficiency with magnesium defect and Epstein-Barr virus infection and neoplasia (XMEN) disease is an X-linked genetic disorder of immune system caused by loss-of-function mutation in gene encoding Magnesium transporter 1 (MAGT1). Individuals with XMEN disease are prone to developing Epstein Barr Virus (EBV)-associated lymphomas. Herein, we report the first known case of an EBV+ EMZL associated with XMEN disease.Case presentationThe patient was an 8-year-old Chinese boy who suffered from recurrent infections from birth. Six months before, the patient presented with a painless mass on his upper lip and excisional biopsy revealed an EBV-positive extra-nodal marginal zone lymphoma (EBV+ EMZL). Furthermore, molecular investigations with next-generation sequencing identified a novel germline mutation in MAGT1 (c.828_829insAT) in the patient. The c.828_829insAT variant was predicted to cause premature truncation of MAGT1 (p.A277M.fs*11) and consequently was defined as likely pathogenic. The mutation was inherited from his asymptomatic heterozygous carrier mother. Hence the patient was diagnosed with an XMEN disease both clinically and genetically.ConclusionOur results expand the genetic spectrum of XMEN disease and also the clinical spectrum of EBV+ EMZL. We highlight the importance of the genetic etiology underlying EBV+ lymphoma in the pediatric population.

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Genetic susceptibility to EBV infection: insights from inborn errors of immunity

Tangye

2020

Hum Genet

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The Many Faces of XMEN Disease, Report of Two Patients with Novel Mutations

Cited by 16 publications

References 4 publications

An Update on XMEN Disease

An Update on XMEN Disease

Case Report: EBV-Positive Extra-Nodal Marginal Zone Lymphoma Associated With XMEN Disease Caused by a Novel Hemizygous Mutation in MAGT1

Genetic susceptibility to EBV infection: insights from inborn errors of immunity

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