CD27 – Lymphoproliferative Syndrome 2

CD27 encodes a TNF family costimulatory receptor essential for T-cell, B-cell and NK-cell responses. Biallelic CD27 loss-of-function variants cause an autosomal recessive immunodeficiency characterized by hypogammaglobulinemia, recurrent infections, hepatosplenomegaly and susceptibility to EBV-driven lymphoproliferation, defining lymphoproliferative syndrome 2 (MONDO:0014054).

Genetic evidence comprises four probands from three unrelated families: two brothers homozygous for c.98G>A (p.Trp33Ter) and c.24G>A (p.Trp8Ter) (PMID:22197273), one girl with c.95A>G (p.Tyr32Cys) (PMID:32041749), and one boy with a novel CD27 variant confirmed by Sanger sequencing (PMID:37002625). Segregation of homozygous alleles in the sibling pair supports recessive inheritance (2 affected relatives) (PMID:22197273).

The variant spectrum includes two truncating alleles and one missense change in the extracellular domain. All identified variants are rare or novel, absent from population databases, and observed in trans or homozygous in affected individuals, consistent with loss-of-function mechanism.

Functional studies demonstrate absence of CD27 expression on patient lymphocytes with resultant impairment of T-cell-dependent B-cell differentiation and NK degranulation (PMID:22197273). RASGRP1-deficient T cells exhibit reduced CD27-mediated proliferation toward CD70-expressing B cells, highlighting the critical role of CD27 co-stimulation in EBV immunity (PMID:29282224).

One heterozygous variant, c.779C>T (p.Pro260Leu), was found in a patient with refractory lymphoma and HLH but deemed non-pathogenic based on family and functional analyses (PMID:38183241).

Overall, the association between CD27 and lymphoproliferative syndrome 2 is supported by multiple unrelated probands, segregation data, and concordant functional assays. CD27 genetic testing should be considered in patients with early-onset hypogammaglobulinemia, EBV-associated lymphoproliferation and recurrent infections.

References

• The Journal of allergy and clinical immunology • 2012 • CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. PMID:22197273
• BMJ case reports • 2020 • Novel mutation in the CD27 gene in a patient presenting with hypogammaglobulinemia, bronchiectasis and EBV-driven lymphoproliferative disease. PMID:32041749
• Iranian journal of allergy, asthma, and immunology • 2023 • New Presentation of CD27 Deficiency; Coronary Ectasia and COVID-19. PMID:37002625
• EMBO molecular medicine • 2018 • Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility. PMID:29282224
• Cell transplantation • 2024 • Relapsed/Refractory Peripheral T-Cell Lymphoma-Associated Hemophagocytic Lymphohistiocytosis With UNC13D and CD27 Germline Mutations. PMID:38183241

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