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CD27-related lymphoproliferative and immune disorder

1. Disease Information

2026-04-20
Falcon MONDO:0014054 Model: Edison Scientific Literature 29 citations

1. Disease Information

1.1 Concise overview

CD27-related lymphoproliferative and immune disorder is a monogenic inborn error of immunity caused by biallelic loss-of-function variants in CD27 (TNFRSF7), characterized by selective susceptibility to Epstein–Barr virus (EBV) with chronic/persistent EBV viremia and EBV-driven complications including lymphoproliferation, hemophagocytic lymphohistiocytosis (HLH), and EBV-associated lymphomas, often accompanied by hypogammaglobulinemia and defective T cell–dependent humoral immunity. (ghosh2020extendedclinicaland pages 2-3, tangye2020primaryimmunodeficienciesreveal pages 7-8, salzer2013combinedimmunodeficiencywith pages 1-2)

1.2 Key identifiers (from available evidence)

Not found in retrieved evidence: MONDO ID, Orphanet ID, ICD-10/ICD-11 codes, MeSH descriptor (would require direct OMIM/Orphanet/MONDO retrieval beyond the obtained full texts).

1.3 Synonyms and alternative names

1.4 Evidence type

Knowledge is derived primarily from aggregated disease-level cohort studies and case series (e.g., multicenter cohorts) plus individual case reports adding phenotypic expansions. (ghosh2020extendedclinicaland pages 2-3, alkhairy2015novelmutationsin pages 4-5, golchehre2023newpresentationof pages 1-2)

2. Etiology

2.1 Disease causal factors

Genetic cause: biallelic pathogenic variants in CD27 (TNFRSF7) causing absent or markedly reduced CD27 surface expression and functional loss of CD27–CD70 costimulation. (montfrans2012cd27deficiencyis pages 2-4, alkhairy2015novelmutationsin pages 7-9, ghosh2020extendedclinicaland pages 2-3)

Inheritance pattern: autosomal recessive; many patients reported from consanguineous families, with heterozygous relatives typically unaffected in early reports. (montfrans2012cd27deficiencyis pages 2-4, alkhairy2015novelmutationsin pages 1-2)

2.2 Risk factors

2.3 Protective factors / gene–environment interactions

No protective variants or environmental protective factors were identified in the retrieved evidence. The dominant gene–environment interaction described is that EBV exposure triggers severe disease manifestations in genetically susceptible hosts (CD27 deficiency). (ghosh2020extendedclinicaland pages 2-3, salzer2013combinedimmunodeficiencywith pages 1-2)

3. Phenotypes

A multicenter cohort (CD27 n=33 within a 49-patient CD27/CD70 cohort) reported: EBV-positive at diagnosis ~90%, lymphoproliferation 70%, lymphoma 43%, autoinflammatory features 43%, and HLH in 9 CD27-deficient patients. (ghosh2020extendedclinicaland pages 2-3)

A separate 17-patient CD27 cohort reported mortality 29%, and that very high EBV plasma loads were often seen (up to ~5×10^6–8×10^6 copies/mL in a table excerpt). (alkhairy2015novelmutationsin pages 5-6, alkhairy2015novelmutationsin pages 7-9)

Table (click to expand)
Feature Description HPO term(s) Frequency/statistics (with cohort/source) Notes
EBV susceptibility / EBV positivity Marked susceptibility to Epstein-Barr virus with chronic/persistent viremia and EBV-driven immune dysregulation HP:0012378 Elevated circulating Epstein-Barr virus load; HP:0002731 Recurrent viral infections EBV-positive at diagnosis in 90% of the CD27/CD70 cohort; in Alkhairy 2015, high EBV loads were documented in 11/12 tested and plasma loads reached up to ~5×10^6–8×10^6 copies/mL (ghosh2020extendedclinicaland pages 2-3, alkhairy2015novelmutationsin pages 5-6) Core disease-defining feature; often precedes lymphoproliferation and lymphoma
Lymphoproliferation Persistent or recurrent EBV-driven lymphadenopathy/hepatosplenomegaly and benign or malignant lymphoid expansion HP:0002716 Lymphadenopathy; HP:0001433 Hepatosplenomegaly; HP:0002841 Lymphoproliferative disorder Lymphoproliferation reported in 70% of the multicenter cohort (49 total; 33 CD27-deficient) (ghosh2020extendedclinicaland pages 2-3) Can mimic CVID, ALPS, chronic active EBV, or lymphoma
Lymphoma Increased risk of EBV-associated lymphoma, including Hodgkin and non-Hodgkin lymphoma HP:0002665 Lymphoma; HP:0012197 Hodgkin lymphoma; HP:0100827 Non-Hodgkin lymphoma Lymphoma in 43% of the Ghosh 2020 cohort; cases in Alkhairy 2015 included DLBCL, extranodal EBV-related LPD, and classical Hodgkin lymphoma (ghosh2020extendedclinicaland pages 2-3, alkhairy2015novelmutationsin pages 5-6) Malignant transformation is a major indication for HSCT
Hemophagocytic lymphohistiocytosis (HLH) Hyperinflammatory episodes triggered by EBV with hemophagocytosis/HLH phenotype HP:0003125 Hemophagocytosis; HP:0032243 Hemophagocytic lymphohistiocytosis 9 CD27-deficient patients developed HLH in the Ghosh cohort; HLH also described in earlier cases and pooled reviews (ghosh2020extendedclinicaland pages 2-3, kishore2020novelmutationin pages 4-5) Severe, potentially life-threatening presentation
Hypogammaglobulinemia / antibody deficiency Low immunoglobulins and impaired humoral immunity, sometimes CVID-like HP:0004313 Decreased circulating IgG level; HP:0010701 Hypogammaglobulinemia; HP:0002845 Functional abnormality of humoral immunity Primary hypogammaglobulinemia in 3/17 in Alkhairy 2015; secondary/treatment-related hypogammaglobulinemia also common (rituximab/chemotherapy) (alkhairy2015novelmutationsin pages 4-5) May be present at onset or emerge after EBV disease/treatment
Impaired vaccine / protein antigen responses Defective T-cell–dependent antibody responses despite some preserved vaccine responses to other antigens HP:0034335 Abnormality of immune response to vaccination Montfrans 2012: severely impaired antibody responses to repeated protein antigens (rabies, tetanus), despite preserved responses to polysaccharide/conjugate vaccines (montfrans2012cd27deficiencyis pages 6-7) Supports combined immunodeficiency rather than isolated antibody deficiency
Memory B-cell defect Abnormal or reduced memory B-cell generation; absent/reduced CD27 expression on B cells HP:0011839 Abnormal B-cell subset distribution; HP:0011813 Reduced memory B cell count Ghosh 2020 reported aberrant generation of memory B and T cells; Alkhairy 2015 and related cases documented absent/reduced CD27 expression and reduced memory-cell compartments (ghosh2020extendedclinicaland pages 2-3, alkhairy2015novelmutationsin pages 7-9) CD27 itself is a canonical memory B-cell marker, so interpretation requires genotype context
T-cell dysfunction / paucity of EBV-specific T cells Impaired expansion and effector differentiation of EBV-specific CD8 T cells; reduced cytotoxic antiviral immunity HP:0003202 Abnormal T-cell proliferation; HP:0011832 Abnormality of CD8-positive T cells Ghosh 2020: paucity of EBV-specific T cells and impaired CD8 effector function; Montfrans 2012: reduced IL-2 production by EBV-specific CD8 T cells (ghosh2020extendedclinicaland pages 2-3, montfrans2012cd27deficiencyis pages 6-7) Mechanistically central to failure of EBV control
NK / iNKT abnormalities In some severe patients, reduced NK-cell function and/or low iNKT cells HP:0011837 Abnormal natural killer cell count; HP:0011838 Abnormal natural killer cell function Salzer 2013: in severely affected patients, iNKT-cell numbers and NK-cell function were reduced; Alkhairy 2015 reported reduced NK/NKT function in 5/7 measured (alkhairy2015novelmutationsin pages 7-9) Not universal; may correlate with more severe phenotypes
Recurrent respiratory infections Recurrent sinopulmonary infections, often preceding EBV-LPD recognition HP:0002205 Recurrent respiratory infections Frequent across reports; highlighted in case reports and pooled reviews (kishore2020novelmutationin pages 2-3, kishore2020novelmutationin pages 4-5) Often leads initially to a CVID diagnosis
Bronchiectasis Chronic airway damage from recurrent respiratory infections HP:0002110 Bronchiectasis Reported in the Kishore 2020 case with long-standing recurrent infections and hypogammaglobulinemia (kishore2020novelmutationin pages 2-3) Represents chronic morbidity from delayed diagnosis
Hepatosplenomegaly Enlarged liver and spleen, often with EBV-LPD HP:0001433 Hepatosplenomegaly Seen in Montfrans 2012 and Kishore 2020 case descriptions (montfrans2012cd27deficiencyis pages 2-4, kishore2020novelmutationin pages 2-3) Common accompaniment of lymphoproliferation/HLH
Uveitis / inflammatory complications Immune dysregulation can include ocular and systemic inflammatory disease HP:0000554 Uveitis; HP:0002721 Immune dysregulation EBV-associated uveitis reported in Montfrans 2012; autoinflammatory features occurred in 43% of the Ghosh cohort (montfrans2012cd27deficiencyis pages 2-4, ghosh2020extendedclinicaland pages 2-3) Broadens phenotype beyond infection and malignancy
Autoinflammation Periodic fever, arthritis, uveitis, and other inflammatory manifestations HP:0012649 Autoinflammation; HP:0001945 Fever; HP:0001369 Arthritis Autoinflammatory features in 21/49 overall (43%) in Ghosh 2020 (ghosh2020extendedclinicaland pages 2-3) Important because disease may present as immune dysregulation rather than infection alone
Coronary ectasia / aneurysm Unusual cardiovascular inflammatory phenotype reported in a recent child with CD27 deficiency HP:0031364 Coronary artery aneurysm; HP:0031363 Coronary artery ectasia Single 2023 case report of a 20-month-old boy with coronary ectasia/aneurysm plus EBV-associated lymphoma and COVID-19 (golchehre2023newpresentationof pages 1-2, golchehre2023newpresentationof pages 2-4) Recent phenotype expansion; causality uncertain (EBV, lymphoma, inflammation, or CD27 deficiency itself)
Mortality Substantial disease-related mortality without curative treatment in severe cases HP:0003826 Reduced life expectancy Mortality 29% in Alkhairy 2015 (approximately 5/17); two of eight died in Salzer 2013; pooled review summarized mortality as 30% (6/18) (alkhairy2015novelmutationsin pages 4-5, kishore2020novelmutationin pages 4-5) Deaths attributed to malignancy, sepsis, aplastic anemia, hepatic failure, and severe EBV disease
Response to rituximab Anti-CD20 B-cell depletion can reduce EBV load and improve EBV-LPD/HLH, sometimes transiently HP:0031370 Abnormal response to treatment Rituximab used in 6/17 in Alkhairy 2015; favorable but sometimes transient responses reported; Salzer 2013 reported repeated anti-CD20 therapy in one patient (alkhairy2015novelmutationsin pages 4-5, alkhairy2015novelmutationsin pages 1-2) Useful for EBV-driven B-cell disease but not curative
HSCT outcome Allogeneic HSCT is the only curative immune reconstitution approach for severe disease HP:0012337 Abnormality of immune system physiology Ghosh 2020: 19 patients underwent allogeneic HSCT with 95% overall survival; Alkhairy 2015: 3/17 received cord blood HSCT and were alive; Salzer 2013: 2 underwent HSCT successfully (ghosh2020extendedclinicaland pages 2-3, alkhairy2015novelmutationsin pages 4-5, alkhairy2015novelmutationsin pages 7-9) Strong real-world evidence supporting HSCT in severe EBV-LPD/lymphoma or refractory disease

Table: This table summarizes the major clinical features of CD27-related lymphoproliferative and immune disorder, with suggested HPO terms and quantitative observations from key cohorts and case reports. It is useful for knowledge-base curation because it links phenotype labels to disease frequency, mechanism-relevant findings, and treatment context.

Additional phenotype expansions (2023–2024 prioritized)

A 2023 case report described a 20-month-old with CD27 deficiency and EBV-associated lymphoma plus coronary artery ectasia/aneurysm (Kawasaki-like phenotype) and SARS-CoV-2 infection, which the authors presented as an expansion beyond the canonical EBV phenotype spectrum. (golchehre2023newpresentationof pages 1-2, golchehre2023newpresentationof pages 2-4)

4. Genetic / Molecular Information

4.1 Causal gene

4.2 Pathogenic variants (examples)

Multiple pathogenic variants (nonsense and missense) have been reported across cohorts, including c.24G>A (p.W8X), p.C53Y, p.C10X, p.R78W, p.C96Y, p.R107C, p.W110X, and additional novel alleles across multicenter studies. (montfrans2012cd27deficiencyis pages 2-4, alkhairy2015novelmutationsin pages 4-5, alkhairy2015novelmutationsin pages 7-9)

Table (click to expand)
Variant (cDNA/protein as reported) Variant type Inheritance / zygosity Key phenotype highlights Key treatment / outcome notes Primary source(s) with year / journal / URL
c.24G>A, p.W8X Nonsense / truncating Homozygous AR in affected siblings; heterozygous carrier parents/unaffected sib Persistent symptomatic EBV viremia; severe EBV-driven lymphadenopathy; fever; hepatosplenomegaly; EBV-associated uveitis; hypogammaglobulinemia with impaired T-cell–dependent antibody responses; one sibling died of aplastic anemia with sepsis. EBV detected in purified B cells; viral loads reported as ~3000 and 2050 copies/µg DNA in one report. Broader pooled reports associate this variant with very high EBV loads and EBV-LPD/lymphoma. (montfrans2012cd27deficiencyis pages 2-4, montfrans2012cd27deficiencyis pages 6-7, alkhairy2015novelmutationsin pages 1-2) Immunoglobulin replacement used in surviving patient with stabilization; no HSCT/rituximab described in Montfrans excerpt. Included among variants in later pooled series/case summaries. (montfrans2012cd27deficiencyis pages 2-4, alkhairy2015novelmutationsin pages 4-5, kishore2020novelmutationin pages 4-5) van Montfrans 2012, J Allergy Clin Immunol, https://doi.org/10.1016/j.jaci.2011.11.013; Alkhairy 2015, J Allergy Clin Immunol, https://doi.org/10.1016/j.jaci.2015.02.022 (montfrans2012cd27deficiencyis pages 2-4, alkhairy2015novelmutationsin pages 1-2)
c.G158A, p.C53Y Missense Homozygous AR in 3 independent families (8 patients total in Salzer cohort) Phenotypic range from asymptomatic memory B-cell deficiency to EBV-associated hemophagocytosis/HLH, lymphoproliferative disorder, and malignant lymphoma; after EBV infection, hypogammaglobulinemia developed in at least 3 affected individuals; reduced iNKT cells and impaired NK function in severe cases. (salzer2013combinedimmunodeficiencywith pages 1-2, alkhairy2015novelmutationsin pages 1-2) Two of 8 patients died; two underwent allogeneic HSCT successfully; one received repeated anti-CD20 (rituximab) therapy. (salzer2013combinedimmunodeficiencywith pages 1-2) Salzer 2013, Haematologica, https://doi.org/10.3324/haematol.2012.068791; Alkhairy 2015, J Allergy Clin Immunol, https://doi.org/10.1016/j.jaci.2015.02.022 (salzer2013combinedimmunodeficiencywith pages 1-2, alkhairy2015novelmutationsin pages 1-2)
c.C30A, p.C10X Nonsense / truncating Reported in pooled CD27-deficient cohort; zygosity not specified in excerpt Listed among pathogenic CD27 variants in patients with EBV viremia / EBV-related LPD / HLH / lymphoma and hypogammaglobulinemia spectrum. (kishore2020novelmutationin pages 4-5, alkhairy2015novelmutationsin pages 4-5) Included in cohorts where rituximab often produced favorable but sometimes transient responses and HSCT was curative in selected severe cases; variant-specific outcome not isolated in excerpt. (alkhairy2015novelmutationsin pages 4-5, kishore2020novelmutationin pages 4-5) Alkhairy 2015, J Allergy Clin Immunol, https://doi.org/10.1016/j.jaci.2015.02.022; Kishore 2020, BMJ Case Rep, https://doi.org/10.1136/bcr-2019-233482 (alkhairy2015novelmutationsin pages 4-5, kishore2020novelmutationin pages 4-5)
c.C232T, p.R78W Missense Reported in pooled cohort; zygosity not specified in excerpt In silico prediction damaging; associated within pooled CD27-deficiency series with EBV viremia/LPD, lymphoma, HLH, and antibody deficiency spectrum. (alkhairy2015novelmutationsin pages 5-6, kishore2020novelmutationin pages 4-5) Variant-specific treatment not isolated; pooled cohort treatments included IVIG, rituximab, chemotherapy, and HSCT. (alkhairy2015novelmutationsin pages 5-6, kishore2020novelmutationin pages 4-5) Alkhairy 2015, J Allergy Clin Immunol, https://doi.org/10.1016/j.jaci.2015.02.022; Kishore 2020, BMJ Case Rep, https://doi.org/10.1136/bcr-2019-233482 (alkhairy2015novelmutationsin pages 5-6, kishore2020novelmutationin pages 4-5)
c.G287A, p.C96Y Missense Reported in pooled cohort; zygosity not specified in excerpt In silico prediction damaging; reported among pathogenic variants in CD27 deficiency with EBV-related disease, including chronic/persistent EBV viremia, LPD, lymphoma, and hypogammaglobulinemia. (alkhairy2015novelmutationsin pages 5-6, kishore2020novelmutationin pages 4-5) Variant-specific treatment not isolated; pooled treatment experience includes IVIG, rituximab, conventional chemotherapy, and HSCT. (alkhairy2015novelmutationsin pages 4-5, kishore2020novelmutationin pages 4-5) Alkhairy 2015, J Allergy Clin Immunol, https://doi.org/10.1016/j.jaci.2015.02.022; Kishore 2020, BMJ Case Rep, https://doi.org/10.1136/bcr-2019-233482 (alkhairy2015novelmutationsin pages 5-6, kishore2020novelmutationin pages 4-5)
c.C319T, p.R107C Missense Reported in pooled cohort; one report notes structural misfolding prediction; zygosity not specified in excerpt Associated with EBV viremia / EBV-related extranodal LPD / Hodgkin or diffuse large B-cell lymphoma / HLH spectrum in pooled cases; impaired CD27 expression and high EBV loads reported across affected cohort. (alkhairy2015novelmutationsin pages 5-6, kishore2020novelmutationin pages 4-5) Variant-specific response not isolated; pooled cohort notes rituximab can be favorable but transient, chemotherapy responses variable, and HSCT successful in selected cases. (alkhairy2015novelmutationsin pages 4-5, alkhairy2015novelmutationsin pages 7-9) Alkhairy 2015, J Allergy Clin Immunol, https://doi.org/10.1016/j.jaci.2015.02.022; Kishore 2020, BMJ Case Rep, https://doi.org/10.1136/bcr-2019-233482 (alkhairy2015novelmutationsin pages 5-6, kishore2020novelmutationin pages 4-5)
c.G329A, p.W110X Nonsense / truncating Reported in pooled case summary; zygosity not specified in excerpt Listed among CD27 pathogenic variants in patients with recurrent infections, hypogammaglobulinemia/CVID-like disease, persistent lymphadenopathy/hepatosplenomegaly, high EBV titers, EBV-driven LPD, HLH, and lymphoma. (kishore2020novelmutationin pages 4-5, izawa2017inheritedcd70deficiency pages 10-11) Variant-specific treatment not isolated; broader cohort experience supports rituximab for EBV-driven B-cell disease and HSCT as definitive therapy in severe disease. (kishore2020novelmutationin pages 4-5, tangye2020primaryimmunodeficienciesreveal pages 7-8) Kishore 2020, BMJ Case Rep, https://doi.org/10.1136/bcr-2019-233482; Izawa 2017 mechanistic comparison, J Exp Med, https://doi.org/10.1084/jem.20160784 (kishore2020novelmutationin pages 4-5, izawa2017inheritedcd70deficiency pages 10-11)
Homozygous CD27 variant (not specified in excerpt) Not specified in excerpt Homozygous AR 20-month-old boy with CD27 deficiency; EBV-associated lymphoma (EBER-positive), dysgammaglobulinemia / impaired antibody responses in disease background, coronary artery ectasia / aneurysm, and later SARS-CoV-2 infection; authors note >35 CD27-deficient patients reported. (golchehre2023newpresentationof pages 1-2, golchehre2023newpresentationof pages 2-4) Treated with IVIG and aspirin for Kawasaki-like/coronary presentation; lymphoma treated with ABVD and COPP; coronary aneurysm size decreased with aspirin/Plavix; short-term survival reported. (golchehre2023newpresentationof pages 2-4) Golchehre 2023, Iran J Allergy Asthma Immunol, https://doi.org/10.18502/ijaai.v22i1.12013 (golchehre2023newpresentationof pages 1-2, golchehre2023newpresentationof pages 2-4)
Multiple biallelic CD27 variants (16 distinct mutations across cohort) Mixed: nonsense, missense, other LOF Predominantly homozygous / biallelic AR; some compound heterozygous In the largest multicenter cohort of CD27/CD70 defects, 90% were EBV-positive at diagnosis; lymphoproliferation 70%; lymphoma 43%; 9 CD27-deficient patients developed HLH; autoinflammatory features in 43%; aberrant memory B/T-cell generation and paucity of EBV-specific T cells. (ghosh2020extendedclinicaland pages 2-3) 19 patients underwent allogeneic HSCT with 95% overall survival and no disease recurrence reported; timely HSCT advocated, especially for malignant transformation. (ghosh2020extendedclinicaland pages 2-3, ghosh2020extendedclinicaland pages 3-4) Ghosh 2020, Blood (cohort summarized in retrieved evidence), DOI noted in excerpt as 10.1182/blood.2020006738 (ghosh2020extendedclinicaland pages 2-3, ghosh2020extendedclinicaland pages 3-4)
Mixed CD27 cohort variants including c.24G>A/p.W8X, c.G158A/p.C53Y, c.C30A/p.C10X, c.C232T/p.R78W, c.G287A/p.C96Y, c.C319T/p.R107C Mixed Mixed biallelic AR; many from consanguineous families 17-patient cohort: EBV disease prominent; high EBV plasma loads in 11/12 tested, up to ~5×10^6–8×10^6 copies/mL; DLBCL, extranodal EBV-related LPD, classical Hodgkin lymphoma, HLH, and hypogammaglobulinemia/secondary HGG all reported; mortality 29%. (alkhairy2015novelmutationsin pages 5-6, alkhairy2015novelmutationsin pages 7-9, alkhairy2015novelmutationsin pages 4-5) Rituximab used in 6/17 with favorable sometimes transient response; conventional chemotherapy responses variable; 3/17 underwent cord blood HSCT and were alive. (alkhairy2015novelmutationsin pages 4-5, alkhairy2015novelmutationsin pages 7-9) Alkhairy 2015, J Allergy Clin Immunol, https://doi.org/10.1016/j.jaci.2015.02.022 (alkhairy2015novelmutationsin pages 4-5, alkhairy2015novelmutationsin pages 5-6, alkhairy2015novelmutationsin pages 7-9)

Table: This table compiles reported pathogenic CD27 (TNFRSF7) variants from the retrieved evidence and links each variant to the clinical phenotype spectrum, EBV-related manifestations, and available treatment/outcome data. It is useful for quickly mapping genotype to phenotype and identifying where variant-specific versus cohort-level evidence is currently available.

4.3 Functional consequence

The consistent mechanistic interpretation is loss of CD27 function (reduced/absent CD27 expression and/or impaired CD70 binding/costimulation), leading to defective EBV-specific T-cell expansion and impaired post-germinal-center B-cell responses. (montfrans2012cd27deficiencyis pages 8-10, tangye2020primaryimmunodeficienciesreveal pages 7-8, izawa2017inheritedcd70deficiency pages 1-2)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

No specific modifier genes, epigenetic signatures, or recurrent chromosomal abnormalities were identified in the retrieved evidence.

5. Environmental Information

The key environmental/infectious factor is EBV as a trigger for disease expression and progression to LPD/HLH/lymphoma. (ghosh2020extendedclinicaland pages 2-3, salzer2013combinedimmunodeficiencywith pages 1-2)

A 2023 report noted concomitant SARS-CoV-2 infection in an infant with CD27 deficiency, but causal contribution to the phenotype remains uncertain. (golchehre2023newpresentationof pages 1-2)

6. Mechanism / Pathophysiology

6.1 Core molecular mechanism (CD27–CD70 costimulation)

CD27 is a TNFR superfamily costimulatory receptor expressed on multiple immune subsets, and its ligand CD70 is induced on activated and EBV-infected B cells. CD27–CD70 engagement provides costimulation that enhances T-cell activation, survival, proliferation, and differentiation, which is required for effective anti-EBV immunity. (tangye2020primaryimmunodeficienciesreveal pages 7-8, izawa2017inheritedcd70deficiency pages 1-2, ghosh2020extendedclinicaland pages 2-3)

Direct abstract-supported statement (example): Salzer et al. reported: “CD27… interacts with CD70 and influences T-, B- and NK-cell functions. Disturbance of this axis impairs immunity and memory generation against viruses including Epstein Barr virus (EBV).” (salzer2013combinedimmunodeficiencywith pages 1-2)

6.2 Causal chain (from genotype to clinical manifestations)

  1. Biallelic CD27 LOF → absent/reduced CD27 signaling. (montfrans2012cd27deficiencyis pages 2-4, alkhairy2015novelmutationsin pages 7-9)
  2. Activated/EBV-infected B cells upregulate CD70, but cannot deliver effective CD70→CD27 costimulation to T cells. (tangye2020primaryimmunodeficienciesreveal pages 7-8, izawa2017inheritedcd70deficiency pages 1-2)
  3. Impaired EBV-specific T-cell expansion/effector function → failure of EBV control → chronic EBV viremia and EBV-driven lymphoproliferation and lymphoma. (ghosh2020extendedclinicaland pages 2-3, tangye2020primaryimmunodeficienciesreveal pages 7-8)
  4. Parallel humoral defects (post-germinal-center/plasma-cell biology and memory generation abnormalities) contribute to hypogammaglobulinemia and recurrent infections. (montfrans2012cd27deficiencyis pages 8-10, ghosh2020extendedclinicaland pages 2-3)

6.3 Cell types involved (Cell Ontology suggestions)

6.4 Pathway / ontology mapping suggestions

(These GO mappings are consistent with costimulatory receptor biology described in primary texts but were not enumerated as GO terms in the retrieved papers.)

7. Anatomical Structures Affected

Primary systems/organs: - Lymphoid system: lymph nodes (lymphadenopathy/LPD), spleen and liver (hepatosplenomegaly). Suggested UBERON: lymph node (UBERON:0000029), spleen (UBERON:0002106), liver (UBERON:0002107). (montfrans2012cd27deficiencyis pages 2-4, ghosh2020extendedclinicaland pages 2-3) - Respiratory system: recurrent airway infections and bronchiectasis. Suggested UBERON: lung (UBERON:0002048), bronchus (UBERON:0002185). (kishore2020novelmutationin pages 2-3) - Eye: uveitis in EBV context. Suggested UBERON: uvea (UBERON:0001769). (montfrans2012cd27deficiencyis pages 2-4) - Cardiovascular system (recent report): coronary artery ectasia/aneurysm. Suggested UBERON: coronary artery (UBERON:0001621). (golchehre2023newpresentationof pages 2-4)

8. Temporal Development

Onset: typically childhood (mean age of disease manifestation ~7.3 years in one multicenter cohort). (ghosh2020extendedclinicaland pages 3-4)

Course: variable; patients may be asymptomatic early, or develop progressive EBV viremia leading to LPD/HLH/lymphoma; autoinflammatory features may occur. (ghosh2020extendedclinicaland pages 2-3, salzer2013combinedimmunodeficiencywith pages 1-2)

9. Inheritance and Population

9.1 Epidemiology

No robust population-level prevalence/incidence estimates were identified in the retrieved evidence. The disease is described via rare-case aggregation, with authors noting “more than 35 patients” reported as of 2023. (golchehre2023newpresentationof pages 1-2)

9.2 Population genetics and counseling-relevant points

Carrier frequencies and founder effects were not extractable from the obtained texts (gnomAD and population-genetic databases were not queried by tools in this run).

10. Diagnostics

10.1 Clinical and laboratory tests

10.2 Genetic testing

Approaches used in reported studies include: - Targeted Sanger sequencing of CD27 and related differential genes (e.g., SH2D1A, XIAP, PRF1 in one report). (montfrans2012cd27deficiencyis pages 2-4) - Whole-exome sequencing with confirmatory Sanger sequencing and family segregation. (salzer2013combinedimmunodeficiencywith pages 1-2, alkhairy2015novelmutationsin pages 1-2)

10.3 Differential diagnosis (examples from retrieved evidence)

11. Outcome / Prognosis

12. Treatment (current applications / real-world implementation)

12.1 Supportive care

12.2 EBV-driven lymphoproliferation: B-cell–directed therapy

  • Rituximab (anti-CD20): used in 6/17 in one cohort; reported to yield favorable (sometimes transient) responses in EBV-related LPD/HLH/lymphoma contexts. (alkhairy2015novelmutationsin pages 4-5)

12.3 Hyperinflammation / HLH

12.4 Lymphoma therapy

12.5 Curative therapy: allogeneic HSCT

MAXO term suggestions (not exhaustive): hematopoietic stem cell transplantation; immunoglobulin replacement therapy; anti-CD20 monoclonal antibody therapy; antimicrobial prophylaxis; chemotherapy; HLH treatment protocol.

Clinical trials: No CD27-deficiency–specific interventional trials were identified via the clinical trials tool in this run.

13. Prevention

No disease-specific primary prevention strategies exist beyond genetic counseling and early diagnosis; however, practical risk reduction includes: - Early identification and monitoring for EBV DNAemia and lymphoproliferation. (montfrans2012cd27deficiencyis pages 2-4, ghosh2020extendedclinicaland pages 2-3) - Family testing/cascade screening in autosomal recessive pedigrees once a familial variant is known. (montfrans2012cd27deficiencyis pages 2-4)

14. Other Species / Natural Disease

No naturally occurring veterinary CD27-deficiency disease analogs were identified in the retrieved evidence.

15. Model Organisms and Experimental Systems

15.1 Mouse models

Mouse studies cited in human CD27-deficiency literature indicate that Cd27−/− impacts antiviral T-cell biology (e.g., impaired primary/memory CD4/CD8 responses and reduced IL-2–producing CD8 memory cells), supporting biological plausibility for human EBV susceptibility. (montfrans2012cd27deficiencyis pages 7-8, salzer2013combinedimmunodeficiencywith pages 1-2)

15.2 Human in vitro / ex vivo systems

  • EBV-transformed B-cell lines (LCLs) and patient T cells are used to demonstrate that CD70 on B cells and CD27 on T cells are required for robust T-cell proliferation/costimulation in EBV contexts; CRISPR-modified CD70-deficient LCLs and CD27-blocking antibodies were used in mechanistic experiments. (izawa2017inheritedcd70deficiency pages 10-11)
  • Patient-derived systems in early reports included EBV-specific T-cell assays and lysis of autologous EBV-transformed B cells, plus detailed immunophenotyping and functional B-cell differentiation assays. (montfrans2012cd27deficiencyis pages 6-7)

Notes on evidence gaps (limitations of this run)

  • MONDO, Orphanet, ICD-10/11, MeSH identifiers were not recovered from the obtained documents.
  • Population prevalence/incidence, carrier frequency estimates (gnomAD), and founder effects were not extracted.
  • No figures/tables could be retrieved via the image tool due to an extraction error for the key cohort paper.

References

  1. (ghosh2020extendedclinicaland pages 2-3): S Ghosh, SK Bal, and ES Edwards. Extended clinical and immunological phenot pe and transplant outcome in cd27 and cd70 deficienc.,(23), 2638-2655. doi: 10.1182/blood. 2020006738 …. Unknown journal, 2020.

  2. (tangye2020primaryimmunodeficienciesreveal pages 7-8): Stuart G. Tangye and Sylvain Latour. Primary immunodeficiencies reveal the molecular requirements for effective host defense against ebv infection. Blood, 135:644-655, Feb 2020. URL: https://doi.org/10.1182/blood.2019000928, doi:10.1182/blood.2019000928. This article has 128 citations and is from a highest quality peer-reviewed journal.

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  4. (golchehre2023newpresentationof pages 1-2): Zahra Golchehre, Samin Sharafian, Nader Momtazmanesh, Zahra Chavoshzadeh, Abdollah Karimi, Hassan Abolhassani, Maryam Kazemi Aghdam, Koroush Vahidshahi, Seyedehatefeh Hashemimoghaddam, Farid Kosari, Zahra Khafafpour, Bibi Shahin Shamsian, and Mohammad Keramatipour. New presentation of cd27 deficiency; coronary ectasia and covid-19. Iranian Journal of Allergy, Asthma and Immunology, Feb 2023. URL: https://doi.org/10.18502/ijaai.v22i1.12013, doi:10.18502/ijaai.v22i1.12013. This article has 7 citations.

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  7. (alkhairy2015novelmutationsin pages 4-5): Omar K. Alkhairy, Ruy Perez-Becker, Gertjan J. Driessen, Hassan Abolhassani, Joris van Montfrans, Stephan Borte, Sharon Choo, Ning Wang, Kiki Tesselaar, Mingyan Fang, Kirsten Bienemann, Kaan Boztug, Ana Daneva, Francoise Mechinaud, Thomas Wiesel, Christian Becker, Gregor Dückers, Kathrin Siepermann, Menno C. van Zelm, Nima Rezaei, Mirjam van der Burg, Asghar Aghamohammadi, Markus G. Seidel, Tim Niehues, and Lennart Hammarström. Novel mutations in tnfrsf7/cd27: clinical, immunologic, and genetic characterization of human cd27 deficiency. The Journal of allergy and clinical immunology, 136 3:703-712.e10, Sep 2015. URL: https://doi.org/10.1016/j.jaci.2015.02.022, doi:10.1016/j.jaci.2015.02.022. This article has 160 citations.

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  9. (alkhairy2015novelmutationsin pages 7-9): Omar K. Alkhairy, Ruy Perez-Becker, Gertjan J. Driessen, Hassan Abolhassani, Joris van Montfrans, Stephan Borte, Sharon Choo, Ning Wang, Kiki Tesselaar, Mingyan Fang, Kirsten Bienemann, Kaan Boztug, Ana Daneva, Francoise Mechinaud, Thomas Wiesel, Christian Becker, Gregor Dückers, Kathrin Siepermann, Menno C. van Zelm, Nima Rezaei, Mirjam van der Burg, Asghar Aghamohammadi, Markus G. Seidel, Tim Niehues, and Lennart Hammarström. Novel mutations in tnfrsf7/cd27: clinical, immunologic, and genetic characterization of human cd27 deficiency. The Journal of allergy and clinical immunology, 136 3:703-712.e10, Sep 2015. URL: https://doi.org/10.1016/j.jaci.2015.02.022, doi:10.1016/j.jaci.2015.02.022. This article has 160 citations.

  10. (alkhairy2015novelmutationsin pages 5-6): Omar K. Alkhairy, Ruy Perez-Becker, Gertjan J. Driessen, Hassan Abolhassani, Joris van Montfrans, Stephan Borte, Sharon Choo, Ning Wang, Kiki Tesselaar, Mingyan Fang, Kirsten Bienemann, Kaan Boztug, Ana Daneva, Francoise Mechinaud, Thomas Wiesel, Christian Becker, Gregor Dückers, Kathrin Siepermann, Menno C. van Zelm, Nima Rezaei, Mirjam van der Burg, Asghar Aghamohammadi, Markus G. Seidel, Tim Niehues, and Lennart Hammarström. Novel mutations in tnfrsf7/cd27: clinical, immunologic, and genetic characterization of human cd27 deficiency. The Journal of allergy and clinical immunology, 136 3:703-712.e10, Sep 2015. URL: https://doi.org/10.1016/j.jaci.2015.02.022, doi:10.1016/j.jaci.2015.02.022. This article has 160 citations.

  11. (kishore2020novelmutationin pages 4-5): Rashmi Kishore, Aditya Gupta, Aditya Kumar Gupta, and Sushil Kumar Kabra. Novel mutation in the cd27 gene in a patient presenting with hypogammaglobulinemia, bronchiectasis and ebv-driven lymphoproliferative disease. BMJ Case Reports, 13:e233482, Feb 2020. URL: https://doi.org/10.1136/bcr-2019-233482, doi:10.1136/bcr-2019-233482. This article has 8 citations and is from a peer-reviewed journal.

  12. (montfrans2012cd27deficiencyis pages 6-7): Joris M. van Montfrans, Andy I.M. Hoepelman, Sigrid Otto, Marielle van Gijn, Lisette van de Corput, Roel A. de Weger, Linda Monaco-Shawver, Pinaki P. Banerjee, Elisabeth A.M. Sanders, Cornelia M. Jol–van der Zijde, Michael R. Betts, Jordan S. Orange, Andries C. Bloem, and Kiki Tesselaar. Cd27 deficiency is associated with combined immunodeficiency and persistent symptomatic ebv viremia. The Journal of allergy and clinical immunology, 129 3:787-793.e6, Mar 2012. URL: https://doi.org/10.1016/j.jaci.2011.11.013, doi:10.1016/j.jaci.2011.11.013. This article has 259 citations.

  13. (golchehre2023newpresentationof pages 2-4): Zahra Golchehre, Samin Sharafian, Nader Momtazmanesh, Zahra Chavoshzadeh, Abdollah Karimi, Hassan Abolhassani, Maryam Kazemi Aghdam, Koroush Vahidshahi, Seyedehatefeh Hashemimoghaddam, Farid Kosari, Zahra Khafafpour, Bibi Shahin Shamsian, and Mohammad Keramatipour. New presentation of cd27 deficiency; coronary ectasia and covid-19. Iranian Journal of Allergy, Asthma and Immunology, Feb 2023. URL: https://doi.org/10.18502/ijaai.v22i1.12013, doi:10.18502/ijaai.v22i1.12013. This article has 7 citations.

  14. (izawa2017inheritedcd70deficiency pages 10-11): Kazushi Izawa, Emmanuel Martin, Claire Soudais, Julie Bruneau, David Boutboul, Rémy Rodriguez, Christelle Lenoir, Andrew D. Hislop, Caroline Besson, Fabien Touzot, Capucine Picard, Isabelle Callebaut, Jean-Pierre de Villartay, Despina Moshous, Alain Fischer, and Sylvain Latour. Inherited cd70 deficiency in humans reveals a critical role for the cd70–cd27 pathway in immunity to epstein-barr virus infection. The Journal of Experimental Medicine, 214:73-89, Jan 2017. URL: https://doi.org/10.1084/jem.20160784, doi:10.1084/jem.20160784. This article has 181 citations.

  15. (ghosh2020extendedclinicaland pages 3-4): S Ghosh, SK Bal, and ES Edwards. Extended clinical and immunological phenot pe and transplant outcome in cd27 and cd70 deficienc.,(23), 2638-2655. doi: 10.1182/blood. 2020006738 …. Unknown journal, 2020.

  16. (montfrans2012cd27deficiencyis pages 8-10): Joris M. van Montfrans, Andy I.M. Hoepelman, Sigrid Otto, Marielle van Gijn, Lisette van de Corput, Roel A. de Weger, Linda Monaco-Shawver, Pinaki P. Banerjee, Elisabeth A.M. Sanders, Cornelia M. Jol–van der Zijde, Michael R. Betts, Jordan S. Orange, Andries C. Bloem, and Kiki Tesselaar. Cd27 deficiency is associated with combined immunodeficiency and persistent symptomatic ebv viremia. The Journal of allergy and clinical immunology, 129 3:787-793.e6, Mar 2012. URL: https://doi.org/10.1016/j.jaci.2011.11.013, doi:10.1016/j.jaci.2011.11.013. This article has 259 citations.

  17. (izawa2017inheritedcd70deficiency pages 1-2): Kazushi Izawa, Emmanuel Martin, Claire Soudais, Julie Bruneau, David Boutboul, Rémy Rodriguez, Christelle Lenoir, Andrew D. Hislop, Caroline Besson, Fabien Touzot, Capucine Picard, Isabelle Callebaut, Jean-Pierre de Villartay, Despina Moshous, Alain Fischer, and Sylvain Latour. Inherited cd70 deficiency in humans reveals a critical role for the cd70–cd27 pathway in immunity to epstein-barr virus infection. The Journal of Experimental Medicine, 214:73-89, Jan 2017. URL: https://doi.org/10.1084/jem.20160784, doi:10.1084/jem.20160784. This article has 181 citations.

  18. (kishore2020novelmutationin pages 1-2): Rashmi Kishore, Aditya Gupta, Aditya Kumar Gupta, and Sushil Kumar Kabra. Novel mutation in the cd27 gene in a patient presenting with hypogammaglobulinemia, bronchiectasis and ebv-driven lymphoproliferative disease. BMJ Case Reports, 13:e233482, Feb 2020. URL: https://doi.org/10.1136/bcr-2019-233482, doi:10.1136/bcr-2019-233482. This article has 8 citations and is from a peer-reviewed journal.

  19. (ghosh2020extendedclinicaland pages 8-8): S Ghosh, SK Bal, and ES Edwards. Extended clinical and immunological phenot pe and transplant outcome in cd27 and cd70 deficienc.,(23), 2638-2655. doi: 10.1182/blood. 2020006738 …. Unknown journal, 2020.

  20. (montfrans2012cd27deficiencyis pages 7-8): Joris M. van Montfrans, Andy I.M. Hoepelman, Sigrid Otto, Marielle van Gijn, Lisette van de Corput, Roel A. de Weger, Linda Monaco-Shawver, Pinaki P. Banerjee, Elisabeth A.M. Sanders, Cornelia M. Jol–van der Zijde, Michael R. Betts, Jordan S. Orange, Andries C. Bloem, and Kiki Tesselaar. Cd27 deficiency is associated with combined immunodeficiency and persistent symptomatic ebv viremia. The Journal of allergy and clinical immunology, 129 3:787-793.e6, Mar 2012. URL: https://doi.org/10.1016/j.jaci.2011.11.013, doi:10.1016/j.jaci.2011.11.013. This article has 259 citations.