Lymphoproliferative syndrome (CD27/CD70 deficiency)

CD27 and CD70 deficiencies are rare autosomal recessive primary immune regulatory disorders. They are characterised by Epstein-Barr virus (EBV)-associated immune dysregulation. Presentation is typically in childhood or adolescence with severe infectious mononucleosis, haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and hypogammaglobulinaemia. The condition is associated with a significant predisposition to malignancy.

Both CD27 and CD70 deficiencies present similarly with the following clinical features:

• recurrent viral infections;
• severe or recurrent EBV-related infections (infectious mononucleosis);
• increased risk of EBV-associated lymphoproliferation, such as splenomegaly and/or enlarged lymph nodes;
• increased risk of EBV-associated lymphoma, including Hodgkin and non-Hodgkin types;
• hypogammaglobulinaemia;
• increased risk of HLH; and/or
• (less frequently) autoinflammatory manifestations, such as uveitis, arthritis or periodic fever.

The age of onset is variable, from early childhood to adolescence, with severity ranging from an asymptomatic immunodeficiency to a life-threatening EBV-driven disease.

CD27 deficiency is caused by biallelic pathogenic variants in the TNFRSF7 gene. TNFRSF7 encodes CD27, which is an immune checkpoint receptor.

CD70 deficiency is caused by biallelic pathogenic variants in the CD70 gene. CD70 encodes CD70, which is the ligand for the CD27 receptor.

A wide variety of variants have been implicated in both conditions, including large-deletion, nonsense, missense and splice-site variants.

Clinical features suggestive of lymphoproliferative syndrome should prompt laboratory investigation, starting with the most common causes (X-linked lymphoproliferative syndrome (XLP)). In females, and in males where XLP has been excluded, CD27 and CD70 expression can be analysed.

Genetic testing confirms the diagnosis and differentiates CD27 and CD70 deficiency from the other forms of immune dysregulatory disorder.

This condition may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to clinical immunology services. Please refer to the local pathway for your region for this condition.

For information about testing, see Presentation: Infant or child with severe, recurrent, persistent and/or unusual infections.

Lymphoproliferative syndrome is caused by biallelic pathogenic genetic variants in the CD27 or CD70 genes. It has autosomal recessive inheritance and is a rare primary immunodeficiency.

A family history should be taken; parents and other potentially affected family members should be identified and screened as appropriate. De novo variants may also arise.

If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:

• 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected.
• 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves.
• 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

CD27 and CD70 deficiency can present variably and this will determine management options.

Patients with HLH should be managed using standard HLH treatment based on current protocols, as described by Henter J-I and others. Initial therapy consists of etoposide and dexamethasone for eight weeks in varying doses. Patients with CNS involvement may require intrathecal methotrexate. In some cases, emapalumab targeting interferon-γ has been used successfully.

The primary curative treatment is haematopoietic stem cell transplantation (HSCT). This involves replacing stem cells from a patient’s bone marrow with that of a compatible donor. Patients who receive allogeneic HSCT soon after birth tend to have the best outcomes with fewer complications. Reduced intensity conditioning regimens have been demonstrated to be beneficial in patients with XLP, particularly with coexisting inflammatory bowel disease.

Patients should receive multidisciplinary care with:

• immunoglobulin replacement therapy;
• infection prophylaxis; and
• regular monitoring for HLH/EBV infections, including lymphoma surveillance as appropriate.

This condition may be identified before any symptoms appear, for example through the Generation Study. Therefore, management of these individuals may differ from those presenting symptomatically.

For clinicians

• OMIM: 615122 Lymphoproliferative syndrome 2
• OMIM: 618261 Lymphoproliferative syndrome 3

References

• Abolhassani H, Edwards ES, Ikinciogullari A and others. ‘Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency‘. Journal of Experimental Medicine 2017: volume 214, issue 1, pages 91–106. DOI: 10.1084/jem.20160849
• Ghosh S, Köstel Bal S, Edwards ESJ and others. ‘Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency‘. Blood 2020: volume 136, issue 23, pages 2,638–2,655. DOI: 10.1182/blood.2020006738
• Henter J-I, Horne A, Aricó M and others. ‘HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis‘. Pediatric Blood & Cancer 2007: volume 48, issue 2, pages 124–131. DOI: 10.1002/pbc.21039

For patients

• Immunodeficiency UK: Primary Immunodeficiency