ADA2 deficiency complicated by EBV-driven lymphoproliferative disease

Abstract

A 29-year old male with recurrent respiratory and skin infections, anaemia and neutropaenia during childhood required immunoglobulin replacement for antibody deficiency from age 16. He remained relatively well until age 28 when he presented with a two-week history of fatigue, sore throat, fever and productive cough. He was found to have EBV viraemia and splenomegaly and a diagnosis of EBV-driven lymphoproliferative disease was made following bone marrow trephine. Family history was notable with three siblings: a healthy sister and two brothers with anaemia and neutropaenia; one who succumbed to septicaemia secondary to neutropaenic enterocolitis age 5 and another who developed intestinal vasculitis and antibody deficiency and had a successful haemopoetic stem cell transplant. The proband's DNA underwent targeted sequencing of 279 genes associated with immunodeficiency (GRID panel). The best candidates were two ADA2 variants, p.Arg169Gln (R169Q) and p.Asn370Lys (N370K). Sanger sequencing and co-segregation of variants in the parents, unaffected sister and all three affected brothers was fully consistent with compound heterozygous inheritance. Subsequent whole genome sequencing of the proband identified no other potential causal variants. ADA2 activity was consistent with a diagnosis of ADA2 deficiency in affected family members. This is the first description of EBV-driven lymphoproliferative disease in ADA2 deficiency. ADA2 deficiency may cause susceptibility to severe EBV-induced disease and we would recommend that EBV status and viral load is monitored in patients with this diagnosis and allogeneic SCT is considered at an early stage for patients whose ADA2 deficiency is associated with significant complications.

Keywords: ADA2; Antibody deficiency; EBV; Immunodeficiency; Lymphoproliferative disease; Viraemia.

Fig. 1

A: PET-CT scan demonstrating active disease on both sides of the diaphragm and marrow involvement. i) Single slice coronal low dose CT image. ii) Single slice coronal attenuation corrected PET image. iii) Fused CT and PET images (i and ii). B: Bone marrow trephine biopsy immunostains: i) PAX5 ii) EBER. C: Pedigree diagram, showing co-segregation of ADA2 variants (N370K and R169Q) and ADA2 activity (measured at Viapath, Purine Research Laboratory, St Thomas' Hospital; in brief sera incubated with adenosine and ADA1 inhibitor for 3 h, products (inosine and hypoxanthine) separated and measured by high performance liquid chromatography; adult normal range in plasma 8.7–30.0 IU/L). Arrow indicates proband. D: Sanger confirmation in i) Mother ii) Father. i Mother: Top row shows wild-type sequence. Lower row shows change from G to A at position 506 in the mother changing the codon from CGG (Arginine, R) to CAG (Glutamine, Q): c.506G > A, p.R169Q. ii Father: Top row shows wild-type sequence. Lower row shows change from C to A at position 1110 in the father changing the codon from AAC (Asparagine, N) to AAA (Lysine, K): c.1110C > A, p.N370K.