Telomere biology disorders (TBD) are rare multisystem disorders characterized by a wide array of clinical presentations, including bone marrow failure, pulmonary fibrosis, and malignancy predisposition due to premature telomere apoptosis. Definitive treatment requires allogenic bone marrow transplant (BMT), though it may not ameliorate organ-specific complications. Pathogenic variants in TERT and PARN have been described in both autosomal dominant (AD) and autosomal recessive (AR) inheritance patterns.
We describe a patient post-allogenic BMT for myelodysplastic syndrome (MDS) with both germline and donor-derived variants in TBD genes, presenting with recurrent EBV-associated lymphoproliferation and recurrent lymphomas.
The patient is a 57-year-old male who was referred for recurrent EBV lymphoproliferation. The patient underwent an unrelated allogenic stem cell transplant in 2008 for myelodysplastic syndrome. Off immunosuppression, he developed Hodgkin lymphoma (2011) and EBV-positive polymorphic post-transplant lymphoproliferative disorders (PTLD) (2015). Later, diffuse large B cell lymphoma was discovered on colonic biopsy (2024). He received rituximab-containing chemoimmunotherapy with complete remission, and weekly rituximab for recurrent low-level EBV viremia with response. Genetic testing was sent in whole blood and fibroblasts to test for germline and donor-derived inborn error of immunity (IEI). He did not have antecedent evidence of pulmonary fibrosis, cirrhosis, or nail dystrophy.
DNA from skin fibroblast culture revealed a novel variant of uncertain significance (VUS) in TERT c.1148C>A p.Pro 383His. Whole blood demonstrated a likely pathogenic heterozygous variant in PARN c.1293del (P.Tyr432llefs*2). Flow fluorescence in situ hybridization (FISH) telomere testing from blood revealed lymphocytes <1st percentile, granulocytes 1–10th percentile, naive T cells <1st percentile, memory T cells 1–10th percentile, and natural killer (NK) cells in normal range; reduced telomere length was identified in multiple lineages. Flow revealed low CD4 (0.28 × 10E9/L), elevated CD8 (2.29 × 10E9/L), undetectable CD19 (<0.01 × 10E9/L; 4 months after rituximab), and normal CD16/56 cells (0.10 × 10E9/L). Chimerism was complete in whole blood and T cell compartments.
While definitive treatment for many IEIs is a BMT, there is a very rare risk of donor-related immunogenic complications. While he has reduced telomere lengths, it is unclear if the EBV-associated lymphoproliferation is related to the PARN variant, TERT variant, or neither. This probable donor-acquired pathogenic variant is a highly unexpected finding and raises ethical and clinical considerations when found.
