Background and Aims

Malignancy is not an infrequent presentation of PIDD. High index of suspicion and rapid confirmation of radio-sensitive PIDDs are crucial for timely therapy modification.

Methods

Molecular variants were identified via NGS. Flow cytometry was utilized to assess DNA repair in patient 2 via measurement of phosphorylated [p]ATM and γH2AX in lymphocytes following exposure to 2Gy radiation.

Results

Patient 1 presented at 12 years with pre-T cell ALL and received standard therapy. Persistent disease prompted therapy escalation including cranial radiation and nelarabine. Nelarabine was held following disclosure of balance issues in toddlerhood. Her course was complicated by significant ataxia and severe lymphopenia. She re-presented at 20 years with alpha-beta hepatosplenic T cell lymphoma and succumbed to disease. Results available post-mortem identified a pathogenic variant in ATM (p.V242G).

In comparison, patient 2 presented at age 6 years with peripheral T cell lymphoma-NOS. Clumsiness, drooling, and an atypical malignancy raised concern for radiosensitive PIDD. Upfront genetic sequencing identified a pathogenic variant (c.2921+1G>A) and a VUS (c.8041G>A; p.V2681M) in ATM. A rapid flow radiosensitivity assay demonstrated an inability to autophosphorylate ATM at 1h post-low dose irradiation (2Gy), and lack of dephosphorylation of γH2AX at 24h post-irradiation confirmed pathogenicity of the VUS and diagnosis of ataxia telangiectasia (AT). Initial consideration of an autologous transplant was abandoned in favor of reduced intensity allogeneic transplant based on these results.

Conclusions

Rapid genetic testing and functional confirmation of suspected radiosensitive PIDD, such as AT, presenting as malignancy is essential to mitigating therapy-related toxicities and optimizing survival.