Diagnostic and Treatment Dilemmas From Statewide Newborn Screening for Severe Combined Immunodeficiency

Introduction:  Newborn Screening (NBS) for Severe Combined Immunodeficiency (SCID) began in 2008 in the state of Wisconsin. It is predicted that early detection through NBS will improve hematopoietic cell transplant (HCT) outcomes for infants diagnosed with SCID. Two patients were diagnosed by NBS with absent T cell receptor excision circles (TRECs).  The results of their workup and HCT outcomes are reported here. These two patients emphasize the dilemmas faced since implementation of NBS SCID screening. Results:  Both patients were non-dysmorphic, demonstrated thymic tissue on ultrasound, were negative for maternal engraftment, and lacked a genetic diagnosis despite extensive expedited gene sequencing. Patient 1 had a classical SCID phenotype with T-B-NK+ immunophenotype and markedly diminished PHA response. There was concern for a radiosensitive form of SCID in patient 1; therefore, a skin fibroblast line was established.  Just prior to transplantation mild, radiosensitivity was reported.  Patient 2 had a non-classical SCID phenotype with T^loB+NK+ immunophenotype and normal PHA response at birth. Patient 2 was placed in protective isolation and prophylaxis while extensive workup ensued. During this observation period, TRECs remained undetectable and immunophenotype did not change. Further T cell analysis demonstrated normal spectratyping, but diminished T cell response to CD3 crosslinking.   B cell functional analysis revealed normal isoagglutinnin titers and a positive response to killed rabies vaccination. The decision to transplant was made based on abnormal anti-CD3 response, persistently undetectable TRECs, asymptomatic low-level CMV detection, and excellent donor source. At 2.5 months of age, patient 1 underwent a 9/10 UCB HCT, and at 16.5 months of age, patient 2 underwent an MSD HCT.  Both patients received RIC conditioning with Busulfan (CSS 400-600 ng/ml), Fludarabine, and ATG, and CSA with MMF or MTX for GVHD prophylaxis. Engraftment occurred on days +28 (patient 1) and +24 (patient 2).  Neither patient developed GVHD.  Post-HCT complications for patient 1 included bacteremia and for patient 2 included transaminitis, mild SOS, and CMV reactivation. Both patients are alive and well at 830 (patient 1) and 53 days (patient 2) post-HCT.  Conclusions:  These two patients illustrate the successes and challenges of NBS for SCID. For example, rapid radiosensitive assays are needed along with widely available and standardized protocols for assessing B cell function in infants.  Large, multicenter, prospective trials are needed to define criteria for HCT, optimal conditioning regimen, and age for HCT in clinically well newborns lacking a genetic diagnosis.