Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants

Abstract

The purpose of this study was to characterize a large group of infants with complete DiGeorge anomaly and to evaluate the ability of thymus transplantation to reconstitute immune function in these infants. DiGeorge anomaly is characterized by varying defects of the heart, thymus, and parathyroid glands. Complete DiGeorge anomaly refers to the subgroup that is athymic (< 1%). The characteristics of 54 subjects at presentation and results from 44 consecutive thymus transplantations are reported. Remarkably, only 52% had 22q11 hemizygosity and only 57% had congenital heart disease requiring surgery. Thirty-one percent developed an atypical phenotype with rash and lymphadenopathy. To date, 33 of 44 subjects who received a transplant survive (75%) with post-transplantation follow-up as long as 13 years. All deaths occurred within 12 months of transplantation. All 25 subjects who were tested 1 year after transplantation had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Adverse events developing after transplantation included hypothyroidism in 5 subjects and enteritis in 1 subject. In summary, diagnosis of complete DiGeorge anomaly is challenging because of the variability of presentation. Thymus transplantation was well tolerated and resulted in stable immunoreconstitution in these infants.

Figure 1

Kaplan-Meyer plot of survival of recipients of a thymus transplant. (A) Survival of 35 of 54 subjects who were enrolled. (B) Survival of 33 of 44 subjects who received a transplant.

Figure 2

T-cell development as determined by T-cell subset antibody staining and T-cell proliferative responses to mitogens for subjects past 1 year after thymus transplantation. Fourteen subjects who did not receive immunosuppression (A-C,G) are compared with 12 subjects who did receive immunosuppression (D-F,H); (A,D) CD3, (B,E) CD4, (C,F) CD8, (G,H) PHA responses. Each subject is represented by a separate line. The x-axis is years after transplantation. The y-axis for panels A to F is cells/mm³. The y-axis for panels G and H is counts per minute. Note the T-cell amplifications seen in panels A to C for 4 subjects who developed the atypical form of DiGeorge anomaly shortly after transplantation.

Figure 3

CD4 TCRBV repertoire diversity as assessed by spectratyping. (A) D_KL values for 16 subjects with typical complete DiGeorge anomaly. (B) D_KL values for 7 subjects with atypical complete DiGeorge anomaly. (C) CD4 spectratyping profiles for subject DIG005 at 7 years after transplantation. The Jurkat control panel is in the lower right. The D_KL value for this spectratype is 0.11.

Figure 4

Infections after thymus transplantation. The number of infections per patient per year is presented for the first 6 months after transplantation before normal T-cell function has developed and for the remainder of follow-up time. All 44 patients who received a transplant are included in the data for the initial 6 months, resulting in 19 patient-years of follow-up. The follow-up time from 6 months after transplantation until the end of November 2006 totaled 82 patient-years of follow-up. A decrease in rate of infections is seen.