Successful cord blood transplantation for a CHARGE syndrome with CHD7 mutation showing DiGeorge sequence including hypoparathyroidism

Abstract

It is rare that coloboma, heart anomalies, choanal atresia, retarded growth and development, and genital and ear anomalies (CHARGE) syndrome patients have DiGeorge sequence showing severe immunodeficiency due to the defect of the thymus. Although the only treatment to achieve immunological recovery for these patients in countries where thymic transplantation is not ethically approved would be hematopoietic cell transplantation, long-term survival has not been obtained in most patients. On the other hand, it is still not clarified whether hypoparathyroidism is one of the manifestations of CHARGE syndrome. We observed a CHARGE syndrome patient with chromodomain helicase DNA-binding protein 7 mutation showing DiGeorge sequence including the defect of T cells accompanied with the aplasia of the thymus, severe hypoparathyroidism, and conotruncal cardiac anomaly. He received unrelated cord blood transplantation without conditioning at 4 months of age. Recovery of T cell number and of proliferative response against mitogens was achieved by peripheral expansion of mature T cells in cord blood without thymic output. Although he is still suffering from severe hypoparathyroidism, he is alive without serious infections for 10 months.

CHARGE syndrome: a review of the immunological aspects

“…For 23 of 26 (88%) patients, T-cell lymphopenia was concomitant with T-cell dysfunction. 14,17,18,20,[22][23][24][25][26][27][28][29][30][31]33,[35][36][37] In our collected cohort, B-and/or NK-cell numbers were reported in only 29 of 59 patients, and of these 29 patients, 1 had low B-cell numbers, 1 had high B-cell numbers, 1 had low NK-cells numbers and 3 had high NK-cell numbers. The reported B-and NK-cells numbers of other patients were normal.…”

“…T-cell lymphopenia in our collected cohort was associated with thymic aplasia or hypoplasia in 21 of 22 (95%) patients. [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] T-cell function by response on mitogens was available for 28 of 59 patients and of these 28 patients 24 (86%) had a low or absent response on mitogen. For 23 of 26 (88%) patients, T-cell lymphopenia was concomitant with T-cell dysfunction.…”

CHD7 mutations and CHARGE syndrome: the clinical implications of an expanding phenotype

“…In particular, thymus aplasia and hypoparathyroidism are increasingly recognised in CHARGE syndrome and mark the clinical overlap with the DiGeorge phenotype of 22q11 deletions 50 51. In approximately 85% of VCFS patients, a common 3 Mb heterozygous deletion of 22q11.2 is present, resulting in TBX1 haploinsufficiency.…”

Severe Combined Immunodeficiency Disorders

“…[131][132][133][134][135][136][137] For complete DiGeorge anomaly, a review of 17 treated patients demonstrated 41% overall survival. 136 Although patients develop normal T cell numbers through clonal expansion and normal proliferative responses to PHA, a significant issue that remains unaddressed involves persistent lack of thymic function.…”