A novel DKC1 mutation, severe combined immunodeficiency (T⁺B^–NK^– SCID) and bone marrow transplantation in an infant with Hoyeraal–Hreidarsson syndrome

Abstract

Summary. X-linked Hoyeraal-Hreidarsson syndrome (XL-HHS) is the severe infantile variant of X-linked dyskeratosis congenita (XL-DC) and both are due to mutations in the DKC1 gene within Xq28. We report a novel missense mutation in DKC1 exon 3 (T113fiC, Ile38Thr) in a Sardinian infant with XL-HHS in whom the disease was characterized by ÔT + B -NK -Õ severe combined immunodeficiency and bone marrow failure. He underwent sibling bone marrow transplantation using a conditioning regimen (fludarabine, rabbit antithymocyte globulin, low-dose melphalan) selected according to the HHS/DC phenotype. This was associated with low toxicity, prompt engraftment with adequate immune reconstitution and full donor haemopoiesis.

Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita

“…Various regimens have been examined, but there is not yet a commonly accepted standard. 9,12,14,[18][19][20][21][22][23][24][25][26][27][28][29][30] Table 3 summarizes the reported experience of HCT for patients with DC using reducedintensity conditioning, including specifics of donors, regimens and outcomes. Kaplan-Meier analysis revealed that overall cumulative survival was 65%, with related donor recipients having better survival compared with unrelated donor transplants (91 vs 30%, respectively, P ¼ 0.05).…”

Unrelated cord blood transplantation in a girl with Hoyeraal–Hreidarsson syndrome

“…However, null mutations have not been described, suggesting that this would be lethal. 7 Mutations in the genes responsible for X-linked and autosomal-dominant DC (DKC1 and TERC, respectively) have not been identified in females with HHS, suggesting that other loci are involved.…”

“…7 Telomerase function is important in development, differentiation and activation of human lymphocytes. An increased in vitro sensitivity to radiation and alkylating agent in circulating lymphocytes and fibroblasts was demonstrated in a 7-year-old HHS boy.…”

“…1,7,8 Cossu et al 7 chose a non-BU, non-TBI-containing regimen consisting of fludarabine, rabbit antithymocyte globulin and low-dose melphalan. This particular patient encountered prompt and sustained engraftment, from an HLAmatched elder sibling donor, at the time of publication 1-year post-BMT.…”

“…This particular patient encountered prompt and sustained engraftment, from an HLAmatched elder sibling donor, at the time of publication 1-year post-BMT. 7 Knight et al 1 report the use of an unrelated BMT in a 23-month-old boy; unfortunately, no information was provided regarding the conditioning regimen. At the time of publication, this patient was still alive 37 months post-BMT and experiencing significant medical and developmental complications of the underlying condition and the immune reconstitution process.…”