Successful umbilical cord blood stem cell transplantation in a patient with Rothmund–Thomson syndrome and combined immunodeficiency

Abstract

The ATP-dependent DNA helicase Q4 (RECQL4) belongs to a family of conserved RECQ helicases that are felt to be important in maintaining chromosomal integrity (Kitao et al., 1998, Genomics: 54 (3): 443-452). Deletions in the RECQL4 gene located on chromosome 8 region q24.3 have been associated with Rothmund-Thomson syndrome (RTS, OMIM 268400), a condition characterized by poikiloderma, sparse hair, small stature, skeletal abnormalities, cataracts and an increased risk of malignancy. We present a patient with a molecularly confirmed diagnosis of RTS with two unique genetic alterations in RECQL4 (IVS16-2A>T and IVS2+27_51del25), who at the age of 7 months nearly succumbed to Pneumocystis carinii pneumonia. Evaluation of his immune system demonstrated a T- B+ NK- phenotype with agammaglobulinemia consistent with combined immunodeficiency (CID). Studies to evaluate for known genetic causes of CID were not revealing. The patient received an umbilical cord blood (UCB) transplant with complete immune reconstitution. This report represents the first description of a CID phenotype and UCB transplantation in a patient with RTS.

The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis

“…B cell differentiation is impaired from the pre-proB cell stage onward in the BM, and T cell development appears to be compromised by the loss of BM-derived thymic reseeding cell populations. There are reports of immune compromise in patients with RTS (67,68). The hematopoietic abnormality in 1 of these patients was corrected by an allogeneic cord blood stem cell transplant (68), confirming that, as in the mouse, this is a hematopoietic-intrinsic requirement for RECQL4.…”

“…There are reports of immune compromise in patients with RTS (67,68). The hematopoietic abnormality in 1 of these patients was corrected by an allogeneic cord blood stem cell transplant (68), confirming that, as in the mouse, this is a hematopoietic-intrinsic requirement for RECQL4. The range of severity of immune phenotypes and lineages affected in RTS patients may be reflective of retained function of the mutant RECQL4 protein.…”

Rothmund-Thomson syndrome

“…3. The types of observed mutations are: i) nonsense mutations that change an aminoacid to a stop codon and lead to termination of protein translation; ii) insertions and/or deletions, which lead to reading frameshift and subsequent termination of protein translation; iii) mis-splicing alterations including substitutions at canonical splice junctions or at splice site consensus sequences that cause the skipping of exons and a downstream frameshift and subtle intronic deletions, which reduce intron size below the threshold (<80 bp) required for correct splicing [83-85] and iv) missense mutations that cause an aminoacid change in the protein. Most of the mutations identified in RTS are nonsense or frameshift mutations, which destabilise the mature mRNA through nonsense mediated-decay.…”

A recurrent R936X mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma

“…At least one patient of Rothmund Thomson syndrome with two unique genetic alterations in RECQL4 (IVS16-2A>T and IVS2+27_51del25) and combined immunodeficiency with T -B + NKphenotype agammaglobulinemia has been described. [6] However, whether such cases are new phenotypes or are fortuitous associations remains conjectural due to the paucity of reported cases.…”