Malignant myeloid transformation with isochromosome 7q in Shwachman–Diamond syndrome

Abstract

Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by exocrine pancreatic dysfunction, bony metaphyseal dysostosis, various degrees of cytopenia, and a striking tendency to develop myelodysplastic syndrome and acute myeloblastic leukemia. Isochromosome 7 [i(7q)] is a rare non-random cytogenetic abnormality of myeloid cells in hematological malignancy. We report two cases of Shwachman-Diamond syndrome in which patients developed myelodysplastic syndrome and i(7q), detected by G-banding karyotype analysis and fluorescence in situ hybridization. Three other children have been previously reported to have myelodysplastic syndrome in association with i(7q); two of them had Shwachman-Diamond syndrome. Isochromosome 7q may be a fairly specific marker of myeloid malignant transformation in this syndrome and play a role in its pathogenesis.

Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome

“…Two recurrent cytogenetic anomalies have been observed, i(7)(q10) and del(20q), which can be indolent and sometimes even transient. [25][26][27][28][29][30][31][32][33] However, these same abnormalities can also announce or be associated with a frank malignant outcome, [34][35][36] as we observed in two cases in this survey. In addition to the patients with i(7)(q10) and del(20q), we also observed an indolent profile in two other patients, one with t(16;20) in addition to i(7)(q10) and one with a complex abnormality of chromosome 9 (Online Supplementary Table S1).…”

The isochromosome i(7)(q10) carrying c.258+2t>c mutation of the SBDS gene does not promote development of myeloid malignancies in patients with Shwachman syndrome

“…18 However, some exceptions to the rule that SDS patients with i(7)(q10) do not develop MDS/AML may exist, as suggested by two old reports of patients carrying this cytogenetic abnormality who developed refractory anaemia. 19,20 The c.258 þ 2T4C mutation modifies the usual splice site at the donor site of intron 2 and, in turn, a cryptic splice site present at position 251-252 in exon 2 becomes active, resulting in an 8-bp deletion in mRNA sequence, which also causes a premature truncation of the encoded protein by frameshift (p.84Cfs3). 2 However, the c.258 þ 2T4C mutation, either in homozygous condition or in association with a rare mutation such as c.505C4T (p.R169C), still allows the production of some amount of normal protein.…”

Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway

“…However, during the study, an unsuspected marrow cytogenetic abnormality of clonal isochromosome (7q) was unmasked in one patient (UPN 1). 4 Results of patients' marrow studies were compared to those of 11 hematologically healthy bone marrow donors. Consent for the study was obtained from all patients or their parents and from all controls.…”

“…[1][2][3] Furthermore, it has been noted recently that patients with the syndrome have a marked propensity for myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML); these occur in up to one third of the patients. [1][2][3][4][5][6] The genetic or molecular defects of the disease and the factors that predispose patients to these complications are still unknown. We have previously shown that the bone marrow of patients with SDS is characterized by a decreased frequency of CD34 ϩ cells and that marrow CD34 ϩ cells have a reduced ability to form hematopoietic colonies in vitro.…”