The route to development of myelodysplastic syndrome/acute myeloid leukaemia in Shwachman-Diamond syndrome: the role of ageing, karyotype instability, and acquired chromosome anomalies

An investigation of 22 new patients with Shwachman-Diamond syndrome
(SDS) and the follow-up of 14 previously reported cases showed that
(i) clonal chromosome changes of chromosomes 7 and 20 were present in the
bone marrow (BM) of 16 out of 36 cases, but if non-clonal changes were
taken into account, the frequency of anomalies affecting these chromosomes
was 20/36: a specific SDS karyotype instability was thus confirmed; (ii) the
recurrent isochromosome i(7)(q10) did not include short arm material,
whereas it retained two arrays of D7Z1 alphoid sequences; (iii) the deletion
del(20)(q11) involved the minimal region of deletion typical of
myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML);
(iv) only one patient developed MDS, during the rapid expansion of a BM
clone with a chromosome 7 carrying additional material on the short arms;
(v) the acquisition of BM clonal chromosome anomalies was age-related. We
conclude that karyotype instability is part of the natural history of SDS
through a specific mutator effect, linked to lacking SBDS protein, with
consequent clonal anomalies of chromosomes 7 and 20 in BM, which may
eventually promote MDS/AML with the patients’ ageing.