CYTOGENETIC AND MOLECULAR DETERMINANTS OF TRASFORMATION IN SCHWACHMAN DIAMOND SYNDROME

Among the Inherited Bone Marrow Failure Syndromes (IBMFS), the Shwachman-Diamond syndrome (SDS) is an excellent model to analyze patterns of transformation. SDS is an autosomal recessive disease (OMIM #260400) caused by mutations in the SBDS gene in at least 90% of cases.1 It is characterized by exocrine pancreatic insufficiency, skeletal abnormalities, bone marrow failure with variable severity of neutropenia, thrombocytopenia and anaemia.2 Clonal chromosome changes are often found in the bone marrow (BM) of SDS patients, and the most frequent are an isochromosome for the long arms of chromosome 7, i(7)(q10), and an interstitional deletion of the long arms of chromosome 20, int del(20)(q11.21q13.32).3 The relationship between these and other chromosome changes in BM cells and the risk of developing a myelodysplastic syndrome (MDS) and/or acute myeloid leukaemia (AML) are topics of debate.4 The proportion of SDS patients who develop MDS/AML was evaluated to be 19% at 20 years and 36% at 30 years,5 but we observed that the acquisition of BM chromosome anomalies is age-related too.6 The molecular consequences of the two major chromosome changes in BM are topics of discussion on the determinants of transformation. The i(7)(q10) has been considered in the past as herald of malignant transformation, but in some cases it is associated with an indolent course and it may be even transient.7 Then, it has been associated with a lower risk and a more benign course:5 Minelli et al8 demonstrated that one of the recurrent mutation of the SBDS gene, c.258+2T>C, is duplicated on the i(7)(q10); this mutation has been demonstrated to allow the production of a small amount of the normal SBDS protein. This should be considered the reason why the i(7)(q10) indicates a benign course and is probably not a determinant of transformation. Convincing evidence is available in the literature of a benign course of SDS also in patients with the int del (20)(q11.21q13.32).9,10 One of the functions of SBDS protein relates to the ribosome biogenesis acting on the release of the EIF6 protein from the pre-60S ribosome, allowing the formation of actively translating 80S ribosome. The EIF6 gene is located on the long arms of chromosome 20 in the band q11.22: we demonstrated that it is included in the region deleted in our patients, and we postulated that the benign prognosis of the SDS patient with the int del (20)(q11.21q13.32) is due to gene/dosage effect for the EIF6 protein in the cells of the abnormal clone.1