Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study.
OBJECTIVE
Shwachman-Diamond syndrome (SDS) is characterized by varying degrees of marrow failure. Retrospective studies suggested a high propensity for malignant myeloid transformation into myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The study's aims were to determine the cellular and molecular characteristics as well as the clinical course of malignant myeloid transformation and clonal marrow disease in patients with SDS.


METHODS
This is a longitudinal prospective study of 14 patients recruited for annual hematological evaluations. Results of baseline and serial hematological assessments for up to 5 years are reported.


RESULTS
Clonal marrow cytogenetic abnormalities (CMCA) were detected in 4 patients (29%) on first testing or at follow-up. The abnormalities were del(20q) in two patients, i(7q) in one, and combined del(20q) and i(7q) in one. The following tests did not distinguish patients with CMCA from other SDS patients: severity of peripheral cytopenia, fetal hemoglobin levels, percentage of marrow CD34+ cells, colony growth from marrow CD34+ cells, cluster-to-colony ratio, marrow stromal function, percentage of marrow apoptosis cells, and granulocyte colony-stimulating factor receptor expression. RAS and p53 mutation analysis and AML blast colony assays were uniformly negative. No patients showed progression into more advanced stages of MDS or into AML. In one patient, the abnormal clone became undetectable after 2 years of follow-up.


CONCLUSIONS
We conclude that although CMCA in SDS is high, progression into advanced stages of MDS or to overt AML may be slow and difficult to predict. Treatment should be cautious since some abnormal clones can regress.
Department of Paediatrics, Divisions of Hematology and Oncology, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada. yigal.dror@sickkids.ca
Yigal
Y
Dror
Peter
P
Durie
Hedy
H
Ginzberg
Rebecca
R
Herman
Anu
A
Banerjee
Martin
M
Champagne
Kevin
K
Shannon
David
D
Malkin
Melvin H
MH
Freedman
D000208:Acute Disease; D000293:Adolescent; D017209:Apoptosis; D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000473:pathology*; D001855:Bone Marrow Diseases / Q000097:blood / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002999:Clone Cells / Q000473:pathology; D003114:Colony-Forming Units Assay; D018450:Disease Progression; D010188:Exocrine Pancreatic Insufficiency / Q000097:blood / Q000235:genetics / Q000473:pathology; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis; D005500:Follow-Up Studies; D016158:Genes, p53; D011905:Genes, ras; D006130:Growth Disorders / Q000097:blood / Q000235:genetics / Q000473:pathology; D006801:Humans; D007223:Infant; D007951:Leukemia, Myeloid / Q000209:etiology; D008297:Male; D009190:Myelodysplastic Syndromes / Q000209:etiology; D011446:Prospective Studies; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000032:analysis; D013577:Syndrome; D019014:fas Receptor / Q000032:analysis
D016188:Receptors, Granulocyte Colony-Stimulating Factor; D019014:fas Receptor; D005319:Fetal Hemoglobin