The Shwachman-Diamond Syndrome Registry: Hematologic Complications

The Shwachman-Diamond Syndrome Registry (SDSR) was established in December 2008 with the goal of understanding the natural history and biology of SDS to improve the lives of people with SDS. The SDSR has enrolled 220 patients with biallelic SBDS mutations or SDS-Like features. Longitudinal data has been collected for 176 patients with a median duration of follow-up of 10.7 (0.3-52.8) years. Biallelic SBDS mutations were noted in 117 patients, and biallelic DNAJC21 mutations in one patient. Sequencing of genetically undefined cases did not identify EFL1 or SRP54 mutations. Ongoing characterization of SBDS mutation-negative individuals has identified subgroups of clinically defined SDS individuals, as well as a more heterogenous subgroup with features of SDS but who do not meet classic diagnostic criteria. Clinical characteristics and outcomes of patients with biallelic SBDS mutations were examined. AML developed in 5 patients and MDS in 11 patients at a median age 37.9 years (range, 19.5-47.3) and 10.7 years (range, 1-45) respectively. No solid tumors were diagnosed. 21 individuals have undergone stem cell transplantation. Overall survival was 91% in the 10 years since registry establishment, with deaths mainly caused by myelodysplasia (MDS) (n=3) and acute myeloid leukemia (AML) (n=4). One individual with MDS died of hepatic failure unrelated to MDS.

Hematologic parameters, trends over time, and clinical correlations were examined.. Cytopenias were almost universal (98.8%) and often intermittent, with neutropenia the most frequent in 98.8%, anemia in 16.5% and thrombocytopenia in 45.3%. Bone marrow evaluations were available in 98, with 88.2% demonstrating marrow hypoplasia. Notable, marrow hypoplasia was progressive, with average marrow cellularity of 74% in patients <1 year of age (n=13), 45% in marrows of children 1-19 years of age (n=277), and 38% in marrows of adults 19-43 years of age (n=38). Cases with discordance between marrow cellularity and cytopenias were noted, so a systematic analysis of the patterns of marrow cellularity and blood counts is ongoing. Marrow dysmorphologies were common and present in in 40.9%, 49.5%, and 28% of the erythroid, myeloid and megakaryocyte lineages respectively, highlighting the need for review from pathologists experienced in the baseline dysmorphologies common in SDS. Marrow cytogenetic data were available for 89 patients of whom 30 (33%) developed clonal abnormalities diagnosed at median age of 8.67 years (range, 0.3-38.9). The most common clonal abnormalities were iso(7q) (n=4) and del(20q) (n=13). Blood count patterns associated with these clonal abnormalities were variable. Notably, iso7q clones were transient while the majority of del20q clones were persistent. One patient with a history of an iso(7q) clone and one with a del(20q) clone progressed to MDS.

There is a paucity of evidence to guide optimal surveillance strategies for leukemia predisposition syndromes. The SDSR revealed wide variation in clinical practice amongst local hematologists including: 1) no surveillance for well-appearing patients, 2) intermittent blood counts, or 3) bone marrow exams of variable frequency with variable testing of cytogenetics and FISH. Some patients were not followed by hematology because they looked well until they presented with AML. In one illustrative case, a teenage patient with a transient iso7q clone had improving hemoglobin, platelet counts, absolute neutrophil counts, and reduction in red cell macrocytosis over the year prior to diagnosis of MDS. Additional clinical and laboratory studies are underway to provide evidence-based guidelines and to develop more sensitive tests for optimal surveillance of patients with predisposition to myeloid malignancies.