Clinical and Genetic Characteristics of Patients with Shwachman-Diamond Syndrome in Japan

Background: Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) characterized by bone marrow failure and pancreatic insufficiency. Patients with SDS have propensity to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Although it is the third most common IBMFS following Fanconi anemia and Diamond-Blackfan anemia in western countries, the incidence of SDS has been considered to be much lower in Japan. Patients and methods:In addition to the cases of SDS diagnosed by SBDSgene mutation analysis at Kyoto University, we captured those from the central review system of the Japanese Society of Pediatric Hematology and Oncology and the targeted sequencing system for IBMFS at Nagoya University as well as the previous Japanese nationwide survey for SDS that was conducted in 2010. Results:A total of 47 cases from 43 families with biallelic SBDSgene mutation were captured. After the previous nationwide survey, 21 cases were accumulated in the past 8 years: 2.6 cases per year in average. Median age at presentation is 0 year, and median age at diagnosis is two years. Male-female ratio of the patients was 2.1:1. Birth weight was less than 2500g in approximately half of the patients. Most common mutation was 183-184TA>CT/258+2T>C (73%) followed by 258+2T>C/258+2T>C (6.6%). Notably, a patient with heterozygous 258+2T>C mutation was shown to have exon 3 deletion in the SBDS gene by whole exome sequencing. Clinical features at initial visit were various kinds of cytopenia, failure to thrive, steatorrhea, liver dysfunction, short stature, and skeletal abnormalities. Pancreatic insufficiency and/or pancreatic abnormality in imaging studies were found in almost all patients. Neutropenia was documented in one-third of the cases at initial visit; however, eventually 89% of the patients had neutropenia. Other hematological abnormalities were anemia (64%), thrombocytopenia (69%), and pancytopenia (40%). Bone marrow examination revealed hypoplasia (60%), dysplasia (36%), and chromosome abnormalities (23%) including del(20q), i(7q), and complex chromosome abnormalities. Four male patients (8.5%) of the cohort were documented to develop AML. Age at onset of AML was more than 18 years in three patients. Three patients complicated with AML and two patients with severe bone marrow failure underwent hematopoietic stem cell transplantation (HSCT). Interestingly, one patient with AML harboring normal karyotype is alive without relapse 20 years after HSCT. Three patients (6%) died; the cause of death was AML in two and complication of HSCT in one. Conclusion: Along with growing recognition of the disease among physicians and establishment of mutation analysis system, newly diagnosed cases of SDS were accumulated constantly. SDS may be more common than previously thought in our country. Clinical characteristics are similar to those that were reported in previous studies. As shown in a recent study on a large MDS cohort from an international registry of HSCT, patients with SDS may develop AML in adulthood and have very poor prognosis. The SDS cohort in Japan may provide a platform to investigate clinical and genetic factors associated with severity and phenotypes of the disease under a relatively uniform ethnic background.