Shwachman-Diamond-Bodian Syndrome (SBDS): Long-Term Follow-Up of 31 Patients.

Shwachman-Bodian-Diamond syndrome (SBDS) is an autosomal recessive multisystem disorder primarily affecting the bone marrow, exocrine pancreas, and skeleton. As with other constitutional bone marrow failure syndromes, there is a predisposition to malignant myeloid transformation. The risk can only be estimated and varies considerably in the literature. Significant hematologic abnormalities can be present from early childhood with requirement of growth factor treatment (granulocyte-colony stimulating factor, erythropoietin). Since the first description of mutations in the SBDS gene, most clinically diagnosed patients have been genetically analyzed meanwhile, which now allows for genotype-phenotype correlations. Here, we report long-term clinical data of 31 SBDS patients (10 female, 21 male; 27 patients alive, 3 expired, 1 lost to follow up) with regard to different genotypes collected by the European Branch of the Severe Chronic Neutropenia International Registry since 1994: Severe Neutropenia (ANC <500/μl) is present in 11 patients, of whom 9 receive G-CSF treatment. In 16 of the remaining 22 untreated patients, the median ANC is below 1500/μl. G-CSF doses range from 0.4 to 7.7 μg/kg/day (mean G-CSF dose: 3.15 μg/kg/d). One patient is treated with granulocyte-macrophage colony stimulating factor (GM-CSF). Two of the G-CSF-treated patients have received a combination of G-CSF plus erythropoietin prior to stem cell transplantation. In 4 patients, G-CSF therapy was started within the first year of life, in 1 patient at the age of 20 months, and in 2 patients at the age of 8 and 13 years, respectively. MDS-like leukemic transformation occurred in 2 (1 male/1 female) out of 31 patients (6.5 %) at an age of 5.3 and 7.0 years. Both patients had additional cytogenetic abnormalities (monosomy 7 and complex aberrant karyotype). One patient had received G-CSF for 22 months at a dose of 3.8 μg/kg/d prior to SCT. In the other patient, pancytopenia including severe neutropenia started at the time cytogenetic aberrations were detectable. Both patients received stem cell transplantation (SCT) from unrelated donors (1 MUD, 1 haploident.). 14 months after MUD-SCT the girl is in a good clinical condition with full hematologic reconstitution, whereas the boy died within the first month after haploident. SCT from septicemia. SCT was also performed in 4 non-leukemic patients due to pancytopenia and prior to lung transplantation (2 HLA ident SCT: alive, 2 MUD SCT: 1 alive, 1 expired). SBDS gene analysis has been carried out in 14 of 19 German patients. Ten of 14 patients (71%) were compound heterozygous for 183–184TA>CT/258+2T>C. The rare genotypes 199A>G/258+2T>C, 297–300delAAGA/258+2T>C, and TGC>TGG/258+2T>C were observed in single patients. In another individual, a complex aberration with 7 mutations (Rosendahl et al, 2006) was found. Interestingly, two of the latter four patients presented with severe hematological anomalies early in life. One of them died from SCT after leukemic transformation. The third patient has developed severe osteoporosis and diabetes mellitus type 1. The fourth is on continuous G-CSF treatment. Our data demonstrate the importance of hematologic follow-up and regular cytogenetic evaluation of the bone marrow in SBDS patients. Patients with rare SBDS gene mutations seem to develop a more severe phenotype, but it requires a larger patient cohort for statistical proof.