Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease.

Summary:Patient population and methodsThe charts of 350 consecutive patients between the ages of Thyroid function abnormalities in 270 adult patients post-BMT are described. Various conditioning regimens 16 and 57 years transplanted at this Institute from June 1970 to May 1994 and who survived at least 1 year from were used and the effects of three TBI and one chemotherapy only based regimens are compared. The overall transplant were reviewed. Reports of thyroid-related clinical abnormalities confirmed on laboratory testing as well incidence of elevated TSH is 8.9; 3.8, 7.2 and 16.7% in those patients who received 300, 500 and 1200 cGy as routine TSH, T3 and T4 levels were collected. Eighty patients from this cohort were excluded for lack of recorded respectively and 11.7% in those who received BuCy conditioning. Three cases (1.1%) of clinial hypothyroidism TSH levels. Males and females were approximately equally represented, respectively 136 vs 134 patients in the 270 were observed. Compensated hypothyroidism defined as an elevated TSH in the presence of normal T3, T4 levels available patients. The hematological diagnoses included, CML 98 patients; AML 93; ALL 27; AA 23; MDS 9; nonand transient in some cases, was the most common finding. All but four cases occurred in the first 2 years after Hodgkin's lymphoma (NHL) 8; others 12. Two hundred and ten patients received total body irradiation (TBI) from BMT. In the remaining four, three occurred in patients with chronic GVHD. The results reported here show a a 60 Co source at 50-90 cGy/min as a component of the conditioning regimen (Table 1) The remainder received cyclolower prevalence than observed in most other reviews, particularly for children. A trend was observed with phosphamide and busulfan. increasing radiation doses. The results are not significantly different from those we observed in the BuCy regimen.Results Keywords: allogeneic; BMT; thyroid Twenty-four of the 270 patients (10 males, 14 females) were found to have elevated TSH levels ( Table 2). The conditioning regimens in these patients included single fraction With the increase in the number of allogeneic bone marrow TBI in 12 (one received 300 cGy), fractionated TBI in five transplants performed over the last two decades, and the and no TBI in seven. This represents 3.8% of the patients concomitant decrease in early mortality due to infection, in the cohort treated with a single 300 cGy fraction, 7.2% graft failure and GVHD, long-term sequelae of transplanof those treated with a single 500 cGy fraction, 16.7% of tation have become more evident. 1-3 Endocrine abnormalithose treated with 1200 cGy in six fractions and 11.7% of ties, notably hypopituitarism, hypogonadism and hypothythose treated with no radiation in the conditioning regimen. roidism have been reported, primarily in transplanted This trend did not reach statistical significance. Significant children. 4,5 The frequency of hypothyroidism was found to acute GVHD (grade II-IV) developed in 18 of these be as high as 40%, 6-8 and appeared t...

Diamond-Blackfan anemia (DBA) features hypoplastic anemia and congenital malformations, largely caused by mutations in various ribosomal proteins. The aim of this study was to characterize the spectrum of genetic lesions causing DBA and identify genotypes that correlate with phenotypes of clinical significance. Seventy-four patients with DBA from across Canada were included. Nucleotide-level mutations or large deletions were identified in 10 ribosomal genes in 45 cases. The RPS19 mutation group was associated with higher requirement for chronic treatment for anemia than other DBA groups. Patients with RPS19 mutations, however, were more likely to maintain long-term corticosteroid response without requirement for further chronic transfusions. Conversely, patients with RPL11 mutations were less likely to need chronic treatment. Birth defects, including cardiac, skeletal, hand, cleft lip or palate and genitourinary malformations, also varied among the various genetic groups. Patients with RPS19 mutations had the fewest number of defects, while patients with RPL5 had the greatest number of birth defects. This is the first study to show differences between DBA genetic groups with regards to treatment. Previously unreported differences in the rate and types of birth defects were also identified. These data allow better patient counseling, a more personalized monitoring plan, and may also suggest differential functions of DBA genes on ribosome and extra-ribosomal functions.