Inherited bone marrow failure syndrome (IBMFS) including Shwachman Diamond Syndrome (SDS) can present initially to the hematologist with myelodysplastic syndrome (MDS). Accurate diagnosis affects choice of chemotherapy, donor selection, and transplant conditioning. We report a case of delayed diagnosis of SDS in a family with another child with aplastic anemia, and review reported cases of SDS in Asia. This highlights the gap in identifying inherited bone marrow failure syndromes in adults with hematologic malignancies.

The recent characterization of clonal hematopoiesis in a large segment of the aging population has raised tremendous interest and concern alike. Mutations have been documented in genes associated with hematological cancers and in non-driver candidates. These mutations are present at low frequency in the majority of individuals after middle-age, and principally affect the epigenetic modifiers DNMT3A and TET2. In 10%-40% of cases, the clone will progress to meet the diagnostic criteria for Clonal Hematopoiesis of Indeterminate Potential, which is associated with an increased risk of hematological cancer and cardiovascular mortality. Blood cell parameters appear unmodified in these individuals, but a minority of them will develop a hematologic malignancy. At this time, the factors put forward as potentially influencing the risk of cancer development are clone size, specific gene, specific mutation, and the number of mutations. Specific stress on hematopoiesis also gives rise to clonal expansion. Genotoxic exposure (such as chemotherapy), or immune attack (as in aplastic anemia) selects/provides a fitness advantage to clones with a context-specific signature. Clonal hematopoiesis offers a new opportunity to understand the biology and adaptation mechanisms of aging hematopoiesis, and provides insight into the mechanisms underlying malignant transformation. Furthermore, it might shed light on common denominators of age-associated medical conditions, and help devise global strategies that will impact the prevention of hematologic cancers and promote healthy aging. Stem Cells 2018; 00:000-000.

Bone marrow transplantation is the definitive treatment of severe aplastic anemia; however, with the absence of this option, combined immunosuppressive therapy with antithymocyte globulin (ATG) and cyclosporine A is used as a first-line therapy. This case report highlights the possible delay in response to ATG protocol in treating aplastic anemia.

Telomerase consists of the catalytic protein TERT and the RNA TERC. Mutations in TERC are linked to human diseases, but the underlying mechanisms are poorly understood. Here we report that the RNA-binding protein HuR associates with TERC and promotes the assembly of the TERC/TERT complex by facilitating TERC C106 methylation. Dyskeratosis congenita (DC)-related TERC U100A mutation impair the association of HuR with TERC, thereby reducing C106 methylation. Two other TERC mutations linked to aplastic anemia and autosomal dominant DC, G107U, and GC107/108AG, likewise disrupt methylation at C106. Loss-of-HuR binding and hence lower TERC methylation leads to decreased telomerase activity and telomere shortening. Furthermore, HuR deficiency or mutation of mTERC HuR binding or methylation sites impair the renewal of mouse hematopoietic stem cells, recapitulating the bone marrow failure seen in DC. Collectively, our findings reveal a novel function of HuR, linking HuR to telomerase function and TERC-associated DC.

Studies of chromosomal aberrations in blood or bone marrow of patients with Fanconi anemia (FA) have focused on their associations with leukemic transformation. The role of such abnormalities on outcomes after hematopoietic cell transplantation (HCT) is unclear. We used genome-wide single nucleotide polymorphism (SNP) arrays to identify chromosomal aberrations in pre-HCT blood samples from 73 patients with FA who received unrelated donor HCT for severe aplastic anemia between 1991-2007. Outcome data and blood samples were available through the Center for International Blood and Marrow Transplant Research. For survival analyses, we used the Kaplan-Meier estimator to calculate the survival probabilities and the exact log-rank test to compare the survival differences across groups. Chromosomal aberrations were detected in 16 patients (22%); most frequent were: clonal copy-loss in chromosome 7 (9.6%), clonal copy-gains in the long arm (q) of chromosome 1 (chr1q+; 8.2%), and clonal or complete copy-gains in the q arm of chromosome 3 (chr3q+; 8.2%). Seven patients (9.6%) had alterations in 3 or more chromosomes. Poor post-HCT overall survival (OS) was noted in patients with chr3q+ (p=0.04), or those with abnormalities in ≥3 chromosomes (p=0.03). The 1-yr OS=0% vs. 45% in patients with either alteration versus its absence. No statistically significant differences in OS were noted in patients carrying deletions in chr7 (1-year OS=29% vs. 42%, respectively, log-rank p=0.74). The study is limited by the small sample size. A larger, prospective study is warranted to validate our findings in light of recent improvement in transplant modalities and outcomes.

Sinonasal organized hematoma, which has locally aggressive characteristics, is a non-neoplastic disease. We report a rare case of sphenoid sinus organized hematoma causing acute visual loss. A 35-year-old male presented with progressive headaches, retro-orbital pain, and frequent epistaxis. He had a medical history of aplastic anemia and of taking warfarin for a valvular heart disease. On image studies, an expansive soft tissue density lesion with bony destruction was found in his left sphenoid sinus. While waiting for elective surgery, acute visual loss occurred. Emergent endoscopic surgery was performed after correction of abnormal hematological profiles, but his visual disturbance did not improve. Although sphenoid sinus organized hematoma is a rare disease, organized hematoma should be considered in the differential diagnosis for sphenoid sinus lesion with acute visual loss. Rapid and correct diagnosis and timely treatment are essential to prevent permanent sequela.