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Acute myeloid leukemia with germline CEBPA mutation is a subtype of acute myeloid leukemia that is associated with a favorable prognosis. Most of the reported cases of acute myeloid leukemia with CEBPA germline variants involve a germline variant in the N-terminus and a somatic variant in the C-terminus. There are only a few reported cases where the CEBPA germline variant has been identified in the C-terminus and the somatic variant in the N-terminus. This case report and review of the literature illustrates that, although acute myeloid leukemia with CEBPA N- or C-terminal germline variants have certain similarities such as atypically young age at diagnosis, frequent relapse, and favourable overall prognosis, there are also significant differences such as lower life-time penetrance of acute myeloid leukemia and shorter time to relapse for germline C-terminal cases. These findings add important information on the natural history and clinical outcomes of acute myeloid leukemia with germline CEBPA C-terminal variants and these findings should be considered in the management of patients and their family members.

TERC variant telomere biology disorders (TBDs) are a rare, heterogenous group of disorders that arise from germline variants in TERC , a gene that encodes for the RNA component of telomerase. Variants in TERC lead to accelerated telomere attrition and can manifest as many different phenotypes. In this case series, we aimed to add to the literature describing TERC variant TBDs by reporting cases from two unrelated families from Atlantic Canada. The first case, a previously described germline TERC variant, n.107G>T (NR_001566.1), was identified in a young woman with myelodysplastic syndrome (MDS) and found to segregate with cytopenias in the family. This case represents a unique phenotypic presentation: this variant has not previously been described in patients with MDS and adds important segregation data to the literature. The second case, a novel TERC n.437T>G variant, was identified in a patient with both aplastic anemia and pulmonary fibrosis manifesting in his early 30s. We report these novel cases of germline TERC variants in order to help clinicians recognize TBDs, as well as to add important supporting information for the pathogenicity of these variants. J Hematol. 2021;10(3):130-135 doi: https://doi.org/10.14740/jh826

Rationale: Alemtuzumab is a monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Many autoimmune-mediated adverse events have been associated with alemtuzumab, including renal-limited anti-glomerular basement membrane (GBM) disease. Presenting concern: A 52-year-old female with RRMS presented with acute kidney injury 39 months after receiving 1 cycle of alemtuzumab. She had a history of alemtuzumab-associated hypothyroidism and thrombocytopenia, urinary tract infections, and chronically abnormal urinalyses. Diagnosis: A diagnosis of renal-limited anti-GBM disease was made based on renal biopsy and positive anti-GBM serology. Alemtuzumab was thought to be the trigger of the anti-GBM disease as there were no other exposures or serologic findings suggesting other causes. Interventions: She was treated with corticosteroids, cyclophosphamide, and plasmapheresis. She required hemodialysis for acute renal failure. Outcomes: Despite treatment, the patient’s renal function did not recover. She remained dialysis-dependent and anti-GBM antibody titers remained elevated 6 months after presentation. Teaching points: Anti-GBM disease is a life-altering adverse event that can be associated with alemtuzumab. Our case highlights the limitations of monitoring urinalyses as a trigger for anti-GBM antibody testing in patients who have received alemtuzumab and have baseline abnormal urinalyses; such patients may require further protocolized anti-GBM antibody testing, although the optimal frequency of such antibody screening remains unclear.

Approximately 35% of the human genome can be identified as sequence devoid of a selected-effect function, and not derived from transposable elements or repeated sequences. We provide evidence supporting a known origin for a fraction of this sequence. We show that: 1) highly degraded, but near full length, ribosomal DNA (rDNA) units, including both 45S and Intergenic Spacer (IGS), can be found at multiple sites in the human genome on chromosomes without rDNA arrays, 2) that these rDNA sequences have a propensity for being centromere proximal, and 3) that sequence at all human functional rDNA array ends is divergent from canonical rDNA to the point that it is pseudogenic. We also show that small sequence strings of rDNA (from 45S + IGS) can be found distributed throughout the genome and are identifiable as an "rDNA-like signal", representing 0.26% of the q-arm of HSA21 and ∼2% of the total sequence of other regions tested. The size of sequence strings found in the rDNA-like signal intergrade into the size of sequence strings that make up the full-length degrading rDNA units found scattered throughout the genome. We conclude that the displaced and degrading rDNA sequences are likely of a similar origin but represent different stages in their evolution towards random sequence. Collectively, our data suggests that over vast evolutionary time, rDNA arrays contribute to the production of junk DNA. The concept that the production of rDNA pseudogenes is a by-product of concerted evolution represents a previously under-appreciated process; we demonstrate here its importance.

TERC variant telomere biology disorders are a rare and heterogenous group of disorders that arise from germline variants in TERC, a gene that encodes for the RNA component of telomerase. Variants in TERC lead to accelerated telomere attrition and can manifest as a wide array of clinical phenotypes affecting multiple organ systems. In this case series, we aim to add to the literature describing TERC variant telomere biology disorders by reporting cases from two unrelated families from Eastern Canada, one of whom was found to have a novel germline TERC variant and the other had a unique phenotypic presentation of previously described TERC variant. The proband of family A presented intrapartum at the age of 19 with moderate thrombocytopenia but was otherwise healthy. Her past medical history was significant for premature greying of hair as a teenager. The patient went on to have a bone marrow biopsy post-partum, as the thrombocytopenia was persistent. The bone marrow biopsy revealed a diagnosis of myelodysplastic syndrome (MDS). When she was 30 years of age, proband A's father was subsequently diagnosed with MDS. He was 53 years of age at the time of his diagnosis and he passed away of his disease 1 year later. Proband A has not required any treatment for her MDS as her blood counts have remained stable, and she now has three children. Given the family history, the proband of family A and her three children were referred to adult and pediatric hematology, respectively and medical genetics. The two youngest children, an 11-year-old male and a 9-year-old female, were found to have leukopenia and thrombocytopenia, respectively. On next generation sequencing, the proband and the two youngest children were found to have a TERC n.107 G>T (NR_001566.1) variant. The eldest child, who's CBC was normal, was not a carrier. This variant has been previously reported in the literature however it has not been reported with MDS as the phenotype. The findings in this family support allelic segregation of this variant with disease, which changes the classification of the variant from "likely pathogenic" to "pathogenic" according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification of sequence variants. The proband of family B is a male who presented to his primary care provider at the age of 35 with symptoms of generalized fatigue and was found to have macrocytic anemia and thrombocytopenia on his complete blood count. His past medical history was significant for premature greying of hair, diabetes mellitus type 2, obesity and smoking. He underwent a bone marrow biopsy that revealed a diagnosis of aplastic anemia. One year later, he was also diagnosed with pulmonary fibrosis. This diagnosis was made based on a CT scan that was done because of proband B's strong maternal family history of pulmonary fibrosis affecting his mother, maternal uncle and grandfather. Proband B was referred to hematology and medical genetics for further testing. Next generation sequencing revealed a TERC n.437 T>G (NR_001566.1) variant. Unfortunately, there was no tissue available for testing from the other affected family members as they had passed away from complications related to pulmonary fibrosis. This is the first report of this TERC variant in the literature. Reporting novel presentation of known TERC variants and/or novel TERC variants is important to help clinicians recognize and diagnose telomere biology disorders as this has important implications for the management of patients, their families, and future generations. Disclosures No relevant conflicts of interest to declare.