ALBERT

Description: Mutations in the essential telomerase components hTERT and hTR cause dyskeratosis congenita, a bone marrow failure syndrome characterized by mucocutaneous features. Some (∼ 3%) sporadic aplastic anemia (AA) and idiopathic pulmonary fibrosis cases also carry mutations in hTERT and hTR. Even though it can affect clinical outcome, because the mutation frequency is rare, genetic testing is not standard. We examined whether the cooccurrence of bone marrow failure and pulmonary fibrosis in the same individual or family enriches for the presence of a telomerase mutation. Ten consecutive individuals with a total of 36 family members who fulfilled these criteria carried a germline mutant telomerase gene (100%). The mean age of onset for individuals with AA was significantly younger than that for those with pulmonary fibrosis (14 vs 51; P 〈 .0001). Families displayed autosomal dominant inheritance and there was an evolving pattern of genetic anticipation, with the older generation primarily affected by pulmonary fibrosis and successive generations by bone marrow failure. The cooccurrence of AA and pulmonary fibrosis in a single patient or family is highly predictive for the presence of a germline telomerase defect. This diagnosis affects the choice of bone marrow transplantation preparative regimen and can prevent morbidity.

Description: Short telomeres have been linked to cancer risk, yet other evidence supports them being tumor suppressive. Here, we report cancer outcomes in individuals with germline mutations in telomerase and other telomere-maintenance genes. Among 180 individuals evaluated in a hospital-based setting, 12.8% had cancer. Solid tumors were rare (2.8%); nearly all were young male DKC1 mutation carriers, and they were generally resectable with good short-term outcomes. Myelodysplastic syndrome (MDS) was most common, followed by acute myeloid leukemia (AML); they accounted for 75% of cancers. Age over 50 years was the biggest risk factor, and MDS/AML usually manifested with marrow hypoplasia and monosomy 7, but the somatic mutation landscape was indistinct from unselected patients. One- and 2-year survival were 61% and 39%, respectively, and two-thirds of MDS/AML patients died of pulmonary fibrosis and/or hepatopulmonary syndrome. In one-half of the cases, MDS/AML patients showed a recurrent peripheral blood pattern of acquired, granulocyte-specific telomere shortening. This attrition was absent in age-matched mutation carriers who did not have MDS/AML. We tested whether adult short telomere patients without MDS/AML also had evidence of clonal hematopoiesis of indeterminate potential–related mutations and found that 30% were affected. These patients also primarily suffered morbidity from pulmonary fibrosis during follow-up. Our data show that the Mendelian short telomere syndromes are associated with a relatively narrow cancer spectrum, primarily MDS and AML. They suggest that short telomere length is sufficient to drive premature age-related clonal hematopoiesis in these inherited disorders.

Description: Abnormally short telomeres give rise to a group of premature aging, cancer-prone disorders known as the telomere syndromes. They are caused by germline mutations in telomerase and telomere genes. Although bone marrow failure was one of the first complications to be described in dyskeratosis congenita, there is increasing appreciation that this classic presentation is rare. Extra-hematopoietic telomere-mediated disease is frequently the first and predominant presentation in adults and leads to significant morbidity and mortality in patients with bone marrow failure (BMF), especially after bone marrow transplantation. It shows stereotypic manifestations that are age-dependent. Enterocolitis can precede the onset of BMF in infants with Hoyeraal-Hreidarsson syndrome, and it represents an intestinal epithelial defect that progresses in the setting of immunodeficiency. In adults with familial lung disease, idiopathic pulmonary fibrosis and emphysema are the predominant manifestations. These patients show variable degrees of BMF and are at risk for clonal abnormalities. In the lung transplant setting, adult telomere syndrome patients have an increased risk of complications due to immunosuppressive medications which challenge their reserves in the bone marrow, intestinal tract and elsewhere. Liver disease, often manifesting as hepatopulmonary syndrome, causes organ failure in approximately 10% of cases. The molecular mechanisms underlying telomere-mediated disease outside the bone marrow likely involve stem cell failure. For example, in the lung, alveolar stem cell senescence is sufficient to drive remodeling, inflammation, and susceptibility to injury, which are hallmark features of pulmonary fibrosis and emphysema. The stem cell failure mechanism has implications for approaching treatment in these lung disorders which have heretofore been considered mediated by inflammation. This session will present evolving scientific evidence that sheds light on the mechanisms and natural history of telomere syndromes. Considerations in the diagnostic work-up of suspected cases and the implications for patient care will be reviewed. Disclosures No relevant conflicts of interest to declare.