Clinical and Genetic Heterogeneity of Telomere Diseases.
Authors: Townsley Danielle M. , Dumitriu Bogdan , Kajigaya Sachiko , Calado Rodrigo T. , Scheinberg Phillip , Young Neal S. 
Published: October 2019

Abstract
Abstract 2373
Genetic defects in telomerase genes are associated with a variety of clinical syndromes that includes marrow failure, cirrhosis and pulmonary fibrosis. Mutations in the RNA template (TERC) and the catalytic subunit (TERT) have been associated to adult onset aplastic anemia without the characteristic physical abnormalities observed in inherited forms of marrow failure where telomerase genes can be mutated. Clinical presentations can vary and a careful personal and family history often provides clues to an underlying telomeropathy. The implications for therapy are still evolving and the best strategy in approaching these patients not yet defined. At NHLBI we have systematically tested patients evaluated in our bone marrow failure clinic for telomere length and often for mutational analysis of telomerase genes, and have observed a range of phenotypes associated with telomere disorders. In this analysis we describe some of these phenotypes.
We reviewed the clinical data of all patients referred to the Hematology Branch bone marrow failure clinic since 2003, when we began routinely testing for telomere disorders. One hundred fourteen patients were diagnosed as having a telomere disease, either by the presence of a telomerase gene mutation and/or very short peripheral blood leukocyte' telomere lengths (below the first percentile as compared to age-matched controls). Sixty-seven mutations or gene variants were identified: 40% in TERT (46/114), 15% in TERC (17/114), 2 cases in DKC1, 1 case in TERF2 and 1 case in TINF2. Disease presentation varied: 42% (n=48) of patients had severe aplastic anemia (SAA) (including 2 hepatitis-associated SAA), 30% (n=34) were diagnosed with moderate aplastic anemia (MAA), 6% (n=7) had large granular lymphocytosis (LGL), and 11% (n=12) myelodysplasia (MDS). Eleven of 114 cases had liver disease and 10/114 cases had pulmonary fibrosis. Only 45/114 had family histories suggestive of a telomere disorder, such as a family member affected with a hematologic disorder, liver disease or pulmonary fibrosis. Hematologic disorders were reported in the vast majority (37/45) of cases who had a positive family history. A history of multiple malignancies within the family was not prominent in the cohort. In addition, 14/114 cases had paroxysmal nocturnal hemoglobinuria (PNH) clones. 8/114 cases had very small PNH clones (<5% of granulocytes) and only 5/14 had expanded PNH clones that were clinically significant (>30% of granulocytes).
In addition, we report treatment outcomes for patients in the cohort who received immunosuppression therapy (IST) with anti-thymocyte globulin, cyclophosphamide and/or alemtuzumab at our institution: 28/114 patients received immunosuppression for SAA, of whom 13 demonstrated a clinically meaningful hematologic response of which 5 later relapsed.
This data describes the various clinical presentations of telomeropathies in our clinic. Important points that can be inferred from our data set: 1) a family history need not be present in patients who present with an underlying genetic defect in telomerase genes suggesting that screening based on family history alone may not be adequate; 2) the presence of PNH or an LGL clone does not rule out the presence of an underlying telomeropathy; 3) the presence of a mutation in telomere genes and PNH or LGL clones suggests that an immune disarray may coexist with an underlying genetic defect in some cases; 4) hematologic recovery after immunosuppression in some mutants suggests that the genetic defect may not be the dominant pathogenic determinant in some cases and does not rule out the possibility of an immunomodulatory responsive disease.

Disclosures:
No relevant conflicts of interest to declare.