LAUSR

Dyskeratosis congenita and related telomere biology disorders (DC/TBDs) are multisystem illnesses caused by germline pathogenic variants (PV) in telomere biology genes resulting in very short telomeres. The inheritance varies and includes autosomal dominant (AD), autosomal recessive (AR) and X-linked (XLR) disease. Young patients may present with bone marrow failure (BMF) and the mucocutaneous triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia, whereas adults may be identified with isolated BMF, pulmonary fibrosis (PF), or liver disease. In addition to BMF, DC/TBDs are associated with high risk of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), head and neck squamous cell cancer (HNSCC) and many other medical problems. Hematopoietic cell transplant (HCT), lung, and/or liver transplantation may be required. A limited number of genotype-phenotype studies suggest the mode of inheritance to be associated with phenotypes. We studied 229 individuals (144 males, 85 females) with DC/TBDs enrolled in an IRB-approved longitudinal cohort study of inherited BMF syndromes (NCT00027274) between 01/2002 and 05/2019. Questionnaires and medical records were reviewed and a subset of 93 patients (40.6%) was systematically evaluated at the NIH Clinical Center (CC) during a 5-day visit. The median age at diagnosis for the entire cohort was 23.4 (0-82.2) years and median follow-up time was 4.2 (0-36.2) years. The PV was identified in 180 (78.6%) patients: 98 had AD disease (TERT, TERC, RTEL1, ACD, or PARN), 58 had XLR or AR (TERT, RTEL1, ACD, WRAP53, PARN, or DKC1) and 24 TINF2 (AD or de novo). In the entire cohort of 229 patients, 69 (30.1%) required HCT for BMF [median age 14.9 (0.9-63.1) years] and 58% of these had AR/XLR or TINF2-associated disease. Eight patients received lung transplant for PF [median age 51.4 (13.1-62.4) years]. Liver transplant was required in 5 patients [median age 25.8 (9.9-56.7) years]. Twenty-seven non-HCT patients developed cancer [median age of 42.1 (18.2-67.5) years]. In 5 patients, cancer occurred after HCT [median time since HCT=4.6 (1.8-14.6) years] and 3 developed post-HCT lymphoproliferative disease. Ninety-three patients were systematically phenotyped at the CC; 52 (55.9%) had >=1 triad feature and 33 (35.5%) had severe BMF. Three non-HCT patients had a history of cancer. PF was present in 6 patients and 3 had severe liver disease (portal hypertension and/or liver cirrhosis/fibrosis). Esophageal strictures were present in 7 and 5 had hip avascular necrosis (AVN, non-HCT). Median follow-up time after CC visit was 7.1 (0-17.1) years with median age at last follow-up of 29.6 (2.2-79.5) years . During follow-up, 9 patients progressed to severe BMF, and 8 developed cancer (4 post-HCT). Ten developed PF (5 post-HCT), and 9 advanced to pulmonary arteriovenous malformations (8 post-HCT). Eight patients progressed to severe liver disease (7 post-HCT). Gastrointestinal telangiectasias were seen in 6 individuals. Four patients developed esophageal stricture and 10 AVN (7 after radiotherapy and/or HCT). At last follow up of the entire cohort, 92 (40.2%) of 229 patients were deceased. The main causes of death were lung disease (28.3%), treatment-related complications (19.6%), cancer (16.3%), or BMF (14.1%). The median overall survival was 54.2 years [95% confidence interval (CI) 47.3-59.8] and HCT-free median survival was 46.9 years (95% CI 37.9-54.2). Overall survival was significantly better in patients with AD versus XLR/AR or TINF2 disease (p<0.0001, log-rank test, median survival 66.5 versus 33.2 years, respectively). Our study systematically quantified the presence and progression of DC/TBDs clinical manifestations and illustrates the significant morbidity faced by patients with these multisystem disorders. Long term survival is poor overall, but significantly better in patients with AD disease compared with other inheritance patterns. Although HCT has improved outcomes related to BMF, this study illustrates the pressing need to develop therapies for patients with DC/TBDs. These data also form the foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines, risk stratification, and possibly treatment decisions in patients with DC/TBDs. No relevant conflicts of interest to declare.