Short Telomere Syndromes Research Articles

Hepatopulmonary Syndrome Is a Frequent Cause of Dyspnea in the Short Telomere Disorders

Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease. Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita. Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed. This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.

Lung fibrosis, bone marrow fibrosis and liver cirrhosis: A Short Telomere Syndrome or a casual association?

Background: Telomere-mediated disease has diverse presentations that span the age spectrum. Their type, age of onset, and severity depend on the extent of the telomere length defect. During adult life, telomerase mutations may represent risk factors rather than genetic determinants and need other factors to contribute to disease development. This is case of diseases such as aplastic anemia, pulmonary fibrosis and liver cirrhosis which may occur as single disease or together in a syndromic clustering. Here we report a case of a man most likely affected by a short telomere syndrome. Case report: A 58 years old man, presented for evaluation of pulmonary fibrosis diagnosed few years earlier in a different medical center. He also presented a mild bone marrow fibrosis and a liver cirrhosis, both diagnosed one year prior evaluation with a bone marrow analysis and liver biopsy. The patient was an active smoker, obese, with digital clubbing and inspiratory Velcro crackles at the right lower lobe. Laboratory tests showed thrombocytopenia and liver enzymes alteration. He rapidly developed ascites and progression of the pulmonary fibrosis, the patient became oxygen-dependent in few months. Methods: Sequencing and mutation analysis of hTERT and hTERC genes, Leukocyte Telomere length (LTL) and Telomerase activity (TA) were evaluated. Results: In our patient LTL was shorter and TA reduced compared to the controls. Genes sequencing did not show any hTERT and hTERC mutations. Conclusions: This is a report on a short telomere syndrome involving lung, liver and bone marrow, associated to very short telomere and absent telomerase activity not in the setting of dyskeratosis congenita.The fact that short telomeres mediate inflammation and fibrosis provides a rationale for pursuing translational strategies aimed at preventing telomere shortening or its cellular consequences as a therapeutic approach.