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Complications for a Hoyeraal-Hreidarsson Syndrome Patient with a Germline DKC1 A353V Variant Undergoing Unrelated Peripheral Blood Stem Cell Transplantation.

ABSTRACT: Hoyeraal-Hreidarsson syndrome (HHS), caused by several different germline mutations resulting in severe telomeropathy, presents with early-onset growth anomalies and neurologic/developmental disorders including characteristic cerebellar hypoplasia. Early mortalities may arise from immunodeficiency and bone marrow failure if not successfully salvaged by allogeneic hematopoietic stem cell transplantation (HSCT). Few reports have characterized the persistent somatic progression of HHS after successful HSCT. We present an HHS patient with an X-linked recessive DKC1 c.1058C > T; Ala353Val mutation who successfully underwent unrelated HSCT at 5 years of age. After months of early infections and organ toxicities immediately post-transplant, he had more than two years of excellent quality of life with correction of bone marrow failure and immunodeficiency. However, episodic massive variceal bleeding and progressive respiratory insufficiency, which were secondary to non-cirrhotic portal hypertension and pulmonary arteriovenous shunts, respectively, developed over 2 years after HSCT and resulted in his death from respiratory failure 4 years after HSCT. This outcome suggests that while HSCT can correct bone marrow failure and immunodeficiency, it may fail to prevent or even aggravate other fatal processes, such as portal hypertension and pulmonary arteriovenous shunting.

SUBMITTER: Chen RL

PROVIDER: S-EPMC6651050 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Complications for a Hoyeraal-Hreidarsson Syndrome Patient with a Germline <i>DKC1</i> A353V Variant Undergoing Unrelated Peripheral Blood Stem Cell Transplantation.

Chen Rong-Long RL Lin Kuanyin K KK Chen Liuh-Yow LY

International journal of molecular sciences 20190702 13

Hoyeraal-Hreidarsson syndrome (HHS), caused by several different germline mutations resulting in severe telomeropathy, presents with early-onset growth anomalies and neurologic/developmental disorders including characteristic cerebellar hypoplasia. Early mortalities may arise from immunodeficiency and bone marrow failure if not successfully salvaged by allogeneic hematopoietic stem cell transplantation (HSCT). Few reports have characterized the persistent somatic progression of HHS after success ...[more]

PMID: 31269755

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Project description:BackgroundEukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR) and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency.Methodology/principal findingsWe studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3' overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types.Conclusions/significanceAltogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease.

Dataset Information

Complications for a Hoyeraal-Hreidarsson Syndrome Patient with a Germline DKC1 A353V Variant Undergoing Unrelated Peripheral Blood Stem Cell Transplantation.

Publications

Complications for a Hoyeraal-Hreidarsson Syndrome Patient with a Germline <i>DKC1</i> A353V Variant Undergoing Unrelated Peripheral Blood Stem Cell Transplantation.

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