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Pulmonary complications post hematopoietic stem cell transplant in dyskeratosis congenita: analysis of oxidative stress in lung fibroblasts

Bone Marrow Transplantation volume 52, pages 765–768 (2017)Cite this article

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Dyskeratosis congenita (DC) is a congenital bone marrow failure (BMF) disorder characterized by abnormal skin pigmentation, nail dystrophy, oral leukoplakia and cancer predisposition.1 Tissue-specific pathologies arise in DC due to the presence of critically short telomeres, often in cells with higher replicative capacities. The most commonly mutated gene in DC is DKC1 encoding dyskerin, located on the long arm of the X-chromosome, and is generally considered to manifest a more severe phenotype.1 Pulmonary disease is common in DC and includes abnormal pulmonary vasculature or pulmonary fibrosis.1, 2 Pulmonary decline may present early in life, usually after the onset of BMF,3 or later in life with or without typical hematologic or mucocutaneous findings.4 The high incidence of pulmonary disease/complications post hematopoietic stem cell transplant (HSCT) in DC patients suggests an underlying predisposition to lung injury. Furthermore, HSCT-related morbidity may be related to an underlying sensitivity to cytotoxic agents due to aberrant cellular DNA damage repair and dysregulated reactive oxidative species.5 Reduced-intensity conditioning (RIC) HSCT preparative regimens have been employed with variable success.6, 7 Here we describe an adolescent DC patient with a history of respiratory disease, who underwent a RIC HSCT and subsequently developed fatal pulmonary complications. Collection of lung tissue post-mortem provided an opportunity to more fully characterize the molecular consequences of defective telomerase in a disease-specific target organ.

Our patient presented to the Hematology Service at 1 year of age for isolated macrocytic anemia. Within 3 years he developed mild thrombocytopenia with dyskeratotic nail changes. Gene testing revealed a pathogenic DKC1 mutation (A353V), and over the following 10 years he developed esophageal and urethral strictures, retinal hemorrhages and osteopenia. At 10 years of age, Danazol therapy was initiated for worsening pancytopenia, but was discontinued after 5 years with concerns of hepatic toxicity. HSCT referral was made due to imminent transfusion dependency. Pre-HSCT workup demonstrated a hypocellular marrow (5–10%) without myelodysplastic features. He had been followed by the Pulmonary Service since 8 years of age for asthma-like symptoms and was prescribed inhaled bronchodilators. Chest CT scan revealed pulmonary blebs. Pulmonary function testing (PFT), starting at 10 years of age, showed a progressive decline in diffusing capacity for carbon monoxide (DLCO), from 95–75% by age 17.

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Acknowledgements

This work was supported through the Children’s of Alabama Kaul Pediatric Research Institute.

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Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Pediatrics, University of Kentucky, Lexington, KY, USA

    C Sorge

  2. Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    L Pereboeva

  3. Division of Hematology-Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    E Westin & F Goldman

  4. Division of Pediatric Pulmonology and Sleep Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    W T Harris

  5. Department of Pathology and Laboratory Medicine, and Department of Pathology, Children's of Alabama, University of Alabama at Birmingham, Birmingham, AL, USA

    D R Kelly

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  1. C Sorge
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Correspondence to F Goldman.

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Sorge, C., Pereboeva, L., Westin, E. et al. Pulmonary complications post hematopoietic stem cell transplant in dyskeratosis congenita: analysis of oxidative stress in lung fibroblasts. Bone Marrow Transplant 52, 765–768 (2017). https://doi.org/10.1038/bmt.2016.353

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