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An Update on the Biology and Management of Dyskeratosis Congenita and Related Telomere Biology Disorders

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An Update on the Biology and Management of Dyskeratosis Congenita and Related Telomere Biology Disorders Expert Review of Hematology ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: https://www.tandfonline.com/loi/ierr20 An update on the biology and management of dyskeratosis congenita and related telomere biology disorders Marena R. Niewisch & Sharon A. Savage To cite this article: Marena R. Niewisch & Sharon A. Savage (2019) An update on the biology and management of dyskeratosis congenita and related telomere biology disorders, Expert Review of Hematology, 12:12, 1037-1052, DOI: 10.1080/17474086.2019.1662720 To link to this article: https://doi.org/10.1080/17474086.2019.1662720 Accepted author version posted online: 03 Sep 2019. Published online: 10 Sep 2019. Submit your article to this journal Article views: 146 View related articles View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ierr20 EXPERT REVIEW OF HEMATOLOGY 2019, VOL. 12, NO. 12, 1037–1052 https://doi.org/10.1080/17474086.2019.1662720 REVIEW An update on the biology and management of dyskeratosis congenita and related telomere biology disorders Marena R. Niewisch and Sharon A. Savage Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA ABSTRACT ARTICLE HISTORY Introduction: Telomere biology disorders (TBDs) encompass a group of illnesses caused by germline Received 14 June 2019 mutations in genes regulating telomere maintenance, resulting in very short telomeres. Possible TBD Accepted 29 August 2019 manifestations range from complex multisystem disorders with onset in childhood such as dyskeratosis KEYWORDS congenita (DC), Hoyeraal-Hreidarsson syndrome, Revesz syndrome and Coats plus to adults presenting Telomere; dyskeratosis with one or two DC-related features. congenita; telomere biology Areas covered: The discovery of multiple genetic causes and inheritance patterns has led to the disorder; pulmonary fibrosis; recognition of a spectrum of clinical features affecting multiple organ systems. Patients with DC and Revesz syndrome; associated TBDs are at high risk of bone marrow failure, cancer, liver and pulmonary disease. Recently, Hoyeraal-Hreidarsson vascular diseases, including pulmonary arteriovenous malformations and gastrointestinal telangiecta- syndrome; Coats plus; bone sias, have been recognized as additional manifestations. Diagnostics include detection of very short marrow failure; cancer leukocyte telomeres and germline genetic testing. Hematopoietic cell transplantation and lung trans- plantation are the only current therapeutic modalities but are complicated by numerous comorbidities. This review summarizes the pathophysiology underlying TBDs, associated clinical features, manage- ment recommendations and therapeutic options. Expert opinion: Understanding TBDs as complex, multisystem disorders with a heterogenous genetic background and diverse phenotypes, highlights the importance of clinical surveillance and the urgent need to develop new therapeutic strategies to improve health outcomes. 1. Introduction within the same family. Patients with DC are at very high risk of bone marrow failure, cancer, pulmonary fibrosis, liver dis- Dyskeratosis congenita (DC) was first described by Zinsser in ease, and other medical problems. The exact prevalence of DC 1906 in a case report of two brothers presenting with leuko- in the general population is unknown but it is generally plakia, abnormal skin pigmentation, nail dystrophy [1]. estimated at about one in a million [10] with approximately Subsequent detailed case reports by Engman in 1926 [2] and 900–1000 cases published, to date [11–19]. Cole in 1930 [3] led to its designation Zinsser-Engman-Cole This group of DC-related illnesses has been termed in the syndrome. The X-linked gene, dyskerin (DKC1), was discovered literature as telomeropathies, short telomere syndromes, in affected males in 1998 [4] and mutations were shown to impaired telomere maintenance spectrum disorders, and telo- result in decreased telomerase activity and short telomeres, mere biology disorders (TBDs). We favor the TBD designation establishing the connection between telomere biology and because it reflects the underlying biology that unites these human disease [5]. disorders [6,20–22]. Over the last two decades, advances in genomics and an increased understanding of telomeres in disease have led to the discovery of pathogenic germline genetic variants in at 2. Telomeres and telomere biology disorders least fourteen different telomere biology genes [6–9] asso- 2.1. Telomere biology ciated with DC and related disorders. This has led to a growing appreciation of variable genetic penetrance and Telomeres are specialized nucleoprotein structures at the expressivity as well as recognition of a broad DC-related phe- ends of eukaryotic chromosomes that protect chromosome notypic spectrum (Table 1). The classical phenotype consists of ends and are essential for maintaining genome stability. the mucocutaneous triad of dysplastic finger and toenails, oral They consist of double-stranded TTAGGG nucleotide repeats leukoplakia, and lacy, reticular skin pigmentation (Figure 1). and a six-protein complex called shelterin [23]. Human tel- Some patients present in early childhood with complex multi- omerelengthsrangefromtwoto14kilobases[24]andvary system illnesses (e.g. Hoyeraal-Hreidarsson syndrome, Revesz depending on cell type, age, inheritance, ancestry, and syndrome, or Coats plus) whereas others present later in life measurement method [24–27]. The addition of nucleotide with fewer medical problems. This variability occurs even repeats to telomeric ends is accomplished by the CONTACT Sharon A. Savage [email protected] Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr., Rm. 6E456, MSC 9772, Bethesda, MD 20859-9772, USA © 2019 Informa UK Limited, trading as Taylor & Francis Group 1038 M.R.NIEWISCHANDS.A.SAVAGE telomerase holoenzyme complex consisting of telomerase Article highlights reverse transcriptase (encoded by TERT), its RNA component TERC (also known as hTR, encoded by TERC), dyskerin ● Dyskeratosis congenita (DC) and related telomere biology disorders (TBDs) are caused by germline mutations in telomere biology genes (encoded by DKC1), NOP10, NHP2, NAF1 and GAR1 [28]. resulting in very short telomeres. Telomere structure poses two main challenges related to ● The phenotypic spectrum affects all organ systems ranging from DNA repair and replication: 1) they may be recognized by DNA classic DC, Hoyeraal-Hreidarsson syndrome, Revesz syndrome and Coats plus to apparently isolated aplastic anemia, pulmonary fibrosis damage repair machinery as double-stranded DNA breaks, or liver disease. and 2) the ‘end replication problem’ that results in ongoing ● Better understanding of the genetic etiology has led to the recogni- telomere nucleotide repeat loss due to semiconservative repli- tion of additional TBD-related manifestations such as vascular disease and structural brain abnormalities. cation of DNA ends during DNA replication. ● Patients with TBDs are at high risk of bone marrow failure, pulmonary The DNA damage response (DDR) could lead to recognition of disease, liver disease, and cancer. telomere ends as double-strand DNA breaks, resulting in check- ● To date, there are no curative therapeutic approaches other than hematopoietic cell transplantation for TBD-related bone marrow point activation, degradation and initiation of inadequate repair. failure. Telomeres are protected from DDR, in part, by their T-loop ● The complex medical problems in patients with TBDs require close structure. Telomeres contain both a C-rich lagging strand and clinical surveillance and highlight the need for new therapeutic approaches. a G-rich leading strand, which contains a 3ʹoverhang consisting of single-stranded nucleotide repeats. The G-strand overhang This box summarizes key points contained in the article. forms a lariat-like structure through invasion of the terminal single stranded 3ʹ overhang into the proximal double stranded telomeric region, forming the so-called T-loop and displacing the Table 1. Germline genetics of telomere biology disorders. Protein complex/ Functional consequence of disease- Mode of Gene (protein product names) function associated mutation TBD subtype inheritancea DKC1 (DKC1, dyskerin) Telomerase enzyme complex/ Reduced TERC stability and telomerase DC, HH, PF Female carriers XLR telomerase assembly, TERC activity may have subtle findings stability TERC (hTR, human telomerase RNA Telomerase enzyme complex/ Reduction of telomerase activity DC, AA, PF, LD, MDS, AML, AD component) telomere elongation HH TERT (TERT, telomerase reverse Telomerase enzyme complex/ Reduction telomerase recruitment, DC, AA, PF, LD, MDS, AML AD transcriptase) telomere elongation/telomerase processivity and/or activity HH AR recruitment NOP 10 (NOP10, NOLA3, NOLA Telomerase enzyme complex/ Reduced TERC stability and telomerase DC AR nuclear protein family A, telomerase assembly, TERC activity member 3) stability NHP2 (NHP2, NOLA2, nucleolar Telomerase enzyme complex/ Reduced TERC stability and telomerase DC AR protein family A, member 2) telomerase assembly, TERC activity stability NAF1 (NAF1, nuclear assembly Telomerase enzyme complex/ Reduced TERC stability and telomerase PF, LD, MDS AD factor 1 ribonucleoprotein) telomerase assembly, TERC activity
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