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Dyskeratosis Congenita
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The first DC-associated gene, X-linked recessive DKC1, was discovered by linkage analysis in 1998. With the identification of mutations in DKC1, the first diagnostic tests became available. DKC1 (DKC gene 1 at Xq28) mutations are the most frequent, appearing in up to 40% of DC patients. The DKC1 gene encodes the nucleolar protein dyskerin, which is ubiquitously expressed, and this protein is involved in ribosomal RNA processing telomere maintenance. Over 50 mutations have been found in DKC1. DKC1 mutation has been associated with DC phenotypes as well as and its variants such as Hoyeraal−Hreidarsson syndrome (HHS) and idiopathic pulmonary fibrosis (IPF). DKC1 has been found to be a direct target of the c-MYC oncogene, strengthening the connection between DC and malignancy.
Genodermatoses affecting the nail
Published in Eckart Haneke, Histopathology of the NailOnychopathology, 2017
Dyskeratosis congenita (DC) of Zinsser-Cole-Engman (OMIM 305000) is an inherited bone marrow failure and cancer predisposition syndrome characterized by germline mutations in telomere biology. It can be inherited as an X-linked, autosomal dominant (AD) (on chromosome Xq28), or autosomal recessive (AR) type (OMIM 615190, 224239). De novo germline mutations are rather frequent in DC. About 70% of DC patients have an identifiable germline mutation.94 It is clinically heterogeneous and usually diagnosed by the mucocutaneous triad of progressively dystrophic nails, abnormal pigmentation, and leukoplakias of the oral mucosa, often associated with severe periodontitis. Hoyeraal–Hreidarsson syndrome (HH) is a clinically severe variant of DC also including cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation.95 The germline mutation is in one of nine genes, the products of which are all involved in telomere biology. DC is very rare with an annual incidence of <1 per million. Patients with DC show considerable disease diversity in terms of age at onset, symptoms, and severity. Even with the same gene mutation, the disease manifestations are variable making it sometimes difficult to reach a correct diagnosis.96 Due to the heredity pattern, females may have less severe clinical features.97 Approximately 90% of patients suffer from nail dystrophy affecting the fingernails first and then the toenails. It begins with ridging and longitudinal splitting and gradually progresses, resulting in small, rudimentary, or absent nails.
What is the future of telomere length testing in telomere biology disorders?
Published in Expert Review of Hematology, 2023
The first link between germline defects in telomere biology genes and human disease was made in 1999 when mutations in dyskerin (encoded by DKC1) resulting in very short telomeres were identified as the cause X-linked recessive dyskeratosis congenita (DC) [2,3]. DC, the prototypic TBD, is clinically diagnosed by the presence of the mucocutaneous triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia. Patients with DC are at very high risk of bone marrow failure (BMF), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), head and neck squamous cell carcinoma (SCC), anogenital SCC, pulmonary fibrosis, liver disease, and many other complications. Young children with Hoyeraal-Hreidarsson syndrome, Revesz syndrome, or Coats plus have features of DC and additional other complications. Some individuals may develop only one feature of DC in middle age, such as pulmonary fibrosis or aplastic anemia [4–6].
An update on the biology and management of dyskeratosis congenita and related telomere biology disorders
Published in Expert Review of Hematology, 2019
Marena R. Niewisch, Sharon A. Savage
The original description of two brothers with cerebellar hypoplasia and pancytopenia was published by Hoyeraal in 1970, followed by a case description of a boy with progressive pancytopenia, microcephaly, cerebellar hypoplasia, and growth retardation by Hreidarsson in 1988 [108,109]. The name Hoyeraal-Hreidarsson syndrome (HH) was subsequently proposed by the following fourth case report in 1995 [110] and the identification of DKC1 mutations [111] as well as short telomeres in HH patients connected it to the TBD spectrum. To date germline pathogenic variants causing HH have been identified in DKC1 [112], TERT [64], TERC [65], TINF2 [85,113], WRAP53 [71], RTEL1 [83], PARN [114], and ACD [73]. Most HH is due to XLR or AR inheritance, except for all patients with heterozygous TINF2 and one reported patient with heterozygous TERC [65]. HH typically presents in infancy with numerous complications including cerebellar hypoplasia, microcephaly, developmental delay, immunodeficiency, intrauterine growth retardation (IUGR), as well as progressive bone marrow failure. HH-related immunodeficiency may be non-specific and challenging to diagnose [80,112,115]. Due to the young age at onset, the DC-associated mucocutaneous triad might not be present at diagnosis of HH but often develops over time [69,116]. Other HH-associated clinical features may include nonspecific enteropathy and intracranial calcifications [117]. Cerebellar hypoplasia is considered a requirement to establish the diagnosis of HH in the setting of DC-related features.
Germ line predisposition to myeloid malignancies appearing in adulthood
Published in Expert Review of Hematology, 2018
Martina Crysandt, Kira Brings, Fabian Beier, Christian Thiede, Tim H Brümmendorf, Edgar Jost
TBD result from mutations in at least 10 genes and, depending on the affected gene, inheritance may be X-linked, autosomal recessive or autosomal dominant. X-linked inheritance pattern is linked to mutations found in the DKC1 gene located on the X-chromosome and responsible for proper telomerase function. DKC can also be inherited in an autosomal recessive way when mutations in NOP10, NPH2, PARN, TCAB1, or C16orf57 are the causative event [73]. Autosomal dominant forms of TBD are related to mutations in telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), TERF1 interacting nuclear factor 2 (TINF2), and regulator of telomere elongation helicase 1 (RTEL1) genes. Telomere length (TL) is routinely measured using the gold-standard technique flow-FISH and TL is reported in relation to the healthy population by using percentile calculation [74]. Telomeres below the 5–10th percentile should trigger additional genetic work up for known mutations [75]. The severity of the disease can be influenced by monoallelic or biallelic mutations of these genes. Mutations in TIN2 lead to very short telomeres with very early onset of DKC [76] and mutations in RTEL1 to Hoyeraal-Hreidarsson syndrome [68]. Patients with DKC have an approximately 200-fold increased risk of developing AML and variants of the TERT gene have been observed in about 8% of AML patients [77]. Chromosomal instability induced by telomere shortening is probably the mechanism responsible for the development of a myeloid disease [78], which may appear first in early adulthood. Treatment of AML with TBD is particularly challenging because of high toxicity of chemotherapy and poor response to treatment. Apart from experimental approaches using androgen treatment in subtypes of TBDs [69,79], the only way to obtain long-term remission is allogeneic hematopoietic stem cell transplantation. However, due to the systemic premature aging character of TBD, high organ toxicity is observed even when the conditioning regimen is fludarabine-based and alkylating agents are dose reduced [80,81]. Liver and lung function are often severely impaired during the course of transplantation and lung fibrosis is the major cause of death in TBD patients. The 10-year overall survival rate is only approx. 25% in TBD patients transplanted for AA [61,82]. In addition, other types of secondary cancer observed in TBD cannot be avoided and might be accelerated by immune suppression related to stem cell transplantation [61].