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Dyskeratosis Congenita
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
In addition to the associated features of DC, patients with Revesz syndrome (RS) are defined on the presence of bilateral exudative retinopathy, often in association with intracranial calcification and IUGR. Mutation in TINF2 is the most common identified genetic cause of this syndrome.
Haematology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
TINF2, the second most commonly mutated gene in DC encodes TINF2, a member of the telomereassociated shelterin complex, which plays integral roles in the structure and function of telomeres. TINF2 mutations are usually associated with extremely short telomeres, earlier onset of disease and bone marrow failure that usually occurs prior to manifestation of any signs of the classic triad of DC (Fig. 11.36). All reported mutations are heterozygous and most arise de novo. Retinal abnormalities are seen in about 20% of patients with DC (Figs 11.37, 11.38). In Revesz syndrome (Mendelian Inheritance in Man #268130), a severe DC variant caused by TINF2 mutations, bilateral exudative retinopathy is a defining feature along with intrauterine growth retardation, intracranial calcification and cerebellar hypoplasia.
Reticular hyperpigmentation
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Alexander C. Katoulis, Efthymia Soura
DKC is characterized by a wide variety of symptoms. Typical features of the disorder include the triad of reticulated hyperpigmentation, nail dystrophy, and leukoplakia, usually accompanied by bone marrow failure.71 In addition to these, a number of other manifestations might be present. These include teeth abnormalities (malformation, aberrant spacing, or extensive caries), continuous lacrimation (due to lacrimal duct atresia), increased risk for hematological malignancies (myelodysplasia, acute myelogenous leukemia, and Hodgkin’s lymphoma), immunological deficiencies, developmental delay, testicular atrophy, liver cirrhosis, pulmonary fibrosis, and an increased risk for a variety of carcinomas (including squamous cell carcinomas of the oral cavity, anus, cervix, vagina, esophagus, and skin and gastrointestinal carcinomas).71 A subtype of DKC, Revesz syndrome, has been additionally associated with neurological manifestations, such as intracranial calcifications, exudative retinopathy, and progressive neurological deterioration. Bone marrow failure is considered a very common feature of DKC, affecting the majority of patients and occurring during the second or third decade of life.71 In order for a diagnosis to be made, two of the four major features of the mucocutaneous triad and bone marrow failure and two or more of the other somatic symptoms should be present. Early diagnosis of the condition is extremely important since the prognosis is grave, with most patients dying (on average) by the age of 16 due to bone marrow failure, malignancy, pulmonary complications, or opportunistic infections.71
The biology and management of dyskeratosis congenita and related disorders of telomeres
Published in Expert Review of Hematology, 2022
Hemanth Tummala, Amanda Walne, Inderjeet Dokal
In some patients with clinical features of DC, HH, AA, and Revesz syndrome (RS), heterozygous TINF2 variants have been identified [19,20]. This discovery extended the spectrum of diseases even further. RS is characterized by bilateral exudative retinopathy, nail dystrophy, BM failure, fine hair, cerebellar hypoplasia, and growth restriction [21]. Patients with TINF2 variants frequently have severe disease associated with very short telomeres. A significant number of the variants affect amino acids 280–292 of TIN2. It is notable that in TINF2 families, the majority of patients have de novo variants. This is a very different situation to families with TERT and TERC variants, where affected individuals in the first generation usually have minimal or no clinical features and those in succeeding generations have more severe disease. It has been noted that patients in the second and third generations usually have shorter telomeres compared to the first generation. This phenomenon of genetic anticipation adds complexity to making prognostic predictions [22,23].
Ophthalmic findings and a novel CTC1 gene mutation in coats plus syndrome: a case report
Published in Ophthalmic Genetics, 2021
Tingyi Liang, Xiang Zhang, Yu Xu, Peiquan Zhao
We reported here the ophthalmic findings in a patient with Coats plus syndrome. The patient showed notable retinal vasculopathy, and was initially diagnosed as FEVR due to extensive peripheral avascularity, abnormal vascular anastomosis and retinal neovascularization in both eyes. Then the development of vitreous hemorrhage and TRD were also consistent with FEVR. However, the subsequent systemic manifestations and genetic testing results ultimately led to a diagnosis of Coats plus syndrome. The phenotype of the patient can be considered a Coats-like disease, which is presented with typical retinal telangiectatic vessels and exudation like those seen in Coats disease; however, the patient is not marked by severe exudative retinopathy but by the presence of retinal neovascularization and hemorrhagic disease, which is not consistent with the nature history of Coats disease. Similar disease phenotype is also seen in some syndromes, such as Revesz syndrome, dyskeratosis congenita and facioscapulohumeral dystrophy (10–12). The overlapping phenotype indicated that these syndromes may share similar pathogenic basis of telomere dysfunction, while the exact pathogenesis remains unclear.
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
Telomeres are localized at the end of eukaryotic chromosomes and protect the integrity of the genome. Telomeres both reflect and limit the replicative potential of normal somatic cells and consequently, undergo accelerated and replication-dependent shortening in disease states with increased stem cell turnover (reviewed in [63]. Inherited bone marrow failure syndromes are frequently related to TBD and cause a predisposition not only for AA [64,65] but also for the development of MDS and AML [66]. DKC is a paradigmatic disease to study telomere maintenance disorders characterized by very high risk for the development of AA and/or a malignant hematological disorder and/or solid tumor in childhood or at young adult age. Additionally, patients present nail dystrophy, abnormal reticular skin pigmentation and oral leukoplakia [67]. In contrast to typical DKC, Hoyeraal-Hreidarsson or Revesz syndrome represent very severe forms of DKC with growth retardation, immunodeficiency, and cerebellar hypoplasia [68] leading to death in early childhood. In recent years, growing evidence from registries such as the Aachen Telomeropathy Registry (ATR) suggests that especially adult TBD patients showing oligo/mono-symptomatic and/or atypical clinical presentation are frequently underdiagnosed [69]. These late-onset adult (cryptic) DKC patients suffer from isolated AA without typical DKC stigmata, isolated lung fibrosis, emphysema, and/or liver cirrhosis [70,71] and are at substantially increased risk of developing solid tumors such as squamous head and neck cancer, particularly oral cavity cancers (Table 5) [72].