Telomeres protect the ends of chromosomes but shorten following cell division in the absence of telomerase activity. When telomeres become critically short or damaged, a DNA damage response is activated. Telomeres then become dysfunctional and trigger cellular senescence or death. Telomere shortening occurs with ageing and may contribute to associated maladies such as infertility, neurodegeneration, cancer, lung dysfunction and haematopoiesis disorders. Telomere dysfunction (sometimes without shortening) is associated with various diseases, known as telomere biology disorders (also known as telomeropathies). Telomere biology disorders include dyskeratosis congenita, Høyeraal-Hreidarsson syndrome, Coats plus syndrome and Revesz syndrome. Although mouse models have been invaluable in advancing telomere research, full recapitulation of human telomere-related diseases in mice has been challenging, owing to key differences between the species. In this Review, we discuss telomere protection, maintenance and damage. We highlight the differences between human and mouse telomere biology that may contribute to discrepancies between human diseases and mouse models. Finally, we discuss recent efforts to generate new 'humanized' mouse models to better model human telomere biology. A better understanding of the limitations of mouse telomere models will pave the road for more human-like models and further our understanding of telomere biology disorders, which will contribute towards the development of new therapies.

Dyskeratosis congenita (DC) is a rare telomerase disorder affecting high turnover cells. Malfunction of protective proteins in DC results in patient genomes with shortened germline telomeres leading to genetic instability, cellular apoptosis, and overall cellular lifespan degradation. Classically, reports of DC described a triad of dysplastic nails, reticular skin pigmentation, and oral leukoplakia. However, more recent reports have focused on disease presentation affecting other high turnover organ systems including the gastrointestinal system. Patients may present with dysphagia because of esophageal stricture/web, diarrhea secondary to enteropathy or enterocolitis. We present a pediatric patient who presented with feeding difficulty secondary to an esophageal stricture as the primary manifestation of DC. She was diagnosed with Revesz Syndrome, a rare subtype of DC, along with a novel genetic variant not previously reported. This report serves to bring awareness to gastroenterologists that DC, though classically thought to present with dermatological findings, can present with primary gastrointestinal manifestations. Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. A majority of individuals with DC/TBD have abnormally short telomeres for their age, as determined by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on lymphocyte subsets. To date, ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD and to result in very short telomeres. Pathogenic variants in one of these 16 genes have been identified in approximately 80% of individuals who meet clinical diagnostic criteria for DC/TBD. Treatment of manifestations: Treatment is tailored to the individual. Hematopoietic cell transplantation (HCT) is the only curative treatment for BMF and leukemia, but long-term outcome has historically been poor due to treatment toxicity; if a suitable donor is not available, androgen therapy may be considered for BMF. Treatment of other cancers is tailored to the type of cancer. Of note, cancer therapy may pose an increased risk for prolonged cytopenias as well as pulmonary and hepatic toxicity. Treatment of pulmonary fibrosis is primarily supportive, although lung transplantation may be considered. Surveillance: For BMF: complete blood count (CBC) annually if normal and more often if abnormal; annual bone marrow aspirate and biopsy. For those on androgen therapy: routine monitoring of CBC, liver function, liver ultrasound, and endocrinology evaluation. For cancer risk: monthly self-examination for oral, head, and neck cancer; annual cancer screening by an otolaryngologist and dermatologist; annual gynecologic examination. For pulmonary fibrosis: annual pulmonary function tests starting either at diagnosis or when the individual can perform the test (often age ~8 years); bubble echocardiogram to look for pulmonary arteriovenous malformations if suspected based on clinical symptoms. Routine dental screening every six months and good oral hygiene are recommended. Agents/circumstances to avoid: Blood donation by family members if HCT is being considered; non-leukodepleted and non-irradiated blood products; the combination of androgens and granulocyte colony-stimulating factor in treatment of BMF (has been associated with splenic rupture); toxic agents implicated in tumorigenesis (e.g., smoking, excessive sun exposure). Evaluation of relatives at risk: If a relative has signs or symptoms suggestive of DC/TBD or is being evaluated as a potential HCT donor, telomere length testing – or, if the pathogenic variant(s) in the family are known, molecular genetic testing – is warranted. The mode of inheritance of DC/TBD varies by gene: X-linked: DKC1. Autosomal dominant: NAF1, RPA1, TERC, TINF2, and ZCCHC8. Autosomal dominant or autosomal recessive: ACD, PARN, RTEL1, and TERT. Autosomal recessive: CTC1, NHP2, NOP10, POT1, STN1, and WRAP53. Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Once the DC/TBD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Dyskeratosis congenita (DC) is a multisystem syndrome characterized by mucocutaneous abnormalities, bone marrow failure, and predisposition to cancer. Studies over the last 25 years have led to the identification of 18 disease genes. These have a principal role in telomere maintenance, and patients usually have very short/abnormal telomeres. The advances have also led to the unification of DC with a number of other diseases, now collectively referred to as the telomeropathies or telomere biology disorders. Clinical features, genetics, and biology of the different subtypes. Expert view on diagnosis, treatment of the hematological complications and future. As these are very pleotropic disorders affecting multiple organs, a high index of suspicion is necessary to make the diagnosis. Telomere length measurement and genetic analysis of the disease genes have become useful diagnostic tools. Although hematological defects can respond to danazol/oxymetholone, the only current curative treatment for these is hematopoietic stem cell transplantation (HSCT) using fludarabine-based conditioning protocols. New therapies are needed where danazol/oxymetholone is ineffective and HSCT is not feasible.

Revesz syndrome is a rare telomeropathy characterized by bone marrow failure and exudative retinopathy. We report the case of a 2-year-old male child, initially treated with bilateral laser photocoagulation for retinopathy of prematurity. He developed exudative changes in the right eye, presumed to be Coats disease. Later, the left eye developed a total vitreous hemorrhage. Proliferative retinopathy was noted intraoperatively. Systemic features of bone marrow failure, growth retardation, and nail pigmentation were present. Genetic testing confirmed the diagnosis of Revesz syndrome. We describe our approach to diagnosis and surgical management of the case. [Ophthalmic Surg Lasers Imaging Retina 2022;53(6): 346-348.].

To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record. Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor. GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.