Rolles Benjamin, Tometten Mareike, Meyer Robert, Kirschner Martin, Beier Fabian, Brümmendorf Tim H
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Transfus Med Hemother. 2024 Jul 30;51(5):292-309. doi: 10.1159/000540109. eCollection 2024 Oct.
Telomeres are the end-capping structures of all eukaryotic chromosomes thereby protecting the genome from damage and degradation. During the aging process, telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis. Premature aging due to critically short telomere length (TL) can also result from pathogenic germline variants in the telomerase complex or related genes that typically counteract replicative telomere shortening in germline and certain somatic cell populations, e.g., hematopoetic stem cells. Inherited diseases that result in altered telomere maintenance are summarized under the term telomere biology disorder (TBD).
Since TL both reflects but more importantly restricts the replicative capacity of various human tissues, a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin). Consequently, altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis.
The recognition of a potential congenital origin in approximately 10% of adult patients with clinical BMF is of utmost importance for the proper diagnosis, appropriate patient and family counseling, to prevent the use of inefficient treatment and to avoid therapy-related toxicities including appropriate donor selection when patients have to undergo stem cell transplantation from related donors. This review summarizes the current state of knowledge about TBDs with particular focus on the clinical manifestation patterns in children (termed early onset TBD) compared to adults (late-onset TBD) including typical treatment- and disease course-related complications as well as their prognosis and adequate therapy. Thereby, it aims to raise awareness for a disease group that is currently still highly underdiagnosed particularly when it first manifests itself in adulthood.
端粒是所有真核生物染色体的末端帽状结构，从而保护基因组免受损伤和降解。在衰老过程中，端粒随着每次细胞分裂而持续缩短，直到极短的端粒阻止进一步增殖，此时细胞经历终末分化、衰老或凋亡。由于端粒酶复合物或相关基因中的致病种系变异，也可导致端粒长度（TL）极短而引起早衰，这些基因通常可抵消种系和某些体细胞群体（如造血干细胞）中复制性端粒缩短。导致端粒维持改变的遗传性疾病统称为端粒生物学障碍（TBD）。
由于TL既反映又更重要地限制了各种人体组织的复制能力，因此足够的端粒储备在具有高增殖活性的细胞（如造血、免疫细胞、肠道细胞、肝脏、肺和皮肤）中尤为重要。因此，在TBD中观察到的端粒维持改变通常会导致相应器官系统中过早的复制性细胞耗竭，最终导致危及生命的并发症，如骨髓衰竭（BMF）、肺纤维化和肝硬化。
认识到约10%临床诊断为BMF的成年患者可能存在先天性病因，对于正确诊断、为患者及其家属提供适当咨询、避免使用无效治疗以及避免治疗相关毒性（包括患者必须接受来自相关供体的干细胞移植时进行适当的供体选择）至关重要。本综述总结了关于TBD的当前知识状态，特别关注儿童（称为早发性TBD）与成人（晚发性TBD）的临床表现模式，包括典型的治疗和疾病过程相关并发症及其预后和适当治疗。因此，它旨在提高对一个目前仍诊断不足的疾病群体的认识，特别是当它首次在成年期表现出来时。
