Clinical manifestations of telomere biology disorders in adults

Abstract

Telomere biology disorders (TBDs) are a spectrum of inherited bone marrow failure syndromes caused by impaired telomere function due to pathogenic germline variants in genes involved in telomere maintenance. TBDs can affect many organ systems and are often thought of as diseases of childhood. However, TBDs may present in mid- or even late adulthood with features similar to but not always the same as the childhood-onset TBDs. Adult-onset TBDs are often cryptic with isolated pulmonary, liver, or hematologic disease, or cancer, and may lack the classic disease-defining triad of abnormal skin pigmentation, nail dysplasia, and oral leukoplakia. Diagnostics include detection of very short leukocyte telomeres and germline genetic testing. Notably, adult-onset TBDs may show telomeres in the 1st to 10th percentile for age, and some cases may not have an identifiable genetic cause. TBD genetic etiology includes all modes of inheritance, with autosomal dominant the most frequent in adult-onset disease. Variable symptom onset due to incomplete penetrance, variable expressivity, and genetic anticipation add to the diagnostic challenges. Adult-onset TBDs are likely underrecognized, but their correct identification is of utmost importance, since affected patients are faced with numerous clinical complications, including but not limited to an increased risk of malignancies requiring close surveillance for early detection. Currently lung, liver, or hematopoietic cell transplants are the only curative therapeutic approaches but can be complicated by comorbidities, despite improved medical care. This review highlights the challenges of identifying adult-onset TBDs and addresses currently recommended clinical screening measures and therapy options.

Graphical abstract

Figure 1.

Clinical manifestations of telomere biology disorders in two adults. (A) Computed tomography scan (coronal plane) of a 35-year-old male with cryptogenic hepatic disease (case 1). Transjugular intrahepatic portosystemic shunt was set in place at the age of 21 years. Blue arrow indicates heterogenous liver parenchyma, green arrow transjugular intrahepatic portosystemic shunt, and red arrow splenomegaly. (B) Image of the hypocellular bone marrow biopsy of a 35-year-old TBD patient with severe cytopenia (case 1). (C) Pulmonary high-resolution computed tomography scan (axial plane) of a 54-year-old female with a TBD due to a heterozygous TERC mutation (case 2). Pulmonary bases bilaterally show peripheral interstitial and ground-glass opacities with early honeycombing. Findings are consistent with usual interstitial pneumonia pattern of pulmonary fibrosis. For all images written permission from patients was obtained. Figure 1C was previously published in Giri et al. 2019.

Figure 2.

When to consider telomere length measurements in adults. *Includes unexplained, persistent cytopenia, aplastic anemia. †Consider chromosome breakage testing to exclude Fanconi anemia. ‡Includes liver cirrhosis, fibrosis, hepatopulmonary syndrome, idiopathic portal hypertension. ^§Mucocutaneous triad consisting of leukoplakia, reticular skin pigmentation, and nail dysplasia. FH, family history; HPV, human papilloma virus.

Figure 3.

Genetic etiology of telomere biology disorders: genes and associated inheritance patterns primarily to consider in adults. Depicted are typical age groups for clinical manifestations of each gene and associated inheritance pattern. Yellow shade indicates AD, green AR, and blue X-linked disease. Genes in bold are more frequently reported. For all genes, de novo occurrence is possible but most frequently reported for TINF2 and DKC1. *De novo TINF2 is associated with a severe phenotype and onset in childhood. †The combination of germline variants in TYMS and ENOSF1 appear to follow an AR inheritance but are the result of digenic inheritance. There are some pathogenic gene variations in combination with specific inheritance patterns that are to date solely reported in children and therefore not depicted. These include the following genes with the associated inheritance pattern in brackets: POT1 (AR), STN1 (AR), CTC1 (AR), DCLRE1B (AR).

Figure 4.

Telomere lengths in cases 1 and 2. Depicted are lymphocyte telomere length by fluorescent in situ hybridization and flow cytometry (flow FISH) of 3 patients with TERC-associated TBD. The green circle shows lymphocyte telomere length of a 36-year-old male with liver disease and bone marrow failure (case 1). Yellow diamonds indicate 2 lymphocyte TL taken over time in a female patient with pulmonary fibrosis and bone marrow failure (case 2). Orange circles show lymphocyte TL of the child of patient 2 who presented with thrombocytopenia and dysplastic fingernails and was found to carry the same TERC variant as their mother.