Late-onset telomere biology disorders in adults: clinical insights and treatment outcomes from a retrospective registry cohort

Pathogenic germ line variants affecting proper telomere maintenance result in premature telomere shortening and cause telomere biology disorders (TBDs). Although classical dyskeratosis congenita in children is rather well defined, late-onset ("cryptic") TBDs remain underrecognized, resulting in underdiagnosis and inadequate treatment in affected adults. Here, we present a series of adult TBD cases collected through the German TBD reference center between 2014 and 2024. Patients aged ≥18 years with an age-matched telomere length (TL) <10th percentile in lymphocytes, a detection of either a variant of uncertain significance, a pathogenic, or a likely pathogenic variant in TBD-associated genes, and available clinical data were included in this analysis. Based on this, a novel point-based algorithm for categorization into proven, probable, and suspected-only TBD cases was developed. Of 1537 TL analyses, 42 patients with proven (n = 29) or probable (n = 13) TBD were identified. The median age at first clinical manifestation and at diagnosis was 20.0 and 34.1 years, respectively. Bone marrow failure (BMF) was the most frequent manifestation observed in our cohort (73.8%), followed by liver or interstitial lung diseases (50.0% and 41.5%, respectively). Immunosuppressive therapy was administered in 6 patients with BMF, but none of them responded. In comparison, 8 of 8 evaluable patients treated with androgen derivatives showed hematologic response. Our data provide novel real-world insights into the clinical manifestation spectrum, diagnosis, clinical course, and treatment of TBD in adult, late-onset cases of this hereditary disease.

Authors

Institutions

Publication Details

Journal
Blood Advances
Published
2025-02-12
DOI
https://doi.org/10.1182/bloodadvances.2024014632
Citations
7
Primary Topic
Telomeres, Telomerase, and Senescence
Type
article
Field-Weighted Citation Impact
8.15
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Late-onset telomere biology disorders in adults: clinical insights and treatment outcomes from a retrospective registry cohort

Martin Kirschner, Steffen Koschmieder, Michael Kreuter, Jens Panse et al.
7 citations
Blood Advances
Telomeres, Telomerase, and Senescence
8.15
article

Late-onset telomere biology disorders in adults: clinical insights and treatment outcomes from a retrospective registry cohort

Martin Kirschner, Steffen Koschmieder, Michael Kreuter, Jens Panse, Ingo Kurth, Marcin W. Włodarski, Markus P. Radsak, Miriam Elbracht, Jörg Chromik, Stefan Balabanov, Tim H. Brümmendorf, Kim Kricheldorf, Alexander Röth, Michael Heuser, Philippe Schafhausen, Fabian Beier, Britta Höchsmann, Margherita Vieri, Mareike Tometten, Selim Corbacioglu, Uwe Platzbecker, Jeanette Walter, Claas Hinze, Robert Meyer, Yannic Schumacher
article en
7 citations

Abstract

Pathogenic germ line variants affecting proper telomere maintenance result in premature telomere shortening and cause telomere biology disorders (TBDs). Although classical dyskeratosis congenita in children is rather well defined, late-onset ("cryptic") TBDs remain underrecognized, resulting in underdiagnosis and inadequate treatment in affected adults. Here, we present a series of adult TBD cases collected through the German TBD reference center between 2014 and 2024. Patients aged ≥18 years with an age-matched telomere length (TL) <10th percentile in lymphocytes, a detection of either a variant of uncertain significance, a pathogenic, or a likely pathogenic variant in TBD-associated genes, and available clinical data were included in this analysis. Based on this, a novel point-based algorithm for categorization into proven, probable, and suspected-only TBD cases was developed. Of 1537 TL analyses, 42 patients with proven (n = 29) or probable (n = 13) TBD were identified. The median age at first clinical manifestation and at diagnosis was 20.0 and 34.1 years, respectively. Bone marrow failure (BMF) was the most frequent manifestation observed in our cohort (73.8%), followed by liver or interstitial lung diseases (50.0% and 41.5%, respectively). Immunosuppressive therapy was administered in 6 patients with BMF, but none of them responded. In comparison, 8 of 8 evaluable patients treated with androgen derivatives showed hematologic response. Our data provide novel real-world insights into the clinical manifestation spectrum, diagnosis, clinical course, and treatment of TBD in adult, late-onset cases of this hereditary disease.

Blood AdvancesVol. 9(9)
Goethe University Frankfurt (DE), St. Jude Children's Research Hospital (US), Universität Hamburg (DE), Universität Ulm (DE), Johannes Gutenberg University Mainz (DE), German Red Cross (DE), University Hospital Regensburg (DE), Medizinische Hochschule Hannover (DE), University Medical Center of the Johannes Gutenberg University Mainz (DE), Integrated Oncology (United States) (US), University Hospital of Zurich (CH), University Hospital Münster (DE), University Medical Center Hamburg-Eppendorf (DE), Essen University Hospital (DE), Universitätsklinikum Aachen (DE), University Hospital Leipzig (DE), Immungenetics (Germany) (DE), University Hospital Frankfurt (DE), University Hospital Ulm (DE), Technische Hochschule Ulm (DE), University of Duisburg-Essen (DE), Martin Luther University Halle-Wittenberg (DE), RWTH Aachen University (DE)
Good health and well-being
Openalex Percentile: Top 3%
Telomeres, Telomerase, and Senescence
8.15
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.