https://orcid.org/0000-0002-4556-6353
Key Points
Clinical manifestation patterns of TBDs in adults differ significantly from children and adolescents.
TBDs are still severely underdiagnosed in adults, and proper diagnosis is often substantially delayed following first clinical manifestation
Pathogenic germline variants affecting proper telomere maintenance result in premature telomere shortening and cause telomere biology disorders (TBDs). While 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 ≥18 years with an age-matched telomere length (TL) < 10th percentile in lymphocytes and 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. On this basis, a novel point-based algorithm for categorization into proven, probable and suspected-only TBD cases, respectively, was developed. Out of a total of 1,537 TL analyses, 42 patients with proven (n=29) or probable (n=13) TBD were identified. Median age at first clinical manifestation and at diagnosis was 20.0 years 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 carried out in six patients with BMF, none of them responded. In comparison, eight of eight evaluable patients treated with androgen derivatives showed hematologic response. Our data provide novel real-world insight into the clinical manifestation spectrum, diagnosis as well as clinical course and treatment of TBD in adult, late-onset cases of this hereditary disease.
