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.