Very short telomeres are a feature of Dyskeratosis congenita associated telomere biology diseases (DC/TBDs), which are caused by germline pathogenic mutations in telomere biology genes. All organs can be affected, and inheritance patterns include autosomal dominant (AD), autosomal recessive (AR), X-linked (XLR), and de novo inheritance. The relationship between method of inheritance, phenotypes, and long-term clinical consequences was investigated by the researchers for a study. In the National Cancer Institute’s Inherited Bone Marrow Failure Syndrome Study, 231 people with DC/TBDs (144 men, 86.6% known genotype, median age at diagnosis 19.4 years [range 0 to 71.6]) had extensive clinical examinations and longitudinal follow-up (median follow-up 5.2 years [range 0 to 36.7]). Patients were divided into 3 groups based on their inheritance patterns: AD-nonTINF2, AR/XLR, and TINF2 variations.
In AR/XLR or TINF2 illness, severe bone marrow failure (BMF), severe liver disease, and gastrointestinal telangiectasias were more common, but pulmonary fibrosis was more common in people with AD disease. After controlling for age at DC/TBD diagnosis, they found that AR/XLR people had the greatest cancer risk. At the time of the final follow-up, 42% of patients had died, with a median overall survival (OS) of 52.8 years (95% CI 45.5-57.6) and a median hematopoietic cell or solid organ transplant-free survival of 45.3 years (95% CI 37.4-52.1). Patients with AD showed a significantly better OS than those with AR/XLR/TINF2 disease (P<.01), whereas those with AR/XLR and TINF2 disease had similar survival rates. The long-term investigation of the clinical manifestations of DC/TBDs laid the groundwork for integrating the mode of inheritance into evidence-based clinical treatment guidelines and risk stratification in patients with DC/TBD.
