Telomeropathies

Telomeropathies, or telomere biology disorders, describe a spectrum of inherited diseases caused by defective maintenance of telomeres, resulting in critically short telomeres. The group includes dyskeratosis congenita and related conditions with similar telomere biology abnormalities. Clinically, they present with multi-organ manifestations that reflect tissue vulnerability to short telomeres, particularly hematopoietic, pulmonary, hepatic, and mucocutaneous tissues.

Genetics and mechanisms: Most are due to mutations in genes involved in telomere elongation or protection, including TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin), and shelterin or telomere processing genes such as TINF2, RTEL1, PARN. Modes of inheritance include autosomal dominant, autosomal recessive, and X-linked; germline telomere length is often shortened across generations (anticipation).

Clinical features: The classic mucocutaneous triad of DC (nail dystrophy, abnormal skin pigmentation, oral leukoplakia) occurs in some patients, but many have only hematologic dysfunction such as bone marrow failure, or progressive fibrosing lung disease, liver disease, or growth impairment. Hoyeraal-Hreidarsson is a severe DC variant with prenatal growth retardation, immunodeficiency, and neurodevelopmental issues. Malignancy risk is elevated.

Diagnosis and management: Diagnosis relies on measuring telomere length (often by flow-FISH, i.e., flow cytometry–fluorescence in situ hybridization) and genetic testing for known telomere biology genes. Treatment is supportive and organ-specific; or hematopoietic stem cell transplantation in selected marrow failure cases; androgens like danazol may modestly increase telomere length and blood counts. Patients require surveillance for pulmonary, hepatic, and neoplastic complications. Given the genetic nature, family counseling is advised.