Clinical Information

Telomeres are highly specialized structures composed of TTAGGG nucleotide repeats and proteins that protect chromosome ends. Under normal circumstances, telomeres shorten with every cycle of DNA replication. Telomerase is an enzyme complex that can extend the length of the telomere, thus helping to slow the shortening process. Telomerase is most active in highly proliferative tissues, such as lymphocytes, skin, intestine, and bone marrow.

Telomere biology disorders (TBD) include a complex group of syndromes characterized by abnormally short telomeres. Telomere length analysis in leukocyte subsets is usually performed by flow fluorescent in situ hybridization. The severity of TBD syndromes is variable, and they may present in children or adults. Symptoms of TBD include bone marrow failure, pulmonary fibrosis, liver disease, gastrointestinal disease, and mucocutaneous abnormalities. The prevalence of cancer in the short telomere syndromes is increased. These cancers are mainly hematological malignancies, such as myelodysplastic syndrome and acute myelogenous leukemia, although some solid tumor prevalence is also increased (eg, oral squamous cell carcinoma). Recognition and diagnosis of underlying TBD is important, as it can help guide treatment decisions.

Dyskeratosis congenita (DC) was the first TBD to be described. The subsets of DC include classic DC, Hoyeraal Hreidarsson syndrome (HHS), Revesz syndrome, DC-like conditions, Coats plus syndrome, and isolated subtypes.

Patients with the classic forms of DC are usually diagnosed in childhood with a triad of mucocutaneous features, including dysplastic nails, anomalies of skin pigmentation, and oral leukoplakia. Other features may include bone marrow failure, gastrointestinal disease, liver disease, pulmonary fibrosis, a predisposition to certain cancers, and other medical problems. Alternatively, some patients may have one of the 3 classic features of classic DC along with a hypocellular bone marrow. These patients all have very short telomeres (<1% percentile of age) in leukocytes.

Patients with HHS have the features of classic DC but additionally have cerebellar hypoplasia, neurological conditions, and severe immunodeficiency. They can also have low T-cell numbers with severe B and natural killer (NK) cell lymphopenia (T±B- NK-) reminiscent of severe combined immunodeficiency.

In Revesz syndrome, patients have bilateral exudative retinopathy along with other features of DC. Coats plus syndrome is also characterized by bilateral exudative retinopathy in addition to gastrointestinal problems and other symptoms.

When a TBD manifests in adulthood, the presentation can be variable according to the severity of the telomere length defect relative to age. A broad umbrella of clinical features could include bone marrow failure, pulmonary fibrosis, liver disease not otherwise classified, myelodysplastic syndrome, acute myeloid leukemia, or early onset of malignancies within the DC grouping.

A classification of DC-like may be applied for patients who do not meet the diagnostic criteria of DC but have several features reminiscent of the disease. This could include presence of bone marrow failure, developmental delay, familial history of pulmonary fibrosis, and no other clear diagnosis.

The TBD can be inherited in a variety of patterns, including X-linked recessive, autosomal dominant, and autosomal recessive. Approximately 60% to 80% of patients with TBD have variants in the genes evaluated by this panel. In autosomal dominant DC, phenotypes may present at a younger age and more severely in successive generations (genetic anticipation). The genetic anticipation is mediated by the shortened telomeres that are inherited together with the disease-causing variant.

It is increasingly recognized that TBD also include syndromes characterized by abnormally long telomeres. Telomere length is controlled, and like short telomeres, long telomeres also have consequences, mainly increased risk of cancers. The genetic basis of these short and long telomere syndromes may be linked to different disease-causing variants in the same genes. Loss-of-function variants in TERT lead to short telomere syndromes as described earlier, whereas gain-of-function variants lead to increased telomere length and autosomal dominant familial melanoma. Similarly, disease-causing variants in ACD and TINF2 have been described to cause both long and short telomers. Long telomeres caused by these variants lead to increased cancer risk (familial melanoma and thyroid cancer).