Size matters in telomere biology disorders ‒ expanding phenotypic spectrum in patients with long or short telomeres

Abstract

The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment.

Keywords: Cancer predisposition; Long telomeres; Lung fibrosis; Short telomeres; Telomere biology disorders.

Fig. 1

The components of the telomere. The outermost part of the telomeres is protected by a Shelterin complex consisting of six proteins: TRF1, TRF2, TIN2, POT1, TPP1 and RAP1. The telomeres are maintained at each cell division by a telomerase consisting of telomerase reverse transcriptase (TERT) and an RNA part that acts as a template when the nucleotides must be inserted during replication of the telomeres (TERC and DKC1). In addition, a number of proteins contribute to the maintenance and function of the telomeres. This applies to the CST complex (CTC1, STN1 and TEN1) and RTEL1, TCAB1 and PARN. The inheritance pattern is implicated by coloring. Pink: autosomal recessive inheritance; Yellow: autosomal dominant inheritance; Blue: autosomal recessive and autosomal dominant inheritance; Red: X-linked recessive inheritance. Proteins shown but not yet reported associated with TBD are colored in gray

Fig. 2

The most common clinical manifestations of telomere biology disorders (TBD). Arrows and icons show organ system affected by TBD

Fig. 3

High Resolution Computerised Tomography (HRCT) showing lung fibrosis in a patient with a pathogenic variant in TERC. A and B Severe fibrotic and cystic changes in a patient with TBD and dyskeratosis congenita due to a pathogenic variant in TERC prior to lung transplantation. C HRCT in a patient with no lung disease and TBD