Dyskeratosis congenita and telomere biology disorders

Abstract

Numerous genetic discoveries and the advent of clinical telomere length testing have led to the recognition of a spectrum of telomere biology disorders (TBDs) beyond the classic dyskeratosis congenita (DC) triad of nail dysplasia, abnormal skin pigmentation, and oral leukoplakia occurring with pediatric bone marrow failure. Patients with DC/TBDs have very short telomeres for their age and are at high risk of bone marrow failure, cancer, pulmonary fibrosis (PF), pulmonary arteriovenous malformations, liver disease, stenosis of the urethra, esophagus, and/or lacrimal ducts, avascular necrosis of the hips and/or shoulders, and other medical problems. However, many patients with TBDs do not develop classic DC features; they may present in middle age and/or with just 1 feature, such as PF or aplastic anemia. TBD-associated clinical manifestations are progressive and attributed to aberrant telomere biology caused by the X-linked recessive, autosomal dominant, autosomal recessive, or de novo occurrence of pathogenic germline variants in at least 18 different genes. This review describes the genetics and clinical manifestations of TBDs and highlights areas in need of additional clinical and basic science research.

Graphical abstract

Figure 1.

Examples of clinical manifestations of telomere biology disorders. (A) Tongue leukoplakia in Clinical Case 1; (B) hyper- and hypopigmentation on the trunk in Clinical Case 2; (C) nail dysplasia in Clinical Case 2; (D) examples of lymphocyte telomere lengths measured by flow cytometry with in situ hybridization from NCT00027274 study participants. Circle color codes by sex and causative gene: red, male with heterozygous TINF2; green, male with DKC1; gray, male with DKC1; orange, female with autosomal recessive RTEL1; blue, male with heterozygous TERT; purple, female with heterozygous TERC. Clinical Case 2 is designated with a black X; (E) TBD phenotype progression in Clinical Cases 1 and 2 by age group with age at diagnosis noted. AVM, arteriovenous malformation; SCC, squamous cell carcinoma.

Figure 2.

Clinical features underlying TBDs and possible diagnostic evaluation results. Telomere length testing should be considered for all patients with the indications shown. All patients with BMF or head/neck squamous cell carcinoma (HNSCC) should also have chromosome breakage testing of blood (and skin, if indicated) to rule out Fanconi anemia. Family history may be helpful if it is present, but many patients do not have affected relatives due to variable disease penetrance, expressivity, and/or genetic anticipation. HNSCC, head and neck squamous cell carcinoma; IUGR, intrauterine growth restriction.

Figure 3.

Schematic of the telomere and functions of the proteins affected in TBDs. Protein function and the reported consequences of mutations in the respective gene are summarized in Table 2. Components are grouped approximately based on their function. Shown in green: the components of the telomerase enzyme complex (DKC1, TERC, TERT, NAF1, NOP10, NHP2), telomerase or hTR regulators (TCAB1, PARN, and ZCCHC8), and regulator of telomere elongation helicase 1 (RTEL1). Dark blue: the shelterin (TPP1, TIN2, and POT1) and the CST (CTC1 and STN1) complexes. Red: the proteins primarily involved in DNA repair. Red line: Apollo interacts with TRF1. NPM1 is involved in ribosomal RNA maturation and interacts with NOP10 and NHP2. MDM4 is not shown because it does not directly act at the telomere. Gray symbols: known key telomere biology proteins not yet attributed to human disease (GAR1 in telomerase complex; TRF1, TRF2, RAP1 in shelterin; TEN1 in CST). Yellow asterisk: autosomal dominant; light-blue asterisk: autosomal recessive; orange asterisk: X-linked recessive. Complete protein name (gene name): Apollo (DCLRE1B); 1, CTC1, conserved telomere maintenance component 1 (CTC1); DKC1, dyskerin (DKC1); MDM4, MDM4 regulator or p53 (MDM4); NAF1, nuclear assembly factor 1 ribonucleoprotein (NAF1); NHP2, NOLA2 nucleolar protein family A, member 2 (NHP2); NOP10, nuclear protein family A, member 3 (NOP10); NPM1, nucleophosmin 1 (NPM1); PARN, poly (A)-specific ribonuclease (PARN); POT1, protection of telomeres 1 (POT1); RPA1, replication protein A1 (RPA1); RTEL1, regulator of telomere elongation helicase 1 (RTEL1); STN1, CST complex subunit (STN1); TCAB1, telomere Cajal body–associated protein 1 (WRAP53); TERC, hTR, human telomerase RNA component (TERC); TERT, human telomerase reverse transcriptase (TERT); TIN2, TRF1-interacting nuclear factor 2 (TINF2); TPP1: telomere protection protein 1 (ACD); ZCCHC8: Zinc finger CCHC domain-containing protein 8 (ZCCHC8). Figure adapted with permission from Niewisch and Savage.