An update on the biology and management of dyskeratosis congenita and related telomere biology disorders

Abstract

Introduction: Telomere biology disorders (TBDs) encompass a group of illnesses caused by germline mutations in genes regulating telomere maintenance, resulting in very short telomeres. Possible TBD manifestations range from complex multisystem disorders with onset in childhood such as dyskeratosis congenita (DC), Hoyeraal-Hreidarsson syndrome, Revesz syndrome and Coats plus to adults presenting with one or two DC-related features.Areas covered: The discovery of multiple genetic causes and inheritance patterns has led to the recognition of a spectrum of clinical features affecting multiple organ systems. Patients with DC and associated TBDs are at high risk of bone marrow failure, cancer, liver and pulmonary disease. Recently, vascular diseases, including pulmonary arteriovenous malformations and gastrointestinal telangiectasias, have been recognized as additional manifestations. Diagnostics include detection of very short leukocyte telomeres and germline genetic testing. Hematopoietic cell transplantation and lung transplantation are the only current therapeutic modalities but are complicated by numerous comorbidities. This review summarizes the pathophysiology underlying TBDs, associated clinical features, management recommendations and therapeutic options.Expert opinion: Understanding TBDs as complex, multisystem disorders with a heterogenous genetic background and diverse phenotypes, highlights the importance of clinical surveillance and the urgent need to develop new therapeutic strategies to improve health outcomes.

Keywords: Coats plus; Hoyeraal-Hreidarsson syndrome; Revesz syndrome; Telomere; bone marrow failure; cancer; dyskeratosis congenita; pulmonary fibrosis; telomere biology disorder.

Figure 1.. Examples of clinical manifestations of telomere biology disorders.

a) Nail dysplasia and palmar pigmentation changes; b) Hyperpigmentation of the neck and upper chest; c) Oral leukoplakia on the tongue, designated by arrow; d) Hypocellular bone marrow biopsy; e) Peripheral interstitial and ground-glass opacities with honeycombing consistent with usual interstitial pneumonia pattern of pulmonary fibrosis; f) Telangiectasias of the small bowel lumen.

Figure 2:. Schematic depiction of the telomere and key components of telomere maintenance.

Protein names are shown. DKC1: dyskerin (encoding gene DKC1); TERC: hTR, human telomerase RNA component (TERC); TERT: human telomerase reverse transcriptase (TERT); NOP10: nuclear protein family A, member 3 (NOP10); NHP2: NOLA2 nucleolar protein family A, member 2 (NHP2); NAF1: nuclear assembly factor 1 ribonucleoprotein (NAF1); GAR1: nucleolar protein family A, member 1 (GAR1); PARN: poly (A)-specific ribonuclease (PARN); TCAB1: telomere Cajal body associated protein 1 (WRAP53); TPP1: telomere protection protein 1 (ACD); STN1: CST complex subunit (STN1); CTC1: conserved telomere maintenance component 1 (CTC1); RTEL1: Regulator of telomere elongation helicase 1 (RTEL1); TIN2: TERF1 (TRF1)-interacting nuclear factor 2 (TINF2); TRF1: telomeric repeat binding factor 1 (TERF1); TRF2: telomeric repeat binding factor 2 (TERF2); RAP1: TERF2 interacting protein (RAP1). Components are grouped based on their function. Colored shapes indicate proteins with known telomere biology disorders associated mutations and inheritance pattern is implicated by type coloring. Blue: autosomal recessive inheritance; Yellow: autosomal dominant inheritance; Green: autosomal recessive and autosomal dominant inheritance; Red: X-linked recessive inheritance. Proteins shown but not yet reported associated with TBD are colored in gray.

Figure 3.. Example results of lymphocyte telomere lengths measured by flow cytometry with in situ hybridization.

Circle color codes, 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; female with heterozygous TERC