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:

• Telomere
• dyskeratosis congenita
• telomere biology disorder
• pulmonary fibrosis
• Revesz syndrome
• Hoyeraal-Hreidarsson syndrome
• Coats plus
• bone marrow failure
• cancer

Article highlights

• Dyskeratosis congenita (DC) and related telomere biology disorders (TBDs) are caused by germline mutations in telomere biology genes resulting in very short telomeres.

• The phenotypic spectrum affects all organ systems ranging from classic DC, Hoyeraal-Hreidarsson syndrome, Revesz syndrome and Coats plus to apparently isolated aplastic anemia, pulmonary fibrosis or liver disease.

• Better understanding of the genetic etiology has led to the recognition of additional TBD-related manifestations such as vascular disease and structural brain abnormalities.

• Patients with TBDs are at high risk of bone marrow failure, pulmonary disease, liver disease, and cancer.

• To date, there are no curative therapeutic approaches other than hematopoietic cell transplantation for TBD-related bone marrow failure.

• The complex medical problems in patients with TBDs require close clinical surveillance and highlight the need for new therapeutic approaches.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, and fellowship support for M.R.N. from the Mildred-Scheel-Postdoctoral Fellowship Program by the German Cancer Aid.