What is Dyskeratosis Congenita (a rare genetic disorder characterized by premature aging)?

From the Guidelines

Dyskeratosis congenita is a rare genetic disorder that should be managed with a multidisciplinary approach, including hematopoietic stem cell transplantation for severe bone marrow failure, androgen therapy, and granulocyte colony-stimulating factors, as well as regular cancer screening and genetic counseling, as recommended by the most recent study 1.

Key Features of Dyskeratosis Congenita

• Dyskeratosis congenita (DC) is a telomere biology disorder characterized by nail dystrophy, lacy skin pigmentation, and oral leukoplakia, caused by mutations in genes involved in telomere maintenance, such as DKC1, TERC, TERT, and others 1.
• The disease typically presents in childhood with the classic triad, but can also manifest with bone marrow failure, pulmonary fibrosis, liver disease, and increased cancer risk, particularly for head and neck cancers 1.
• The underlying pathophysiology involves shortened telomeres, which leads to premature cellular aging and tissue failure in highly proliferative tissues 1.

Management and Treatment

• Treatment is primarily supportive and symptom-based, including:
  • Hematopoietic stem cell transplantation for severe bone marrow failure 1.
  • Androgen therapy (such as danazol or oxymetholone) to improve blood counts 1.
  • Granulocyte colony-stimulating factors for neutropenia 1.
• Regular cancer screening is essential due to the increased malignancy risk, particularly for head and neck cancers 1.
• Genetic counseling is recommended for affected families 1.

Surveillance and Monitoring

• Patients with DC should undergo regular surveillance for hematologic malignancies, including complete blood counts with differential and reticulocyte count, bone marrow aspirate and biopsy, and somatic gene panel testing 1.
• The frequency of surveillance should be individualized based on the patient's risk factors and clinical presentation, but should be at least annual 1.

From the Research

Definition and Characteristics of Dyskeratosis Congenita

• Dyskeratosis congenita is an inherited bone marrow failure syndrome caused by defects in telomere maintenance 2, 3.
• It is characterized by the triad of abnormal nails, reticular skin pigmentation, and oral leukoplakia, and is associated with high risk of developing aplastic anemia, myelodysplastic syndrome, leukemia, and solid tumors 3.
• Patients have very short germline telomeres, and approximately half have mutations in one of six genes encoding proteins that maintain telomere function 3.

Treatment Options for Dyskeratosis Congenita

• Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure because of dyskeratosis congenita 2, 4.
• However, HSCT is characterized by a marked decline in long-term survival due to late deaths from pulmonary complications 2.
• A prospective study using danazol showed promising results in gain in telomere length and hematologic responses, and may support the recommendation that HSCT is not indicated for patients with dyskeratosis congenita; instead, they should receive androgen, particularly danazol, as a first-line therapy 2.
• Lung transplantation may be considered for patients with dyskeratosis congenita who develop pulmonary fibrosis with no concurrent evidence of multi-organ failure 5.

Outcomes and Prognostic Factors for HSCT in Dyskeratosis Congenita

• Overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively, in a cohort of 94 patients with dyskeratosis congenita 4.
• Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor 4.
• Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis 4.
• A non-myeloablative conditioning regimen appeared to be most advisable 4.