Clinical characteristics: Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. The classic triad may not be present in all individuals. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include: abnormal pigmentation changes not restricted to the upper chest and neck, eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), and dental abnormalities (caries, periodontal disease, taurodauntism). Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome). Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.
Diagnosis/testing: All individuals with DC have abnormally short telomeres for their age, as determined by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on white blood cell (WBC) subsets. To date, ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53 are the genes in which pathogenic variants are known to cause DC and result in very short telomeres. Pathogenic variants in one of these 11 genes have been identified in approximately 70% of individuals who meet clinical diagnostic criteria for DC.
Management: Treatment of manifestations: Treatment is tailored to the individual. Hematopoietic cell transplantation (HCT) is the only curative treatment for BMF and leukemia but historically has had poor long-term efficacy; if a suitable donor is not available, androgen therapy may be considered for BMF. Treatment of other cancers is tailored to the type of cancer. Of note, cancer therapy may pose an increased risk for prolonged cytopenias as well as pulmonary and hepatic toxicity. Treatment of pulmonary fibrosis is primarily supportive, although lung transplantation may be considered.
Surveillance: For BMF: complete blood count (CBC) annually if normal and more often if abnormal; consider annual bone marrow aspirate and biopsy. For those on androgen therapy: routine monitoring of liver function. For cancer risk: monthly self-examination for oral, head, and neck cancer; annual cancer screening by an otolaryngologist and dermatologist; annual gynecologic examination. For pulmonary fibrosis: annual pulmonary function tests starting either at diagnosis or when the individual can perform the test (often around age eight years). Routine dental screening every six months and good oral hygiene are recommended.
Agents/circumstances to avoid: Blood donation by family members if HCT is being considered; non-leukodepleted and non-irradiated blood products; the combination of androgens and G-CSF in treatment of BMF (has been associated with splenic rupture); toxic agents implicated in tumorigenesis (e.g., smoking).
Evaluation of relatives at risk: If a relative has signs or symptoms suggestive of DC or is being evaluated as a potential HCT donor, telomere length testing is warranted or molecular genetic testing if the pathogenic variant(s) in the family are known.
Genetic counseling: The mode of inheritance of DC varies by gene:
Autosomal dominant: TERC and TINF2
Autosomal dominant or autosomal recessive: ACD, RTEL1, and TERT
Autosomal recessive: CTC1, NHP2, NOP10, PARN, and WRAP53
Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Once the DC-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
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