Clinical characteristics: Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD 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: A majority of individuals with DC/TBD have abnormally short telomeres for their age, as determined by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on lymphocyte subsets. To date, ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD and to result in very short telomeres. Pathogenic variants in one of these 16 genes have been identified in approximately 80% of individuals who meet clinical diagnostic criteria for DC/TBD.
Management: Treatment of manifestations: Treatment is tailored to the individual. Hematopoietic cell transplantation (HCT) is the only curative treatment for BMF and leukemia, but long-term outcome has historically been poor due to treatment toxicity; 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; annual bone marrow aspirate and biopsy. For those on androgen therapy: routine monitoring of CBC, liver function, liver ultrasound, and endocrinology evaluation. 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 age ~8 years); bubble echocardiogram to look for pulmonary arteriovenous malformations if suspected based on clinical symptoms. 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 granulocyte colony-stimulating factor in treatment of BMF (has been associated with splenic rupture); toxic agents implicated in tumorigenesis (e.g., smoking, excessive sun exposure).
Evaluation of relatives at risk: If a relative has signs or symptoms suggestive of DC/TBD or is being evaluated as a potential HCT donor, telomere length testing – or, if the pathogenic variant(s) in the family are known, molecular genetic testing – is warranted.
Genetic counseling: The mode of inheritance of DC/TBD varies by gene:
Autosomal dominant: NAF1, RPA1, TERC, TINF2, and ZCCHC8
Autosomal dominant or autosomal recessive: ACD, PARN, RTEL1, and TERT
Autosomal recessive: CTC1, NHP2, NOP10, POT1, STN1, 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/TBD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
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