Dyskeratosis congenita (DC) is a rare ectodermal dysplasia that often presents with the classic triad of nail dysplasia, skin pigmentary changes, and oral leukoplakia associated with a high risk of bone marrow failure (BMF) and cancer.
Prevalence is estimated at 1/ 1,000,000 in Europe.
DC has a wide phenotypic spectrum and age onset. It usually manifests during childhood with the triad of dysplastic nails, lacy reticular pigmentation and atrophy of the skin at the level of the neck and upper chest, and oral leukoplakia. Patients show an increased risk for progressive BMF and may develop myelodysplastic syndrome or acute myelogenous leukemia (see these terms) at any age (the risk increasing with age). There is also an increased risk for solid tumors, typically squamous cell carcinoma of head and neck (see this term) or anogenital cancer. Various additional clinical findings have been reported and may include: developmental delay, short stature, microcephaly, blepharitis, epiphora, periodontal disease, taurodontism, decreased teeth/root ratio, esophageal stenosis, liver disease, urethral stenosis, osteoporosis, avascular necrosis of femur and/or humerus, premature hair greying/alopecia, or abnormal eyelashes. Individuals with DC are at high risk of pulmonary fibrosis.
DC is caused by mutations in the CTC1 (17p13.1),DKC1 (Xq28),TERC (3q26.2), TERT (5p15.33), TINF2 (14q12), NHP2 (5q35.3), NOP10 (15q14-q15), RTEL1 (20q13.3), or WRAP53 (17p13.1) genes which code for proteins involved in telomere maintenance and affecting telomere length. The USB1 gene (16q13) is also involved but it is not known to be related to telomere biology. Clinical phenotypic outcome depends on the gene mutated, its penetrance and expressivity. Patients with Hoyeraal Hreidarsson syndrome, a clinically severe variant of DC, may have mutations in RTEL1, DKC1, TERTor TINF2, and patients with Revesz syndrome (see these terms), another DC variant, have mutations in TINF2.
Diagnosis should be considered if at least 2 characteristics of the triad are present or one feature in addition to two other primary clinical findings (e.g. head/neck, anogenital cancer, or BMF). Clinical diagnosis may be confirmed by telomere length testing by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH), and genetic testing.
Differential diagnosis includes palmoplantar keratoderma-spastic paralysis syndrome, nail-patella syndrome, autosomal dominant nail dysplasia, poikiloderma with netropenia, Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond Anemia, idiopathic aplastic anemia, idiopathic pulmonary fibrosis, Coats plus syndrome (see these terms).
In case of family history, prenatal genetic diagnosis by chorionic villus sampling or preimplantation genetic diagnosis may be available.
Autosomal dominant (TERC, TERT, TINF2, RTEL1), autosomal recessive (TERT, CTC1, RTEL1, WRAP53, NHP2, NOP10) or X-linked (DKC1) transmissions have been reported.
Management includes regular complete clinical examinations (e.g. dermatologic, dental, hematologic, ophthalmic, neurologic). BMF management and treatment currently follows the Fanconi anemia consensus guidelines. To date hematopoietic stem cell transplantation (HSCT) is the only cure for BMF. Androgen therapy may be considered first when no related donor is available. Treatment of cancer uses individualized chemotherapy and radiotherapy regimens.
Life expectancy ranges from infancy to well into the 7th decade. Up to 40% of patients will have BMF by the age of 40. Major causes of morbidity include BMF, cancer and pulmonary complications.
Last update: September 2014