Knowledge on rare diseases and orphan drugs

Dyskeratosis congenita (DC) prevalence is unknown. More than 400 families are reported in the world.

DC has a wide phenotypic spectrum and age onset. It classically 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 are at high risk of progressive BMF and may develop myelodysplastic syndrome or acute myelogenous leukemia 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 or anogenital cancer. 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, urethral stenosis, osteoporosis, avascular necrosis of femur and/or humerus, premature hair greying/alopecia, or abnormal eyelashes. Patients with DC may also develop pulmonary fibrosis, pulmonary arteriovenous malformations, gastrointestinal telangiectasias, and liver disease. It is important to note that the clinical features of DC progress over time and that all features, including the mucocutaneous triad, may not be present.

DC is caused by germline mutations in genes important in telomere biology. De novo cases also occur. X-linked recessive DC is due to mutations in DKC1 (Xq28). The autosomal dominant genes associated with DC are TERC (3q26.2), TERT (5p15.33), TINF2 (14q12), RTEL1 (20q13.3), PARN (16p13.12), and ACD (16q22.1). Autosomal recessive genes include TERT (5p15.33), NHP2 (5q35.3), NOP10 (15q14-q15), RTEL1 (20q13.3), WRAP53 (17p13.1), ACD (16q22.1). Mutations in CTC1 (17p13.1), POT1 (7q31.33) and STN1 (10q24.33) are rare causes of DC.

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. 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.

In case of family history, prenatal genetic diagnosis by chorionic villus sampling or preimplantation genetic diagnosis may be available.

The disorder may be inherited in X-linked recessive (XLR), autosomal dominant (AD), or autosomal recessive (AR) patterns.

Management includes regular complete clinical examinations. 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: August 2019 - Expert reviewer(s): Dr Sharon SAVAGE