Definition
Dyskeratosis congenita (OMIM: #127550, #30500, #615190, #613987, and #613989) is a telomeropathy characterized by the classic clinical triad of nail dystrophies, oral leukoplakia, and pigment disorders affecting the upper thoracic aperture and the cervical region. There is an increased risk of progressive bone marrow failure and the development of myeloid neoplasia, solid tumors, and pulmonary fibrosis. The clinical symptoms vary, and often lack the classic triad.
Key Data
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Synonyms | DC, telomere syndromes, Zinsser-Cole-Engman syndrome |
Genes | ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, WRAP53 (30% of cases with clinical DC have not yet been genetically classified to date) |
Gene products | All gene products play a role in telomere biology. TERC encodes an RNA. |
Function | Stability and maintenance of telomeres, which in turn are essential for chromosomal stability |
Heredity |
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Prevalence | At least 400 families around the world in 2015 |
Genotype-phenotype correlation | Extensive studies are lacking. Severe progressions (shorter telomeres than classic DC):
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Penetrance | Currently not very well understood. High degree of inter-individual and intra-familial variations with an age-dependent onset of symptoms; penetrance appears to be incomplete. Anticipation phenomenon. |
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Diagnosis
Classic DC Diagnostic Triad (Not Present in All DC Patients)
Nail dysplasia
Pigment disorders, cervical / upper thoracic aperture
Oral leukoplakia
Diagnostics
Leukocyte telomere length testing (multicolor flow-FISH, PCR, or restriction fragment analysis). A lymphocyte telomere length below the first age percentile has a 97% sensitivity and 91% specificity for DC.
Molecular genetic testing (serial single-gene testing, multiple-gene panel, exome/genome sequencing)
Differential Diagnoses
Congenital bone marrow failure (Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome)
Acquired bone marrow failure
Idiopathic pulmonary fibrosis (IPF)
Diseases associated with nail dystrophies (nail patella syndrome, 20-nail dystrophy, keratoderma with nail dystrophy and sensorimotor neuropathy, poikiloderma with neutropenia).
Clinical Presentation
Typical Presentation
Progressive bone marrow failure: thrombopenia, leukopenia, anemia (50% up to the age of 40)
Lungs: idiopathic pulmonary fibrosis (65%), broncholitis obliterans, chronic hypersensitivity pneumonia, emphysema
Liver: histological heterogenic pattern of inflammation, hemochromatosis, hepatocytic necrosis, fibrosis, nodular regenerative hypoplasia
Dermatology: nail dystrophies, pigment disorders, hyperhidrosis
Growth and development: small stature, growth restriction (including intrauterine) and developmental retardation
Eyes: epiphora, abnormal eyelash growth, bilateral exudative retinopathy
ENT: oral leukoplakia, deafness (rare)
Cardiovascular: ASD, VSD, myocardial fibrosis, dilatative cardiomyopathy
Gastrointestinal: esophageal stenosis, enteropathy, liver fibrosis, hepatic-pulmonary syndrome (HPS), vascular ectasia, gastrointestinal bleeding that is sometimes life-threatening
Urogenital: urethral stenosis
Musculoskeletal: osteoporosis, osteopenia, avascular necrosis in the shoulder and hip
Psychiatry: schizophrenia
Endocrine: hypogonadism
Immunology: immunodeficiency
Severe Progressions
Hoyeraal-Hreidarsson syndrome: early childhood onset; the classic DC features plus cerebellar hypoplasia, developmental retardation, immunodeficiency, intrauterine growth restriction, bone marrow failure
Revesz syndrome: early childhood onset; the features of DC plus bilateral exudative retinopathy, intracranial calcifications, intrauterine growth restriction, bone marrow failure, sparse and thin hair, nail dystrophies, oral leukoplakia
Krebsprädisposition
Myeloid neoplasia (MDS, AML)
Squamous epithelial carcinomas and adenocarcinomas of the oropharynx (HNSCC), GI tract, and anogenital region
The risk of a malignant disease is 11 times higher compared to the healthy population. Onset from the third decade of life.
Therapeutic Considerations
Monthly oral self-monitoring for changes in the mucous membranes
Treatment according to the manifestation
Androgens / bone marrow transplant in the event of bone marrow failure
Avoid collecting blood reserves from related donors if a bone marrow transplant is being considered
Do not combine androgens with G-CSF (associated with splenic rupture)
Avoid carcinogenic noxious agents (nicotine, alcohol)
Surveillance Recommendations
Surveillance Recommendations
Evidence-based standards for tumor screening and clinical management are lacking due to the rarity of the disease. The following are the recommendations from the AACR consensus meeting in October 2016.
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Hematology-oncology |
Medical history and physical examination, annual blood count, annual bone marrow puncture and punch biopsy if corresponding clinical symptoms have been diagnosed, early referral to a transplant center, HPV vaccination, annual ENT checkups as of adolescence, (HNSCC evaluation) |
Immunology |
Monitoring of the immunoglobulin levels according to immunological recommendations |
Dermatology |
Annual skin screening |
Pulmonology |
Baseline function testing with regular routine follow-up |
Gastroenterology and nutrition |
Annual liver function testing, more frequently in tandem with androgen therapy (six-monthly hepatic ultrasound, three-monthly liver function testing) |
Endocrinology |
Annual screening for diabetes, growth monitoring |
Neurology |
cMRT examination for cerebellar hypoplasia if a diagnosis has been made, early supportive therapy in the event of developmental retardation |
Ophthalmology |
Annual examinations, monitoring, and early intervention in the event of lacrimal duct stenosis |
Orthopedics |
Evaluation of aseptic bone necrosis of the hip and shoulder according to clinical symptoms |
Dental |
Six-monthly checkups |
ENT |
Baseline hearing status |
Cardiology |
Baseline evaluation for AV and cardiac malformations |
Urogenital tract |
Baseline examination for urogenital malformations |
Gynecology |
Annual examination |