Dyskeratosis Congenita – Definition
Dyskeratosis congenita (OMIM: #127550, #30500, #615190, #613987, #613989) is a telomeropathy characterized by the clinically classic triad of nail dystrophies, oral leukoplakia and pigmentary abnormalities in the upper thoracic aperture and cervical region. There is an increased risk of progressive bone marrow failure and the development of myeloid neoplasms, solid tumors, and pulmonary fibrosis. The clinical picture is variable, and the classic triad is often absent.
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 are currently not yet genetically classified)
Gene products:
All gene products play a role in telomere biology. TERC codes for an RNA.
Function:
Stability and preservation of telomeres, which in turn are essential for chromosomal stability
Pattern of inheritance:
- X-linked: DKC1
- Autosomal dominant: TERC and TINF2
- Autosomal dominant or autosomal recessive: ACD, RTEL1, TERT
- Autosomal recessive: CTC1, NHP2, NOP10, PARN and WRAP53
Prevalence:
at least 400 families worldwide in 2015
Genotype-phenotype correlation:
Extensive studies are lacking. Severe progressions (shorter telomeres than classic DC):
- Hoyeraal-Hreidarsson syndrome
- Revesz syndrome
Penetrance:
Not yet well understood. There is high inter-individual and intra-family variability and with age-dependent symptom onset, apparent incomplete penetrance. This is a phenomenon of anticipation.
Dyskeratosis Congenita – Diagnosis
Classic DC Diagnosis Triad (Not Present in All DC Patients)
- Nail dysplasia
- Pigmentary 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 is 97% sensitive and 91% specific for DC.
- Molecular genetic testing (serial single gene testing, multigene 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%), bronchiolitis 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 Forms of Progression
- 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
Cancer Predisposition
- Myeloid neoplasms (MDS, AML)
- Squamous cell carcinomas and adenocarcinomas of the oropharynx (HNSCC), GI tract and anogenital area
The risk of malignant disease is 11 times higher than in the healthy population. It occurs in the third decade of life.
Special Features of the Treatment
- 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)
Diagnosis of Dyskeratosis Congenita- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Diagnosis of Dyskeratosis Congenita- What's Next?
Once diagnosed, it is recommended that the patient be managed by a cancer predisposition specialist. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. There is also some additional information at the end of this page, including links to support groups.
Recommendations for Early Detection in Your Patients
Due to the rarity of the disease, evidence-based standards for tumor screening and clinical management are lacking. Below you will find a recommendation from the AACR consensus meeting in October 2016.
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Hemato-oncology |
Medical history and physical examination, annual blood count, annual bone marrow puncture and bone marrow biopsy upon diagnosis and according to clinical symptoms, early referral to a transplant center, HPV vaccination, annual ENT check-ups from adolescence (HNSCC evaluation) |
Immunology |
Monitoring of immunoglobulin levels according to immunological recommendations |
Dermatology |
Annual skin screening |
Pulmonology |
Baseline functional testing with regular routine follow-up |
Gastroenterology & Nutrition |
Annual liver function test, more frequent under androgen therapy (semi-annual liver ultrasound, 3-monthly liver function test) |
Endocrinology |
Annual diabetes screening, growth monitoring |
Neurology |
cMRI examination for cerebellar hypoplasia at diagnosis, early supportive therapy for developmental retardation |
Ophthalmology |
Annual examinations, monitoring and early intervention for lacrimal duct stenosis |
Orthopaedics |
Evaluation of aseptic bone necrosis of the hip and shoulder by clinic |
Dentist |
Half-yearly check-ups |
ENT |
Baseline hearing status |
Cardiology |
Baseline evaluation for AV and cardiac malformations |
Urogenital tract |
Baseline examination for urogenital malformations |
Gynecology |
Annual examination |
