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
  • X-bound: DKC1
  • Autosomal dominant: TERC and TINF2
  • Autosomal dominant or autosomal recessive: ACD, RTEL1, and TERT
  • Autosomal recessive: CTC1, NHP2, NOP10, PARN, and WRAP53
Prevalence At least 400 families around the world in 2015
Genotype-phenotype correlation Extensive studies are lacking. Severe progressions (shorter telomeres than classic DC):

  • Hoyeraal-Hreidarsson syndrome
  • Revesz syndrome
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
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