Zinsser-Engman-Cole Syndrome (Dyskeratosis Congenita)

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome characterized by the classical triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. It represents a telomere biology disorder with multi-system involvement.

Key Points

• Prevalence: 1 in 1,000,000 individuals
• Inheritance: X-linked recessive (common), autosomal dominant, or autosomal recessive
• Age of Onset: Typically in early childhood
• Male Predominance: 3:1 ratio
• Associated with premature mortality (median age 30-40 years)

Clinical Manifestations

1. Mucocutaneous Triad (Diagnostic Triad)

• Skin Pigmentation Changes:
  • Reticulated hyperpigmentation
  • Poikiloderma - areas of hyper and hypopigmentation
  • Predominantly affects neck, upper chest, and face
  • Typically appears by age 10
• Nail Dystrophy:
  • Progressive nail changes
  • Ridging and longitudinal splitting
  • Complete nail loss in severe cases
  • Usually first manifestation (80% of cases)
• Oral Leukoplakia:
  • White patches on oral mucosa
  • High risk of malignant transformation
  • Usually appears by teenage years
  • Affects tongue, buccal mucosa, and oropharynx

2. Other Manifestations

• Ophthalmologic:
  • Epiphora (excessive tearing)
  • Blepharitis
  • Conjunctivitis
  • Nasolacrimal duct obstruction
• Dental Abnormalities:
  • Severe caries
  • Early tooth loss
  • Periodontal disease
• Gastrointestinal:
  • Esophageal strictures
  • Liver disease
  • Enteropathy
• Neurological:
  • Learning difficulties
  • Developmental delay
  • Cerebellar hypoplasia

Genetic Basis & Inheritance

Molecular Genetics

• Known Causative Genes:
  • DKC1 (X-linked form)
    • Encodes dyskerin protein
    • Essential for telomerase function
  • TERC (autosomal dominant)
    • Telomerase RNA component
  • TERT (autosomal dominant)
    • Telomerase reverse transcriptase
  • Other genes: TINF2, NOP10, NHP2, WRAP53, CTC1, RTEL1
• Inheritance Patterns:
  • X-linked (30-40% of cases)
  • Autosomal dominant (AD)
  • Autosomal recessive (AR)

Pathophysiology

• Telomere Biology:
  • Defective telomere maintenance
  • Progressive telomere shortening
  • Premature cellular aging
• Impact on Stem Cells:
  • Reduced stem cell reserves
  • Impaired tissue regeneration
  • Progressive organ dysfunction

Major Complications

1. Bone Marrow Failure

• Progressive pancytopenia
  • Thrombocytopenia (earliest)
  • Anemia
  • Neutropenia
• Main cause of early mortality
• Usually manifests by age 20-30

2. Pulmonary Disease

• Pulmonary fibrosis
  • Progressive dyspnea
  • Restrictive lung disease
  • Second most common cause of mortality

3. Malignancy Risk

• Increased risk of:
  • Head and neck squamous cell carcinoma
  • Skin cancers
  • Anorectal cancer
  • Cervical cancer
  • Acute myeloid leukemia (AML)

Diagnostic Approach

Clinical Diagnosis

• Major Criteria:
  • Classical mucocutaneous triad
  • Bone marrow failure
  • Family history
• Supporting Features:
  • Other organ system involvement
  • Early onset features
  • Characteristic radiological findings

Laboratory Studies

• Genetic Testing:
  • Multi-gene panel testing
  • Whole exome sequencing
• Telomere Length Analysis:
  • Flow-FISH analysis
  • qPCR measurement
• Hematologic Studies:
  • Complete blood count
  • Bone marrow aspiration/biopsy
  • Cytogenetic analysis

Treatment & Management

Multidisciplinary Approach

• Hematologic Management:
  • Regular monitoring of blood counts
  • Androgen therapy for bone marrow failure
  • Hematopoietic stem cell transplantation (HSCT)
  • Transfusion support as needed
• Pulmonary Care:
  • Regular pulmonary function tests
  • Early recognition of fibrosis
  • Lung transplantation consideration
• Cancer Surveillance:
  • Regular dermatologic examinations
  • Oral cancer screening
  • Age-appropriate cancer screening
• Supportive Care:
  • Genetic counseling
  • Psychological support
  • Physical therapy
  • Occupational therapy

Prevention & Monitoring

• Regular Follow-up:
  • Quarterly blood counts
  • Annual bone marrow examination
  • Pulmonary function tests
  • Cancer screening protocols
• Lifestyle Modifications:
  • Sun protection
  • Smoking avoidance
  • Regular dental care

Further Reading

Clinical Resources & References

• GeneReviews - Dyskeratosis Congenita
• NORD - Dyskeratosis Congenita
• Orphanet - Dyskeratosis Congenita
• OMIM - Dyskeratosis Congenita 1
• Dyskeratosis Congenita Outreach Inc.