Dyskeratosis congenita (DC)

Introduction and Epidemiology

• Dyskeratosis congenita (DC) is a rare, inherited multisystem telomere disorder classically characterized by mucocutaneous abnormalities and progressive bone marrow failure.
• The estimated incidence of DC in childhood is approximately 4 cases per 1 million population per year.
• Historically, the condition was defined by a classic diagnostic mucocutaneous triad consisting of dysplastic nails, lacy reticular pigmentation of the upper chest and neck, and oral leukoplakia.
• It is now recognized that this triad is not present in all individuals, and hematological manifestations (particularly bone marrow failure) are actually the most common clinical features.

Pathophysiology and Genetics

Telomere Biology

• DC is fundamentally a telomeropathy; the clinical phenotype results from deficient telomerase activity and impaired telomere maintenance.
• Telomerase is responsible for adding DNA sequences back to the ends of chromosomes (telomeres) that erode with each cycle of DNA replication.
• Due to the inability to maintain telomere length, tissues with rapid cellular turnover—such as the basal layer of the epidermis, squamous epithelium of the oral cavity, and hematopoietic stem cells (HSCs)—are profoundly affected.
• The progressive attrition and depletion of HSCs due to premature senescence, apoptosis, and chromosomal instability ultimately manifests as pancytopenia and bone marrow failure.
• Type II alveolar epithelial cells also express telomerase, explaining the high susceptibility of DC patients to progressive pulmonary fibrosis.

Genetic Mutations

• DC is genetically heterogeneous, with mutations identified in genes encoding components of the telomerase complex (TERT, TERC), telomere-capping complex (CTC1, STN1), T-loop unwinding and replication (RTEL1, RPA1), telomerase trafficking (WRAP53/TCAB1), TERC-associated factors (DKC1, NOP10, NHP2, NAF1), TERC-maturation factors (PARN), and the telomere-shelterin complex (TINF2, POT1, ACD).
• Approximately 70% of individuals meeting the clinical diagnostic criteria for DC have an identifiable pathogenic variant in one of the known DC-related genes.
• X-linked recessive inheritance: Maps to Xq28 and is caused by mutations in the DKC1 gene, which encodes the nucleolar protein dyskerin. DKC1 mutations are the most common, accounting for 20–25% of cases.
• Autosomal dominant inheritance: Caused by mutations in TINF2 (12–20% of cases), TERC (5–10%), TERT, RTEL1, ACD, NAF1, and RPA1.
• Autosomal recessive inheritance: Linked to mutations in NOP10, NHP2, WRAP53/TCAB1, CTC1, STN1, TERT, TERC, RTEL1, PARN, and ACD.
• Affected members within the same family may exhibit wide variability in clinical presentation and severity, indicating the influence of modifying genes or environmental factors.

Clinical Manifestations

The Mucocutaneous Triad

• Skin Pigmentation (89%): Lacy reticulated hyperpigmentation typically affecting the face, neck, chest, and arms. It usually appears in the first decade of life and progresses with age, sometimes involving the entire skin surface with a telangiectatic erythematous component.
• Nail Dystrophy (88%): Affects both hands and feet, frequently presenting as the initial symptom. It begins with longitudinal ridging, splitting, or pterygium formation and can progress to complete nail loss.
• Oral Leukoplakia (78%): Typically involves the tongue, but leukoplakia can also be found on the conjunctiva and the anal, urethral, or genital mucosa. It may present later than the skin and nail changes.
• Additional ectodermal findings include premature graying of hair, hair loss, hyperhidrosis of the palms and soles, and extensive dental caries or tooth loss.

Hematologic Manifestations

• Bone marrow failure develops in approximately 90% of patients at some point in their lives, with 80% developing it by 30 years of age.
• The initial hematologic presentation is usually isolated thrombocytopenia or anemia, which progressively evolves into generalized pancytopenia and severe aplastic anemia (SAA).
• The median age for the onset of pancytopenia is roughly 10 years.
• Patients typically present with a macrocytic anemia and elevated fetal hemoglobin (HbF).
• Immunodeficiency is a significant complication, characterized by progressive cellular and humoral defects, including reduced B- and T-lymphocyte counts and absent lymphocyte proliferative responses to phytohemagglutinin (particularly in DKC1-associated disease).

Non-Hematologic Organ System Involvement

• Pulmonary: Pulmonary fibrosis and restrictive lung disease with reduced diffusion capacity occur in approximately 20% of patients. It is a unique and often fatal complication of DC.
• Ophthalmic: Excessive tearing (epiphora) due to nasolacrimal duct obstruction is seen in about 30% of patients. Blepharitis, conjunctivitis, loss of eyelashes, cataracts, strabismus, and optic atrophy also occur.
• Gastrointestinal and Hepatic: Liver fibrosis, esophageal webs and strictures, peptic ulceration, and severe GI bleeding caused by vascular lesions.
• Neurological: Learning difficulties and developmental delay are observed in approximately 25% of patients.
• Skeletal: Osteoporosis, avascular necrosis of the hips and shoulders, abnormal bone trabeculation, scoliosis, and mandibular hypoplasia.
• Genitourinary: Hypoplastic testes, hypospadias, phimosis, urethral stenosis, and horseshoe kidney.

Severe Variant Syndromes

• Hoyeraal-Hreidarsson Syndrome: A severe, early-childhood multisystem variant characterized by the classic DC triad plus cerebellar hypoplasia, intrauterine growth restriction (IUGR), severe immunodeficiency, and early-onset bone marrow failure. It is primarily caused by X-linked recessive DKC1 mutations.
• Revesz Syndrome: Presents in early childhood with DC features plus bilateral exudative retinopathy (essential for diagnosis) and intracranial calcifications. It is primarily an autosomal dominant condition linked to TINF2 mutations.
• Coats Plus Syndrome: Caused by compound heterozygous mutations in CTC1 or STN1. It overlaps with DC (sparse/graying hair, dystrophic nails, anemia) but is distinguished by retinal telangiectasia and exudates, leukodystrophy, brain cysts, intracranial calcifications, osteopenia, and portal hypertension secondary to vascular ectasias in the GI tract and liver.

Cancer Predisposition

• DC patients carry a markedly increased, premature risk of developing both hematologic malignancies and solid tumors, typically emerging in the third and fourth decades of life.
• Hematologic Malignancies: The actuarial risk for clonal and malignant myeloid disease (myelodysplastic syndrome [MDS] and acute myeloid leukemia [AML]) is 25% by 18 years of age.
• Solid Tumors: Approximately 40% of cancers in DC patients are squamous cell carcinomas (SCCs) of the head and neck (tongue, mouth, pharynx).
• SCCs of the skin, esophagus, stomach, and colon, as well as anorectal adenocarcinomas, are also highly prevalent.
• Patients are prone to developing multiple separate primary tumors simultaneously.

Diagnostic Evaluation

Laboratory Findings

• Complete blood count (CBC) reveals cytopenias (thrombocytopenia, anemia) or full pancytopenia with macrocytosis and elevated HbF.
• Early bone marrow aspirates and biopsies may show normocellular or hypercellular marrow, which eventually undergoes symmetric depletion of all hematopoietic lineages, replacing hematopoietic space with fat.
• Primary skin fibroblasts in culture display abnormal morphology, poor doubling rates, and spontaneous unbalanced chromosomal rearrangements (dicentrics, tricentrics, translocations) in the absence of clastogenic agents like diepoxybutane (DEB) or mitomycin C (MMC).
• Unlike Fanconi anemia, DC cells do not exhibit significant hypersensitivity to DNA cross-linking agents, distinguishing the two conditions.

Confirmatory Testing

• Clinical Criteria: The classic diagnosis requires at least two of the four major features (abnormal skin pigmentation, nail dystrophy, leukoplakia, bone marrow failure) plus two or more minor somatic features.
• Telomere Length Measurement: The hallmark diagnostic test is automated multicolor flow-fluorescence in situ hybridization (flow-FISH) of peripheral blood leukocyte subsets. Telomere lengths below the 1st percentile for age yield a 97% sensitivity and 91% specificity for DC. However, older adult patients or those with specific genetic variants may occasionally have telomeres in the low-normal range rather than below the 1st percentile.
• Molecular/Genetic Testing: Next-generation sequencing (NGS) panels targeting known telomere biology genes or whole-exome sequencing (WES) should be employed to establish the exact genetic diagnosis.
• Imaging Precautions: Due to inherent genomic instability, imaging modalities utilizing ionizing radiation should be strictly limited to those necessary for acute management.

Management and Treatment

Medical Therapy

• Supportive care includes judicious use of irradiated, leukocyte-depleted blood products, antimicrobials, and antifibrinolytic agents for symptomatic cytopenias.
• Androgen Therapy: Agents such as oxymetholone or danazol can stimulate hematopoiesis and induce a clinically meaningful improvement in bone marrow function in approximately 70% of DC patients.
• Responses to androgens can normalize trilineage counts for years, but patients generally require lifelong therapy at the lowest effective dose.
• Over time, patients inevitably become refractory to androgens due to progressive stem cell depletion. DC patients are highly sensitive to androgen side effects, requiring frequent monitoring.
• Granulocyte colony-stimulating factor (G-CSF) and erythropoietin may produce transient responses but are not definitive treatments. Immunosuppressive therapy (IST) is entirely ineffective.

Hematopoietic Stem Cell Transplantation (HSCT)

• Allogeneic HSCT is the only curative option for the bone marrow failure, MDS, and leukemia associated with DC.
• Transplantation is indicated for patients with severe marrow failure who have an HLA-matched related or alternative donor and lack absolute contraindications.
• Standard myeloablative conditioning regimens cause unacceptable mortality because DC patients have exquisite sensitivity to radiation and alkylating agents, and a high baseline risk for fatal interstitial pulmonary fibrosis and hepatic veno-occlusive disease.
• Immunoablative or reduced-intensity conditioning (RIC) regimens (typically avoiding total body irradiation) are the standard of care to minimize pulmonary toxicity and the secondary nonhematologic cancer risk.
• Even with optimized regimens, long-term HSCT outcomes remain guarded due to early infectious complications, chronic graft-versus-host disease (cGVHD), and progressive pulmonary fibrosis or secondary malignancies that occur post-transplant.

Prognosis

• DC is marked by extreme phenotypic and prognostic heterogeneity based on the specific genetic variant inherited.
• Patients with monoallelic TERC or TERT mutations often present later in adulthood with isolated aplastic anemia or pulmonary/hepatic fibrosis, without classic multisystem anomalies.
• Conversely, patients with DKC1, TINF2, PARN, ACD, or RTEL1 mutations generally exhibit earlier onset of the mucocutaneous triad, rapid progression to aplastic anemia, and a higher risk of early-onset malignancies.
• The median overall survival for patients with classic DC is approximately 40 to 45 years, though those diagnosed in early childhood have a mean age of death closer to 30 years.
• The primary causes of mortality are bone marrow failure, progressive pulmonary fibrosis, complications related to HSCT, severe gastrointestinal hemorrhage, and secondary malignancies.