Dyskeratosis congenita

Overview

Dyskeratosis congenita (DC) is a rare, inherited disorder that primarily affects the skin, nails, mucous membranes, and bone marrow. It is considered a form of telomere biology disorder, meaning it results from defects in the maintenance of telomeres, the protective caps at the ends of chromosomes. Over time, shortened telomeres impair the ability of cells to divide and renew, leading to premature aging and failure of tissues with high turnover, such as blood cells and epithelial tissue. DC can present in childhood or adulthood and may lead to life-threatening complications, particularly bone marrow failure and cancer.

Causes

Dyskeratosis congenita is caused by mutations in genes involved in telomere maintenance. The most commonly affected genes include:

• DKC1 (X-linked recessive)

• TERC, TERT, TINF2, NOP10, NHP2 (autosomal dominant or recessive)

These genes are responsible for producing components of the enzyme telomerase or related proteins that maintain telomere length. Mutations lead to progressive telomere shortening, especially in rapidly dividing cells, resulting in cellular dysfunction and clinical features of DC. The condition can be inherited in X-linked, autosomal dominant, or autosomal recessive patterns, depending on the mutated gene.

Symptoms

The classic clinical triad of Dyskeratosis congenita includes:

• Nail dystrophy: Brittle, ridged, or absent fingernails and toenails

• Skin pigmentation: Lacy, reticulated hyperpigmentation, typically on the neck and upper chest

• Oral leukoplakia: White patches on the tongue or inside the cheeks that can potentially become cancerous

Additional symptoms may develop over time and include:

• Bone marrow failure: Leading to anemia, low white blood cells, and low platelets (pancytopenia)

• Pulmonary fibrosis: Progressive scarring of lung tissue causing respiratory issues

• Liver disease: Including cirrhosis or portal hypertension

• Gastrointestinal issues: Esophageal or anal strictures

• Eye abnormalities: Including tearing, irritation, or eyelash loss

• Infertility or hypogonadism: In males and females

• Increased cancer risk: Especially squamous cell carcinoma and hematologic malignancies like myelodysplastic syndrome (MDS) or leukemia

Diagnosis

Diagnosis of Dyskeratosis congenita involves a combination of clinical assessment, family history, genetic testing, and evaluation of telomere length. Steps include:

• Clinical examination: Looking for the characteristic triad and other systemic signs

• Telomere length testing: Flow-FISH (fluorescence in situ hybridization with flow cytometry) is commonly used to measure telomere length in white blood cells; shortened telomeres are diagnostic

• Genetic testing: To identify mutations in DC-associated genes

• Bone marrow biopsy: Performed if pancytopenia is present to evaluate marrow function and rule out malignancy

Because DC can be part of a broader spectrum of telomere biology disorders, it’s important to distinguish it from related conditions such as Revesz syndrome and Hoyeraal-Hreidarsson syndrome.

Treatment

There is no cure for Dyskeratosis congenita, but management focuses on treating complications, especially bone marrow failure and organ dysfunction. Key treatments include:

• Hematologic support:

  • Androgens (e.g., danazol) to stimulate blood cell production

  • Hematopoietic growth factors

  • Red blood cell and platelet transfusions

  • Bone marrow (stem cell) transplantation: the only curative option for bone marrow failure, though it carries significant risks, especially in DC patients with other organ involvement

• Lung care: Management of pulmonary fibrosis with oxygen, antifibrotic agents, and lung transplantation in select cases

• Surveillance for cancer: Regular monitoring for skin, oral, and hematologic malignancies

• Liver and GI management: Monitoring and treatment of hepatic complications and strictures

• Genetic counseling: Important for affected individuals and family members due to inheritance risks

Prognosis

The prognosis for individuals with Dyskeratosis congenita varies based on the severity of telomere shortening and organ involvement. Bone marrow failure typically develops in childhood or adolescence and is the leading cause of early morbidity and mortality. Pulmonary fibrosis and liver disease are also serious complications that affect long-term outcomes. With supportive care and advancements in bone marrow transplantation, some individuals survive into adulthood, though life expectancy is generally reduced. Lifelong monitoring and multidisciplinary care are essential to managing complications and improving quality of life.