Dyskeratosis Congenita

Dyskeratosis congenita (DC) is characterized by ectodermal dysplasia and hematopoietic failure. The classic triad of ectodermal dysplasia consists of abnormal skin pigmentation, dystrophic nails, and leukoplakia of mucous membranes. In addition to the classic triad, there are a number of other somatic findings in DC. The most common of these are epiphora (tearing due to obstructed tear ducts), developmental delay, pulmonary disease, short stature, esophageal webs, dental caries, tooth loss, premature gray hair, and hair loss. Other ocular, dental, skeletal, cutaneous, genitourinary, gastrointestinal, and CNS abnormalities have also been reported.

The median age for the onset of mucocutaneous abnormalities is 6-8 years. Nail changes occur first. The median age for the onset of pancytopenia is 10 years. Approximately 50% of patients develop severe aplastic anemia and greater than 90% develop at least a single cytopenia by 40 years of age. The anemia is associated with a high MCV and elevated fetal hemoglobin. In a number of cases, aplastic anemia precedes the onset of abnormal skin, dystrophic nails, or leukoplakia. As with FA it is the nonhematologic manifestations of DC that are of particular concern especially when hematopoietic stem cell transplantation for bone marrow failure is considered.

Pathophysiology

Recent evidence establishes DC to be the result of deficient telomerase activity. Telomerase adds DNA sequence back to the ends of chromosomes that are eroded with each DNA replication. Telomerase activity is found in tissues with rapid turnover such as the basal layer of the epidermis, squamous epithelium of the oral cavity, hematopoietic stem cells and progenitors, and in other tissues affected in DC. The lack of telomerase activity also gives rise to chromosome instability resulting in the high rate of premature cancer observed in these tissues. Epithelial malignancies develop at or beyond the third decade of life. About one in five patients will develop progressive pulmonary disease characterized by fibrosis, resulting in diminished diffusion capacity and/or restrictive lung disease. Of note, type 2 alveolar epithelial cells express telomerase. It is likely that more pulmonary disease would be evident if patients did not succumb earlier to the complications of severe aplastic anemia and cancer.

Genetics

Dyskeratosis congenita is most commonly inherited as an X-linked recessive gene with 86% of patients being male, although some of these represent autosomal dominant or recessive inheritance. The gene responsible for the X-linked form was mapped to Xq28 and subsequently identified as DKC1. DKC1 codes for dyskerin, a nucleolar protein associated with nucleolar RNAs. Dyskerin is also associated with the telomerase complex. This later function appears to be the one involved in the pathophysiology of DC, as the dominant form has recently been mapped to a gene that encodes telomerase RNA (hTR). Autosomal recessive forms have been inferred from pedigrees, in particular those described with brother-sister pairs in consanguineous families. All three genetic subtypes have many common features; however, autosomal recessive patients appear to have a more severe phenotype. Affected members within the same family may exhibit wide variability in clinical presentation, suggesting the influence of modifying genes and environmental factors.

Clinical Course

• Bone marrow failure: Sixty-seven percent of the deaths are a consequence of bone marrow failure, and 9% die of lung disease with or without HSCT.

• Malignancy: Almost 9% of patients develop cancer (MDS, Hodgkin disease, and carcinoma). The degree of predisposition to leukemia is yet to be clearly defined.

• Immunodeficiency: Significant progressive immunodeficiency occurs in DC. The vast majority of patients (80%), with or without neutropenia, die from infection, some opportunistic, usually before 30 years of age. Although DC is predominantly a cellular immune defect, it is reasonable to assume that immunodeficiency as well as neutropenia play a significant role in the infectious morbidity and mortality in DC.

• Outcome: Median survival of approximately 35 years for both X-linked and autosomal recessive forms of DC. There are too few autosomal dominant cases for such an analysis. The prognosis for patients with DC is poor.

Therapy

Responses to androgens, G-CSF or GM-CSF, as well as erythropoietin and rarely splenectomy, have been documented. However, for the most part these responses have been transient. Immunomodulatory therapy is ineffective. Supportive care with blood products, antibiotics, and antifibrinolytic agents is similar to that used for idio-pathic aplastic anemia. Once these measures are required, HSCT should be considered for those patients with an HLA-matched related donor or an acceptable alternative donor and no DC-related contraindications. The results have been poor with failure due predominantly to pulmonary complications. All DC patients are at a high risk of interstitial pulmonary disease when undergoing HSCT. Unfortunately, there have been too few transplant survivors to determine whether an increase in the prevalence of cancer will follow as a consequence of HSCT. An immunoablative rather than a myeloablative approach may reduce the incremental risk of pulmonary toxicity as well as the potential for nonhematologic cancer risk.

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