SUMMARY
1. Dyskeratosis Congenita (DKC) is a syndrome characterized by progressive bone marrow failure (pancytopenia), immunodeficiency, cancer predisposition, and somatic abnormalities resulting from defective telomere maintenance. X-linked, autosomal dominant, and autosomal recessive forms of disease have been described.
2. Telomeres are structures at the end of linear chromosomes that prevent the loss of genetic material that normally occurs with every cell division. Once telomeres reach a critical length, cell senescence and apoptosis occurs.
3. Certain highly proliferative cell types such as hematopoietic stem cells and lymphocytes express telomerase, and enzyme that catalyzes DNA synthesis to extend telomere length and thus maintain cell viability.
4. The classically described somatic triad in this disease includes nail dystrophy, skin abnormalities and oral leukoplakia. However, other more clinically relevant features include pancytopenia, severe enteropathy, GI tract strictures, and pulmonary fibrosis.
5. The median age at diagnosis for DKC is 15 years. However, the age at initial presentation can range from infancy to the 8th decade of life. The infant form of the disease (previously known as Hoyeraal-Hreidarsson syndrome) presents with a SCID-like phenotype with invasive and opportunistic infections. Some patients may have milder recurrent sinopulmonary infections or no infectious complications.
6. Lymphopenia is a common abnormality seen in patients at initial presentation. T cell numbers are usually normal but B and NK cell numbers can be markedly decreased. As a result, patients may have a T+B-NK- phenotype. Hypogammaglobulinemia occurs as a result of low B cell numbers. Although T cell numbers can be normal, abnormal T cell proliferation to specific antigens (but not to mitogens) is a common finding. Neutropenia can also develop as a result of progressive marrow failure.
7. To date, six causative DKC genes have been identified. Five genes encode for telomerase complex proteins (TERC, TERT, DKC1, NOP10, NHP2) while one gene encodes for a shelterin complex protein (TINF2).
8. Diagnosis involves demonstration of short telomere lengths on lymphocytes followed by mutation analysis (however one-half of all patients remain genetically uncharacterized). Humoral and cell mediated immune studies are necessary to establish the degree of immunodeficiency.
9. Supportive therapies for immune abnormalities include IVIG (for hypogammaglobulinemia) and PJP prophylaxis with trimethoprim-sulfamethoxazole. Some patients with pancytopenia are responsive to androgen therapy. G-CSF can be used to treat neutropenia.
10. The only definitive cure for the bone marrow failure remains a stem cell transplant. However this procedure is associated with high morbidity and mortality. It is reserved for patients who develop severe pancytopenia refractory to medical therapy.
11. Immune abnormalities can precede the development of clinically relevant anemia or thrombocytopenia by many years. Thus, it is important to maximize therapy for immunodeficiency prior to the onset of more complete pancytopenia.
OVERVIEW
Telomeres are structures at the ends of linear chromosomes that prevent the loss of genetic material that normally occurs with every cell division (50-200 bases of DNA are lost per division). They consist of hundreds to thousands of six nucleotide repeats (TTAGGG) on the leading strand. As telomeres shorten and reach a critical length, cell growth arrest and senescence/apoptosis will be triggered. Certain highly proliferative cell types such as hematopoietic stem cells and lymphocytes express telomerase, an enzyme that catalyzes DNA synthesis to extend telomere length to maintain cell viability through repeated cycles of cell division.
Dyskeratosis Congenita (DKC) is a rare syndrome characterized by immunodeficiency, bone marrow failure (pancytopenia), and cancer predisposition resulting from defective telomere maintenance. The classic somatic findings in this syndrome include nail dystrophy, skin abnormalities, and oral leukoplakia. However, other clinically significant findings include severe enteropathy, GI tract strictures, and pulmonary fibrosis. There is a wide spectrum of disease severity and age at initial presentation. Patients can have severe infant-onset disease (resembling SCID) or may present much later in adulthood (the median age of onset is 15 years old).
Immunodeficiency and infectious complications are the main cause of mortality in DKC. Immune defects can often precede the development of other bone marrow abnormalities such as anemia and thrombocytopenia by many years. Lymphopenia is a common abnormality found in patients at initial presentation. Immunophenotyping of lymphocytes may reveal very low B and NK cell numbers but relatively preserved T cell numbers (sometimes referred to as a T+B-NK- phenotype). Low immunoglobulin levels secondary to depressed B cell numbers is common. Although T cell numbers are typically normal, T cell function in response to specific antigens (but not to mitogen stimulation) is often reduced.
The severe infant form of DKC was previously known as Hoyeraal-Hreidarsson (HH) syndrome. However, the demonstration of DKC mutations in these patients confirmed that HH syndrome is in fact a severe variant of DKC. Patients with infant-onset forms of disease present with IUGR, failure to thrive, microcephaly, cerebellar hypoplasia, and severe enteropathy. Significant immunodeficiency resulting in infectious complications (Pneumocystis jiroveci pneumonia, candidemia, sepsis) can be seen in these patients. The presence of lymphopenia, opportunistic infections, failure to thrive, and severe diarrhea in infant DKC patients can be clinically confused with SCID with maternal T-cell engraftment or HIV infection.
The risk of malignancies is greatly increased in DKC. Squamous cell carcinoma of the skin, oropharynx, and GI tract as well as leukemia are common. These cancers typically develop in the third and fouth decades of life.
PATHOGENESIS
To date, mutations in five genes encoding for telomerase complex proteins (TERC, TERT, DKC1, NOP10, NHP2) and one gene encoding for a shelterin protein (TINF2) have been identified. Approximately one-half of DKC patients continue to be genetically uncharacterized.
Certain somatic tissues that require constant renewal, hematopoietic stem cells, lymphocytes, and germ line cells require telomerase to maintain telomere length through multiple rounds of cell division. As a result, DKC patients develop bone marrow abnormalities as well as somatic abnormalities in the skin, nails, and GI tract.
The adaptive immune system requires rapid clonal expansion in response to specific antigen stimulation. B cells may be more sensitive than T cells to dysfunction of telomerase because B cells undergo antigen induced clonal expansion followed by additional expansion during somatic hypermutation while T cells only undergo antigen induced clonal expansion.
The finding of decreased proliferation to specific antigens (but not to mitogens) may be explained by the fact that memory T cells have undergone greater antigen induced clonal expansion than naïve T cells resulting in shorter telomeres. This results in premature senescence of memory T cells and resultant impaired proliferation to antigen re-exposure.
EVALUATION
DKC should be considered in patients with characteristic somatic findings, immunologic abnormalities, or evidence of marrow failure.
Step 1: Screening for A-T and ATLD
- CBC with Differential
- Lymphocyte subset enumeration by flow cytometry
- IgG, IgA, IgM levels
- Specific Antibody levels
- T cell proliferation to Mitogens (PHA, Con A, PWM)
- T cell proliferation to Antigens (Candida, Tetanus)
-CBC with differential may reveal lymphopenia, neutropenia, anemia, or thrombocytopenia
-Lymphocyte flow cytometry may reveal low B and NK cell numbers but relatively preserved T cell numbers.
-Low total immunoglobulins and poor specific antibody levels may be present due to low B cell numbers
-T cell proliferation to mitogens is typically intact but proliferation to antigens is reduced.
Step 2: Telomere Length Measurement
The following tests may provide additional support for a diagnosis of SCID and can be helpful in certain clinical situations but not necessarily required.
-Telomere length (Flow-FISH)
-This test is used to detect telomere length on lymphocytes and is commercially available through Repeat Diagnostics.
-Telomere lengths are markedly decreased in DKC but not not in other bone marrow failure syndromes.
Step 3: Mutational analysis (for patients with decreased telomere lengths)
-Gene sequencing for X-linked DKC (DKC1)
-Gene sequencing for AD DKC (TERT, TERC, TINF2)
-Gene sequencing for AR DKC (NOP10, NHP2)
-Testing for all 6 gene mutations is commercially available through Ambry Genetics. One-half of patients remain genetically uncharacterized.
MANAGEMENT
1. The following consensus management recommendations resulted from the first DKC NIH Clinical Research Workshop 2008:
-Annual skin exam by a dermatologist and limitation of sun exposure (due to increased risk of skin cancer)
-Annual oral, head, and neck cancer screening by an otolaryngologist
-Annual liver function tests and liver ultrasounds (if on androgen therapy)
-Annual pulmonary function tests (to screen for pulmonary fibrosis)
-Calcium and vitamin D supplementation (for osteoporosis)
-Bi-annual complete blood counts
-Baseline bone marrow biopsy at diagnosis. Consider annual bone marrow biopsy.
-Treatment of bone marrow failure should be considered if the hemoglobin is less than 8 g/dl, platelets less then 30,000/mm3, and neutrophils below 1,000/mm3. In addition to the above guidelines, baseline immune screening studies including IgG, IgM, IgA, specific antibody titers to vaccines, lymphocyte flow cytometry, and T cell function studies (proliferation to mitogens and antigens) should be performed.
2. Immunodeficiency and Marrow Failure (medical management):
-Patients with low IgG or poor specific antibody titers should be treated with IVIG replacement therapy.
-Trimethoprim-sulfamethoxazole prophylaxis should be considered for patients with decreased T-cell numbers or function.
-Patients with neutropenia may respond to G-CSF therapy
-Erythropoietin may be used to treat anemia
-Patients with significant marrow failure (pancytopenia) may respond to treatment with androgen therapy (60% of patients respond). Oxymetholone 0.5-1mg/kg per day is a typical dose (It may take 2-3 months to see an effect). Baseline liver and spleen ultrasound as well as monitoring of liver enzymes is important while on this therapy.
-The combination of GCSF and Androgens should be avoided due to the risk of developing splenic peliosis (blood filled cysts that can rupture and cause life-threatening internal hemorrhage).
3. Immunodeficiency and Marrow Failure (Hematopoietic stem cell transplant):
-Hematopoietic Stem Cell Transplant (HSCT) is the only definitive cure for the bone marrow failue and immune deficiency seen in DKC.
-Severe marrow failure refractory to medical therapy (androgens, G-CSF) or leukemia would be an indication for this procedure if there is a fully matched donor.
-DKC patients appear to be at greater risk from radiochemotherapy and post-transplant complications (graft failure, GVHD, sepsis, pulmonary fibrosis, cirrhosis, and veno-occlusive disease). Use of reduced-intensity conditioning regimens may improve post-transplant outcomes in the future.
-It should be noted that the HSCT will not have any effect on the somatic findings (oral leukoplakia, nail dystrophy, severe enteropathy, pulmonary fibrosis) or the risk of malignancies.
RESOURCES
Diagnostic Resources
1. Repeat Diagnostics - Telomere Length Assay (Flow-FISH)
2. Ambry Genetics - 6 Gene Panel
Literature Resources
1. Savage 2009
DKC Review
2. Savage 2009
NIH DKC Clinical workshop and guidelines
3. Calado 2009
Telomere diseases NEJM
Severe Enterocolitis in infants DKC