Clinical Diagnosis

Individuals with characteristic clinical findings described below who have very short telomeres and/or a mutation in one of the genes known to be associated with dyskeratosis congenita (DC) should be considered as having DC. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic DC as well as those with very short telomeres and an isolated physical finding [Armanios 2009, Kirwan & Dokal 2009, Savage & Alter 2009, Savage & Bertuch 2010].

Dyskeratosis congenita (DC) should be suspected in individuals with the following findings [Vulliamy et al 2006, Savage & Bertuch 2010]:

Physical abnormalities

• At least two features of the classic clinical triad of (Figure 1):

  • Dysplastic nails. May be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nails

  • Lacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck.

  • Oral leukoplakia

• One feature of the classic triad plus two or more of the following [Vulliamy et al 2006]:

  • Epiphora

  • Blepharitis

  • Abnormal eyelashes

  • Prematurely gray hair

  • Alopecia

  • Periodontal disease

  • Taurodontism (enlarged tooth pulp chambers) or decreased tooth root/crown ratio

  • Developmental delay

  • Short stature

  • Microcephaly

  • Hypogonadism

  • Esophageal stenosis

  • Urethral stenosis

  • Liver disease

  • Osteoporosis

  • Avascular necrosis of the hips or shoulders.

Figure

Figure 1. Examples of the dyskeratosis congenita diagnostic triad
A. Skin pigmentation
B. Dysplastic fingernails and toenails
C. Oral leukoplakia

Note: Individuals with DC may have none of the above additional findings; the findings may appear or worsen with age.

Progressive bone marrow failure (BMF). May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen.

Myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). May be the presenting sign.

Solid tumors, usually head/neck or anogenital cancer, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC in individuals who do not have BMF.

Pulmonary fibrosis. See Primary Pulmonary Fibrosis.

Testing

Telomere length. Telomeres are long nucleotide repeats (TTAGGG)_n and a protein complex at chromosome ends that are essential to chromosomal integrity. All individuals with a telomere disorder have abnormally short telomeres for their age, as determined by automated multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on white blood cell (WBC) subsets. Telomere length testing for DC and related telomere biology disorders is available from a CLIA-certified laboratory.

Telomere length in total leukocytes and in leukocyte subsets (granulocytes, total lymphocytes, naïve T-cells, memory T-cells, B-cells, and natural killer [NK] cells) was determined by flow-FISH on cells from persons with DC, their relatives, and persons with other inherited bone marrow failure syndromes (IBMFS). Data from 400 healthy controls (newborn through age 100 years) was used to generate percentiles of normal telomere length; values below the first percentile for age were considered “very short.”

The diagnostic sensitivity and specificity of very short telomeres was more than 90% in total lymphocytes, naïve T-cells, and B-cells for the diagnosis of DC in comparison with healthy relatives of persons with DC or persons with non-DC IBMFS. Rare healthy relatives with very short telomeres were later shown to have mutations in the same DC-related gene as the proband. Evaluation of the panel of six leukocyte subsets provided the greatest degree of sensitivity and specificity; the best statistical performance characteristics were obtained by finding very short telomeres in at least three or four of the subsets; granulocytes were the least specific cell type [Alter et al 2007]. A follow-up study with a much larger sample size confirmed this finding [Alter et al 2012]. It also suggested that if the clinical suspicion of DC is high, total lymphocyte telomere length is sufficient for diagnosis. The positive predictive value was 85% in individuals with telomere length below the first percentile for age and a clinical suspicion of DC. However, in less straightforward cases, the six-panel test may be more sensitive and specific.

Note: Another study [Du et al 2009b] performed in a different research laboratory using a different technique suggested that peripheral blood mononuclear cell telomere length was less specific for the diagnosis of classic DC; however, the significant differences between the laboratories and analytic methods used suggest that these studies are not directly comparable.

Molecular Genetic Testing

Genes. To date, DKC1, TERC, TERT, TINF2, WRAP53, NHP2, and NOP10 are the only genes in which mutations are known to cause DC and short telomeres (Figure 3).

Figure

Figure 3. Telomere length and structure are regulated by a host of proteins. Mutations affecting a subset of these proteins have been implicated in telomere biology disorders. The percentages indicate the approximate number of cases resulting from mutations (more...)

Evidence for locus heterogeneity. Mutations in one of the seven genes mentioned above have been identified in approximately half of individuals who meet clinical diagnostic criteria for DC.

Table 1. Summary of Molecular Genetic Testing Used in Dyskeratosis Congenita

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Gene Symbol	Mode of Inheritance	Proportion of DC Attributed to Mutations in This Gene 1	Test Method	Mutations Detected	Test Availability
DKC1	XL 2	17%-36%	Sequence analysis	Sequence variants 3, 4	Clinical
			Deletion / duplication analysis 5, 6	Exonic or whole-gene deletions 7, 8
TERC	AD 9	6%-10%	Sequence analysis	Sequence variants 3	Clinical
			Deletion / duplication analysis 5	Exonic or whole-gene deletions 8
TERT	AD and AR 10	1%-7%	Sequence analysis	Sequence variants 3	Clinical
			Deletion / duplication analysis 5	Exonic or whole-gene deletions 8
TINF2	AD 11	11%-24%	Sequence analysis	Sequence variants 3, 12	Clinical
			Sequence analysis of select exons	Sequence variants of exon 6 13
NHP2	AR 14	<1%	Sequence analysis of select exons	Sequence variants of exon 4 13	Clinical
NOP10	AR 15	<1%	Sequence analysis of select exons	Sequence variants of exon 2 15	Clinical
WRAP53 (TCAB1)	AR 16	3%	Sequence analysis	Sequence variants 3	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Data from Vulliamy et al [2006], Walne et al [2007], Savage et al [2008], Vulliamy et al [2008], Walne et al [2008]

2. Knight et al [1999b]

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis. Sequence analysis of genomic DNA cannot detect deletion of an exon(s) or whole-gene deletions on the X chromosome in carrier females.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. See CMA.

6. Deletion/duplication analysis may be useful to confirm a putative exonic or whole-gene DKC1 deletion on the X chromosome in affected males after failure of PCR amplification. If such a deletion is identified in a male, this test would be useful for carrier testing of female relatives.

7. One 3’ deletion involving DKC1 in a female carrier of dyskeratosis congenita has been reported [Vulliamy et al 1999].

8. No deletions or duplications involving DKC1, TERC, or TERT as causative of dyskeratosis congenita have been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

9. Vulliamy et al [2004]

10. Marrone et al [2007b], Vulliamy et al [2005]

11. Savage et al [2008]

12. Note: All TINF2 mutations described to date have been located in exon 6.

13. All mutations described to date have been located in this exon.

14. Vulliamy et al [2008]

15. Walne et al [2007]

16. Zhong et al [2011]

Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found at www.eurogentest.org [Dokal et al 2011; see full text].

Interpretation of test results. Tissue-restricted mosaicism has been observed in a limited number of individuals heterozygous for a TERC germline mutation. Specifically, a pathogenic TERC germline mutation that was not observed by molecular genetic testing of DNA extracted from peripheral blood cells was detected in DNA extracted from other cells (e.g. skin fibroblasts) of the individual [Jongmans et al 2012]. Tissue-restricted mosaicism resulted from revertant somatic mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells, particularly in individuals with DC without bone marrow failure. The assumption is that the selective advantage of the revertant hematopoietic cells allows them to populate the bone marrow, resulting in the inability to detect the mutation in DNA extracted from these cells. To date, this has only been observed in individuals with germline TERC mutations. Molecular genetic testing of a second tissue source should be considered in individuals who meet the diagnostic criteria for DC but do not have a disease-causing mutation identified on molecular genetic testing of peripheral blood cells.

For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. Individuals with suspected DC should undergo leukocyte telomere length testing by automated multicolor flow-FISH in the six-cell panel assay. Telomere length less than the first percentile for age in lymphocytes is 97% sensitive and 91% specific for DC. In individuals with complex or atypical DC, the six-cell panel may be more informative than the two-panel test of total lymphocytes and granulocytes [Alter et al 2012].

Molecular genetic testing should be considered if telomere length testing reveals telomere lengths less than the first percentile for age.

• If male, begin with DKC1 sequence analysis.

• Further molecular genetic testing can be prioritized based on:

  • Likely mode of inheritance as per the family history (Table 1),

  • The probability that mutation of a given gene is causative (Table 1), and

  • The clinical phenotype (see Genotype-Phenotype Correlations).

• Note: Individuals who appear to fulfill diagnostic criteria for DC (especially those without bone marrow failure) but in whom molecular genetic testing of DNA extracted from peripheral blood fails to identify a disease-causing mutation warrant consideration of testing of a second tissue (e.g., skin fibroblasts) because of the possibility of tissue-restricted mosaicism for a deleterious germline mutation (see Interpretation of test results).

Carrier testing for relatives at risk for X-linked dyskeratosis congenita (caused by mutations in DKC1) requires prior identification of the disease-causing mutation in the family.

Note: (1) Female carriers are heterozygotes for the X-linked form. The development of clinical manifestations in female carriers is extremely rare. (2) Identification of female carriers requires either prior identification of the disease-causing mutation in the family or, if an affected male is not available for testing, sequence analysis. If sequence analysis results are negative, deletion/duplication analysis should be performed to identify heterozygous exonic, multiple exonic, or whole-gene deletions that are not detectable by sequence analysis in carrier females.

Carrier testing for relatives at risk for autosomal recessive dyskeratosis congenita (caused by mutations in TERT, WRAP53, NHP2, or NOP10) requires prior identification of the disease-causing mutations in the family.

Note: Heterozygotes for these autosomal recessive disorders may not be at increased risk of developing the disorder. However, mutations in TERT can cause both autosomal dominant and autosomal recessive DC; the effect of heterozygosity for one mutant TERT allele in individuals from families with autosomal recessive DC mutations is not known.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family or, if a mutation is not identified in an affected family member, documentation of short telomere length in an affected relative.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies for most known types of DC require prior identification of the disease-causing mutation(s) in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Acquired aplastic anemia has been associated with germline mutations in TERC and TERT [Yamaguchi et al 2003, Yamaguchi et al 2005]. Some persons with apparently acquired aplastic anemia may actually have undiagnosed DC or a milder form of this telomere biology disorder.

Idiopathic pulmonary fibrosis has been associated with mutations and single-nucleotide polymorphisms in TERT and TERC [Armanios et al 2007, Tsakiri et al 2007, Alder et al 2008]. This is also a telomere biology disorder closely related to DC (See Primary Pulmonary Fibrosis.)

Liver cirrhosis associated with germline mutations in TERT or TERC has been reported in up to 7% of affected individuals [Hartmann et al 2011, Calado et al 2011].

All of these disorders overlap clinically with features of DC and appear to be part of the spectrum of telomere biology disorders, of which classic DC is the most severe [Armanios 2009, Savage & Bertuch 2010].

Natural History

Classic Dyskeratosis Congenita (DC)

The classic triad of abnormal fingernails and toenails, lacy, reticular pigmentation of the neck and upper chest, and oral leukoplakia is diagnostic (Figure 1); however, these features are not present in all individuals with DC and may or may not develop over time after the appearance of other complications listed below [Savage & Bertuch 2010, Dokal 2011]. The time of onset for these medical problems varies among individuals and thus the manifestations of DC do not progress in a predictable pattern. The spectrum ranges from individuals who develop bone marrow failure (BMF) first, and then years later develop other classic findings such as nail abnormalities, to others who have severe nail problems and abnormalities of skin pigmentation but normal bone marrow function.

Dermatologic. Lacy, reticular pigmentation primarily of the neck and chest may be subtle or diffuse hyper- or hypopigmentation. Changes in skin pigmentation may become more pronounced with age. People with DC may lose dermatoglyphics with age.

Dysplastic fingernails and toenails may worsen significantly over time and nails may eventually “disappear.”

Hyperhydrosis is noted in some individuals.

Growth and development. Short stature has been reported but height is variable.

Intrauterine growth retardation has been noted in children with the more severe Hoyeraal Hreidarsson syndrome or Revesz syndrome variants.

Developmental delay may be present in some. It can be more pronounced in persons with the Hoyeraal Hreidarsson syndrome or Revesz syndrome variants.

Ophthalmic. Epiphora caused by stenosis of the lacrimal drainage system can result in blepharitis.

Abnormal eyelash growth includes sparse eyelashes, ectropion, entropion, and trichiasis, which can lead to corneal abrasions, scarring, or infection if not treated.

Bilateral exudative retinopathy seen in the Revesz syndrome variant can lead to blindness.

Dental. Dental caries and periodontal disease had been reported to occur at early ages and at higher rates than in the general population; however, they may currently be less frequent because of improved dental hygiene.

Decreased root/crown ratio is attributed to abnormal tooth development.

Taurodontism (enlarged pulp chambers of the teeth) may be noted on dental x-ray.

Ears, nose, and throat. Oral leukoplakia is part of the diagnostic triad. It may be a presenting sign found in childhood or it may develop over time.

Deafness has been reported but is rare.

Squamous cell carcinoma of the head and neck. Persons with DC are at very high risk for these cancers.

Cardiovascular. Rare reported congenital heart defects include atrial and ventricular septal defects, myocardial fibrosis, and dilated cardiomyopathy.

Respiratory. Pulmonary fibrosis may be a presenting sign or may develop over time. Pulmonary fibrosis is manifest as bibasilar reticular abnormalities, ground glass opacities, or diffuse nodular lesions on high-resolution computed tomography and abnormal pulmonary function studies that include evidence of restriction (reduced vital capacity with an increase in FEV1/FVC ratio) and/or impaired gas exchange (increased P_(A-a)O₂ with rest or exercise or decreased diffusion capacity of the lung for carbon monoxide).

Gastrointestinal. Esophageal stenosis has been reported in several persons with DC and may worsen over time.

Enteropathy, which may result in poor growth, has been reported.

Liver fibrosis is a potential complication that has been noted and may occur at variable rates.

Hepatopulmonary syndrome has been reported.

Elevated risk of anorectal adenocarcinomas has been reported in DC.

Genitourinary. Urethral stenosis in males may be present at diagnosis or develop over time.

Elevated risk of cervical squamous cell cancer has been reported in DC.

Musculoskeletal. Osteoporosis and osteopenia have been reported. The contribution of prior treatment and co-morbid conditions to these complications is not known.

Avascular necrosis of the hips and shoulders can result in pain and reduced function. Several individuals have required hip replacement surgery at young ages.

Neurologic. Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the Hoyeraal Hreidarsson syndrome and Revesz syndrome variants. Cerebellar hypoplasia is present in the Hoyeraal Hreidarsson syndrome variant (Figure 2) and intracranial calcifications of unknown significance have been reported in the Revesz syndrome variant. In addition, microcephaly has been reported in some persons with DC.

Figure

Figure 2. MRI of cerebellar hypoplasia in an individual with the Hoyeraal Hreidarsson variant of dyskeratosis congenita. Arrow indicates the hypoplastic cerebellum.

Psychiatric. Schizophrenia has been reported in two persons. A small study of six children and eight adults with DC found higher than expected rates of neuropsychiatric complications. However, the true prevalence of disorders such as depression and bipolar disorder in individuals with CD is unknown [Rackley et al 2012].

Endocrine. Hypogonadism has been noted in a small number of severely affected males.

Hematologic. Bone marrow failure is a common presenting sign and may progress over time.

Individuals with DC are at increased risk for leukemia (see Cancer).

Immunologic. Immunodeficiency of variable severity has been reported in DC. It has not been fully characterized, but it appears that some individuals may have reduced numbers of B-cells, T-cells, and/or NK cells.

Cancer. Persons with DC are at high risk for leukemia and squamous cell cancer of the head and neck or anogenital region.

The first study to quantify these risks evaluated reports of cancer in persons with DC from the DC cohort study at the National Cancer Institute (NCI) and from the scientific literature [Alter et al 2009]. The median age of onset for all cancers was 37 years (range 25-44 years) in the NCI cohort and 29 years (range 19-70 years) in the literature cases.

The most frequent solid tumors were head and neck squamous cell carcinomas (40% in both groups), followed by skin and anorectal cancer. In the NCI cohort, the ratio of observed to expected (O/E) cancers was 11-fold greater in persons with DC compared to the general population. The highest O/E ratios were for tongue cancer (1154-fold increase) and acute myeloid leukemia (AML) (195-fold increase). Myelodysplastic syndrome (MDS) also occurs at increased rates in persons with DC [Alter et al 2009]. In this study, the median age of MDS was 35 years (range 19-61 years) and the O/E ratio of MDS was 2362-fold that of the general population.

Genotype-Phenotype Correlations

Genotype-phenotype correlations have not yet been studied comprehensively.

In general, persons with DKC1 and TINF2 mutations appear to have more clinical features and complications than persons with mutation of the other genes known to cause DC [Alter et al 2012]. Persons with DKC1 or TINF2 mutations may have Hoyeraal Hreidarsson syndrome. Persons with Revesz syndrome may have TINF2 mutations. Some individuals with TINF2 mutations developed bone marrow failure manifest as aplastic anemia by age ten years; others may be silent carriers [Walne et al 2008, Savage & Bertuch 2010].

Individuals with Hoyeraal Hreidarsson and Revesz syndrome have shorter telomeres than individuals with classic DC.

Persons with autosomal dominant, heterozygous TERT mutations may present as adults with isolated bone marrow failure or isolated pulmonary fibrosis, and thus may be the least affected of all those with DC. Individuals with autosomal recessive TERT mutations may have the severe phenotype Hoyeraal Hreidarsson syndrome.

Those with TERC mutations appear to have variability in severity. Some individuals with TERC mutations may present with isolated bone marrow failure rather than the classic mucocutaneous features seen with, for example, DKC1 mutations.

Individuals with DC who do not have a mutation in one of the seven known genes often have the most clinically severe phenotypes, including multiple features of DC, Hoyeraal Hreisdarsson syndrome, or Revesz syndrome [Alter et al 2012].

The two individuals reported with WRAP53 compound heterozygous mutations had classic DC with the mucocutaneous phenotype and bone marrow failure. One of these individuals also had tongue squamous cell cancer.

Penetrance

Individuals with mutations in one of the known DC-related genes have variable clinical phenotypes, even within the same family. However, abnormally short telomeres are present in all individuals with mutation(s) in one of the genes known to cause DC regardless of clinical phenotype.

Anticipation

Some studies have suggested that shorter telomeres and an earlier age of onset of symptoms may occur in successive generations in families affected by DC; however, it is unclear whether this observation reflects anticipation or the bias of ascertainment that occurs when diagnosis of a severely affected individual results in identification of mild manifestations in earlier generations in a family. The families in which the younger generations had more severe clinical features than their parents had mutations in TERC, TERT or TINF2 [Armanios et al 2005, Vulliamy & Dokal 2008, Savage & Bertuch 2010].

Nomenclature

Revesz syndrome [Revesz et al 1992] and Hoyeraal Hreidarsson syndrome [Hoyeraal et al 1970, Hreidarsson et al 1988], previously thought to be distinct disorders, are now recognized to be part of the phenotypic spectrum of dyskeratosis congenita.

A few case reports of a syndrome of ataxia and pancytopenia are actually describing DC caused by mutations in TINF2 [Tsangaris et al 2008].

Prevalence

The prevalence of DC in the general population is not known.

DC of all causes is rare.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with dyskeratosis congenita (DC), it is important to note that the clinical spectrum of DC is broad and signs and symptoms develop at various ages and rates. Suggested studies to consider include:

• Dermatologic. Thorough skin and nail examination

• Growth and development evaluation

• Ophthalmic. Thorough examination for complications related to lacrimal duct stenosis, abnormal eyelash growth, and retinal disorders including exudative retinopathy

• Dental. Baseline evaluation for oral hygiene, leukoplakia, and oral squamous cell cancer

• Otolaryngology. Baseline evaluation for leukoplakia and squamous cell head/neck cancer

• Gastrointestinal and hepatic. History of potential swallowing difficulties and/or enteropathy; baseline liver function tests

• Genitourinary. For males, assessment for urethral stenosis

• Musculoskeletal. Consideration of baseline bone mineral density scan; history of any joint problems

• Neurologic. If early-onset neurologic findings (e.g., ataxia) or many of the complications listed above are present, consideration of brain MRI to evaluate for cerebellar hypoplasia or intracranial calcifications

• Bone marrow failure (BMF)

  • Evaluation by a hematologist to determine if signs of BMF are present. Evaluation may include complete blood count and bone marrow aspiration and biopsy.

  • Consider HLA typing of the affected individual, sibs, and parents in anticipation of possible need for hematopoietic stem cell transplantation (HSCT)

• Pulmonary fibrosis

  • Baseline pulmonary function tests (PFTs) including carbon monoxide diffusion capacity

  • Evaluation by a pulmonologist if the individual is symptomatic or PFTs are abnormal

  • Smoking cessation, if applicable

• Increased risk of cancer

  • Evaluation by an otolaryngologist and dentist as soon as the individual is able to cooperate with the examination

  • Gynecologic examination for females starting by age 16 years or when sexually active

• Genetics consultation

Treatment of Manifestations

The specific treatment for DC-related complications must be tailored to the individual [Savage & Alter 2009, Savage et al 2009]. The recommendations below were discussed at the first DC clinical research workshop in 2008 [Savage et al 2009] but because of the rarity of DC are not based on large-scale clinical trials. Affected individuals may have few or many of the complications associated with DC. Comprehensive coordinated care among specialties is required.

Bone marrow failure (BMF). Following the model of the Fanconi anemia consensus guidelines [Eiler et al 2008], treatment of BMF is recommended if the hemoglobin is consistently below 8 g/dL, platelets lower than 30,000/mm³, and neutrophils below 1000/mm³. If a matched-related donor is available, HSCT should be the first consideration for treatment for hematologic problems such as BMF or leukemia regardless of age. HSCT from an unrelated donor can be considered, although a trial of androgen therapy (e.g., oxymetholone or danazol) may be considered first.

Persons with DC may be more sensitive to androgens than individuals with Fanconi anemia, and the dose must be adjusted to reduce side effects such as impaired liver function, virilization, or behavioral problems (e.g., aggression, mood swings). The suggested starting dose of oxymetholone is 0.5 to 1 mg/kg/day, half the dose used in Fanconi anemia. It may take two to three months at a constant dose to see a hematologic response.

Side effects, including liver enzyme abnormalities, need to be monitored carefully. Baseline and follow-up liver ultrasound examinations should be performed for individuals receiving androgen therapy because of the possibility of liver adenomas and carcinomas, which have been reported in Fanconi anemia and in persons using androgens for benign hematologic diseases or for non-hematologic disorders [Velazquez & Alter 2004].

Hematopoietic growth factors may be useful in BMF. However, splenic peliosis and splenic rupture have been reported in two individuals with DC receiving androgens and G-CSF [Giri et al 2007]. G-CSF with erythropoietin has occasionally been useful but perhaps should also not be used in combination with androgens.

HSCT is the only curative treatment for severe BMF or leukemia in DC. It should be performed at centers experienced in treating DC. Reported problems include graft failure, graft-versus-host disease (GVHD), sepsis, pulmonary fibrosis, hepatic cirrhosis, and veno-occlusive disease [Berthou et al 1991, de la Fuente & Dokal 2007] that is caused in part by underlying pulmonary and liver disease [Yabe et al 1997, Dror et al 2003, Brazzola et al 2005, de la Fuente & Dokal 2007, Ostronoff et al 2007]. As a result, long-term survival of persons with DC following HSCT has been poor. Reduced-intensity preparative regimens being studied in a few institutions may improve long-term outcomes [Dietz et al 2011, Nishio et al 2011, Vuong et al 2010].

The range of clinical phenotypes seen in DC and the possibility of non-manifesting or very mildly affected heterozygotes within families may complicate the selection of related HSCT donors [Fogarty et al 2003, Denny et al 2008]. Potential related HSCT donors should be tested either for the mutation present in the proband or, if the mutation is not known, for telomere length.

Cancer. Specific treatment should be tailored to the type of cancer.

Affected individuals undergoing chemotherapy for cancer may have increased risk for prolonged cytopenias as a result of underlying BMF. This risk has not been quantitated; studies are ongoing.

Individuals with DC may be at increased risk of therapy-related pulmonary and hepatic toxicity. Pulmonary function tests and liver function should be monitored carefully.

Long-term data on the effects of cancer radiotherapy in DC are not available. Affected individuals may be at increased risk for radiotherapy-related complications based on observations in persons undergoing radiotherapy in HSCT.

Although the risk of MDS is high in DC, many persons have abnormal cytogenetic clones and/or morphologic changes consistent with abnormal myelopoiesis but may not have severe cytopenias.

Pulmonary fibrosis. The options for therapy in persons with DC and pulmonary fibrosis are primarily supportive care. Lung transplantation may be considered in severe cases. (See Familial Pulmonary Fibrosis.)

Surveillance

The recommendations below were discussed at the first DC clinical research workshop in 2008 [Savage et al 2009] but because of the rarity of DC are not based on large-scale clinical trials. Most of the recommendations are modeled after the Fanconi anemia consensus guidelines [Eiler et al 2008].

Bone marrow failure

• Consider repeating a complete blood count (CBC) once a year if CBCs are normal. CBCs should be obtained more frequently at the discretion of the treating hematologist.

• Consider annual bone marrow aspirate and biopsy that includes morphologic examination and cytogenetic studies.

Patients on androgen therapy for bone marrow failure

• Check liver function tests prior to starting and then every three months.

• Perform liver ultrasound examination semiannually for adenomas.

• Check cholesterol and triglycerides prior to starting and every six months.

Cancer surveillance. Most solid tumors develop after the first decade (median onset is age 28 years).

• Monthly self-examination for oral, head, and neck cancer

• Annual cancer screening by an otolaryngologist

• Annual gynecologic examination

• Annual skin cancer screening by a dermatologist

Pulmonary fibrosis. Perform annual pulmonary function tests starting either at diagnosis or at an age when the patient is able to appropriately perform the test (typically age ~8 years).

Oral and dental surveillance

• Schedule routine screening and dental hygiene visits every six months.

• Maintain good oral hygiene.

• The patient’s dentist should be made aware of the increased risk of head and neck squamous cell cancers and perform a thorough examination at each visit.

• Oral leukoplakia should be monitored carefully and suspicious lesions should be biopsied.

Agents/Circumstances to Avoid

Blood transfusions

• Transfusions of red cells or platelets should be avoided or minimized for those who are candidates for HSCT.

• To minimize the chances of sensitization, family members must not act as blood donors if HSCT is being considered.

• All blood products should be leukodepleted and irradiated.

Radiation. It is prudent to minimize exposure to therapeutic radiation since data on radiation side effects are limited.

Androgens and growth factors. The combination of androgens and G-CSF was associated with splenic peliosis and rupture in two individuals; thus, the combination should be avoided [Giri et al 2007].

Cancer prevention. Given the increased susceptibility of individuals with DC to developing leukemias and other malignancies, individuals with DC are advised to avoid toxic agents that have been implicated in tumorigenesis, including smoking.

Evaluation of Relatives at Risk

If a relative has signs or symptoms suggestive of DC or is being evaluated as a potential HSCT donor, telomere length testing is warranted or molecular genetic testing if the disease-causing mutation(s) in the family are known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Studies of the effectiveness of danazol, a modified testosterone, are underway in DC and the related telomere biology disorders. Danazol may have fewer side effects than oxymetholone. The response and optimal dosing in DC is not yet defined.

DC-specific HSCT studies are ongoing at several institutions.

Studies to improve the clinical and molecular characterization of DC are underway at the National Cancer Institute (marrowfailure.cancer.gov).

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

NCI Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
Phone: 800-518-8474
Email: lisaleathwood@westat.com
Web: www.marrowfailure.cancer.gov

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Dyskeratosis congenita (DC) caused by mutations in DKC1 is inherited in an X-linked manner.

DC caused by mutations in TERC and TINF2 is inherited in an autosomal dominant manner.

DC caused by mutations in TERT may be inherited in an autosomal dominant or autosomal recessive manner.

DC caused by mutations in WRAP53, NHP2, and NOP10 is inherited in an autosomal recessive manner.

Risk to Family Members – Autosomal Dominant DC

Parents of a proband

• Some individuals diagnosed with autosomal dominant dyskeratosis congenita have an affected parent.

• The family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected. The rate of germline and somatic mosaicism in DC is not known.

• A proband with autosomal dominant dyskeratosis congenita may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown, although it appears that the majority of TINF2 mutations are de novo in the proband [Savage et al 2008, Walne et al 2008, Sasa et al 2012].

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.

• Although no instances of germline mosaicism have been reported, it remains a possibility. Walne et al [2008] reported a family with two affected sibs, in one of whom a TINF2 mutation was identified; neither parent had the mutation, suggesting germline mosaicism in a parent.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include telomere length testing and, if identified as short, molecular genetic testing of the family-specific mutation. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• The sibs of a proband with clinically unaffected parents are still at increased risk for the disorder because of the possibility of reduced penetrance in a parent.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant dyskeratosis congenita has a 50% chance of inheriting the mutation.

Other family members of a proband

• The risk to other family members depends on the status of the proband's parents.

• If a parent is affected, his or her family members may be at risk.

Risk to Family Members –X-linked DC

Parents of the proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.

• In a family with more than one affected male, the mother of an affected male is an obligate carrier.

• If a woman has more than one affected son and the disease-causing mutation cannot be detected in her DNA, she has germline mosaicism.

• When an affected male is the only affected individual in the family; several possibilities regarding his mother's carrier status need to be considered:

  • He has a de novo disease-causing mutation in DKC1 and his mother is not a carrier.

  • His mother has a de novo disease-causing mutation in DKC1, either (a) as a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) as "germline mosaicism" (i.e., present in some of her germ cells only).

  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Sibs of the proband

• The risk to sibs depends on the carrier status of the mother.

• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.

• If the disease-causing mutation cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

• Germline mosaicism has not been definitively demonstrated in this condition. However, it is possible that even if the disease-causing mutation has not been identified in the mother’s DNA, sibs of the proband are still at increased risk of inheriting the disease-causing mutation.

Offspring of the proband. Males will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members of the proband. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of female relatives at risk for X-linked DC is possible if the disease-causing mutation has been identified in the family.

Risk to Family Members – Autosomal Recessive DC

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive dyskeratosis congenita are obligate heterozygotes (carriers).

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing of family members at risk for autosomal recessive DC is available once the mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

X-linked DC. If the DKC1 mutation has been identified in a family member, prenatal testing is possible for pregnancies at increased risk. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

Autosomal dominant or autosomal recessive DC. Prenatal diagnosis for pregnancies at increased risk for some forms of autosomal dominant or autosomal recessive DC is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation(s) have been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Dyskeratosis congenita (DC) is thought to be a disorder of telomere biology. The telomere is a complex structure (Figure 3). The TTAGGG nucleotide repeats at the chromosome end fold back to create a t-loop. Many proteins bind to the t-loop and others bind to those proteins to form a stable telomere “cap.” Seven different genes (DKC1, TERC, TERT, TINF2, NOP10, NHP2, WRAP53) encoding critical components of the telomere have been found to be mutated in individuals with DC.

The proteins encoded by DKC1, NHP2, and NOP10 are members of the H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family, which is involved in various aspects of rRNA processing and modification [Walne & Dokal 2008]. The proteins encoded by the genes DKC1, NHP2, and NOP10 localize to the dense fibrillar components of nucleoli and to coiled (Cajal) bodies in the nucleus. Both 18S rRNA production and rRNA pseudouridylation are impaired if any one of the four proteins is depleted. These H/ACA snoRNP proteins are also components of the telomerase complex.

Telomerase (TERT) is a reverse transcriptase which uses its RNA component, TERC, to add the TTAGGG nucleotide repeats to the chromosome ends. WRAP53 (TCAB1) is required for the transport of telomerase to Cajal bodies for assembly of the holoenzyme complex. TINF2 encodes the TIN2 protein, which is a part of the shelterin telomere protection complex (reviewed in Palm & de Lange [2008]). Shelterin consists of six proteins encoded by the genes TINF2, TERF1, TERF2, POT1, ACD (TPP1), and TERF2IP (RAP1). TERF1 (TRF1), TERF2 (TRF2), POT1, and ACD (TPP1) proteins bind to the telomeric DNA and their interactions with TIN2 and TERF2IP (RAP1) create a stable complex. Figure 3 shows some of these interactions.

TERC

Normal allelic variants. TERC is a non-coding RNA of 451 bp comprising one exon.

Pathologic allelic variants. See Table 3.

Table 3. Selected TERC Pathologic Allelic Variants

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RNA Nucleotide Change (Alias 1)	Reference Sequence	Literature Reference 2
r.-240delct	NR_001566​.1	Field et al [2006]
(C-99G) 3		Keith et al [2004]
r.2g>c (G2C)		Marrone et al [2007a]
Contiguous gene deletion 4 (1- 316)		Vulliamy et al [2004]
r.21c>u		Fogarty et al [2003]
r.28_34del7 (28-34)		Xin et al [2007]
r.35c>u		Du et al [2009b]
r.37a>g (A37G)		Vulliamy et al [2006]
r.48a>g (A48G)		Vulliamy et al [2006]
r.52_55delcuaa		Vulliamy et al [2006]
r.53_87del35		Marrone et al [2007a]
r.58g>a (G58A)		Dokal & Vulliamy [2003]
r.72c>g		Dokal & Vulliamy [2003]
r.79delc		Vulliamy et al [2006]
r.96-97delcu		Vulliamy et al [2004]
r.98g>a (G98A)		Calado & Young [2008]
r.100u>a (T100A)		Du et al [2009b]
c.110_113delgact		Walne & Dokal [2004]
c.107_108gc>ag		Vulliamy et al [2001]
r.116c>u (C116T)		Walne & Dokal [2004]
r.117a>c (A117C)		Ly et al [2005]
r.143g>a (G143A)		Vulliamy et al [2004]
r.178g>a (G178A)		Marrone et al [2007a]
r.180c>u (C180T)		Marrone et al [2007a]
r.204c>g (C204G)		Fogarty et al [2003]
r.216_229del14 (Del 216-229)		Vulliamy et al [2006]
r.228G>A (G228A)		Walne & Dokal [2004]
r.305g>a (G305A)		Fogarty et al [2003]
r.322g>a (G322A)		Fogarty et al [2003]
r.323c>u (C323T)		Calado & Young [2008]
(del 378 through 3’ end of TERC)		Vulliamy et al [2004]
r.378_415del38		Dokal & Vulliamy [2003]
r.391_392delcc (389-390)		Ly et al [2005]
r.408c>g		Vulliamy et al [2001]
r.408c>a		Marrone et al [2005]
r.410c>g		Vulliamy et al [2001]
r.450g>a		Walne & Dokal [2004]
(16u>c, 16bp downstream of 3’ transcript of TERC)		Fogarty et al [2003]
(821-bp deletion including 3' end of TERC)		Vulliamy et al [2001]

See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). For this gene: the prefix "r." is used to indicate that a change is described at RNA level; numbering is relative to the transcription start site; nucleotides are designated by the bases (in lower case); bases are a (adenine), c (cytosine), g (guanine), and u (uracil).

1. Variant designation that does not conform to current naming conventions

2. First literature reference given when possible

3. Promoter mutation in a patient with paroxysmal nocturnal hemoglobinuria

4. Deletion of 2980 bp extending from nucleotide 835 in the 3’ UTR of ACTRT3 (ARPM1), through the intergenic and TERC promoter sequences, to nucleotide 316 of TERC.

Normal gene product. TERC encodes a non-coding RNA; no protein product is made. It serves as the RNA template for telomerase, the reverse transcriptase which adds nucleotide repeats to the telomere.

Abnormal gene product. Not applicable

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Author Notes

Web: marrowfailure.cancer.gov

Acknowledgments

Drs. Blanche Alter and Neelam Giri, NCI, contributed invaluable advice and insight into patient diagnosis and management. I would also like to thank Dr. Guillermo Seratti, NHGRI, for assistance with the mutation tables.

This work was supported (in part) by the intramural research program of the National Cancer Institute, National Institutes of Health.

Revision History

• 10 May 2012 (me) Comprehensive update posted live

• 12 November 2009 (me) Review posted live

• 15 May 2009 (sas) Original submission