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Dyskeratosis Congenita

Synonyms: Hoyeraal Hreidarsson Syndrome, Revesz Syndrome, Zinsser-Cole-Engman Syndrome
, MD, FAAP
Investigator, Clinical Genetics Branch
Division of Cancer Epidemiology and Genetics
National Cancer Institute, NIH
Bethesda, Maryland

Initial Posting: ; Last Revision: January 3, 2013.

Summary

Disease characteristics. Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. However, the classic triad may not be present in all individuals. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include: abnormal pigmentation changes not restricted to the upper chest and neck, eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), and dental abnormalities (caries, periodontal disease, taurodauntism). Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome). Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF.

Diagnosis/testing. All individuals with DC have abnormally short telomeres for their age, as determined by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on white blood cell (WBC) subsets. To date, CTC1, DKC1, TERC, TERT, TINF2, NHP2, NOP10, and WRAP53 are the genes in which mutations are known to cause DC and result in very short telomeres. Mutations in one of these eight genes have been identified in approximately half of individuals who meet clinical diagnostic criteria for DC.

Management. Treatment of manifestations: Treatment is tailored to the individual. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for BMF and leukemia but historically has had poor long-term efficacy; if a suitable donor is not available, androgen therapy may be considered for BMF. Treatment of other cancers is tailored to the type of cancer. Of note, cancer therapy may pose an increased risk for prolonged cytopenias as well as pulmonary and hepatic toxicity. Treatment of pulmonary fibrosis is primarily supportive, although lung transplantation may be considered.

Surveillance: For BMF: complete blood count (CBC) annually if normal and more often if abnormal; consider annual bone marrow aspirate and biopsy. For those on androgen therapy: routine monitoring of liver function. For cancer risk: monthly self-examination for oral, head, and neck cancer; annual cancer screening by an otolaryngologist and dermatologist; annual gynecologic examination. For pulmonary fibrosis: annual pulmonary function tests starting either at diagnosis or when the patient can perform the test (often around age eight years). Routine dental screening every six months and good oral hygiene are recommended.

Agents/circumstances to avoid: Blood donation by family members if HSCT is being considered; non-leukodepleted and non-irradiated blood products; the combination of androgens and G-CSF in treatment of BMF (has been associated with splenic rupture); toxic agents implicated in tumorigenesis (e.g., 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.

Genetic counseling. The mode of inheritance of DC varies by gene: DKC1 (X-linked), TERC and TINF2 (autosomal dominant), TERT (autosomal dominant or autosomal recessive), CTC1, WRAP53, NHP2, and NOP10 (autosomal recessive). Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. If the disease-causing mutation(s) in the family have been identified, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

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 DC clinical triad (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 1

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, CTC1, DKC1, TERC, TERT, TINF2, WRAP53, NHP2, and NOP10 are the only genes in which mutations are known to cause DC and short telomeres (Figure 2).

Figure 2

Figure

Figure 2. 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 further 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

Gene 1Mode of InheritanceProportion of DC Attributed to Mutations in This Gene 2Test MethodMutations Detected 3
DKC1XL 417%-36%Sequence analysis 5Sequence variants 6
Deletion/duplication analysis 7, 8 Exonic or whole-gene deletions 9, 10
TERCAD 116%-10%Sequence analysis 5Sequence variants
Deletion/duplication analysis 7Exonic or whole-gene deletions 10
TERTAD and AR 121%-7%Sequence analysis 5Sequence variants
Deletion/duplication analysis 7Exonic or whole-gene deletions 10
TINF2AD 1311%-24%Sequence analysis 5Sequence variants 14
Sequence analysis of select exonsSequence variants of exon15
NHP2 AR 16<1%Sequence analysis 5Sequence variants
Sequence analysis of select exonsSequence variants of exon15
NOP10 AR 17<1%Sequence analysis 5Sequence variants 17
Sequence analysis of select exonsSequence variants of exon17
WRAP53 (TCAB1)AR 183%Sequence analysis 5Sequence variants
CTC1AR 191%-3%Sequence analysis 5Sequence variants

1. See Table A. Genes and Databases for chromosome locus and protein name

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

3. See Molecular Genetics for information on allelic variants.

4. Knight et al [1999b]

5. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. 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.

7. Testing that identifies exonic or whole-gene 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.

8. 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.

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

10. 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.)

11. Vulliamy et al [2004]

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

13. Savage et al [2008]

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

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

16. Vulliamy et al [2008]

17. Walne et al [2007]

18. Zhong et al [2011]

19. Walne et al [2013]

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.

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.

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 CTC1, 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 pathogenic allelic variant(s) in the family.

Clinical Description

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.”

Hyperhidrosis 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 3) 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 3

Figure

Figure 3. 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.

Severe Forms of DC

Hoyeraal Hreidarsson syndrome, a very severe form of DC, presents in early childhood [Walne & Dokal 2008]. In addition to features of DC, cerebellar hypoplasia is required to establish the diagnosis (Figure 3). The findings in the original cases included cerebellar hypoplasia, developmental delay, immunodeficiency, intrauterine growth retardation, and BMF, as well as the DC diagnostic triad [Hoyeraal et al 1970].

Revesz syndrome has many of the features of DC and presents in early childhood [Revesz et al 1992]. In addition to features of DC, bilateral exudative retinopathy is required to establish the diagnosis. The original cases included individuals with intracranial calcifications, intrauterine growth retardation, BMF, and sparse, fine hair in addition to nail dystrophy and oral leukoplakia.

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.

Persons with CTC1 mutations may not have the mucocutaneous triad but often do have cytopenias, retinal exudates, intracranial calcifications or cysts, ataxia, IUGR, osteopenia, and/or poor bone healing.

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.

Differential Diagnosis

Dyskeratosis congenita (DC) can be challenging to diagnose because of its clinical heterogeneity.

  • DC should be considered as a possible cause of bone marrow failure (BMF) in persons in whom Fanconi anemia has been excluded based on normal chromosome breakage studies with diepoxybutane (DEB) or mitomycin C (MMC).
  • Head/neck or anogenital cancer may be the first manifestation of DC in persons younger than age 50 years who do not have other risk factors or BMF.
  • BMF may be the first manifestation of DC in individuals of any age. Telomere length testing should be performed if chromosome breakage is normal.
  • It should be noted that telomere length studied in individuals with Fanconi anemia, Diamond-Blackfan anemia, and Shwachman Diamond syndrome is typically greater than the first percentile for age [Alter et al 2007].

Disorders with clinical features that overlap those of DC include the following.

  • Disorders with nail dysplasia
  • Fanconi anemia (FA), characterized by physical abnormalities, bone marrow failure, and increased risk of malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. By age 40 to 48 years, the estimated cumulative incidence of bone marrow failure is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) 10%-33%; and of nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 28%-29%. The diagnosis of FA rests upon the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Mutations in one of at least 15 genes are causative. Mutations in the genes for all but one of the Fanconi anemia complementation groups are inherited in an autosomal recessive manner. FANCB mutations are inherited in an X-linked manner.
  • Diamond-Blackfan anemia (DBA), in its classic form characterized by a profound isolated normochromic and usually macrocytic anemia with normal leukocytes and platelets; congenital malformations in 25%-50% of affected individuals; and growth retardation in 30%. The hematologic complications occur in 90% of affected individuals during the first year of life (median age of onset is two months). Eventually 40% of affected individuals are corticosteroid dependent, 40% are transfusion dependent, and 20% go into remission. The phenotypic spectrum ranges from a mild form (e.g., mild anemia; no anemia with only subtle erythroid abnormalities; physical malformations without anemia) to a severe form of fetal anemia resulting in non-immune hydrops fetalis. DBA is associated with an increased risk of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma. DBA has been associated with mutations in nine genes that encode ribosomal proteins. A mutation in one of these nine genes is identified in approximately 53% of individuals with DBA. DBA is inherited in an autosomal dominant manner; approximately 55%-60% of affected individuals have a de novo mutation.
  • Shwachman Diamond syndrome (SDS), characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure, hematologic abnormalities with single- or multi-lineage cytopenia and susceptibility to myelodysplasia syndrome (MDS) and acute myelogeneous leukemia (AML), and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common. The diagnosis of SDS relies on clinical findings, including pancreatic dysfunction and characteristic hematologic problems. SBDS is the only gene currently known to be associated with SDS and biallelic mutations are found in more than 90% of cases. Inheritance is autosomal recessive.
  • Acquired aplastic anemia, characterized by tri-lineage bone marrow cytopenias [Young et al 2008]. It is often progressive and may occur at any age. Telomere length testing helps identify the subset of individuals with later onset aplastic anemia who have a telomere biology disorder; these individuals may have a few or none of the other clinical findings of DC. Other known causes of aplastic anemia include an immune process, infection, or drug reaction. In many individuals the cause of acquired aplastic anemia is unknown.
  • Idiopathic pulmonary fibrosis (IPF), the most frequent idiopathic interstitial pneumonia. It results in progressive fibrotic lung disease and has high morbidity and mortality. Persons with DC may develop IPF and it is conceivable that IPF in a young person could be the first manifestation of DC and, thus, DC should be considered in young persons with IPF. In some individuals, IPF, like aplastic anemia, may be a manifestation of a telomere biology disorder. See Familial Pulmonary Fibrosis.
  • Coats plus syndrome (OMIM 612199), an autosomal recessive disorder characterized by the presence of intracranial calcifications, leukodystrophy, retinal telangiectasia and retinal exudates. Affected individuals may also have osteopenia with poor bone healing, and vascular ectasias of the stomach, small intestine, and liver. Some individuals with Coats plus have hair, skin, and nail findings similar to those seen in DC. Anemia has also been reported. The retinal findings and intracranial classifications are similar to those seen in Revesz syndrome. Coats plus is caused by autosomal recessive mutations in an important telomere biology gene, CTC1 [Polvi et al 2012, Savage 2012, Anderson et al 2012] (Figure 2).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

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

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

DC caused by mutation of CTC1, 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 mutation is unknown, although it appears that the majority of TINF2 mutations occur 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 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 pathogenic variant, suggesting germline mosaicism in a parent.
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include telomere length testing and, if identified as short, molecular genetic testing of the family-specific pathogenic variant. 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 pathogenic variant 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 pathogenic variant.

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 pathogenic allele.
  • 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 pathogenic variant 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:

Sibs of the proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the variant will be carriers and will usually not be affected.
  • If the pathogenic variant 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 pathogenic variant has not been identified in the mother’s DNA, sibs of the proband are still at increased risk of inheriting the variant.

Offspring of the proband. Males will pass the pathogenic variant 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 –X-Linked DC

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 – Autosomal Recessive DC

Carrier testing of family members at risk for autosomal recessive DC may be possible once the pathogenic variants 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

X-linked DC. If the DKC1 pathogenic variant 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 pathogenic variant.

Autosomal dominant or autosomal recessive DC. If the pathogenic variant(s) have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

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 an option for some families in which the pathogenic variant (s) have been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Dyskeratosis Congenita Outreach, Inc.
    Phone: 773-503-0529
    Email: joecarlson@ymail.com
  • Madisons Foundation
    PO Box 241956
    Los Angeles CA 90024
    Phone: 310-264-0826
    Fax: 310-264-4766
    Email: getinfo@madisonsfoundation.org
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: LisaLeathwood@Westat.com; cancergovstaff@mail.nih.gov
  • NCI Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    National Cancer Institute
    Phone: 800-518-8474
    Email: lisaleathwood@westat.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Dyskeratosis Congenita: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Dyskeratosis Congenita (View All in OMIM)

127550DYSKERATOSIS CONGENITA, AUTOSOMAL DOMINANT, 1; DKCA1
187270TELOMERASE REVERSE TRANSCRIPTASE; TERT
224230DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE, 1; DKCB1
300126DYSKERIN; DKC1
305000DYSKERATOSIS CONGENITA, X-LINKED; DKCX
602322TELOMERASE RNA COMPONENT; TERC
604319TRF1-INTERACTING NUCLEAR FACTOR 2; TINF2
606470NUCLEOLAR PROTEIN FAMILY A, MEMBER 2; NOLA2
606471NUCLEOLAR PROTEIN FAMILY A, MEMBER 3; NOLA3
612661WD REPEAT-CONTAINING PROTEIN ANTISENSE TO TP53; WRAP53
613988DYSKERATOSIS CONGENITA, AUTOSOMAL RECESSIVE, 3; DKCB3

Molecular Genetic Pathogenesis

Dyskeratosis congenita (DC) is thought to be a disorder of telomere biology. The telomere is a complex structure (Figure 2). 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.

The CST complex is an essential telomeric capping complex that consists of CTC1 (encoded by CTC1), STN1 (OBFC1), and TEN1 (TEN1) [Miyake et al 2009; Surovtseva et al 2009]. This complex is proposed to promote efficient priming of telomeric C-strand synthesis.

Figure 2 shows some of these interactions.

DKC1

Gene structure. DKC1 comprises 15 exons and spans a genomic region of 15,734 base pairs. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. More than 40 pathogenic variants are described for DKC1; the majority are missense mutations that change the amino acid residue. See Table 2.

Table 2. Selected DKC1 Pathogenic Variants

DNA Nucleotide Change Protein Amino Acid Change Reference SequencesLiterature Reference
c.-142C>G-- NM_001363​.3
NP_001354​.1
Walne & Dokal [2004]
c.5C>Tp.Ala2ValDokal & Vulliamy [2003]
c.29C>Tp.Pro10LeuMarrone et al [2005]
c.91C>Gp.Gln31Glu
c.91C>Ap.Gln31LysVulliamy et al [2006]
c.106T>Gp.Phe36ValHeiss et al [1998]
c.109_111delCTTp.Leu37del
c.113T>Cp.Ile38ThrDokal & Vulliamy [2003]
c.115A>Gp.Lys39Glu
c.119C>Gp.Pro40ArgHeiss et al [1998]
c.121G>Ap.Glu41LysDokal & Vulliamy [2003]
c.127A>Gp.Lys43Glu
c.146C>Tp.Thr49MetKnight et al [1999a]
c.194G>Cp.Arg65ThrDokal & Vulliamy [2003]
c.196A>Gp.Thr66Ala
c.200C>Tp.Thr67IleMarrone et al [2005]
c.204C>Ap.His68Gln
c.361A>Gp.Ser121GlyKnight et al [1999a]
c.472C>Tp.Arg158TrpKnight et al [2001]
c.838A>Cp.Ser280Arg
c.911G>Ap.Ser304AsnDu et al [2009b]
c.949C>Tp.Leu317PheDokal & Vulliamy [2003]
c.941A>Gp.Lys314ArgMarrone et al [2005]
c.949C>Tp.Leu317Phe
c.949C>Gp.Leu317ValDu et al [2009b]
c.961C>Gp.Leu321ValDokal & Vulliamy [2003]
c.965G>Ap.Arg322Gln
c.1049T>Cp.Met350ThrKnight et al [2001]
c.1050G>Ap.Met350IleDokal & Vulliamy [2003]
c.1058C>Tp.Ala353ValKnight et al [2001]
c.1075G>Ap.Asp359AsnMarrone et al [2005]
c.1150C>Tp.Pro384SerDokal & Vulliamy [2003]
c.1151C>Tp.Pro384LeuKnight et al [2001]
c.1156G>Ap.Ala386ThrMarrone et al [2005]
c.1193T>Cp.Leu398ProDokal & Vulliamy [2003]
c.1205G>Ap.Gly402GluHeiss et al [1998]
c.1204G>Ap.Gly402ArgDokal & Vulliamy [2003]
c.1223C>Tp.Thr408IleMarrone et al [2005]
c.1226C>Tp.Pro409Leu
c.1205G>Ap.Gly402GluKirwan et al [2008]

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The primary transcript of DKC1 (isoform 1, NP_001354.1) encodes a protein of 514 amino acids. Isoform 2 uses an alternate in-frame splice site in the 3' coding region, compared to variant 1, resulting in a shorter isoform of 509 amino acids (reference sequence NP_001135935.1). Dyskerin plays multiple roles in human cells. It binds H/ACA and telomerase RNAs (TERC) via its PUA domain. It also functions in ribosomal (r)RNA processing, ribosomal subunit assembly, and centromere and microtubule binding.

Abnormal gene product. Most disease-causing mutations in DKC1 occur in the PUA domain, suggesting that DC arises from abnormal RNA binding.

TERC

Gene structure. TERC is a non-coding RNA of 451 bp comprising one exon. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 3.

Table 3. Selected TERC Pathogenic Variants

RNA Nucleotide Change
(Alias 1)
Reference SequencesLiterature Reference 2
r.-240delctNR_001566​.1Field et al [2006]
(C-99G) 3Keith et al [2004]
r.2g>c
(G2C)
Marrone et al [2007a]
Contiguous gene deletion 4
([increment]1- 316)
Vulliamy et al [2004]
r.21c>uFogarty et al [2003]
r.28_34del7
([increment]28-34)
Xin et al [2007]
r.35c>uDu et al [2009b]
r.37a>g
(A37G)
Vulliamy et al [2006]
r.48a>g
(A48G)
Vulliamy et al [2006]
r.52_55delcuaaVulliamy et al [2006]
r.53_87del35Marrone et al [2007a]
r.58g>a
(G58A)
Dokal & Vulliamy [2003]
r.72c>gDokal & Vulliamy [2003]
r.79delcVulliamy et al [2006]
r.96-97delcuVulliamy et al [2004]
r.98g>a
(G98A)
Calado & Young [2008]
r.100u>a
(T100A)
Du et al [2009b]
c.110_113delgactWalne & Dokal [2004]
c.107_108gc>agVulliamy 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_415del38Dokal & Vulliamy [2003]
r.391_392delcc
([increment]389-390)
Ly et al [2005]
r.408c>gVulliamy et al [2001]
r.408c>aMarrone et al [2005]
r.410c>gVulliamy et al [2001]
r.450g>aWalne & 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]

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).

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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

TERT

Gene structure. TERT comprises 16 exons. NM_198253.2 is a transcript of 4018 nucleotides. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 4.

Table 4. Selected TERT Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change DisorderReference SequencesLiterature Reference
Benignc.915G>Ap.Ala305AlaNormal variantNM_198253​.2
NP_937983​.2
Vulliamy et al [2005]
c.2097 C>T p.Ala699AlaNormal variantVulliamy et al [2005],
Yamaguchi et al [2005]
c.2178 G>A p.Thr726ThrNormal variantVulliamy et al [2005],
Yamaguchi et al [2005]
c.3039 C>Tp.His1013His Normal variantVulliamy et al [2005],
Yamaguchi et al [2005]
Pathogenicc.97C>Tp.Pro33SerIdiopathic pulmonary fibrosisTsakiri et al [2007]
c.164T>Ap.Leu55GlnIdiopathic pulmonary fibrosis
c.164T>Ap.Leu55GlnIdiopathic pulmonary fibrosisArmanios et al [2007]
p.112delCp.Leu38TrpfsTer40Idiopathic pulmonary fibrosisArmanios et al [2007]
c.430G>Ap.Val144MetIdiopathic pulmonary fibrosisTsakiri et al [2007]
c.604G>Ap.Ala202ThrAplastic anemiaYamaguchi et al [2005]
c.835G>Ap.Ala279ThrDyskeratosis congenita / aplastic anemia Vulliamy et al [2005]
c.1234C>Tp.His412TyrAplastic anemiaYamaguchi et al [2005]
c.1378_1380delCAGp.441GludelNormal variantYamaguchi et al [2005]
c.1456C>Tp.Arg486CysIdiopathic pulmonary fibrosisTsakiri et al [2007]
c. 1710(G>T;G>C) 2p.Lys570AsnDyskeratosis congenitaXin et al [2007]
c.1892G>Ap.Arg631GlnThrombocytopenia/
pulmonary fibrosis
Kirwan et al [2008]
c.2045G>Ap.Gly682AspDyskeratosis congenitaXin et al [2007]
c.2029G>Tp.Gly677CysDyskeratosis congenita/ aplastic anemiaYamaguchi et al [2005]
c.2080G>Ap.Val694MetAplastic anemiaYamaguchi et al [2005]
c.2110C>Tp.Pro704SerDyskeratosis congenitaDu et al [2009b]
c.2147C>Tp.Ala716ValAplastic anemiaDu et al [2009b]
c.2162C>Gp.Pro721ArgDyskeratosis congenitaVulliamy et al [2006]
c.2177C>Tp.Thr726MetDyskeratosis congenitaXin et al [2007]
c.2240delTp.Val747AlafsTer20Idiopathic pulmonary fibrosisTsakiri et al [2007]
c.2315A>Gp.Tyr772CysIdiopathic AAYamaguchi et al [2005]
c.2431C>Tp.Arg811CysAutosomal recessive DCMarrone et al [2007b]
c.2537A>Gp.Tyr846CysAplastic anemiaDu et al [2009b]
c.259G>Ap.Arg865HisIdiopathic pulmonary fibrosisTsakiri et al [2007]
c.2628C>Gp.His876GlnAplastic anemiaDu et al [2008]
c.2701C>Tp.Arg901TrpAutosomal recessive DCMarrone et al [2007b]
c.2706G>Cp.Lys902AsnDyskeratosis congenitaArmanios et al [2007]
c.2935C>Tp.Arg979TrpDyskeratosis congenitaVulliamy et al [2005],
Savage et al [2006]
c.3329C>Tp.Thr1110MetIdiopathic pulmonary fibrosisArmanios et al [2007]
c.3043T>Cp.Cys1015ArgAplastic anemiaDu et al [2009b]
c.3184G>Ap.Ala1062ThrAplastic anemiaYamaguchi et al [2005]
c.3268G>Ap.Val1090MetAplastic anemia Yamaguchi et al [2005]
c.3404_3580del177
(3346_3522del)
Idiopathic pulmonary fibrosisTsakiri et al [2007]
c.219+1G>A
(IVS1+1G>A)
--Usual interstitial pneumonia Armanios et al [2007]
c.2613-2A>G
(IVS9-2 A>C)
--Idiopathic interstitial pneumonia Armanios et al [2007]

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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

2. Uncertainty of nucleotide change in parenthesis

Normal gene product. The telomerase protein comprises 1132 amino acids. Telomerase is a ribonucleoprotein polymerase (reverse transcriptase) that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity encoded by this gene and an RNA component that serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis [Armanios 2009].

Abnormal gene product. Mutations in telomerase that are associated with DC, IPF, or aplastic anemia typically result in loss or reduced expression of the enzyme.

TINF2

Gene structure. TINF2 comprises nine exons (isoform 2, NM_012461.2). An alternative isoform consists primarily of the first six exons (NM_001099274.1). NM_001099274.1 is a transcript of 1869 base pairs.

The contribution of these alternative isoforms to human disease is not yet known. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. All of the TINF2 mutations described to date have been located in exon 6. It is not yet known if mutations elsewhere in the gene cause disease. See Table 5.

Table 5. Selected TINF2 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference SequencesLiterature Reference
c.805C>Tp.Gln269TerNM_001099274​.1
NP_001092744​.1
Sasa et al [2012]
c.811C>Tp.Gln271TerSasa et al [2012]
(Ex6+234A>G)(Lys280Glu) 2Savage et al [2008]
c.838A>Tp.Lys280TerWalne et al [2008]
Sasa et al [2012]
c.839delAp.Lys280ArgfsTer37
(K280Rfs*36)
c.844C>Tp.Arg282Cys
(Ex6+240C>A)(Arg282Ser) 2Savage et al [2008]
c.847C>Tp.Pro283SerWalne et al [2008]
c.847C>Gp.Pro283Ala
c.848C>Ap.Pro283His
c.850A>Gp.Thr284Ala
c.849dupC
(849_850insC)
p.Thr284HisfsTer8
c.860T>Cp.Leu287Pro
c.862T>Cp.Phe288Leu 3Du et al [2009a]
c.865CC>AGp.Pro289SerWalne et al [2008]
c.871A>Gp.Arg291Gly
c.892delCp.Gln298ArgfsTer19
c.706C>Tp.Pro236Ser 3
c.734C>Ap.Ser245Tyr 3
c.841G>Ap.Glu281Lys 3

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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

2. Predicted from in silico analyses identifying putative exonic splicing enhancers [Savage et al 2008]

3. Patient with bone marrow failure only

Normal gene product. TINF2 encodes the TIN2 protein, which is an important part of the shelterin telomere protection complex. TIN2 binds to TERF1 and TERF2, which bind directly to the telomeric DNA.

Abnormal gene product. The functional consequences of TINF2 mutations are not yet known. They occur in a highly evolutionarily conserved region of the protein and are predicted to have significant effects on protein function.

NHP2 (NOLA2) — Autosomal Recessive

Gene structure. NHP2 has four exons. NM_017838.3 is transcript variant 1, comprising 867 nucleotides. An alternative isoform lacks exon 3 (NM_001034833.1). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. All NHP2 pathogenic variants described to date are in exon 4. See Table 6.

Table 6. Selected Pathogenic Variants of NHP2 (NOLA2) — Autosomal Recessive

DNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesLiterature Reference
c.376 G>Ap.Val126MetNM_017838​.3
NP_060308​.1
Vulliamy et al [2008]
c.415 T>C 1p.Tyr139His
c.460T>A 1p.Ter154ArgextTer51

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Compound heterozygous mutant alleles observed in one affected individual

Normal gene product. The H/ACA ribonucleoprotein complex subunit 2 protein comprises 153 amino acids.

Abnormal gene product. Mutations in NHP2 reported in two families resulted in reduced levels of TERC and shortened telomeres.

NOP10 (NOLA3) — Autosomal Recessive

Gene structure. NOP10 comprises two exons. The transcript has 552 base pairs. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. One family with a NOP10 mutation has been described (see Table 7).

Table 7. Selected Pathogenic Variant of NOP10 (NOLA3) — Autosomal Recessive

DNA Nucleotide ChangeProtein Amino Acid ChangeReference SequenceLiterature Reference
c.100C>Tp.Arg34TrpNM_018648​.3
NP_061118​.1
Walne et al [2007]

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. NOP10 encodes an H/ACA ribonucleoprotein complex subunit 3 protein that comprises 64 amino acids.

Abnormal gene product. The reported mutation resulted in reduced TERC levels and shortened telomeres.

WRAP53 (TCAB1)

Gene structure. WRAP53 comprises ten exons. Alternatively spliced transcript variants that differ only in the 5' UTR have been found for the gene. NM_018081.2 is the longest transcript; other variants encode the same protein [provided by RefSeq, Mar 2011]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 8.

Table 8. Selected Pathogenic Variants of WRAP53

DNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesLiterature Reference
c.492C>Ap.Phe164LeuNM_018081​.2 NP_060551​.2Zhong et al [2011]
c.1192C>Tp.Arg398Trp
c.1126C>T p.His376Tyr
c.1303G>Ap.Gly435Arg

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. WRAP53 encodes the TCAB1 protein, which is required for the transportation of telomerase to Cajal bodies in the nucleus for assembly of the telomerase ribonucleoprotein complex.

Abnormal gene product. Compound heterozygous mutations in WRAP53 result in loss of its protein product, TCAB1, from Cajal bodies and mislocalization of telomerase.

CTC1

Gene structure. CTC1 comprises 23 exons spanning 23,273 bp of genomic sequence on chromosome 17p13.1. The primary isoform results from the NM_025099.5 transcript. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. CTC1 pathogenic variants reported include missense mutations and deletions causing a frameshift.

Normal gene product. CTC1 is a 134.5-kd protein which consists of 1217 amino acids (NP_079375.3). The CTC1 protein is an essential component of the CST complex which is implicated in telomere protection and DNA metabolism. The human CST complex has only recently been defined.

Abnormal gene product. Compound heterozygous mutations in CTC1 appear to result in short telomeres for age. CTC1 mutations reported include missense mutations and deletions causing a frameshift. The specific effect of the mutations on protein function is currently being studied.

References

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Chapter Notes

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

  • 3 January 2013 (cd) Revision: mutations in CTC1 found to cause dyskeratosis congenita
  • 13 September 2012 (cd) Revision: sequence analysis of the entire coding regions of NHP2 and NOP10 available clinically
  • 10 May 2012 (me) Comprehensive update posted live
  • 12 November 2009 (me) Review posted live
  • 15 May 2009 (sas) Original submission

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