Dyskeratosis Congenita

Clinical 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. 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, ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53 are the genes in which pathogenic variants are known to cause DC and result in very short telomeres. Pathogenic variants in one of these 11 genes have been identified in approximately 70% of individuals who meet clinical diagnostic criteria for DC.

Management.

Treatment of manifestations: Treatment is tailored to the individual. Hematopoietic cell transplantation (HCT) 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 individual 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 HCT 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 HCT donor, telomere length testing is warranted or molecular genetic testing if the pathogenic variant(s) in the family are known.

Genetic counseling.

The mode of inheritance of DC varies by gene:

• X-linked: DKC1
• Autosomal dominant: TERC and TINF2
• Autosomal dominant or autosomal recessive: ACD, RTEL1, and TERT
• Autosomal recessive: CTC1, NHP2, NOP10, PARN, and WRAP53

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. Once the DC-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

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 (white patches in the mouth)
• One feature of the classic triad plus two or more of the following [Vulliamy et al 2006]:
  • Epiphora (excessive watering of the eye[s])
  • Blepharitis (inflammation of the eyelids, often due to epiphora)
  • 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.

Examples of the dyskeratosis congenita diagnostic triad A. Skin pigmentation

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 squamous cell cancer or anogenital adenocarcinoma, 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 Familial Pulmonary Fibrosis.

Shortened telomere length. Individuals with suspected DC should undergo leukocyte telomere length testing by automated multicolor flow-FISH in the six-cell panel assay. (Click here for details on this testing). 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].

For more information about telomeres, see Supplemental Material-Telomeres (pdf).

Establishing the Diagnosis

The diagnosis of DC is established in a proband with identification of a pathogenic variant (or variants) by molecular genetic testing in one of the genes listed in Table 1A or 1B.

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing can be considered if clinical findings, laboratory findings, ancestry, or inheritance pattern indicate that mutation of a particular gene is most likely. See Table 1A for information on mode of inheritance and relative frequency of the most common genes associated with this condition.

• Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish ancestry for the c.3791G> A (p.Arg1264His) pathogenic variant in RTEL1.

A multigene panel that includes the genes listed in Table 1A and Table 1B, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes the genes listed in Table 1A and 1B) fails to confirm a diagnosis in an individual with features of DC. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Approximately 70% of individuals who meet clinical diagnostic criteria for DC have a pathogenic variant(s) in one of the 11 known DC-related genes.

See Table 1A for the most common genetic causes (i.e., pathogenic variants of any one of the genes included in this table account for >1% of DC) and Table 1B for less common genetic causes (i.e., pathogenic variants of any one of the genes included in this table are reported in only a few families).

Tissue-restricted mosaicism has been observed in a limited number of individuals heterozygous for a TERC germline pathogenic variant. Specifically, a TERC germline pathogenic variant 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 pathogenic variant in DNA extracted from these cells. This has only been observed in individuals with germline TERC pathogenic variants. 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 pathogenic variant identified on molecular genetic testing of peripheral blood cells.

Clinical Description

The classic dyskeratosis congenita (DC) 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 considerably among individuals even within the same family 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.

Two forms of DC with more severe manifestations have been identified: Hoyeraal Hreidarsson syndrome and Revesz syndrome (see Severe Forms of DC).

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.

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

People with DC may lose dermatoglyphics with age.

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. It may be more common in individuals who have had a hematopoietic cell transplant. 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).

Pulmonary arterio-venous malformations have recently been reported in individuals with DC. They may be present in individuals with hypoxia in the absence pulmonary fibrosis and can be diagnosed by bubble echocardiography.

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.

Vascular ectasias and bleeding may occur.

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 have been reported in the Revesz syndrome variant. In addition, microcephaly has been reported in some persons with DC.

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, may develop at any age and may progress over time. Approximately one-half of individuals with DC develop some degree of bone marrow failure by age 40 years.

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 squamous cell skin cancers and anorectal adenocarcinoma. 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.

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

In general, persons with DKC1, TINF2, and autosomal recessive PARN, RTEL1, and ACD pathogenic variants appear to have more clinical features and complications than persons with pathogenic variants in other genes known to cause DC [Alter et al 2012, Ballew et al 2013a, Ballew et al 2013b, Deng et al 2013, Le Guen et al 2013, Walne et al 2013, Guo et al 2014, Kocak et al 2014, Moon et al 2015, Tummala et al 2015]. Persons with DKC1 or TINF2 pathogenic variants may have Hoyeraal Hreidarsson syndrome. Persons with Revesz syndrome may have TINF2 pathogenic variants. Some individuals with TINF2 pathogenic variants developed bone marrow failure manifest as aplastic anemia by age ten years; others may be asymptomatic heterozygotes [Ballew & Savage 2013, Dokal et al 2015, Glousker et al 2015, Bertuch 2016].

Individuals with autosomal dominant heterozygous RTEL1 or ACD pathogenic variants may develop clinical manifestations at older ages than those with recessive pathogenic variants in these genes.

Persons with autosomal dominant, heterozygous TERT pathogenic variants 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 pathogenic variants may have the severe phenotype Hoyeraal Hreidarsson syndrome.

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

Individuals with DC who do not have a pathogenic variant in one of the 11 known genes often have the most clinically severe phenotypes, including multiple features of DC, Hoyeraal Hreisdarsson syndrome, or Revesz syndrome [Alter et al 2012, Ballew et al 2013a, Ballew et al 2013b, Deng et al 2013, Le Guen et al 2013, Walne et al 2013, Guo et al 2014, Kocak et al 2014, Moon et al 2015, Tummala et al 2015].

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

Persons with CTC1 pathogenic variants 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

The penetrance of DC and DC-associated medical complications is not well understood. Due to the variability between individuals (even within the same family) and the observation that medical complications may increase with age, penetrance may appear incomplete, but additional studies are needed.

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 pathogenic variants 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 pathogenic variants in TINF2 [Tsangaris et al 2008].

Prevalence

The prevalence of DC in the general population is not known and believed to be rare. As of 2015, the author is aware of at least 400 families in the world.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
• Hematologic
  • Evaluation by a hematologist to determine if signs of bone marrow failure are present. Evaluation may include complete blood count and bone marrow aspiration and biopsy.
  • Consideration of HLA typing of the affected individual, unaffected sibs, and parents in anticipation of possible need for hematopoietic cell transplantation (HCT)
• Pulmonary
  • Baseline pulmonary function tests (PFTs) including carbon monoxide diffusion capacity
  • Consideration of bubble echocardiography to evaluate for pulmonary arteriovenous malformations
  • Evaluation by a pulmonologist if the individual is symptomatic or PFTs are abnormal
• 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
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The specific treatment for DC-related complications must be tailored to the individual. The recommendations in this section were first discussed at a DC clinical research workshop in 2008 and subsequently at a meeting of experts convened to review the publication of the first edition of the Dyskeratosis Congenita and Telomere Biology Disorders: Diagnosis and Management Guidelines [Savage et al 2009, Savage & Cook 2015] Because of the rarity of DC, the recommendations 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] and updated on the DC treatment guidelines [Savage & Cook 2015], 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, hematopoietic cell transplantation (HCT) should be the first consideration for treatment for hematologic problems such as BMF or leukemia regardless of age.

HCT from an unrelated donor can be considered, although a trial of androgen therapy (e.g., oxymetholone or danazol) may be considered first [Khincha et al 2014].

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