Dyskeratosis Congenita and Related Telomere Biology Disorders

Clinical characteristics.

Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD 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.

A majority of individuals with DC/TBD have abnormally short telomeres for their age, as determined by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on lymphocyte subsets. To date, ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8 are the genes in which pathogenic variants are known to cause DC/TBD and to result in very short telomeres. Pathogenic variants in one of these 16 genes have been identified in approximately 80% of individuals who meet clinical diagnostic criteria for DC/TBD.

Management.

Treatment of manifestations: Treatment is tailored to the individual. Hematopoietic cell transplantation (HCT) is the only curative treatment for BMF and leukemia, but long-term outcome has historically been poor due to treatment toxicity; 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; annual bone marrow aspirate and biopsy. For those on androgen therapy: routine monitoring of CBC, liver function, liver ultrasound, and endocrinology evaluation. 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 age ~8 years); bubble echocardiogram to look for pulmonary arteriovenous malformations if suspected based on clinical symptoms. 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 granulocyte colony-stimulating factor in treatment of BMF (has been associated with splenic rupture); toxic agents implicated in tumorigenesis (e.g., smoking, excessive sun exposure).

Evaluation of relatives at risk: If a relative has signs or symptoms suggestive of DC/TBD or is being evaluated as a potential HCT donor, telomere length testing – or, if the pathogenic variant(s) in the family are known, molecular genetic testing – is warranted.

Genetic counseling.

The mode of inheritance of DC/TBD varies by gene:

• X-linked: DKC1
• Autosomal dominant: NAF1, RPA1, TERC, TINF2, and ZCCHC8
• Autosomal dominant or autosomal recessive: ACD, PARN, RTEL1, and TERT
• Autosomal recessive: CTC1, NHP2, NOP10, POT1, STN1, 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/TBD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

A telomere biology disorder (TBD), including dyskeratosis congenita (DC), should be suspected in individuals with the following clinical findings.

Physical characteristics. One of the following:

• At least two features of the classic DC clinical triad (Figure 1):
  • Dysplastic nails. Findings 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 or suggestive family history (occurrence of bone marrow failure [BMF], myelodysplastic syndrome [MDS], acute myelogenous leukemia [AML], early-onset head/neck squamous cell cancer [HNSCC], and/or pulmonary fibrosis [PF] in a first- or second-degree relative) in combination with:
  • Progressive BMF. May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen.
  • MDS or AML. May be the presenting sign.
  • Solid tumors, usually HNSCC or anogenital adenocarcinoma, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC/TBD in individuals who do not have BMF.
  • PF. See Pulmonary Fibrosis Predisposition Overview.
• Any feature of the classic triad plus two or more of the following:
  • Epiphora (excessive watering of the eye[s])
  • Blepharitis (inflammation of the eyelids, often due to epiphora)
  • Abnormal eyelash growth
  • Prematurely gray hair
  • Alopecia
  • Taurodontism (enlarged tooth pulp chambers) or decreased tooth root-to-crown ratio
  • Developmental delay
  • Short stature
  • Microcephaly
  • Hypogonadism
  • Esophageal stenosis
  • Urethral stenosis
  • Liver disease
  • Osteoporosis
  • Avascular necrosis of the hips or shoulders
  • Gastrointestinal telangiectasias
  • Pulmonary arteriovenous malformations
  Note: Individuals with TBDs may have none of the above additional findings or the findings may appear or worsen with age.

Establishing the Diagnosis

The diagnosis of DC/TBD is established in a proband with characteristic clinical findings and either of the following:

• Shortened telomere length as determined by lymphocyte telomere length testing by automated multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) in the six-cell panel assay. Telomere length less than the first centile for age in lymphocytes is 97% sensitive and 91% specific for DC/TBD. In individuals with complex or atypical DC/TBD, the six-cell panel may be more informative than the two-panel test of total lymphocytes and granulocytes [Alter et al 2012].
• Identification of biallelic pathogenic (or likely pathogenic) variants in one of the six genes known to solely cause autosomal recessive DC/TBD; or a heterozygous pathogenic (or likely pathogenic) variant in one of the five genes known to cause autosomal dominant DC/TBD; or a mono- or biallelic pathogenic (or likely pathogenic) variant in one of the four genes associated with autosomal recessive and dominant DC/TBD; or a hemizygous pathogenic (or likely pathogenic) variant in DKC1 known to cause X-linked DC/TBD (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of DC/TBD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

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 related telomere biology disorders (DC/TBD) and may or may not develop over time after the appearance of other complications listed here [Savage & Bertuch 2010, Dokal 2011, Ward et al 2018, Niewisch et al 2022]. The time of onset for these medical complications varies considerably among individuals even within the same family and thus the manifestations of DC/TBD 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.

Three forms of DC/TBD with more severe manifestations have been identified: Hoyeraal Hreidarsson syndrome, Revesz syndrome, and Coats plus syndrome (see Severe Forms of DC/TBD).

Dermatologic. Lacy, reticular pigmentation primarily of the neck and chest may be subtle or diffuse hyper- or hypopigmentation. Changes in skin pigmentation may not be present at time of diagnosis, but may develop or become more pronounced over time.

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

Additional common skin findings in DC/TBD include epiphora, loss of dermatoglyphics, early graying, palmoplantar hyperkeratosis, eyelash loss, and hair loss from scalp [Ward et al 2018]. Dermatoglyphics may be lost with age.

Hyperhidrosis is noted infrequently in some individuals.

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

Deafness has been reported but is rare.

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 Revesz syndrome or Coats plus syndrome can lead to blindness.

Dental. Decreased root-to-crown ratio is attributed to abnormal tooth development.

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

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

Intrauterine growth restriction (IUGR) has been noted in children with the more severe Coats plus syndrome, Hoyeraal Hreidarsson syndrome, or Revesz syndrome.

Developmental delay may be present in some. It can be more pronounced in persons with Hoyeraal Hreidarsson syndrome, Revesz syndrome, or Coats plus syndrome.

Neurologic. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay / intellectual disability is present in Hoyeraal Hreidarsson syndrome and Revesz syndrome. Cerebellar hypoplasia is present in Hoyeraal Hreidarsson syndrome (Figure 2), and intracranial calcifications have been reported in Revesz syndrome and Coats plus syndrome. Microcephaly has also been reported in some persons with DC/TBD, most commonly in Hoyeraal Hreidarsson syndrome and Revesz syndrome.

Psychiatric. Clinically significant psychiatric diagnosis was reported in 27% of 44 individuals with DC/TBD in a recent retrospective study. The psychiatric diagnoses in adults included depression and/or anxiety/panic attacks, autism spectrum disorder, and bipolar disorder [Bhala et al 2019]. However, the true prevalence of psychiatric disorders is unknown.

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

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

Enteropathy, which may result in poor growth, has been reported, specifically in Hoyeraal Hreidarsson syndrome.

Liver disease, including nodular regenerative hyperplasia, fibrosis, cirrhosis, portal hypertension, and hepatopulmonary syndrome, is increasingly recognized as a potential severe complication of DC/TBD and may lead to liver transplant [Gorgy et al 2015, Kapuria et al 2019, Niewisch et al 2022]. Individuals who have undergone hematopoetic cell transplant (HCT) need close monitoring for liver disease.

Gastrointestinal telangiectasias and bleeding may occur in the context of portal hypertension or independently.

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

Musculoskeletal. Osteoporosis and osteopenia have been reported. The contribution of prior treatment and comorbid conditions to these complications is not known. Some individuals have reported bone fractures after minor trauma.

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

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

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/TBD develop some degree of bone marrow failure by age 40 years.

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

Immunologic. Immunodeficiency of variable severity has been reported in DC/TBD. 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/TBD are at high risk for leukemia and squamous cell cancer of the head and neck or anogenital region. Elevated risk of cervical squamous cell cancer has also been reported in DC/TBD.

Investigators at the National Cancer Institute analyzed data from 15 years of follow up in a longitudinal cohort study to further quantify cancer risk in individuals with DC/TBD (n=197). The median age of onset for all cancers was 38 years (range 18-63 years), with an O/E (observed deaths to expected deaths) ratio of 4.2 compared to the normal population. The most frequent solid tumors were head and neck squamous cell carcinomas (with an O/E ratio of 74), followed by leukemia, non-Hodgkin lymphoma, and anorectal carcinoma. Of note, the risk of tongue cancer was increased by 216-fold over the normal population. In this study, myelodysplastic syndrome (MDS) was observed at a 578-fold increased risk, and the median age of MDS onset was 31 years (range 4-73 years).

Respiratory. Pulmonary fibrosis may be a presenting sign or may develop over time. It may be more common in individuals who have had HCT. 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 arteriovenous malformations have recently been reported in individuals with DC/TBD [Khincha et al 2017]. They may be present in individuals with hypoxia in the absence of pulmonary fibrosis and can be diagnosed by bubble echocardiography.

Phenotype Correlations by Gene

Classic DC with severe bone marrow failure and mucocutaneous triad features is associated with autosomal recessive, X-linked, or TINF2-related autosomal dominant DC/TBD. Significant better overall survival is observed in those with DC/TBD with an underlying autosomal dominant variant (excluding TINF2) versus those with DC associated with other types of variants [Niewisch et al 2022].

Individuals with autosomal recessive or X-linked DC/TBD have been reported to show more neurologic findings than those with autosomal dominant DC/TBD [Bhala et al 2019].

Pulmonary fibrosis without prior HCT is more frequently reported in individuals with autosomal dominant forms of DC/TBD [Armanios et al 2007, Giri et al 2019, Niewisch et al 2022].

Genotype-Phenotype Correlations

Due to the rarity of DC/TBD, no specific genotype-phenotype correlations have been identified.

Penetrance

The penetrance of DC/TBD and DC/TBD-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. Recent studies report somatic TERT promotor variants as possible modifiers to germline pathogenic variants [Maryoung et al 2017, Gutierrez-Rodrigues et al 2019]. However, additional studies are needed to further understand the components leading to variable penetrance of DC/TBD-causing variants.

Nomenclature

Revesz syndrome [Revesz et al 1992], Hoyeraal Hreidarsson syndrome [Hoyeraal et al 1970, Hreidarsson et al 1988], and Coats plus syndrome [Linnankivi et al 2006, Briggs et al 2008], 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/TBD caused by pathogenic variants in TINF2 [Tsangaris et al 2008].

Prevalence

The prevalence of DC/TBD in the general population is not known; DC/TBD is believed to be rare. As of March 2022, the authors are aware of approximately 800-1,000 affected individuals.

Disorders with Nail Dysplasia

Inherited Bone Marrow Failure Syndromes

Bone marrow failure syndromes are a complex set of related disorders that may have bone marrow failure as the first presenting sign.

Acquired Aplastic Anemia

Characterized by tri-lineage bone marrow cytopenias [Young 2018], acquired aplastic anemia 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/TBD. 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

Idiopathic pulmonary fibrosis (IPF) is the most frequent idiopathic interstitial pneumonia. It results in progressive fibrotic lung disease and has high morbidity and mortality. Persons with DC/TBD may develop IPF and it is conceivable that IPF in a young person could be the first manifestation of DC/TBD; thus, DC/TBD should be considered in young persons with IPF. See Pulmonary Fibrosis Predisposition Overview.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with dyskeratosis congenita (DC) or a related telomere biology disorder (TBD), it is important to note that the clinical spectrum of DC/TCB is broad and signs and symptoms develop at various ages and rates. The evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The specific treatment for DC/TBD-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/TBD, the recommendations are not based on large-scale clinical trials. Affected individuals may have few or many of the complications associated with DC/TBD. Comprehensive coordinated care among specialties is required.

Clinical care guidelines are also available at Team Telomere.

Surveillance

The recommendations in this section were discussed at the first DC clinical research workshop in 2008 and updated in 2014 at a consensus conference that led to 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/TBD, the recommendations are not based on large-scale clinical trials.

Agents/Circumstances to Avoid

Blood transfusions

• Transfusions of red cells or platelets should be avoided or minimized for those who are candidates for hematopoietic cell transplantation (HCT).
• To minimize the chances of sensitization, family members must not act as blood donors if HCT is being considered.
• All blood products should be leukodepleted and irradiated.

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

Androgens and growth factors. The combination of androgens and granulocyte colony-stimulating factor was associated with splenic peliosis ("blood lakes") 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/TBD to developing leukemias and other malignancies, individuals with DC/TBD are advised to avoid toxic agents that have been implicated in tumorigenesis (including smoking cigarettes or drinking alcohol), to use sunscreen regularly, and to avoid excessive sun exposure.

Evaluation of Relatives at Risk

For early diagnosis and treatment. It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from preventive measures, hematologic surveillance, and prompt initiation of treatment.

Evaluations include:

• Telomere length testing;
• Molecular genetic testing if a molecular diagnosis has been established in the proband.

For hematopoietic cell transplantation (HCT) donor evaluation. Any relative who is a potential HCT donor should undergo telomere length testing or molecular genetic testing (if the pathogenic variant[s] in the family are known).

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

Pregnancy Management

Individuals with DC/TBD who become pregnant may develop pancytopenia or existing cytopenias may worsen. They should be followed closely by a perinatologist.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

The mode of inheritance of dyskeratosis congenita and related telomere biology disorders (DC/TBD) depends on the associated gene (see Table 8).

Note: If the causative pathogenic variant(s) have not been identified in an affected family member, telomere length testing of first-degree relatives is recommended (see Management, Evaluation of Relatives at Risk).

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the DKC1 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected male, the mother of an affected male is an obligate heterozygote. If a woman has more than one affected child and the DKC1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%:
  • Males who inherit the pathogenic variant will be affected.
  • Females who inherit the pathogenic variant will be heterozygotes. Clinical manifestations in females heterozygous for DKC1 pathogenic variants have been reported, including skin pigmentation abnormalities, nail dysplasia, and bone marrow failure [Vulliamy et al 2006, Xu et al 2016, Hirvonen et al 2019].
• If the proband represents a simplex case and if the DKC1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males transmit the DKC1 pathogenic variant to:

• All their daughters, who will be heterozygotes;
• None of their sons.

Other family members. The maternal aunts and maternal cousins of a male proband may be at risk of having a DKC1 pathogenic variant.

Heterozygote detection. Heterozygote testing for at-risk female relatives requires prior identification of the DKC1 pathogenic variant in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Some individuals diagnosed with autosomal dominant DC/TBD have an affected parent.
• A proband with autosomal dominant DC/TBD may have the disorder as the result of a de novo DC/TBD-causing pathogenic variant. With the exception of TINF2 – in which the majority of pathogenic variants appear to occur de novo in the proband [Savage et al 2008, Walne et al 2008, Sasa et al 2012] – the proportion of individuals with DC/TBD caused by a de novo pathogenic variant is unknown.
• If the causative pathogenic variant has been identified in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the causative pathogenic variant has not been identified in the proband, telomere length testing of the parents is recommended.
• If the proband has a known pathogenic variant that cannot be detected in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Walne et al [2008] reported a family with two affected sibs, in one of whom a TINF2 pathogenic variant was identified (the other was deceased and could not be tested); neither parent had the pathogenic variant, suggesting germline mosaicism in a parent.
  • The proband inherited a DC/TBD-causing pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the pathogenic variant. This scenario may cause a false negative molecular result when testing leukocyte DNA. Note: To date, this has only been observed in individuals with germline TERC or RPA1 pathogenic variants.
• The family history of some individuals diagnosed with autosomal dominant DC/TBD may appear to be negative because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The age of onset and manifestations of DC/TBD may vary considerably among heterozygous family members (see Penetrance).
• If the DC/TBD-causing pathogenic variant found in the proband cannot be detected in the DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of:
  • The possibility of parental germline mosaicism [Walne et al 2008]; or
  • A false negative result in a parent due to preferential loss of the chromosome with the DC/TBD-causing pathogenic variant. Note: Revertant mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells has only been observed in individuals with germline TERC or RPA1 pathogenic variants.
• If the parents are clinically unaffected but they have not undergone molecular genetic testing or telomere testing, sibs are presumed to be at increased risk for DC/TBD for one of two possible reasons:
  • A parent has germline mosaicism; or
  • A parent is heterozygous but does not have apparent manifestations of DC/TBD because of phenotypic modification resulting from additional genetic events that confer a protective effect.

Offspring of a proband. Each child of an individual with autosomal dominant DC/TBD has a 50% chance of inheriting the DC/TBD-causing pathogenic variant.

Other family members. 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 of having the DC/TBD-causing pathogenic variant and the associated clinical manifestations including leukemia and squamous cell cancer (see Clinical Description).

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for one DC/TBD-causing pathogenic variant.
• If the causative pathogenic variants have been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a DC/TBD-causing pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes may or not may not be affected.
  • Pathogenic variants in ACD, PARN, RTEL, or TERT can cause both autosomal dominant and autosomal recessive DC/TBD; the effect of heterozygosity for one ACD, PARN, RTEL, or TERT pathogenic variant in individuals from families in which DC/TBD has been inherited in an autosomal recessive manner has not been thoroughly studied, but these individuals may be at elevated risk of DC/TBD-related complications.
  • Heterozygotes for a pathogenic variant in CTC1, NHP2, NOP10, PARN, POT1, or WRAP53 are predicted to be asymptomatic for DC/TBD manifestations. Individuals who are heterozygous for a POT1 pathogenic variant should be evaluated for POT1 tumor predisposition.

Sibs of a proband

• If both parents are known to be heterozygous for a DC/TBD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two DC/TBD-causing pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial DC/TBD-causing pathogenic variants.
• The age of onset and manifestations of DC/TBD may vary considerably among family members with biallelic pathogenic variants.
• Heterozygotes may or not may not be affected.
  • Pathogenic variants in ACD, PARN, RTEL, or TERT can cause both autosomal dominant and autosomal recessive DC/TBD; the effect of heterozygosity for one ACD, PARN, RTEL, or TERT pathogenic variant in individuals from families in which DC/TBD has been inherited in an autosomal recessive manner has not been thoroughly studied but these individuals may be at elevated risk of DC/TBD-related complications.
  • Heterozygotes for a pathogenic variant in CTC1, NHP2, NOP10, PARN, POT1, or WRAP53 are predicted to be asymptomatic for DC/TBD manifestations. Individuals who are heterozygous for a POT1 pathogenic variant should be evaluated for POT1 tumor predisposition.

Offspring of a proband. The offspring of an individual with autosomal recessive DC/TBD are obligate heterozygotes for a DC/TBD-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a DC/TBD-related pathogenic variant.

Heterozygote detection. Heterozygote testing for at-risk relatives requires prior identification of the DC/TBD-related pathogenic variants 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, treatment, and evaluation as a potential hematopoietic cell transplantation donor.

Predictive testing for at-risk asymptomatic family members requires prior identification of the pathogenic variant(s) in the family or, if the causative pathogenic variant(s) in the family are unknown, documentation of short telomere length in an affected relative.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 heterozygous, or are at risk of being heterozygous.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The telomere is a complex structure consisting of long nucleotide repeats (TTAGGG)n and a protein complex at chromosome ends that are essential to chromosomal integrity. 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." Pathogenic variants in 16 different genes (ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RPA1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53, and ZCCHC8) encoding critical components of the telomere have been found in individuals with DC/TBD (Figure 3).

Mechanism of disease causation. DC/TBD are caused by a loss-of-function mechanism [Bertuch 2016].

Notable variants by gene. See Table 9.

Note: The Telomerase Database, which is maintained by the Arizona State University, is a widely used tool in the telomere research community. Specifically, it includes a collection of variants published in the context of DC/TBD that may be useful in interpreting detected variants in individuals with suspected DC/TBD [Podlevsky et al 2008].

Author Notes

Website: marrowfailure.cancer.gov

Acknowledgments

Drs Blanche Alter, Neelam Giri, and Lisa McReynolds, NCI, contributed invaluable advice and insight into patient diagnosis and management.

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

Revision History

• 19 January 2023 (sw/sas) Revision: updated number of families with pathogenic variants in WRAP53 detected by sequence analysis (see Table 1)
• 31 March 2022 (ha) Comprehensive update posted live
• 21 November 2019 (aa) Revision: added mode of inheritance and OMIM links for idiopathic pulmonary fibrosis
• 26 May 2016 (ha) Comprehensive update posted live
• 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

Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Dyskeratosis Congenita and Related Telomere Biology Disorders" is in the public domain in the United States of America.

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