Telomere biology disorders, including Dyskeratosis congenita

INTRODUCTION — 

Telomere biology disorders (TBDs), also called telomeropathies, are inherited disorders characterized by bone marrow failure (BMF), cancer predisposition, and somatic (ie, nonhematologic) abnormalities. TBDs are caused by mutations that interfere with the normal maintenance of telomeres, the regions at the ends of the chromosomes that protect nucleated cells from the loss or gain of genetic material. Dyskeratosis congenita (DC) and other TBDs are rare syndromes associated with short telomeres.

This topic discusses the evaluation, diagnosis, and management of TBDs.

The approach to the diagnostic evaluation of unexplained BMF, and other inherited BMF syndromes, including Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), and Diamond-Blackfan anemia (DBA), are presented separately.

●(See "Acquired aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Approach to the adult with pancytopenia".)

●(See "Clinical manifestations and diagnosis of Fanconi anemia" and "Management and prognosis of Fanconi anemia".)

●(See "Shwachman-Diamond syndrome".)

●(See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

Clinical syndromes associated with long telomeres are discussed separately.

●(See "Inherited susceptibility to melanoma".)

●(See "Risk factors for brain tumors".)

PATHOPHYSIOLOGY

Role of telomeres — Telomeres are specialized structures at the end of chromosomes, comprised of nucleic acid and protein components that maintain the integrity of chromosome ends, protecting the natural ends of chromosomes from loss of DNA, abnormal fusion to other chromosomes, and from activation of DNA damage pathway responses that normally would occur in response at free ends of DNA created by strand breaks [1]. Telomeric DNA consists of tandem repeats of the six-base TTAGGG sequence. Most of the telomeric DNA exists as duplex DNA, with a terminal single-stranded overhang of typically approximately 150 to 200 nucleotides of the G-rich strand [2]. The shortening of the duplex DNA portion of telomeres is most characteristic of telomere biology disorders (TBDs).

At birth, the length of telomeric DNA from somatic cells such as lymphocytes, ranges from 8 to 14 kilobases (kb) [3]. With each cell division, 50 to 100 base pairs of this telomeric DNA is removed due to incomplete replication of the 3' ends. When telomeres reach a critically short threshold, the cell can no longer divide properly and undergoes apoptosis or senescence [4]. In most somatic cells, shortening of telomere length is a normal consequence of aging. As an example, average lymphocyte telomere length declines from approximately 11 kb at birth to only approximately 4 kb in centenarians. Thus, telomeres have been referred to as the "biological clock" within a cell that determines the number of possible cell divisions. (See "Basic genetics concepts: Chromosomes and cell division", section on 'Mitosis' and "Basic genetics concepts: Chromosomes and cell division", section on 'Parts of the chromosome'.)

By contrast to the limited normal replicative capacity of most somatic cells, certain cell types that require constant replicative regeneration are capable of restoring and maintain longer telomere length to enable a greater number of divisions [5]. Examples include embryonic stem cells, multipotent stem cells in high-turnover tissues such as epithelial tissues, and bone marrow, and malignant tumors [6,7]. This increased replicative capacity is made possible by the action of the telomerase complex, a ribonuclear protein complex (RNA and proteins) that counteracts telomere shortening by adding back DNA to the ends of chromosomes. The ability of telomerase to lengthen telomeres is regulated by several other mechanisms. The nucleoprotein factors contributing to these mechanisms, and consequently the genes encoding these factors in which mutations lead to TBDs (figure 1), have been subdivided into five categories [8]:

●Telomerase activity – Telomerase is a reverse transcriptase that adds TTAGGG repeats to the chromosome end. It consists of TERT, a catalytic protein; and TR, an RNA template. Assembly and stability of telomerase requires the action of several small nucleolar ribonucleoproteins (snoRNPs) including dyskerin, NHP2, and NOP10. The protein encoded by NAF1 is a box H/ACA RNA biogenesis factor similar to dyskerin that may regulate TR levels [9].

●Telomerase trafficking and recruitment to telomeres – Once telomerase is assembled, it must be recruited to the telomere. Trafficking mediated by the protein TCAB1, which binds to TR directly, is critical to this process [10,11]. The shelterin complex, which consists of the proteins TRF1, TRF2, RAP1, TIN2, TPP1, and POT1, serves the function of creating a "t-loop" (TRF2), resulting in the recruitment of additional proteins that create a stable telomere "cap." TRF1 and TRF2 recruit TNF2 to the telomere, which in turn recruits a heterodimer of TPP1/POT1. TPP1 then recruits telomerase to the telomere via its TEL patch motif [12].

●Telomere replication – After elongation of the G-rich strand of telomere DNA by telomerase, the CTC1/STN1/TEN1 (CST) complex promotes extension of the C-rich strand, resulting in extension of the duplex telomere DNA component. Phosphorylated POT1 binds CTC1 to recruit the CST complex. Mutations of CTC1 and POT1 found in patients with the Coats Plus syndrome specifically block this interaction, indicating that C-strand synthesis by CST requires release from POT1 through dephosphorylation [13].

●Telomere stability – RTEL1 (regulator of telomere length 1) is a DNA helicase that contributes both to the integrity of duplex telomere DNA replication and the dismantling of structures called D-Loops that could otherwise result in telomere DNA loss through excision repair mechanisms.

●Unknown or multifactorial roles – While TIN2 contributes to telomerase recruitment, mutations in TIN2 appear to play a dominant-negative role in telomere maintenance through as yet undetermined mechanisms. In addition, the exoribonuclease PARN may impact RNA transcript stability of other telomerase-associated factors [14].

Mutations of genes encoding the factors implicated in telomere function lead to abnormally short telomeres (figure 1). Mutations that are known to cause TBDs encode the proteins involved in telomerase activity and trafficking, formation of the shelterin "capping" complex, and telomere stability. These mutations and their associated inheritance patterns and named syndromes are listed below. (See 'Genetics' below and 'Inheritance patterns' below.)

Compared with the normal rate of telomere shortening in unaffected individuals of approximately 60 bp per year, individuals with telomere disorders lose telomeric DNA at approximately 120 bp per year [15]. Furthermore, successive generations of affected individuals may be born with progressively shorter telomeres (a phenomenon known as disease anticipation) [16,17]. Premature telomere shortening in TBDs leads to premature cell death, senescence, or genomic instability, which in turn leads to impaired organ and tissue function, altered homeostasis, or inappropriate growth [18]. Clinical consequences are described below. (See 'Clinical features' below.)

DC is the prototypic TBD [19,20]. It is one of several inherited bone marrow failure syndromes (IBMFS), each of which is characterized by its own spectrum of associated clinical findings. However, the initial descriptions of DC, referred to at the time as Zinsser-Cole-Engman syndrome, focused on its skin findings [21]. Subsequently, the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia have come to define DC. However, other well-recognized complications are often the major causes of morbidity in DC, particularly bone marrow failure (BMF).

In addition to DC and other TBDs, certain inherited and acquired cancer syndromes are associated with mutations in telomerase complex and shelterin complex without BMF. Examples include familial melanoma, leukemias, and others [22]. (See "Inherited susceptibility to melanoma" and "Familial disorders of acute leukemia and myelodysplastic syndromes".)

By contrast to the TBDs, the abnormally short telomeres in certain progeria (premature aging) syndromes appear to affect different populations of cells; there is virtually no clinical overlap between premature aging syndromes and TBDs, with the exception of increased mortality due to disease complications in both cases. (See "Emery-Dreifuss muscular dystrophy", section on 'Laminopathies' and "Hutchinson-Gilford progeria syndrome".)

Familial syndromes associated with long telomeres have also been described. By contrast with TBDs (in which critically short telomeres limit stem cell renewal), long telomere syndromes have greater proliferative capacity and altered apoptosis/senescence [23,24]. Long telomere syndromes are associated with distinct phenotypes, including clonal hematopoiesis and increased risk for solid tumors. Most long telomere syndromes are associated with loss of function mutations in POT1 [23], but other abnormalities have also been described [23,25-28]. Long telomere syndromes are discussed separately. (See "Inherited susceptibility to melanoma" and "Risk factors for brain tumors".)

Genetics — Mutations in genes encoding components of the telomerase complex, shelterin proteins, and other telomerase regulators have been described in individuals with TBDs. Causative gene mutations continue to be identified.

It is estimated that up to 70 percent will have a pathogenic mutation in one of the following genes [29] (table 1):

●ACD (adrenocortico dysplasia homolog) – Autosomal dominant DC, autosomal recessive DC, Hoyeraal-Hreidarsson syndrome. ACD encodes the TPP1 protein. (See 'Hoyeraal-Hreidarsson syndrome' below.)

●CTC1 (conserved telomere maintenance component 1) – Autosomal recessive DC, autosomal recessive Coats plus syndrome, also known as cerebroretinal microangiopathy with calcifications and cysts (CRMCC). (See 'Coats plus syndrome' below.)

●DKC1 – X-linked DC, Hoyeraal-Hreidarsson syndrome. (See 'Hoyeraal-Hreidarsson syndrome' below.)

●MDM4 – Germline missense pathogenic variant (of a gene that encodes a protein that increases p53 activity) associated with BMF and short telomeres in a family with features of DC, including tongue squamous cell carcinoma and acute myeloid leukemia [30].

●NAF1 (NEF-associated factor 1; also called TNFAIP3-interacting protein 1 [TNIP1]) – Autosomal dominant TBD features including pulmonary fibrosis [9].

●NHP2 (nonhistone protein 2; also called nucleolar protein family A, member 2 [NOLA2]) – Autosomal recessive DC or autosomal dominant TBD features including pulmonary fibrosis.

●NOP10 (nucleolar protein 10; also called nucleolar protein family A, member 3 [NOLA3]) – Autosomal recessive DC.

●NPM1 – Heterozygous germline pathogenic variants that disrupted protein translation without modulating telomeres [31].

●PARN (polyadenylate-specific ribonuclease) – Autosomal recessive DC, pulmonary fibrosis, Hoyeraal-Hreidarsson syndrome. (See 'Hoyeraal-Hreidarsson syndrome' below.)

●POT1 (Protection of Telomeres 1) – Autosomal recessive TBD that drives Coats Plus phenotype [32].

●RTEL1 (regulator of telomere elongation helicase 1) – Autosomal dominant DC, autosomal recessive DC, pulmonary fibrosis, Hoyeraal-Hreidarsson syndrome [33]. (See 'Hoyeraal-Hreidarsson syndrome' below.)

●STN1 – Autosomal recessive Coats Plus syndrome [34]. (See 'Coats plus syndrome' below.)

●TERC – Autosomal dominant DC, pulmonary fibrosis [35,36].

●TERT (telomerase reverse transcriptase) – Autosomal dominant DC, autosomal recessive DC, familial melanoma, pulmonary fibrosis.

●TINF2 (TRF1-interacting nuclear factor 2) – Autosomal dominant DC, Hoyeraal-Hreidarsson syndrome, Revesz syndrome. (See 'Other specific syndromes' below.)

●WRAP53 (WD repeat-containing protein antisense to TP53; encodes the TCAB1 protein) – Autosomal recessive DC.

●ZCCHC8 (required for telomerase RNA maturation) – Autosomal dominant pulmonary fibrosis [37].

Mutations in specific genes have been demonstrated to segregate with clinical effects in the TBDs and genotype-phenotype correlations for specific mutations within individual genes are increasingly recognized [38]. In general, the more clinically severe variants of DC are associated with the greatest reduction in telomere length [20].

Inheritance patterns — Various inheritance patterns have been observed for TBDs, depending on the affected gene. (See 'Genetics' above.)

●Autosomal dominant – Autosomal dominant disease has been observed with mutations in ACD, PARN, RTEL1, TERC, TERT, TINF2, ZCCHC8, MDM4, NPM1, and NAF1 [17,39-47]. Disease manifestations may become more severe over generations (disease anticipation) in individuals with TERC or TERT mutations, which has been attributed to the transmission of progressively shorter telomeres from one generation to the next [16,17]. Patients with TINF2 mutations have extremely short telomeres and frequently present with BMF before five years of age [43].

●Autosomal recessive – Autosomal recessive disease has been observed with mutations in ACD, CTC1, NHP2, NOP10, PARN, RTEL1, STN1, TERT, and WRAP53 [11,48-51].

●X-linked – The only X-linked DC syndrome that has been reported involves mutations in the DKC1 gene [52]. Heterozygous females show skewed X-chromosome inactivation patterns, suggesting a survival advantage for cells that express the normal DCK1 allele [53]. These females are considered unaffected carriers; however, a retrospective analysis of six heterozygous individuals found that five had nail dystrophy and skin pigmentation changes characteristic of DC, and two had clinically significant delays in wound healing [54].

EPIDEMIOLOGY — 

The true prevalence of TBDs is unknown, in part due to the incomplete penetration of disease features in many individuals.

It is likely that some individuals with gene mutations affecting telomere length are not diagnosed because of a subtle clinical phenotype. Some cases are initially diagnosed with other conditions, such as idiopathic aplastic anemia, idiopathic pulmonary fibrosis, idiopathic cirrhosis, or sporadic congenital abnormalities. Conversely, severe forms of DC may be underdiagnosed due to high mortality rates.

The prevalence of DC has been estimated to be approximately 1 in 1 million people in the general population [55]. Approximately 2 to 5 percent of patients with bone marrow failure are identified to have DC. Children are more likely to be diagnosed with DC than adults, however other TBDs resulting in pulmonary fibrosis and liver disease that present in adulthood are increasingly being recognized [56,57]. Initial reports suggested an increased frequency in males, but this may be related to an earlier belief that DC was solely an X-linked disorder [21].

Certain forms of DC appear to be more common in certain populations, such as the increased incidence of Hoyerall-Hreidarsson syndrome due to biallelic RTEL1 mutations in Ashkenazi Jews [58].

CLINICAL FEATURES — 

TBDs can affect the bone marrow, immune system, skin, lung, liver, and teeth. Patients are also at increased risk of a number of malignancies. These features can be variable and include the classic presentations of DC or atypical presentations in which only a subset of findings are present (table 2).

Common findings include:

●Mucocutaneous changes (see 'Classic DC presentation' below)

●Bone marrow failure (BMF) (see 'Bone marrow failure' below)

●Various somatic abnormalities (see 'Additional somatic features' below)

●Increased risk for certain cancers (see 'Cancer predisposition' below).

Classic DC presentation — Initially, DC was recognized clinically by a triad of mucocutaneous findings (picture 1):

●Abnormal skin pigmentation – Lacy reticular hyperpigmentation involving the upper chest and neck.

●Nail dystrophy – Small, thin nail plates with longitudinal ridges that disappear with age. Nails of the hands and feet are affected.

●Oral leukoplakia – Oral leukoplakia involves the oral mucosa and tongue.

This classic presentation is helpful for diagnosis, when present, but many individuals do not have all three features upon presentation. In a review of approximately 500 reported cases up to the year 2000 (ie, when diagnosis was based solely on clinical features, before the genetic basis for DC was identified), it was determined that approximately three-fourths of patients had at least one of these three classic manifestations, and slightly fewer than half had all three findings [21]. Notably, the median age at diagnosis was 14 years (range, birth to 75 years), which was approximately seven years later than that of Fanconi anemia in the same analysis. However, with increasing recognition of the features of DC, many patients are being diagnosed at younger ages. In some families, findings may become more severe in successive generations due to genetic anticipation. (See 'Pathophysiology' above.)

Bone marrow failure — Bone marrow failure (BMF) can present at any age, and in many cases, it may be the presenting finding of a TBD. Nearly one-half of patients with classic DC will develop signs of BMF by age 40.

Thrombocytopenia and anemia are often the first signs of BMF, although cytopenias in early childhood are not necessarily due to bone marrow aplasia. Cytopenias may also be immune-mediated, due to immune dysregulation; or caused by organ dysfunction and/or bleeding. In some cases, patients have presented early in life with what are thought to be isolated immune cytopenias within a single lineage, only to develop true pancytopenia in later childhood or adolescence.

A longitudinal study of 231 individuals with TBDs reported severe BMF in 48 percent, with 30 percent undergoing allogeneic hematopoietic cell transplantation (HCT) at a median age of 15 years [59]. In the London DC Registry, the median age of onset of BMF was 10 years [18,60].

Patients with TBDs develop a unique pattern of clonal hematopoiesis compared with other bone marrow failure syndromes. Compensatory mutations in the TERT promoter and loss of function mutations in POT1 occurring frequently, as well as mutations in the splicing factor U2AF1 and in TP53 [61].

Additional somatic features — Patients with TBDs are also at risk of developing other clinical features, including a wide array of organ manifestations.

Some features typically appear in childhood, although the age of onset is also highly variable. Early in life, patients may begin to develop features including esophageal strictures, lacrimal duct destruction, severe dental or periodontal disease, recurrent infections due to immune deficiency, enteropathy/enterocolitis, short stature, hypogonadism, urethral strictures, retinopathy, pulmonary and gastrointestinal vascular changes, and cognitive developmental impairment [62]. However, many of these somatic abnormalities may be absent in early childhood.

As patients enter the second decade of life and beyond, they are at increasing risk for pulmonary fibrosis; liver disease including hepatopulmonary syndrome and cirrhosis; lung or gastrointestinal hemorrhage [63,64]; vascular malformations, osteoporosis, and other bone abnormalities; premature graying of the hair; and neuropsychiatric disorders.

Disease manifestations appear to vary according to the inheritance pattern of TBDs, including autosomal dominant (AD), autosomal recessive (AR), and X-linked (XLR). A longitudinal cohort study of 231 individuals evaluated at the United States National Cancer Institute reported the following [59]:

●Severe BMF – 48 percent

●Pulmonary fibrosis – 7 percent

●Liver disease – 3 percent

●Esophageal strictures – 8 percent

●Kidney structural abnormalities – 3 percent

●Hypothyroidism or diabetes mellitus – 13 percent

●Avascular necrosis – 6 percent

Other series have reported similar findings [18,21,56,60,63,65-75].

Pulmonary fibrosis and liver cirrhosis deserve specific attention, as these complications typically present in adulthood (fourth or fifth decade) and may be the first presenting feature of TBDs, other than DC [76]. The reported incidence of pulmonary fibrosis varies with the median age of the patients and the historical age of the cohort. More recent reports describe a higher incidence because the median age of patients is generally higher and because TBD is diagnosed in some adults based on isolated pulmonary fibrosis; conversely, the incidence was lower in earlier reports because fewer patients survived to develop this complication. Pulmonary fibrosis is seen in approximately one-fifth of individuals with DC [77]. Further, up to 15 percent of familial and 5 percent of sporadic cases of idiopathic pulmonary fibrosis are associated with mutations in TERT, TERC, PARN, or RTEL1 [78,79].

The combination of pulmonary fibrosis and bone marrow hypoplasia is emerging as a strong predictor of a telomere disorder [80]. A retrospective study of 38 consecutive individuals referred for evaluation of pulmonary fibrosis and/or BMF who lacked mucocutaneous findings of DC found that 10 had a germline mutation in TERT or TERC and evidence of impaired telomerase activity [36].

Cancer predisposition — Individuals with germline TBD genotypes are at an increased risk for various cancers, and the risk appears to vary with the genotype.

A longitudinal cohort study reported that the risk of cancer in 230 individuals with TBDs was more than three-fold higher than the general population (observed:expected 3.35 [95% CI 2.32-4.68]) [81]. Individuals with AR or XLR inheritance patterns had the highest risk for any cancer (19-fold increase), solid tumors (24-fold), and head and neck squamous carcinomas (276-fold). The median onset of cancer is 37 years, and the risk increased after hematopoietic stem cell, lung, or liver transplantation.

Patients with classic DC are at high risk for developing many types of cancer. The incidence of cancer in patients with DC is <10 percent by 20 years but rises to 20 to 30 percent by age 50, with the first cancer diagnosis at a median age of 29 years. A report involving 775 cases of DC defined the incidence of specific malignancies in DC [82-84]. These common types of cancers reported in DC, and the proportion of all cancers in DC that they account for, are as follows:

●Head/neck squamous cell carcinoma (40 percent of all cancers)

●Stomach/esophageal (17 percent)

●Anorectal (12 percent)

●Skin (12 percent)

●Acute leukemia (8 percent; myeloid more common than lymphoid)

●Liver (5 percent)

Hematopoietic neoplasms, such as myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML), and solid tumors, including squamous cell cancers of the head and neck, have a similar incidence to that seen in Fanconi anemia (FA), although these appear to develop at a later age in DC than they do in FA [85]. Other reported cancers include Hodgkin lymphoma and cancers of the lung, pancreas, colon, and cervix. Given the numerous vascular malformations and ectasias seen in DC, it is also notable that two adolescent/young adult patients with DC have been reported to have angiosarcomas involving the liver, a tumor that is extremely rare in this age group [86,87].

Management of malignancy in patients with DC is discussed below and in separate topic reviews:

●Hematologic neoplasms – (See 'AML or MDS' below and "Familial disorders of acute leukemia and myelodysplastic syndromes".)

●Solid tumors – (See 'Solid tumors' below and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)" and "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

Other specific syndromes

Hoyeraal-Hreidarsson syndrome — Hoyeraal-Hreidarsson syndrome (HHS) is a clinically severe form of DC with disease manifestations beginning in early childhood [88].

HHS was originally associated with X-linked mutations in DKC1, referred to as X-linked dyskeratosis congenita (DKCX; also called Zinsser-Cole-Engman syndrome); the syndrome was subsequently found to occur with recessive mutations in ACD, RTEL1, TERT, and PARN, along with autosomal dominant mutations in TINF2 [38,46,89,90]. (See 'Genetics' above.)

In addition to the classic mucocutaneous and somatic features of DC, patients with HHS have the following clinical features [58,88,91]:

●Intrauterine growth retardation

●Cerebellar hypoplasia

●Microcephaly

●Developmental delay

●Severe immunodeficiency (worse than classic DC)

●Early-onset progressive BMF

As the diagnosis of HHS has evolved over time, cerebellar hypoplasia has become a diagnostic requirement [38].

As noted above, HHS is seen at increased frequency in individuals of Ashkenazi Jewish ancestry, due to a founder mutation (c.3791G>A [p.R1264H]). (See 'Epidemiology' above.)

Revesz syndrome — In addition to having often severe features of DC, patients with Revesz syndrome (RS) are defined based on the presence of bilateral exudative retinopathy; often there are also intracranial calcifications and intrauterine growth restriction. Mutations in TINF2 are the primary known genetic cause of Revesz syndrome, though other cases have yet to identify a genetic cause. (See 'Genetics' above.)

Coats plus syndrome — Coats plus syndrome is an autosomal recessive disorder characterized by retinal telangiectasias with exudates, intracranial calcifications, cerebellar movement disorder, osteopenia, leukodystrophy, poor growth, and bone marrow abnormalities [92]. It is caused by autosomal recessive mutations in CTC1, POT1, or STN1, components of the CST telomere replication complex involved in duplex telomere DNA elongation [34,93]. Telomeres may be quite short in patients with Coats plus syndrome caused by CTC1 mutation, though some patients may have normal telomere lengths, suggesting telomere dysfunction apart from telomere shortening may drive disease features in Coats plus syndrome [94,95].

CTC1 mutations are also seen in patients with classic DC features, highlighting the overlap between Coats plus syndrome and other short telomere syndromes [94,96].

DIAGNOSIS — 

A TBD should be considered in an individual of any age with bone marrow failure or pulmonary fibrosis, with or without accompanying nail dystrophy, abnormal skin pigmentation, oral leukoplakia, and other somatic findings.

Overview of diagnosis — The diagnosis of a TBD has evolved from purely clinical findings of specific syndromes to documentation of shortened telomeres and genetic testing for specific abnormalities known to affect telomeres.

DC is reserved for patients who have classic mucocutaneous findings (ie, nail, skin, oral mucosa abnormalities), while previously described clinical syndromes, including Hoyeraal-Hreidarsson, Revesz, Coats Plus, and DC, are all considered TBD subtypes. Additionally, patients who have no syndromic features but are found to have short telomeres, an associated clinical disease (eg, bone marrow failure [BMF], pulmonary fibrosis), with or without a mutation in a TBD-associated gene, are also considered to have a TBD. (See 'Classic DC presentation' above.)

Diagnosis of a new proband is generally made using a combination of clinical findings and laboratory testing. Diagnosis of affected relatives can then be based on clinical features and the known familial pathogenic variant. The diagnosis of TBD is most easily suspected in individuals with the classic presentation of mucocutaneous findings, BMF, and other organ system involvement, or in individuals from a family with a known TBD-associated mutation. Additional clues to the underlying diagnosis may include isolated cytopenias, pulmonary fibrosis, liver disease, immunodeficiencies, and/or early graying of the hair. The co-occurrence of BMF and pulmonary fibrosis is highly suggestive of an underlying telomere disorder, as discussed above. (See 'Additional somatic features' above.)

Patients for whom the diagnosis of a TBD is considered should have a thorough family history, personal medical history, and physical examination to assess for features of TBDs. It is especially important to identify a TBD because patients may benefit from surveillance for additional clinical manifestations, including cancer and organ dysfunction. This also helps to identify relatives who share the pathogenic gene variant but have less penetrant disease features, and it enables screening for the condition in siblings who could serve as potential donors for hematopoietic cell transplantation (HCT). Potential related donors must be screened for the patient's TBD.

Clinical criteria — Clinical criteria for the diagnosis of TBDs have evolved and are not universally agreed upon. Initially, registration in the DC registry required a family to have an index case with the classic triad of mucocutaneous findings that define DC. (See 'Classic DC presentation' above.)

Subsequently, two different sets of diagnostic criteria have been adopted:

●In the first set of criteria, patients with any of the following combinations of features are defined as having DC [97]:

•All three classic mucocutaneous findings of abnormal skin pigmentation, nail dystrophy, and leukoplakia (see 'Classic DC presentation' above)

•One of three mucocutaneous features plus BMF and at least two other somatic features known to occur in DC (see 'Additional somatic features' above)

•Four or more features of the Hoyeraal-Hreidarsson syndrome (eg, intrauterine growth retardation [IUGR], developmental delay, severe immune deficiency, BMF, cerebellar hypoplasia)

•Aplastic anemia, myelodysplastic syndrome, or pulmonary fibrosis in the setting of a known pathogenic genetic variant affecting telomerase function

•Two or more features of DC and laboratory evidence of short telomeres (ie, less than the 1^st percentile for age by multicolor flow cytometry with fluorescence in situ hybridization [flow-FISH] in several subsets of lymphocytes)

●The second set of criteria differentiates findings suggestive of DC versus testing required to definitively establish the diagnosis. In this scheme, suggestive findings that lead to a suspected diagnosis of DC include the following [74]:

•At least two of the three classic mucocutaneous features

•One classic mucocutaneous feature plus two somatic features

•Progressive BMF, MDS, or AML

•Solid tumors associated with DC and that are otherwise atypical for age

•Pulmonary fibrosis

•Short lymphocyte telomeres (below the 1^st percentile for age)

According to these criteria, a pathogenic variant must be identified in a DC-associated gene to definitively establish the DC diagnosis.

In addition to the above criteria, a family member of an index patient may be diagnosed with DC or a TBD if they share the same genetic variant with the proband and are identified to have short telomeres.

Laboratory testing and bone marrow — The diagnostic testing for DC consists of telomere length analysis and genetic testing for specific mutations. (See 'Pathophysiology' above.)

The approach used depends on the patient's presentation:

●Telomere length analysis – In all individuals with a de novo presentation and/or a family history consistent with a TBD, Flow-FISH (multi-color flow cytometry with fluorescence in situ hybridization) is performed on peripheral blood lymphocytes using peptide nucleic acid probes for telomeric DNA [4,98].

Average telomere length below the 1^st percentile for age is considered indicative of abnormally short telomeres and is consistent with DC or a related TBD. Even in cases with a known familial mutation, telomere length analysis is recommended to help predict the degree to which an individual family member may be affected by disease-related complications. In patients where total lymphocyte telomere length is at or near the 1^st percentile for age, telomere lengths of lymphocyte subsets may be valuable in establishing the diagnosis.

●Molecular sequencing – All patients who are suspected to have a TBD based on clinical criteria and telomere length analysis should have genetic testing performed to identify a causative mutation. This testing is critical for definitive establishment of a genetic diagnosis and enabling testing of first degree relatives for potential carrier or disease status, and to determine family member eligibility to be an HCT donor.

There are three general ways in which sequencing can be performed:

•Sequential single gene testing – Single gene testing was initially the only method available for molecular testing in patients with DC. For the most part, this approach has been replaced by multi-gene next-generation sequencing panels, which are more cost-effective and take less time than sequential single gene testing in most cases. However, for patients in whom mutations in a specific gene are highly suspected based on clinical presentation (eg, p.R1264H variant in RTEL1 in individuals with Ashkenazi Jewish ancestry, CTC1 mutations in patients presenting with features of Coats plus syndrome), this approach may be optimal.

•Next-generation sequencing (NGS) panels – An NGS gene panel is generally the most recommended approach for identifying gene mutations in patients with DC. A number of commercial panels are available that include the genes most commonly associated with TBDs. Results from these panels are typically available within six to eight weeks. Notably, though, these panels may vary in sensitivity, genes tested, and whether specific deletion duplication analysis is included. The genes that are most often affected are presented above. (See 'Genetics' above.)

•Whole-exome sequencing (WES) – WES, which uses NGS methods to sequence the entire exome (coding regions of genes), is also readily commercially available. WES has the advantage of being able to identify mutations in genes that were not previously associated with telomere disorders. The disadvantages of WES are that coverage is often not 100 percent for all DC-associated genes (eg, TERC mutations cannot be identified by WES), insurance coverage may be hard to obtain, and the turnaround time on testing is typically longer than for NGS panels.

A list of clinical laboratories that perform telomere length testing and molecular genetic testing for DC is available on the Genetic Testing Registry website, and additional information about NGS panels and WES is presented separately. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Whole-genome sequencing is available in certain areas. This technique has the advantage of identifying intronic and other regulatory gene variants that lead to alterations of expression and/or gene product function that may otherwise be missed by whole exome sequencing.

Identification of a pathogenic TBD-associated mutation is considered diagnostic in the appropriate clinical setting, as noted above. However, negative results from genetic testing do not eliminate the possibility of a TBD, since a significant proportion of patients lack identifiable mutations. We anticipate that other genes involved in telomere maintenance will be discovered.

In addition to the above testing, determining whether a patient has BMF or myelodysplastic syndrome/neoplasms (MDS) is often useful in the diagnosis of a TBD. BMF is defined as a hypocellular marrow, typically <25 percent of the age-expected cellularity, along with the presence of peripheral blood cytopenias. MDS is defined as cytopenias and characteristic cytogenetic abnormalities, with or without morphologic abnormalities. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

Assessments for BMF and MDS should include:

●Complete blood count (CBC) with mean corpuscular volume (MCV) and absolute reticulocyte count (ARC). Patients with DC typically have elevated MCV and low ARC.

●Unilateral bone marrow aspirate and biopsy (>1 cm) for morphologic review. Typical bone marrow findings in TBDs such as DC include hypocellularity, decreased megakaryocytes, and some degree of dyspoiesis [21].

●Genetic studies on the bone marrow aspirate including:

•G-banding cytogenetic analysis of at least 20 metaphases to assess for acquired chromosomal aberrations.

•FISH analysis for specific aberrations including 5q-, monosomy 7, 7q-, trisomy 8, and 20q-.

•Next-generation sequencing (NGS) panel assessing for somatic gene mutation commonly associated with MDS.

There are no pathognomonic bone marrow findings for TBDs; the bone marrow abnormalities may be indistinguishable from other inherited BMF syndromes, and the CBC abnormalities are found in various conditions.

Bone marrow examination is not required for diagnosis of a TBD in all individuals. As an example, individuals with TBDs that are primarily associated with pulmonary fibrosis, particularly if they have normal blood counts, may not require bone marrow examination. However, surveillance with serial bone marrow examination is important for severe forms of TBD such as DC. (See 'Management' below.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of DC depends on the presenting clinical features and may include other inherited or acquired bone marrow failure (BMF) syndromes, acquired/de novo hematologic malignancies, other causes of congenital anomalies, and other causes of interstitial lung disease (ILD).

●Other inherited BMF syndromes – Other inherited BMF syndromes include Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anemia (DBA), and congenital amegakaryocytic thrombocytopenia (CAMT). Like DC, most of these syndromes can have variable presentations with variable cytopenias and degrees of bone marrow hypocellularity. Unlike DC, these disorders are not associated with pulmonary fibrosis or hepatic fibrosis, most of these patients do not have short telomeres, and they do not have pathogenic mutations in genes that encode telomerase components. These other syndromes and an approach to distinguishing among them is presented separately. (See "Clinical manifestations and diagnosis of Fanconi anemia" and "Shwachman-Diamond syndrome" and "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

●Familial MDS or AML – Familial myelodysplastic syndrome/neoplasms (MDS) and familial acute myeloid leukemia (AML) are inherited syndromes associated with increased risk of hematologic neoplasms. Like TBDs, they can present in childhood with multiple affected family members. Furthermore, patients with these syndromes who have developed MDS or AML may have very short telomeres on diagnostic testing; however, these short telomeres are due to the underlying clone and are only present in blood and bone marrow cells. Unlike TBDs, these syndromes are not associated with organ system involvement typical of TBDs or pathogenic mutations affecting telomerase components. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

●Acquired BMF – Acquired causes of BMF include various infectious and toxic exposures, idiopathic acquired aplastic anemia, and paroxysmal nocturnal hemoglobinuria (PNH). Like TBDs, these conditions are associated with cytopenias and bone marrow abnormalities. Unlike TBDs, these conditions are not associated with congenital anomalies, organ system involvement (with the exception of hepatitis in virally-induced aplastic anemia), or pathogenic mutations affecting telomerase components. Most acquired BMF conditions are not associated with short telomeres, with the exception of hepatitis-associated acquired aplastic anemia [99]. The causes of acquired BMF are discussed separately. (See "Acquired aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis" and "Treatment of acquired aplastic anemia in children and adolescents".)

●Genetic syndromes with overlapping dermatologic features – Rothmund-Thomson syndrome is a disease associated with thin, brittle hair, telangiectasias, thin skin and somatic features including enteropathy, poor dentition, and poor growth/short stature. It is caused by mutations in RECQL4. Patients who have poikiloderma with neutropenia have mutations in USB1 (previously C16orf57), and present with skin dyspigmentation, telangiectasias, and atrophy, along with immune deficiency and neutropenia. Patients with pachyonychia congenita, caused by mutations in genes that encode keratin proteins, present with nail dystrophy, hypertrophic skin on palms/soles, oral leukokeratosis that mimics leukoplakia, and hyperhidrosis. Unlike patients with TBDs, patients with these conditions have normal telomere length, do not develop hypocellular BMF, and do not have mutations in genes that affect telomerase function. (See "Kindler epidermolysis bullosa", section on 'Differential diagnosis'.)

●Other causes of ILD – ILD is a broad term that applies to conditions that diffusely affect the lung parenchyma. There are numerous underlying causes, including infection, immune defects, hypersensitivities, and systemic disorders. Telomere disorders have been estimated to account for 1 to 3 percent of sporadic cases of pulmonary fibrosis and 8 to 15 percent of familial cases of pulmonary fibrosis [35,100]. As noted above, families with pulmonary fibrosis and bone marrow hypoplasia have a very high likelihood of a TBD. (See 'Additional somatic features' above.)

Like TBDs, other causes of ILD may present in childhood and show evidence of pulmonary fibrosis. Unlike TBDs, these disorders are not associated with bone marrow hypoplasia, abnormally short telomeres, or pathogenic mutations affecting telomerase components. Discussions of the other causes of ILD are presented separately. (See "Approach to the infant and child with diffuse lung disease (interstitial lung disease)" and "Approach to the adult with interstitial lung disease: Clinical evaluation".)

MANAGEMENT — 

Patients with TBDs should be managed at a center with expertise in these disorders.

Initial and ongoing screening — All patients diagnosed with a TBD, based on the above studies, should have a comprehensive assessment, including family and medical history and a thorough physical examination, performed in a dedicated center with expertise in the management of patients with TBDs. Specific aspects of initial and ongoing screening include the following:

●Assessment for bone marrow failure/myelodysplastic syndrome/neoplasms – Initial screening for bone marrow failure (BMF) and myelodysplastic syndrome/neoplasms (MDS) should include a complete blood count (CBC) with differential count and mean corpuscular volume (MCV, which is typically elevated in patients with DC) and a reticulocyte count.

For patients with a TBD such as DC, which is associated with severe BMF, analysis of the bone marrow aspirate/biopsy includes G-banding metaphase karyotype cytogenetic analysis, fluorescence in situ hybridization (FISH) for specific abnormalities including 5q-, 7q-/monosomy 7, trisomy 8, and 20q-, and an NGS panel looking for clonal mutations in a myeloid disease gene panel that includes genes such as TERT, POT1, U2AF1, and TP53.

Ongoing screening and monitoring depends on the results of the initial screening:

•For patients with normal CBC, normal bone marrow cellularity, and no cytogenetic abnormality, ongoing screening with annual CBC with differential is sufficient, with any significant change in the CBC warranting repeat bone marrow studies and more frequent monitoring.

•For patients with moderate cytopenias not requiring transfusion support, CBC monitoring every three to six months and annual bone marrow studies are recommended. For any patient with cytogenetic abnormalities, morphologic features suggestive of worsening MDS, such as excess blasts (see 'AML or MDS' below), or with severe cytopenias approaching transfusion thresholds, more intensive monitoring is required, with planning for therapies directed at cytopenias.

●Screening and preventive care for solid tumors – Screening guidelines for solid tumors were established in 2015 for patients with DC and TBDs [84]. Of note, screening may need to begin earlier than general guidelines indicate for patients who have previously undergone hematopoietic cell transplantation (HCT), particularly for those affected by post-HCT graft-versus-host disease (GVHD). Guidelines for specific cancers include the following:

•Squamous cell carcinoma of the head and neck – Thorough dental examinations (or oral surgery consultation as indicated, depending on the dentist's degree of experience with oral cancer) every six months beginning in early childhood (eg, age three to five years). Nasolaryngoscopy should be performed every one to three years beginning at age 10 by an otolaryngologist with specific experience in head and neck cancer. Preventive care education should focus on good oral hygiene as well as avoidance of smoking, oral tobacco products, and alcohol.

•Anorectal cancer – In some centers, anorectal endoscopy screening begins at 18 years. In others, this procedure is only performed with concerning symptoms. Human papilloma virus (HPV) vaccination should be given because HPV may play a role in the increased anorectal cancer incidence in DC.

•Esophageal cancer – Esophagoscopy screening is done every three to five years beginning by age 18. For patients with symptoms of esophageal dysfunction, screening should start earlier and should be repeated annually.

•Liver cancer – Initial screening should include liver enzyme testing, and bilirubin testing, and right upper quadrant ultrasound. Ongoing screening should consist of annual liver enzyme and bilirubin assessments, with liver ultrasound repeated every three to five years. Additional assessments for other hepatic manifestations are noted below.

Preventative measures include avoidance of all alcohol consumption, and use of chelation therapy if iron overload from red blood cell transfusions has developed. (See "Iron chelation: Choice of agent, dosing, and adverse effects".)

•Skin cancer – Annual examinations by a dermatologist beginning at age 5 years. Preventative education includes training of the patient and family in skin evaluations and sun protection measures such as sun avoidance and use of sunscreen.

•Gynecologic cancer – Annual gynecologic examinations beginning at age 16. As noted above, HPV vaccination should be administered due to the possible role of HPV in gynecologic cancers in individuals with DC [101,102] and is recommended for all children in the United States starting at nine years of age.

•Lung cancer – Avoidance of smoking and other exposures that increase the risk of pulmonary fibrosis should be emphasized, as discussed below. Some experts offer chest radiography after age 40.

●Pulmonary manifestations – Initial screening for pulmonary fibrosis should begin by age 10 in all patients with TBDs who are developmentally able to perform pulmonary function testing (PFT). Studies should include pulse oximetry for Sp0₂ assessment, spirometry, and assessment of the diffusion capacity of the lung for carbon monoxide (DLCO). For patients <7 years in whom pulmonary abnormalities are suspected, a six-minute walk test may be performed. Contrast echocardiography ("bubble echo"), which assesses for right-to-left shunting, should be performed in any patient with cyanosis, clubbing, or PFT/DLCO testing suspicious for pulmonary arteriovenous malformation and/or hepatopulmonary syndrome.

PFT should be repeated every three to five years if normal or annually if significant abnormalities are identified. The use of routine computed tomography (CT) scans for screening remains controversial in DC, given the concerns about radiation exposure. However, in patients with abnormal PFT/DLCO testing, high-resolution CT may be useful to further define the extent of pulmonary fibrosis present. In patients who have undergone HCT, an initial PFT/DLCO assessment is recommended by one year after HCT, and many centers perform more frequent screening.

Education to avoid exposures that increase the risk of pulmonary fibrosis is highly recommended for patients with DC, as well as for family members who are asymptomatic but possess telomere disorder-associated familial gene mutations. Exposures for which avoidance is recommended include the following [103]:

•Tobacco or cannabis smoking, vaping, and exposure to second-hand smoke

•Drugs associated with lung dysfunction (eg, nitrofurantoin, amiodarone, busulfan)

•Elective general anesthesia when possible, due to associated injury of lung epithelium

•Occupational environments where exposure to high particulate air concentrations is likely, or use of filtering respirator masks in such environments

•Respiratory illnesses, through adherence to immunization schedules and good hand-hygiene practices

●Hepatic manifestations – Due to risks for portal hypertension and liver cirrhosis, all patients require an annual examination for liver size and measurement of liver enzymes, bilirubin, albumin, and prothrombin time. A baseline liver ultrasound should be obtained at the time of diagnosis and reassessed every three to five years. Ultrasound or magnetic resonance imaging (MRI) may be useful for detecting liver fibrosis. Doppler assessment of portal venous flow should be performed in patients with splenomegaly or with other clinical features that could indicate the presence of portal hypertension. Liver biopsy may be appropriate if significant abnormalities are identified by laboratory testing or imaging studies. Notably, patients receiving androgen therapy are at increased risk of developing hepatic dysfunction and should be monitored more closely. Preventative management focuses on avoidance of alcohol consumption and medications with known hepatic toxicities.

●Endocrine manifestations – All patients with a TBD should have consultation with an endocrinologist by age 10 years, with earlier consultation for patients with severe bone health, growth, or other hormone deficiencies. Patients who have undergone allogeneic hematopoietic cell transplantation (HCT) and those who are receiving androgen therapy should have an annual assessment by an endocrinologist because of the high risk of endocrine complications in these patients.

•Thyroid – Baseline assessment of thyroid hormone function (including TSH), especially if HCT is anticipated.

•Bone health – Poor bone health/osteopenia is common in patients with TBDs. We obtain screen serum calcium, magnesium, and 25-hydroxy vitamin D levels annually and supplement any deficiencies. Patients with Coats Plus have a particularly high rate of pathologic fractures in long bones and thus should have routine monitoring with bone health specialists.

At ages 12 to 14 years, we perform initial dual-energy x-ray absorptiometry (DXA) screening and repeat the assessment every three to five years, depending on coexistent risk factors. Patients should be educated about signs and symptoms of fracture and avascular necrosis of the hip and shoulder joints.

•Short stature – Patients with short stature should have an assessment of growth hormone axis function by an endocrinologist, although most patients with DC who have short stature do not have growth hormone deficiency [104].

•Gonadal function/fertility – While infertility is not a common feature of TBDs, patients with hypogonadism and/or pubertal delay should have an assessment by an endocrinologist for bone age, testosterone, LH, and FSH levels.

Women with DC or TBD typically have normal menarche, but they may need fertility assistance and they have a higher rate of pregnancy complications. A multi-disciplinary approach, including maternal-fetal medicine and hematology is helpful [65].

●Additional screening – We also perform the following screening tests:

•Eyes – Annual ophthalmology evaluations, with initial screening for epiphora and retinal changes including exudative retinopathy and neovascularization.

•Hearing – Formal hearing examination, with follow-up audiologic assessment of any abnormalities.

•Gastrointestinal – Upper and lower endoscopy, both for cancer screening as indicated above as well as for any patient with dysphagia suggestive of esophageal stricture or evidence of upper or lower gastrointestinal bleeding.

•Genito-urinary – Urology consultation for any patient with urethral or hymenal strictures, phimosis, or hypogonadism.

•Immunity – Assessment for immune deficiency, with initial screens that include quantitative immunoglobulin levels (IgE, IgA, IgM, and IgG), cellular immunology panel assessing absolute, T, B, and NK cell numbers/subsets, and lymphocyte proliferation to mitogens. The need for ongoing screening is determined by the initial screening results. Patients with selective B cell deficiency, a common finding in some forms of TBDs, may benefit from immune globulin replacement.

•Neurology – Neurologic assessment is important for individuals with certain TBDs.

Patients with Hoyeraal-Hreidarsson syndrome (HHS) should have an initial MRI, and patients with Revesz syndrome should have CT of the brain for intracranial calcifications. (See 'Hoyeraal-Hreidarsson syndrome' above and 'Revesz syndrome' above.)

•Mental health – Psychologic/psychiatric/social work assessment, with an initial assessment for all patients newly diagnosed with DC to determine the need for ongoing services to help with coping strategies related to the diagnosis of a chronic medical disease; formal assessment for neuropsychiatric disorders associated with disease; and assistance in developing an individualized education plan to maximize educational and occupational achievements. Ongoing screening should be determined based on individual needs.

Screening of family members and relatives — If a pathogenic gene mutation has been identified in the proband, first degree family members (especially siblings) should be tested as soon as feasible. This is important for identifying clinically occult disease that may require interventions, and for determining eligibility as an HCT donor should HCT be necessary for the index patient or other affected family members. Testing for known familial mutations can also be pursued for other interested family members in addition to siblings. Testing should be accompanied by counseling with a genetic counselor or clinician with expertise in DC.

Prenatal testing is possible if needed, using cells obtained by chorionic villus sampling, amniocentesis, or cordocentesis. In vitro fertilization with prenatal genetic diagnosis (PGD) is another method utilized to detect disease or carrier status prior to implantation of sibling embryos. (See "Preimplantation genetic testing".)

If a pathogenic mutation has not been identified and the proband's diagnosis is based on short telomeres along with characteristic clinical features, we recommend telomere length analysis in both parents, along with in any first-degree relative with shared clinical features of DC. Notably, this testing should be done with the assistance of a genetic counselor to facilitate active discussion with the involved family members regarding the implications of test results. (See "Genetic counseling: Family history interpretation and risk assessment" and "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)

Treatment of specific complications

Treatment of bone marrow failure — As noted above, individuals with DC should have a bone marrow evaluation at the time of diagnosis (see 'Laboratory testing and bone marrow' above and 'Initial and ongoing screening' above). This may show hypocellularity and some degree of dyspoiesis [21]. Some individuals may have clonal cytogenetic abnormalities, myelodysplasia and/or acute leukemia.

For those with evidence of bone marrow hypocellularity and moderate to severe cytopenias, cytogenetic abnormalities, or dysplasia, referral to a transplant center with expertise in managing inherited bone marrow failure syndromes (IBMFS) is appropriate, in order to facilitate planning and review the indications for HCT. (See 'Hematopoietic cell transplantation' below.)

Supportive care — Transfusions may be required for severe anemia or thrombocytopenia. We use a judicious approach, as extensive transfusions may be associated with worse outcomes from HCT, due to transfusional iron overload and/or alloimmunization against red blood cell or HLA antigens. Erythropoietin is generally not used due to concerns it may increase the risk of MDS or AML in this susceptible population. We limit the use of granulocyte colony-stimulating factor (G-CSF; filgrastim) to individuals with an absolute neutrophil count (ANC) below 200/microL or those with known active invasive bacterial or fungal infection and an ANC <1000/microL, due to concerns that G-CSF may also increase the risk of MDS and AML in patients with BMF syndromes.

As mentioned below, danazol may improve blood counts, although this improvement is not permanent and is lost with drug cessation; we might use danazol to improve blood counts if we anticipated a delay in starting HCT for a patient with DC, or if a patient were ineligible to receive HCT (see 'Therapies to enhance telomere function' below). Notably, the combination of growth factors with androgens should be avoided, as this led to splenic peliosis and rupture in two individuals with DC [21].

Hematopoietic cell transplantation — Allogeneic HCT remains the only curative option for BMF in patients with DC, and our approach is to pursue HCT with the best available donor for all pediatric patients with DC who have BMF and who are transplant-eligible, based on organ function criteria. However, this approach has many risks [105]. Additionally, HCT does not treat the extra-hematopoietic complications of DC and related syndromes. HCT may actually increase the risk of nonhematologic malignancies. Importantly, potential sibling (or other related) donors must be evaluated for DC and demonstrated not to have the familial mutation. (See 'Screening of family members and relatives' above.)

Early studies of HCT in patients with DC used myeloablative preparative regimens, resulting in very poor short-term and long-term survival, with fewer than 30 percent of patients surviving 10 to 15 years after HCT [106]. While the sensitivity to genotoxic agents is similar to patients with Fanconi anemia (FA), the adverse sequelae differ. Individuals with DC who received standard myeloablative conditioning regimens had high rates of hepatic and pulmonary fibrosis, with late-onset veno-occlusive disease of the liver [21]. As a result, reduced intensity conditioning (RIC) regimens are universally used for HCT in patients with DC.

DC-specific RIC regimens have been published [107-110]. However, a systematic review that included 109 patients who underwent HCT for DC showed that even for patients receiving conventional RIC regimens after the year 2000, five-year overall survival was only 70 percent [111]. HCT using an unaffected matched sibling donor conveyed a significant survival advantage over receiving alternative donor HCT (92 to 58 percent) and performing HCT at age <20 years may also be associated with a survival advantage. Causes of death have included graft failure, sepsis, pulmonary fibrosis, hepatic veno-occlusive disease, GVHD, and solid tumors.

A pilot study involving four patients with DC who underwent HCT from an unrelated donor demonstrated the efficacy of an alkylator- and radiation-free conditioning regimen consisting of fludarabine and alemtuzumab [112]. All patients experienced engraftment, there were no deaths, no patient developed significant organ toxicities, and only one patient developed mild chronic GVHD. This promising approach has been extended into a multicenter clinical trial, for which results are awaited [113].

Importantly, dermatologic, hepatic, and enteropathy manifestations of DC may be mistaken for GVHD in patients who have undergone HCT [106]. Biopsies of the affected tissues may help to distinguish these entities based on the extent of inflammatory infiltrates and pathognomonic features of GVHD such as crypt drop-out in gut biopsies or portal tract loss in liver biopsies. However, the sensitivity and specificity of these findings in patients with TBDs are not well established. Most modern regimens, including the fludarabine and alemtuzumab regimen, use T cell depletion of donor grafts to mitigate the risks of GVHD in patients with DC. This may be done in vivo (with alemtuzumab or anti-thymocyte globulin) or ex vivo (prior to graft infusion for example T cell receptor alpha-beta T cell depletion).

Additional details of HCT for patients with DC and other TBDs and transplant outcomes are presented separately. (See "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Dyskeratosis congenita'.)

Alternatives for those who do not have access to HCT (eg, due to comorbidities that preclude transplant, lack of a suitable donor, cost) or prefer not to pursue HCT include treatment with androgenic steroids and supportive care with transfusions and growth factors. (See 'Therapies to enhance telomere function' below and 'Supportive care' above.)

AML or MDS — As with other inherited BMF conditions, pre-HCT chemotherapy is unlikely to be tolerated in patients with a TBD due to prolonged myelosuppression. Patients with low-grade MDS should proceed to HCT directly, although the optimal HCT regimen for such patients has yet to be defined.

The general management of AML or MDS in patients with BMF is discussed separately. (See "Management and prognosis of Fanconi anemia", section on 'Hematologic neoplasms'.)

Solid tumors — There are no specific guidelines that suggest how to adjust the intensity of cytotoxic chemotherapy or radiation therapy in patients with TBDs, but anecdotal evidence suggests that reduced intensity is indicated to prevent prolonged cytopenias, pulmonary toxicity, hepatotoxicity, and, in the case of radiation therapy, severe local toxicity at the site of treatment [74]. Oncologists treating patients with TBDs for solid tumors should develop an individualized treatment plan in coordination with a BMF specialist who has experience treating TBDs. Further information on these solid tumors including oral leukoplakia is presented separately. (See "Oral lesions".)

Treatment of nonmalignant skin, nail, and hair lesions — Hyperkeratotic skin lesions of the palms and soles have been treated effectively with agents such as urea creams and/or salicylic acid creams. There are no treatments known to improve the skin dyspigmentation seen in many patients with TBDs, but moisturizers may be helpful in reducing the roughened texture of some of these skin areas.

Patients with hyperhidrosis may benefit from anticholinergic therapy, although this should be done in conjunction with an experienced dermatologist. Minoxidil may help with thinning hair or alopecia, and the ophthalmic solution bimatoprost may help with eyelash regrowth [114]. Normal nail health is unlikely, but breakage can be reduced using nail lacquers to strengthen nails, avoidance of excessive detergent exposure/hand washing, and avoidance of artificial nails. Biotin may be of benefit in strengthening nails and hair. Additional information is provided separately:

●Nail disorders – (See "Overview of nail disorders" and "Principles and overview of nail surgery".)

●Skin hyperpigmentation – (See "Acquired hyperpigmentation disorders".)

Treatment of pulmonary fibrosis — Pulmonary fibrosis affects approximately one-fifth of individuals with DC, and 5 to 15 percent of individuals with pulmonary fibrosis have mutations in TERT or TERC. A whole exome sequencing study of 262 individuals with idiopathic pulmonary fibrosis reported that 11 percent of case subjects had an identifiable pathogenic variant in TERT, RTEL1, or PARN [79]. (See 'Additional somatic features' above.)

One of the most important aspects of treating patients with pulmonary fibrosis is ensuring that testing is sent to diagnose a telomere disorder, as this may have profound implications for treatment, as discussed separately. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

All individuals with DC and findings on PFTs or lung CT that suggest pulmonary fibrosis should be referred to a pulmonologist for further evaluation and management. Reports of patients with DC who have undergone lung transplantation for pulmonary fibrosis suggest that this approach is feasible, although complications may be increased compared to individuals without DC [115]. Other aspects of the management of pulmonary fibrosis are discussed in detail separately. (See "Treatment of idiopathic pulmonary fibrosis".)

Therapies to enhance telomere function — Therapy that restores normal telomere function is appealing because it has the potential to treat all organ system manifestations of DC. A variety of approaches to increasing telomerase activity are under investigation.

●Androgen therapy – Patients with DC and related telomere biology disorders have long been treated with androgen hormone therapies, which have been observed to increase blood counts in patients with cytopenias. In a 2016 study, the androgen danazol was shown to be associated with consistent telomere elongation [15]. The study involved a prospective series of 27 individuals ages 17 and older who had at least one cytopenia associated with a telomere disorder other than classic DC, diagnosed based on short telomere length or genetic testing. Danazol (400 mg) was administered twice daily for two years. The study was stopped early after the first 11 patients reached the two-year evaluation because the effect on the prespecified primary endpoint (20 percent reduction in telomere shortening) was much more dramatic than expected. Telomere elongation was documented in 89 percent of patients at 12 months and 92 percent at 24 months. Hematologic responses were seen in 79 percent of patients at three months and 83 percent at 24 months. Stabilization of the DLCO occurred in all seven patients for whom pre- and post-treatment results were available. The most common adverse events were liver enzyme elevations (41 percent), muscle cramps (33 percent), edema (26 percent), and lipid abnormalities (26 percent). Among eight individuals for whom telomere measurements were performed after danazol was stopped, all reverted to telomere shortening, suggesting this therapy would need to be given indefinitely.

In a 2014 observational cohort study that included 16 younger patients (median age, 11 years), many of whom had classic DC features, the impact of androgen therapy was less pronounced. While 69 percent showed a hematologic response, none had changes in the expected, age-related telomere decline. Additionally, one patient developed a concerning hyperechoic liver lesion, and two patients developed splenic peliosis, which led to splenic rupture in one patient [116].

The difference in outcomes of these two studies suggests that more studies are needed to define whether favorable outcomes for androgen therapy are dependent upon the specific androgen used, with danazol showing the most benefit thus far, or whether benefit depends upon the population studied, with androgen therapy perhaps having a more favorable risk/benefit profile in older patients with milder genetic defects in telomerase function.

•For patients who have BMF and meet eligibility criteria for HCT, including having a suitably matched related or unrelated donor, we use HCT rather than androgen therapy. Danazol use may be appropriate in patients with transfusion-dependent cytopenias in whom HCT cannot be performed safely if a long delay prior to HCT is expected. (See 'Treatment of bone marrow failure' above.)

•For patients who have other organ dysfunction (including pulmonary fibrosis) associated with a TBD, androgen therapy should be restricted to prospective clinical trials. (See 'Treatment of pulmonary fibrosis' above.)

On danazol, blood counts need to be monitored closely (at least monthly initially), and close monitoring for adverse effects (eg, hepatotoxicity, lipid abnormalities, accelerated growth, splenic peliosis) is required [116,117]. Patients on androgen therapy require liver function assessments every three months, liver ultrasounds yearly, and yearly screens for dyslipidemia. Androgens should not be used in combination with growth factors, as this led to splenic peliosis and rupture in two individuals with DC [21]. (See 'Supportive care' above.)

●Therapies targeting Wnt signaling – Preclinical studies using induced pluripotent stem (iPS) cells derived from patients with DC or animal models have suggested that upregulating signaling through the Wnt pathway in tissue-specific stem cells may ameliorate telomerase dysfunction in DC [118-120]. Known agonists of Wnt signaling, including lithium chloride, are being studied in these preclinical models, but clinical trials testing this approach in patients with telomere disorders have not been initiated.

●Gene therapy – Gene therapy for TBDs is promising, but it is currently limited to clinical studies.

Challenges of applying gene therapy to the TBDs include the need for unique targeting strategies for each affected gene, and autologous gene correction in specific tissues (eg, liver, hematopoietic cells) will not correct the molecular abnormality in other tissues that are affected by telomerase dysfunction.

There is an ongoing study of gene therapy for DC (NCT04211714).

●Nucleotide Metabolism – Preclinical studies have demonstrated that knocking out thymidine (dT) production by the thymidylate synthase gene or decreasing dT salvage shortens telomere lengths, but inactivation of the nucleotide targeting enzyme deoxynucleoside triphosphohydrolase lengthens telomeres. Supplementation with dT drives telomere elongation in healthy cells as well as in induced pluripotent stem cells from patients with TBDs. Clinical trials of dT treatment are being planned [121].

PROGNOSIS — 

Outcomes and clinical manifestations of TBDs vary with the inheritance pattern. The prognosis has improved over the decades.

Survival varies with the inheritance pattern of the TBD: autosomal dominant (AD), autosomal recessive (AR), and X-linked recessive (XLR). Among 231 individuals with TBDs, median overall survival (OS) was 52.8 years [59]. OS was better with AD inheritance (median 64.9 years; excluding TINF2 variants) compared with AR/XLR (31.8 years) and TINF2 (37.9 years). Survival of males is shorter than females, even when excluding XLR disorders.

Causes of mortality in individuals with TBDs include bone marrow failure and its consequences (eg, bleeding, infection) and transplant-related mortality [18]. Solid tumors, pulmonary fibrosis, and hepatic disease also cause mortality.

Survival has improved in association with better management of organ system involvement, improved outcomes with hematopoietic cell transplantation, and improved recognition of individuals with milder phenotypes who were diagnosed using telomere measurements and genetic testing.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)

SUMMARY AND RECOMMENDATIONS

●Description – Telomeres are specialized structures at the ends of chromosomes that shorten with each cell division. In telomere biology disorders (TBDs), mutations in genes that maintain telomere length (table 1 and figure 1) lead to premature cell death, senescence, genomic instability, and impaired organ function. (See 'Pathophysiology' above.)

●Clinical features – The spectrum of findings is highly variable and can affect bone marrow, immunity, skin, lung, liver, and teeth (table 2 and picture 1). Some features typically appear in childhood, but pulmonary fibrosis and liver cirrhosis typically present in adulthood and may be the first presenting feature of TBDs other than Dyskeratosis congenita (DC). (See 'Clinical features' above.)

●Diagnosis – A TBD should be considered in an individual of any age with bone marrow failure (BMF) or pulmonary fibrosis, with or without accompanying nail dystrophy, abnormal skin pigmentation, oral leukoplakia, and/or other somatic findings.

Diagnosis of a new proband is generally based on clinical findings suggestive of a TBD, followed by identification of a pathogenic gene variant, using telomere length analysis, genetic testing, and bone marrow evaluation. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis includes other causes of inherited or acquired BMF, hematologic malignancies, congenital anomalies, or interstitial lung disease. (See 'Differential diagnosis' above.)

●Management – All patients with TBDs should have a comprehensive assessment in a center with expertise in the management of patients with TBDs.

•Surveillance – Patients require ongoing surveillance for BMF, myelodysplastic syndrome/neoplasms (MDS), certain solid tumors, pulmonary fibrosis, liver disease, thyroid function, osteopenia, and other manifestations. If a pathogenic variant was identified, siblings and other first-degree family members should be tested promptly to identify clinically occult disease and to determine eligibility as a donor for hematopoietic cell transplantation (HCT). Prenatal testing is also possible if needed. (See 'Initial and ongoing screening' above and 'Screening of family members and relatives' above.)

•Bone marrow failure – Transfusions may be required for severe anemia or thrombocytopenia. We pursue HCT for all medically eligible pediatric patients with TBDs who have moderate to severe BMF. However, HCT is associated with significant adverse effects, it does not treat the extra-hematopoietic complications of TBDs, and it may increase the risk of nonhematologic malignancies. (See 'Treatment of bone marrow failure' above.)

Danazol may be helpful for selected individuals who cannot undergo HCT, but androgens should not be used in combination with hematopoietic growth factors due to the risk of splenic rupture. (See 'Therapies to enhance telomere function' above.)

•Other management – Treatment for hematopoietic neoplasms, solid tumors, skin and nail findings, and pulmonary fibrosis are discussed above and in separate topic reviews listed above. (See 'AML or MDS' above and 'Solid tumors' above and 'Treatment of nonmalignant skin, nail, and hair lesions' above and 'Treatment of pulmonary fibrosis' above.)