ORPHA: 2032, 88;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p15.33 | Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 1 | 614742 | Autosomal dominant | 3 | TERT | 187270 |
A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-1 (PFBMFT1) is caused by heterozygous mutation in the TERT gene (187270) on chromosome 5p15.
Shortened telomeres can cause a wide variety of clinical features that constitute a phenotypic spectrum. The most severe form is dyskeratosis congenita (see, e.g., 127550), characterized by early childhood onset of skin abnormalities, bone marrow failure, predisposition to malignancy, and risk of pulmonary and hepatic fibrosis. Adult-onset pulmonary fibrosis is the most common manifestation of mutant telomerase genes, but hepatopulmonary syndrome may precede the pulmonary fibrosis. Other manifestations include aplastic anemia due to bone marrow failure, liver disease, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and squamous cell carcinoma. Phenotype, age at onset, and severity are determined by telomere length, not just telomerase mutation (Armanios, 2009; Schratz et al., 2023).
The genetic diagnosis of telomere-related bone marrow failure and pulmonary fibrosis has implications for treatment because affected individuals generally do not respond to immunosuppression and may be at increased risk for fatal complications after bone marrow or lung transplantation (Parry et al., 2011).
Genetic Heterogeneity of Telomere-Related Pulmonary Fibrosis and/or Bone Marrow Failure Syndromes
Also see PFBMFT2 (614743), caused by mutation in the TERC gene (602322) on chromosome 3q26; PFBMFT3 (616373), caused by mutation in the RTEL1 gene (608833) on chromosome 20q13; PFBMFT4 (616371), caused by mutation in the PARN gene (604212) on chromosome 16p13; PFBMFT5 (618674), caused by mutation in the ZCCHC8 gene (616381) on chromosome 12q24; PFBMFT6 (619767), caused by mutation in the RPA1 gene (179835) on chromosome 17p13; PFBMFT7 (620365), caused by mutation in the NAF1 gene (617868) on chromosome 4q32; PFBMFT8 (620367), caused by mutation in the POT1 gene (606478) on chromosome 7q31; and PFBMFT9 (620400), caused by mutation in the NOP10 gene (606471) on chromosome 15q14.
Yamaguchi et al. (2005) reported 7 unrelated patients with aplastic anemia who had heterozygous germline mutations in the TERT gene (187270.0001-187270.0005). The patients ranged in age from 31 to 75 years. Bone marrow showed low cellularity, and patient leukocytes had short telomeres (most below 10% of controls) and low telomerase enzymatic activity (most less than 1% of controls). Four patients had family members with hematologic disorders, including myelodysplastic syndrome and acute myeloid leukemia. In 1 family, members carrying the mutation also had short telomeres and reduced telomerase activity but no evident hematologic abnormalities.
Armanios et al. (2007) reported 5 families in which at least 2 members had adult-onset pulmonary fibrosis. The age at onset ranged from 48 to 77 years. Presenting symptoms included dyspnea or cough, and pulmonary function tests were below predicted values. Only 2 probands had a smoking history. Lung biopsy showed usual interstitial pneumonia or idiopathic interstitial pneumonia. None of the patients had skin abnormalities or cytopenias. Telomere lengths in lymphocytes of affected individuals were at or below 10% of control values.
Kirwan et al. (2009) reported 2 unrelated families with variable manifestations of telomere-related pulmonary fibrosis and/or bone marrow failure-1. The proband in 1 family had adult-onset aplastic anemia and fibrosing alveolitis, whereas his father had adult-onset myelodysplastic syndrome. In the second family, the proband presented with adult-onset myelodysplastic syndrome and acute myeloid leukemia, whereas her sister had aplastic anemia.
Diaz de Leon et al. (2011) compared pulmonary, blood, skin, and bone parameters for 20 subjects from 11 kindreds with familial pulmonary fibrosis with heterozygous TERT mutations and 20 family members who had not inherited a TERT mutation to identify the spectrum of phenotypes associated with mutations in this gene. The 2 groups were matched for sex, age, and cigarette smoking. Three of the TERT mutation carriers already met diagnostic criteria for idiopathic pulmonary fibrosis. The other carriers were apparently healthy. Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (DLCO), impaired recruitment of DLCO with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. Red blood cell and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentrations were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status was most accurately predicted by short telomere lengths than by any of the measured phenotypes.
Parry et al. (2011) demonstrated that a personal and family history of both aplastic anemia and pulmonary fibrosis is highly predictive for the presence of a germline mutation in the TERT or the TERC gene. They performed a retrospective study of 10 patients referred for bone marrow failure or pulmonary fibrosis who had a family history of the other disorder. Six cases presented initially with aplastic anemia and 4 initially with interstitial lung disease. Six of the 10 were subsequently diagnosed with a second feature, including pulmonary or hepatic fibrosis, or hypoplastic marrow. The mean age at diagnosis for those who presented with aplastic anemia was significantly younger than those with pulmonary fibrosis (14 vs 51 years). All patients had at least 1 other first-degree relative with bone marrow failure or pulmonary disease, and the transmission pattern was consistent with autosomal dominant inheritance. In 8 of 10 families, there was phenotypic heterogeneity across generations: older generations first manifested with pulmonary fibrosis, whereas subsequent generations manifested with bone marrow failure at an earlier age. Although none had skin manifestations, most had premature graying of the hair before age 25 years. All 10 probands had a mutation in either the TERT (7 probands) (see, e.g., 187270.0018-187270.0020) or the TERC (3 probands) (see, e.g., 602322.0008 and 602322.0012) gene, and the mutations segregated with the disorder. The mutant genes were associated with very short telomerase length in patient lymphocytes (less than 1% of control values). Parry et al. (2011) concluded that the complex of bone marrow failure and pulmonary fibrosis is highly specific for the presence of a germline telomerase defect. Gansner et al. (2012) reported a 56-year-old man with telomere-related pulmonary fibrosis and bone marrow failure-1. He was diagnosed with pulmonary fibrosis at age 49. He had mild pancytopenia with moderately hypocellular bone marrow. The patient had a family history of a similar disorder: his father and 1 sister had pulmonary fibrosis, a second sister had pulmonary fibrosis and thrombocytopenia, and a third sister had pulmonary fibrosis and acute myeloid leukemia. Telomere lengths in the proband were less than 1% of control values.
Gorgy et al. (2015) diagnosed hepatopulmonary syndrome (HPS) in 9 (21%) of 42 cases with short telomere syndromes and progressive dyspnea who did not have parenchymal lung disease or had only minimal fibrosis that could not explain the hypoxia. The age at presentation was younger than that of pulmonary fibrosis and emphysema (25 vs 55 years). Features included cyanosis, digital clubbing, splenomegaly, elevated liver enzymes, pulmonary vascular abnormalities, and portal hypertension. Affected individuals had evidence of intra- and extra-pulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Liver biopsy also showed iron deposits and noncirrhotic portal hypertension. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplant was 6 years. After liver transplant, dyspnea and hypoxia improved, but pulmonary fibrosis progressed. Additional variable syndromic features found in these patients included bone marrow failure, premature hair graying, and mucocutaneous features of DKC. Family history was positive for pulmonary fibrosis, DKC, and aplastic anemia in some cases. All patients had abnormally short telomeres. Six of the 9 cases carried a mutation in the TERT (4 patients), DKC1 (1 patient), or RTEL1 (1 patient) genes. The authors concluded that HPS may cause dyspnea in telomerase gene mutation carriers.
Schratz et al. (2023) identified 16 invasive solid tumors in 14 of 226 adults with short telomere syndromes due to mutations in several genes, including at least 1 patient with a TERT mutation. Nearly all (88%) of the tumors were derived from the squamous cell epithelium, most commonly of the head and neck, followed by anal squamous cell carcinoma and skin squamous cell carcinoma. In contrast, there was a lower than expected number of common age-related solid cancers among these patients. Most of the patients who developed squamous cell solid tumors were male. Development of the tumors was associated with CD4+ T-cell lymphopenia, suggesting impaired tumor surveillance by T cells and age-related T-cell exhaustion. Of note, all 3 anal cancers and 1 laryngeal cancer were associated with HPV infection, and 4 of 10 patients with T-cell lymphopenia had secondary causes for the lymphopenia (lung or liver transplant or iatrogenic immunosuppression).
The transmission pattern of PFBMFT1 in the families reported by Armanios et al. (2007) was consistent with autosomal dominant inheritance with incomplete penetrance. Moreover, mutation carriers who did not have symptoms of the disease were on average 11 years younger than probands at the time of diagnosis, suggesting that onset of the disease is age-dependent.
In 8 of 10 families with telomerase mutations, Parry et al. (2011) observed phenotypic heterogeneity across generations: older generations first manifested with pulmonary fibrosis, whereas subsequent generations manifested with bone marrow failure at an earlier age. These findings suggested that genetic anticipation due to telomere shortening is not only associated with early age of onset across generations, but also with a changing pattern of disease manifestations.
By genomewide linkage analysis of 2 large Caucasian families with idiopathic pulmonary fibrosis or interstitial lung disease, Tsakiri et al. (2007) found linkage to chromosome 5p15 (maximum lod score of 2.8).
Because mutations had been found in the TERC gene in families with aplastic anemia (Vulliamy et al., 2002), Yamaguchi et al. (2005) screened blood or bone marrow cells from 124 patients with apparently acquired aplastic anemia for mutations in the TERT gene and identified 5 heterozygous, nonsynonymous germline mutations in 7 unrelated patients (see 187270.0001-187270.0005). Leukocytes from these patients had short telomeres and low telomerase enzymatic activity. Other family members carrying the mutations also had short telomeres and reduced telomerase activity but no evident hematologic abnormalities. Yamaguchi et al. (2005) concluded that heterozygous TERT mutations impair telomerase activity by haploinsufficiency and are a risk factor for marrow failure.
In 5 of 73 probands with adult-onset familial idiopathic pulmonary fibrosis and no skin manifestations suggestive of DKC, Armanios et al. (2007) found 5 different heterozygous mutations in the TERT gene (see, e.g., 187270.0010; 187270.0015-187270.0016). Armanios et al. (2007) chose to screen telomerase genes after noting that members of a family with a null TERT mutation (Armanios et al., 2005) showed dominant inheritance of pulmonary fibrosis and variable features of bone marrow failure without the classic skin manifestations of DKC (DKCA2; 613989). Armanios et al. (2007) found that the average telomere length in lymphocytes from the 5 probands with adult-onset pulmonary fibrosis and in asymptomatic mutation carriers was significantly less compared to those who did not carry a TERT mutation and was less than 10% of controls, indicating that mutant telomerase was associated with short telomeres. These findings also suggested that asymptomatic carriers may also be at risk for the disease. Armanios et al. (2007) proposed that the fibrotic lesions in these patients may be provoked by a loss of alveolar cells due to cell death, rather than by a primary fibrogenic process. However, there was no difference in the pulmonary phenotype between patients with TERT mutations and those without mutations. The findings extended the spectrum of disease caused by telomerase shortening.
In 2 large Caucasian families with interstitial lung disease mapping to chromosome 5p15, many cases of which met the clinical criteria for pulmonary fibrosis, Tsakiri et al. (2007) sequenced the candidate TERT gene and identified heterozygosity for a missense mutation (187270.0008) and a frameshift mutation (187270.0009) that cosegregated with pulmonary disease in the 2 families, respectively. Analysis of the TERT gene in probands of 44 additional unrelated families and 44 sporadic cases of interstitial lung disease revealed 5 other heterozygous mutations. Although all family members with pulmonary fibrosis who were sequenced were heterozygous for these mutations, some carriers had no evidence of pulmonary disease; however, heterozygous carriers of TERT mutations had shorter telomeres than age-matched family members without the mutations. Tsakiri et al. (2007) concluded that mutations in TERT that result in telomere shortening confer a dramatic increase in susceptibility to adult-onset pulmonary fibrosis.
In affected members of 2 unrelated families with variable manifestations of telomere-related pulmonary fibrosis and/or bone marrow failure-1, Kirwan et al. (2009) identified 2 different heterozygous mutations in the TERT gene. One mutation carrier in each family presented with myelodysplastic syndrome. Each family contained at least 1 asymptomatic member who carried the mutation, suggesting incomplete penetrance and that the mutations are risk factors for development of the disease. Mutation carriers had short telomeres, and there was a correlation between shorter telomere length and disease manifestation. Overall, Kirwan et al. (2009) identified TERT or TERC mutations in 4 of 20 families presenting with MDS/AML.
Alder et al. (2011) identified a founder mutation in the TERT gene (187270.0017) in affected members from 2 families with telomere-related pulmonary fibrosis-1. A common ancestor had emigrated from the British Isles to the United States in the 18th century. All mutation carriers had telomere lengths below the 10th percentile, and 6 of 9 mutation carriers had lengths below the 1st percentile. Most mutation carriers had adult-onset pulmonary fibrosis, 2 had liver abnormalities, 1 had cytopenia, and 1 developed acute myeloid leukemia. None had abnormal skin findings.
Alder, J. K., Cogan, J. D., Brown, A. F., Anderson, C. J., Lawson, W. E., Lansdorp, P. M., Phillips, J. A., III, Loyd, J. E., Chen, J. J.-L., Armanios, M. Ancestral mutation in telomerase causes defects in repeat addition processivity and manifests as familial pulmonary fibrosis. PLoS Genet. 7: e1001352, 2011. Note: Electronic Article. [PubMed: 21483807] [Full Text: https://doi.org/10.1371/journal.pgen.1001352]
Armanios, M., Chen, J.-L., Chang, Y.-P. C., Brodsky, R. A., Hawkins, A., Griffin, C. A., Eshleman, J. R., Cohen, A. R., Chakravarti, A., Hamosh, A., Greider, C. W. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Nat. Acad. Sci. 102: 15960-15964, 2005. [PubMed: 16247010] [Full Text: https://doi.org/10.1073/pnas.0508124102]
Armanios, M. Y., Chen, J. J.-L., Cogan, J. D., Alder, J. K., Ingersoll, R. G., Markin, C., Lawson, W. E., Xie, M., Vulto, I., Phillips, J. A., III, Lansdorp, P. M., Greider, C. W., Loyd, J. E. Telomerase mutations in families with idiopathic pulmonary fibrosis. New Eng. J. Med. 356: 1317-1326, 2007. [PubMed: 17392301] [Full Text: https://doi.org/10.1056/NEJMoa066157]
Armanios, M. Syndromes of telomere shortening. Annu. Rev. Genomics Hum. Genet. 10: 45-61, 2009. [PubMed: 19405848] [Full Text: https://doi.org/10.1146/annurev-genom-082908-150046]
Diaz de Leon, A., Cronkhite, J. T., Yilmaz, C., Brewington, C., Wang, R., Xing, C., Hsia, C. C. W., Garcia, C. K. Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations. Chest 140: 753-763, 2011. [PubMed: 21349926] [Full Text: https://doi.org/10.1378/chest.10-2865]
Gansner, J. M., Rosas, I. O., Ebert, B. L. Pulmonary fibrosis, bone marrow failure, and telomerase mutation. (Letter) New Eng. J. Med. 366: 1551-1553, 2012. [PubMed: 22512499] [Full Text: https://doi.org/10.1056/NEJMc1200999]
Gorgy, A. I., Jonassaint, N. L., Stanley, S. E., Koteish, A., DeZern, A. E., Walter, J. E., Sopha, S. C., Hamilton, J. P., Hoover-Fong, J., Chen, A. R., Anders, R. A., Kamel, I. R., Armanios, M. Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders. Chest 148: 1019-1026, 2015. [PubMed: 26158642] [Full Text: https://doi.org/10.1378/chest.15-0825]
Kirwan, M., Vulliamy, T., Marrone, A., Walne, A. J., Beswick, R., Hillmen, B., Kelly, R., Stewart, A., Bowen, D., Schonland, S. O., Whittle, A. M., McVerry, A., Gilleece, M., Dokal, I. Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Hum. Mutat. 30: 1567-1573, 2009. [PubMed: 19760749] [Full Text: https://doi.org/10.1002/humu.21115]
Parry, E. M., Alder, J. K., Qi, X., Chen, J. J.-L., Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117: 5607-5611, 2011. Note: Erratum: Blood 127: 1837 only, 2016. [PubMed: 21436073] [Full Text: https://doi.org/10.1182/blood-2010-11-322149]
Schratz, K. E., Flasch, D. A., Atik, C. C., Cosner, Z. L., Blackford, A. L., Yang, W., Gable, D. L., Vellanki, P. J., Xiang, Z., Gaysinskaya, V., Vonderheide, R. H., Rooper, L. M., Zhang, J., Armanios, M. T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers. Cancer Cell 41: 807-817, 2023. [PubMed: 37037617] [Full Text: https://doi.org/10.1016/j.ccell.2023.03.005]
Tsakiri, K. D., Cronkhite, J. T., Kuan, P. J., Xing, C., Raghu, G., Weissler, J. C., Rosenblatt, R. L., Shay, J. W., Garcia, C. K. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Nat. Acad. Sci. 104: 7552-7557, 2007. [PubMed: 17460043] [Full Text: https://doi.org/10.1073/pnas.0701009104]
Vulliamy, T., Marrone, A., Dokal, I., Mason, P. J. Association between aplastic anaemia and mutations in telomerase RNA. Lancet 359: 2168-2170, 2002. [PubMed: 12090986] [Full Text: https://doi.org/10.1016/S0140-6736(02)09087-6]
Yamaguchi, H., Calado, R. T., Ly, H., Kajigaya, S., Baerlocher, G. M., Chanock, S. J., Lansdorp, P. M., Young, N. S. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. New Eng. J. Med. 352: 1413-1424, 2005. [PubMed: 15814878] [Full Text: https://doi.org/10.1056/NEJMoa042980]