ORPHA: 2032;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.33 | Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 3 | 616373 | Autosomal dominant | 3 | RTEL1 | 608833 |
A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-3 (PFBMFT3) is caused by heterozygous mutation in the RTEL1 gene (608833) on chromosome 20q13.
For a discussion of genetic heterogeneity of telomere-related pulmonary fibrosis and/or bone marrow failure, see PFBMFT1 (614742).
Stuart et al. (2015) reported 5 unrelated families with susceptibility to pulmonary fibrosis and/or unspecified lung disease. Affected family members had shortened telomeres (less than 1-2% of control length). None were noted to have features of bone marrow failure.
Cogan et al. (2015) reported 9 families in which multiple individuals were diagnosed with interstitial pneumonia between 45 and 87 years of age (mean, 64.8 years). All affected and unaffected mutation carriers had extremely short telomeres, at least less than the tenth percentile for age. None of the families had a history or clinical features of bone marrow failure, hematopoietic malignancy, or dyskeratosis congenita.
Gorgy et al. (2015) diagnosed hepatopulmonary syndrome (HPS) in a 49-year-old man (patient 9) with PFBMFT3 who had progressive dyspnea with only minimal pulmonary fibrosis that could not explain the hypoxia. Features included cyanosis, digital clubbing, splenomegaly, elevated liver enzymes, portal hypertension, and intractable ascites. Liver biopsy showed nodular regenerative hyperplasia. There was evidence of intra- and extra-pulmonary arteriovascular malformations that caused shunt physiology. Dyspnea and portal hypertension were progressive, and he underwent liver transplant at age 53, which resolved the shunting defects. However, pulmonary fibrosis progressed. Bone marrow was normocellular. The authors concluded that HPS can 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 RTEL1 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 telomere-related pulmonary fibrosis in the families reported by Stuart et al. (2015) was consistent with autosomal dominant inheritance and incomplete penetrance. There was also evidence of environmental influences, e.g., smoking and occupational factors.
In affected members of 5 unrelated families with telomere-related pulmonary fibrosis, Stuart et al. (2015) identified 5 different heterozygous mutations in the RTEL1 gene (see, e.g., 608833.0014-608833.0017). The mutations were found by whole-exome sequencing of 99 probands with a family history of pulmonary fibrosis. Among all families, at least 5 clinically unaffected individuals carried a pathogenic mutation, consistent with incomplete penetrance. Functional studies of the variants were not performed.
Lamm et al. (2009) and Deng et al. (2013) reported that a relative of sibs with biallelic RTEL1 mutations, who carried a heterozygous mutation (M492I; 608833.0003), died of pulmonary fibrosis at age 58 years.
In 9 unrelated families with PFBMFT3, Cogan et al. (2015) identified 9 different heterozygous mutations in the RTEL1 gene (see, e.g., 608833.0002; 608833.0018-608833.0020). The mutation in the first family was found by whole-exome sequencing of 25 families; subsequent mutations were found by sequencing the RTEL1 gene in 163 additional kindreds with the disorder. Overall, RTEL1 mutations were identified in 9 (4.7%) of 188 families who underwent sequencing. Peripheral blood cells derived from mutation carriers showed shortened telomeres and increased T-circle formation compared to controls, consistent with a loss of RTEL1 function.
Cogan, J. D., Kropski, J. A., Zhao, M., Mitchell, D. B., Rives, L., Markin, C., Garnett, E. T., Montgomery, K. H., Mason, W. R., McKean, D. F., Powers, J., Murphy, E., and 27 others. Rare variants in RTEL1 are associated with familial interstitial pneumonia. Am. J. Resp. Crit. Care Med. 191: 646-655, 2015. [PubMed: 25607374] [Full Text: https://doi.org/10.1164/rccm.201408-1510OC]
Deng, Z., Glousker, G., Molczan, A., Fox, A. J., Lamm, N., Dheekollu, J., Weizman, O.-E., Schertzer, M., Wang, Z., Vladimirova, O., Schug, J., Aker, M., Londono-Vallejo, A., Kaestner, K. H., Lieberman, P. M., Tzfati, Y. Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal-Hreidarsson syndrome. Proc. Nat. Acad. Sci. 110: E3408-E3416, 2013. Note: Electronic Article. [PubMed: 23959892] [Full Text: https://doi.org/10.1073/pnas.1300600110]
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]
Lamm, N., Ordan, E., Shponkin, R., Richler, C., Aker, M., Tzfati, Y. Diminished telomeric 3-prime overhangs are associated with telomere dysfunction in Hoyeraal-Hreidarsson syndrome. PLoS One 4: e5666, 2009. Note: Electronic Article. [PubMed: 19461895] [Full Text: https://doi.org/10.1371/journal.pone.0005666]
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]
Stuart, B. D., Choi, J., Zaidi, S., Xing, C., Holohan, B., Chen, R., Choi, M., Dhawadkar, P., Torres, F., Girod, C. E., Weissler, J., Fitzgerald, J., and 9 others. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nature Genet. 47: 512-517, 2015. [PubMed: 25848748] [Full Text: https://doi.org/10.1038/ng.3278]