ORPHA: 2032;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.12 | Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4 | 616371 | Autosomal dominant | 3 | PARN | 604212 |
A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-4 (PFBMFT4) is caused by heterozygous mutation in the PARN gene (604212) on chromosome 16p13.
For a discussion of genetic heterogeneity of telomere-related pulmonary fibrosis and/or bone marrow failure, see PFBMFT1 (614742).
Stuart et al. (2015) reported 6 unrelated families with pulmonary fibrosis and/or unspecified lung disease. Affected family members had shortened telomeres (less than 1-30% of control length). A few patients had premature graying of the hair, but none were noted to have features of bone marrow failure.
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 mutation in the PARN gene. 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 6 unrelated families with telomere-related pulmonary fibrosis, Stuart et al. (2015) identified 6 different heterozygous mutations in the PARN gene (see, e.g., 604212.0005-604212.0008). Five of the mutations were truncating, consistent with haploinsufficiency; 1 was a missense mutation. The mutations were found by whole-exome sequencing of 99 probands with a family history of pulmonary fibrosis. Among all families, at least 9 clinically unaffected individuals carried a pathogenic mutation, consistent with incomplete penetrance. Cells from patients with truncating mutations showed reduced protein expression, but additional functional studies were not performed.
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]