TY - JOUR
T1 - Tissue-specific telomere shortening and degenerative changes in a patient with TINF2 mutation and dyskeratosis congenita
AU - Roake, Caitlin M.
AU - Juntilla, Marisa
AU - Agarwal-Hashmi, Rajni
AU - Artandi, Steven
AU - Kuo, Christin S.
N1 - Funding Information:
We would like to thank the patient and her family for participating in this case study. We thank the members of the Department of Pathology, Stanford University School of Medicine for their contributions to the patient case. We thank Nicole Almanzar for final formatting of manuscript. Patient and family consented to participating in research studies and autopsy. A chart review was also conducted and approved by Stanford University's research compliance office (IRB # 30096). M.J. and C.K. conceived the study. C.M.R and M.J. and C.K. analyzed the data and wrote the paper. S.A. supported the study and the telomere experiments. R.A. reviewed the manuscript and Bone Marrow Transplant specifics. C.M.R. was supported by MSTP training grant GM007365 and by a Gerald J Lieberman Fellowship. S.E.A is supported by NIH grant #AG056575. C.S.K is supported by Doris Duke Charitable Foundation Grant # 2018105.
Funding Information:
C.M.R. was supported by MSTP training grant GM007365 and by a Gerald J Lieberman Fellowship. S.E.A is supported by NIH grant #AG056575. C.S.K is supported by Doris Duke Charitable Foundation Grant # 2018105.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/9
Y1 - 2021/9
N2 - Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.
AB - Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.
KW - Dyskeratosis congenita
KW - Hypoxemia
KW - Pediatric bone marrow failure
KW - Telomere length
UR - http://www.scopus.com/inward/record.url?scp=85109160773&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85109160773&partnerID=8YFLogxK
U2 - 10.1016/j.ehpc.2021.200517
DO - 10.1016/j.ehpc.2021.200517
M3 - Article
C2 - 34522616
AN - SCOPUS:85109160773
SN - 2214-3300
VL - 25
JO - Human Pathology: Case Reports
JF - Human Pathology: Case Reports
M1 - 200517
ER -