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Dyskeratosis Congenita 101 Dyskeratosis Congenita 101 Sharon A. Savage, M.D. Chief, Clinical Genetics Branch Clinical Director, Division of Cancer Epidemiology & Genetics Camp Sunshine September 2018 2012 2016 Dyskeratosis Congenita – early descriptions Year Author(s) Reference Atrophia Cutis Reticularis cum Pigmentatione, Dystrophia 1906 Zinsser, F Unguium et Leukoplakia oris, Ikonogr Derm (Kioto), p 219 A Unique Case of Reticular Pigmentation of the Skin with 1910 Engman, MF, Sr Atrophy, Society Transactions, Arch Derm Syph 13:685 Cole, HN, Dyskeratosis Congenita with Pigmentation, Dystrophia 1930 Rauschkolb JE, Unguis, and Leukokeratosis Oris, Arch Derm Syph 21:71 and Toomey J Archives of Dermatology Vol 88, Sept. 1963 People with telomere biology disorders may face multiple medical problems and always Remember: Ø Everyone is different Ø These problems don’t happen to everyone Ø Things change with age Ø We learn more everyday Diagnostic Triad 1. Dysplastic Nails Diagnostic Triad 2. Skin pigmentation Diagnostic Triad 3. Oral leukoplakia Hematopoietic (blood) system Bone marrow failure Failure to produce enough blood cells Myelodysplastic syndrome Abnormal looking blood cells associated with low numbers and leukemia risk Leukemia Cancer of the blood forming cells Respiratory system Head and neck squamous cell cancer Pulmonary fibrosis Pulmonary arterio- venous malformations (AVMs) Abnormal blood vessel formation in lungs Gastrointestinal (GI) system Esophageal stenosis Liver disease Narrowing of the esophagus Fibrosis and/or abnormal blood vessel connections between liver, spleen, and/or lungs Bleeding in stomach or intestines Poor absorption of food malabsorption Ano-genital cancer Genitourinary system Narrowing of the urethra Urethral stenosis Small head Nervous system microcephaly Developmental delay Small cerebellum Balance problems Psychiatric illnesses Stay tuned for more information in Sonia Bhala’s presentation Skeletal system Avascular necrosis of Low bone density shoulders or hips Osteopenia or osteoporosis Fractures Eye-related complications Abnormal eyelash growth Tear duct narrowing Abnormal blood vessels in retina Tsilou et al, Ophthalmology 2010;117(3):615-22 What’s in a name? • Zinsser – Cole – Engman syndrome • Dyskeratosis Congenita • Hoyeraal Hreidarsson syndrome • Revesz syndrome Telomere Biology Disorder • Coats plus • Aplastic anemia • Familial pulmonary fibrosis • Familial liver fibrosis How are these disorders connected? Traditional DC diagnosis: Diagnostic Triad or 1 of the triad, + BMF + 2 other findings, Vulliamy et al, Blood, 2006, 107(7):2680-5 A Classic DC Family Dysplastic nails at 15 BMF at 17 Died at 32 of BMF Dysplastic nails, abnormal skin pigmentation, oral leukoplakia, mild BMF at 13, microcephaly Mild BMF at 2, microcephaly Severe BMF at 4 Abnormal skin & nails, oral leukoplakia, cerebellar hypoplasia BMF, bone marrow failure Dyskeratosis Congenita – connecting telomere biology with human disease • Germline mutations in dyskerin (DKC1) found in X-linked recessive DC • Heiss et al, Nature Genet 1998 • Dyskerin (DKC1) associates with H/ACA small nucleolar RNAs and hTr (human telomerase RNA, TERC) • DKC1 mutant patient-derived cells have low telomerase, very short telomeres • Mitchell and Collins, Nature 1999 • Accounted for ~20% of DC at the time DKC1 What are telomeres? • Barbara McClintock: • Maize chromosomes stuck together after exposure to X-rays • Something normally protects chromosome ends from this fate • Hermann Muller: • Greek: “telos” = end “meros” = part Reviewed in de Aguiar-Perecin et al., Genet Mol Biol 2000 Telomeres are in algae, humans, and everything in between Photo: Dr. Peter Lansdorp Molecular structure of telomeres • Repeats of DNA bases (TTAGGG)n form single-strand overhang • Single-strand region gets folded over and tucked in Telomere TTAGGGTTAGGG(TTAGGG)nTTAGGG-3’ AATCCC-5’ Telomeres are protected/regulated by a complex network of proteins PCNA PARN Histones XRCC6 BRCA1 SIRT1 EXO1 TERRA ATM/ATR CHK1/CHK2 p53 p21 Why do we need telomeres? DNA damage is a constant threat. Telomeres help keep chromosome ends stable cellular replication ultra-violet light chemicals metabolism Why do we need telomeres? Repair of a DNA break Repair • Two types of DNA ends: • DNA breaks • Normal ends of chromosome • What happens if the cell can’t tell the difference? “Repair” of a normal end: Repair Telomeres protect DNA ends from being recognized as DNA damage, and “repaired” Repair of a DNA break: NO “repair” of a normal end: Repair Repair Why do we need telomeres? They give a limit to the number of times cells can divide, which can limit accumulation of DNA damage Senescence (cells with short telomeres stop dividing) Telomere length # Cell divisions Telomeres get shorter as we age Normal Lymphocytes 14.0 1%ile 12.0 10%ile 50%ile 10.0 90%ile 99%ile 8.0 6.0 4.0 Telomere Length, kb Length, Telomere 2.0 0.0 0 20 40 60 80 100 Age , ye ars Baerlocher and Lansdorp, Methods Cell Biol 2004 Alter et al, Blood 2007 Why do telomeres shorten? • End Replication Problem* - DNA replication machinery can’t fully copy the ends of DNA • Susceptibility to DNA damage Shoelace image: Elizabeth Blackburn, PhD, Nobel Lecture 2009 *Watson, 1972; Olovnikov, 1973 Without functional telomeres, chromosome ends can fuse. This causes massive genetic instability Normal telomeres in mouse cells Telomeres missing a critical protein component (TRF2) Okamoto et al., Nature 2013 Telomeres: Dual Roles in Cancer Development lengthening Longer telomeres permit more cell divisions and accumulation of somatic mutations shortening Cell division Telomere shortening Continued cell division with chromosomal abnormalities and genomic instability 31 Development of the Diagnostic Test for DC White blood cell flow-FISH Telomere Length Lymphocytes LymphocytesLymphocytes 14.014.014 DCDC HH Lymphocyte 12.012.012 HH RSRS st SilentSilent telomeres <1 %ile 10.010 10.0 DCDC Rels Rels for age are 8.08.08 >95% sensitive and 6.06.06 99th %ile specific 90th %ile 4.04.04 50th %ile Telomere Length, kb Length, Telomere Telomere Length, kb Length, Telomere Lymphocytes kb Length, Telomere 10th %ile 2.02.02 1st %ile 14.0 DC 0.00.00 0 2020 4040 6060 8080 100100 12.0 HH RS AgeAge,Age , , ye yearsye ars ars Silent 10.0 DC Rels Alter et al, Haematologica 2012;97(3):353-9 8.0 Alter et al. Blood 2007;110(5):1439-1447 6.0 4.0 Telomere Length, kb Length, Telomere 2.0 0.0 0 20 40 60 80 100 Age , ye ars DC-related Telomere Biology Disorders: Earlier onset, distinct complications • Hoyeraal Hreidarsson (HH) Syndrome • Cerebellar hypoplasia • IUGR • Immune Deficiency • Revesz Syndrome • Bilateral exudative retinopathy • Intracranial calcifications • IUGR DC-related Telomere Biology Disorders: Earlier onset, distinct complications • Coats Plus/CRMCC • Retinal telangiectasias • Exudative retinopathy • Intracranial calcifications and/or cysts • Leukodystrophy • GI vascular ectasias • Osteopenia, fractures, poor bone healing Anderson et al, Nature Genetics 2012 DC-related Telomere Biology Disorders: Later onset, fewer complications • Apparently isolated disease Leukemia, 60 Thrombocytopenia, • Pulmonary fibrosis cirrhosis, 38 Gray hair, 23 SAA, 33 • Aplastic Anemia (bone marrow failure) Died at 47, HSCT complications SAA, 12 Mutation carrier • Liver disease Nail dystrophy, gray hair, teens • Head and neck squamous cell carcinoma Normal Lymphocytes 14.0 1%ile 12.0 10%ile • Classic features of DC may not be 50%ile 10.0 90%ile 99%ile present 8.0 6.0 4.0 Telomere Length, kb Length, Telomere • Family history may not be present proband maternal 2.0 grandmother 0.0 0 20 40 60 80 100 Age , ye ars 35 What causes telomere biology disorders? • Genetic changes in genes critical in telomere biology • 14 genes associated with TBDs, to date, account for ~75% of patients • Different genes are associated with certain complications RTEL1 NHP2 DKC1 NAF1 TPP1 NOP10 TIN2 TERT POT1 TCAB1 TERC PARN STN1 CTC1 Details coming up next in Ann Carr’s talk Acknowledgements NCI’s IBMFS and Telomere Molecular Epidemiology teams Team Telomere Blanche Alter, MD, MPH Neelam Giri, MD Lisa Leathwood, RN Clinical Care Consortium of Functional Studies Ann Carr, CGC Telomere-Associated Ailments S. Artandi: Stanford University S. Agarwal, Harvard Lisa Mirabello, PhD A. Bertuch: Baylor College of Medicine Shahinaz Gadalla MD, PhD A. Bertuch, Baylor J. Tolar, Univ Minnesota T. de Lange: Rockefeller University Payal Khincha, MD Y. Liu: NIA F. Boulad, MSKCC Lisa McReynolds, MD, PhD C. Keegan: University of Michigan K. Myers, Cincinnati Sonia Bhala P. Lansdorp: University of British Columbia Ashley Thompson J.K. Nadakumar: University of Michigan Epidemiology J. Petrini, Memorial Sloan Kettering NCI Cancer Genomics Telomere Length Flow-FISH I. De Vivo: Harvard S. Smith: New York University Research Laboratory P. Lansdorp, Univ R. Hayes: NYU J. Wong: University of British Columbia British Columbia M. Alavanja: NCI And many more… G. Baerlocher, University Bern L. Hou: Northwestern A. Aviv: UMDNJ www.marrowfailure.cancer.gov.
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