Clinical Case Study References Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: E.C. Guinan, Fanconi Anemia Research Foundation. Stock Ownership: None declared. Honoraria: None declared. Research Funding: None declared. Expert Testimony: E.C. Guinan, case related to missed diagnosis of dyskeratosis congenita. Patents: None declared. Acknowledgments: We are grateful to Repeat Diagnostics Inc., North Vancouver, British Columbia, Canada, for providing the telomere length test data in Fig. 1.
1. Kirwan M, Dokal I. Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet 2008;73:103–12. 2. Savage SA. Dyskeratosis congenita. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews™. Seattle: University of Washington; 2009 Nov 12 (updated 2012 Sep 13). http://www.ncbi.nlm.nih.gov/books/ NBK22301 (Accessed October 2012). 3. Keller RB, Gagne KE, Usmani GN, Asdourian GK, Williams DA, Hofmann I, Agarwal S. CTC1 mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer 2012;59:311– 4. 4. Mason PJ, Bessler M. The genetics of dyskeratosis congenita. Cancer Genet 2011;204:635– 45. 5. Calado RT, Young NS. Telomere diseases. N Engl J Med 2009;361:2353– 65. 6. Baerlocher GM, Vulto I, de Jong G, Lansdorp PM. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protoc 2006;1:2365–76. 7. Alter BP, Rosenberg PS, Giri N, Baerlocher GM, Lansdorp PM, Savage SA. Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica 2012;97:353–9. 8. Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 2004;36:447–9. 9. Jongmans MC, Verwiel ET, Heijdra Y, Vulliamy T, Kamping EJ, Hehir-Kwa JY, et al. Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. Am J Hum Genet 2012;90:426 –33. 10. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in dyskeratosis congenita. Blood 2009;113:6549 –57.
Commentary Todd E. Druley*
The authors present a classic case of dyskeratosis congenita (DC) and nicely summarize the variability in clinical and diagnostic findings in patients with inherited bone marrow failure syndromes (IBMFSs). Owing to end-organ dysfunction, an increased risk for various cancers, and the need for appropriate genetic counseling, accurate diagnosis is essential. Although this patient demonstrates the classic findings of DC, many patients present with more subtle findings, making the distinction between IBMFS subtypes and acquired bone marrow failure difficult, further highlighting the necessity to combine clinical and diagnostic modalities for proper diagnosis. There is tremendous heterogeneity in the clinical presentation of IBMFSs, likely because of comparable diversity in genetic causation and penetrance across the various subtypes. As this case demonstrates, a genetic cause is found in only about 50% of individuals with DC. Because the genetic underpinnings of DC remain incompletely characterized, variants in genes associated with telomere
Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, MO. * Address correspondence to the author at: Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Fax 314-362-3245; e-mail
[email protected]. Received October 16, 2012; accepted October 17, 2012. DOI: 10.1373/clinchem.2012.192310
50 Clinical Chemistry 59:1 (2013)
maintenance are often assumed to be causative, when, in some cases, they may be of ethnic or private origin and have little effect on telomere biology when analyzed functionally, potentially leading to misdiagnosis (1 ). Telomere length analysis offers high sensitivity, but limited specificity, for distinguishing between IBMFS and acquired bone marrow failure. Unaffected individuals—particularly family members of affected individuals— or individuals with other causes of bone marrow failure may also demonstrate telomere shortening. Alternatively, the natural histories are little known for individuals with similar clinical findings but less severe telomere shortening (e.g., Clericuzio-type poikiloderma). In a patient with marrow failure, however, the finding of normal telomere length obviates the diagnosis of DC (2 ). Thus, no single approach— clinical, sequencing, or telomere length—is adequate as a stand-alone method. As high-throughput genomics penetrates clinical diagnostics, a more comprehensive genetic characterization of these patients should become standard practice.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Clinical Case Study Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: T.E. Druley, Guidepoint Global Advisors. Stock Ownership: None declared. Honoraria: None declared. Research Funding: None declared. Expert Testimony: None declared. Patents: None declared.
References 1. Vogiatzi P, Perdigones N, Mason PJ, Wilson DB, Bessler M. A family with Hoyeraal-Hreidarsson syndrome and four variants in two genes of the telomerase core complex. Pediatr Blood Cancer. Forthcoming 2012. 2. Du H-Y, Pumbo E, Ivanovich J, An P, Maziarz RT, Reiss UM, et al. TERC and TERT gene mutations in patients with bone marrow failure and significance of telomere length measurements. Blood 2009;113:309 –16.
Commentary Timothy S. Olson* and Monica Bessler
In this case study, Guinan and Agarwal present an adult patient with progressive bone marrow failure (BMF) displaying many classic features of dyskeratosis congenita (DC), including dystrophic nails, reticular pigmentation, and leukoplakia. Despite the lack of a molecular diagnosis, the presence of classic clinical features, the family history, and the characteristic short telomeres in peripheral blood lymphocytes support the clinical diagnosis of DC and suggest that the patient’s BMF is caused by the excessively short telomeres. This case also highlights that not all patients present with classic features at the time when BMF becomes manifest, or that these features may be subtle and easily missed. Furthermore, even for patients with classic clinical features, a molecular diagnosis can be obtained only in about twothirds of patients. The remaining patients may lack a molecular diagnosis because (a) clinical genetic testing of individual genes is expensive, limiting how many genetic tests can feasibly be performed; (b) current clinical testing misses certain genetic aberrations, such as large deletions or mutations in regulatory sequences within known DCcausing genes; or (c) additional genes leading to clinical DC remain undiscovered. Currently, mutations in 8 genes have been associated with DC. These mutations all participate in telomere maintenance but fall into 3 distinct telomeremaintenance pathways: the telomerase complex, which elongates telomeres in stem cells [disease genes TERC, TERT, DKC1, NOP10, NHP2, and WRAP53 (formerly TCAB1)]; the shelterin complex, which protects telomere ends and regulates telomerase recruitment (disease gene TINF2); and the CTS complex, which partic-
Children’s Hospital of Philadelphia, Philadelphia, PA. * Address correspondence to this author at: Children’s Hospital of Philadelphia, 3401 Civic Center Blvd., Philadelphia, PA 19104. Fax 215-590-3770; e-mail
[email protected]. Received October 11, 2012; accepted October 17, 2012. DOI: 10.1373/clinchem.2012.192302
ipates in telomere replication and regulates telomerase activity at the telomere end (disease gene CTC1) (1 ). Distinct gene mutations cause patterns of clinical DC that, although possessing considerable phenotypic overlap, may vary widely in terms of organ system involvement, age of onset, and disease severity. In addition, unique clinical features are also associated with specific gene mutations (2 ). Although mutations in the telomerase and/or shelterin complexes have very short telomeres at the time of BMF, whether BMF caused by CTC1 mutations is always associated with very short telomeres remains to be seen (3 ).
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article. Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: M. Bessler, Alexion Pharmaceuticals, Inc. Stock Ownership: None declared. Honoraria: M. Bessler, American Society of Hematology. Research Funding: M. Bessler, NIH/National Cancer Institute grant 2R01 CA105312. Expert Testimony: None declared. Patents: None declared.
References 1. Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet 2012; 13:693–704. 2. Mason PJ, Bessler M. The genetics of dyskeratosis congenita. Cancer Genet 2011;204:635– 45. 3. Walne A, Bhagat T, Kirwan M, Gitaux C, Desguerre I, Leonard N, et al. Mutations in the telomere capping complex in bone marrow failure and related syndromes. Haematologica [Epub ahead of print 2012 Aug 16].
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