F a n c o n i A n e m i a : G u i d e Fanconi l i n e s f o r D i Anemia a g n o s i s a n d M a Guidelines for Diagnosis n a g and Management e m e n Third Edition • 2008 t • T h i r d E d i t i o n • 2 0 0 8 RF ea sn ec ao rcn h Fi An ue nm d , Inia c . Fanconi Anemia Guidelines for Diagnosis and Management Third Edition • 2008 Fanconi Anemia Research Fund, Inc. We are deeply grateful to the following generous donors, who made this publication possible: The Autzen Foundation Pat and Stephanie Kilkenny Phil and Penny Knight Disclaimer Information provided in this handbook about medications, treatments or products should not be construed as medical instruction or scientific endorsement. Always consult your physician before taking any action based on this information. copyright© 1999; second edition 2003; third edition 2008 Fanconi Anemia Guidelines for Diagnosis and Management Third Edition • 2008 Editors: Mary Ellen Eiler, Dave Frohnmayer, JD, Lynn Frohnmayer, MSW, Kim Larsen, and Joyce Owen, PhD Layout and Design: Melanie Fee These guidelines for the clinical care of Fanconi anemia (FA) were developed at a conference held April 10-11, 2008 in Chicago, Illinois. We owe a tremendous debt of gratitude to Eva Guinan, MD, for serving as moderator of the confer- ence, as she did for the consensus conferences for the first two editions, and for her skill in helping the participants arrive at consensus. We would like to thank all the participants for donating their time and expertise to develop these guidelines. The names and contact information of all participants appear in the Appendix. These guidelines are posted on our website and are available from: Fanconi Anemia Research Fund, Inc. 1801 Willamette Street, Suite 200 Eugene, Oregon 97401 Phone: 541-687-4658 or 888-326-2664 (US only) FAX: 541-687-0548 E-mail: [email protected] Website: www.fanconi.org Material from this book may be reprinted with the permis- sion of the Fanconi Anemia Research Fund, Inc. iv Fanconi Anemia: Guidelines for Diagnosis and Management The Fanconi Anemia Research Fund, Inc., was founded in 1989 to provide support to FA fami lies and to raise money for scient ific research. The Fund publishes a newslet ter twice a year, sponsors an annual family meeting, and provides resource identification and counseling support to families. To aid research into FA, the Fund gives grants to scientists and sponsors scientific conferences, including an annual scientific symposium. Board of Directors Barry Rubenstein, JD, President David Frohnmayer, JD, Vice President Ruby Brockett, Secretary/Treasurer Deane Marchbein, MD Kevin S. McQueen Peg Padden Mark K. Pearl Kevin Rogers Robert D. Sacks Michael L. Vangel Peter H. von Hippel, PhD Joyce L. Owen, PhD, Director Emeritus Advisor to the Board Lynn Frohnmayer, MSW Staff Jeanne Negley, Executive Director Teresa Kennedy, Family Support Coordinator Melanie Fee, Publications Coordinator Kristi Keller, Administrative Assistant and Bookkeeper Kim Larsen, Grant Writer and Conference Coordinator Scientific Advisory Board Grover C. Bagby, Jr., MD, Chair Manuel Buchwald, PhD, OC, Emeritus Joseph Califano, MD Marc Coltrera, MD Richard Gelinas, PhD Eva Guinan, MD Hans Joenje, PhD Christopher Mathew, PhD Stephen Meyn, MD, PhD Raymond J. Monnat, Jr., MD Elaine Ostrander, PhD Bhuvanesh Singh, MD, PhD Erich M. Sturgis, MD, MPH Neal S. Young, MD Table of Contents Introduction ..................................................................7 Chapter 1: Clinical Management Checklist ................13 Chapter 2: Diagnostic Evaluation of FA Blanche P. Alter, MD, MPH, FAAP ...........................33 Chapter 3: Treatment of Hematologic Abnormalities in Fanconi Anemia Akiko Shimamura, MD, PhD......................................49 Chapter 4: Gastrointestinal, Hepatic, and Nutritional Problems in FA Sarah Jane Schwarzenberg, MD and Nada Yagizi, MD .........................................................76 Chapter 5: Hand and Arm Differences in FA Scott H. Kozin, MD ....................................................97 Chapter 6: Gynecologic and Fertility Issues in Female FA Patients Pamela Stratton, MD, Rahel Ghebre, MD, and Jill Huppert, MD, MPH ............................................121 Chapter 7: Endocrine Disorders in Fanconi Anemia Susan R. Rose, MD, Anna Petryk, MD, and Constantine A. Stratakis, MD ...................................134 Chapter 8: Hearing and Ear Abnormalities in Fanconi Anemia H. Jeffrey Kim, MD, FACS, Christopher Zalewski, MA, and Carmen C. Brewer, PhD ............................165 Chapter 9: Matched Sibling Donor Hematopoietic Stem Cell Transplantation Farid Boulad, MD .....................................................178 vi Fanconi Anemia: Guidelines for Diagnosis and Management Chapter 10: Unrelated Donor Hematopoietic Stem Cell Transplantation John E. Wagner, MD, Jakub Tolar, MD, K. Scott Baker, MD, and Margaret L. MacMillan, MD ..........197 Chapter 11: Late Effects in Fanconi Anemia Patients Post-Transplant Margaret L. MacMillan, MD, K. Scott Baker, MD, and John E. Wagner, MD ..........................................223 Chapter 12: Novel Treatment Options Jakub Tolar, MD, PhD ..............................................236 Chapter 13: Head and Neck Squamous Cell Carcinoma in Fanconi Anemia Patients Bhuvanesh Singh, MD, PhD .....................................250 Chapter 14: The Adult FA Patient Alfred Gillio, MD and Eva Guinan, MD ..................264 Chapter 15: Genetic Counseling Heather Zierhut, MS, CGC, and edited by Ann Carr, MS, CGC ..................................................275 Chapter 16: Psychosocial Issues Nancy F. Cincotta, MSW, CCLS ..............................291 Chapter 17: A Mother’s Perspective: The Grieving Process and the Physician’s Role Lynn Frohnmayer, MSW ..........................................307 Appendix: Participants and Contributors ................317 Glossary ....................................................................331 Index .........................................................................372 Introduction This edition of guidelines for the care of patients with Fanconi anemia is the result of a Consensus Conference held by the Fanconi Anemia Research Fund in Chicago, Illinois on April 11 and 12, 2008. It is intended as a complete replacement for earlier versions published in 1999 and 2003. Our audience is physicians who provide primary care for FA patients, and patients and families who wish to secure optimal treatment through medical understanding, consultation and appropriate referral. These guidelines begin with a comprehensive checklist for physicians and medical specialists and diagnostic criteria. Subsequent chapters examine more specific issues faced by the FA patient. The guidelines conclude with important psychosocial considerations that bear upon the well-being of the patient and extended family. Where possible, the guidelines rely on evidence-based medicine. Where adequate data are lacking because of limitations of numbers, time frame or present knowl- edge, the consensus of expert opinion underlies the rec- ommendations. All chapters have been peer-reviewed and speak to the state of best practices as of the date of each chapter. To avoid being excessively prescrip- tive, the title of this book has been changed deliberately from “Standards” to “Guidelines.” From the discussions at the Consensus Conference, the authors realize that a more robust clinical database must be developed to gather additional evidence upon which to base recom- mendations. FA-related science has advanced significantly in the five years since the last publication in 2003: 8 Fanconi Anemia: Guidelines for Diagnosis and Management • At least 13 FA genes now have been identified. The understanding of interactions among molec- ular pathways has become increasingly complex and sophisticated. Genotype determination and mutation analysis for each patient bear directly on the appropriateness of some treatment choices. • Phenotypic and genotypic predictors of the natural history and outcome of the disease are beginning to emerge. • The identification of BRCA2 and other FA genes linked to breast cancer susceptibility has brought an influx of new scientific talent and interest to the field of FA research. The rele- vance of these findings to heterozygotes is being evaluated. • The introduction of fludarabine (Fludara) into FA hematopoietic stem cell transplantation protocols has continued to produce dramatic improvements in patient outcomes. As a conse- quence, stem cell transplantation from unrelated or mismatched donors is a realistic treatment option for increasing numbers of FA patients. • A growing cohort of post-transplant adult FA survivors presents new medical surveillance and treatment issues. • The availability of preimplantation genetic diag- nosis (PGD) for FA and for HLA determination provides a potential parental choice for secur- ing an HLA-matched umbilical cord stem cell transplantation. Introduction 9 • Evaluation of adult FA patients reveals a striking and ominous incidence of squamous cell carci- nomas (SCC), especially of the head and neck and gynecological tract. This underscores the need for continuous monitoring and more effec- tive treatment options throughout the patient’s lifetime. General Considerations The Consensus Conference was guided by the follow- ing general considerations that form the underlying basis for more specific recommendations. FA is a very rare genetic disorder. • Accuracy in diagnosis is crucial and requires sophisticated expertise. • The mode of inheritance is important for fur- ther genetic testing of siblings; finding matched donors; identification of genotype for purpose of predicting onset of symptoms and conse- quences; family planning (including PGD); and genetic counseling to the family. • Expertise in FA treatment is highly specialized and to date is concentrated only in a few, criti- cally important centers. Many patients do not have access to such expertise locally, but the use of referral networks and provider cooperation should help provide adequate care. FA is a complex and chronic disorder. • Well-orchestrated multidisciplinary care across several medical and surgical specialties is typically required for adequate monitoring and treatment.