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Guidelines for Diagnosis and Management Third Edition • 2008 Fanconi Anemia Fanconi Anemia: Guidelines for Diagnosis and Management Third Edition 2008 Fanconi Anemia Research Fund, Inc.
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Fanconi Anemia
ia Research Fund, Inc.
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
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.
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:
Material from this book may be reprinted with the permis- sion of the Fanconi Anemia Research Fund, Inc.
Fanconi Anemia: Guidelines for Diagnosis and Managementiv
The Fanconi Anemia Research Fund, Inc., was founded in 1989 to provide support to FA fami lies and to raise money for scien tific 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
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
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
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:
• 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.
Fanconi Anemia: Guidelines for Diagnosis and Management8
• 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.
• Clinical trials or at least the collection of longi- tudinal data are required to inform treatment choices for patients with FA in the future.
FA must be considered a multi-system disease.
• The name of the disorder, Fanconi anemia, may disserve patients since hematologic manifesta- tions of FA are not the sole (or even the most important) problem for many patients.
• The FA phenotype is quite variable and leads to misdiagnosis and failure of diagnosis. Patient monitoring must include hearing evaluation, assessment of endocrine system and GI tract issues, and long-term cancer surveillance.
• For the majority of patients, hematopoietic stem cell transplantation is the ultimate therapy for marrow dysfunction. Consequently, early involvement with a major transplant center experienced in FA transplants and with a multi- disciplinary consultation team is optimal.
FA is a cancer-prone disorder.
• Close monitoring, especially for the high incidence of SCC, is a special consideration throughout the FA patient’s lifetime, even post- transplant.
• The intrinsic genetic instability of the FA patient means that exposure to ionizing radiation, envi- ronmental carcinogens and chemotherapeutic agents could pose special risks to the patient. Consequently, diagnostic x-ray exposure and some otherwise routine medical tests or agents may themselves pose undesirable risks.
Fanconi Anemia: Guidelines for Diagnosis and Management10
FA is a psychosocially demanding disorder.
• The pressures on the patients, parents and siblings over an extended time can be over- whelming, particularly where there are multiple affected family members.
• Patients, families and providers must be sensi- tive to issues of expense, the sophistication and availability of medical and family counseling, and the significant and continuing emotional trauma resulting from this diagnosis.
The underlying diagnosis and the many drugs often necessary for treatment may put FA patients at particular risk for hazardous pharmaceutical cross- reactions.
• The family and primary physician must continu- ously coordinate and monitor prescribed and over-the-counter medications taken by a patient.
The authors recognize that a significant proportion of affected families seek out and utilize “alternative” medicine.
• We accept this approach but at the same time ask families to be open in discussing what they are doing. Effective therapies may emerge and need to be shared. However, we also caution that unforeseen toxicities and drug interactions need to be identified.
We commend these guidelines in the profound hope that they will better serve the lives of patients afflicted with this serious and life-threatening disorder. We welcome comments that may inform future improvements in care and treatment.
Dave Frohnmayer President and Professor of Law University of Oregon Co-founder, Fanconi Anemia Research Fund, Inc. Vice President, Board of Directors
Eva Guinan, MD Moderator, Consensus Conference Associate Director, Center for Clinical and Translational Research Dana-Farber Cancer Institute Medical Director, Harvard Catalyst Laboratory for Innovative Translational Technologies Director, Harvard Catalyst Linkages Program Associate Professor of Pediatrics Harvard Medical School Jeffrey M. Lipton, MD, PhD Chief, Pediatric Hematology/Oncology and Stem Cell Transplantation Schneider Children’s Hospital Professor of Pediatrics Albert Einstein College of Medicine Investigator and Professor, Elmezzi Graduate School of Molecular Medicine The Feinstein Institute for Medical Research
Fanconi Anemia: Guidelines for Diagnosis and Management12
Chapter 1 Clinical Management Checklist
Fanconi anemia is a complex disease that can affect many systems of the body. Patients are at risk for bone marrow failure, leukemia, and squamous cell carci- noma. They also can be affected by other facets of the disease, such as endocrine, gastrointestinal or radial ray abnormalities.
This checklist, a compendium of suggestions from many of the authors of the handbook, is not all inclu- sive and does not take the place of reading the compre- hensive information in the book. Many of the tests and procedures mentioned will not be appropriate for every individual patient nor does the checklist present an exhaustive list of possible tests or treatments that each FA patient should undergo. Rather, it should be used at the discretion of the patient’s physician and should be specifically tailored to the needs of the patient.
Diagnostic Testing
• If FA is suspected, the patient should be referred to a hematologist to arrange for a diepoxybu- tane (DEB) or mitomycin C (MMC) chromo- some fragility test of blood lymphocytes at a clinically-certified laboratory with expertise in FA diagnostic testing. The Fanconi Anemia Research Fund website ( pro- vides a listing of such testing centers.
• If diagnostic test results of blood are not con- clusive and there is a high probability of FA, skin fibroblasts should be obtained for more
complete testing. If the result remains inconclu- sive, additional diagnostic testing is available and described in this book.
• All children suspected of having the congenital anatomic abnormalities referred to as VACTERL should be tested for Fanconi anemia.
• All full siblings of the FA patient, regardless of whether they show physical signs or symptoms, must be tested to rule out FA.
Complete History and Physical
Patients diagnosed with FA should undergo a complete work-up and physical examination, which include the following:
• Family history, including consanguinity and history of prior family members with anemia, physical abnormalities or cancer.
• Past medical history, including an assessment of prior blood counts, congenital malformations, and medications used.
• Hematologic assessment, including a complete blood count and differential, and a bone marrow aspiration, biopsy, and cytogenetic evaluation.
• Hepatic assessment, including liver enzymes and total bilirubin.
• Renal assessment, including serum electro- lytes and creatinine, and ultrasound to rule out renal dysplasia, hydronephrosis, and/or bladder anomalies.
• Urologic examination to assess for genitouri- nary (GU) reflux, urinary tract infections, and GU malformations. If a renal abnormality is found in a female, the patient should be assessed for reproductive tract malformations.
Fanconi Anemia: Guidelines for Diagnosis and Management14
• Endocrine evaluation, including thyroid func- tion, serum glucose and/or glucose tolerance, lipid assessment, and bone mineral density.
• Ear and hearing examination to assess for hear- ing loss and/or structural abnormalities of the ears.
• Eye examination by an ophthalmologist, if clini- cally indicated.
• Examination for head and neck cancer by an otolaryngologist (ear, nose, and throat special- ist), beginning at age ten.
• Gynecological examination (see page 22). • Examinations by other specialists, depending on
the individual needs of the patient.
Complementation Group Assignment
• Identification of the complementation group can guide medical management of the FA patient and help the family determine cancer risk in patients and in carriers. It can also guide family planning efforts and may be important for pro- spective gene therapy trials. Complementation group typing is available through FA-specialized laboratories.
• Genes not currently identifiable by complemen- tation group testing include FANCD1/BRCA2, D2, I, M, and N. Mutation analysis is necessary to classify individuals into one of these five groups.
Mutation Analysis
• Mutation analysis determines and/or confirms the initial complementation group result and is also used to perform other genetic tests, such as carrier testing or prenatal testing. Mutation
15Chapter 1: Clinical Management Checklist
analysis is available at certain FA-specialized diagnostic laboratories.
Genetic Counseling
• At diagnosis, the FA patient and family should be referred to a genetic counselor, who can explain the genetic testing process, clarify the mode of inheritance of FA, and provide repro- ductive counseling.
Medical Management after Diagnosis
The care of most FA patients should be coordinated by a hematologist with expertise in Fanconi anemia, in conjunction with the patient’s local family physician. See Chapter 3 for a thorough discussion of ongoing hematological care.
Bone Marrow Failure
Most Fanconi anemia patients develop bone marrow failure, but the age of onset is variable, even among affected siblings. Patients with or without marrow involvement should be monitored by a hematologist with experience in managing FA patients.
• Cytopenias: Cytopenias in FA patients warrant a thorough hematologic work-up to rule out additional treatable causes other than primary bone marrow failure.
• Myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML): Patients are at high risk of developing MDS and AML. They should be monitored closely to assess possible onset of MDS or frank leukemia and to identify the presence of cytogenetic abnormalities that may warrant immediate intervention.
Fanconi Anemia: Guidelines for Diagnosis and Management16
Bone marrow aspiration with or with- out biopsy should be done annually to allow comparison of marrow to patient’s previous specimens. See Chapter 3 for an individualized schedule for clinical monitoring of bone marrow and timing of referral for discussion with a trans- plant center.
• HLA typing: Early high-resolution HLA typing of the patient and immediate family members is recommended to assess the availability of potential bone marrow donors, should a trans- plant be necessary. To allow for the most appro- priate medical plan, a donor search—if there is no identified sibling donor—should be initiated well before the need for transfusions or develop- ment of MDS or AML.
Blood Transfusions and Iron Overload
• Transfusions: High transfusion burden may adversely
affect transplant outcomes. Family mem- bers should not be used as blood donors for the patient. Timely consideration of transplant is recommended if transfu- sions are required.
• For patients who receive transfusions: Patients who receive multiple transfu-
sions of red blood cells are at risk for accumulating toxic levels of iron. The liver, heart, and endocrine organs are primary sites of iron accumulation, and end-organ damage may result (e.g., hepatic cirrhosis, heart failure, endo- crine dysfunction). For an extensive
17Chapter 1: Clinical Management Checklist
discussion of the management of iron overload, refer to Chapter 3.
Referral to a pediatric gastroenterologist or hematologist with expertise in iron toxicity is indicated for monitoring of iron overload.
• For patients post-transplant: If a patient has received a significant
number of red blood cell transfusions, an assessment of total body iron should be performed no later than one year after transplant.
Depending on the result, monthly phle- botomy or chronic iron chelation may be necessary.
The involvement of multiple subspecialists introduces the risk that medications prescribed by one physician will interact adversely with those prescribed by another or that the use of non-prescription drugs may interact adversely with prescribed medication. All subspecialists must communicate with the primary physician—usually the hematologist—to coordinate care, and the patient should identify all prescription and non-prescription drugs used for each provider.
Radiation Exposure
Because FA patients have increased sensitivity to radia- tion, the primary FA physician involved in managing the patient should consult the family and other doctors of the patient to reduce exposure to diagnostic radiation as much as possible.
Fanconi Anemia: Guidelines for Diagnosis and Management18
Hand and/or Arm Abnormalities
Patients with hand or arm abnormalities should be assessed at diagnosis by an orthopedic surgeon with experience in congenital limb differences and with a Certificate of Added Qualification in Hand Surgery. Early referral (in the first few months of life) of the patient to an orthopedic upper extremity specialist is highly recommended to obtain the best possible result if surgery is required.
Recommended management by the orthopedic surgeon includes:
If the patient has not been assessed for a possible diagnosis of FA:
• Consider and/or rule out the diagnosis of Fan- coni anemia if patient presents with radial ray or thumb abnormalities or other characteristic features of FA (see Chapters 2 and 5).
If the patient has FA:
• Consult with patient’s primary physician/ hematologist.
• Assess for musculoskeletal problems. • Assess for thumb anomalies. • Assess for forearm anomalies. • The…