A Family’s Battle with Fanconi Anemia
From the moment she was born, Amy Frohnmayer has been fighting against the odds. With her two older sisters, Kirsten and Katie, already diagnosed with Fanconi anemia (FA), Amy’s parents wanted to make sure that their next daughter wasn’t also affected.1 A brief period of relief was found after prenatal tests showed that Amy would be healthy. Unfortunately, when Amy was born it was clear that the doctors made a mistake.1 Amy had FA just like her two older sisters.1 With three out of five of their children affected (their two sons were not affected), the Frohnmayers made sure that they did all they could learn about the disease and to raise awareness.1,2 Unfortunately in 1991 Katie died from complications related to FA at the age of 12, and six years later, 24-year-old Kirsten also passed away due to the disease.2,3 FA is a rare disease that greatly impacts its patients and, due to its hereditary nature, it also poses a threat to their families.
Fanconi anemia affects 1 in 160,000 people throughout the world.4 It is found equally in males and females (1.2:1 ratio) and found in all ethnicities, however, it is more prevalent among Ashkenazi Jews, Northern Europeans, Afrikaners, sub-Saharan Blacks and Spanish Romani peoples.2,4-6 FA is a disease that is inherited primarily through an autosomal recessive pattern (~99% of cases).4-7 When Amy’s oldest sister Kirsten was diagnosed with the disease, it gave an indication that subsequent Frohnmayer siblings had a 25% chance of inheriting the disorder as well.6 Therefore, although Amy’s brothers do not have FA, they still might have inherited one copy of the defective allele, which, in turn, can affect future generations. FA is associated with at least 19 genes, 15 of which are linked to the autosomal recessive mode of inheritance.2,4 Subsequently, out of these 15 genes, mutations in three of these genes (FANCA, FANCC, FANCG) are found to be responsible for about 80-90% of cases of FA.2,8 Overall, these genes are involved in activating DNA repair in the FA pathway.4,8 However, when these genes are defective, DNA damage in the FA pathway accumulates, which eventually results in either abnormal cell death or uncontrolled cell growth (cancer).4,7,8 Abnormal cell death particularly affects fast-dividing cells such as bone marrow cells, which in turn result in decreased blood cells.8 Alternatively, uncontrolled cell growth can result in acute myeloid leukemia (AML) and other cancers.8 The variability of present symptoms in FA patients is due to the severity of genetic defects, ranging from completely nonfunctional to partially functional.5
Fanconi anemia has been diagnosed in patients up until 49 years old; however, most diagnoses occur at younger ages (about half are diagnosed before they turn ten years old).5,8 Due to it affecting almost the entire body, there are a variety of tests that can be done to properly diagnose a person for FA. These include a bone marrow biopsy to test for bone marrow failure, blood tests to test for aplastic anemia (a decrease in all blood cell types) and AML, developmental tests and molecular testing for any mutated FA-associated genes.5-8 The most definitive test for FA diagnosis is the Chromosome Breakage Test which checks for chromosomal damage by adding diepoxybutane (DEB) and mitomycin C (MMC) to the patient’s blood sample.2,5-8 This test can be done prenatally and in all ages.2,6 Diagnosis may be difficult since it involves multiple tests, but it is important that it is done early due to patients’ increased sensitivity to chemotherapy for FA complications such as tumors and AML.5
Although FA is a rare disease, it is the most common disease of the inherited bone marrow failure syndromes (IBMFSs) family.5,7 In addition to affecting the bone marrow, 75% of patients with the disease may also present physical abnormalities such as irregular skin colouring; malformed thumbs, kidneys, ears; abnormalities in the urinary tract, gastrointestinal tract (GI), eyes, heart, genitalia, and reproductive system, as well as the brain and spinal cord.2,4,6,7 Patients with the disease also have an increased risk (about 10-30%) for a variety of cancers, mainly AML and tumors of the head, neck, skin, GI, and genital tract.2,4,6,7 The risk of developing AML in patients with FA is 500 times more likely compared to the general population, where diagnoses typically occur between 15 and 35 years old.5,6 AML is a cancer that affects bone marrow cells and, thus, blood cells. Bone marrow failure is one of the most common complications of FA patients.8 Bone marrow is found in the center of long bones such as the thigh bone and is responsible for producing all blood cell types: red blood cells, which carry oxygen throughout our bodies, white blood cells, which help fight infections, and platelets, which help with forming clots to stop bleeding.8 When the bone marrow fails, patients experience a decrease in all blood cell types (aplastic anemia) and, consequently, may experience fatigue, frequent infections, and hemorrhages.2,4,5,7 AML involves the uncontrolled production of immature white blood cells which ultimately affects the circulation of normal blood cells.6 Amy is one of the FA patients who developed AML, and in her case, an aggressive form.3 Despite her FA diagnosis, she was living a nearly healthy life with no complications up until this point.3 About four months after her latest bone marrow check up came back negative for any abnormalities, Amy experienced shoulder and back pains that resulted in her being hospitalized.3 While in the hospital she found out that almost all of her cells were leukemic.3 Like most patients, she underwent chemotherapy; however, it was unsuccessful as she relapsed a few months later.3
Throughout the years the increasing advances in medical technology have increased the life expectancies of people with FA to 30-33 years old.2,5 Once diagnosed, FA patients are regularly monitored for any complications arising from the disease. In patients like Amy who were nearly healthy, they were subjected to constant bone marrow tests and monitoring for solid tumors. On the other hand, patients who had a mild to moderate severity of the disease may have had to undergo treatments such as bone marrow transplant, hormone therapy, growth factors, antibiotics, and surgery for solid tumors.2,6-8 So far, bone marrow transplant is the only long-term treatment; however, it does come with difficulties and risks. First, patients must find a donor who has the same tissue type (a match).7 Second, a transplant does not eliminate the risk of cancer, so the patient must still be monitored after transplant.3,6 Third, patients risk potentially fatal complications like organ toxicity and graft-versus-host disease, the latter of which Amy’s oldest sister, Kirsten died from.2 Since FA is a hereditary disease, people who are related to FA patients may also face risks. Therefore, it is important for the relatives of FA patients to know whether or not they carry a defective allele for them to be aware of the potential of passing it down to their children. This can be done through DEB/MCC testing and molecular testing.5,6 A few clinical trial drugs are also being developed, one of which is from Markus Grompe and his colleagues.3 This drug was found to be successful at delaying or preventing FA mice from developing aplastic anemia.3 The target of this drug is to do the same for FA patients.3 Currently, this drug is en route to starting clinical trials within the next year or two after being approved for a 10 million dollar grant from the National Institutes of Health.3
After battling FA with two of their children, Amy’s FA diagnosis was devastating for the Frohnmayer family. However, throughout her life, Amy did not present with any complications associated with the disease, and she was seen as a generally healthy person. She was monitored and tested regularly to ensure early detection of any possible abnormalities that may arise.3 Despite carrying this burden since her birth, Amy never let her diagnosis deter her way of life as she was a very athletic person, running a full marathon and several half-marathons, and studious as she completed a Master’s Degree in psychology at Stanford University with the hopes to complete another one.3 Even after being diagnosed with AML, Amy kept living her life to the fullest as she married her fiancé, Alex Winn.3 Unfortunately, on October 2, 2016, she passed away at the age of 29 years old with her family by her side.2,3 Due to the impact of the disease on their family, the Frohnmayers started the Fanconi Anemia support group in 1986, which soon evolved into the Fanconi Anemia Research Fund just three years later in 1989, raising about $35 million during that brief period.1,2 The Frohnmayers’ goal was to raise awareness of the rare disease that nearly crippled their family and to help other families by providing them with the information they have learned while self-educating themselves about the disease. In addition to raising awareness and providing information, the Fanconi Anemia Research Fund has used the money they have raised to “sponsor 183 research grants in 54 laboratories worldwide.”2 Many of the laboratories are based in institutions and universities such as the Dutch National Cancer Institute in Amsterdam, which is focusing on developing a way to correct mutation in genes associated with FA, and Harvard University, which is working on finding ways to prevent damage to FA blood and bone marrow cells.2 The Frohnmayers can know that they are helping to make a difference in the lives of patients and families who are affected by this rare genetic disease as the funds they raise have been used in the development of a molecule called N-acetyl cysteine (NAC).2 NAC protects FA cells and improves blood cell counts in order to help prevent bone marrow failure and other FA complications.2 In 2014, NAC was approved for clinical trials in four countries including Canada and the United States.2
1. Epps G. The Man Who Wrestled Death to a Draw. The Atlantic Web site. http://www.theatlantic.com/politics/archive/2015/03/the-man-who-wrestled-death-to-a-drw/387760/ Published on March 15, 2015.
2. What is Fanconi anemia? Fanconi Anemia Research Fund Web site. http://fanconi.org/index.php/learn_more.
3. Terry L. Youngest daughter of late Dave Frohnmayer becomes third to die of rare genetic disorder. Oregon Live Web site. http://www.oregonlive.com/health/index.ssf/2016/10/youngest_daughter_of_late_dave.html Published on October 3, 2016.
4. Fanconi anemia. Genetics Home Reference Web site. https://ghr.nlm.nih.gov/condition/fanconi-anemia Published in 2012.
5. Lipton JM. Fanconi Anemia. Medscape Web site. http://emedicine.medscape.com/article/960401-overview Updated on February 10, 2016.
6. Mehta PA., Tolar J. Fanconi Anemia. GeneReviews [Internet]. Available from https://www.ncbi.nlm.nih.gov/books/NBK1401/ Published on February 14, 2002.
7. Fanconi anemia. MedlinePlus Web site. https://medlineplus.gov/ency/article/000334.htm Reviewed on March 16, 2016.
8. Fanconi Anemia. National Organization for Rare Disorders Web site. https://rarediseases.org/rare-diseases/fanconi-anemia/.
Cite This Article:
Macatangay K., Zheng K., Chan G., Ho J.
A Family's Battle with Fanconi Anemia. Rare Disease Review. January 2017. DOI:10.13140/RG.2.2.34844.28805.