What is Fanconi Anemia (FA)?

FA is a rare, often fatal, inherited bone marrow failure (BMF) disorder^1–4

Predominantly an autosomal recessive disease, FA gradually destroys the ability of bone marrow to produce blood cells and is associated with an increased risk of hematologic malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).^1,5

While allogeneic hematopoietic stem cell transplant (aHSCT) is the current standard of care, it has its own significant limitations.¹ Additionally, patients with FA have a higher risk of developing squamous cell carcinoma (SCC) of the head and neck, as well as skin cancer.^1,6

FA is extremely rare, with only 200 to 275 cases in the US and Europe annually,⁷ but if you know what to look for, you can help diagnose these patients earlier.

FA can be caused by mutations in more than 20 genes, but mutations in the FANCA gene account for 60% to 70% of cases.⁸

The FA Diagnostic Challenge

Signs and symptoms of FA can be subtle, seem unrelated, or mimic other diseases. For that reason, diagnosis is often delayed as the disease continues to progress.^1,2,8,9

Whether you play a role in assessing or referring a child you may suspect has FA, it is important to do so early, before disease progression. If you see any of the following, consider the possibility that it could be FA^1,2,8:

Low birth weight and shorter length
Skeletal malformations (eg, hypoplastic thumb, hypoplastic or absent radius)
Renal anomalies (eg, misshapen, horseshoe, or missing kidney)
Heart manifestations (eg, patent ductus arteriosus, atrial septal defect)
Abnormal skin pigmentation (eg, café au lait macules, hypopigmentation)

The median age of FA diagnosis is 7 years old and often involves multiple specialists¹

THE URGENCY TO DIAGNOSE FA

FA can lead to BMF, hematologic malignancies, and head and neck cancers.¹ Early and careful monitoring of the disease may result in better management and earlier detection of these associated risks.

Patients with FA have an elevated risk of developing hematological malignancies, including myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML). These patients also have an elevated risk of solid tumors, including squamous cell carcinoma (SCC) of the head and neck as well as skin cancer.¹

A confirmed and early diagnosis of FA may¹:

Facilitate early initiation of appropriate monitoring and management of hematological issues
Give patients and families information to help them reduce the risks associated with solid cancers (eg, head and neck, skin)
Ensure congenital defects are addressed at appropriate times by the appropriate specialists
Lead to monitoring and management of FA manifestations in individual organs and systems
Help educate families about the genetic risk and point them to reproductive counseling for future children. Additionally, inform families that all biological siblings of an individual with FA should undergo genetic testing
Help connect patients and caregivers to social networks, educational and advocacy organizations, and other families for support through their journey living with FA

80% of patients experience BMF necessitating aHSCT with the average age of onset being 7.6 years old.^5,10

Testing for FA

If you suspect FA, there are tests to confirm a diagnosis.

Clinicians may order broad panels for patients in whom a genetic disease is suspected.¹¹

The definitive laboratory assessment for FA is a chromosome breakage test, involving either the cross-linking agent diepoxybutane (DEB) or mitomycin C (MMC). The chromosome breakage test is performed on a patient's peripheral blood sample by a cytogenetic laboratory.¹²

Additionally, germline genetic testing (gene sequencing) is commonly used clinically to confirm the diagnosis and to identify the specific FA-causing variants. It is also used as a first-line diagnostic test, often for multiple potential genetic abnormalities in newborns and infants.¹²

Both DEB/MMC chromosome breakage on peripheral blood and germline genetic testing should be performed to obtain a precise diagnosis of suspected FA.¹²

TREATMENT OF FA

As of today, aHSCT is the standard of care for treating FA, but it has significant limitations.¹

Prior to undergoing an aHSCT, patients with FA who are experiencing BMF can receive androgens for a transitory improvement in red blood cell (RBC) and platelet (PLT) counts. RBC and PLT transfusions are also used to maintain hemoglobin and platelet counts, respectively. However, both options are supportive only. They do not address or treat the underlying disease.¹

In addition to the fact that aHSCT only restores the hematologic stability of FA patients with severe BMF, the treatment also presents risks of 100-day mortality, graft failure, graft-vs-host disease (GvHD), and conditioning-related increases in cancer risk.¹

Beyond these potential complications, most patients don’t have a human leukocyte antigen-matched sibling donor which can result in lower success rates and can increase the risk of GvHD. Navigating the complex process of treatment with an aHSCT can pose a significant burden on patients and their families.¹

FA is an active area of research with new treatment approaches under investigation to meet these challenges.

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References: 1. Fanconi Cancer Foundation. Fanconi anemia clinical care guidelines. Fifth Ed. 2020. Accessed April 15, 2024. https://www.fanconi.org/images/uploads/other/Fanconi_Anemia_Clinical_Care_Guidelines_5thEdition_web.pdf 2. Alter BP. Inherited bone marrow failure syndromes: considerations pre- and posttransplant. Blood. 2017;130(21):2257-2264. 3. Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood. 2003;101(4):1249-1256. 4. Risitano AM, Marotta S, Calzone R, Grimaldi F, Zatterale A; RIAF Contributors. Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned. Haematologica. 2016;101(3):319-327. 5. Sebert M, Gachet S, Leblanc T, et al. Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia. Cell Stem Cell. 2023;30(2):153-170.e9. 6. Kutler DI, Auerbach AD, Satagopan J, et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg. 2003;129(1):106-112. 7. Data on file, Rocket Pharmaceuticals, Inc. 8. Mehta PA, Ebens C. Fanconi anemia. Updated June 3, 2021. GeneReviews [Internet]. Accessed April 18, 2024. https://www.ncbi.nlm.nih.gov/books/NBK1401 9. Fiesco-Roa MO, Giri N, McReynolds LJ, Best AF, Alter BP. Genotype-phenotype associations in Fanconi anemia: A literature review. Blood Rev. 2019;37:100589. 10. Fanconi Cancer Foundation. Fanconi anemia clinical care guidelines. Chapter 3 Clinical care of fanconi anemia: hematologic issues 2023. https://fanconi.org/wp-content/uploads/2024/03/Chapter_3-_Hematologic_Issues_July2023.pdf. Accessed May 7, 2024. 11. Dokal I, Tummala H, Vulliamy T. Inherited bone marrow failure in the pediatric patient. Blood. 2022;140(6):556-570. 12. Fanconi Cancer Foundation. Fanconi anemia clinical care guidelines. Chapter 2 Diagnosis 2023. https://fanconi.org/wp-content/uploads/2024/03/Chapter_2._Diagnosis__July_2023_.pdf. Accessed May 7, 2024.

What is Fanconi Anemia (FA)?

FA is a rare, often fatal, inherited bone marrow failure (BMF) disorder1–4

Signs and symptoms of FA can be subtle, seem unrelated, or mimic other diseases. For that reason, diagnosis is often delayed as the disease continues to progress.1,2,8,9

FA can lead to BMF, hematologic malignancies, and head and neck cancers.1 Early and careful monitoring of the disease may result in better management and earlier detection of these associated risks.