Fanconi Anemia: Symptoms, Types, Causes and Treatment

Fanconi anemia (FA) is a rare, inherited disorder that profoundly impacts the lives of affected individuals and their families. Known for its remarkable complexity, FA is characterized by a wide array of symptoms ranging from congenital abnormalities and bone marrow failure to an increased risk of cancer. Understanding FA is crucial for early detection, optimal treatment, and improved quality of life. In this article, we’ll explore the major symptoms, different types, underlying causes, and current treatment options for Fanconi anemia, synthesizing the latest research and clinical insights.

Symptoms of Fanconi Anemia

Fanconi anemia does not present the same way in every individual—its symptoms can be highly variable, even among patients within the same family. Recognizing the spectrum of clinical features is key to early diagnosis and management.

Symptom	Description	Frequency/Impact	Sources
Congenital	Physical anomalies at birth	60–75% of patients	2 4 7
Bone Marrow	Pancytopenia, aplastic anemia	~90% develop over time	2 4 8
Cancer Risk	Increased susceptibility to leukemia, solid tumors	High, especially after age 10	2 4 7 8
Endocrine	Growth delay, hypothyroidism, diabetes	Common	4 8

Table 1: Key Symptoms

Congenital Abnormalities

The majority of FA patients are born with one or more congenital anomalies. These can include:

• Skeletal abnormalities, especially of the thumbs and forearms (radial ray defects)
• Short stature and microcephaly (small head)
• Skin pigmentation changes, such as café-au-lait spots
• Abnormalities of the kidneys and urinary tract
• Cardiac and gastrointestinal malformations
• Eye and ear anomalies 2 4 7 8

Not every child with FA will have all these features. Some may have only subtle or no visible congenital anomalies, making clinical diagnosis a challenge.

Progressive Bone Marrow Failure

Nearly all patients with FA develop bone marrow failure, usually within the first decade of life. This manifests as:

• Anemia: Fatigue, pallor, and poor exercise tolerance due to low red blood cells
• Neutropenia: Recurrent infections from low white blood cell counts
• Thrombocytopenia: Easy bruising, bleeding, and poor clotting from low platelets 2 4 7

Over time, this can progress to life-threatening aplastic anemia.

Increased Cancer Risk

Individuals with FA have a dramatically increased risk of developing cancers, particularly:

• Acute myeloid leukemia (AML)
• Myelodysplastic syndrome (MDS)
• Solid tumors, especially of the head, neck, and gynecological organs 2 7 8

The risk of malignancy rises sharply with age and after certain treatments such as hematopoietic cell transplantation.

Endocrinopathies and Other Manifestations

FA is also associated with a range of endocrine disorders, including:

• Hypothyroidism
• Growth hormone deficiency leading to short stature
• Glucose intolerance or diabetes mellitus
• Pubertal delay 4 8

Other symptoms may include infertility, hearing loss, and neurodevelopmental delays.

Types of Fanconi Anemia

Fanconi anemia is not a single disease but a collection of genetically distinct subtypes, each linked to mutations in different genes. Understanding these types helps clinicians predict outcomes and personalize therapy.

Type/Subtype	Gene(s) Involved	Distinct Features	Sources
FA-A	FANCA	Most common, variable severity	5 8 18
FA-G	FANCG	Second most frequent in some populations	5 8
FA-B	FANCB (X-linked)	Severe, early-onset in males	6 8
FA-D1/D2, FA-S, etc.	BRCA2, BRCA1, others	Associated with cancer susceptibility	8 10 11

Table 2: Fanconi Anemia Subtypes

Major FA Complementation Groups

At least 23 FA subtypes (complementation groups) have been identified, each caused by mutations in a specific gene involved in the FA DNA repair pathway. The most common are:

• FA-A (FANCA gene): Accounts for 60–65% of cases worldwide. Presents with a broad range of symptoms and generally better survival than some other types 5 8 18.
• FA-G (FANCG gene): The second most prevalent type in certain populations, including Japan 5.
• FA-B (FANCB gene): The only X-linked form, causing more severe and earlier-onset disease in affected males 6.
• Other types: Mutations in other genes, including BRCA2 (FA-D1), BRCA1 (FA-S), and others, often present with higher cancer risks and more complex clinical phenotypes 8 10 11.

Genotype-Phenotype Correlations

Research has shown that the specific gene and type of mutation can influence the severity and clinical course of FA:

• Mutations in the upstream complex genes are linked with milder phenotypes, while those affecting the ID complex or downstream genes tend to have more severe symptoms and earlier bone marrow failure 8.
• Particular mutations within a gene (e.g., certain exons in FANCA) may also be associated with increased risk of solid tumors 8.
• FANCB deletions or truncations lead to more severe disease compared to missense mutations that retain some protein function 6.

Rarity and Diversity

Some subtypes, such as those caused by biallelic mutations in BRCA1 (FANCS), are extremely rare but provide important insights into the overlap between FA and hereditary cancer syndromes 10. The diversity of genetic causes underpins the clinical variability seen in FA and highlights the necessity for genetic testing in all suspected cases.

Causes of Fanconi Anemia

Understanding the root causes of FA reveals why the disease is so complex and why it affects so many body systems.

Cause	Mechanism	Impact on Body	Sources
Genetic Mutations	Defects in FA/BRCA DNA repair pathway	Genome instability, cell death	3 5 8 9 11 13
DNA Repair Failure	Impaired interstrand crosslink repair	Bone marrow failure, cancer	3 11 13
Inheritance	Autosomal recessive/X-linked	Family transmission	5 7 13

Table 3: Key Causes of Fanconi Anemia

Genetic Basis

FA is primarily caused by inherited mutations in any of at least 23 genes that form the FA/BRCA DNA repair pathway 5 8 11. Most forms are autosomal recessive, meaning both copies of the gene must be mutated. One subtype, FA-B, is X-linked, affecting males more severely 6 7.

• The most commonly mutated genes are FANCA, FANCG, and FANCB 5 8.
• Rare mutations in genes like BRCA1, BRCA2, and ERCC4 can also cause distinct FA subtypes 9 10.

DNA Repair Deficiency and Genome Instability

All FA genes participate in a critical DNA repair process—specifically, the repair of DNA interstrand crosslinks (ICLs), which are especially toxic to rapidly dividing cells like those in the bone marrow 3 13. When this repair pathway fails:

• Damaged DNA accumulates, leading to genome instability
• Cells, especially hematopoietic stem cells, undergo death or malfunction
• There is an increased risk for mutations that predispose to cancer 3 8 11 13

Inheritance Patterns

• Autosomal Recessive: Both parents are usually carriers but unaffected; each child has a 25% chance of inheriting FA 5 7.
• X-linked: Mothers are typically carriers; affected sons manifest disease, while daughters are usually unaffected (unless both X chromosomes carry the mutation) 6 7.

Other Pathogenic Mechanisms

Emerging research points to additional factors influencing FA pathology:

• Inflammation and Premature Aging: Chronic activation of the type-I interferon pathway and TGF-β signaling may contribute to bone marrow failure and early aging features 3 17.
• Cellular Hypersensitivity: FA cells are extremely sensitive to DNA-damaging agents (e.g., diepoxybutane, mitomycin C), a feature used in diagnostic testing 1 7.

Treatment of Fanconi Anemia

Treatment for FA is rapidly evolving, aiming not only to address bone marrow failure but also to prevent and manage cancer, endocrine issues, and overall quality of life. While there is no universal cure, significant progress has been made.

Treatment	Goal/Indication	Main Considerations	Sources
Hematopoietic Stem Cell Transplant (HSCT)	Cure bone marrow failure	Best outcome in young patients, matched donors	14 15 16
Supportive Care	Manage cytopenias, infections	Transfusions, antibiotics, growth factors	2 4 7
Androgen Therapy	Stimulate blood cell production	Temporary, variable response	4
Gene Therapy	Correct underlying defect	Experimental, promising for FA-A	18
Cancer Surveillance	Early detection/treatment	Regular screenings essential	7 8 16

Table 4: Treatment Approaches

Hematopoietic Stem Cell Transplantation (HSCT)

HSCT is currently the only proven curative therapy for the hematologic (bone marrow) manifestations of FA 14 15 16. Key points include:

• Best outcomes are achieved when transplantation is done at a young age, before the onset of MDS or leukemia, and from an HLA-matched sibling donor 14 16.
• Unrelated donor transplants are possible but carry higher risks of complications such as graft-versus-host disease and secondary malignancies 15 16.
• Transplant protocols have evolved, with fludarabine-based conditioning and avoidance of high-dose radiation improving survival 15 16.

Supportive Care

Before and after HSCT, or in cases where transplant is not possible, supportive measures are vital:

• Transfusions of red cells and platelets to manage anemia and bleeding
• Antibiotics and growth factors to prevent and treat infections
• Hormonal/endocrine therapies to address growth and puberty issues 2 4 7

Androgen Therapy

Some patients benefit from androgens, which can temporarily boost blood cell production. However, side effects and variable efficacy limit their use 4.

Gene Therapy

Exciting advances in gene therapy are showing promise, especially for patients with the FA-A subtype:

• Lentiviral-mediated gene correction of hematopoietic stem cells can lead to lasting engraftment and improved blood counts in FA patients, even without preconditioning 18.
• Gene therapy may become a low-toxicity alternative or complement to traditional HSCT in the future.

Cancer Surveillance and Management

Given the lifelong increased risk of cancer, regular surveillance is crucial:

• Annual screenings for hematological malignancies (MDS/AML) and solid tumors (especially head, neck, gynecologic cancers)
• Early intervention and tailored cancer treatments, as FA patients are extremely sensitive to standard DNA-damaging chemotherapies and radiation 7 8 16

Emerging and Future Therapies

• TGF-β pathway inhibitors are being investigated as a way to rescue hematopoietic stem cell function and delay bone marrow failure 17.
• Ongoing research aims to better understand the molecular mechanisms of FA to develop targeted therapies with fewer side effects 3 17 18.

Conclusion

Fanconi anemia is a complex, multisystem disorder with significant variability in symptoms, genetic causes, and outcomes. Here’s a quick summary of what we’ve covered:

• Symptoms: Range from congenital anomalies and bone marrow failure to a high risk of cancer and endocrine disorders.
• Types: Over 23 genetic subtypes, each linked to mutations in specific DNA repair genes; FA-A is most common, but severity varies widely.
• Causes: Inherited mutations disrupt the FA/BRCA DNA repair pathway, leading to genome instability, bone marrow failure, and cancer susceptibility.
• Treatment: Includes hematopoietic stem cell transplantation, supportive care, androgen therapy, emerging gene therapy, and lifelong cancer surveillance.

Early diagnosis, personalized treatment, and ongoing research are key to improving outcomes and quality of life for people living with Fanconi anemia.