Overview
Definition:
Fanconi anemia (FA) is a rare, autosomal recessive (or less commonly X-linked) inherited disorder characterized by progressive bone marrow failure, a constellation of congenital abnormalities, and an increased risk of malignancy, particularly acute myeloid leukemia (AML) and squamous cell carcinomas
It is caused by mutations in genes involved in the DNA repair pathway, primarily the homologous recombination pathway, leading to genomic instability.
Epidemiology:
The incidence of Fanconi anemia is estimated to be between 1 in 30,000 to 1 in 500,000 live births, with varying prevalence across different ethnic groups
It affects males and females equally, though specific gene mutations may show slight variations in prevalence.
Clinical Significance:
Fanconi anemia represents a critical area of study in pediatric hematology due to its life-threatening nature, complex management, and implications for long-term patient outcomes
Early diagnosis and appropriate management are crucial to improve survival and quality of life, and understanding its genetic basis is vital for genetic counseling and prenatal diagnosis
Its association with malignancies highlights the importance of vigilant screening.
Clinical Presentation
Symptoms:
Presentations vary widely in severity and age of onset
Common symptoms include: Recurrent infections due to neutropenia
Easy bruising or bleeding due to thrombocytopenia
Fatigue and pallor due to anemia
Short stature
Developmental delay
Abnormalities of the skin, eyes, ears, heart, kidneys, and bones
Absence of thumbs or radius (radial aplasia)
Café-au-lait spots.
Signs:
Physical examination may reveal: Short stature below the 3rd percentile
Hyperpigmentation of the skin, particularly in the neck and trunk
Characteristic facial dysmorphisms (e.g., microphthalmia, epicanthal folds, abnormal ear shape)
Skeletal anomalies, especially of the upper limb (e.g., hypoplastic or absent thumb, radial club hand)
Genitourinary abnormalities (e.g., hypospadias, cryptorchidism, renal anomalies)
Cardiac defects
Thrombocytopenia may present as petechiae or purpura
Neutropenia can lead to signs of infection.
Diagnostic Criteria:
Diagnosis is suspected based on clinical findings and confirmed by laboratory tests
Key diagnostic criteria include: Presence of at least two typical physical abnormalities
Hematological abnormalities (cytopenias)
Confirmation by a chromosomal breakage test, such as the diepoxybutane (DEB) or mitomycin C (MMC) test, which shows increased chromosomal aberrations in FA cells upon exposure to DNA cross-linking agents
Genetic testing to identify the causative gene mutation.
Diagnostic Approach
History Taking:
A thorough family history is crucial to identify affected relatives or carriers
Inquire about: History of recurrent infections, unexplained bleeding or bruising, or anemia in the patient or siblings
Presence of congenital anomalies at birth or diagnosed later
Developmental milestones and growth patterns
History of malignancies in the family
Exposure to radiation or certain chemicals, though less common in typical FA.
Physical Examination:
A detailed head-to-toe examination focusing on: Growth parameters (height, weight, head circumference)
Skin examination for café-au-lait spots and hyperpigmentation
Assessment of skeletal anomalies, particularly upper limb development
Examination of facial features for dysmorphism
Cardiac auscultation for murmurs
Abdominal palpation for organomegaly
Genitourinary examination
Neurological assessment for developmental delays.
Investigations:
Complete blood count (CBC) with differential and peripheral blood smear to assess for pancytopenia or specific cytopenias
Reticulocyte count
Bone marrow aspirate and biopsy to assess cellularity, morphology, and presence of dysplasia
Chromosomal breakage assays (DEB or MMC) are the gold standard for confirmation
Genetic testing (sequencing of known FA genes, e.g., FANCA, FANCB, FANCC, etc.)
Imaging studies as needed to evaluate congenital anomalies (e.g., renal ultrasound, echocardiogram, skeletal X-rays).
Differential Diagnosis:
Conditions to consider include: Other bone marrow failure syndromes (e.g., Diamond-Blackfan anemia, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, aplastic anemia of other causes)
Myelodysplastic syndromes (MDS)
Leukemia
Severe congenital neutropenia
Constitutional aplastic anemia
Genetic syndromes with cytopenias.
Management
Initial Management:
Immediate management focuses on supportive care and addressing complications: Blood product transfusions (packed red blood cells for anemia, platelets for thrombocytopenia)
Antibiotics and prompt treatment of infections
Hematopoietic stem cell transplantation (HSCT) is the only curative option, typically considered early in the disease course, especially in younger patients or those with rapidly progressing marrow failure.
Medical Management:
Androgen therapy (e.g., oxymetholone, danazol) can stimulate hematopoiesis and improve cytopenias in some patients, although it does not correct the underlying genetic defect and has significant side effects
It is typically used for patients not eligible for or awaiting HSCT
Erythropoietin and G-CSF may be used adjunctively to manage specific cytopenias but are less effective than androgens or HSCT
Novel therapeutic strategies targeting DNA repair pathways are under investigation.
Surgical Management:
Surgical interventions are primarily aimed at correcting congenital anomalies if feasible and desired
Management of complications like bleeding may require surgical or interventional radiology procedures
HSCT is a complex procedure with surgical aspects related to catheter placement and post-transplant care.
Supportive Care:
Essential components of supportive care include: Prophylactic antibiotics and antifungals to prevent infections
Vigilant monitoring of blood counts and for signs of bleeding or infection
Nutritional support, especially if growth is affected
Genetic counseling for affected families and for reproductive planning
Screening for malignancies (e.g., oral cavity examinations for squamous cell carcinoma, regular CBC for AML).
Complications
Early Complications:
Severe anemia leading to heart failure
Profound thrombocytopenia leading to life-threatening hemorrhage
Severe neutropenia leading to overwhelming sepsis
Congenital anomalies may lead to immediate functional deficits.
Late Complications:
Development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)
Increased risk of solid tumors, particularly squamous cell carcinomas of the head and neck, vulva, and esophagus
Pulmonary fibrosis, especially in those who have undergone HSCT
Infertility.
Prevention Strategies:
Early diagnosis and timely HSCT are key to preventing long-term complications and improving survival
Genetic counseling and carrier screening can help prevent recurrence in families
Regular surveillance for malignancies can allow for early detection and intervention.
Prognosis
Factors Affecting Prognosis:
Prognosis is highly variable and depends on the severity of marrow failure, the presence and severity of congenital anomalies, the response to treatment (especially HSCT), and the development of malignancies
The availability of a matched sibling donor for HSCT significantly improves outcomes.
Outcomes:
With modern management, including early HSCT, survival rates have improved significantly
Patients who undergo successful HSCT can achieve long-term survival and a good quality of life
However, survivors may still be at increased risk for certain long-term complications, including secondary malignancies and infertility
Without HSCT, median survival is typically in the range of 10-20 years, often limited by marrow failure or transformation to leukemia.
Follow Up:
Long-term follow-up is essential for all FA patients, regardless of transplant status
This includes: Regular CBC monitoring
Surveillance for secondary malignancies through physical exams and imaging as indicated
Monitoring for late effects of HSCT (e.g., graft-versus-host disease, organ toxicity, endocrine dysfunction)
Genetic counseling for affected individuals and their families
Fertility preservation discussions for adolescents.
Key Points
Exam Focus:
Fanconi anemia is an autosomal recessive disorder of DNA repair leading to progressive bone marrow failure, congenital anomalies, and cancer predisposition
Chromosomal breakage assays (DEB/MMC) are diagnostic
Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy
Increased risk of AML and squamous cell carcinomas.
Clinical Pearls:
Always suspect FA in a child with pancytopenia and congenital anomalies, especially radial defects
A family history of similar issues or early deaths should raise suspicion
Early referral to a specialized center for HSCT evaluation is critical
Remember the triad: BM failure, congenital anomalies, cancer risk.
Common Mistakes:
Delayed diagnosis by attributing cytopenias solely to other causes without considering underlying genetic syndromes
Underestimating the cancer risk and failing to implement adequate surveillance
Not performing chromosomal breakage tests when FA is suspected, leading to a missed diagnosis
Inadequate pre-HSCT workup or post-HSCT care.