What Is Fanconi Anemia?

Overview

Fanconi anaemia (FA) is a rare inherited disease characterized by bone marrow failure, skeletal deformities, cancer predisposition, and multi-organ involvement. People with FA are at an increased risk of developing blood disorders and cancer. FA is caused by a mutation in the FA genes, which is responsible for DNA repair. An accurate diagnosis of FA is made by chromosome breakage tests and molecular testing.

Understanding fanconi anaemia

Fanconi anaemia (FA) is a rare inherited disease characterized by bone marrow failure, skeletal deformities, cancer predisposition, and multi-organ involvement.^1,2

Fanconi anaemia is an autosomal recessive inherited disease, meaning both parents carry the gene for their child to inherit it and show symptoms. Autosomal recessive inherited disease differs from an autosomal dominant inherited disease, where it takes only one parent to pass the gene for the disease to manifest.

The FA genes are involved in DNA repair and maintenance through the FA pathway.¹ Mutations in the FA gene are associated with sporadic cancers and defective haematopoiesis.^3,4 FA results from a mutation in the various FA genes. A mutation in the FA genes could lead to the accumulation of chromosomal instability, which increases the risk of cancers in the long term.⁵ In an autosomal recessive inherited disease, some people carry the mutated FA gene responsible for the disease but don’t have symptoms. These people are known as carriers.

Clinical features

Clinical features of FA are mostly based on growth retardation and congenital defects in combination with life-threatening bone marrow failure, which usually starts between 5 and 10 years of age.⁶

Physical features

The following physical features affect approximately 75% of affected persons:^2,7,8

• Low birth weight
• Prenatal and/or postnatal short stature
• Abnormal skin pigmentation e.g., light-brown skin pigmentation (café au lait macules), hypopigmentation, and hyperpigmentation. The areas of hyperpigmentation are primarily on the trunk, neck, groin and armpits
• Structural abnormalities in the upper and lower limbs, such as
  • Absent or bifid thumb (two thumbs present in one hand), 
  • Hypoplastic thumb (undeveloped thumb), 
  • Hypoplastic radius, 
  • Dysplastic ulna (short or missing ulnar bone), 
  • Polydactyly (more than five fingers on one hand), 
  • Short toes, 
  • Club foot, 
  • Flat feet, 
  • Hip dislocation, 
  • Abnormal femur
  • Thigh osteoma (a noncancerous tumour in your thigh)
• Skeletal abnormalities such as head and face anomalies,
  • Microcephaly (small head) and hydrocephaly (water in the brain), 
  • Frontal bossing (an unusually prominent forehead), 
  • Flathead, 
  • Sloped forehead, 
  • Webbed and short neck, 
  • Low hairline, 
  • Spina bifida (split spine), 
  • Scoliosis, 
  • Abnormal ribs 
  • Extra vertebrae
• Face characteristics such as a triangular face, bilateral epicanthic folds (monolid eyes), micrognathia (small lower jaw than usual), and middle facial hypoplasia
• Ophthalmic anomalies e.g.,
  • Proptosis (bulging eyes), 
  • Ptosis (droopy eyes), 
  • Cataracts, 
  • Blindness, 
  • Epiphora (watery eyes), 
  • Microphthalmia (one or both eyes are small), 
  • Astigmatism, 
  • Strabismus (crossed eye)
• Ear anomalies such as absent eardrums, small or large pinnae (the external part of the ear), and closed or absent ear canal
• Less genitalia development, e.g., undescended and absent testis, phimosis, hypospadias, micropenis (abnormally small penis) in men, and vaginal atresia (absent or closed vagina) in women
• Physical features of low blood cell levels such as pallor, petechiae and bruising, and coldness of the hands and feet

Laboratory findings

FA patients may present the following laboratory findings^2,7,8:

• Macrocytosis (large red blood cells)
• Increased fetal haemoglobin (often precedes anaemia)
• Cytopenia, especially thrombocytopenia (low platelets count), leukopenia (low white blood cell count), neutropenia (low neutrophil count), and pancytopenia (low levels of all blood cell types)
• Low levels of hormones such as growth hormone and thyroid hormone
• Abnormal semen analysis in men e.g., oligospermia (low sperm count) or azoospermia (complete absence of sperm)

Pathology findings

The following pathological findings show in some FA patients:^2,7,8

• Progressive bone marrow failure
• Adult-onset aplastic anaemia
• Myelodysplastic syndrome (MDS)
• Acute myelogenous leukemia (AML)
• Early-onset solid tumours (e.g., squamous cell carcinomas of the head and neck, oesophagus, and vulva; cervical cancer; liver tumours)
• Inordinate toxicities from chemotherapy or radiation

Other clinical features of Fanconi anaemia

Other clinical features that may be present in some FA patients are:^2,8

• Heart anomalies
• Gastrointestinal abnormalities (usually seen in rare cases) such as tracheoesophageal fistula, oesophagal, duodenal or jejunal atresia, imperforate anus (absence of anal opening at birth), annular pancreas and intestinal malrotation
• Infertility in both males and females
• Central nervous system anomalies such as pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus (excess fluid buildup in the brain), dilated ventricles
• Neurodevelopmental delays and intellectual disability

Complications of fanconi anaemia

The complications of FA are aplastic anaemia, myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), solid tumours, bone marrow failure, and risks of cancer.^7,10

Diagnosis

FA can affect almost every body system, and its characteristics overlap with several clinical manifestations of other syndromes.⁸

Differential diagnosis of Fanconi anaemia

While conducting a differential diagnosis, your doctor may look out for the physical features of Fanconi Anaemia (FA) and conduct clinical tests to narrow the diagnosis. Clinical tests may include a complete blood count, a reticulocyte count to assess blood cells, bone marrow aspiration, and a biopsy to check for bone marrow failure. Others include X-rays for bone defects and magnetic resonance imaging (MRI) to identify brain abnormalities.⁷

The following are congenital structural defects that are associated with FA and haematological problems that may manifest clinically as FA:⁷

• Acquired aplastic anaemia - this is the destruction of the bone marrow caused by various toxicogenic agents
• Denovo myelodysplastic syndrome (MDS) - is characterized by ineffective hematopoiesis and peripheral cytopenias and is different from myelodysplastic syndrome, which is associated with FA
• Drug-induced or infection-associated pancytopenia - low blood cells due to drugs and viral and bacterial infections
• Paroxysmal nocturnal hemoglobinuria (PNH) - blood in the urine
• Other inherited bone marrow failure syndrome such as Diamond-Blackfan anaemia (failure to produce red blood cells), Schwachman-diamond syndrome (bone marrow failure primarily associated with low levels of neutrophils), and congenital amegakaryocytic thrombocytopenia (characterized by low platelet levels)

Although FA can show laboratory and pathological findings discussed above, an accurate diagnosis is by chromosome breakage test and molecular testing.^2,7,8

Chromosome breakage test

A chromosomal breakage test is usually carried out in those with severe pancytopenia (overall low levels of blood cell types). FA cells are fragile and highly sensitive to chemical agents such as diepoxybutane (DEB) and mitomycin C (MMC). Diepoxybutane and mitomycin C stimulate the breakage of the chromosomes in the FA cells.^7,9 Breakage in cells means a positive chromosomal breakage testing, which could indicate FA.

Molecular testing

Clinical professionals recommend FA gene sequencing in patients with positive chromosomal breakage testing. The identification of genetic defects confirms FA and excludes other chromosome breakage syndromes.7 Molecular tests such as gene sequencing specifically identify FA genes containing the genetic mutation.⁶

Treatment and management

Treatment and management of FA include symptom management, haematopoietic stem cell transplantation (HSCT), androgen therapy, gene therapy, and supportive treatment like blood transfusions.⁷

Management of the symptoms of Fanconi anaemia

Fanconi anaemia (FA) affects several body systems and, therefore, causes symptoms other than bone marrow failure. Your doctor will have to manage and treat these other symptoms.^2,7 

Doctors perform surgeries to manage structural deformities and remove cancerous growths. Other surgeries could include congenital heart defect surgery, repair of trachea-oesophagus fistulas, and imperforate anus. Your doctor may also treat growth deficiency, limb anomalies, ocular anomalies, renal malformations, genital anomalies, hypothyroidism, cardiac anomalies, dermatologic manifestations, and eye problems.

Hematopoeitic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for the hematologic manifestations of Fanconi anaemia (FA).^2,7 Although effective, HSCT increases the risk of malignancies and accelerates the appearance of late malignancies.^2,10 Clinical professionals reserve HSCT as a treatment option for FA patients with severe myelodysplastic syndrome and leukaemia (blood cancer).⁷

Androgen therapy

Oral androgens such as oxymetholone effectively improve blood counts (red cells and platelets) in individuals with Fanconi Anaemia (FA).² Androgens stimulate haematopoietic stem cell proliferation, which makes it a good option for FA patients who are unsuitable for or cannot access HSCT.^2,7,10 FA patients who receive androgen treatment for bone marrow failure are also at increased risk for liver tumours.^2,7

Supportive treatment

Blood transfusions are the best supportive therapy for Fanconi anaemia (FA).⁷ Usually, these will contain packed red blood cells (RBCs) and platelet transfusions. Your doctors will also avoid blood donations from family members as it can cause immune sensitizations in FA patients.^2,7 Granulocyte colony-stimulating factor also improves the neutrophil count in some people with FA.^2,7

Gene therapy

Gene therapy is a modern developing technique for treating FA and is still experimental but offers the most encouraging results when performed in the early phases of a bone marrow failure.^7,10 Gene therapy is the replacement of an abnormal gene by a normal gene. It is a way to correct defective gene cells by replacing them. There are early-phase clinical trials of gene therapy for treating individuals with FA.²

Monitoring of fanconi anaemia

Individuals with Fanconi anaemia (FA) need comprehensive monitoring and care plans that start at diagnosis and continue throughout life. Such long-term follow-up will help detect complications related to the disease or treatment.^7,10 Regular medical check-ups are necessary for the constant monitoring of individuals with FA.

Individuals with FA will also require the support and care of family and friends amidst healthcare providers. It will be beneficial if family members (especially the family member providing care) and friends educate themselves on FA. It will help them understand what the individual with FA is going through and how best to care for them.

Genetic counselling for fanconi anaemia

Genetic counselling is needed to educate parents on how Fanconi anaemia (FA) is inherited or passed to their children. A mutation in the FA gene is what causes FA. If a child inherits a defective FA gene from both parents, the child becomes symptomatic and shows the typical clinical features of FA. However, if a child inherits only one defective FA gene from any of the parents, they will be asymptomatic and carriers of FA. A carrier can pass the defective gene to their children.

When both parents have the defective FA gene, their children might have Fanconi Anemia. For each child born to these parents, there is:¹⁰

• 25% chance the child will get both copies of the defective gene and be affected by FA (show symptoms)
• 25% chance the child will get two normal FA genes and be healthy
• 50% chance the child will get one defective gene and one normal FA gene. They will not have the disease

If one child in a family is diagnosed with Fanconi anaemia, other siblings might also have the disease but not show any symptoms. To check for this, all siblings should take diagnostic tests for FA.

X-Linked recessive inheritance

There are cases of Fanconi anaemia (FA) that are X-linked (linked to a particular sex).^2,10 If a man is affected, but his partner is not, their children will inherit some genes differently.

The male sex chromosomes are XY, whereas females have XX chromosomes. The male partner always provides the Y chromosome. The male child of a man who carries the defective FA genes will not inherit the defective gene because males get their Y chromosome from their father.

A child has to inherit the defective gene from both parents for FA to manifest. Since the FA is X-linked, the male child will not inherit the defective gene because his father (a carrier) cannot pass on the X chromosome to his son (XY). If he did, the child would be a daughter (XX), and that daughter would be a carrier.

Summary

Fanconi anaemia (FA) is a rare inherited disease characterized by bone marrow failure, skeletal deformities, cancer predisposition, and multi-organ involvement. FA is caused by a mutation in the FA genes responsible for DNA repair.

Clinical features of FA are mostly based on growth retardation and congenital defects in combination with life-threatening bone marrow failure. Laboratory findings include macrocytosis, increased fetal haemoglobin, and cytopenia, amongst others. The major complications of FA are aplastic anaemia, myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), solid tumours, bone marrow failure, and risks of cancer. FA is diagnosed by chromosome breakage test and molecular testing to detect the defective FA gene.

Treatment and management of FA include managing the symptoms of FA, haematopoietic stem cell transplantation (HSCT), androgen therapy, gene therapy, and supportive treatment like blood transfusions. Genetic counselling is needed to educate parents on how Fanconi anaemia is inherited or passed to their children. Individuals with FA need comprehensive monitoring and care, especially from family and loved ones.