Fanconi's Anaemia

Synonyms: Fanconi anaemia (FA), Inherited Bone Marrow Failure Syndrome

This condition was first described by Fanconi in 1927.¹ It is the commonest of a group of relatively rare diseases known as the Inherited Bone Marrow Failure Syndromes (IBMFS). It is usually inherited in an autosomal recessive fashion and is due to a disorder of chromosomal stability. A number of affected genes have been identified and sufferers are homozygous for one, or heterozygous for two separate loci. The exact pathophysiology is not understood, as the role of the proteins produced by the defective genes are multifunctional and not fully elucidated. The proteins are thought to form a nucleoprotein complex important for DNA damage response mechanisms.

The condition tends to cause:

• Congenital dysmorphic features
• Pancytopenic bone marrow failure
• Susceptibility to cancer:
  • Acute myeloid leukaemia (AML)
  • Solid tumours - head and neck squamous cell carcinoma (HNSCC), and gynaecological cancers, particularly vulval and vaginal

Incidence

A rare condition with approximately 3 per million population with heterozygote frequency estimated at 1 in 300 in Europe and USA.² It affects many ethnic groups and appears to have a higher carrier frequency (~ 1 in 80) amongst Ashkenazi Jews³ and Afrikaners.

Most are diagnosed before 7 years old but 9% are diagnosed as adults.⁴ Consider the diagnosis in adult patients presenting with:

• Aplastic anaemia
• Myelodysplastic syndrome
• AML
• HNSCC
• Gynaecological cancers in women less than 50 years old

There appears to be a correlation between the presence of significant birth defects and the age of onset of anaemia.⁵

Physical abnormalities

About 75% will have detectable physical abnormalities that can be relatively subtle:

• The skin may be hyperpigmented with café-au-lait spots.
• Often low birth weight and small for age.
• The face may be triangular in shape.
• The thumbs and radii can show structural abnormalities (usually aplasia or hypoplasia), as can the fingers and toes. There are a range of associated skeletal abnormalities.
• Microcephaly, microphthalmia and deafness occur.
• Cardiac and renal malformations are encountered.
• The gonads in older patients tend to be atrophic or dysmorphic with a range of associated genitourinary abnormalities, causing reduced fertility.

Haematological disease

Usually presents in childhood as:

• Bleeding tendency
• Anaemia
• Susceptibility to infection

It may present as leukaemia in about 10% and myelodysplastic syndrome in about 5% (usually teenagers/young adults) who have not had an antecedent history of anaemia.⁶

Solid tumours

The cumulative incidence of solid tumours by age 45 is about 30%, which continues to rise with patient's age.⁶

• Liver adenoma/hepatomas predominantly affect those who have had anaemia treated by androgens.
• Head and neck, oesophageal and gynaecological/genital tumours may occur.
• The risk of oral cancers appears to be increased by bone marrow transplantation.
• There does not appear to be an overall increased incidence of cancer in heterozygotes but an increased risk of breast cancer has been found in carrier grandmothers, so a heterozygote allele may confer susceptibility to breast cancer.⁷

• FBC may show macrocytosis with mild anaemia through to trilineage pancytopenia. Initial presentation may be with isolated thrombocytopenia or leukopenia.
• Bone marrow biopsy/aspiration reveals progressively hypocellular marrow with loss of myeloid and erythroid precursors and megakaryocytes, eventually becoming typical of aplastic anaemia with fatty marrow.
• Cytogenetics can provide definitive diagnosis. The metaphase appearance of multiple chromosomal breaks in lymphocytes stimulated by a clastogen such as mitomycin C is diagnostic in combination with clinical features, in most cases. Some patients have haematopoietic stem cell mosaicism and require cytogenetic testing of cultured skin fibroblasts to confirm diagnosis.² Direct testing for the known genetic abnormalities is usually only conducted for research purposes currently.⁵
• Skeletal x-ray survey and echocardiography/liver and renal US are used to detect other abnormalities.

• Acquired aplastic anaemia
• Thrombocytopenia Absent Radii (TAR) syndrome
• VATER association
• Diamond-Blackfan anaemia
• Nijmegen breakage syndrome (NBS) - extremely rare syndrome of immune deficiency, microcephaly, ionising radiation sensitivity and haematopoietic abnormality with a Slavic preponderance
• Immune pancytopenia
• Myelodysplastic syndrome

• Families should be offered genetic counselling and cytogenetic testing. Apparently unaffected siblings should be tested for FA homozygosity. The potential for phenotypic variability within a family should be explained.
• Further investigations to find associated abnormalities may be conducted.
• Androgens may be used to boost haematopoiesis but there are many complications including liver tumours, inappropriate masculinization and epiphyseal fusion.
• Colony stimulating factors can be used in conjunction with androgens or in place of them if they have failed.
• Blood transfusions are used to maintain counts and treat symptomatic problems.
• Bone marrow/haematopoietic stem cell transplantation using related donors (where possible) is the only curative treatment. Special 'conditioning' regimens are used with low-dose alkylating agents and less or no radiation (due to increased susceptibility) and have achieved medium term survival rates of around 70%.^2,8,9 After transplantation, careful monitoring for evidence of leukaemia/solid tumours is necessary.

Cumulative incidences (to 48 years old):¹⁰

• Leukaemia - 10%
• Death from bone marrow failure - 11%
• Solid tumour - 29%
• Bone marrow transplantation - 43%

As individuals survive longer with bone marrow transplants, there is likely to be an increased risk of solid tumour as the deaths from aplastic anaemia decrease.

Median survival is around 30 years but is improving with advances in therapy and screening for tumours. Patients usually have normal intelligence and have normal educational and employment prospects depending on the course of their illness.

Genetic counselling for affected families to enable carriers/potential carriers to make reproductive choices. Prenatal diagnosis is possible - radial ray abnormalities raise suspicion on antenatal ultrasound¹¹ and flow cytometry/genetic testing on fetal cells (extracted via amniocentesis, chorionic villis sampling or cord blood) can provide diagnosis.¹² Preimplantation genetic diagnosis is also possible using assisted reproductive techniques. These can similarly be used to produce a HLA-matched, unaffected sibling for future bone marrow transplantation needs.¹³