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 most common of a group of relatively rare diseases known as the inherited bone marrow failure syndromes (IBMFS). It is inherited in an autosomal recessive fashion apart from one gene (FANCB) which is found on the X chromosome.²It is due to a disorder of chromosomal stability. 14 affected genes have been identified to date and those affected are homozygous for one, or heterozygous for two separate loci. The proteins are believed to be integral to mechanisms that repair damage to DNA, by removing faulty interstrand cross links. This results in the bases of opposing DNA strands being covalently linked, inhibiting critical cellular processes such as transcription and replication. Cells derived from Fanconi's anaemia patients are severely sensitive to DNA cross-linking agents, including mitomycin C, psoralen-UVA, cisplatin and diepoxybutane.³

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.

Epidemiology²

Incidence

It is a rare condition. The incidence in Europe and America is estimated at 1:360,000 births, based on a carrier frequency of 1 in 300 and an autosomal recessive model in Europe and USA. It affects many ethnic groups and appears to have a higher carrier frequency (~ 1 in 100) amongst Ashkenazi Jews, Spanish gypsies and Afrikaners.²

Presentation⁴

Most are diagnosed before 7 years of age but 9% are diagnosed as adults.⁵ Consider the diagnosis in adult patients presenting with:

• Aplastic anaemia.

• Myelodysplastic syndrome.

• AML.

• HNSCC.

• Gynaecological cancers in women less than 50 years of age.

There appears to be a correlation between the presence of significant birth defects and the age of onset of anaemia.⁶

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 various 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% (irrespective of age).⁷

Solid tumours

The cumulative incidence of solid tumours by age 40-50 is 25-30%, which continues to rise with the patient's age.²

• 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 relatives but an increased risk of breast cancer has been found in carrier grandmothers, so a heterozygote allele may confer susceptibility to breast cancer.⁸⁹

Investigations²

• FBC may show macrocytosis with mild anaemia through to pancytopenia. Initial presentation may be with isolated thrombocytopenia or leukopenia.⁴

• 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.

• The diagnosis chiefly depends upon the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC).

• Direct testing for the known genetic abnormalities is difficult due to the large number of genes involved but may be possible if the particular gene group can be identified from familial studies.

• Echocardiography/liver and renal ultrasound are used to detect other abnormalities.

• Radiographic studies solely for the purpose of surveillance (as opposed to the investigation of symptoms) should be avoided due to the risk of tumour production.

Differential diagnosis

• Acquired aplastic anaemia.

• Thrombocytopenia absent radii (TAR) syndrome.

• VATER association: vertebral defects (V), anal atresia (A), tracheoesophageal fistula with (o)esophageal atresia (TE) and radial or renal dysplasia (R).

• 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.

Management²

• Families should be offered genetic counselling and cytogenetic testing. Apparently unaffected siblings should be tested for Fanconi's anaemia homozygosity. The potential for phenotypical 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 masculinisation 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 but the high risk of solid tumors remains.

• Blood products that are not filtered (leukodepleted) or irradiated and toxic agents that have been implicated in tumourigenesis should be avoided.

Complications

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 increased risk of solid tumour as the deaths from aplastic anaemia decrease.

Prognosis¹¹

Studies report variable median survival ages ranging from 14-25 years. This is likely to be because patients with Fanconi's anaemia have widely differing phenotypes. It is emerging that some phenotypes have a much better prognosis than others.

Prevention²

• Genetic counselling for affected families to enable carriers/potential carriers to make reproductive choices.

• Molecular genetic testing is possible if the family-specific genetic variant has been identified. Analysis of DNA extracted from fetal cells obtained by amniocentesis can usually be performed at approximately 15 weeks of gestation or chorionic villus sampling at approximately 10-12 weeks of gestation. If the genetic variant is not known, cytogenetic testing in the presence of DEB/MMC to evaluate for increased chromosomal breakage can be performed.

• Ultrasound for fetal abnormalities is nonspecific and not sensitive for the diagnosis of Fanconi's anaemia but may be used as an adjunct (eg, identification of abnormalities of the radial ray).

• Pre-implantation genetic diagnosis has enabled unaffected at-risk embryos to be identified and HLA-matched to affected siblings.