Fanconi anaemia (FA) is an autosomal recessive disease characterized by congenital abnormalities, defective haemopoiesis and a high risk of developing AML and certain solid tumours.
FA can be caused by mutations in more than 22 individual genes. For individuals of Ashkenazi descent mutations in the FANCC genes are the most common.
FA is a very heterogeneous condition clinically and patients can have a wide variety of abnormalities.
Physical abnormalities (present to variable degree in more than 75% patients) including:
- Hyperpigmentation with café-au-lait spots.
- Low birth weight or small for age, short stature in later childhood.
- Triangular shaped facies.
- Skeletal abnormalities- in particular radial ray defects such as hypoplasia of the thumbs and radial hypoplasia are the most common; other skeletal defects which may occur include congenital hip dislocation, scoliosis and vertebral anomalies.
- Microcephaly, microphthalmia and conductive deafness can occur.
- Cardiac malformations such as PDA, VSD, PS, AS and coarctation.
- Renal abnormalities are present in approximately 1/3 patients and include unilateral renal aplasia, renal hypoplasia, horseshoe kidneys or double ureters.
- Atrophic or dysmorphic gonads with associated genitourinary abnormalities and resultant reduced fertility.
- Bone marrow failure with bleeding tendency from thrombocytopenia, pallor from anaemia and susceptibility to infection from leukocytopenia.
- At birth the blood count is usually normal and macrocytosis is often the first detected abnormality, followed by thrombocytopenia and neutropenia.
- Pancytopenia typically presents between 5-10years.
- In a small group of patients FA presents as leukaemia.
Solid tumours (the cumulative incidence is increasing and by the age of 50 more than 30%. It continues to rise with the patients’ age):
- Liver adenomas / hepatomas mainly affect those who have had anaemia treated with androgens.
- Head and neck, oesophageal and gynaecological/genital tumours are common also in younger patients with an increasing incidence, in particular after haematopoietic stem cell transplantation.
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- FA is the commonest type of inherited bone marrow failure syndrome.
- FA cells are characterized by chromosomal hypersensitivity to cross linking agents, and the resulting increase in chromosome breakage provides the basis for a diagnostic test.
- FA type C is caused by mutations in the FANCC gene.
- The incidence of FA in Europe and America is approximately 1:350,000 births; with a carrier frequency of 1:300.
- FA type C is the most common form of FA found in the Ashkenazi Jewish (AJ) population who have a FA type C carrier frequency of 1 in 89.
- FA has been reported in many ethnic groups – founder mutations have also been described in Afrikaaners, where the carrier frequency is estimated at 1:83, and other populations.
- Full blood count– macrocytosis with mild anaemia through to pancytopaenia.
- Initial presentation may be with isolated thrombocytopaenia or leukopaenia.
- 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.
- Echo / liver and renal ultrasound are used to detect other abnormalities.
- Diagnosis is confirmed by demonstration of chromosomal aberrations (breaks, rearrangements, radials and exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane or mitomycin C. In some cases showing signs of genetic reversion from somatic mosaicism testing of fibroblasts can be helpful, as this cell type does not revert.
- Direct testing for the known genetic abnormalities can be difficult due to the large number of genes involved (at least 15) but this approach is more frequently used with modern sequencing technology. It is helpful if the particular gene group can be identified considering family or ethnic background , or if the relevant complementation group can be identified by complementation analysis, so that molecular testing can be directed to the appropriate gene.
- Targeted mutation analysis for the common Ashkenazi Jewish FANCC mutation is possible.
Treatment of manifestations:
- Androgens may be used to boost haematopoiesis (effective in approximately 50% of individuals) but there are many complications including liver tumours, inappropriate masculinization and epiphyseal fusion, which need close monitoring.
- Granulocyte colony-stimulating factor improves the neutrophil count in some patients.
- Blood transfusions to maintain counts and treat symptomatic problems.
- Bone marrow / haematopoietic stem cell transplantation is currently the only curative treatment for haematological manifestations of FA. The high risk of solid tumours remains.
- Other manifestations such as endocrine and renal abnormalities are common and require specialist input similar to non-FA affected individuals.
- For affected patients follow up surveillance for solid malignancies and other problems developing in adolescence and adulthood, such as hypothyroidism becomes increasingly important.
- Family members should be offered genetic counselling and testing where appropriate. Siblings should be tested also if they do not have clinical features as the phenotype can be discordant even with the same mutation.
- Individuals with FA have a shortened life-span.
- Cumulative incidences (up to age 50):
- Leukaemia -10%, but decreasing due to successful haematopoietic stem cell transplantation (HSCT).
- Death from bone marrow failure – 11%, but decreasing due to successful HSCT.
- Solid tumour – 30%, but increasing with longer life expectancy after successful HSCT.
- For children exhibiting features of FA type C, suggested initial referral would be to a paediatrician. For Ashkenazi Jewish patients, it is important to note the child’s ancestry and higher prevalence of FA type C in the Jewish population.
- For patients that have received a positive diagnosis of FA
- On-going management is usually under the joint care of haematologists and paediatricians plus other appropriate specialists according to how the condition presents in each affected patient.
- Families should be referred to a clinical genetics service to explore carrier status in other family members as appropriate.
- Transition from paediatric to adult management should go through an appropriate adolescent unit where possible.
Fanconi Hope is a charity that works with medical professionals to produce reliable information and raise awareness about Fanconi anaemia, supports families and raises money for family events and research. Their website has information for families, clinicians and researchers and other resources.
Tel: 0845 271 2811
This USA-based Research Fund works to help find effective treatments and a cure for Fanconi anemia and to provide education and support services to affected families worldwide. The site has fact sheets, guidelines for diagnosis and management and has an active bulletin board.
Written by Dr Jacky Megitt, Jnetics researcher
Reviewed by Dr Stefan Meyer, Honorary Consultant Paediatric Oncologist at the Royal Manchester Children’s Hospital
Last review date: 15.06.2018