Fanconi Anaemia

Fanconi anaemia (FA) was named after Dr Guido Fanconi, the Swiss paediatrician who was the first to describe this condition in 1927. (1)
It is characterised by bone marrow failure (that leads to pancytopenia), predisposition to malignancies (haematological and solid tumours) and congenital abnormalities. 

D61.0 Constitutional aplastic anaemia

The incidence reported is approximately 3 in 1 000 000. (2) It is more prevalent in Askenazi Jewish population and Afrikaners population in South Africa. (3-5)

Fanconi anaemia is primarily inherited as an autosomal recessive disorder (homozygous or compound heterozygous), but X-linked recessive inheritance has also been reported.

There are 22 currently identified genes linked to this condition,, 20 of which have AR inheritance, 1 has autosomal dominant and 1 has X-linked recessive. (6-9) The most prevalent genes are FANCA, FANCC, FANCG, and FANCD2. (10)
The mutation affects FA genes that are responsible for production of proteins that detect and repair damaged DNA. Therefore, the cells of individuals with FA have chromosome instability and inability to repair DNA which makes them predisposed to malignancies.

There are three main groups of clinical features caused by the mutation in FA genes: bone marrow failure, structural abnormalities, and predisposition to malignancies. 
The bone marrow failure occurs in most patients and leads to pancytopenia. Symptoms and signs include symptoms of anaemia, thrombocytopaenia (epistaxis, petechiae and wounds that continue to bleed) and leukopenia (recurrent infections).
The structural abnormalities present as described below. Diagnosis of FA is more challenging in individuals without congenital abnormalities which can delay treatment. 
Malignancies associated with FA include haematological cancers (leukaemia, myelodysplastic syndrome) and solid tumours (most commonly squamous cell carcinoma, liver, brain, renal tumors). (11)

There is a wide range of associated structural abnormalities. (12) Most common findings are short stature, radial ray defects, absent/abnormal thumb (bifid, duplicated, rudimentary etc.), and skin hypo- or hyperpigmentation (café-au-lait spots). 
Head abnormalities include microcephaly, facial abnormalities (triangular facies, elfin like), eye malformations (strabismus, hypo- or hypertelorism), ear malformations (deafness (usually conductive due to abnormal ear canal), dysplastic outer ear). 
Urogenital abnormalities described are renal (abnormal shape or placement of kidneys, dysplastic kidneys, renal agenesis, hydronephrosis), undescended/absent testes and penile abnormalities (micropenis, hypospadias) in males, bicornuate uterus and hypogondism in females. Fertility is reduced in the individuals with FA. (13)
Cardiac abnormalities are less common and include atrial septal defect, ventricular septal defect, coarctation, situs inversus and truncus arteriosus. 
Minority will also have gastrointestinal (atresia, imperforate anus, tracheoesophageal fistula) and brain abnormalities (absent corpus callosum, cerebellar hypoplasia, dilated ventricles). 
Developmental delay has been reported in 10% of affected individuals. (12)

If it is inherited as autosomal recessive disorder the recurrence risk in future offspring is 25%. In rare cases of X-linked recessive inheritance it depends on which parent is affected by the mutation. If fertile, a male with the mutation will always be affected but will have no affected children but his daughters will be carriers. A female carrier will have 50% chance that a male child will present with Fanconi anaemia and a female child will be a carrier.

The chromosome breakage test is the most commonly used diagnostic test. Normal cells should be able to repair DNA damage and cells affected with FA gene abnormalities show increased chromosome breakage when exposed to DNA cross linking agents like diepoixybutane (DEB) and mitomycin C (MMC) with no ability to repair. This test can be performed antenatally on amniocytes, fetal blood cells or chorionic villi cells (14). 
The alternative to chromosome breakage test is flow cytometry cell cycle testing which reveals elevated G2-phase cell fractions in FA. (15) If either of the tests are positive, gene sequencing should be performed to confirm the diagnosis. 

Differential diagnosis includes a great variety of other inherited or acquired causes of bone marrow failure, chromosome breakage syndromes and conditions with the overlapping structural abnormalities.  
Inherited causes of bone marrow failure include dyskeratosis congenita, Diamond–Blackfan anemia, Shwachman–Diamond syndrome, severe congenital neutropenia, amegakaryocytic thrombocytopenia and Thrombocytopenia absent radii syndrome. The acquired types of bone marrow failure are pancytopaenia of various causes (drug, chemical or radiation induced, associated with infectious disease or autoimmune disease), paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes. 

Some of the chromosome breakage syndromes are Nijmegen breakage syndrome, xeroderma pigmentosum, Bloom syndrome, Seckel syndrome, Warsaw breakage syndrome and ataxia telangiectasia. The main distinguishable feature is that they do not cause bone marrow failure.   

Syndromes that present with radial ray defects are the most difficult to differentiate from FA antenatally. These include Holt–Oram syndrome, Okihiro syndrome, thrombocytopenia with absent radius, Rapadilino syndrome, Townes–Brocks syndrome, Edward’s syndrome and VACTERL association. (16)

There is no available screening for Fanconi anaemia and prenatal diagnosis of this condition is extremely difficult. The scan findings in Fanconi anaemia overlap with multiple other syndromes and it is not possible to establish the diagnosis from the scan alone. It can be suspected in cases with radial ray defects and abnormal/absent thumb, particularly in families who previously had affected child or diagnosis of FA within the family. 
Fanconi anaemia should also be considered as the differential diagnosis in cases of fetal anaemia of unknown etiology, particularly if combined with the structural abnormalities described above.

Unfortunately, there is no definitive treatment for Fanconi anaemia. As the condition is serious and life limiting, termination of pregnancy can be offered if diagnosed prenatally. (17)
The only curative therapy available is for the bone marrow failure and the haematological malignancies and it is achieved by hematopoetic stem cell transplantation (HCT). (18)
Transfusions of different blood products are the mainstay of supportive treatment. Androgen therapy has been shown to improve pancytopenia, particularly red blood cell count. However, it carries the increased risk of developing liver adenomas. (19, 20)
The main challenge of patients with FA is the treatment of solid tumours as the options are limited due to their sensitivity to radiation and chemotherapy (particularly alkylating agents).

The prognosis has dramatically improved since the haematopoetic stem cell transplantation (HCT) was introduced. Early diagnosis and timely treatment is crucial.
As the life span of these patients has been prolonged by HCT the incidence of malignancies has increased. The median age reported for surviving free of any malignancy was 29 years. The main causes of death in FA include complications from aplastic anemia, haematopoetic stem cell transplantation, and cancer. The median survival reported in the last two decades is 29 years of age. (12) The prognosis can be worsened further by the presence of significant congenital abnormalities. 

1.    Fanconi G. Familiäre infantile perniziosaartige Anämie (perniziöses Blutbild und Konstitution). Jahrbuch für Kinderheilkunde und physische Erziehung (Wien). 1927;117:257-80.
2.    Tischkowitz MD, Hodgson SV. Fanconi anaemia. Journal of Medical Genetics. 2003;40(1):1-10.
3.    Rosendorff J, Bernstein R, Macdougall L, Jenkins T. Fanconi anemia: another disease of unusually high prevalence in the Afrikaans population of South Africa. Am J Med Genet. 1987;27(4):793-7.
4.    Verlander PC, Kaporis A, Liu Q, Zhang Q, Seligsohn U, Auerbach AD. Carrier frequency of the IVS4 + 4 A-->T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population. Blood. 1995;86(11):4034-8.
5.    Rosenberg PS, Tamary H, Alter BP. How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi Anemia in the United States and Israel. Am J Med Genet A. 2011;155a(8):1877-83.
6.    Rodríguez A, D'Andrea A. Fanconi anemia pathway. Curr Biol. 2017;27(18):R986-r8.
7.    Meetei AR, Levitus M, Xue Y, Medhurst AL, Zwaan M, Ling C, et al. X-linked inheritance of Fanconi anemia complementation group B. Nat Genet. 2004;36(11):1219-24.
8.    Wang W. Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet. 2007;8(10):735-48.
9.    García-de-Teresa B, Rodríguez A, Frias S. Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences. Genes (Basel). 2020;11(12).
10.    Soulier J. Fanconi anemia. Hematology Am Soc Hematol Educ Program. 2011;2011:492-7.
11.    Kutler DI, Singh B, Satagopan J, Batish SD, Berwick M, Giampietro PF, et al. A 20-year perspective on the International Fanconi Anemia Registry (IFAR). Blood. 2003;101(4):1249-56.
12.    Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev. 2010;24(3):101-22.
13.    Tsui V, Crismani W. The Fanconi Anemia Pathway and Fertility. Trends Genet. 2019;35(3):199-214.
14.    Auerbach AD, Sagi M, Adler B. Fanconi Anemia: Prenatal Diagnosis in 30 Fetuses at Risk. Pediatrics. 1985;76(5):794-800.
15.    Bechtold A, Friedl R, Kalb R, Gottwald B, Neveling K, Gavvovidis I, et al. Prenatal exclusion/confirmation of Fanconi anemia via flow cytometry: a pilot study. Fetal Diagn Ther. 2006;21(1):118-24.
16.    Vergult S, Hoogeboom AJ, Bijlsma EK, Sante T, Klopocki E, De Wilde B, et al. Complex genetics of radial ray deficiencies: screening of a cohort of 54 patients. Genet Med. 2013;15(3):195-202.
17.    Bhatt RK, Dwivedi A, Dua RP, Singh LB, Kulshrestha S. Prenatal Diagnosis of Radial Ray Defect Associated with Fanconi Anemia: a Case Report. Journal of Fetal Medicine. 2021;8(1):75-9.
18.    Ebens CL, MacMillan ML, Wagner JE. Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations. Expert Rev Hematol. 2017;10(1):81-97.
19.    Dufour C, Svahn J. Fanconi anaemia: new strategies. Bone Marrow Transplant. 2008;41 Suppl 2:S90-5.
20.    Paustian L, Chao MM, Hanenberg H, Schindler D, Neitzel H, Kratz CP, et al. Androgen therapy in Fanconi anemia: A retrospective analysis of 30 years in Germany. Pediatr Hematol Oncol. 2016;33(1):5-12.

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