Fanconi anaemia

Patients with Fanconi anaemia (FA) experience a progressive reduction in the production of normal blood cells in the bone marrow. They may also have short stature, limb malformations, microcephaly, genitourinary and ophthalmic anomalies.

Patients with FA can have a variety of the following features:

• short stature;
• thumb and/or arm anomalies;
• skeletal anomalies of the hips/ribs/spine;
• renal anatomical conditions;
• cafe-au-lait spots;
• microcephaly;
• small, crossed and/or widely spaced eyes;
• low birth weight;
• gastrointestinal conditions;
• micro-orchidism;
• structural heart anomalies;
• bone marrow failure, so as:
  • easy bruising (due to low platelets; often the first bone marrow cell type to reduce in number);
  • lethargy, weakness and/or sleepiness (due to low red cells/anaemia); and/or
  • predisposition to infections (due to low white cells); and
• an increased probability of cancer, such as:
  • acute myeloid leukaemia;
  • head and neck tumours;
  • gastrointestinal tumours; and
  • gynaecological tumours.

Genetically, FA is a spectrum of conditions that span a related phenotype. The majority of these conditions occur because of a heritable inability of cells to repair damaged chromosomes, resulting in chromosomal instability (whereby they break and rearrange their genetic code more readily).

Pathogenic variants in at least 18 genes have been causally associated with the development of FA, with all encoding components of the FA pathway of DNA damage repair.

• The vast majority of cases are caused by variants in three genes: FANCA, FANCC and FANCG, which produce components of the ‘FA core’ protein complex.
• In rarer cases, variants affect BRCA2, BRIP1, FANCB, FANCD2, FANCE, FANCF, FANCI, ERCC4, FANCL, FANCM, PALB2, RAD51C, SLX4 or UBE2T.

The time of progression to bone marrow failure varies depending upon the genotype.

Some patients can have a mosaic phenotype owing to reversion variants. This is when a further genetic change occurs, initially in one cell, which restores the normal function of the gene. This leads to a survival advantage to the cell, and the cells derived from it. Overtime these cells become more widespread, especially in high turnover tissues like blood. This leads to a population of bone marrow and blood cells with some DNA repair capacity, which in turn improves the clinical prognosis.

There are several tests available in the National Genomic Test Directory that may diagnose FA. Test selection depends on the clinical features, in particular the specificity of the presentation. For information about testing, see Presentation: Clinical suspicion of Fanconi anaemia.

It is important to note that some tests analyse the DNA sequence to look for causative variants, while others look for the presence of chromosome breakage itself. As such, these techniques can synergise to help establish a diagnosis; for instance, if variants of uncertain significance are found then the presence or absence of chromosome breakage may help to upgrade or downgrade the variant. Alternatively, if the diagnosis is specifically suspected but molecular testing has not identified a variant, the presence of chromosome breakage may indicate that the patient may have an as yet undiscovered genomic cause.

DNA testing requires an EDTA (typically a purple topped) tube while chromosome breakage testing requires a lithium heparin (typically a green topped) tube. Check with the receiving laboratory on procedures for delivery, for example some may request advanced warning of lithium heparin tube arrival as it will need to be promptly processed.

The vast majority of FA are inherited in an autosomal recessive manner. A detailed family history should be taken. Careful consideration should be given to the possibility that other family members may be affected. Screening/testing for the familial variant should be offered as appropriate. This is often supported by the clinical genetics service.

As the condition is autosomal recessive it is likely that parents are carriers, though de novo variants can arise. If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:

• 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected.
• 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
• 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

Reproductive options are available and carrier couples should be offered prenatal counselling prior to conception where possible. Options may include testing in early pregnancy and preimplantation genetic testing.

Depending on the gene in question, there may be implications for the carrier parents beyond the reproductive risk, as variants in certain Fanconi anaemia-associated genes – including BRCA2, PALB2, BRIP1 – are associated with an increased probability of cancer in the heterozygous state. Referral to clinical genetics should be considered.

FANCB (which underlies less than 1% of cases of FA) is located on the X chromosome and inheritance is in an X-linked recessive pattern, meaning that men with a pathogenic variant in this gene will develop FA and women will be carriers. The implications for family members, including reproductive, must be carefully considered.

Autosomal dominant FA can very rarely occur due to a variant in RAD51. To date, such cases have resulted from a de novo variant.

Management of children with FA is complex and should be delivered via a multidisciplinary team. Some of the management approaches are listed below.

Supportive therapies:

• genomic counselling;
• orthopaedic surgery, physiotherapy and occupational therapy for skeletal anomalies;
• cardiology and cardiothoracic surgery input for structural cardiac anomalies;
• prophylactic antibiotics and anti-fungal medicines for children with significant neutropenia;
• blood product transfusions; and
• use of sunscreen, avoiding smoking.

Curative therapies:

• bone marrow transplantation; and
• gene therapy, which is available as part of several clinical trials for FANC–A Fanconi anaemia.

For further information, see the Fanconi Anemia Research Fund’s clinical care guidelines.

For clinicians

• ClinicalTrials.gov
• Fanconi Anemia Research Fund: Fanconi anaemia clinical care guidelines 2020 (PDF, 276 pages)
• GeneReviews: Fanconi anemia
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Fanconi anaemia
• NHS England: National Genomic Test Directory
• Patient.info (article for medical professionals): Fanconi anaemia

References:

• Río P, Navarro S and Bueren JA. ‘Advances in Gene Therapy for Fanconi Anemia‘. Human Gene Therapy 2018: volume 29, issue 10, pages 1,114–1,123. DOI: 10.1089/hum.2018.124

For patients

• The Aplastic Anaemia Trust: Fanconi anaemia
• Child Growth Foundation
• Fanconi Anemia Research Fund
• Fanconi Hope