Fanconi anaemia

Patients with Fanconi anaemia (FA) have a variety of dysmorphic features, as well as a progressive reduction in the production of normal blood cells in the bone marrow.

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:
  • 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);
  • predisposition to infections (due to low white cells);
• increased cancer risk:
  • 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, 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, leading to a population of bone marrow and blood cells with some DNA repair capacity.

For information about testing, see Clinical suspicion of Fanconi anaemia.

The vast majority of FA is inherited in an autosomal recessive manner. The parents of most affected individuals are heterozygous carriers for the condition. Any child born to a couple who are both carriers of a likely pathogenic variant in the same Faconi anaemia-associated gene will have a 25% (one in four) chance of being affected. Depending on the gene in question, there may be implications for the carrier parents beyond this reproductive risk, as variants in certain Fanconi anaemia-associated genes – including BRCA2, PALB2, BRIP1 – are associated with increased cancer risk in the heterozygous state.

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 males with a pathogenic variant in this gene will develop FA and women will be carriers.

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:

• genetic 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
• 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:

• Mehta PA and Ebens C. ‘Fanconi anemia‘. GeneReviews (National Library of Medicine) 2021.
• Río P, Navarro S, Bueren JA. ‘Advances in Gene Therapy for Fanconi Anemia’. Human Gene Therapy 2018: volume 29, issue 10, pages 1,114–23. DOI: 10.1089/hum.2018.124

For patients

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