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Clinical features

Patients with Fanconi anaemia (FA) can have a variety of these features:

  • short stature;
  • thumb and/or arm abnormalities;
  • skeletal anomalies of the hips/ribs/spine;
  • renal anatomical disorders;
  • cafe-au-lait spots;
  • microcephaly;
  • small/crossed/widely spaced eyes;
  • low birth weight;
  • gastrointestinal disorders;
  • micro-orchidism;
  • structural heart defects;
  • bone marrow failure:
    • easy bruising (due to low platelets; often the first bone marrow cell type to reduce in number);
    • lethargy/weakness/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.

Genes

Genetically, FA is a spectrum of disorders that span a related phenotype. The majority of these are 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 mutations, leading to a population of bone marrow and blood cells with some DNA repair capacity.

Inheritance and genetic counselling

The vast majority of FA is inherited in an autosomal recessive manner. The parents of most affected individuals are carriers for the condition and therefore have a 25% (1-in-4) chance of another child being affected.

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

Management of children with FA is complex and should be delivered via a multidisciplinary team. Management approaches include:

Supportive therapies:

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

Curative therapies:

  • bone marrow transplantation; and
  • gene therapy is available in the context of clinical trials for FANC-A Fanconi anaemia.

The Fanconi Anemia Research Fund has published detailed management guidelines – find this and other sources of information in the resources section below.

Resources

For clinicians

References:

For patients

Tagged: Short stature

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  • Last reviewed: 09/02/2022
  • Next review due: 09/02/2023
  • Authors: Hassan Shakeel
  • Reviewers: Dr Amy Frost, Dr Ellie Hay, Dr Emile Hendricks, Dr Anne Kelly