Fanconi anaemia
Last update: August 2025
Fanconi anaemia (FA; ORPHA:84, ICD 3A70.0, OMIM 227645, 227646, 227650, 300514, 600901, 603467, 609053, 609054, 610832, 613390, 613951, 614082, 614083, 617883; MONDO 0054748, 0011584, 0012187, 0009215, 0010351, 0009213, 0009214, 0010953, 0011325, 0013565, 0012186, 0013566, 0012565, 0013248, 0013499) is a rare group of genetic disorders with impaired DNA-repair with a birth incidence of about 1 in 300,000. FA is a multi-system disease characterized by a broad and highly variable spectrum of clinical manifestations, which mainly include early-onset bone marrow failure (occurring in approximately 80% of patients during the first decade of life), congenital abnormalities (such as growth deficiency and skeletal malformations or abnormal skin pigmentation) and increased risk for malignancies (both hematologic and solid tumours).
FA is a rare disease caused by pathogenic germline variants in several genes involved in DNA repair (such as BRCA1, BRCA2, BRIP1, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, PALB2, RAD51C, and SLX4). The inability to repair DNA defects (specifically bonds between DNA strands, also known as inter-strand crosslink) leads to DNA instability promoting cancer development in a wide variety of cell types. Functional testing of lymphocytes and/or fibroblasts (chromosome breakage) can be carried out in specialised centres to establish the clinical diagnosis, to be confirmed with genetic analysis.
Alterations in different FA genes are associated with different presentations and cancer risks. In particular, some biallelic pathogenic variants in the BRCA2 gene result in a lower frequency of bone marrow suppression and developmental abnormalities, if compared to typical FA. In this condition, also known as “Inherited cancer-predisposing syndrome due to biallelic BRCA2 pathogenic variants” (ORPHA:319462, OMIM: 605724), the risk of cancer is however extremely high, as well as in patients with biallelic pathogenic variants in the BRCA1 and PALB2 genes.
Most cases of FA are inherited in an autosomal recessive way. This means that pathogenic variants in both alleles (usually one from each parent) of one of the autosomal recessive FA genes are required to cause the disorder. If both parents are carriers of one pathogenic variant, each of their children has a 25% chance to inherit both variants and, consequently, to develop the disease. In rare cases, inheritance can be X-linked (affecting only males) or autosomal dominant. Depending on the counrty there might be options for prenatal testing and preimplantation genetic testing when the causative pathogenic variants are known.
Patients with FA have increased risks of hematologic neoplasms and solid tumours, especially head and neck squamous cell carcinomas (HNSCC) and gynaecological squamous cell carcinomas. Therefore, intensive cancer surveillance is recommended (GeneReviews®).
For hematologic neoplasm and bone marrow failure, surveillance should start as soon as the patient is diagnosed. Haematopoietic stem cell transplantation can be considered in case of hematologic manifestations (tailored considering the increased risk for toxicity associated with this syndrome) and unaffected family members can be considered as donors. For HNSCC, regular examinations by dentist or oral surgeon familiar with FA and should begin at the age of 10 years. Girls are advised to start gynaecological surveillance from 13-16 years. Due to the association between human papillomavirus (HPV) infection and squamous cell carcinoma, vaccination against HPV is strongly recommended.
Surveillance should also be adapted based on gene specific cancer risks or for particular clinical conditions (i.e., post-bone marrow transplantation). Surveillance should preferably be performed at specialised centres, which are present in different countries.
Cancer risk (namely breast/ovarian/prostate) is also increased in heterozygous carriers of pathogenic germline variants in certain FA genes (such as BRCA1/2, BRIP1, PALB2, RAD51 and RAD51C), so for these individuals tailored preventative and surveillance options are available, see ERN GENTURIS - HBOC).
This paragraph discusses aspects of the disease for which there is currently limited evidence. These aspects can be the subject of studies and research but are not yet part of current clinical practice.
Alterations in other genes, such as ERCC4, FAAP100, REV7, RFWD3, UBE2T and XRCC2, have been proposed as causative of FA, but to date they have only been identified in individual or few patients, and the evidence supporting their association with the disease has not yet been definitively established. Therefore, further studies are needed to clarify their possible role in FA.
Some types of therapies have proven effective in FA patients (such as stem cell transplantation), and several studies on many other types (such as gene therapy in FANCA/FANCC-related FA patients, CAR-T therapy for different types of FA cancers) are underway, but they are currently in the preliminary stages. In any case, this is certainly an important topic for future FA research.
More information regarding Fanconi Anaemia can be found on:
Orphanet: Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
ClinGen / OMIM Fanconi Anaemia complementation group S (OMIM617883, BRCA1), group D1 (OMIM605724, BRCA2), group J (OMIM609054, BRIP1), group A (OMIM227650, FANCA), group B (OMIM300514, FANCB), group C (OMIM227645, FANCC), group D2 (OMIM227646, FANCD2), group E (OMIM600901, FANCE), group F (OMIM603467, FANCF), group G (OMIM614082, FANCG), group I (OMIM609053, FANCI), group L (OMIM614083, FANCL), group N (OMIM610832, PALB2), group O (OMIM613390, RAD51C), group P (OMIM613951, SLX4)
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Clinical practice guidelines |
ERN GENTURIS care pathway |
ERN GENTURIS patient journey |
ERN GENTURIS publications |
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Thematic Group 4: Other rare – predominantly malignant – genturis |
ERN GENTURIS webinars - Thematic group 4: Other rare genturis
A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.