Fanconi anemia
Fanconi Anemia (FA; ORPHA:84, (ICD 3A70.0; OMIM 227645, 227646, 227650, 300514, 600901, 603467 , 609053, 609054, 610832, 613390, 613951, 614082, 614083, 615272, 616435, 617243, 617244, 617247, 617883)) 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 tumors).
FA is a rare disease caused by pathogenic germline variants in more than 20 genes involved in DNA repair. 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 (chromosome breakage) can be carried out to establish the diagnosis.
FA is in most cases inherited in an autosomal recessive way. This means that two pathogenic variants (usually one from each parent) in one of the FA genes are required to cause the disorder. Therefore, if both parents are carriers of one pathogenic variant and healthy, each child has a 25% chance to inherit both variants and, consequently, to have the disease. In rare cases, inheritance can be X-linked or autosomal dominant. The latter usually present as sporadic cases due to de novo germline mutations, while in the former only males are affected. Prenatal genetic testing should be performed by targeted variant analysis if the causative pathogenic variants are known. Alternatively, preimplantation genetic testing can be performed after an in vitro fertilization.
FA affected patients have increased risk of hematologic neoplasms and solid tumors, especially head and neck squamous cell carcinomas (HNSCC) and gynecological squamous cell carcinoma. Pathogenic variants in some genes (ie, BRCA2) are associated with higher risks of some specific cancers. Therefore, for affected individuals, a cancer surveillance program is highly recommended.
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 and unaffected family members can be considered as donors. For HNSCC, surveillance should begin at age of 10 years. Girls are advised to start gynecological 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).
Cancer risk (namely breast/ovarian) is also increased in healthy carriers of pathogenic germline variants (heterozygotes) in autosomal recessive FA genes, for whom tailored preventative options are available.
More information regarding Fanconi Anemia can be found on:
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Clinical practice guidelines |
ERN GENTURIS care pathway |
ERN GENTURIS patient journey |
ERN GENTURIS publications |
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ERN GENTURIS webinars - Thematic group 4: Other rare genturis
ERN GENTURIS webinars - General
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.