FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANG, FANCI, ERCC4, FANCL, MAD2L2, UBE2T, SLX4 genes
Also known as: Fanconi pancytopenia
Includes:
– OMIM#227650 https://omim.org/entry/227650
– OMIM#300514 https://omim.org/entry/300514
– OMIM#227645 https://omim.org/entry/227645
– OMIM#227646 https://omim.org/entry/227646
– OMIM#603467 https://omim.org/entry/603467
– OMIM#600901 https://omim.org/entry/600901
– OMIM#614082 https://omim.org/entry/614082
– OMIM#609053 https://omim.org/entry/609053
– OMIM#615272 https://omim.org/entry/615272
– OMIM#614083 https://omim.org/entry/614083
– OMIM#617243 https://omim.org/entry/617243
– OMIM#616435 https://omim.org/entry/616435
– OMIM#613951 https://omim.org/entry/613951
1. The disease:
A rare genetic multisystem disorder characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations, and predisposition to develop hematological or solid tumors.
2. The symptoms:
The first signs of Fanconi anaemia (FA) are typically non-haematological features. Limb anomalies typically affect the extremities, are unilateral or (usually asymmetric) bilateral. Minor anomalies can also be present such as low birth length and weight, microcephaly and/or microphthalmia. Skin pigmentation abnormalities (café-au-lait spots) and hypoplastic thenar eminence are frequent. Lack of early signs or symptoms does not exclude the diagnosis.
- Almost 20% of patients have ear malformations with or without hearing loss. Congenital malformations may involve other organ systems and vary within families.
- Bone marrow failure (BMF) occurs at a median age of 7 years, developing in 90% of patients by 40 years of age.
- Short stature is syndromic and/or associated to endocrinopathies.
3. Actions to take in case of early diagnosis:
- FA is genetically heterogeneous, and the implicated variants are involved in DNA repair and genomic stability. More than 90% of patients have mutations within FANCA, FANCC, FANCG or FANCD2 genes.
- Correlation with increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC) can also help.
- FA is a lifelong disease requiring lifetime management and regular follow-up with a Haematology Center. Management is provided by multidisciplinary team.
- Supportive care includes transfusions of packed red blood cells (RBC) or leucodepleted platelets but if regular transfusion is required, hematopoietic stem cell transplantation (HSCT) should be considered.
- Currently, the only curative treatment for hematologic manifestations is HSCT.
- Symptomatic treatment includes oral androgen administration, which improves blood counts in most patients but is associated with severe liver toxicity and does not suppress the leukemic risk. Administration of G-CSF, best after bone marrow aspirate, should be considered in patients with acute severe infections.
- Regular screening for haematological malignancies is recommended during childhood in non-transplanted patients; except for 1q anomalies, identification of a clonal event should lead to transplantation. Screening for solid tumours should start in adolescence, especially in the post-transplant setting; risk may be higher in patients with chronic graft versus host disease (GVHD).
- Genetic counselling should be offered to at-risk family members.