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The expected prevalence at birth is at least 1/160,000.

The first signs of Fanconi anemia (FA) are typically non-hematological 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. Almost 20% of patients have ear malformations with or without hearing loss. Congenital malformations may involve other organ systems and vary within families. Short stature is syndromic and/or associated to endocrinopathies. Fertility is frequently impaired in males, and is highly disturbed in half of females. When congenital malformations are not prominent, diagnosis may be delayed until the onset of hematological anomalies. Bone marrow failure (BMF) occurs at a median age of 7 years, developing in 90% of patients by 40 years of age. The first manifestations are macrocytosis (very early) and thrombocytopenia. In patients with somatic mosaïcism, blood counts may stay normal until occurrence of hematological malignancy. In general, patients are highly predisposed to solid tumors (most frequently head and neck or anogenital regions).

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. Mutations in genes with an upstream role in the FA-core complex are associated with classic FA. Some of ''Downstream'' variants (e.g.BRCA2) are associated with a very high risk of solid tumors in infancy and early childhood.

Diagnosis relies on the evaluation of chromosomal breakage induced by diepoxybutane (DEB) or mitomycin C (MMC). This test may be normal in patients with somatic mosaicism; in which case, tests should be performed on fibroblasts.

FA clinical manifestations overlap with many malformation syndromes (Dubowitz, Seckel, Holt-Oram, Baller-Gerold, thrombocytopenia-absent radius, Nijmegen breakage syndromes, VACTERL association, dyskeratosis congenital, Blackfan-Diamond anemia) and diagnosis of FA is often delayed until a patient develops BMF or malignancies. FA should be considered in the differential diagnosis of all young patients with BMF of unknown etiology, and in other cancer predisposition syndromes (Bloom, Rothmund-Thomson or Werner syndromes) or syndromes with either constitutional or acquired BMF.

Prenatal diagnosis is feasible with a chromosomal breakage assay on fetal blood or, when the mutation is known, by genetic testing.

The disorder is usually autosomal recessive. Very rarely, X-linked (FANCB, < 1%) or autosomal dominant (FANCR, <1%) transmission may occur. If the variant is known, medical assisted reproduction should be offered to parents.

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 hematological malignancies is recommended during childhood in non-transplanted patients; with the exception of 1q anomalies, identification of a clonal event should lead to transplantation. Screening for solid tumors should start in adolescence, especially in the post-transplant setting; risk may be higher in patients with chronic GVHD. Any suspect lesion should be biopsied. When malignancies develop, treatment is complicated by the sensitivity to radiation and chemotherapy of FA patients.

HSCT efficiently treats BMF. Solid tumors prevention and treatment are the main challenge for transplanted patients.

Last update: December 2020 - Expert reviewer(s): Dr Thierry LEBLANC | ITHACA*

* European Reference Network