Fanconi anemia

Recommended panel testing at Breda Genetics for this condition:



Fanconi anemia (FA) is a rare disorder characterized by physical abnormalities such as short stature, skeletal malformations, skin pigmentation abnormalities, microcephaly, genitourinary tract defects, early onset bone marrow failure, and a peculiar predisposition to develop early-onset tumors.

Detailed clinical description

About ¾ of FA patients display physical anomalies such as pre- and post-natal growth retardation with low birthweight and short stature, skin pigmentation abnormalities (hyper- or hypo-pigmentation, café-au-lait spots), and mono or bilateral malformations of the upper limbs such as radial ray anomalies (hypoplastic or aplastic radius, absent or anomalous thumbs, and dysplastic ulnae). More rarely FA patients present with skeletal defects of the lower limbs such as congenital hip dislocation and foot abnormalities. Other skeletal defects may involve the spine (scoliosis) and ribs. Microcephaly and ophthalmic anomalies (microphthalmia, visual loss, ptosis, etc.) occur in about 20% of affected individuals. Genitourinary tract anomalies are also seen in about 20% of cases and include structural renal defects such as aplastic, dysplastic, horseshoe or absent kidney, cryptorchidism, micropenis, and reduced fertility in males, and small ovaries, bicornuate uterus and infertility in females. Other features observed include hearing loss, congenital heart defects, gastrointestinal and central nervous system anomalies. Intellectual disability has been found in about 10% of cases. As much as 25% of FA patients only display a few or none of these physical abnormalities.

Patients with FA usually develop some degree of bone marrow dysfunction with variable onset that can range from mild cytopenia to severe aplastic anemia, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML). Additionally, FA patients have a much higher predisposition to develop solid tumors compared to the general population, primarily head and neck squamous cell carcinomas, but also esophageal, genitourinary tract malignancies and brain tumors.

The diagnosis of FA in suspected patients is establish by the laboratory finding of increased chromosome breakage and tri- or quadri-radial chromosome forms in patient’s lymphocytes treated with diepoxybutane or mitomycin C.

The prevalence of FA heterozygous carrier has been estimated to be 1:181 in North America and 1:93 in Israel. Some populations have founder mutations in specific genes with increased carrier frequency, such as Ashkenazi Jews, northern Europeans, Afrikaners, Spanish Gypsies, etc.

Molecular genetics

FA is primarily inherited as autosomal recessive trait. Biallelic mutations in the following genes cause this disorder: FANCA (60-70% of cases), FANCC (14%), XRCC9 (FANCG, 10%), BRCA2 (3%), FANCD2 (3%), FANCE (3%), BRIP1 (2%), FANCF (2%), FANCI (1%). Less common causes of FA include BRCA1, ERCC4, FANCM (uncertain), MAD2L2, PALB2, PHF9 (FANCL), RAD51C, RFWD3, SLX4, UBE2T, XRCC2. Mutations in the FANCB gene cause X-linked recessive FA and account for about 2% of cases. Heterozygous mutations in the RAD51 gene cause an autosomal dominant form of the disease.

Differential diagnosis

Bloom syndrome (BS): BS is a rare condition characterized by increased chromosome breakage and sister-chromatid exchanges. As in FA, BS patients display severe pre- and post-natal growth restriction, however congenital malformations are absent. Affected individuals usually present sun-sensitive skin lesions, immunodeficiency with increased susceptibility to otitis and pneumonia, and may develop diabetes as adults although their characteristic lean constitution. Biallelic mutations in the BLM gene cause this disease.

Ataxia-telangiectasia (AT) and AT-like disorder: AT is characterized by progressive cerebellar dysfunction resulting in unsteady gait and difficulty standing (ataxia), progressive oculomotor apraxia, slurred speech and involuntary movements that are not seen in FA patients. Biallelic mutations in the ATM gene cause this syndrome. AT-like disorder is caused by biallelic mutations in the MRE11 gene.

Nijmegen breakage syndrome (NBS): in addition to growth retardation, recurrent infections, and increased susceptibility to early onset malignancies, NBS patients display progressive disproportionate microcephaly and progressive decline in intellectual abilities. Biallelic mutations in the NBN gene cause this syndrome while mutations in the RAD50 gene cause the NBS-like disorder.

Rothmund-Thomson syndrome: caused by biallelic mutations in the RECQL4 gene, it is characterized by growth delay, poikiloderma congenita and skin pigmentation anomalies, telangiectasia, atrophic nails, dental anomalies, skeletal defects, and alopecia. Hematologic anomalies are usually absent.  Allelic defects include Baller-Gerold and RAPADILINO syndrome.

Werner syndrome: in addition to short stature, hypogonadism, and skin changes affected individuals display progeroid features, osteoporosis, premature atherosclerosis, and cataracts. The syndrome is caused by biallelic mutations in the RECQL2 gene.

Seckel syndrome: affected individuals display the characteristic bird-headed facial appearance, with growth retardation, severe microcephaly, and intellectual disability. Breda Genetics offers a specific gene panel for this syndrome (Pan 112).

Thrombocytopenia with absent radius (TAR): it is characterized by radial ray anomalies with thumb preservation and thrombocytopenia. Other systems may be involved such as the gastrointestinal tract, the kidneys, and the heart. It is caused by biallelic mutations in the RBM8A gene.

Disorders with bone marrow failure and/or pancytopenia have also to be considered in the differential diagnosis. Examples include dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome.

Recommended testing workflow

Breda Genetics offers the analysis of FA genes in panels based on either Mendeliome, exome or full genome sequencing. Large deletions, duplications and insertions can account for up to 30% of all FA mutations, depending on the gene involved. Hence, large deletion/duplication testing of FA genes is highly recommended. If the panel is negative, one may proceed to an add-on panel to test the genes included in the differential diagnosis or to the upgrade of the analysis of all data from exome or genome sequencing.

Recommended panel testing at Breda Genetics for this condition:



Fanconi Anemia. Mehta PA, Tolar J. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2002 Feb 14 [updated 2018 Mar 8]. PMID: 20301575

Recent advances in understanding hematopoiesis in Fanconi Anemia. Bagby G. F1000Res. 2018 Jan 24;7:105. PMID: 29399332

Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. Mamrak NE, Shimamura A, Howlett NG. Blood Rev. 2017 May;31(3):93-99. PMID: 27760710

Update of the human and mouse Fanconi anemia genes. Dong H, Nebert DW, Bruford EA, Thompson DC, Joenje H, Vasiliou V. Hum Genomics. 2015 Nov 24;9:32. PMID: 26596371

OMIM 227650210900251260613078208900268400277700210600274000

Fanconi Anemia: Guidelines for Diagnosis and Management (4th Ed. 2014)

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