A Narrative Review on Fanconi Anemia: Genetic and Diagnostic Considerations

Abstract

Fanconi anemia (FA) is an autosomal recessive disorder, both genetically and phenotypically. It is characterized by chromosomal instability, progressive bone marrow failure, susceptibility to cancer, and various other congenital abnormalities. It involves all the three cell lines of blood. So far, biallelic mutations in 21 genes and one x-linked gene have been detected and found to be associated with FA phenotype. Signs and symptoms start setting in by the age of 4 to 7 years, mainly hematological symptoms. This includes pancytopenia, that is, a reduction in the number of white blood cells (WBCs), red blood cells (RBCs), and platelets. Therefore, the main criteria for diagnosis of FA include skeletal malformations, pancytopenia, hyperpigmentation, short stature, urogenital abnormalities, central nervous system, auditory, renal, ocular, and familial occurrence. Patients showing signs and symptoms of FA should be thoroughly evaluated. A complete blood count will reveal a reduced number of RBC, WBC, and platelets, that is, pancytopenia. Chromosomal breakage study/stress cytogenetics should be done in patients with severe pancytopenia. Momentousness timely diagnosis of current disease, prenatal diagnosis, and genetic counseling should be emphasized.

Keywords

Fanconi anemia / pancytopenia / acute myeloid leukemia / stress cytogenetics

References

[1] Auerbach AD.Fanconi anemia and its diagnosis. Mutat Res 2009; 668(1-2): 4-10

[2] García-de-Teresa B, Rodríguez A, Frias S. Chromosome instability in Fanconi anemia: from breaks to phenotypic consequences. Genes (Basel) 2020; 11(12): 1528

[3] Rosenberg PS, Tamary H, Alter BP.How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi anemia in the United States and Israel. Am J Med Genet A 2011; 155A(08): 1877-1883

[4] D'Andrea AD, Grompe M. The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 2003; 3(01): 23-34

[5] Bhandari J, Thada PK, Puckett Y. Fanconi anemia. [Updated 2022 Jan 2]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Accessed June 02, 2022 at: https://www.ncbi.nlm.nih.gov/books/NBK559133/

[6] Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum Mol Genet 2001; 10(20): 2253-2259

[7] Meetei AR, Levitus M, Xue Y.et al.X-linked inheritance of Fanconi anemia complementation group B. Nat Genet 2004; 36(11): 1219-1224

[8] Wang AT, Kim T, Wagner JE.et al.A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Mol Cell 2015; 59(03): 478-490

[9] Bagby G.Recent advances in understanding hematopoiesis in Fanconi anemia. F1000 Res 2018; 7: 105

[10] Chandrasekharappa SC, Lach FP, Kimble DC.et al; NISC Comparative Sequencing Program. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood 2013; 121(22): e138-e148

[11] Kee Y, D'Andrea AD. Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes Dev 2010; 24(16): 1680-1694

[12] George M, Solanki A, Chavan N.et al.A comprehensive molecular study identified 12 complementation groups with 56 novel FANC gene variants in Indian Fanconi anemia subjects. Hum Mutat 2021; 42(12): 1648-1665

[13] Adachi D, Oda T, Yagasaki H.et al.Heterogeneous activation of the Fanconi anemia pathway by patient-derived FANCA mutants. Hum Mol Genet 2002; 11(25): 3125-3134

[14] Yamashita T, Barber DL, Zhu Y, Wu N, D'Andrea AD. The Fanconi anemia polypeptide FACC is localized to the cytoplasm. Proc Natl Acad Sci U S A 1994; 91(14): 6712-6716

[15] Youssoufian H.Localization of Fanconi anemia C protein to the cytoplasm of mammalian cells. Proc Natl Acad Sci U S A 1994; 91(17): 7975-7979

[16] Hoatlin ME, Christianson TA, Keeble WW.et al.The Fanconi anemia group C gene product is located in both the nucleus and cytoplasm of human cells. Blood 1998; 91(04): 1418-1425

[17] McMahon LW, Walsh CE, Lambert MW. Human alpha spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex. J Biol Chem 1999; 274(46): 32904-32908

[18] Yamashita T, Kupfer GM, Naf D.et al.The Fanconi anemia pathway requires FAA phosphorylation and FAA/FAC nuclear accumulation. Proc Natl Acad Sci U S A 1998; 95(22): 13085-13090

[19] Li R, Murray AW.Feedback control of mitosis in budding yeast. Cell 1991; 66(03): 519-531

[20] Hoyt MA, Totis L, Roberts BT.S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 1991; 66(03): 507-517

[21] Lara-Gonzalez P, Westhorpe FG, Taylor SS.The spindle assembly checkpoint. Curr Biol 2012; 22(22): R966-R980

[22] Musacchio A, Salmon ED.The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 2007; 8(05): 379-393

[23] Glanz A, Fraser FC.Spectrum of anomalies in Fanconi anaemia. J Med Genet 1982; 19(06): 412-416

[24] Ogilvie P, Hofmann UB, Bröcker EB, Hamm H. [Skin manifestations of Fanconi anemia]. Hautarzt 2002; 53(04): 253-257

[25] Yamashita T, Nakahata T.Current knowledge on the pathophysiology of Fanconi anemia: from genes to phenotypes. Int J Hematol 2001; 74(01): 33-41

[26] Alter BP.Fanconi's anemia and malignancies. Am J Hematol 1996; 53(02): 99-110

[27] Young NS, Alter BP.Clinical features of Fanconi's anemia. In: Young NS, Alter BP. eds. Aplastic anemia, Acquired and Inherited. Philadelphia, PA: Saunders; 1994: 275-309 . 20

[28] Faivre L, Guardiola P, Lewis C.et al; European Fanconi Anemia Research Group. Association of complementation group and mutation type with clinical outcome in Fanconi anemia. Blood 2000; 96(13): 4064-4070

[29] Wajnrajch MP, Gertner JM, Huma Z.et al.Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry. Pediatrics 2001; 107(04): 744-754

[30] Hou JW, Wang TR.Differentiation of Fanconi anemia from aplastic anemia by chromosomal breakage test. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1997; 38(02): 121-126

[31] Talmoudi F, Kilani O, Ayed W.et al.Differentiation of Fanconi anemia and aplastic anemia using mitomycin C test in Tunisia. C R Biol 2013; 336(01): 29-33

[32] Gadhiya K, Wills C. Diamond Blackfan Anemia. [Updated 2022 Jan 31]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Jan. Accessed June 02, 2022 at: https://www.ncbi.nlm.nih.gov/books/NBK545302/?report=classic

[33] Burroughs L, Woolfrey A, Shimamura A.Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am 2009; 23(02): 233-248

[34] Vekaria R, Bhatt R, Saravanan P, de Boer RC. Bloom's syndrome in an Indian man in the UK. BMJ Case Rep 2016; 2016: bcr2015212297

[35] Hafsi W, Badri T, Rice AS. Bloom Syndrome. [Updated 2021 Jul 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; HHS Vulnerability Disclosure. Accessed June 02, 2022 at: https://www.hhs.gov/vulnerability-disclosure-policy/index.html

[36] Al-Qahtani FS.Congenital amegakaryocytic thrombocytopenia: a brief review of the literature. Clin Med Insights Pathol 2010; 3: 25-30

[37] Schroeder TM, Anschütz F, Knopp A. [Spontaneous chromosome aberrations in familial panmyelopathy]. Humangenetik 1964; 1(02): 194-196

[38] Auerbach AD, Sagi M, Adler B.Fanconi anemia: prenatal diagnosis in 30 fetuses at risk. Pediatrics 1985; 76(05): 794-800

[39] Auerbach AD, Min Z, Ghosh R.et al.Clastogen-induced chromosomal breakage as a marker for first trimester prenatal diagnosis of Fanconi anemia. Hum Genet 1986; 73(01): 86-88

[40] Auerbach AD.Diagnosis of Fanconi anemia by diepoxybutane analysis. In: Dracopoli NC, Haines JL, Korf BR, Moir DR, Morton CC, Seidman CE, Seidman JG, Smith DR. eds. Current Protocols Human Genetics. Supplement. Vol. 37. Hoboken, NJ: John Wiley & Sons, Inc; 2003: 8.7.1-8.7.15

[41] Auerbach AD, Liu Q, Ghosh R, Pollack MS, Douglas GW, Broxmeyer HE.Prenatal identification of potential donors for umbilical cord blood transplantation for Fanconi anemia. Transfusion 1990; 30(08): 682-687

[42] Seyschab H, Friedl R, Sun Y.et al.Comparative evaluation of diepoxybutane sensitivity and cell cycle blockage in the diagnosis of Fanconi anemia. Blood 1995; 85(08): 2233-2237

RIGHTS & PERMISSIONS

2022 Global Medical Genetics