Fanconi’s AnemiaGary Oh

History of IllnessSwiss pediatrician who originally

described this disorder, Guido Fanconi.

1927 - 3 brothers with pancytopenia and physical abnormalities, “perniziosiforme”

It should not be confused with Fanconi syndrome, a kidney disorder also named after Fanconi.

A 3-year-old patient with Fanconi anemia. Note the multiple birth defects, including short stature, microcephaly, microphthalmia, hyperpigmentation of the skin, epicanthal folds, dangling thumbs, congenital dislocated hips, and rocker bottom feet.

98% AR with 2% X-linked variant1/350,000 births1,000 persons worldwide

currently suffer from the diseaseAshkenazi Jews and Afrikaners

Epidemiology

S/SDx between six and nine years of ageVariable progressive course Congenital malformations: SGA, short, skin

pigmentation (café au lait spots)Pancytopenia (50%) within 10 yearsFirst sign often hemorrhagic manifestations

(petechiae and bruises) secondary to thrombocytopenia

Fatigue and pallor caused by progressive macrocytic anemia

Fever, mucosal ulcerations, and bacterial infections resulting from neutropenia

The gene is located on chromosome 16q24.3 (chromosome 16, region 2, band 4, sub-band 3)

-17 FA or FA-like genes (FA-A to FA-Q):FANC-AFANC-BFANC-C

FANC-D1 (BRCA2)FANC-D2FANC-EFANC-FFANC-GFANC-I

FANC-J (BRIP1)FANC-LFANC-MFANC-N (PALB2)FANC-P

(SLX4)FANC-S (BRCA1)RAD51CXPF

Genetics

BiochemistryFA proteins maintain genomic stability, mainly

through the repair of DNA interstrand crosslinksMutation lead to less effective DNA repairDynamic cell division occurs in the bone

marrow. Thus, patients are more likely to develop bone marrow failure, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)

With BM failure and diminished WBCs, RBCs and platelets, the body's capabilities to fight infection, deliver oxygen, and form clots are all diminished.

FA core complex (8 proteins) activated when DNA stops replicating because of damage.

Assembly is activated by:◦ Replicative stress (particularly DNA damage caused by

cross-linking agents(mitomycin C or cisplatin)◦ Reactive oxygen species (ROS) that is detected by the

FANC-M protein. FANC-A, -B, -C, -E, -F, -G, -L and –M assemble to form a core

protein complex in the cytoplasm that moves to the nucleus. Ubiquitin is added, a small protein that combines with

BRCA2 in another cluster to repair DNA. Following assembly, the protein core complex activates

FANCL protein which acts as an E3 ubiquitin-ligase and monoubiquitinates FANC-D2.

Monoubiquitinated FANC-D2, also known as FANC-D2-L, then goes on to interact with a BRCA1/BRCA2 complex.

FA gene FANC-D1 is identical to BRCA2, one of the breast cancer susceptibility genes involved with DNA repair. 

At the end of the process, ubiquitin is removed

TxTreatment with androgens and

hematopoietic (blood cell) growth factors can help bone marrow failure temporarily, but the long-term treatment is bone marrow transplant if a donor is available.

Because of the genetic defect in DNA repair, cells from people with FA are sensitive to drugs that treat cancer by DNA crosslinking, such as mitomycin C.

Px60–75% congenital defects.Many patients do not reach adulthood. Median age of

death was 30The overarching medical challenge is a failure of their

bone marrow to produce blood cells. 90% unable to produce blood cells by age 40.  

75% of patients have some form of endocrine problem. Older patients are extremely likely to develop AML,

MDS, head and neck, esophageal, gastrointestinal, vulvar and anal cancer

Patients who have had a successful bone marrow transplant and cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer

References Connor F; Bertwistle D; Mee PJ et al. (1997). Tumorigenesis and a DNA repair defect in mice with a

truncating Brca2 mutation. Nat. Genet. 17 (4): 423–430. Cortez D, Wang Y, Qin J, Elledge SJ (1999). Requirement of ATM-dependent phosphorylation of brca1 in

the DNA damage response to double-strand breaks. Science 286 (5442): 1162–1166. Deans AJ, West SC (December 2009). FANCM connects the genome instability disorders Bloom's

Syndrome and Fanconi Anemia. Mol. Cell 36 (6): 943–53. Garcia-Higuera I; Taniguchi T; Ganesan S et al. (2001). Interaction of the Fanconi anemia proteins and

BRCA1 in a common pathway. Mol. Cell 7 (2): 249–262. Howlett NG, Taniguchi T, Olson S, et al. (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science

297:606. Li Y, Youssoufian H, Ma A (1997) overexpression reveals a common genetic link in four Fanconi anemia

complementation groups. J Clin Invest 100:2873. Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L, et al. (1996) Expression cloning of a cDNA for the

major Fanconi anaemia gene, FAA. Nat Genet 14:320. Medhurst AL, Laghmani el H, Steltenpool J, et al. (2006) Evidence for subcomplexes in the Fanconi

anemia pathway. Blood 108:2072. Offit K, Levran O, Mullaney B, et al. (2003) Shared genetic susceptibility to breast cancer, brain tumors,

and Fanconi anemia. J Natl Cancer Inst 95:1548. Schwartz, Robert S.; d'Andrea, Alan D. (May 2010). Susceptibility pathways in Fanconi's anemia and

breast cancer. N. Engl. J. Med. 362 (20): 1909–1919. Vandenberg CJ; Gergely F; Ong CY et al. (2003). BRCA1-independent ubiquitination of FANCD2. Mol. Cell

12 (1): 247–254. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (2000). BASC, a super complex of BRCA1- associated

proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14 (8): 927–39.