Fanconi anemia is a rare genetic disorder that affects DNA repair and increases cancer risk. It is caused by mutations in one of several genes involved in the FA DNA repair pathway. Symptoms include bone marrow failure, physical abnormalities, and blood cancers. While there is no cure, treatment focuses on managing symptoms and complications through blood transfusions, antibiotics, bone marrow transplants, and cancer therapies.

1. BY :
RAMYA RAYAPATI
15MSG0020

2.  Fanconi anemia (FA) is a very rare genetic disease with an
incidence of 1 in 160,000 individuals worldwide.
 Fanconi anemia is a condition that affects many parts of the
body. People with this condition may have bone marrow failure,
physical abnormalities, organ defects, and an increased risk of
certain cancers.
 Fanconi anemia is the result of a genetic defect in a cluster of
proteins responsible for DNA repair.

3. What genes are related to Fanconi Anemia :
 Mutations in at least 15 genes can cause Fanconi anemia. Proteins
produced from these genes are involved in a cell process known as
the “FA pathway.”
 The FA pathway is turned on (activated) when the process of
making new copies of DNA, called DNA replication, is blocked
due to DNA damage.
 The FA pathway sends certain proteins to the area of damage,
which trigger DNA repair so DNA replication can continue.

4.  The FA pathway is particularly responsive to a certain type of DNA
damage known as interstrand cross-links (ICLs).
 ICLs occur when two DNA building blocks (nucleotides) on
opposite strands of DNA are abnormally attached or linked
together, which stops the process of DNA replication.
 ICLs can be caused by a buildup of toxic substances produced in
the body or by treatment with certain cancer therapy drugs.
 Eight proteins associated with Fanconi anemia group together to
form a complex known as the FA core complex.

5.  The FA core complex activates two proteins, called FANCD2 and
FANCI. The activation of these two proteins brings DNA repair
proteins to the area of the ICL so the cross-link can be removed
and DNA replication can continue.
 Eighty to 90 percent of cases of Fanconi anemia are due to
mutations in one of three genes, FANCA,FANCC, and FANCG.
 Mutations in any of the many genes associated with the FA core
complex will cause the complex to be nonfunctional and disrupt
the entire FA pathway.

6.  As a result, DNA damage is not repaired efficiently and ICLs
build up over time.
 The ICLs stall DNA replication, ultimately resulting in either
abnormal cell death due to an inability make new DNA molecules
or uncontrolled cell growth due to a lack of DNA repair
processes.
 Cells that divide quickly, such as bone marrow cells and cells of
the developing fetus, are particularly affected.
 The death of these cells results in the decrease in blood cells and
the physical abnormalities characteristic of Fanconi anemia.

7.  When the buildup of errors in DNA leads to uncontrolled cell
growth, affected individuals can develop acute myeloid leukemia
or other cancers.

8. How do people inherit Fanconi anemia?
 Fanconi anemia is most often inherited in an autosomal recessive
pattern, which means both copies of the gene in each cell have
mutations.
 The parents of an individual with an autosomal recessive
condition each carry one copy of the mutated gene, but they
typically do not show signs and symptoms of the condition.
 Very rarely, this condition is inherited in an X-linked recessive
pattern. The gene associated with X-linked recessive Fanconi
anemia is located on the X chromosome

9. Other Functions of FA genes :
 DNA Repair
 Cell Cycle control
 Oxygen sensitivity
 Apoptosis and Telomere maintenance
 Haemopoiesis

10. SIGNS AND SYMPTOMS :
 Low Birth Weight

11.  Short Stature
This is a thirty year old boy
suffering from Fanconi
Anemia.

12.  Café-au-lait spots

13.  Absence of or malformity in hands and arms, for example
the absence of a thumb or the presence of polydactyly .

14.  Presence of only one kidney or of a horseshoe kidney

15. PATHOGENESIS
 Clinically, hematological abnormalities are the most serious
symptoms in FA. By the age of 40, 98% of FA patients will have
developed some type of hematological abnormality.
 However, there are a few cases in which older patients have died
without ever developing them. Symptoms appear progressively,
and often lead to complete bone marrow failure and many other
diseases.

16. Bone marrow failure :
 Major haematological complication associated with FA is bone
marrow failure, defined as inadequate blood cell production.
 Detection of decreasing blood count is generally the first sign
used to assess necessity of treatment and possible transplant.
 Patients are initially responsive to androgen therapy and
haemopoietic growth factors, these have been shown to promote
leukemia, and have severe side effects, including hepatic
adenomas and adenocarcinomas

17. Acute myeloid leukemia :
 FA patients are at elevated risk for the development of acute
myeloid leukemia (AML), defined as presence of 20% or more of
myeloid blasts in the marrow or 5 to 20% myeloid blasts in the
blood.
 Myelomonocytic and acute monocytic are the most common
subtypes observed. Many MDS patients will evolve into AML.
 Furthermore, the risk of developing AML increases with the onset
of bone marrow failure.
 Although risk of developing either MDS or AML before the age
of 20 is only 27%, this risk increases to 43% by the age of 30 and
52% by the age of 40.

18. Myelodysplastic syndromes
 MDS, formerly known as preleukemia, are a group of bone
marrow neoplastic diseases that share many of the morphologic
features of AML.
 Changesin erythroid, granulocytic and megakaryocytic precursor
s, than what is usually seen in cases of AML. These changes
results in delayed apoptosis or a failure of programmed cell
death. When left untreated, MDS can lead to AML in about 30%
of cases.

19. SCREENING
 DEB test (diepoxybutane analysis.)
 MMC test
 Prenatal screening
 Carriers of Fanconi Anemia
 Blood test
 Rapid means of screening population at large
 Immunoblotting and immunofluorescence
 Subtyping
 Retroviral vectors

20. DIAGNOSIS
 DEB and MMC tests
 Diagnosis typically occurs before the age of twelve (Fanconi
Anemia Research Fund, Inc., 2006).
 MMC test is used to diagnose Fanconi Anemia at the
University of Kentucky.
 Subtyping via use of retroviruses needs to be incorporated
into standard protocol when diagnosing a patient with Fanconi
Anemia.

21. TREATMENT
 Retrovirus mediated gene
tranfer
 Lentivirus mediated gene
transfer

22. RISKS OF GENE THERAPY
 Retrovirus potential to stimulate oncogenes.
 Lentivirus association with arthritis and encephalitis in
goats, leukemia in cattle, anemia in horses, and
immunodeficiency in cats, cattle, primates, and humans.

23. GENETIC COUNSELING
Provide knowledge about:
What Fanconi Anemia is
What symptoms are associated
Who can be affected
What the disorder means for
the future of the individual
What treatments are available
and their risks and benefits
Importance of screening other
family members at risk

24. SUMMARY
 Fanconi Anemia is an autosomal recessive disorder that
predisposes individuals to a variety of cancers.
 Screening techniques exist, such as the DEB and MMC
tests, that should be used to screen the population at
large.
 Subtyping of which FA gene(s) is (are) mutated should
become standard protocol with diagnosis.
 Gene therapy may someday eliminate Fanconi Anemia.