SHORT REVIEW ON FANCONI ANEMIA

1. DR Nahar Kamrun
Pediatric hematologist & oncologist

2. • Inherited Bone Marrow Failure Syndrome
• Genomic Instability
* → DNA fragility - Chromosomal Breakage Disorder
• Most frequent of IBMFS
• Mostly autosomal recessive disease [>99%] (rarely X-linked)
• Genetically and phenotypically heterogeneous disease
• All racial & ethnic group are affected.
• Rare - Number of patients ~ 5,000

3. Fanconi Anemia
G. Fanconi. Familiäre, infantile
perniciosähnliche Anämie
(perniziöses Blutbild und
Konstitution). Jahrbuch für
Kinderheilkunde und physische
Erziehung, Wien,1927, 117: 257-
280.

4. • The FA proteins constitute a Nuclear Protein Complex.
The FA pathway coordinates a complex mechanism that enlists DNA
repair pathways in response to genotoxic insults.
• FA cells are characterized by hypersensitivity to chromosomal breakage as
well as hypersensitivity to G2/M cell cycle arrest induced by DNA crosslinking
agents. In addition there is sensitivity to oxygen free radicals and to ionizing
radiation.

5. * Until now 16 FA complementation groups has
been defined. (Somatic cell hybridization studies)
* Additional genes, including FANCT, are being
identified.
* FANCA, C & G represent ~90% of FA. FANCC
and FANCG are the next most common,
representing 10% of cases.
The gene products of these genes have been shown to cooperate in a
common pathway. After FANCM and FA-associated protein FAAP24
detect the DNA damage, 8 of FA proteins (FANCA, B, C, E, F, G, L, &
M) assemble to form FA core complex that is required to mono-
ubiquinate and activate FANCD2 & FANCI. Ubiquinated FANCD2 &
FANCI form a dimer which stabilizes the stalled replication fork and
then in turn interacts in nuclear repair foci with downstream FA gene
products (FANCO, D1, N, J) in FA/BRCA DNA damage repair
pathway. Damage repair is then achieved by late FA proteins in
cooperation with proteins from other DNA repair pathways. Of note
FANCD1 has been identified as BRCA2. Despite the identification of
this pathway, the manner in which disruption in this cascade of events
results in a faulty DNA damage response and genomic instability
leading to hematopoietic failure, birth defects and cancer
predisposition is only incompletely understood.
PHILIP 6TH

6. Repair of Interstrand CrossLinks (ICL) – The FA pathway
Wang et al. Cell 2015
FANCONI ANEMIA

7. • Mostly presented with Clinical characteristics of
pancytopenia along with
1.Multiple constitutional abnormalities
2.Endocrinopathies
3.Bone marrow failure – Hematologic Cancer
susceptibility
4.Epithelial Cancer susceptibility / predisposition

8. Physical Abnormalities
Philip 6th
Fanconi Anemia
(Microcephaly)
hyperreflexia
(deafness)
No anomalies in 20-40%
(hypogenitalism)

9. Upper limb
anomalies
(especially
involving thumb,
radius, and long
bones)
Fig A -child
showing radial ray
abnormalities.
Height and head
circumference are
both below 3rd
centile.
Eye abnormalities
(microphthalmia,
strabismus, ptosis,
nystagmus)
Congenital
anomalies
include
increased
pigmentation of
the skin along
with cafe´-au-
lait and
hypopigmented
areas

10. Cancer Predisposition
Cancer type
Relative Risk
(fold increase)
MDS
Acute
leukemia
6000
500-700
All solid
tumors
38
HNSCC 600
Vulvar SCC 3000
Alter BP. Best Pract Res Clin Haematol 2014
Alter BP et al. BJH 2010
BMF
Fanconi Anemia

12. History & PE:
• Family history
*Review of Systems Pallor and easy bruising
*Physical Examination Flat thenar eminence – Abnl thumbs
Blood picture:
1.Pancytopenia is the usual finding.
CBC: WBC low, - Hgb low - Plts low
Hematologic dysfunction usually presents with macrocytosis (↑MCV), followed by thrombocytopenia,
often leading to progressive pancytopenia and Severe aplastic anemia.
2. BM aspiration:
*No blasts, no evidence of leukemia
*Hypocellularity and fatty replacement consistent with degree of decrease
in myeloid, erythroid and megakaryocytic elements
* Mild non specific dysmorphology like dysplastic erythroid (megaloblastoid changes, multinuclearity) and myeloid
(abnormal granulation) precursors and abnormal megakaryocytes.
*Cytogenetics: Normal

13. Aplastic Anemia or Isolated Severe Single Lineage Cytopenia
Positive testing
BM aspiration
PNH Flow Cytometry
DEB testing
Telomere testing
Negative testing
Treat accordingly ANC: SCN
Hgb: DBA
Plts: CAT
IBMFS gene panel
Whole exome sequencing
No constitutional
Abnormalities
Treat accordingly

15.  Functional testing: Screening tests:
A. Di-epoxy butane (DEB) or Mitomycin C testing
Breakage of chromosomes in T-lymphocytes
– demonstration of Presence & Quantitation (compared to normal control)
- method: It is a blood test; lymphocytes are isolated, stimulated - cultured
in presence of DNA crosslinking agents such as DEB or MMC.
Both agents are carcinogenic.
Both induce DNA cross-linking DNA breakage.
Chromosome fragility includes breaks, gaps, rearrangements, radials, exchanges, and endo-reduplication.
B. Genetic testing (Definitive tests)
- Targeted Mutation analysis by sequencing
- Complementation test
Diganosis of Fanconi Anemia

16. Prenatal diagnosis of FA:
- DEB test can be used in either chorionic villus or amniocentesis derived
samples
Detection of carrier state:
• In a FA family, if proband has been identified to have a defect in one of the
cloned genes, molecular testing is available for the extended family members.
• Population-based screening is only done in at-risk populations
PHILIP 6TH

17. • FA can also present as the VACTERL syndrome
• VACTERL association features
• V – vertebral anomalies
• A – anal atresia
• C – cardiac malformation
• T – tracheo-esophageal fistula
• E – esophageal atresia
• R – renal anomalies
• L - limb defects
Physical Abnormalities

18. GENETIC TESTING FOR IBMFS:
Next Generation Sequencing
Testing of established mutations
of the different IBMFS disorders
Different Labs have different panels
EX: 116 Gene panel ~ Cincinnati
Childrens’ Hospital

19. FOLLOW-UP and MANAGEMENT
FA patients should be followed in a comprehensive manner with
attention to all the elements of the disease, including:
 Hematology Blood counts, Bone marrow
 Genetics Family screening
 Endocrinology Thyroid – Glucose - Growth
 Head and neck cancer screening
 Gynecologic cancer screening
 Orthopedics limb abnormalities
 Other systems:
Cardiac – Renal – GI – Dermatology - Immune

20. PHILIP 6TH

21. *CBC: Degree of cytopenia guides
management as follows:--------------
* Bone marrow assessment:
Aim: to provide evidence of progression
and development or evolution of
cytogenetic abnormalities.
a. Bone marrow aspiration – for
cytology, cytogenetics with FISH
b. Bone marrow biopsy - should be
done for cellularity
Follow up schedule:
 Mild-moderate cytopenia + no
cytogenetic abnormalities:
- CBC every 3-4 monthly & BM
aspiration every yearly.
 Cytopenia+presence of cytogenetic
abnormalities+more significant
dysplasia without frank MDS:
- CBC every 1-2 monthly & BM
aspiration every 1-6 monthly

22. 1. Androgen therapy:
a. Oxymetholone (25 mg/kg/day); tapered to the lowest effective dose (effective in 50% cases).
b. Danazol (Dose ~5 mg/kg) - effective synthetic androgen with less virilizing effects.
2. Cytokines: G-CSF (dose 5 μg/kg/day), if moderate to severe neutropenia.
3. Transfusions: PRBC and platelets if androgen therapy fail .
4. HSCT: prefer HLA-matched related donor.
Before a family member is used as a donor, he/she should be evaluated to exclude a diagnosis of FA.
5. HPV vaccination.
6. Growth hormone therapy: 50% FA has deficient of GH featuring short stature. Up to.
7. Gene therapy: future rx.

23. * With HSCT with matched sibling donor show a long-term DFS of
80-90%.