Chromosomal breakage syndromes are a group of rare, inherited disorders characterized by defects in DNA repair that lead to increased cancer risk. The major types discussed were ataxia telangiectasia, Fanconi anemia, Bloom syndrome, and xeroderma pigmentosum. These syndromes are caused by mutations that disrupt critical DNA repair pathways, leading to genomic instability and improper DNA repair. Common features include cancer predisposition, developmental defects, and skin abnormalities like pigmentation changes. Diagnosis involves genetic testing, cytogenetic analysis of chromosome breaks and rearrangements, and assessing clinical manifestations.

1. CHROMOSOMAL
BREAKAGE SYNDROMES
PRESENTOR : DR. REETIKA MENIA
DNB RESIDENT
MODERATOR: DR.USHA AGRAWAL

5. INTRODUCTION
 These are a group of disorders that are
characterized by a defect in DNA repair
mechanism or genomic instability.
 Patients with these disorders show increased
predisposition to cancer.
 Transmitted in autosomal recessive mode of
inheritence .
 Rare syndromes.

6.  CBS are associated with increase risk of
 Leukemias,lymphomas,
 solid tumors (eg, breast cancer, skin cancer).
 immunodeficiencies,
 growth retardation,
 skeletal abnormalities,
 Hypogonadism and
 abnormal pigmentation.

7. PATHOGENESIS
 Loss of DNA repair.
 Inter strand cross links.
 Genomic instability.
 Increase exchange between sister chromatids.
 Change in nucleotide.
 Double strand DNA breaks.

8. Major types of syndromes
 Ataxia telangiectasia (Louis bar syndrome)
 Fanconi anemia.
 Bloom syndrome.
 Xeroderma pigmentosum.

9. ATAXIA
TELANGIECTASIA

10. ATAXIA TELANGIECTASIA
 This syndrome was first described in 1941
by French physician Denise Louis-Bar.
 It is caused because of chromosomal
instability.
 It is a neuron degenerative disease mainly
affecting cerebellum.
 Patients are particularly sensitive to
ionizing radiation and radiomimetic
compounds.

11. How is it caused?
 It is caused due to
genetic mutation in
ATM gene on
chromosome 11
 Ataxia Telangiectasia
Mutated gene
produces a mutated
ATM protein.

12. ATM gene
 This protein is found in the cell nucleus.
 Acting with other proteins, their role is to activate the
cells to repair damaged DNA.
Mutations in the ATM gene lead to total loss of the
ATM protein which normally recognizes DNA
damage.

14. CLINICAL FEATURES
 AGE: ataxia:1-4 years
At the age of 10 children are usually confined to a
wheelchair
 Telangiectasias:2-8 Years
 Frequency:1 case per 40,000-100,000 live births
 Sex: Males and females affected equally

15. Clinical features

17. Cerebellar degeneration in ataxia

19. DIAGNOSIS
Immunoblotting for the protein for ATM is the preferred test for
diagnosis of ataxia telangiectasia.
Chorionic villi sample: Detect prenatal ataxia telangiectasia
Molecular genetic testing (DNA analysis) is performed to
identify the ATM mutation, if the mutation is detected, the
diagnosis of ataxia telangiectasia is confirmed.
Serum alpha-fetoprotein levels are elevated above 10 ng/mL in
more than 95% of patients with ataxia telangiectasia.

20. Serum immunoglobulin levels of IgA, IgG 2 or total IgG and
IgE are decreased markedly or even absent.
Brain MRI can detect cerebellar atrophy;
Brain single-photon emission computed tomography
(SPECT): indicates cerebellar regional cerebral blood flow
hypoperfusion
Cytogenetic analysis for chromosome breakage in dividing cells
exposed to irradiation.
Karyotyping is performed on peripheral blood.
Persons with ataxia telangiectasia frequently have
abnormalities involving chromosome 14, particularly a 7;14
chromosome translocation

21. MEDICAL CARE
 Antioxidants
 Immunisation
 Systemic steroids
 Intravenous immunoglobulin (IVIG) replacement
therapy.
 Early and continuous physical therapy
 Supportive therapy may lessen drooling,
choreoathetosis, and ataxia.

22. FANCONI ANEMIA

23. Fanconi anemia
 Fanconi anemia is one of the inherited anemias that
causes bone marrow failure.
 It is autosomal recessive disorder.
 There are twelve complementation groups that have
been identified (A B C D1 D2 E F G I L and M) --
FA-A is the most common--

24. FA gene
 It is located on chromosome 16.
 It is a protein coding gene.

25. Functions of FA genes
 DNA repair
 Cell cycle control
 Oxygen sensitivity
 Apoptosis and telomere maintenance
 Haemopoiesis

26. FA pathway
 Proteins produced from these genes are involved in
a cell process known as the FA pathway.
 The FA pathway is activated during the process of
DNA replication
 The replication is blocked due to DNA damage.
 The FA pathway sends certain proteins to the area
of damage, which trigger DNA repair.

27. Continued...
 The FA pathway is particularly responsive to a
certain type of DNA damage known as interstrand
cross-links (ICLs).
 FA proteins produce FA core complex .
 The FA core complex activates two proteins, called
FANCD2 and FANCI
 these two proteins brings DNA repair proteins to
the area of the ICL.

28. FA PATHWAY

29. Mutations in FA gene
Mutations in FA gene
Disrupt FA pathway.
DNA damage is not repaired.
Abnormal cell death or uncontrolled cell growth
CANCER

30. Clinical Manifestations
 AGE: 5-10 years
 Frequency:1 case per1,00,000 live births
 Sex: Males and females affected equally

31. Clinical Manifestations
 Fanconi Anemia is characterized by physical
abnormalities
 Abnormalities of the thumbs, forearms, skeletal
system, eyes, kidneys and urinary tract, ear, heart,
gastrointestinal system, oral cavity and central
nervous system.
 Skin discolorations (hypo pigmented spots and
hyperpgimented spots)

32.  Pancytopenia, bone marrow hypoplasia
 developmental delay,
 increased susceptibility to leukemia and other
malignancies,
 Human papilloma virus (HPV) induced squamous
cell Carcinoma
 Solid tumors - medulloblastoma, Wilm’stumor,
and breast cancer

37. Diagnosis of FA

38. TREATMENT
Bone marrow transplantation of
hematopoietic stem cells (HSC) can be
curative for hematologic symptoms.
Chemotherapy and radiation
Gene therapy

39. BLOOM SYNDROME

40. Bloom syndrome
 It is an autosomal recessive disorder.
 causes sun-sensitive skin changes, an increased risk of
cancer, and other health problems.
 It caused by mutation in BLM gene.
 Life span- 24 yrs.

41. BLM gene
 The BLM gene is located on the long (q) arm of
chromosome 15 at position 2
 It is known as the "caretaker of the genome.“
 It maintains the structure and integrity of DNA.

42. Function of BLM gene
The BLM gene provides instructions for making a
member of a protein family called helicases.
Helicases are enzymes that bind to DNA and
temporarily unwind the two spiral strands (double
helix) of the DNA molecule.

43. Mutations in BLM gene
Mutated BLM gene
Mutated BLM protein
Frequency of sister chromatids exchange increased
Causes chromosome instability with gaps and breaks in
Genetic material
Uncontrolled cell growth
CANCER

44.  Failure to thrive in infancy
 Hyperpigmentation of skin
 Facial telangectasias
 Increased risk of malignancies
 Immunodeficiency
 Growth retardation
Clinical features

45. DIAGNOSIS
 CYTOGENETIC ANALYSIS:Quadriradial
configuration .The 4-armed figure consists of 2
homologous chromosomes caused by chromosome
breaks and rearrangements.
 Another cytogenetic abnormality observed in
Bloom syndrome is a sharply increased SCE level
 IMMUNOGLOBULINS:Decreased

46. Quadriradial arrangement

47. Increase sister chromatid exchange

48. XERODERMA
PIGMENTOSUM

49. XERODERMA PIGMENTOSUM
 It is caused by an abnormality in an individual’s
genome.
 Mutations in the XP genes (except XP-variant) lead
to defective NER and hypersensitivity to UV
 It can also be caused by environmental factors.
 Eight genes are involved in XP: XPA through XPG
and XPV (XP-Variant)
 Autosomal recessive disorder.

50. Cause

51.  severe photosensitivity
 abnormal pigmentation,
 mental retardation,
 develop skin cancer at very young age

53. DIAGNOSIS
Radiosensitivity assay
Molecular genetic testing (DNA analysis)
Cytogenetic analysis
Karyotyping
Prenatal diagnosis :can be made by demonstrating reduced UV-
induced DNA repair synthesis in cultured chorionic villus cells.

54. Thank You