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Fanconi
Fanconi anemia is a rare genetic disorder characterized by bone marrow failure and cancer predisposition. It results from defects in DNA interstrand crosslink repair. The disease was first described in 1927 and shows considerable genetic and clinical heterogeneity. Patients have physical abnormalities and bone marrow failure. The main risks are aplastic anemia, leukemia, and solid tumors. Treatment involves blood transfusions, androgens, and hematopoietic stem cell transplant. Management aims to prevent complications and cancers through surveillance and timely intervention.
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Fanconi
- 1. Fanconi anaemia JG Nel Departmentof Haematology and Cell Biology UFS June 2010
- 2. History • Most frequentlyreported IBFS • First described in 1927 by a Swiss Paediatrician • Noted a family with three brothers who had: ▫ “perniziosiforme anaemia” ▫ Several physical abnormalities Microcephaly Skin hyperpigmentation
- 3. History • Decades ofresearch into FA led Fanconi to believe that a mutation of a single gene could not account for the clinical heterogeneity observed amongst FA patients
- 4. History • In 1960sobserved by several groups that cultured cells from patients with FA had an increased number of chromosomal breaks, the number of breaks were specifically increased with the addition of specific agents • Cell cycle gap in gap2/mitosis also occurred at lower concentrations of clastogens than in normal cells
- 5. In this presentation: Fanconianaemia: • Clinical features • Molecular and cell biology • Principles of management • Morbidity and mortality
- 6. Clinical features • Usuallyinherited as an autosomal recessive trait • Can be X-linked recessive • FA patients display progressive bone marrow failure and an increased predisposition to malignancy
- 7. Physical findings reportedin the literature • 60% of reported patients had at least one feature • Microsomia 40% of cases
- 8. Physical findings reportedin the literature Dermatological 40% • Café au lait • Generalized hyper- pigmentation • Hypo-pigmented areas
- 9. Physical findings reportedin the literature Upper limbs 35% • Thumbs: (35%) ▫ Absent /hypoplastic, bifid, duplicated, rudimentary , attached by a thread, triphalangeal, long, low set • Radii: (7%) ▫ Absent or hypoplastic, absent or weak pulse • Hands: (5%) ▫ Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly • Ulnae: (1%) ▫ Dysplastic, short
- 10. Physical findings reportedin the literature Skeletal • Head: (20%) ▫ Microcephaly, hydrocephaly • Face: (2%) ▫ Triangular, birdlike, dysmorphic, micrognathia, mid face hypoplasia • Neck: (1%) ▫ Spengel, Klippel-Feil, short, low hairline, web • Spine: (2%) ▫ Spina bifida, scoliosis, hemivertebrae, abnormal ribs, coccygeal hypoplasia
- 11. Physical findings reportedin the literature • Eyes: (20%) ▫ Small, strabismus, epicanthal folds, hypotelorism, hypertelorism, cataracts, astignatism • Renal: (20%) ▫ Horseshoe, ectopic or pelvic, abnormal, hypoplastic or dysplastic, absent, hydronephrosis, hydro ureter • Gonads: ▫ Males: (25%) Hypogenitalia, undescended testes, hypospadias, micropenis, absent testes ▫ Females: (1%) Hypogenitalia, bicornuate uterus, malposition, small ovaries
- 12. Physical findings reportedin the literature Gastro-intestinal: (5%) ▫ Atresia, imperforate anus, TOF, annular pancreas, malrotation Cardiopulmonary: (6%) ▫ Cong heart dis, PDA, ASD, VSD, coarctation, situs inversus, truncus arteriosus Central nervous system: (3%) ▫ Small pituitary stalk, pitituiary stalk int synd, absent corpus callosum, cerebral hypoplasia, hydrocephalus
- 13. Clinical features • Affectedindividuals may have one or more somatic abnormalities ▫ Dermatological ▫ Skeletal ▫ Genitourinary ▫ Gastro intestinal ▫ Cardiac ▫ Neurological • 1/3 of patients have no overt somatic abnormalities
- 14. Clinical features • Patientswith a high congenital abnormality score(CABS) are at greater risk for developing aplastic anaemia, whilst patients with lower CABS are at greater risk of developing solid tumours or leukaemia as young adults
- 15. Getting to theheart of the matter…
- 16. Fanconi anaemia: Molecularand cell biology • Wide range of clinical findings can be explained by the fact that FA is a chromosomal instability disorder ▫ Cells from FA patients accumulate damage at an increased rate ▫ Unrepaired DNA damage can: Activate pro-apoptotic pathways –leading to depletion of haematopoietic stem cells… Can lead to mutations and translocations that cause inactivation of cell cycle barriers leading to tumour genesis
- 17. Fanconi anaemia: Molecularand cell biology • Abnormal cell cycle kinetics ▫ Prolonged G2 phase ▫ Increased apoptosis ▫ Accelerated telomere shortening • Most striking cellular hallmark of FA ▫ Hypersensitivity to a class of DNA damaging agents that create DNA interstrand crosslinks(ICL)
- 18. Interstrand crosslinks • Covalentlinks that prevent DNA from unwinding ▫ Blocks transcription and translation • Difficult to repair, a single DNA repair pathway inadequate • Affects both strands of the helix • Main function of the FA pathway is to coordinate several distinct repair activities
- 19. Interstrand crosslinks • Inducedby: ▫ Mitomycin C ▫ DEB ▫ ?products of the endogenous metabolism of certain cells ?products of lipid metanolism in the liver
- 20. The classic FanconiAnaemia genes • Considerable genetic heterogeneity ▫ 13 subtypes/complementation groups identified ▫ Most inherited in an autosomal recessive fashion ▫ FANCB -X linked recessive FANCA FANCB FANCC FANCD1 FANCD2 FANCE FANCF FANCG FANCI FANCJ/BRIP1 FANCL FANCM FANCN/PALB2
- 21. The core complex •Majority of FA proteins form a complex with ubiquitin ligase activity • Majority of FA patients harbour mutations in the genes that encode the core complex
- 22. FANCM and FAAP24:targeting the core complex to DNA • Belong to the endonuclease family • Normally operate as heterodimers • Nuclease domains ▫ Required for dimerization ▫ DNA binding ▫ No nuclease activity • Recognize stalled replication forks • Recruit the core complex to ubiquinate it’s targets
- 23. Ubiquination • Ubiquitin ▫ Smalhighly conserved regulatory protein ▫ Ubiquitously expressed • Ubiquination ▫ Post –translational modification of a protein by the covalent attachment of one or more ubiquitin monomers • Functions: ▫ Labeling proteins for proteasomal degradation ▫ Also modulates Stability Function Intracellular localization
- 24. FANCD2 and FANCI:substrates for ubiquination • Dynamic complex that moves in and out of chromatin • Monoubiquination considered an essential step in FAP activation • Ubiquination of FANCD2-I complexes leads to localization on chromatin foci • DNA repair structures ▫ Interacts with DNA repair proteins BRCA2,BRCA1,RAD51
- 25. FANCD2 and FANCI:substrates for ubiquination ▫ BRCA2 important in DNA repair by homologous recombination Cells lacking BRCA2- inaccurately repair damaged DNA ▫ FANCJ (BRIP1)-”partner of BRCA1” ▫ FANCN(PALB2)-”partner of BRCA2”
- 26. The repair ofinterstrand crosslinks • DNA replication blocked at crosslink • DSB generated by endonucleases ▫ Uncouples one sister chromatid from the other ▫ Crosslinked base can then be unhooked
- 27. The repair ofinterstrand crosslinks ▫ Remaining structure bypassed by specialized polymerases that are able to replicate through DNA lesions ▫ Bypassed unhooked crosslink can be repaired by hydrolysis or nucleotide replacement allowing re-establishment of the replication fork Likely by HR machinery mediated invasion of the repaired chromatid by the sister
- 28. ICL repair pathwayscontrolled by FAP • Nucleotide excision repair (NER) • Homologous recombination (HR) • Translesion synthesis (TLR)
- 29. Nucleotide excision repair •NER endonucleases perform the initial incisions that unhook the crosslink • Cleavage achieved in a highly coordinated manner • Two structure-specific heterodimeric endonucleases ▫ Erccl-XPF ▫ Mus81-Eme1 • Erccl-XPF cleavage step required for efficient recruitment of FANCD2 to the site of ICL repair
- 30. Homologous recombination • Repairinitiated by resection of double strand break ▫ Leaving 3’ single stranded overhangs • Central action of HR is homology search and strand invasion by ssDNA-Rad51 filament • Strand invasion into a homologous sequence is followed DNA synthesis at the invading end
- 31. Homologous recombination • Afterstrand invasion and synthesis, the second DSB end can be captured to form an intermediate • After gap repair, DNA synthesis and ligation the structure is resolved
- 32. Translesion synthesis • DNAdamage tolerance process • Allows the DNA replication machinery to replicate past lesions • Involves switching out regular DNA polymerases for specialized translesion polymerases
- 33. Translesion synthesis • Translesionpolymerases ▫ Larger active sites –that can insert bases opposite damaged nucleotides ▫ Often have low fidelity (high propensity to insert wrong bases) relative to regular polymerases ▫ Many are extremely efficient at inserting the right bases oppsite specific types of damage
- 34. Translesion synthesis • Riskingthe introduction of point mutations during translesion synthesis may be preferable to more drastic mechanisms of DNA repair
- 35. Fanconi anaemia: TheFA/BRCA pathway • FA/BCRA pathway activated by ATR and RAD3 related protein ▫ ATR directly regulates FA pathway Monoubiquination of FANCD2 Phosphorilates FANCD2 at several sites
- 36. Management: HSCT • Onlycure for haematological complications is HSCT • Timing of HSCT remains a challenge ▫ Outcomes are best prior to the development of complications Infections fromCSN High transfusion burden Development of MDS/AML ▫ Many patients do not progress to severe marrow failure or acute leukaemia
- 37. Management: HSCT • Patientswith FA are VERY sensitive to genotoxic agents ▫ Cyclophosphamide ▫ Busulphan ▫ Ionizing radiation • Also sensitive to the damaging effects of graft vs host disease
- 38. Management: HSCT • Reduceddoses for transplant preparative regimens • Nongenotoxic regimens to prevent graft-versus-host disease • The use of reduced-intensity conditioning has resulted in greatly improved transplant outcomes • Fludarabine ▫ Highly immunosuppressive and myelosuppressive nucleotide analog ▫ Minimal damage to other organs ▫ Facilitated the reduction of genotoxic agents without increasing the risk of engraftment failure
- 39. Management: HSCT • Matchedsibling transplants: ▫ Disease free survival -64-89% ▫ Essential to test all potential sibling donors for FA If any abnormality is found sugg. Underlying marrow dysfunction testing should be conducted on skin fibroblasts to rule out somatic mosaicism • Unrelated donor transplants ▫ Discouraging results prior to the advent of Fludarabine (<30% overall survival)
- 40. Management: HSCT • HSCTdoes NOT correct the non-haematological manifestations of FA • Solid tumours: ▫ SCC ▫ risk continues to rise after transplant (4.4 higher age-specific hazard) ▫ Arise at an earlier age
- 41. Management: Androgens • Canimprove cytopenias in all three lineages • Good holding treatment. • Effect most profound for erythroid lineage • Subset of patients does not respond at all • Most patients may respond initially but then become refractory
- 42. Management: Androgens • Doseshould be tapered to the minimum that sustains the blood counts • May exacerbate liver tumours ▫ Regular monitoring of LFT ▫ Screening US
- 43. Management: General • Transfusionsupport • Timely institution of appropriate iron chelation • Treat bleeding ▫ Antifibrinolytics ▫ Platelets • Annual bone marrow aspirates and cytogenetic analysis • Annual surveillance for major solid tumours
- 44. Morbidity/Mortality • More than80% of patients reach an age of 18 years • Major causes of death in FA 1. Bone marrow failure 2. Leukaemia 3. Solid tumours • Median survival free of any malignancy or tumours 29 years
- 45. Morbidity/Mortality Bone marrow failure •Usually presents in childhood ▫ Petechiae, bruising, haemorrhages ▫ Pallor, fatigue ▫ infections • More than 90%develop pancytopenia
- 46. Morbidity/Mortality Leukaemia • 10% ofpatients • Most commonly AML • risk 600 X >general population Myelodysplastic syndromes • 6% of patients • Teens and young adults • May not have had a phase of aplastic anaemia • Risk 5000 X >general population
- 47. Morbidity/Mortality Solid tumours • 10%of patients • Most common: ▫ HNSCC 500X >general population ▫ Liver tumours ▫ Vaginal squamous cell carcinoma 3000X>general population ▫ Brain tumours
- 48. Take home message •Classical phenotypes originally described for IBFS are the severe end of a highly variable spectrum • Early recognition allows appropriate medical management and surveilance