Inherited DNA repair disorder causing variable congenital anomalies, progressive bone marrow failure, and increased cancer risk.

Fanconi Anemia (FA)

Fanconi anemia (FA) is an inherited bone marrow failure syndrome (IBMFS) characterised by:

Progressive bone marrow failure (pancytopenia/aplastic anemia)
Congenital physical anomalies (skeletal, renal, cardiac, skin pigmentation, etc.)
Markedly increased predisposition to malignancy — particularly myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), as well as solid tumours (head & neck squamous cell carcinoma, gynaecological cancers) ^[1]^[2]

The name "Fanconi" comes from the Swiss paediatrician Guido Fanconi who first described the condition in 1927. Do not confuse Fanconi anemia with Fanconi syndrome — the latter is a proximal renal tubular disorder with impaired reabsorption of glucose, amino acids, phosphate, and bicarbonate ^[3]. They are completely unrelated conditions that happen to share a name.

Fanconi Anemia ≠ Fanconi Syndrome

A very common exam pitfall. Fanconi anemia = inherited bone marrow failure syndrome with DNA repair defect. Fanconi syndrome = proximal renal tubular dysfunction causing glycosuria, aminoaciduria, phosphaturia, bicarbonaturia. Different diseases, same eponym.

At its molecular core, FA is a DNA repair disorder — specifically a defect in the Fanconi anemia/BRCA DNA damage repair pathway responsible for repair of interstrand crosslinks (ICLs). When this pathway is broken, cells accumulate unrepaired DNA damage, leading to:

Apoptosis of haematopoietic stem cells (HSCs) → bone marrow failure
Genomic instability → cancer predisposition
Aberrant developmental signalling → congenital malformations

Fanconi anemia is an inherited bone marrow failure syndrome — this framing is explicitly used in lecture slides and is the highest-yield definition for exams ^[1]^[4].

Parameter	Detail
Incidence	~1 in 100,000–160,000 live births worldwide
Carrier frequency	~1 in 200–300 in most populations; higher in certain ethnic groups
High-prevalence populations	Ashkenazi Jews (~1:89 carrier rate for FANCC c.711+4A>T), Spanish Roma, Afrikaners (FANCA founder mutation), Sub-Saharan African populations
Sex ratio	Slight male predominance (~1.2:1 M:F)
Median age at diagnosis	~6–7 years (range: birth to adulthood)
Median age of BM failure onset	~7 years; cumulative incidence of BM failure ~90% by age 40
HK / East Asian context	Relatively uncommon compared to thalassaemia and G6PD deficiency which dominate inherited anemias in Hong Kong; however, FA must always be considered in any child presenting with aplastic anemia, especially if dysmorphic features are present ^[1]^[5]

Aplastic anemia in Asia has an incidence of 4–6 per million per year; FA accounts for a minority but is the most common inherited cause of aplastic anemia in children ^[1]^[6]
50% of aplastic anemia occurs in patients < 30 years — in this age group, inherited causes like FA must be actively excluded ^[6]

High Yield

In any young patient (especially paediatric) presenting with aplastic anemia, always consider inherited bone marrow failure syndromes — Fanconi anemia is the most common one. The lecture slides explicitly list Fanconi anemia under inherited BM failure syndromes causing pancytopenia/aplastic anemia ^[1]^[4].

Since FA is a genetic disorder, the "risk factors" are essentially genetic:

Family history of FA or consanguinity — autosomal recessive (AR) inheritance is the most common pattern; rarely X-linked recessive (XR) ^[2]^[5]
- AR means both parents must be carriers → consanguineous marriages dramatically increase risk
- One complementation group (FANCB) is X-linked recessive
Ethnicity — founder mutations in Ashkenazi Jews (FANCC), Spanish Roma (FANCA), Afrikaners (FANCA)
No environmental or lifestyle risk factors — this is entirely genetic

When asking about risk factors for the complications of FA (i.e., malignancy):

Androgen therapy → potential hepatic adenoma / hepatocellular carcinoma
HPV infection is preventable by vaccination, but many FA-associated SCCs are HPV-independent
Haematopoietic stem cell transplant (HSCT) conditioning regimens → increased risk of secondary solid tumours

4. Anatomy and Function: The FA/BRCA DNA Repair Pathway

To truly understand FA, you need to understand the molecular machinery that is broken.

DNA interstrand crosslinks are covalent bonds that link the two complementary strands of the DNA double helix together. They are among the most toxic forms of DNA damage because they:

Block DNA replication — the replication fork cannot unwind past a crosslink
Block transcription — RNA polymerase stalls
If unrepaired → cell death (apoptosis) or mutagenesis

ICLs are produced by:

Endogenous aldehydes (formaldehyde, acetaldehyde — by-products of normal metabolism)
Exogenous agents: mitomycin C (MMC), diepoxybutane (DEB), cisplatin, nitrogen mustards

The FA pathway is a multi-step DNA repair cascade involving more than 20 FA-associated gene products. Think of it as a relay:

Step 1: DETECTION
   Stalled replication fork at ICL detected
   ↓
Step 2: FA CORE COMPLEX ASSEMBLY (8 proteins)
   FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM
   → Acts as an E3 ubiquitin ligase
   ↓
Step 3: MONOUBIQUITINATION of FANCD2-FANCI complex (the "ID2 complex")
   FANCL (the catalytic E3 ligase) adds ubiquitin to FANCD2 and FANCI
   → This is the KEY ACTIVATION STEP of the pathway
   → Monoubiquitinated ID2 complex localises to chromatin at the site of damage
   ↓
Step 4: DOWNSTREAM REPAIR
   Nucleases (FANCP/SLX4, FANCQ/ERCC4/XPF) incise the crosslinked strand
   Translesion synthesis polymerases bypass the lesion
   Homologous recombination (HR) repairs the double-strand break
   → FANCD1/BRCA2, FANCN/PALB2, FANCJ/BRIP1, FANCO/RAD51C, FANCR/RAD51, FANCS/BRCA1

Key insight: The downstream FA genes overlap with well-known breast/ovarian cancer susceptibility genes (BRCA1, BRCA2, PALB2, RAD51C). This is why:

FA heterozygous carriers of FANCD1/BRCA2 or FANCS/BRCA1 have increased breast/ovarian cancer risk
FA is mechanistically linked to the BRCA pathway

When disease-causing variants impair the FA pathway (usually biallelic, with FANCB and RAD51 exceptions):

ICLs cannot be repaired → accumulation of DNA damage
Haematopoietic stem cells are exquisitely sensitive to endogenous aldehydes → progressive HSC attrition → bone marrow failure
Genomic instability → chromosomal breakages, translocations → clonal evolution to MDS/AML
During embryonic development → impaired proliferation of progenitor cells in multiple organ systems → congenital malformations
Squamous epithelial cells are particularly vulnerable → head/neck and gynaecological SCC

The reason FA cells are sensitive to DEB and mitomycin C is precisely because these agents create interstrand crosslinks — and FA cells cannot repair them. This forms the basis of the diepoxybutane (DEB) chromosome breakage test used for diagnosis ^[2]^[5].

5. Etiology and Pathophysiology

Feature	Detail
Number of complementation groups	More than 20 recognised FA-associated genes
Most common gene mutated	FANCA (~60–65% of cases)
Other common genes	FANCC (frequency varies by population)
Other common genes	FANCG (~10%)
Inheritance	Autosomal recessive (vast majority); FANCB is X-linked recessive; FANCR/RAD51 is autosomal dominant (de novo) ^[2]^[5]
Genotype–phenotype correlation	Exists but imperfect; FANCD1/BRCA2 biallelic mutations → very early onset cancers (medulloblastoma, Wilms tumour, AML) in childhood; severity varies even within the same genotype

5.2 Pathophysiology — From Gene to Disease

Defective ICL repair → accumulation of unrepaired DNA damage in HSCs
HSCs are long-lived, continuously dividing cells exposed to endogenous aldehydes (acetaldehyde from ethanol and endogenous metabolism, normally detoxified by ALDH2; formaldehyde from histone demethylation)
Unrepaired damage activates p53/p21 checkpoint → cell cycle arrest → apoptosis
Progressive loss of the HSC pool → quantitative reduction in all haematopoietic lineages
Initially may present as isolated cytopenia (often thrombocytopenia first, then neutropenia, then anemia) before progressing to full pancytopenia/aplastic anemia
BM biopsy shows profoundly hypocellular marrow with decrease in all elements and replacement by fat/stromal cells ^[6]

FA pathway components interact with developmental signalling pathways (Sonic Hedgehog, Wnt, p53)
Impaired proliferation during organogenesis → structural defects
Particularly affects: radial ray (thumbs, radii), kidneys, skin pigmentation, gonads, heart, CNS, GI tract, ears

Genomic instability → increased rate of chromosomal breaks, radial figures, translocations
Clonal evolution in the BM: gain of 1q, loss of 7/7q, gain of 3q → progression to MDS/AML
Squamous epithelial instability → head/neck SCC, vulvar/cervical/anal SCC
Fanconi anemia carries increased risk of malignancy — specifically MDS and AML ^[2]^[5]
Cumulative incidence of MDS/AML: ~30–40% by age 40
Cumulative incidence of solid tumours: ~25–30% by age 40

FA affects endocrine organs through both direct developmental effects and secondary consequences of chronic illness/treatment:
- Short stature (GH deficiency, hypothyroidism, or direct skeletal effect)
- Hypogonadism → infertility (especially males; impaired spermatogenesis)
- Hypothyroidism
- Glucose intolerance / diabetes mellitus
- Metabolic syndrome

Recent research has shown that ALDH2 (aldehyde dehydrogenase 2) provides a critical backup to protect HSCs from endogenous aldehydes. The ALDH2*2 variant (common in East Asians — ~30–40% prevalence in Chinese, Japanese, Korean populations) causes a near-complete loss of ALDH2 enzyme activity.

In animal models, combined loss of FA genes + ALDH2 → catastrophic bone marrow failure
This has clinical relevance for Hong Kong: patients with FA who also carry ALDH2*2 (very common locally) may have an accelerated, more severe phenotype
This also explains why alcohol (which produces acetaldehyde) is particularly toxic to FA patients

HK Relevance

The ALDH22 polymorphism is extremely common in Hong Kong Chinese (~30–40%). While FA itself is rare in HK, any FA patient who is also ALDH22 heterozygous/homozygous may present with more severe bone marrow failure at an earlier age due to impaired acetaldehyde detoxification.

6. Classification

FA is classified by the specific gene mutated. More than 20 FA-associated genes are recognised. Clinically, the most important distinction is:

Group	Functional Level	Key Genes	Clinical Significance
Upstream / FA Core Complex	Ubiquitin ligase that monoubiquitinates FANCD2/FANCI	FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM	Most common; "classic" FA phenotype
ID2 Complex	Central activation	FANCD2, FANCI
Downstream / Effector	Homologous recombination & nucleolytic repair	FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/XPF, FANCR/RAD51, FANCS/BRCA1	Overlap with BRCA pathway; biallelic BRCA2 → very early childhood cancers

No formal staging system, but clinically patients are grouped by:

Presence/absence of congenital anomalies (~70% have at least one; ~30% have NO physical anomalies — "cryptic FA")
Haematological status — normal counts vs. isolated cytopenia vs. full aplastic anemia (mild/moderate/severe/very severe)
Malignant transformation — absence vs. MDS vs. AML vs. solid tumour

Important

Up to 25–30% of FA patients have NO congenital anomalies at presentation — so-called "cryptic FA." This means you CANNOT rule out FA just because the child looks physically normal. Chromosome breakage testing with diepoxybutane (DEB) should be performed in all children/young adults with aplastic anemia ^[2]^[6].

From the lecture slides and senior notes, FA sits within the classification as follows ^[1]^[4]^[6]:

Aplastic Anemia
├── Primary
│   ├── Idiopathic (70-80%) — likely autoimmune
│   └── Inherited BM Failure Syndromes
│       ├── Fanconi anemia ← MOST COMMON inherited cause
│       ├── Dyskeratosis congenita
│       └── Shwachman-Diamond syndrome
└── Secondary (Acquired)
    ├── Drugs (chloramphenicol, sulphonamides, cytotoxics...)
    ├── Toxins (benzene, toluene)
    ├── Viral infections (hepatitis, HIV, EBV)
    ├── Ionizing radiation
    └── Acquired clonal (PNH association)

7. Clinical Features

7.1 Symptoms

The clinical presentation of FA is a triad: congenital anomalies + progressive bone marrow failure + cancer predisposition. However, the timing of each component varies widely.

Bone marrow failure typically manifests between ages 5–10 years (but can present from birth to adulthood).

Cytopenia	Symptoms	Pathophysiological Basis
Anemia (↓RBC)	Pallor, fatigue, exercise intolerance, dyspnoea on exertion, palpitations, dizziness	Reduced oxygen-carrying capacity due to loss of erythroid precursors in the failing marrow → tissue hypoxia → compensatory tachycardia and vasodilation
Thrombocytopenia (↓Plt)	Mucocutaneous bleeding — easy bruising, petechiae, epistaxis, gingival bleeding, menorrhagia (in post-pubertal females), prolonged bleeding after minor trauma	Loss of megakaryocyte precursors → insufficient platelet production → impaired primary haemostasis. Thrombocytopenia is often the first haematological abnormality in FA
Neutropenia (↓ANC)	Recurrent infections — oral ulcers, skin infections, pneumonia, sepsis	Loss of myeloid precursors → insufficient neutrophil production → impaired innate immunity. Infections are typically bacterial (sepsis, pneumonia, UTI) but invasive fungal infection is an important cause of death ^[6]

Pancytopenia: recurrent infections, mucocutaneous bleeding, anaemic symptoms ^[6]

Typically insidious onset — parents may notice increasing pallor, easy bruising, or frequent infections over months to years
Thrombocytopenia often heralds the onset of marrow failure (because megakaryocytes are the most sensitive lineage in FA)
Macrocytosis (elevated MCV) may precede overt cytopenia by years — this is a red flag for FA

Present from birth; may be the reason FA is first suspected.

Short stature — present in ~60% of patients; due to a combination of:
- Skeletal growth plate abnormalities
- Growth hormone deficiency/resistance
- Hypothyroidism
- Chronic illness
Feeding difficulties in infancy — related to GI anomalies (tracheo-oesophageal fistula, duodenal atresia)
Hearing loss — conductive (middle ear anomalies) or sensorineural
Learning difficulties — variable; related to microcephaly or CNS developmental anomalies

Delayed puberty → hypogonadism (especially males)
Infertility (male > female; due to impaired spermatogenesis from gonadal failure)
Symptoms of hypothyroidism — fatigue, cold intolerance, weight gain, constipation

MDS/AML: worsening cytopenias, new-onset fevers, bone pain, weight loss
Head/neck SCC: oral lesions, dysphagia, hoarseness, neck mass (onset typically in 20s–40s)
Gynaecological SCC: abnormal vaginal bleeding, vulvar lesions (onset in 20s–30s)

7.2 Signs

Sign	Pathophysiological Basis
Pallor (conjunctival, palmar, mucosal)	Anemia → reduced Hb → decreased erythrocyte pigmentation in superficial vascular beds
Petechiae, purpura, ecchymoses	Thrombocytopenia → insufficient platelet plug formation → spontaneous extravasation of blood from capillaries
Oral ulceration, skin infection	Neutropenia → failure to mount adequate inflammatory response → breaches in mucosal/skin barriers become infected
NO lymphadenopathy, NO hepatosplenomegaly	This is a key negative sign. In aplastic anemia (including FA), haematopoietic progenitors are simply absent — there is no proliferative mass. Lymphadenopathy/hepatosplenomegaly would suggest haematological malignancy (e.g., leukaemia infiltration) rather than pure marrow failure ^[6]

NO lymphadenopathy, hepatosplenomegaly (as HSCs are destroyed) → suggestive of haematological malignancies if present ^[6]

The physical anomalies of FA are highly variable — the VACTERL-H association mnemonic is useful because FA overlaps significantly:

System	Anomaly	Frequency	Notes
Skeletal (radial ray)	Thumb abnormalities — absent, hypoplastic, supernumerary, triphalangeal, bifid; absent/hypoplastic radii	~50%	Most classic and recognisable finding. "Radial ray" = the radius bone + thumb (both develop from the same embryological structure). Thumb abnormality in Fanconi anemia ^[6]
Skin	Café-au-lait spots, generalised hyperpigmentation, hypopigmentation	~40%	Due to melanocyte developmental anomalies; café-au-lait spots overlap with NF1 differential
Growth	Short stature	~60%	Multifactorial — skeletal, endocrine, chronic disease
Eyes	Microphthalmia, strabismus, epicanthal folds, ptosis	~25%	Ocular developmental anomalies
Kidneys	Ectopic/horseshoe kidney, renal agenesis, duplicated collecting system	~35%	Renal developmental anomaly; usually asymptomatic but important to image
Ears	Small/absent/malformed ears, hearing loss	~10%
Head	Microcephaly	~25%	Reduced neuronal progenitor proliferation during brain development
Heart	VSD, ASD, PDA, coarctation of aorta	~15%	Cardiac developmental anomalies
GI	Tracheo-oesophageal fistula, oesophageal/duodenal atresia, imperforate anus	~10%	VACTERL overlap
Genitalia	Males: micropenis, cryptorchidism, hypospadias. Females: bicornuate uterus	~25%	Gonadal/genital developmental anomalies
CNS	Hydrocephalus, neural tube defects	Rare

Mnemonic: VACTERL-H and FA

A subset of FA patients have VACTERL-H features:

Vertebral anomalies
Anal atresia
Cardiac defects
Tracheo-Esophageal fistula
Renal anomalies
Limb (radial ray) anomalies
Hydrocephalus

If a child has ≥3 VACTERL features, consider FA and perform chromosome breakage testing!

Sign	Basis
Short stature (< 3rd centile)	GH deficiency + hypothyroidism + skeletal anomaly
Delayed secondary sexual characteristics	Hypogonadism (hypergonadotropic in males; variable in females)
Small testes / cryptorchidism	Primary gonadal failure due to impaired germ cell survival

New hepatosplenomegaly in a previously stable FA patient → ? MDS/AML transformation
Oral leukoplakia, erythroplakia → ? head/neck SCC
Skin lesions → ? SCC

Why are thumbs and radii affected? — The radial ray develops from the limb bud mesenchyme under the influence of developmental signalling pathways (Shh, Wnt, FGF). FA pathway proteins interact with these pathways, so their absence disrupts radial ray patterning specifically.
Why is thrombocytopenia often the first sign? — Megakaryopoiesis appears to be particularly sensitive to DNA damage-induced apoptosis. Additionally, megakaryocytes undergo endomitosis (DNA replication without cell division), which may amplify the impact of unrepaired ICLs.
Why macrocytosis before overt marrow failure? — As the HSC pool shrinks, the remaining cells undergo "stress erythropoiesis" with accelerated cell cycling and skipped divisions, producing larger-than-normal RBCs. Elevated fetal haemoglobin (HbF) also accompanies this stress erythropoiesis.
Why are FA patients at such high risk of SCC specifically? — Squamous epithelial cells have high turnover and are exposed to exogenous mutagens (HPV, alcohol, tobacco). Without functioning ICL repair, these cells rapidly accumulate mutations. The role of HPV varies by tumour site; many FA-associated head and neck cancers are HPV-negative.
Why is the bone marrow failure progressive rather than present from birth? — At birth, the HSC pool is sufficient (established during foetal haematopoiesis). However, ongoing exposure to endogenous aldehydes + lack of repair → progressive attrition of the HSC pool over years → eventual exhaustion.

Feature	Pathophysiological Basis
Progressive pancytopenia	Endogenous DNA damage → HSC apoptosis → marrow exhaustion
Macrocytosis / ↑HbF	Stress erythropoiesis from diminished HSC reserve
Congenital anomalies (radial ray, kidneys, heart, skin)	FA pathway interaction with developmental signalling → impaired organogenesis
Café-au-lait spots / hyper-/hypopigmentation	Melanocyte development/migration anomaly
Short stature	Skeletal + endocrine (GH deficiency, hypothyroidism) + chronic disease
Hypogonadism / infertility	DNA damage → germ cell loss; primary gonadal failure
MDS/AML	Genomic instability → clonal haematopoiesis → malignant transformation
Head/neck & gynaecological SCC	Squamous epithelial genomic instability + defective DNA repair
No hepatosplenomegaly (in pure BM failure)	HSCs are destroyed, not proliferating; no infiltrative mass

High Yield Summary

Fanconi Anemia — Key Points for Exams:

Definition: Inherited BM failure syndrome (most commonly AR) due to defect in the FA/BRCA interstrand crosslink DNA repair pathway
Triad: Congenital anomalies + progressive bone marrow failure + cancer predisposition (MDS/AML, head/neck SCC)
Most common gene: FANCA (~60–65%)
Classic congenital anomaly: Thumb abnormality / radial ray defect — but 25–30% have NO anomalies ("cryptic FA")
Haematological progression: Macrocytosis → thrombocytopenia (usually first cytopenia) → pancytopenia → aplastic anemia
Key diagnostic test: Chromosome breakage analysis with diepoxybutane (DEB) — FA cells show dramatically increased chromosomal breaks
Cancer risk: ~30–40% cumulative risk of MDS/AML by age 40; ~25–30% cumulative risk of solid tumours
Key negative sign: NO hepatosplenomegaly, NO lymphadenopathy in pure marrow failure — their presence suggests malignant transformation
Aplastic anemia classification: FA is the most common inherited cause; always exclude in children/young adults with aplastic anemia, even without dysmorphic features
HK relevance: ALDH2*2 polymorphism (common in East Asians) may accelerate disease by impairing acetaldehyde detoxification

Active Recall - Fanconi Anemia (Definition, Epidemiology, Pathophysiology, Clinical Features)

^[1] Lecture slides: GC 047. Family history of anaemia.pdf ^[2] Lecture slides: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf ^[3] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Fanconi syndrome section) ^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p368–369, Familial and Aplastic Anemia) ^[5] Senior notes: Maksim Medicine Notes.pdf (p168, Aplastic anemia section) ^[6] Senior notes: Ryan Ho Haemtology.pdf (p31–32, Aplastic Anaemia section)

^[19] GeneReviews: Fanconi Anemia (diagnosis, inheritance, supportive treatment and surveillance). ^[20] Fanconi Cancer Foundation: Clinical Care of Fanconi Anemia — Hematologic Issues (marrow monitoring and transplantation).

Differential Diagnosis of Fanconi Anemia

The differential diagnosis of Fanconi anemia (FA) must be approached from two directions simultaneously, because FA can present in two main ways:

A child with congenital anomalies ± cytopenias — here the DDx is other syndromic/congenital conditions with overlapping dysmorphic features
A child/young adult with aplastic anemia/pancytopenia — here the DDx is the full spectrum of causes of pancytopenia and bone marrow failure

Both angles must be considered, because up to 25–30% of FA patients have NO congenital anomalies ("cryptic FA") and present purely with haematological failure, while others present in infancy with congenital anomalies before any blood count abnormality appears ^[4]^[7].

When a patient presents with features suggestive of FA (pancytopenia ± dysmorphism ± family history), you are essentially asking:

Is this truly bone marrow failure? (vs. peripheral destruction/sequestration, vs. nutritional deficiency)
If it is bone marrow failure, is it inherited or acquired?
If inherited, is it FA or another inherited BM failure syndrome (IBMFS)?
If the child has congenital anomalies, could this be a non-haematological syndrome that overlaps phenotypically?

Aplastic anemia = pancytopenia resulting from bone marrow hypoplasia or aplasia — can be classified as congenital or acquired ^[2]^[7]

Before narrowing to FA, you must consider the full differential of pancytopenia, because pancytopenia is the presenting haematological picture. The lecture slides and senior notes provide a comprehensive framework ^[7]^[8]^[9]:

Category	Mechanism	Differential Diagnoses
Congenital BM failure	Inherited defect in HSC maintenance → progressive marrow aplasia	Fanconi anemia, Dyskeratosis congenita, Shwachman-Diamond syndrome ^[1]^[2]^[7]
Acquired BM failure (aplastic anemia)	Immune-mediated (T-cell) destruction of HSCs, or direct toxic injury	Idiopathic AA (70–80%), drug-induced (chloramphenicol, sulphonamides, cytotoxics, carbamazepine, phenytoin), toxins (benzene, toluene), viral infections (non-A/B/C hepatitis, HIV, EBV), ionizing radiation ^[2]^[4]^[7]
BM infiltration — malignant	Replacement of normal marrow by malignant cells	Acute leukaemia (ALL, AML), lymphoma, multiple myeloma, MDS, metastatic cancer ^[8]^[9]
BM infiltration — non-malignant	Replacement by fibrosis or granuloma	Primary myelofibrosis, TB, sarcoidosis ^[8]
Nutritional deficiency	Impaired DNA synthesis → ineffective haematopoiesis	Vitamin B12 deficiency, folate deficiency, copper deficiency ^[8]^[9]
Peripheral destruction/sequestration	Cells produced normally but destroyed or pooled peripherally	Hypersplenism (portal hypertension, storage diseases), autoimmune (SLE) ^[8]
Clonal haematopoietic disorders	Clonal stem cell defect → ineffective haematopoiesis	MDS (pre-leukaemia), PNH ^[5]^[9]
Infections	Direct marrow suppression	HIV, EBV, CMV, parvovirus B19 (pure red cell aplasia specifically) ^[8]^[9]

High Yield — Lecture Slide Point

Aplastic anemia → pancytopenia, no abnormal cells, just the absence of normal cells ^[10]. This is the key distinguishing feature from leukaemia/MDS where you see abnormal cells (blasts, dysplastic cells). In aplastic anemia (including FA), the PBS shows NO abnormal cells — the marrow is simply empty ^[4]^[6].

This is the critical branching point. Once pancytopenia with hypocellular marrow is established, you must determine: Is this inherited or acquired?

Key clinical clues that point towards inherited BM failure syndromes (including FA) ^[2]^[4]^[6]^[7]:

Feature	Inherited (FA, DC, SDS)	Acquired Idiopathic AA
Age of onset	Usually childhood (< 10 years)	Any age, but 50% < 30 years
Congenital anomalies	Present in ~70% of FA	Absent
Dysmorphic features	Thumb abnormality, short stature, café-au-lait spots, microcephaly	None
Family history	Often positive (AR inheritance); consanguinity	Usually negative
Macrocytosis / ↑HbF	Prominent (stress erythropoiesis)	May be present but less marked
Preceding trigger	No trigger (progressive)	May follow drug exposure, hepatitis, pregnancy
Cancer predisposition	Very high (MDS, AML, SCC)	Moderate (MDS, PNH evolution)
Definitive test	Chromosome breakage with DEB/MMC ^[4]^[5]^[6]	Diagnosis of exclusion after ruling out inherited causes

In young patients, if suspecting congenital causes of aplastic anemia: look out for the presence of congenital physical abnormalities → inherited bone marrow failure syndromes, where aplastic anemia is only one of the disorders ^[7]

Chromosome breakage with diepoxybutane for Fanconi anemia esp for children — this is the test that clinches the diagnosis ^[4]^[6]

Critical Exam Point

DNA breaking analysis (if thinking of Fanconi's) ^[10] — this was explicitly highlighted in the Hematology Data Interpretation session. In any child or young adult with aplastic anemia, ALWAYS consider FA and order DEB/MMC chromosome breakage testing, even without dysmorphic features. Missing FA and treating with standard immunosuppression is dangerous because FA patients have abnormal DNA repair and respond catastrophically to standard-dose conditioning regimens for HSCT.

If you have established that the aplastic anemia is inherited, the next step is distinguishing which IBMFS:

Feature	Fanconi Anemia	Dyskeratosis Congenita (DC)	Shwachman-Diamond Syndrome (SDS)	Diamond-Blackfan Anemia (DBA)
Inheritance	AR (most), rarely XR (FANCB) ^[5]	XR (DKC1, most common), AR, AD	AR (SBDS gene)	AD (RPS19 most common), AR, XR
Molecular defect	DNA crosslink repair (FA/BRCA pathway)	Telomere maintenance (telomerase/shelterin) ^[5]	Ribosome biogenesis + pancreatic function	Ribosome biogenesis
Lineages affected	Pancytopenia (all 3 lineages)	Pancytopenia (all 3 lineages)	Neutropenia predominantly, ± pancytopenia	Pure red cell aplasia (isolated anaemia) ^[2]^[7]
Classic triad / features	Radial ray anomalies + café-au-lait spots + short stature	Dystrophic nails + reticular skin pigmentation + oral leukoplakia (mucocutaneous triad) ^[5]^[8]	Exocrine pancreatic insufficiency + skeletal anomalies (metaphyseal chondrodysplasia) + neutropenia ^[4]^[5]	Macrocytic anaemia in infancy + craniofacial anomalies (triphalangeal thumbs, short stature)
Malignancy risk	MDS (6000×), AML (700×), SCC ^[4]	MDS/AML, SCC, also IPF and liver cirrhosis ^[8]	MDS/AML (lower risk than FA)	MDS/AML, osteosarcoma
Diagnostic test	DEB/MMC chromosome breakage (+ve)	Telomere length measurement (very short); DEB test negative	Genetic testing (SBDS); faecal elastase / age-appropriate pancreatic function testing; DEB test negative	Elevated erythrocyte adenosine deaminase (eADA); DEB test negative
BM findings	Hypocellular / aplastic	Hypocellular / aplastic	Hypocellular, may show fatty marrow	Erythroid hypoplasia specifically

High Yield Distinguishing Point

Characteristic DEB/MMC-induced breakage strongly supports FA among the common IBMFS; rare overlapping instability disorders require expert interpretation. Dyskeratosis congenita, Shwachman-Diamond syndrome, and Diamond-Blackfan anemia are all DEB-negative. This makes DEB testing the single most important discriminating investigation when differentiating inherited BM failure syndromes ^[4]^[5]^[6].

Because FA has overlapping dysmorphic features with several other conditions, consider these in the DDx:

Condition	Overlapping Features with FA	Distinguishing Features
VACTERL association	Vertebral, anorectal, cardiac, tracheo-oesophageal, renal, limb anomalies	VACTERL is usually sporadic and genetically heterogeneous; assess for an underlying syndrome — NO bone marrow failure, NO chromosomal breakage on DEB. If a child has VACTERL features + cytopenias, think FA first
Thrombocytopenia-absent radius (TAR) syndrome	Absent radii + thrombocytopenia	Thumbs are PRESENT in TAR (often abnormal, but not invariably absent, in FA); thrombocytopenia in TAR is usually self-limiting; DEB test negative
Holt-Oram syndrome	Radial ray defects + cardiac anomalies	AD inheritance (TBX5 mutation); NO bone marrow failure; NO café-au-lait spots
Neurofibromatosis type 1 (NF1)	Café-au-lait spots	NF1 has ≥ 6 café-au-lait macules + neurofibromas + Lisch nodules + axillary freckling; NO bone marrow failure; NF1 diagnostic criteria are distinct ^[11]
Noonan syndrome	Short stature, café-au-lait spots (may be present), cardiac anomalies	Specific facial features (hypertelorism, low-set ears), pulmonary stenosis; NO bone marrow failure; RAS-MAPK pathway mutations ^[11]
Bloom syndrome	Short stature, café-au-lait spots, ↑cancer risk, chromosomal instability	BLM helicase mutation (AR); characteristic sun-sensitive telangiectatic erythema on face; chromosomal breakage on DEB is not the same pattern as FA (sister chromatid exchanges are characteristic)
Nijmegen breakage syndrome	Microcephaly, short stature, ↑cancer risk, chromosomal instability	NBS1 mutation; immunodeficiency (↓IgG/IgA); characteristic "bird-like" facies

When FA presents without dysmorphic features (cryptic FA), it can be indistinguishable from acquired aplastic anemia clinically. Key acquired conditions to exclude ^[4]^[7]^[8]^[9]^[10]:

Condition	Why It Mimics FA	How to Distinguish
Idiopathic acquired AA	Pancytopenia, hypocellular marrow, no abnormal cells — identical haematological picture	DEB chromosome breakage test NEGATIVE; typically no congenital anomalies; often responds to immunosuppression (ATG + CyA) which FA does NOT respond to well
Hepatitis-associated AA	Hepatitis well known to precede aplastic anemia ^[10]; young males; pancytopenia 2–3 months after hepatitis episode	Seronegative hepatitis (non-A/B/C); LFT abnormalities precede cytopenias; DEB test negative
MDS (hypoplastic MDS)	Can present with pancytopenia + hypocellular marrow in elderly; but rare in children	Cytogenetics abnormal (e.g., del 5q, del 7q, monosomy 7); dysplastic morphology on BM aspirate; ring sideroblasts may be present; DEB negative ^[5]^[9]^[10]
Acute leukaemia (ALL/AML)	Can present with pancytopenia (if "aleukemic" — blasts not spilling into peripheral blood)	Blasts on BM aspirate ≥ 20%; hepatosplenomegaly and lymphadenopathy present (especially ALL) ^[7]^[12]; flow cytometry and cytogenetics diagnostic
PNH	Pancytopenia ± haemolytic anaemia; can coexist with AA (AA/PNH syndrome)	Flow cytometry shows ↓CD55/CD59 (deficiency of GPI-anchored proteins); haemolytic markers positive (↑LDH, ↑bilirubin, ↓haptoglobin); haemoglobinuria ^[4]^[6]^[9]
Megaloblastic anaemia (B12/folate deficiency)	Pancytopenia + macrocytosis — superficially similar	Serum B12 and RBC folate will be low; megaloblastic changes on BM (hypersegmented neutrophils, giant metamyelocytes); responds to replacement therapy ^[4]^[6]^[9]
SLE	Autoimmune cytopenias (can affect all 3 lineages)	ANA/anti-dsDNA positive; clinical features of SLE (rash, arthritis, serositis, nephritis); BM is NOT hypocellular ^[8]
Hypersplenism	Pancytopenia from splenic sequestration	Splenomegaly present (unlike FA where spleen is normal); underlying liver disease/portal hypertension usually evident ^[8]

NO lymphadenopathy, NO hepatosplenomegaly in aplastic anemia (including FA) — suggestive of haematological malignancies if present ^[4]^[6]^[7]

This is a crucial negative finding. In FA/AA, the marrow is empty — there is nothing to infiltrate the liver, spleen, or lymph nodes. If you see organomegaly, pivot your thinking towards leukaemia, lymphoma, or myelofibrosis.

Investigation	What It Rules In / Out	Rationale
DEB/MMC chromosome breakage test	Positive = FA; Negative = other causes ^[4]^[5]^[6]^[10]	FA cells cannot repair ICLs → dramatic chromosomal breakage when exposed to crosslinking agents
BM biopsy + trephine	Hypocellular = AA/FA; Hypercellular = other causes; Blasts ≥ 20% = acute leukaemia ^[4]^[6]^[9]	Required to establish diagnosis and exclude malignant infiltration or fibrosis
Flow cytometry for CD55/CD59	PNH (↓GPI-anchored proteins) ^[4]^[6]^[9]	PNH can coexist with or mimic AA
Cytogenetics on BM	MDS (del 5q, del 7q, monosomy 7); AML-defining translocations ^[9]	Distinguishes hypoplastic MDS from AA
Telomere length	Very short = Dyskeratosis congenita	DC is a telomere maintenance disorder
Serum B12, RBC folate	Megaloblastic anaemia ^[4]^[6]^[9]	Must exclude nutritional cause of pancytopenia
Viral serology (HIV, hepatitis)	Viral-associated AA ^[9]	Hepatitis-associated AA is a well-known entity
ANA, anti-dsDNA	SLE-associated cytopenias ^[9]	Autoimmune destruction of blood cells
Genetic testing (NGS)	Confirms specific FA gene mutation ^[8]	Definitive diagnosis; identifies complementation group for prognosis and family counselling

Scenario 1: A 7-year-old boy with short stature, absent thumbs bilaterally, café-au-lait spots, and CBC showing pancytopenia with macrocytic anaemia.

→ Classic FA presentation. Order DEB chromosome breakage test → if positive, confirm with genetic testing. Short stature, polydactyly, café-au-lait spots → Fanconi anemia ^[13]

Scenario 2: A 12-year-old girl with pancytopenia, no dysmorphic features, no lymphadenopathy, no hepatosplenomegaly. PBS shows no abnormal cells.

→ Could be acquired AA OR cryptic FA. Must perform DEB test in any young patient with AA even without physical anomalies ^[4]^[6]^[10]. This is the "trap" answer in exams.

Scenario 3: Same as Scenario 2, but the patient has hepatosplenomegaly and lymphadenopathy.

→ Organomegaly is atypical of uncomplicated aplasia and prompts investigation for acute leukaemia (especially ALL in a 12-year-old). Do BM aspirate looking for blasts ^[7]^[12].

A 12-year-old girl with pallor, bruises, low-grade fever, bone pain, NO lymphadenopathy or organomegaly → differential includes both aplastic anaemia and acute leukaemia — but the absence of organomegaly in the AOS question favoured ALL because bone pain + low-grade fever are leukemic features ^[14]. This highlights that clinical overlap exists and BM examination is essential.

Scenario 4: A child with absent radii but PRESENT thumbs + thrombocytopenia.

→ This is TAR syndrome, NOT FA. In FA, thumbs may be absent/hypoplastic, but normal thumbs do not exclude FA; radii may be absent. In TAR, radii are absent but thumbs are always present.

High Yield Summary — Differential Diagnosis of Fanconi Anemia

Broad DDx of pancytopenia: Inherited BM failure (FA, DC, SDS), acquired AA (idiopathic, drugs, toxins, viral), leukaemia, MDS, megaloblastic anaemia, PNH, SLE, hypersplenism
Key distinguishing feature of FA from acquired AA: Congenital anomalies (but 25–30% cryptic), positive DEB/MMC test, family history, young age
Key distinguishing feature of FA from other IBMFS: Characteristic DEB/MMC breakage supports FA; interpret with genetic testing; DC has telomere defect + mucocutaneous triad; SDS has pancreatic insufficiency; DBA has isolated red cell aplasia
Key distinguishing feature of AA from leukaemia: NO hepatosplenomegaly, NO lymphadenopathy, NO blasts on PBS in AA/FA; their presence suggests leukaemia
Must-do investigation in ALL young patients with AA: DEB chromosome breakage test — missing FA has dangerous therapeutic implications
TAR vs FA: TAR has absent radii but PRESENT thumbs; FA has absent/hypoplastic thumbs ± absent radii

Active Recall - Differential Diagnosis of Fanconi Anemia

References

^[1] Lecture slides: GC 047. Family history of anaemia.pdf ^[2] Lecture slides: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf ^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p369–370, Aplastic Anemia and Fanconi Anemia) ^[5] Senior notes: Maksim Medicine Notes.pdf (p168, Aplastic anemia section) ^[6] Senior notes: Ryan Ho Haemtology.pdf (p32, Aplastic Anaemia section) ^[7] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p7–8, p12–13) ^[8] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1460, p1465, p1468) ^[9] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p624) ^[10] Senior notes: Block A - Hematology Data Interpretation.pdf (p1) ^[11] Senior notes: Ryan Ho Rheumatology.pdf (p172, NF1 section) ^[12] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p3) ^[13] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf (p42) ^[14] AOS material: AOS - Paeds.pdf (Question 10)

Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities for Fanconi Anemia

1. Diagnostic Criteria

Fanconi anemia does not have a single, universally codified "diagnostic criteria checklist" like, say, the Jones criteria for rheumatic fever. Instead, the diagnosis rests on a two-step process:

Confirm FA using chromosome breakage testing and/or diagnostic genetic findings; normal blood counts do not exclude FA.
Assess marrow involvement and severity separately to guide surveillance and treatment. ^[19]^[20]

The table summarises conventional AA exam criteria. FA-specific transplant decisions also use persistent cytopenias, trends and clonal findings; they do not require every conventional acquired-AA criterion. The reticulocyte threshold below refers to manual counting (automated-count criteria commonly use < 60 × 10⁹/L). ^[4]^[5]^[6]^[20]

Severity	Criteria
Very Severe AA (vSAA)	Meets severe AA criteria AND ANC < 0.2 × 10⁹/L
Severe AA (SAA)	BM cellularity < 25% (or 25–50% if < 30% of residual cells are haematopoietic) AND ≥ 2 of the following: (1) ANC < 0.5 × 10⁹/L (2) Platelet < 20 × 10⁹/L (3) Reticulocyte < 20 × 10⁹/L
Non-severe AA (nSAA)	BM cellularity < 25% (or 25–50% if < 30% residual haematopoietic cells) AND peripheral blood cytopenias not fulfilling criteria for SAA

These severity criteria are explicitly stated in the lecture slides and multiple senior notes ^[4]^[5]^[6] and are high-yield for exams.

Why Does Severity Matter?

Severity grading dictates treatment urgency:

vSAA/SAA → urgent specialist referral for HSCT assessment; immunosuppression is an option for acquired AA, not intrinsic FA marrow failure — 70% 1-year mortality if untreated ^[6]
nSAA → may be observed with supportive care initially, but can progress

In FA specifically, severity grading also influences timing of HSCT: patients with SAA or progressive cytopenias need transplant sooner rather than later.

The diagnosis of FA requires at least one of the following to be positive:

Criterion	Details
Positive chromosome breakage test (DEB or MMC)	Gold-standard functional test. Patient's peripheral blood lymphocytes are exposed to diepoxybutane (DEB) or mitomycin C (MMC) — both are DNA interstrand crosslink-inducing agents. FA cells show dramatically increased chromosomal breaks and characteristic radial figures because they cannot repair ICLs. Normal cells repair these breaks efficiently and show minimal breakage ^[4]^[5]^[6]^[7]^[8]^[9]^[15]
Diagnostic pathogenic variants: biallelic variants in an AR FA gene, a hemizygous FANCB variant, or a recognised heterozygous RAD51 variant	Next-generation sequencing (NGS) identifies the specific complementation group (FANCA, FANCC, FANCG, etc.). This is the definitive confirmatory test and is essential for family counselling, carrier testing, and prenatal diagnosis ^[8]^[9]

Criterion

Details

Positive chromosome breakage test (DEB or MMC)

Gold-standard functional test. Patient's peripheral blood lymphocytes are exposed to diepoxybutane (DEB) or mitomycin C (MMC) — both are DNA interstrand crosslink-inducing agents. FA cells show dramatically increased chromosomal breaks and characteristic radial figures because they cannot repair ICLs. Normal cells repair these breaks efficiently and show minimal breakage ^[4]^[5]^[6]^[7]^[8]^[9]^[15]

Diagnostic pathogenic variants: biallelic variants in an AR FA gene, a hemizygous FANCB variant, or a recognised heterozygous RAD51 variant

Next-generation sequencing (NGS) identifies the specific complementation group (FANCA, FANCC, FANCG, etc.). This is the definitive confirmatory test and is essential for family counselling, carrier testing, and prenatal diagnosis ^[8]^[9]

Supportive (but not diagnostic) features:

Clinical phenotype: congenital anomalies (radial ray, café-au-lait spots, short stature, renal anomalies, microcephaly)
Haematological picture: macrocytic anaemia, elevated HbF, progressive cytopenias
Family history consistent with AR or XR inheritance; rare RAD51-related cases are autosomal dominant

High Yield — GC Lecture Slide

Diagnostic testing for Fanconi anemia: 1. Genetic tests with next-generation sequencing (NGS) to identify mutations 2. Chromosomal breakage test with diepoxybutane (DEB) or mitomycin C (MMC) — Hallmark of FA is defective DNA repair — Addition of DEB leads to chromosomal breakage: Normal patient can repair but FA patient cannot (resulting in +ve chromosomal breakage) ^[8]^[9]

This was stated identically in both the Medicine and Paediatrics senior notes (Felix Lai) and aligns with the GC lecture framing ^[1]^[8]^[9].

Common Exam Pitfall

A negative DEB test does NOT rule out FA in all cases. Somatic mosaicism (where some haematopoietic cells have spontaneously corrected the FA mutation through somatic reversion) can produce a false-negative DEB result on peripheral blood. If clinical suspicion is high and the blood DEB test is negative, repeat the test on skin fibroblasts — non-haematopoietic tissue can reveal FA when blood is mosaic. Coordinate genetic testing and specimen choice with the laboratory; blood sequencing may also be affected by mosaicism.

The diagnostic algorithm integrates clinical assessment, standard aplastic anemia workup, and FA-specific testing. The approach is sequential and logical:

3. Investigation Modalities — Detailed Breakdown

3A. First-Line Blood Investigations

Parameter	Expected Finding in FA	Interpretation / Why
Haemoglobin	↓ (anaemia)	HSC depletion → reduced erythropoiesis
MCV	↑ (macrocytic)	Stress erythropoiesis — the dwindling HSC pool undergoes accelerated cycling with fewer cell divisions per progenitor, producing larger-than-normal RBCs. Elevated HbF may coexist but is not itself the cause of macrocytosis
WBC / ANC	↓ (leukopenia / neutropenia)	Myeloid precursor loss
Lymphocyte count	Typically normal ^[8]^[9]	Lymphocytes may be relatively preserved early, but originate from marrow-derived progenitors; lymphopenia and immune abnormalities can occur
Platelet count	↓ (thrombocytopenia)	Megakaryocyte precursor loss — often the first cytopenia to appear in FA
Reticulocyte count	↓ (reticulocytopenia) ^[4]^[6]^[8]^[9]	The marrow cannot compensate — reticulocytes are the immature RBCs freshly released from BM; a low reticulocyte count in the setting of anaemia indicates production failure (not destruction or loss)

CBC: pancytopenia with normo-/macrocytic anaemia, reticulocytopenia (due to BM failure) ^[4]

Why Reticulocyte Count Is So Important

The reticulocyte count is the single most useful initial test to classify anaemia as hypoproliferative (production problem) vs. hyperproliferative (destruction/loss problem):

Low reticulocyte count + anaemia → marrow isn't making enough RBCs → BM failure, nutritional deficiency, or chronic disease
High reticulocyte count + anaemia → marrow is trying hard but cells are being destroyed → haemolytic anaemia, acute bleeding

In FA with established marrow failure, the reticulocyte count is usually low or inappropriately normal because the fundamental problem is HSC depletion.

Finding	Interpretation
Macrocytosis and anisopoikilocytosis	Stress erythropoiesis; variation in RBC size (anisocytosis) and shape (poikilocytosis) due to disordered erythropoiesis from a failing marrow ^[8]^[9]
NO blasts	Absence of circulating blasts does not exclude leukaemia. Marrow morphology, flow cytometry and genetics are needed; some genetically defined AML entities have lower blast thresholds. ^[15]^[16]
NO dysplastic cells	Dysplasia raises concern for MDS, but its absence on the blood film does not exclude MDS
No leukoerythroblastic picture	A leukoerythroblastic film suggests marrow infiltration; its absence does not exclude it ^[15]

PBS: normocytic RBCs but may be macrocytic, NO abnormal cells ^[4]^[6]

Peripheral blood smear: macrocytosis and anisopoikilocytosis are common findings. Exclude presence of blasts and dysplastic cells ^[8]^[9]

These are performed to rule out acquired causes of pancytopenia before proceeding to BM biopsy and FA-specific testing ^[8]^[9]:

Investigation	Purpose	Rationale
LFT	Detects antecedent or ongoing hepatitis ^[8]^[9]	Hepatitis well known to precede aplastic anemia ^[10] — non-A/B/C (seronegative) hepatitis can trigger acquired AA
RFT	Renal function baseline	Renal anomalies common in FA; also needed pre-treatment
Viral serology: HIV, HAV/HBV/HCV, EBV/CMV	Exclude viral marrow suppression ^[8]^[9]	HIV directly suppresses haematopoiesis; hepatitis viruses trigger immune-mediated marrow destruction; EBV/CMV serology needed if HSCT is being considered
Serum B12 and RBC folate	Exclusion of megaloblastic anaemia ^[4]^[6]^[8]^[9]	B12/folate deficiency causes pancytopenia + macrocytosis → can mimic AA; easily treatable if identified
Serum autoantibodies: ANA, anti-dsDNA	Exclude SLE-associated cytopenias ^[8]^[9]	SLE can cause autoimmune destruction of all 3 cell lines
Haemolysis markers: LDH, bilirubin, haptoglobin	Screen for haemolytic component	May indicate coexisting PNH (haemolytic anaemia + AA)
HbF level	Elevated in FA (stress erythropoiesis)	Not diagnostic alone but supportive; also elevated in other IBMFS and some acquired AA

3B. Bone Marrow Examination

Bone marrow aspiration and trephine biopsy: Required to establish the diagnosis of AA and exclude other causes of pancytopenia ^[4]^[6]^[8]^[9]

Marrow examination establishes aplasia and evaluates clonal disease. FA itself can be diagnosed before marrow failure develops, using functional/genetic testing. ^[19]^[20]

Site: typically posterior iliac crest; alternative anterior iliac crest; sternum for aspiration only ^[15]
Two techniques performed together (1–2 cm apart at same sitting):
- Aspirate: for cytology examination, flow cytometry, and genetic studies
- Trephine biopsy: for histological assessment of marrow cellularity, architectural details, fibrosis, and bone structure ^[15]
Contraindication: severe bleeding disorders (DIC, severe haemophilia) — thrombocytopenia alone is NOT a contraindication (assess bleeding risk and local procedural guidance; routine prophylactic platelet transfusion is not always required) ^[15]

Feature	Finding	Why
Cellularity	Profoundly hypocellular marrow (< 25% in SAA)	HSC pool is depleted — fewer progenitors → fewer dividing cells
Fat content	Replacement by fat cells and marrow stroma	Nature abhors a vacuum — as haematopoietic cells disappear, adipocytes expand to fill the space
Residual cells	Morphologically NORMAL residual haematopoietic cells	Residual cells may appear morphologically normal but still carry the underlying FA genetic defect. Haematopoiesis is NOT megaloblastic ^[4]^[6]^[8]^[9]
Blasts	< 5% (usually < 2%)	Absence of blast excess distinguishes from leukaemia (≥ 20% blasts) and MDS with excess blasts
Fibrosis	NO BM infiltration by fibrosis/malignancy ^[4]^[6]	Fibrosis would suggest myelofibrosis; malignant infiltration would suggest leukaemia, lymphoma, or metastatic cancer
Cytogenetics	Perform karyotyping / FISH to exclude hypocellular MDS ^[8]^[9]	MDS characteristically shows cytogenetic abnormalities (del 5q, del 7q, monosomy 7, trisomy 8). Normal cytogenetics supports AA; abnormal cytogenetics suggests MDS. Note that FA patients who develop secondary MDS/AML will acquire cytogenetic abnormalities

BM biopsy: hypocellular with fat infiltration (> 90%), no malignant infiltration ^[5]

High Yield — GC Lecture Slide

Aplastic anaemia — investigations: Blood count: pancytopenia; macrocytic anaemia; low reticulocyte count Blood film Autoimmune markers Vit B12 and folate levels Bone marrow: trephine biopsy is required for the assessment of cellularity Specialized tests: — Flow cytometry for CD55 and CD59 deficient RBC (to rule out PNH) — Chromosome breakage with diepoxybutane (to screen for Fanconi anaemia) ^[1]^[7]

3C. Specialised Tests — FA-Specific and Exclusionary

Aspect	Detail
Principle	DEB (diepoxybutane) and MMC (mitomycin C) are bifunctional alkylating agents that create interstrand crosslinks (ICLs) in DNA. Normal cells activate the FA/BRCA pathway to repair these ICLs efficiently. FA cells cannot repair them → DNA breaks accumulate → visible as chromosomal aberrations on karyotyping
Sample	Peripheral blood lymphocytes (standard); skin fibroblasts if blood test negative but clinical suspicion high
Method	Lymphocytes are cultured with and without DEB/MMC → metaphase spreads examined for chromosomal breaks and exchanges
Positive result in FA	Dramatically increased chromosomal breaks per cell (typically > 1 break/cell; often 5–10×) + characteristic radial figures (quadriradials, triradials) — these are aberrant chromosomal exchanges where broken chromosomes fuse incorrectly
Normal control	Very few breaks (< 0.1 breaks/cell); no radial figures
False negatives	Somatic mosaicism — spontaneous reversion of one FA allele in a haematopoietic clone → that clone tests DEB-negative. Solution: test skin fibroblasts (which don't revert) or go directly to NGS
False positives	Very rare; other chromosome breakage syndromes (Nijmegen breakage syndrome, Bloom syndrome) can show increased breakage but typically with a different pattern (e.g., Bloom shows sister chromatid exchanges, not radial figures)

DNA breaking analysis (if thinking of Fanconi's) ^[10]

Fanconi's anaemia (AR/XR): Dx: diepoxybutane (DEB) instability test ^[5]

Aspect	Detail
Purpose	Identifies the specific FA gene mutation and complementation group
Method	Targeted gene panel (all known FA genes) or whole exome/genome sequencing
Why it matters	(a) Confirms diagnosis definitively — especially important if DEB test is equivocal or mosaicism is present; (b) Identifies complementation group → prognostic implications (e.g., FANCD1/BRCA2 biallelic = very early cancers); (c) Enables family counselling, carrier testing, and prenatal diagnosis
Limitations	Cannot distinguish pathogenic variants from variants of uncertain significance (VUS) in all cases; requires expert clinical genetics interpretation

Genetic tests with next-generation sequencing (NGS) to identify mutations ^[8]^[9]

Aspect	Detail
Principle	PNH is caused by somatic mutations in the PIGA gene → defective synthesis of GPI (glycosylphosphatidylinositol) anchor → loss of GPI-anchored surface proteins CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis) from blood cell surfaces
Why test in AA workup	PNH can coexist with AA (AA/PNH overlap syndrome); up to ~50% of AA patients have small PNH clones. PNH alone can also cause pancytopenia. Management differs (eculizumab for PNH haemolysis)
Method	Flow cytometry on peripheral blood — MOST useful and accepted method to confirm diagnosis of PNH ^[8]^[9]
Positive result	↓CD55 and ↓CD59 on RBCs and/or granulocytes → indicates GPI-anchor deficiency
Additional PNH tests	Urine haemosiderin (intravascular haemolysis); serum LDH, bilirubin, haptoglobin (haemolysis markers) ^[8]^[9]

Flow cytometry (↓CD55/59) for PNH ^[4]^[6]

Aspect	Detail
Purpose	Distinguish hypocellular MDS from AA. MDS is a clonal disorder with characteristic cytogenetic abnormalities
Key abnormalities in MDS	del(5q), del(7q)/monosomy 7, trisomy 8, del(20q)
In FA	BM cytogenetics are typically normal at diagnosis. However, acquisition of new cytogenetic abnormalities (especially gain of 1q, gain of 3q, monosomy 7) during follow-up signals clonal evolution towards MDS/AML

Perform cytogenetics (karyotyping/FISH) and molecular genetics to exclude hypocellular myelodysplastic syndrome (MDS) ^[8]^[9]

Once FA is diagnosed, a thorough systemic survey is needed because FA affects multiple organ systems:

Investigation	Purpose	Expected Findings
Renal ultrasound	Screen for renal anomalies	Ectopic/horseshoe kidney, renal agenesis, duplicated collecting system (~35% of FA patients)
Echocardiography	Screen for congenital heart defects	VSD, ASD, PDA, coarctation of aorta (~15%)
Skeletal survey / hand X-rays	Document radial ray and other skeletal anomalies	Absent/hypoplastic thumbs, absent radii, vertebral anomalies
Audiometry	Screen for hearing loss	Conductive or sensorineural hearing loss (~10%)
Endocrine panel	Screen for endocrinopathies	GH level/stimulation test (GH deficiency), TFTs (hypothyroidism), fasting glucose/OGTT (diabetes), sex hormones/gonadotrophins (hypogonadism)
Ophthalmological exam	Screen for ocular anomalies	Microphthalmia, strabismus
ALDH2 genotyping	Selected specialist/research contexts, not routine diagnostic testing	ALDH2*2 variant → impaired acetaldehyde detoxification → may accelerate marrow failure
HLA typing	Pre-HSCT workup	Identify matched sibling/unrelated donors for potential transplant

Stage	Investigation	Key Findings / Interpretation
1. Initial screen	CBC + differential + reticulocyte count	Pancytopenia, macrocytic anaemia, reticulocytopenia; lymphocyte count typically normal
	PBS	Macrocytosis, anisopoikilocytosis; NO blasts, NO dysplastic cells
2. Exclude acquired causes	B12, folate, LFT, RFT, viral serology, ANA	Rule out megaloblastic anaemia, hepatitis, HIV, SLE
3. BM examination	Aspirate + trephine biopsy	Hypocellular marrow, fat replacement, normal residual cells, no fibrosis/malignancy
	BM cytogenetics	Normal in FA at diagnosis; abnormal → think MDS
4. FA-specific	DEB/MMC chromosome breakage test	POSITIVE = FA (increased breaks + radials)
	NGS genetic testing	Identifies specific FA gene → confirms diagnosis, enables counselling
5. Exclusionary	Flow cytometry CD55/CD59	Rule out PNH
6. Systemic survey	Renal US, echo, hand XR, audiometry, endocrine panel, ophthalmology	Document congenital anomalies and endocrinopathies
7. Pre-treatment	HLA typing	Donor search for HSCT; ALDH2 testing is not a routine prerequisite

High Yield Summary — Diagnosis of Fanconi Anemia

AA Severity Criteria (must memorise): SAA = BM cellularity < 25% + ≥ 2 of: ANC < 0.5 × 10⁹/L, platelets < 20 × 10⁹/L, reticulocytes < 20 × 10⁹/L (manual count; automated thresholds differ); vSAA = SAA + ANC < 0.2 × 10⁹/L
FA diagnostic confirmation: Positive DEB/MMC chromosome breakage test (gold-standard functional test) + NGS genetic testing (confirmatory, identifies gene)
BM biopsy is MANDATORY to diagnose AA — shows hypocellular marrow with fat replacement, normal residual cells, no fibrosis/malignancy
Specialised tests in AA workup: Flow cytometry for CD55/CD59 (PNH), DEB for FA, cytogenetics for MDS — these three must be ordered in every young patient with AA
False-negative DEB: Somatic mosaicism → repeat on skin fibroblasts or go to NGS
Reticulocytopenia = hallmark of production failure — distinguishes BM failure from haemolysis/peripheral destruction
PBS in AA/FA: Blasts, dysplasia and a leukoerythroblastic picture are usually absent in uncomplicated aplasia, but their absence does not exclude leukaemia, MDS or marrow infiltration; assess the marrow

Active Recall - Diagnostic Criteria and Investigations for Fanconi Anemia

References

^[1] Lecture slides: GC 047. Family history of anaemia.pdf (slide: Aplastic anaemia — investigations) ^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p369, Laboratory findings and Diagnostic criteria) ^[5] Senior notes: Maksim Medicine Notes.pdf (p168, Aplastic anemia) ^[6] Senior notes: Ryan Ho Haemtology.pdf (p32, Laboratory findings and Diagnostic criteria) ^[7] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p9, Investigations) ^[8] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1465, p1468) ^[9] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p621, p624) ^[10] Senior notes: Block A - Hematology Data Interpretation.pdf (p1) ^[15] Senior notes: Ryan Ho Haemtology.pdf (p48, Marrow examination) ^[16] Senior notes: Ryan Ho Fundamentals.pdf (p390–391, Workup)

Management of Fanconi Anemia

Managing FA is fundamentally different from managing acquired idiopathic aplastic anemia, and this distinction is critical for exams and clinical practice. Here's why:

Immunosuppressive therapy (ATG + CyA), the backbone of acquired AA treatment, does not treat intrinsic FA marrow failure — because FA marrow failure is NOT immune-mediated. The HSCs are dying from accumulated DNA damage, not from T-cell attack. This does not preclude ATG in transplant conditioning or immunosuppression for GVHD ^[4]^[5]^[7].
FA patients have defective DNA repair → they are hypersensitive to alkylating agents and radiation. Standard HSCT conditioning regimens (high-dose cyclophosphamide + total body irradiation) that work for acquired AA will cause catastrophic toxicity in FA patients. FA-specific reduced-intensity conditioning (RIC) protocols with fludarabine are essential ^[4].
FA is a multi-system disease, not just a haematological one. Management requires lifelong cancer surveillance, endocrine monitoring, and organ-specific care alongside haematological treatment.
The only curative treatment for the haematological component of FA is allogeneic haematopoietic stem cell transplantation (HSCT) ^[4]^[5]^[7]^[17].

Mx: allogeneic HSCT with androgen Tx while awaiting HSCT ^[4]

Treatment Modalities — Detailed Breakdown

1. Supportive Care (All Patients, All Stages)

Supportive care is the foundation of management from the moment of diagnosis, regardless of whether the patient proceeds to HSCT or not.

Product	Indication	Key Considerations in FA
Packed red cell transfusion	Symptomatic anaemia (Hb typically < 7–8 g/dL, or symptomatic at higher levels) ^[4]^[7]	Use leucodepleted, irradiated blood products in FA patients to: (a) reduce alloimmunisation (important pre-HSCT), (b) prevent transfusion-associated GVHD (FA patients are immunocompromised), (c) reduce CMV transmission risk
Platelet concentrate transfusion	Active bleeding with thrombocytopenia, or prophylactic if platelets < 10 × 10⁹/L (or < 20 if febrile/infected) ^[4]^[7]	Same leucodepletion/irradiation principles. Avoid single-donor platelets from potential HSCT donors (causes sensitisation)

Transfusion for packed cells, platelet concentrate as needed ^[4]

Why irradiated products? FA patients have inherent DNA repair deficiency. Donor lymphocytes in non-irradiated products could engraft and cause transfusion-associated graft-versus-host disease (ta-GVHD). Irradiation prevents donor lymphocyte proliferation. Irradiation prevents ta-GVHD; leucodepletion reduces alloimmunisation. These are distinct purposes.

Agent	Route	Notes
Desferrioxamine (DFO)	SC/IV infusion (8–12 hours, typically overnight)	Standard agent; cumbersome administration but well-established safety
Deferasirox	Oral (once daily)	More convenient; monitor renal and hepatic function
Deferiprone (DFP)	Oral (three times daily)	Particularly effective for cardiac iron; risk of agranulocytosis — problematic in already neutropenic FA patients

Why iron chelation? Each unit of packed RBCs contains ~200–250 mg of iron. The body has no active excretion mechanism for iron — it can only lose ~1 mg/day through cell shedding. Regular transfusions therefore cause progressive iron overload → toxic to heart (cardiomyopathy), liver (cirrhosis), and endocrine organs (diabetes, hypogonadism). Iron chelation binds excess iron for urinary/faecal excretion ^[17].

± iron chelation ^[4]

Measure	Rationale
Antifungal prophylaxis (e.g., fluconazole, posaconazole)	Invasive fungal infection is an important cause of death in FA/AA ^[4]^[6]. Neutropenic patients cannot mount adequate innate immune response against fungi
Antibiotic prophylaxis (e.g., quinolone prophylaxis if ANC < 0.5)	Prevent bacterial sepsis in severely neutropenic patients ^[4]
PCP prophylaxis (cotrimoxazole)	If on immunosuppressive therapy or post-HSCT
Antiviral prophylaxis (aciclovir)	Post-HSCT or if on immunosuppression
Prompt empiric broad-spectrum antibiotics for febrile neutropenia	Neutropenic sepsis is a medical emergency — obtain blood cultures promptly if this does not delay immediate empiric antibiotics

Infection prophylaxis: antifungals, antibiotics ^[4]

This is unique to FA and critically important:

Avoid unnecessary radiation (including excessive diagnostic X-rays/CT scans) — use MRI/USS preferentially
Avoid genotoxic drugs unless absolutely necessary (alkylating agents, anthracyclines at standard doses)
Avoid alcohol — produces acetaldehyde, which is particularly toxic to FA HSCs (especially in ALDH2*2 carriers common in East Asia)
HPV vaccination — protects against vaccine-type HPV disease; many FA-associated SCCs are HPV-independent, so surveillance remains essential

2. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) — The Curative Treatment

Allogeneic HSCT as 1st line for young adult + matched donor ^[4] Pediatric indications for allogeneic HSCT: Fanconi's anemia ^[17]

HSCT replaces the patient's defective FA haematopoietic stem cells with normal donor stem cells that have intact FA/BRCA DNA repair. After successful engraftment:

Normal haematopoiesis is restored → cytopenias resolve
The haematological malignancy risk (MDS/AML) is substantially reduced (though not eliminated entirely)

However, HSCT does NOT fix the DNA repair defect in non-haematopoietic tissues — so the risk of solid tumours (especially SCC) persists and may even be increased by the conditioning regimen and chronic GVHD.

Indication	Urgency
Severe or very severe aplastic anemia (SAA/vSAA)	Urgent — high mortality without treatment
Transfusion dependence	High priority — ongoing transfusions cause iron overload and alloimmunisation
Progressive cytopenias trending towards SAA	Semi-urgent — better to transplant before SAA develops (lower transplant-related mortality)
MDS or AML transformation	Urgent expert-centre HSCT planning; pre-HSCT chemotherapy is individualised
Stable cytopenias not requiring transfusion	Can observe; HSCT may be deferred but should be planned proactively

Key Principle

The best outcomes for HSCT in FA are achieved when transplant is performed before the patient becomes heavily transfused (alloimmunisation worsens engraftment), before severe infections occur, and before clonal evolution to MDS/AML. This is why proactive donor search and early referral are critical.

Priority	Donor Source	Notes
1st choice	HLA-matched sibling donor (MSD)	Best outcomes (> 90% survival in recent series). Sibling must be confirmed not to have FA (genotype tested) ; a healthy heterozygous carrier is not automatically excluded and requires donor assessment
2nd choice	Well-matched unrelated donor (MUD)	8/8 or 10/10 HLA-matched; outcomes improving with modern conditioning and supportive care (> 80% survival)
3rd choice	HLA-haploidentical family donor	With post-transplant cyclophosphamide (PTCy); increasingly used when no MSD or MUD available
4th choice	Cord blood	Advantage: lower GVHD risk; disadvantage: slower engraftment, higher graft failure rate

Definitive treatment: allogenic HSCT (if < 40yo + HLA-matched sibling) ^[5]

This is the most important management point unique to FA:

Standard AA Conditioning	FA-Specific Conditioning	Why the Difference
High-dose cyclophosphamide (200 mg/kg) ± total body irradiation (TBI)	Low-dose cyclophosphamide (20–40 mg/kg) + fludarabine ± low-dose TBI or no TBI	FA cells have defective DNA repair → standard-dose alkylating agents cause excessive DNA damage → catastrophic mucositis, multi-organ failure, treatment-related mortality. Fludarabine ("flud-ARA-bine" = fluorinated adenine analogue) is an immunosuppressive purine analogue that does NOT rely on DNA crosslinking for its effect → much better tolerated by FA patients

Modern FA conditioning typically uses: Fludarabine + low-dose cyclophosphamide ± ATG (for unrelated donors)
TBI is avoided or used at very low doses (2 Gy) because of FA's radiation hypersensitivity and increased secondary malignancy risk
Busulfan is not absolutely prohibited: selected FA-adapted protocols use reduced-dose busulfan with specialist monitoring. Standard-dose regimens must not be extrapolated to FA. ^[20]

Exam-Critical Point

If you are asked about HSCT in FA, you MUST mention reduced-intensity conditioning (RIC) with fludarabine-based regimens and explain WHY: FA patients have defective DNA repair (FA/BRCA pathway) → hypersensitive to alkylating agents and radiation → standard conditioning causes fatal toxicity. This is the most testable management point for FA specifically.

Complication	Mechanism	FA-Specific Considerations
Graft failure	Inadequate engraftment of donor cells	Higher risk in FA if heavily alloimmunised from prior transfusions
Graft-versus-host disease (GVHD)	Donor T cells attack recipient tissues (skin, GI, liver)	Chronic GVHD is a major risk factor for post-HSCT SCC development in FA patients
Infections	Prolonged immunosuppression during engraftment and GVHD prophylaxis	FA patients already neutropenic pre-HSCT; fungal infections remain high risk
Secondary malignancies	Conditioning-related DNA damage + underlying FA genomic instability	Post-HSCT FA patients have markedly elevated risk of head/neck SCC — especially if they had chronic GVHD. Lifelong cancer surveillance is mandatory
Endocrine late effects	Conditioning-related damage to endocrine organs	Growth failure, hypothyroidism, gonadal failure — compounded by pre-existing FA endocrinopathy

3. Androgen Therapy — Bridging Treatment

Androgen Tx while awaiting HSCT ^[4] Consider androgens ^[5]

Agent	Dose	Route
Oxymetholone	2–5 mg/kg/day	Oral
Danazol	5 mg/kg/day (max 800 mg/day)	Oral

Androgens stimulate erythropoiesis (and to a lesser extent, granulopoiesis and thrombopoiesis) through:

Direct stimulation of erythropoietin (EPO) production by the kidneys
Direct stimulation of haematopoietic progenitor cell proliferation in the BM
Upregulation of telomerase activity (TERT) in HSCs — this may slow the rate of HSC attrition

~50–70% of FA patients show a haematological response to androgens (improved Hb, sometimes improved neutrophils and platelets)
Response may take 2–3 months to become apparent
Androgens are a bridge, NOT a cure — they buy time while searching for a donor or while the patient is too young/unfit for HSCT
Response is often incomplete and eventually wanes as the HSC pool continues to shrink

Side Effect	Mechanism	Monitoring
Hepatotoxicity — elevated transaminases, cholestasis	Androgenic effect on hepatocytes	LFTs every 1–3 months
Hepatic adenoma / hepatocellular carcinoma	Chronic androgen stimulation of hepatocyte proliferation	Liver USS every 6 months
Virilisation (in females) — hirsutism, deepening voice, clitoromegaly	Androgenic effects	Clinical assessment; use lowest effective dose
Premature epiphyseal closure (in children)	Androgens accelerate bone maturation	Bone age X-rays; monitor height velocity
Fluid retention / oedema	Sodium and water retention	Clinical assessment; monitor weight
Peliosis hepatis	Blood-filled cysts in liver from androgen exposure	Liver USS

Growth Factors in FA

G-CSF can improve neutrophil counts in selected patients. An FA specialist should guide use, with marrow assessment before treatment and surveillance for clonal evolution. It does not correct the DNA repair defect or replace HSCT. Erythropoietin is not routine therapy for FA marrow failure. ^[19]

This is a crucial distinction from acquired idiopathic AA:

	Acquired Idiopathic AA	Fanconi Anemia
Pathogenesis	T-cell mediated destruction of HSCs ^[4]^[6]	Defective DNA repair → HSC apoptosis from endogenous DNA damage
IST effective?	Yes — ATG + CyA ± eltrombopag is first-line if no matched donor ^[4]^[5]^[7]	No — IST does not address the underlying DNA repair defect
ATG + CyA	Standard regimen	Not a treatment for intrinsic FA marrow failure; transplant uses are distinct
Eltrombopag	Increasingly used with ATG + CyA ^[4]^[5]	Under investigation in FA but NOT standard of care

Immunosuppressive therapy if ineligible for HSCT (or no matched donor) — this statement from the lecture notes applies to acquired AA, NOT FA ^[4]^[7]

The IST regimen of eltrombopag (TPO-agonist) + antithymocyte globulin (ATG) + CyA + steroids ^[4] is for acquired AA. For FA, the equivalent bridging therapy is androgens.

Common Exam Mistake

Do not use ATG + CyA to treat intrinsic FA marrow failure. These drugs may still be used for transplant conditioning or GVHD prevention. This is the treatment for acquired idiopathic AA where the mechanism is T-cell-mediated HSC destruction. In FA, the mechanism is intrinsic DNA repair failure — immunosuppression will not help and will only add toxicity.

Gene therapy represents the theoretical ideal treatment for FA because it addresses the root cause — the defective gene:

Approach: Autologous CD34+ HSCs are harvested, transduced with a lentiviral vector carrying a functional copy of the mutated FA gene (e.g., FANCA), and reinfused
Advantages: No need for a donor; no GVHD risk; no conditioning-related toxicity (minimal conditioning used)
Current status: Phase I/II clinical trials ongoing (particularly for FANCA mutations). Early results show feasibility and some haematological improvement, but long-term safety and efficacy data are still maturing
Challenges: FA HSCs are fragile and few in number → difficult to harvest sufficient cells; insertional mutagenesis risk; gene-corrected cells must have a selective survival advantage to repopulate the marrow

This is not yet standard of care but is the most promising avenue for future FA management.

6. Management of Malignant Complications

MDS/AML is treated with HSCT when feasible — this is the only curative option
Pre-HSCT chemotherapy is individualised; its benefit is uncertain and prolonged myelosuppression is a major risk. Identify a donor before chemotherapy where possible. ^[20]
Standard AML induction (e.g., "7+3" — cytarabine + daunorubicin) at full doses → excessive mucositis, prolonged aplasia, infection, multi-organ failure in FA patients
Prognosis of MDS/AML in FA is worse than in non-FA patients due to treatment limitations

Most can survive into adulthood, but with ↑incidence of solid organ tumors (AA may limit use of chemo/RT) ^[4]

Standard surgical excision ± modified-dose radiotherapy
Chemotherapy doses must be reduced
HPV vaccination is recommended; it does not prevent all FA-associated SCCs
Regular screening: oral examination every 6 months from age 10; gynaecological screening from age 13 or onset of sexual activity

Domain	Frequency	Specific Assessments
Haematological	CBC every 3–4 months; annual BM aspirate/biopsy	Monitor for clonal evolution (new cytogenetic abnormalities → MDS/AML)
Cancer screening	Every 6 months	Oral exam for SCC precursors; gynaecological exam; liver USS (if on androgens)
Endocrine	Annual	Height/weight/growth velocity, TFTs, fasting glucose/HbA1c, gonadal hormones, bone density (DEXA from adolescence)
Hepatic	Every 3–6 months (if on androgens)	LFTs, liver USS
Renal	Annual	RFT, renal USS
Audiological	Annual	Pure tone audiometry
Psychosocial	Ongoing	Developmental assessment, educational support, psychological support, genetic counselling for family

Clinical Scenario	Treatment	Key Points
Stable counts, no cytopenias	Observation + surveillance	Regular CBC, annual BM, cancer screening
Mild/moderate cytopenias	Observation if stable; consider androgens for clinically significant cytopenias when HSCT is deferred	Bridge to HSCT; monitor hepatotoxicity
SAA/vSAA + matched sibling donor	Allogeneic HSCT with FA-specific RIC ^[4]^[5]^[7]^[17]	Best outcomes; fludarabine-based conditioning
SAA/vSAA, no MSD	Androgens + donor search (MUD/haplo/cord) → HSCT when donor found	Transfusion support + infection prophylaxis while searching
MDS/AML transformation	Expert-centre HSCT planning ± individualised low-intensity chemotherapy	Worse prognosis; alkylator/radiation doses must be reduced
Head/neck or gynaecological SCC	Surgery ± modified RT/chemo	Lifelong SCC screening post-HSCT
Post-HSCT	GVHD prophylaxis/treatment + cancer surveillance + endocrine monitoring	Chronic GVHD increases SCC risk; lifelong follow-up

High Yield Summary — Management of Fanconi Anemia

Allogeneic HSCT is the only curative treatment for the haematological component of FA — first-line for SAA/vSAA with a matched donor ^[4]^[5]^[7]^[17]
FA-specific conditioning: FA-adapted reduced-intensity conditioning, often fludarabine-based, is required because FA patients are hypersensitive to alkylating agents and radiation due to defective DNA repair
Androgen therapy (oxymetholone/danazol) is the bridging treatment while awaiting HSCT — improves counts in ~50–70% but is NOT curative ^[4]^[5]
G-CSF may help selected patients with severe neutropenia under specialist supervision; it does not cure marrow failure. EPO is not routine treatment. ^[19]
Immunosuppressive therapy (ATG + CyA) is NOT indicated for FA — the marrow failure is from intrinsic DNA damage, NOT immune-mediated destruction
Supportive care: leucodepleted/irradiated transfusions, iron chelation, infection prophylaxis, avoid DNA-damaging agents, HPV vaccination
HSCT does NOT eliminate solid tumour risk — lifelong cancer surveillance (especially SCC) is mandatory post-HSCT
MDS/AML complicating FA needs an expert transplant plan; pre-HSCT chemotherapy is individualised because of severe toxicity risk

Active Recall - Management of Fanconi Anemia

References

^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p370, Management of AA and Fanconi anemia) ^[5] Senior notes: Maksim Medicine Notes.pdf (p168, Management of idiopathic AA) ^[6] Senior notes: Ryan Ho Haemtology.pdf (p32, Aplastic Anaemia) ^[7] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p11, Severe AA treatment) ^[17] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p28, Indications for Allogeneic HSCT)

Complications of Fanconi Anemia

The complications of Fanconi anemia are best understood by remembering that FA is a multi-system DNA repair disorder, not merely a haematological condition. Complications arise from three fundamental sources:

The disease itself — progressive bone marrow failure + genomic instability + developmental anomalies
The treatment — transfusion-related complications, androgen side effects, HSCT-related toxicity
The interaction — FA's defective DNA repair amplifies treatment-related complications (e.g., conditioning-related secondary malignancies)

1. Complications of Progressive Bone Marrow Failure

These are the direct consequences of pancytopenia — the hallmark of FA.

Complication	Mechanism	Clinical Details
Severe bacterial infections	Neutropenia (ANC often < 0.5 × 10⁹/L in SAA) → inability to mount an innate immune response → bacteria breach mucosal and skin barriers unopposed	Infections are typically bacterial (sepsis, pneumonia, UTI) ^[4]^[6]. Common organisms: Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella, E. coli. Febrile neutropenia is a medical emergency requiring immediate empiric broad-spectrum antibiotics
Invasive fungal infections	Prolonged neutropenia → fungi (which are normally kept in check by neutrophils) invade deep tissues	Invasive fungal infection is an important cause of death ^[4]^[6] in FA/AA patients. Key organisms: Aspergillus spp. (pulmonary aspergillosis), Candida spp. (candidaemia, hepatosplenic candidiasis). Prophylaxis with azole antifungals is standard
Opportunistic viral infections	Lymphocyte function is relatively preserved in early FA, but becomes impaired post-HSCT or with advancing disease	CMV reactivation, EBV-associated lymphoproliferative disease (especially post-HSCT)

Why are infections such a major killer? In FA, the neutrophils aren't just low in number — the few remaining neutrophils are derived from a stressed, genomically unstable marrow and may not function optimally. Additionally, the mucosal barriers (oral, GI) that serve as the first line of defence are often breached by thrombocytopenia-related bleeding or mucositis.

Complication	Mechanism	Clinical Details
Mucocutaneous bleeding	Thrombocytopenia → inadequate primary haemostasis (platelet plug formation fails)	Petechiae, purpura, epistaxis, gingival bleeding, menorrhagia. Usually not life-threatening but significantly impairs quality of life
Life-threatening haemorrhage	Severe thrombocytopenia (Plt < 10 × 10⁹/L) → spontaneous bleeding into critical organs	Intracranial haemorrhage — the most feared complication of severe thrombocytopenia; can be fatal. GI haemorrhage — particularly dangerous if there is coexisting mucosal fragility

Complication	Mechanism
Symptomatic anaemia	Progressive erythroid failure → ↓O₂ carrying capacity → fatigue, exercise intolerance, tachycardia, high-output cardiac failure if severe and chronic
Growth impairment (compounding)	Chronic anaemia contributes to poor growth on top of the intrinsic growth failure of FA (skeletal anomalies + endocrine dysfunction)

2. Malignant Complications — The Defining Danger of FA

This is the most important complication category for exams and clinical practice.

↑risk of malignancy: MDS (6000×), AML (700×), SCCs ^[4]^[6]

Feature	Detail
Risk	6,000-fold increased risk compared to the general population ^[4]^[6]
Cumulative incidence	~30–40% by age 40
Mechanism	FA's defective ICL repair → progressive genomic instability in residual HSCs → accumulation of somatic mutations → clonal haematopoiesis → acquisition of cytogenetic abnormalities (gain of 1q, gain of 3q, monosomy 7, del 7q) → dysplastic differentiation
Why gain of 3q matters	Gain of 3q26 is relatively specific to FA-associated MDS (rare in de novo MDS) and is associated with overexpression of EVI1 oncogene → very poor prognosis, rapid progression to AML
Clinical presentation	Worsening cytopenias in a previously stable FA patient; morphological dysplasia on BM aspirate; new cytogenetic abnormalities on surveillance BM cytogenetics
Treatment	HSCT is the only curative option. Reduced-dose chemotherapy if needed pre-HSCT. Prognosis is worse than for FA patients transplanted before MDS develops

MDS: heterogeneous group of clonal diseases characterised by ineffective/dysmorphic haematopoiesis. Pre-leukaemia: may transform to acute leukaemia ^[5]

Feature	Detail
Risk	700-fold increased risk ^[4]^[6]
Cumulative incidence	~10–15% by age 40 (often arising from prior MDS)
Mechanism	Progression from MDS (clonal evolution with further mutations — "two-hit hypothesis": class I mutations conferring proliferative advantage + class II mutations impairing differentiation ^[18]). Can also arise de novo
Clinical features	As per AML generally — worsening pancytopenia, ≥ 20% blasts on BM aspirate ± new organomegaly
Treatment challenge	FA patients cannot tolerate standard-dose chemotherapy (e.g., "7+3" induction) because their defective DNA repair leads to catastrophic mucositis, prolonged aplasia, and multi-organ failure. Modified, reduced-dose regimens are used. HSCT is the goal. AA may limit use of chemo/RT ^[4]^[6]
Prognosis	Significantly worse than AML in non-FA patients due to treatment limitations

Acute leukaemia risk factors: Genetics — Down's syndrome, Fanconi anemia, Bloom's syndrome ^[5]

High Yield — GC Lecture Slide

Fanconi anemia: predisposition to malignancy including MDS, AML and SCC of H&N ^[4]^[6]^[7]

This triad of malignancies (MDS, AML, SCC) is the most high-yield complication fact about FA for exams.

Feature	Detail
Risk	~500–700-fold increased risk of SCC compared to general population
Cumulative incidence	~25–30% by age 40–50
Most common sites	Head and neck (oral cavity, oropharynx, larynx), vulvar/cervical/vaginal (gynaecological), anal/perianal, oesophageal
Mechanism	Squamous epithelial cells are rapidly dividing and exposed to exogenous mutagens. Without functional FA/BRCA DNA repair: (1) endogenous replication errors accumulate; (2) viral and environmental exposures may modify risk; (3) alcohol and tobacco metabolites create DNA adducts that FA cells cannot clear
HPV connection	HPV vaccination is recommended, but HPV is not a prerequisite for FA-associated SCC; lifelong surveillance remains necessary
Age of onset	Typically in the 20s–40s — much younger than SCC in the general population
Relation to HSCT	Post-HSCT FA patients who develop chronic GVHD have an even higher SCC risk — chronic GVHD causes mucosal inflammation and dysregulated immune surveillance, creating a "perfect storm" with the underlying DNA repair defect

SCC predominance reflects tissue-specific cancer susceptibility; it cannot be explained simply by comparing epithelial turnover rates. Other cancers also occur.

In certain FA complementation groups, additional specific malignancies occur:

Complementation Group	Associated Malignancies	Mechanism
FANCD1/BRCA2 (biallelic)	Childhood medulloblastoma, Wilms tumour, AML — often presenting before age 5	BRCA2 biallelic loss causes profound homologous recombination deficiency → extremely high genomic instability from earliest development
FANCN/PALB2 (biallelic)	Similar to FANCD1 — very early onset cancers	PALB2 is the direct binding partner of BRCA2
Hepatic tumours	Hepatocellular carcinoma, hepatic adenoma	Primarily androgen-related (complication of treatment, not disease per se) but also some FA-intrinsic hepatic oncogenic susceptibility

3. Complications of Treatment

Complications due to long-term red cell transfusion ^[2]^[7] are a major concern in chronically transfused FA patients:

Complication	Mechanism	Prevention/Management
Iron overload (transfusional haemosiderosis)	Each unit of packed RBCs contains ~200–250 mg iron. The body has no active iron excretion mechanism (~1 mg/day passive loss only). Repeated transfusions → progressive iron accumulation in parenchymal organs	Iron chelation therapy (desferrioxamine, deferasirox, deferiprone). Monitor serum ferritin + cardiac/liver MRI T2* for iron quantification
Cardiac iron toxicity	Iron deposits in myocardium → oxidative damage → restrictive then dilated cardiomyopathy → heart failure	Cardiac MRI T2* monitoring; specialist-guided chelation; deferiprone-associated agranulocytosis is particularly concerning in FA
Hepatic iron toxicity	Iron deposits in hepatocytes → oxidative damage → fibrosis → cirrhosis	Liver MRI T2* or FerriScan; LFTs
Endocrine iron toxicity	Iron deposits in pituitary, pancreas, thyroid, gonads → glandular failure	Diabetes mellitus, hypogonadism, hypothyroidism, growth hormone deficiency — all compound FA's pre-existing endocrine dysfunction
Alloimmunisation	Repeated exposure to foreign RBC/platelet antigens → development of alloantibodies	Complicates future transfusion compatibility and HSCT engraftment. Use leucodepleted, extended phenotype-matched products
Transfusion-transmitted infections	Blood-borne viral transmission (HBV, HCV, HIV — now very rare with modern screening)	Serology testing of blood products

The body does not have a good mechanism of iron excretion — iron overload → toxic to the heart. Chelation: Desferrioxamine (DFO), DFP and Deferasirox — bind to iron, excrete from urine and feces ^[17]

Complication	Mechanism	Monitoring
Hepatotoxicity (cholestasis, transaminitis)	Direct androgen hepatotoxicity — 17α-alkylated androgens are hepatotoxic	LFTs every 1–3 months
Hepatic adenoma / hepatocellular carcinoma	Chronic androgenic stimulation of hepatocyte proliferation → benign → malignant transformation	Liver USS every 6 months
Peliosis hepatis	Blood-filled sinusoidal dilatation — hepatic architectural disruption from androgen exposure	Liver USS
Virilisation (females)	Androgenic effects — hirsutism, voice deepening, clitoromegaly	Clinical monitoring; use lowest effective dose
Premature epiphyseal closure (children)	Androgens accelerate bone maturation → premature fusion of growth plates → reduced final adult height	Bone age X-rays; problematic because FA patients are already short

Complications of HSCT ^[18]:

Cx related to high dose chemotherapy: infection, haemorrhage, veno-occlusive disease of liver (VOD)

Cx related to allogeneic HSCT: graft-versus-host disease (GVHD), graft rejection

Cx related to late/long term effects: cataract, immunodeficiency, endocrine dysfunction and infertility, secondary malignancy

In FA patients, these complications are amplified because of the underlying DNA repair defect:

Complication	Standard HSCT Risk	FA-Specific Amplification
Acute GVHD	Donor T cells attack recipient skin, liver, GI	FA patients may have more tissue damage from conditioning → worse GVHD substrate
Chronic GVHD	Multi-organ immune-mediated disease (skin sclerosis, sicca, bronchiolitis obliterans, liver)	Chronic GVHD is the single biggest risk factor for post-HSCT SCC in FA patients — mucosal inflammation + impaired DNA repair + immunosuppression = dramatically accelerated SCC development
Graft failure	Inadequate engraftment → persistent cytopenias	Higher risk if heavily pre-transfused (alloimmunisation)
VOD (sinusoidal obstruction syndrome)	Conditioning damages hepatic sinusoidal endothelium → thrombotic occlusion → painful hepatomegaly, ascites, jaundice	FA patients' endothelial cells may be more susceptible to conditioning-induced damage
Secondary malignancies	All HSCT recipients have ↑risk	FA patients have dramatically elevated risk — their non-haematopoietic tissues still carry the FA mutation + conditioning adds DNA damage + chronic GVHD promotes SCC. Post-HSCT SCC incidence in FA is ~15–25% by 20 years post-transplant
Endocrine dysfunction and infertility	Conditioning → gonadal toxicity, hypothyroidism, growth failure	Compounds pre-existing FA endocrinopathy — many FA patients already have hypogonadism, hypothyroidism, and short stature before HSCT ^[18]^[6]
Cataract	Mainly due to total body irradiation (TBI) ^[18]	FA-specific conditioning avoids or minimises TBI, but even low-dose TBI can cause cataracts; requires ophthalmological follow-up

Endocrine Complication	Mechanism	Prevalence
Short stature	Multifactorial: skeletal anomalies (radial ray defects, vertebral anomalies) + GH deficiency + hypothyroidism + chronic illness + premature epiphyseal closure from androgens	~60%
Hypothyroidism	FA pathway interaction with thyroid development; compounded by iron deposition in thyroid (transfusional) and conditioning-related thyroid damage (post-HSCT)	~30–60%
Glucose intolerance / Diabetes mellitus	Iron deposition in pancreatic β-cells (transfusional siderosis) + intrinsic FA-related β-cell vulnerability + post-HSCT immunosuppressant effects (steroids, CNIs)	~20–30%
Hypogonadism	Primary gonadal failure — germ cells are exquisitely sensitive to DNA damage (they undergo meiotic recombination which generates DSBs requiring HR repair → defective in FA). Also compounded by gonadotoxic conditioning	~70–80% in males; ~50% in females
Infertility	Male: severely impaired spermatogenesis (most males are infertile). Female: premature ovarian insufficiency (but some women have had successful pregnancies, particularly those not requiring HSCT)	Males: ~90% infertile; Females: variable
Osteoporosis	Hypogonadism + steroid use (post-HSCT) + vitamin D deficiency + chronic illness + iron overload	Increasing recognition; DEXA monitoring

These are not "complications" in the traditional sense but rather coexisting structural problems that require ongoing management:

Organ System	Complication	Management
Renal	Ectopic/horseshoe kidney → ↑UTI risk, possible obstruction; renal agenesis → single functioning kidney (vulnerable)	Renal USS surveillance; avoid nephrotoxic drugs; monitor RFT
Cardiac	Congenital heart defects (VSD, ASD, PDA) → may require surgical correction; cardiomyopathy from iron overload	Echocardiography surveillance; cardiac MRI T2* for iron
Auditory	Conductive or sensorineural hearing loss → educational and social impact	Audiometry; hearing aids as needed
GI	Tracheo-oesophageal fistula, duodenal atresia, imperforate anus — typically corrected surgically in infancy	Post-surgical follow-up
Skeletal	Absent/hypoplastic thumbs/radii → functional impairment	Orthopaedic/hand surgery consultation; occupational therapy

Issue	Detail
Chronic illness burden	Lifelong medical appointments, transfusions, medications, surveillance → significant impact on quality of life
Body image	Short stature, skeletal anomalies, skin pigmentation changes, androgen-related virilisation → self-esteem issues, particularly in adolescence
Developmental and educational	Microcephaly, learning difficulties in some patients → need for educational support
Fertility counselling	Most males infertile; females may have premature ovarian insufficiency → requires sensitive discussion; sperm/oocyte cryopreservation before HSCT if feasible
Genetic counselling	AR inheritance → 25% recurrence risk per pregnancy if both parents are carriers. Prenatal diagnosis available via chorionic villus sampling (CVS) with DEB testing or targeted mutation analysis. Pre-implantation genetic diagnosis (PGD) also available
Anxiety about malignancy	Living with dramatically elevated cancer risk → chronic anxiety; need for psychological support

Category	Key Complications	High-Yield Points
BM failure	Infections (bacterial, invasive fungal), haemorrhage (ICH, GI), symptomatic anaemia	Infections and haemorrhage are the leading causes of death in untransplanted FA patients
Malignancy	MDS (6000×), AML (700×), SCC of H&N and gynaecological	Most important long-term complication; cannot be fully prevented even by HSCT (solid tumour risk persists)
Transfusion-related	Iron overload → cardiac, hepatic, endocrine toxicity; alloimmunisation	Iron chelation when iron overload warrants treatment; alloimmunisation worsens HSCT outcomes
Androgen-related	Hepatotoxicity, hepatic adenoma/HCC, virilisation, premature epiphyseal closure	Liver USS q6 months; use lowest effective dose
HSCT-related	GVHD (acute and chronic), graft failure, secondary malignancy, endocrine dysfunction, infertility	Chronic GVHD is the biggest risk factor for post-HSCT SCC in FA
Endocrine	Short stature, hypothyroidism, DM, hypogonadism, infertility, osteoporosis	Disease-intrinsic + treatment-amplified; lifelong monitoring
Psychosocial	Chronic illness, body image, fertility, cancer anxiety	Multidisciplinary support essential

High Yield Summary — Complications of Fanconi Anemia

Malignancy is THE defining complication: MDS (6000×), AML (700×), SCC — lifelong cancer surveillance is non-negotiable, even post-HSCT ^[4]^[6]
Infection and haemorrhage from pancytopenia are the leading causes of death in untransplanted patients. Invasive fungal infections are an important cause of death ^[4]^[6]
Iron overload from chronic transfusion damages heart, liver, and endocrine organs — requires iron chelation
Post-HSCT complications are amplified in FA — especially chronic GVHD → dramatically increases SCC risk; secondary malignancies due to conditioning + underlying DNA repair defect
Treatment of FA malignancies is limited by the defective DNA repair — AA may limit use of chemo/RT ^[4]^[6]; reduced-dose protocols mandatory
Endocrine complications are common — short stature, hypogonadism/infertility (especially males), hypothyroidism, diabetes
HSCT cures the blood disease but NOT the solid tumour risk — non-haematopoietic tissues retain the FA mutation

Active Recall - Complications of Fanconi Anemia

References

^[2] Lecture slides: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf ^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p370, Fanconi anemia section) ^[5] Senior notes: Maksim Medicine Notes.pdf (p168, p173) ^[6] Senior notes: Ryan Ho Haemtology.pdf (p32–33, Aplastic Anaemia and Fanconi anemia) ^[7] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p11–14) ^[17] Senior notes: Block A - Hematology Interactive Tutorial.pdf (p5, Iron overload and chelation) ^[18] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p28, p34); Ryan Ho Haemtology.pdf (p156, HSCT complications)

High Yield Summary

Fanconi Anemia — Key Points for Exams:

Definition: Inherited BM failure syndrome (most commonly AR) due to defect in the FA/BRCA interstrand crosslink DNA repair pathway
Triad: Congenital anomalies + progressive bone marrow failure + cancer predisposition (MDS/AML, head/neck SCC)
Most common gene: FANCA (~60–65%)
Classic congenital anomaly: Thumb abnormality / radial ray defect — but 25–30% have NO anomalies ("cryptic FA")
Haematological progression: Macrocytosis → thrombocytopenia (usually first cytopenia) → pancytopenia → aplastic anemia
Key diagnostic test: Chromosome breakage analysis with diepoxybutane (DEB) — FA cells show dramatically increased chromosomal breaks
Cancer risk: ~30–40% cumulative risk of MDS/AML by age 40; ~25–30% cumulative risk of solid tumours
Key negative sign: NO hepatosplenomegaly, NO lymphadenopathy in pure marrow failure — their presence suggests malignant transformation
Aplastic anemia classification: FA is the most common inherited cause; always exclude in children/young adults with aplastic anemia, even without dysmorphic features
HK relevance: ALDH2*2 polymorphism (common in East Asians) may accelerate disease by impairing acetaldehyde detoxification

High Yield Summary — Differential Diagnosis of Fanconi Anemia

Broad DDx of pancytopenia: Inherited BM failure (FA, DC, SDS), acquired AA (idiopathic, drugs, toxins, viral), leukaemia, MDS, megaloblastic anaemia, PNH, SLE, hypersplenism
Key distinguishing feature of FA from acquired AA: Congenital anomalies (but 25–30% cryptic), positive DEB/MMC test, family history, young age
Key distinguishing feature of FA from other IBMFS: Characteristic DEB/MMC breakage supports FA; interpret with genetic testing; DC has telomere defect + mucocutaneous triad; SDS has pancreatic insufficiency; DBA has isolated red cell aplasia
Key distinguishing feature of AA from leukaemia: NO hepatosplenomegaly, NO lymphadenopathy, NO blasts on PBS in AA/FA; their presence suggests leukaemia
Must-do investigation in ALL young patients with AA: DEB chromosome breakage test — missing FA has dangerous therapeutic implications
TAR vs FA: TAR has absent radii but PRESENT thumbs; FA has absent/hypoplastic thumbs ± absent radii

High Yield Summary — Diagnosis of Fanconi Anemia

AA Severity Criteria (must memorise): SAA = BM cellularity < 25% + ≥ 2 of: ANC < 0.5 × 10⁹/L, platelets < 20 × 10⁹/L, reticulocytes < 20 × 10⁹/L (manual count; automated thresholds differ); vSAA = SAA + ANC < 0.2 × 10⁹/L
FA diagnostic confirmation: Positive DEB/MMC chromosome breakage test (gold-standard functional test) + NGS genetic testing (confirmatory, identifies gene)
BM biopsy is MANDATORY to diagnose AA — shows hypocellular marrow with fat replacement, normal residual cells, no fibrosis/malignancy
Specialised tests in AA workup: Flow cytometry for CD55/CD59 (PNH), DEB for FA, cytogenetics for MDS — these three must be ordered in every young patient with AA
False-negative DEB: Somatic mosaicism → repeat on skin fibroblasts or go to NGS
Reticulocytopenia = hallmark of production failure — distinguishes BM failure from haemolysis/peripheral destruction
PBS in AA/FA: Blasts, dysplasia and a leukoerythroblastic picture are usually absent in uncomplicated aplasia, but their absence does not exclude leukaemia, MDS or marrow infiltration; assess the marrow

High Yield Summary — Management of Fanconi Anemia

Allogeneic HSCT is the only curative treatment for the haematological component of FA — first-line for SAA/vSAA with a matched donor
FA-specific conditioning: FA-adapted reduced-intensity conditioning, often fludarabine-based, is required because FA patients are hypersensitive to alkylating agents and radiation due to defective DNA repair
Androgen therapy (oxymetholone/danazol) is the bridging treatment while awaiting HSCT — improves counts in ~50–70% but is NOT curative
G-CSF may help selected patients with severe neutropenia under specialist supervision; it does not cure marrow failure. EPO is not routine treatment. ^[19]
Immunosuppressive therapy (ATG + CyA) is NOT indicated for FA — the marrow failure is from intrinsic DNA damage, NOT immune-mediated destruction
Supportive care: leucodepleted/irradiated transfusions, iron chelation, infection prophylaxis, avoid DNA-damaging agents, HPV vaccination
HSCT does NOT eliminate solid tumour risk — lifelong cancer surveillance (especially SCC) is mandatory post-HSCT
MDS/AML complicating FA needs an expert transplant plan; pre-HSCT chemotherapy is individualised because of severe toxicity risk

High Yield Summary — Complications of Fanconi Anemia

Malignancy is THE defining complication: MDS (6000×), AML (700×), SCC — lifelong cancer surveillance is non-negotiable, even post-HSCT
Infection and haemorrhage from pancytopenia are the leading causes of death in untransplanted patients. Invasive fungal infections are an important cause of death
Iron overload from chronic transfusion damages heart, liver, and endocrine organs — requires iron chelation
Post-HSCT complications are amplified in FA — especially chronic GVHD → dramatically increases SCC risk; secondary malignancies due to conditioning + underlying DNA repair defect
Treatment of FA malignancies is limited by the defective DNA repair — AA may limit use of chemo/RT ; reduced-dose protocols mandatory
Endocrine complications are common — short stature, hypogonadism/infertility (especially males), hypothyroidism, diabetes
HSCT cures the blood disease but NOT the solid tumour risk — non-haematopoietic tissues retain the FA mutation

References

See the corresponding article tabs for the local lecture and senior-note references.

Fanconi Anemia

1. Definition

2. Epidemiology

3. Risk Factors

4. Anatomy and Function: The FA/BRCA DNA Repair Pathway

4.1 Interstrand Crosslinks (ICLs) — The Problem

4.2 The FA Pathway — How It Normally Works

4.3 What Happens When the FA Pathway Is Broken

5. Etiology and Pathophysiology

5.1 Genetic Basis

5.2 Pathophysiology — From Gene to Disease

A) Bone Marrow Failure

B) Congenital Malformations

C) Cancer Predisposition

D) Endocrine Dysfunction

5.3 Aldehyde Detoxification — A Key Modifier

6. Classification

6.1 By Complementation Group

6.2 By Phenotypic Severity

6.3 Within the Broader Classification of Aplastic Anemia

7. Clinical Features

7.1 Symptoms

A) Symptoms Related to Bone Marrow Failure (Pancytopenia)

B) Symptoms Related to Congenital Anomalies

C) Symptoms Related to Endocrine Dysfunction

D) Symptoms Related to Malignancy (Later in Disease Course)

7.2 Signs

A) Signs Related to Bone Marrow Failure

B) Signs Related to Congenital Anomalies (~70% of patients)

C) Signs Related to Endocrine Dysfunction

D) Signs Suggesting Malignant Transformation

7.3 Key Clinical Pearls — Connecting Features to Pathophysiology

7.4 Summary Table: Clinical Features with Pathophysiological Basis

Active Recall - Fanconi Anemia (Definition, Epidemiology, Pathophysiology, Clinical Features)

References

Organising Framework: Why Think in Layers?

Level 1: Differential Diagnosis of Pancytopenia (The Broad View)

Level 2: Inherited vs. Acquired Aplastic Anemia

Level 3: Fanconi Anemia vs. Other Inherited BM Failure Syndromes

Level 4: FA Congenital Anomalies vs. Other Syndromic Conditions

Level 5: Specific Acquired Mimics to Rule Out

Diagnostic Approach Algorithm (Mermaid Diagram)

Key Differentiating Investigations — Summary Table

Common Exam Scenarios and How to Approach Them

Active Recall - Differential Diagnosis of Fanconi Anemia

1. Diagnostic Criteria

Step 1: Diagnostic Criteria for Aplastic Anemia (Severity Grading)

Step 2: Criteria Specific to Fanconi Anemia Diagnosis

2. Comprehensive Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3A. First-Line Blood Investigations

i) CBC with Differentials + Reticulocyte Count [4][6][8][9]

ii) Peripheral Blood Smear (PBS) [4][6][8][9]

iii) Baseline Biochemistry and Serology (Exclusionary Tests)

3B. Bone Marrow Examination

Technical Details [6][15][16]

Expected Findings in FA / Aplastic Anemia [4][5][6][8][9]

3C. Specialised Tests — FA-Specific and Exclusionary

i) Chromosome Breakage Test with DEB or MMC — THE Diagnostic Test for FA [1][4][5][6][7][8][9][10]

ii) Genetic Testing — Next-Generation Sequencing (NGS) [8][9]

iii) Flow Cytometry for CD55 and CD59 — Exclusion of PNH [1][4][6][7][8][9]

iv) BM Cytogenetics (Karyotyping / FISH) — Exclusion of MDS [8][9]

3D. Additional Investigations for Comprehensive FA Evaluation

4. Summary: Investigation Pathway Table

Active Recall - Diagnostic Criteria and Investigations for Fanconi Anemia

Overarching Principles

Management Algorithm

Treatment Modalities — Detailed Breakdown

1. Supportive Care (All Patients, All Stages)

A) Transfusion Support

B) Iron Chelation

C) Infection Prophylaxis and Treatment

D) Avoidance of DNA-Damaging Agents

2. Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) — The Curative Treatment

Why HSCT Works

Indications for HSCT in FA

Donor Hierarchy

FA-Specific Conditioning Regimen — Reduced-Intensity Conditioning (RIC)

Complications of HSCT

3. Androgen Therapy — Bridging Treatment