Inherited Pancytopenias

1. Fanconi anaemia
2. Shwachman-Diamond Syndrome
3. Dyskeratosis congenita

FANCONI ANAEMIA
Cause + Pathophysiology
Autosomal recessive
11 mutant FANC genes  abnormal DNA damage repair pathway proteins  chromosomal fragility  ↑ marrow
cell apoptosis & O2 radicals can’t be removed  hypoplastic (and fatty) marrow, pancytopenia

Epidemiology
Most common of the constitutional pancytopenias (which account for 1/3 of paed marrow failure)

M:F = 2:1

Presentation
Presents after age 3
Develop pancytopenia within 1st decade of life
Chromosomal fragility also affects other tissues

1. Pancytopenia
First thrombocytopenia, then granulocytopenia, then
macrocytic anaemia

2. Skin
Hyperpigmentation
Café au lait spots
Vitiligo

3. Bone
Thumb defects (e.g. duplex thumb)
Absent radii
Dislocated hips
Feet/leg anomalies

4. Facies
Microcephaly
Epicanthal folds
Small eyes
Abnormal ear shape/position

5. Hormonal
Growth: hypothyroidism, growth hormone deficiency
Abnormal genitalia
Impaired glucose tolerance

6. Renal
Horseshoe, ectopic, duplex, hyoplastic or pelvic kidney

7. Mental retardation in only 10%

8. Cancer
Head and neck
Oesophageal (upper > lower)
Vulva
Anus
Benign and malignant liver tumours
Leukaemia
MDS

Diagnosis
FBC 1st: thrombocytopenia
2nd: granulocytopenia
3rd: anaemia
Film Macrocytic anaemia
Bone marrow Hypocellular, fatty
Chromosomal PB leukocytes cultured, DEB (diepoxybutane) added  further increases chromosomal fragility
breakage Can do this test on AF or CVS sample
study
α-FP Elevated (rapid screening)

Management
1. Observe
2. Treat pancytopenia
a. Transfusions if needed
b. HLA-matched sibling donor  75% 5 year EFS
c. Non-matched donor  30% survival
d. Androgens e.g. oxymetholone
i. In 50% of pts, will lead to a reticulocytosis within 1-2 months, can also slowly improve
WCC and PLT count
ii. Disease can become refractory
iii. Complications
1. Growth acceleration
2. Masculinisation
3. Vascular instability  bleeding
4. Liver problems
a. ↑ liver enzymes
b. Peliosis hepatis (blood filled empty spaces – reversible)
c. Cholestasis
d. Liver tumours
iv. 2nd daily pred can ↓ growth accel and bleeding risk
v. Screen for complications
e. G-CSF
3. Yearly screening for cancer
4. Screen for endocrine problems
a. Hypothyroidism
b. Growth hormone deficiency
c. Impaired glucose tolerance

Prognosis
Median survival > 30yo

Shwachman-Diamond Syndrome
Cause + Pathophysiology
Autosomal recessive
SBDS gene on chr 7q11  90% of cases
Results in:
- Failure of pancreatic acinar development  pancreatic exocrine deficiency, fatty replacement of
pancreatic tissue
- Bone marrow failure
- Neutrophils: impaired cytoskeleton  defective mobility, migration, chemotaxis
- B cell defects: low IgG, low levels of B cells
- Low T cells, NK cells
Epidemiology
No racial predilection

Presentation
1. Symptoms of fat malabsorption from birth
E.g. steatorrhoea
Some pts may have a modest improvement in pancreatic enzyme secretion with advancing age

2. Short stature despite normal growth velocity

4. Bone
Abnormal bone maturation
Bifid thumb
Short/flared ribs, thoracic dystrophy
Metaphyseal dysplasia
Poor teeth

5. Neurocognitive/social skills impairment

COMPLICATIONS

1. MDS and leukaemic transformation: 8-33%

Diagnosis
FBC Neutropenia: can be intermittent, but almost all pts will get it at some point
~60% anaemia or thrombocytopenia
~44% pancytopenia
Film Hypocellular marrow
Fat infiltration
CT/US Fat infiltration of pancrease
Serum trypsinogen ↓
Mutational analysis study Definitive in 90%

DDx:
1. Pearson syndrome
- Refractory sideroblastic anaemia (so look for ringed sideroblasts on BM & vacuolised RBC precursors)
- Mitochondria DNA mutation
- Metabolic acidosis
- More likely to have severe anaemia from birth (Rather than neutropenia)
2. Fanconi anaemia
- Won’t have the pancreatic involvement
- DEB clastogenic stress test will differentiate (chromosome fragility study)

Management
1. Neutropenia
a. Responds well to daily subcut G-CSF
2. Transfusions as needed
3. Allogeneic HSCT
4. Steroids (androgens or prednisolone) – variable response
5. Pancreatic insufficiency
a. Enzyme replacement
b. Fat soluble vitamin supplementation
6. Monitoring for malignant transformation
a. E.g. annual BM aspirate for cytogenetics

Prognosis
Pancreatic insufficiency resolves spontaneously in ~50%
Malignant marrow transformation is ominous
HSCT leads to 50% survival

DYSKERATOSIS CONGENITA
Cause + Pathophysiology
Inherited disorder of mucocutaneous and haematopoietic systems, along with somatic abnormalities.

Inheritance:
- 85% X-linked recessive
- Some AD or AR

Presentation

Median age at dx: 15y

Ectodermal triad
1. Lacy reticulated pigmentation (seen in 1st 10y of life)
2. Dysplastic nails (seen in 1st 10y of life)
3. Oral leukoplakia (usually not seen til adulthood)

Other
- Sparse, greying hair
- Hypogonadism
- Urethral strictures
- Pulmonary fibrosis
- Oesophageal strictures
 - Severe pediatric variants:
o Hoyeraal-Hreidarsson syndrome
 IUGR + DD + microcephaly, immunodeficiency, BM failure, cerebellar hypoplasia
 Revesz syndrome: the above + exudative retinopathy

Complications
- Cancer in 10-15%
- MDS
- Solid tumours: SCC, adenocarcinoma, most commonly in oropharynx or GIT

Diagnosis
FBC Thrombocytopenia, anaemia or both
Then full blown aplastic anaemia
Film Macrocytic anaemia
HbF Initially ↑
BM Initially hypercellular, then hypocellular
Ig Can be ↑ or ↓

Management

1. Androgens improve marrow function in 50%

Acquired Pancytopenias
1. Radiation
2. Chemotherapy
3. Drugs
a. Chloramphenicol
b. Antiepileptics
c. Gold
4. Viruses
a. CMV
b. EBV
c. HCV
d. HBV
e. Seronegative hepatitis (Non A, non B, non C)
f. HIV
5. Immune disease
a. Thymoma
b. Hypoimmunoglobulinaemia
c. Eosinophilic fasciitis
6. Pregnancy
7. Paroxysmal nocturnal haemoglobinuria
8. Marrow replacement
a. Leukaemia
b. Myelodysplasia
c. Myelofibrosis
9. Autoimmune
10. Other