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FANCONI ANEMIA

DEFINITION:

A chromosomal breakage disorder characterized by familial aplastic anemia, various congenital anomalies, and a characteristic chromosomal response to clastogenic stress.

EPIDEMIOLOGY:

incidence: ?
age of onset:
- 90% of males diagnosed by age 12 years; mean of 7.9 years
- 90% of females diagnosed by age 14 years; mean of 8.8 years
risk factors:
- familial - autosomal recessive
  - chrom.#: ?20q13.2-q13.3
  - gene: ?
- M > F (1.3:1)

PATHOGENESIS:

1. Background

considered to be a "chromosomal breakage syndrome"
- one of at least 4 disorders associated with a high frequency of chromosomal defects with an increased risk of lymphoreticular (leukemia) and other malignancies - other syndromes:
  - Ataxia-Telangiectasia
  - Bloom Syndrome
  - Xeroderma Pigmentosum
most common of the heritable aplastic anemias
there is an International Fanconi Anemia Registry

2. Genetic Defect

genetic defect -> in utero disruption of hematopoiesis and malformation of specific body areas between 25-34 days of gestation
hematopoietic defect evident at progenitor cell level
- bone marrow - decreased GM-CFU, E-CFU, E-BFU
- blood - " E-BFU

3. Chromosomal Abnormalities

chromosomal breaks, gaps, and rearrangements
- high frequency of clastogenic-induced chromosomal breaks
- endoreduplication, exchanges, triradials or quadriradials
- involve homologous and nonhomologous chromosomes
number of sister chromatid exchanges per cell is lower than normal
because of the high variation in the number and frequency of clinical abnormalities, (25% of affected patients are structurally normal and phenotypic expression is modified by genetic and environmental factors) the diagnosis must be confirmed cytogenetically
prenatal diagnosis - amniotic fluid cells when treated with di-epoxybutane may demonstrate a higher than normal incidence of chromosomal abnormalities

CLINICAL FEATURES:

1. Haematological Manifestations

1. Pancytopenia

anemia
- develops early to middle childhood
- pallor
- fatigue
thrombocytopenia
- bleeding usually first manifestation and progressive
- easy bruising
leukopenia
- recurrent infections

2. Congenital Anomalies (67% of cases)

1. Craniofacial

broad nasal bridge
epicanthal folds
micrognathia
microcephaly

2. Musculoskeletal

small for gestational age
congenital dislocation of the hip
short stature
radii - hypoplasia or aplasia (if radii affected, thumb too)
thumb - hypoplasia, aplasia, and/or supernumerary

3. Cutaneous

cafe-au-lait spots
hyperpigmentation - on trunk, neck, intertriginous areas
hypopigmented spots

4. Genitourinary

absent kidney
cryptorchidism
duplication of kidney or collecting system
horseshoe kidney
primary testicular failure +/- small penis & testes
renal ectopia

5. Neurological

hyperreflexia
mental retardation

6. Ocular

microophthalmia
strabismus

7. Neoplasms (in 20% of cases)

lymphoreticular tumors
- leukemias - acute nonlymphocytic leukemia
  - AML (in 5-10% of cases)
hepatic
- hepatocellular carcinoma
- hepatomas
- adenomas
others
- squamous cells carcinoma
- GI tumors
- gynecologic tumors

INVESTIGATIONS:

1. Serum

Hb: macrocytic (MCV = 95-105 fL), HbF (5-15%), low reticulocytes
pancytopenia
smear: anisocytosis, poikilocytosis
elevated serum erythropoietin levels
growth hormone deficiency

2. Bone Marrow

hypocellular with increased fatty tissue
prominent reticulum, plasma and mast cells
low erythroid and granulocytic precursors
pancytopenia

3. Chromosome Breakage Analysis

of blood lymphocytes, amniotic cells, or chorionic villus cells
metaphase preparations exposed to clastogenic stress
- exposure to difunctional alkylating agents such as mito-mycin C or diepoxybutane induces a higher than normal rate of chromosomal abnormalities (10-70% compared to <10% in normals)
spontaneous chromosomal breakage rate also higher than normal
needed for diagnosis

4. Imaging Studies

1. Renal Ultrasound

congenital renal anomalies

2. Skeletal X-rays

upper limbs and hands

MANAGEMENT:

1. Supportive

transfusions of PRBC, platelets, antibiotics
treatment of aplastic anemia
- avoid drugs and chemicals which can cause aplastic anemia
splenectomy is not indicated

2. Steroid Therapy

1. Androgens +/- Corticosteriods

oxymetholone most frequently used androgen +/- prednisone
increases Hb (1-2 months), WBC counts, then platelet counts (up to 6-12 months)
50% response rate
may relapse if steroids discontinued
may increase survival rate
SE: obstructive liver disease, peliosis hepatis (hemor-rhagic cysts of the liver), liver tumors, refractory to androgen therapy, masculinization

3. Bone Marrow Transplantation

to prevent/cure aplastic anemia and/or leukemia
chemotherapy and/or radiation may accelerate appearance of secondary malignancies

4. Others

immunotherapy - methylprednisolone, cyclosporin A
lithium
hematopoitic growth factors

Pediatric Database - FANCONI ANEMIA

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