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Definition of «Fanconi anemia»

Fanconi anemiaFanconi anemiaFanconi anemia

Fanconi anemia: A genetic disease that affects all of the bone marrow elements, is associated with a great diversity of malformations as well as pigmentary changes of the skin, and predisposes to malignancy.

Malignancy: Fanconi anemia predisposes particularly to a disturbance of bone marrow growth called myelodysplasia and to acute myeloid leukemia. Patients tend also to develop cancers in areas of the body where cells normally reproduce rapidly, such as the mouth, esophagus, the intestinal and urinary tracts, and the reproductive organs.

Clinical features: Children with Fanconi anemia usually have low birth weight, are smaller than average at birth and tend to have the following birth defects:

  • Skin pigment changes (65% of cases)
    • Cafe-au-lait spots (coffee-with-milk spots) on the skin
    • Brownish pigmentation of the body so it has a suntanned look
    • Large freckles
  • Short stature (60% of cases)
  • Upper limb malformations (50% of cases):
    • Underdeveloped or missing radius (a forearm bone)
    • Misshapen or missing thumbs
    • Clinodactyly (curved fingers), polydactyly (extra fingers), absent finger bones, short fingers
  • Genital abnormalities (40% of cases) including:
    • In males: Small penis and absent, small, or undescended testes; and low or no sperm count.
    • In females: absence of uterus or vagina, bicornuate uterus, ovarian atresia, irregular menses, and early menopause.
  • Vertebral and spinal malformations (30% of cases):
    • Webbed neck with a low posterior hairline
    • Spine abnormalies such as spina bifida and scoliosis
  • Kidney and ureter abnormalities (25% of cases)
    • Pelvic kidney (kidney located down in the pelvis), horseshoe kidney, hypoplastic (underdeveloped) kidney
    • Collecting system abnormalities such as hydronephrosis, hydroureter, reflux of urine
  • Eye abnormalities (25% of cases) including
    • Microphthalmia (abnormally small eye)
    • Strabismus ("crossed eyes")
    • Ptosis (drooping eyelids)
    • Cataracts
  • Mental retardation (25% of cases) and associated:
    • Small head (microcephaly).
    • Learning disabilities.

Inheritance: Fanconi anemia is an autosomal recessive condition. Both parents carry the same mutation (gene change). Each of their children has a 1 in 4 chance of inheriting the mutant gene from both parents resulting in the disease.

However, the genetics of Fanconi anemia are complicated by the fact that there are at least seven different Fanconi anemia genes: A, C, D2, E, F, G and BRAC2. Six of these genes have been cloned. Mutations in the A and C genes account for about 75% of patients worldwide with Fanconi anemia.

Molecular genetics: The Fanconi protein complex incorporates proteins produced by at least five Fanconi anemia genes. The Fanconi complex normally promotes a cascade of changes in a biochemical pathway that ultimately leads to the repair of cellular DNA damage. But if any of the proteins within the complex are mutated, the enzyme PHF9 is disabled and the DNA repair pathway is disrupted. All of the other proteins in the Fanconi complex function through PHF9. PHF9 is a key cog in the DNA repair machinery.

Tests: A laboratory test for Fanconi anemia involves chromosome breakage. White blood or other cells are treated in the laboratory with a chemical, diepoxybutane (DEB) or mitomycin C (MMC), that crosslinks the strands of DNA. Normal cells can correct most of the damage produced by DEB or MMC while Fanconi cells cannot and show marked chromosome breakage. DNA tests can also identify specific mutations in Fanconi families and can be performed on a single cell.

Treatment: The short-term treatment of Fanconi anemia includes blood transfusions for the anemia and antibiotics for infections. Long-term treatment includes giving androgens (male hormones) and hematopoietic (blood-stimulating) growth factors. Androgens stimulate the production of red blood cells, often platelets and sometimes white cells; this treatment may be effective for years, but most patients eventually fail to respond. Growth factors such as G-CSF may boost the production of white cells. Bone marrow transplantation is currently the only long-term cure for the bone marrow disease in Fanconi anemia. Gene therapy trials are in progress.

History: The disease is named for the great Swiss pediatrician Guido Fanconi (1892-1979) who first described it. In 1927 Fanconi reported a family in which 3 brothers with slight stature, skin pigmentation and hypogonadism who had died in childhood from anemia.

Reference: G. Fanconi: Familiare, infantile perniciosahnliche Anamie (pernizioses Blutbild und Konstitution). Jahrbuch fur Kinderheilkunde und physische Erziehung, Wien, 1927, 117: 257-280.

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