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Key Points

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  • Disease summary:

    • Aplastic anemia (AA) is the prototypic disease of hematopoietic stem cell failure. It is characterized by an empty bone marrow resulting in low peripheral blood cell counts (pancytopenia).

    • AA can be acquired or inherited. Most common types of inherited AA are Fanconi anemia, dyskeratosiscongenita, and Shwachman-Diamond syndrome.

    • Acquired AA is an immune-mediated condition in which activated type-1 cytotoxic T cells target hematopoietic stem and progenitor cells in the marrow.

    • Whereas congenital AA is more frequent in the first and second decades of life and is associated with physical abnormalities (café-au-lait spots, hyperpigmentation, short stature, abnormal thumbs in Fanconi anemia; nail dystrophy, leukoplakia, and reticular hyperpigmentation in dyskeratosiscongenita; and exocrine pancreatic insufficiency in Shwachman-Diamond syndrome), the incidence of acquired AA is bimodal, peaking in adolescence (15 years) and greater than 50 years and physical anomalies are absent.

  • Differential diagnosis:

    • Other causes of pancytopenia must be excluded: acute leukemia, myelodysplastic syndrome, pernicious anemia, bone marrow infiltration by other neoplasias.

    • It is not uncommon that a constitutional type of aplastic anemia to manifest without the usual clinical findings. Thus, it is necessary to perform ancillary diagnostic tests for the differential diagnosis of inherited bone marrow failure syndromes (Table 33-1), especially in children. Chromosome breakage test is routinely performed for the diagnosis of Fanconi anemia and telomere length measurement for the diagnosis of dyskeratosis congenita.

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  • Monogenic forms:

    • Fanconi anemia, dyskeratosis congenita, and Shwachman-Diamond syndrome are monogenic forms of constitutional aplastic anemia (Table 33-1).

    • Fanconi anemia: biallelic mutations in one of the at least complementation groups (FANC) (A, B, C, D1 [BRCA2], D2, E, F, G, I, J [BRIP1/BACH1], L, M, N [PALB2], O [RAD51C], and P [SLX4]) are necessary for disease, except for the FANCB gene, which is located in the X chromosome. Mutations in FANCA are etiologic in up to 70% of cases; mutations in FANCC are found in approximately 14% of patients; mutations in FANCG are found in 10% of cases; and mutations in each of the other complementation groups are observed in less than 3% of cases.

    • Dyskeratosiscongenita: the X-linked form is caused by mutations in the DKC1 gene (~30% of cases); the autosomal dominant form may be caused by mutations in TINF2 (~15%), TERC (~10%), or TERT (~10%); the autosomal recessive form is rare and mutations in TERT, TERC, NHP2 (<1%), NOP10 (<1%), or TCAB1 (<1%) are etiologic.

    • Shwachman-Diamond syndrome: biallelic mutations in the SBDS gene are found in approximately 90% of patients.

    • Acquired AA: although the vast majority of cases are immune mediated, heterozygous mutations in TERT, TERC, or SBDS are found in approximately 10% of cases and are considered genetic risk factors for disease.

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  • Family history:

    • Patients with constitutional aplastic anemia usually have a positive family history for aplastic anemia, but also for leukemia or other types of cancer. Of clinical significance, in “acquired”AA, a family history for leukemia, pulmonary fibrosis, or hepatic disease may suggest ...

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