Key Points
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.
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.
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 the presence of a telomerase mutation.
Environmental factors:
Acquired AA is an immune-mediated disease and some environmental factors may play a role, such as viruses in hepatitis-associated AA.
| Syndrome | Gene(s) Involved | Function | Ancillary Diagnostic Testing |
|---|---|---|---|
Dyskeratosis congenita X-linked Autosomal dominant Autosomal recessive | DKC1 TERC, TERT, TINF2 NHP2, NOP10, TCAB1 | Telomere maintenance | Telomere length measurement Mutation screening |
| Fanconi anemia | At least 15 genes FANC-A to FANC-P | DNA repair FA pathway for DNA damage response | Chromosome breakage test with cross-linking agents (diepoxybutane [DEB] or mitomycin C [MMC]) |
| Shwachman-Diamond syndrome | SBDS | Putative RNA processing | Mutation screening |
| Acquired aplastic anemia | TERT, TERC, SBDS in ~10% of cases | – | Telomere length measurement Mutation screening |
Diagnostic Criteria and Clinical Characteristics
Diagnostic evaluation should include
Complete blood counts (CBC) with reticulocyte count peripheral blood smear. CBC will show marked reduction in three or less commonly two of the three cell lines. Peripheral blood smear will demonstrate reduction in cell counts with normal morphology, but usually macrocytosis is present. For severe AA, at least two of the three following criteria are necessary: (1) absolute neutrophil count less than 500/μL; (2) platelet count less than 20,000/μL; (3) reticulocyte count (automated) less than 60,000/μL.
Bone marrow aspirate and biopsy, including cytogenetic analysis. Overall marrow cellularity should be less than 30% (excluding lymphocytes).
Peripheral blood flow cytometry for GPI-anchored proteins to detect associated paroxysmal nocturnal hemoglobinuria (PNH).
Chromosome breakage test with diepoxybutane (DEB) or mitomycin C (MMC) for the diagnosis of Fanconi anemia.
Telomere length measurement may be helpful for overall prognosis and to diagnose a telomere disease when telomere length is less than first percentile (cryptic dyskeratosis congenita or dyskeratosis congenita-like disease).
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