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An acquired form of alpha-thalassemia characterized by a myelodysplastic syndrome (MDS) or more rarely a myeloproliferative disease (MPD) associated with hemoglobin H disease (HbH).
ORPHA:231401Classification level: Disorder
- Acquired HbH disease
- Acquired hemoglobin H disease
- Prevalence: <1 / 1 000 000
- Inheritance: Not applicable
- Age of onset: Adult
- ICD-10: D46.7 D56.0
- OMIM: 300448
- UMLS: C0585216
- MeSH: -
- GARD: -
- MedDRA: -
About 80 cases have been identified to date and most involved patients are of northern European descent. Some cases have been reported in patients from Asia and the Mediterranean area.
ATMDS occurs predominantly in males during the 7th decade of life (male-to-female ratio greater than 6:1). The main clinical features include anemia and other signs associated with MDS such as shortness of breath, weakness, tendency to bruise or bleed and an increased susceptibility to infections. It has occasionally been associated with MPD and in these cases, splenomegaly frequently co-occurs. MDS progresses to leukemia in about 25% of cases and HbH is usually no longer detectable at this time.
ATMDS is due to acquired somatic mutations in the ATRX gene (Xq21.1). There is also evidence that acquired deletions of chromosome 16p may be causative. These defects result in significant down-regulation of alpha-globin gene expression.
Typical hematological findings show hypochromic microcytic red blood cells and striking anisopoikilocytosis, and the presence of HbH inclusions in a proportion of red blood cells that varies depending on the patients. Cytological and cytogenetic analysis of bone marrow cells is required to confirm the diagnosis and to classify the underlying MDS. Direct sequencing of the ATRX gene in DNA samples from blood or bone marrow usually indicates a mosaicism, identified by a single nucleotide mutation.
Differential diagnoses include other causes of anemia, cytopenia or microcytosis. It is especially important to exclude an inherited form of alpha-thalassemia by molecular analysis of the HBA locus.
Management and treatment
Treatment depends on the underlying MDS. Stem cell transplantation is the only curative treatment but it is rarely feasible. Other treatment options may include hypomethylant (azacitabine) therapy and lenalinomide. Supportive care includes blood transfusions, erythropoietin stimulating agents, growth factors, antibiotics (if infections are present), and iron chelation therapy in those undergoing long term transfusion therapy.
Prognosis depends on the sub-type of MDS according to the International scoring system (ISS). The scoring system takes into account the percentage of marrow blasts, the severity of cytopenia, and cytogenetic analysis of bone marrow cells. Death is usually due to leukemic transformation, infections due to neutropenia, bleeding related to thrombocytopenia and, in some cases, to other co-morbidities such as cardiovascular disease.