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BT is prevalent in Mediterranean countries, the Middle East, Central Asia, India, Southern China, North Africa and South America. The overall annual incidence of symptomatic cases of beta-thalassemia is estimated at 1/100,000 worldwide and 1/10,000 in the EU. Annual incidence of BT intermedia is not known.

BT intermedia encompasses a wide clinical spectrum with more severe cases presenting between 2 and 6 years of age with anemia, spleen and sometimes liver enlargement, as well as delayed growth and development. In other cases, patients are completely asymptomatic until adult life with only mild anemia. Hypertrophy of erythroid marrow, with the possibility of extramedullary erythropoiesis, is common and leads to characteristic deformities of the bone and face, osteoporosis with pathologic fractures of long bones and formation of erythropoietic masses primarily affecting the spleen, liver, lymph nodes, chest and spine. Less commonly, erythroid marrow hypertrophy may cause neurological problems (spinal cord compression with paraplegia). Patients may also develop leg ulcers and gallstones. An increased predisposition to thrombosis versus BT major has been reported, especially after splenectomy. Although patients are at risk of iron overload, hypogonadism, hypothyroidism and diabetes are not common. Cardiac involvement may also occur as a result of a high-output state and pulmonary hypertension, while systolic left ventricle function is usually preserved.

BT intermedia is caused by minor and/or silent mutations in the HBB gene (11p15.5) encoding the beta-chains of hemoglobin (Hb), in the homozygous or compound heterozygous state.

Diagnosis is based on clinical findings, hematological tests (Hb level between 7 and 10 g/dl, mean corpuscular volume (MCV) between 50 and 80 fl and mean corpuscular Hb (MCH)between 16 and 24 pg), hemoglobin analysis and molecular genetic testing.

Differential diagnosis is usually simple but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as myelomonocytic leukemia and aplastic anemia).

Transmission is commonly autosomal recessive and autosomal dominant forms have rarely been reported (dominant beta-thalassemia). Genetic counseling provides information for patients and at-risk couples (i.e. both carriers) regarding the mode of inheritance, transmission and clinical phenotype. However, there are not always exact genotype-phenotype correlations and prenatal diagnosis is performed in selected cases.

Treatment is symptomatic. Supplementary folic acid can be prescribed to prevent deficiency from hyperactive bone marrow. Treatment of extramedullary erythropoietic masses is based on radiotherapy, transfusions, or hydroxycarbamide. Main indications for splenectomy are symptoms of splenic enlargement, worsening of anemia (not explained by transient factors such as infection) sometimes associated with leukopenia and/or thrombocytopenia, delayed growth, and heart disease. Iron overload is controlled with chelation therapy. Suitable anticoagulation therapy must be administered before surgery to prevent thrombosis. Pregnant patients need a multidisciplinary approach including specialists in thalassemia care.

Prognosis is usually good with appropriate monitoring and treatment. Patients do not usually have severe hemosiderosis and are less prone to iron overload-related cardiac problems. Pulmonary hypertension, thromboembolic complications, overwhelming postsplenectomy sepsis, and the development of hepatocarcinoma may however reduce survival.

Last update: May 2011 - Expert reviewer(s): Pr Renzo GALANELLO - Dr Raffaella ORIGA