Knowledge on rare diseases and orphan drugs

The annual incidence of symptomatic cases is estimated at 1/100,000 worldwide and 1/10,000 in the EU. The prevalence of this form is not known.

Onset is during infancy with severe anemia, failure to thrive and progressive pallor. Feeding problems, diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the abdomen caused by splenomegaly and hepatomegaly may occur. Untreated or poorly transfused patients show growth retardation, pallor, jaundice, poor musculature, genu valgum, leg ulcers, formation of masses due to extramedullary hematopoiesis, and skeletal changes including deformities in the long bones of the legs and typical craniofacial changes such as bossing of the skull, prominent malar eminence, depression of the bridge of the nose, tendency to a mongoloid slant of the eye, and maxillae hypertrophy, which tends to expose upper teeth. In regularly transfused patients, growth and development tend to be normal but complications related to iron overload may develop, including growth retardation and failure or delay of sexual maturation. Later-onset iron overload complications include dilated myocardiopathy, arrhythmias, liver fibrosis and cirrhosis, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands. Other complications are hypersplenism, venous thrombosis and osteoporosis.

BT is caused by point mutations or, more rarely, deletions in the HBB gene (11p15.5), leading to reduced (beta+) or absent (beta0) synthesis of the beta-chains of hemoglobin (Hb). Mutations causing BT major are homozygous or compound heterozygous.

Diagnosis is suspected in infants younger than 2 years of age with severe microcytic anemia, mild jaundice and hepatosplenomegaly. Blood analysis shows reduced Hb levels (< 7 g/dl), mean corpuscular volume (MCV) > 50 < 70 fl, and mean corpuscular Hb (MCH) > 12 < 20 pg, anisopoikilocytosis and presence of erythroblasts in the peripheral blood smear. Hb analysis and molecular genetic analysis provide diagnostic confirmation.

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

Prenatal diagnosis is possible by amniocentesis. Both disease-causing alleles must be identified before prenatal testing can be performed.

Transmission is autosomal recessive. Genetic counseling provides information for patients and at-risk couples (i.e. both carriers) regarding the mode of inheritance and transmission. Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified.

Treatment is based on lifelong transfusions to correct anemia, suppress erythropoiesis, and inhibition of gastrointestinal iron absorption, which occurs in non-transfused patients due to increased, although ineffective, erythropoiesis. Iron chelation should be started once patients have had 10-15 transfusions or when ferritin levels are above 1000 ng/ml. Management should also include treatment of iron overload-related complications (growth deficiency, delayed puberty, hypogonadism, hypopara- and hypothyroidism, diabetes, and osteoporosis). Splenectomy may be required. Bone marrow transplantation (BMT) is at present the only available definitive cure. Recently a first patient was successfully treated with gene therapy.

Patients who do not receive regular transfusions and iron chelation usually die before the 2nd or 3rd decade whereas survival is higher in regularly transfused and chelated patients. Cardiac complications are still the major cause of death.

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