Knowledge on rare diseases and orphan drugs

HbH disease predominates in people of Southeast Asian, Middle Eastern and Mediterranean descent. Exact prevalence is not known but birth prevalence from newborn screening programs in the USA is estimated at 1/14,000, with individuals of south eastern ethnicity most affected.

Clinical features are highly variable and generally develop in the first years of life. Initial signs may be noticed only during routine hematologic analyses. Patients have variable microcytic hypochromic hemolytic anemia, requiring no or occasional blood transfusions during infectious episodes, exposure to oxidizing agents or pregnancy. Splenomegaly is frequently found. Non-deletional forms of alpha-thalassemia typically have more severe anemia, splenomegaly, hepatomegaly, cholelithiasis, growth retardation, decreased bone density; and have earlier and more frequent transfusion requirements. Skeletal changes mainly affecting the face can rarely occur in non-deletional forms. Iron overload develops secondary to increased intestinal iron absorption even in the absence of transfusion.

HbH disease is usually caused by inactivation of three alpha-globin alleles leading to underproduction of alpha-globin chains of Hb, with the formation of beta-4 tetramers (HbH). HbH tetramers have a high affinity for oxygen, and are highly unstable, precipitating as toxic Heinz bodies which predominate in mature red blood cells, leading to premature hemolysis rather than ineffective erythropoiesis. It is increased under oxidative stress, which explains the hyperhemolysis associated with infection or ingestion of oxidant drugs. The disease is typically caused by compound heterozygous or homozygous variants in either of the alpha globulin genes (HBA1 and HBA2; 16p13.3), accompanied by a heterozygous mutation in the other gene. In some cases, the disease is due to homozygous variants in HBA2. The severity of the disease is related to its molecular basis: patients with non-deletional types of HbH disease, such as Constant Spring mutation, are more severely affected than those with the common deletional types.

HbH disease should be considered in infants or children with mild-to-moderate microcytic hypochromic hemolytic anemia and hepatosplenomegaly. Heinz bodies can be detected on blood smears after cresyl blue staining. Hb biochemical analysis reveals the presence of HbH (5-30%). Diagnosis is confirmed by genetic testing.

Differential diagnosis includes other hemolytic anemias and alpha-thalassemia X-linked intellectual deficit (ATRX).

Prenatal diagnosis is possible when a severe form of HbH disease has previously been identified in a family member.

The pattern of inheritance is autosomal recessive. Genetic counseling depends on the genotype of the parents; where the couple has already an affected offspring, the risk of having an affected offspring in subsequent pregnancies is 25%.

In the more common milder form, patients may require occasional blood transfusion therapy. In more severe cases, regular transfusions are needed. Splenectomy should be performed only in the presence of manifest hypersplenism, because it is associated with increased thromboembolic and infectious complications. Iron overload should be monitored from adolescence by liver magnetic resonance imaging . Iron chelation is indicated in all patients with hemosiderosis. Management also requires ongoing monitoring of growth, bone health, spleen size, and fatigue level. Supplementation with folic acid is recommended.

Overall survival is variable but usually good. Many patients survive into adulthood but some have a more complicated course.

Last update: May 2021 - Expert reviewer(s): Dr Corinne PONDARRE