Hb H disease: clinical course and disease modifiers

Abstract

Hemoglobin H (Hb H) disease is the most common form of thalassemia intermedia and has many features that require careful consideration in management. In the majority of cases, Hb H disease results from double heterozygosity for alpha(0)-thalassemia due to deletions that remove both linked alpha-globin genes on chromosome 16, and deletional alpha(+)-thalassemia from single alpha-globin gene deletions (--/-alpha). However, Hb H disease may occur from interactions between alpha(0)-thalassemia with non-deletional mutations (alpha(T)alpha or alpha(T)) or with abnormal hemoglobins such as Hb Constant Spring, Hb Paksé, Hb Quong Sze, and Hb Pak Num Po. In a steady state, patients with Hb H diseases have hemoglobin levels around 9 to 10 g/dL; however, during hemolytic crisis, which frequently develops in or after acute infections with high fever, the hemoglobin level may drop significantly and patients can develop shock or renal shutdown. Even though splenectomy leads to significant elevation of hemoglobin levels, it is not recommended because the majority of patients do well with said steady-state hemoglobin levels. Patients with non-deletional Hb H disease are usually more anemic with significant splenomegaly, and some may require regular blood transfusions and be even as severe as "Hb H hydrops fetalis." However, there is no clear genotype-phenotype correlation associated with this severe clinical syndrome since patients with identical genotypes do not necessary show the same severity. This suggests that other genetic and environmental factors play a role in modifying the degree of clinical severity in patients with non-deletional Hb H disease.

How I treat thalassemia

“…For these patients, transfusions may be required from infancy, with eventual splenectomy. 10 Genotyping of 836 thalassemia patients in the United States by the National Institutes of Health Thalassemia Clinical Research Network identified 106 (12.7%) with HbH disease, 46 (5.5%) with a nondeletional ␣ mutation, and 44 with HbH and Hb CS, most of them from the west coast. 11…”

“…1 Nearly 70 different nondeletional mutations exist that may be coinherited with deletional mutations or other genetic modifiers that result in variable genotypic and/or phenotypic expression. 10 A diagnosis of ␣-thalassemia can be suspected based on factors, such as a family history of anemia and geographic and ethnic background, particularly if the patient comes from the Middle East, North Africa, and Southeast Asia, areas where ␣-thalassemia is …”

Relationship between neonatal screening results by HPLC and the number of α-thalassaemia gene mutations; consequences for the cut-off value

“…Subsequently, HbH disease or a-thalassaemia with three out of four affected a-globin genes (--/2a), may cause severe anaemia shortly after birth and may lead to transfusion dependency later in life. 4,5 Especially children with a non-deletional HbH disease (Hb Constant Spring) may have growth delay, severe anaemia during infectious illness and require blood transfusion with consequent iron overload. 6 Early detection of this severe disorder by newborn screening leads to improvement of parental information, allows anticipatory prevention, supportive therapy and treatment in case of infectious disease.…”

Homozygous deletion of the major alpha-globin regulatory element (MCS-R2) responsible for a severe case of hemoglobin H disease

“…[2][3][4][5][6][7] It has been shown experimentally that deletion of MCS-R2 alone is sufficient to down-regulate alpha-globin expression to less than 3% of normal, consistent with the notion that MCS-R2 is the most important regulatory element. 8,9 In our patient, the homozygous deletion of MCS-R2 is associated with HbH disease, a phenotype less severe than expected from the predicted reduction of alpha-globin chain expression.…”

“…Most commonly HbH disease results from deletion or dysfunction of 3 of 4 alpha-globin genes, and rarely from deletions in the upstream regulatory region. 2,[4][5][6] Here we describe a severe case of HbH disease in a 11-year-old Italian boy due to deletions of variable extent of both upstream regulatory regions, with all 4 downstream alpha-globin genes intact. The hematologic characteristics of the proband and his family are reported in Figure 1.…”