Hemoglobin H Disease and its Variants

The gene frequencies of alpha-thalassemia exceed those of beta-thalassemia. The loss of alpha-gene function may be secondary to a deletional or nondeletional mutation. Nondeletional mutations are more severe. The inactivation of one alpha-globin gene is insignificant. The inactivation of two alpha-globin genes causes a very mild microcytic, hypochromic anemia. The loss of function of three alpha-globin genes is called hemoglobin H disease. People with hemoglobin H disease have a variable phenotype that can range from mild symptoms to those similar to thalassemia major. Due to phenotypic variability or in utero intervention, more patients with this disorder are being reported.

Hemoglobin H disease is a serious health problem in Southeast Asia and southern China. Thousands of affected patients live in the Middle East, the Mediterranean region, and North America. Many patients require intermittent transfusions. The clinical severity is strongly influenced by the type of mutation. Deletions on chromosome 16 are responsible for 75 percent of hemoglobin H mutations, and these deletions cause a milder form of the disorder. The remaining 25 percent of patients with hemoglobin H disease have two deletions plus a point mutation or insertion in the alpha-globin gene. Nondeletional hemoglobin H is often severe and likely to require transfusions. In both groups, however, there is marked phenotypic variability.

Hemoglobin H deletion

After the newborn period, the diagnosis of deletional hemoglobin H disease is often made only after the detection of complications such as cholelithiasis, exacerbation of the anemia induced by infection, or the findings of splenomegaly and growth failure. The mean hemoglobin in deletional hemoglobin H is quite variable but averages 9.5 g/dL. Twenty-nine to 50 percent of patients with deletional hemoglobin H require intermittent transfusion therapy, but the need for chronic transfusion therapy is uncommon. Pregnancy is often associated with an increased severity of anemia, as well as pre-eclampsia, and may necessitate transfusion.

Iron overload and iron-induced heart failure are increasingly being noted in adult patients not receiving intermittent transfusions. Serum ferritin levels usually underestimate the magnitude of iron overload. Iron deposits in nontransfused patients are in the ferrihydride form, which causes more damage than the goethite iron that results from transfusion. Earlier therapeutic intervention for iron overload in nontransfused hemoglobin H disease is indicated.

Hemoglobin H–Constant Spring

Hemoglobin H–Constant Spring is the most common nondeletional alpha-thalassemia mutation associated with hemoglobin H disease. Hemoglobin H–Constant Spring disease has significantly more ineffective erythropoiesis. The laboratory and clinical course of hemoglobin H–Constant Spring disease is more severe than hemoglobin H disease. The average hemoglobin is 2 g/dL less than in deletional hemoglobin H disease. The mean corpuscular volume is a near-normal 72 fL, compared to 59 fL for deletional hemoglobin H disease. Most patients have moderately severe splenomegaly, and over 50 percent require splenectomy. Splenectomy often results in improved hemoglobin levels but is associated with a high rate of portal vein thrombosis. Ninety percent of patients with hemoglobin H–Constant Spring disease have been intermittently transfused, and up to 40 percent have required repeated transfusions, particularly in early infancy and in later adulthood. Iron overload occurs in 75 percent of patients by adulthood. Rarely, hemoglobin H–Constant Spring disease and other nondeletional hemoglobin H disorders have caused fatal hydrops fetalis syndrome.

Homozygous alpha-thalassemia

Homozygous alpha-thalassemia, caused by a deletion of all four alpha-globin genes, leads to the formation of high levels of hemoglobin Barts in utero. Hemoglobin Barts has an extremely high oxygen affinity, and therefore delivers little oxygen to fetal tissues. The severe hypoxia results in cardiac failure, massive ascites, and intrauterine death. Congenital malformations associated with homozygous alpha-thalassemia include hypospadias, other genitourinary defects, and limb malformations. Infants surviving to delivery without prenatal intervention are usually hydropic and commonly have neurological impairment. Intrauterine transfusions following early detection of homozygous alpha-thalassemia have resulted in the birth of several nonhydropic infants, some but not all of whom have no significant neurological abnormalities or congenital anomalies. Affected infants who survive gestation and the neonatal period subsequently require chronic transfusion therapy or may be appropriate candidates for hematopoietic stem cell transplantation.

Occasionally, infants with homozygous alpha-thalassemia are born without hydrops, even in the absence of intrauterine transfusions. Nondeletional, highly unstable alpha-globin gene mutations may result in a hemoglobin H genotype, causing hydrops fetalis. In pregnancies known to be at risk, chorionic villous sampling with molecular analysis identifies homozygous alpha-thalassemia within the first months.

The ethical issues of managing a fetus known to have homozygous alpha-thalassemia are complex. Obstetric complications and the necessity for long-term transfusion therapy are serious considerations. Increased risk of both maternal and fetal morbidity should be included in counseling families at risk for an affected fetus. Education, screening, and counseling of the family are essential.