Introduction

The clinical expression of haemoglobin H (HbH) disease extends from mild asymptomatic anaemia to severe anaemia with transfusion-dependence and hydrops foetalis [1, 2]. Since phenotype is largely determined by underlying genetic changes, it is important to specify the subtype of HbH disease with the terms deletional (deletion of three α-globin genes) and non-deletional (two or three affected α-globin genes, of which one or more have point mutations) [3]. Individuals with deletional HbH disease usually have mild asymptomatic anaemia that remains unsuspected in many cases until an incidental laboratory finding of anaemia prompts diagnostic workup.

In this chapter, we review clinical presentation and management of deletional HbH disease while the more severe form of HbH disease (non-deletional HbH disease) will be discussed separately in the next chapter (Please see Chapter 3: Clinical presentation and management of non-deletional haemoglobin H disease).

Genetic basis of deletional HbH disease

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The most frequent genotype in deletional HbH disease results from various combinations of α⁺-thalassaemia deletions (-α^3.7, -α^4.2, other) with α⁰-thalassaemia deletions (--^SEA, --^FIL, --^THAI, --^MED, other). Regardless of (more...)

Clinical presentations and complications of deletional HbH disease

Newborn infants diagnosed at birth through a screening programme have asymptomatic perinatal period and infancy. Microcytic, hypochromic anaemia is present at birth with haemoglobin generally at 110-130 g/L. On haemoglobin analysis using high performance liquid chromatography, haemoglobin Bart’s fraction of 25-35% of total haemoglobin can be identified [6, 7]. Haemoglobin follows the expected trend with nadir around 3 months of age (usually staying >75 g/L), following which it slowly increases to reach 85 - 95 g/L by 4 years. After a child reaches puberty, haemoglobin generally is at 100-120 g/L in men and 90 -105 g/L in women [1-3, 6, 8-11].

In those who are identified later in life, laboratory tests also show anaemia, microcytosis, hypochromia, anisocytosis with increase in red cell width (RDW) and target cells while nucleated red blood cells are few or absent on a peripheral blood smear. Such patients may be misdiagnosed with iron deficiency anaemia and prescribed supplemental iron, which can increase the risk of iron overload. However, there is evidence of mild haemolysis with slight increase in bilirubin and reticulocyte count. Haemoglobin electrophoresis demonstrates presence of fast-moving HbH 5-15% of the total haemoglobin. The peaks of HbH and Hb Bart’s are also identified by automatic high-performance liquid chromatography (HPLC) and capillary electrophoresis system, however, the percentage may not be accurately quantitated. HbH inclusion bodies can be visualized with a supravital stain such as methyl violet or brilliant cresyl blue. Genetic testing is essential in every patient to exclude presence of non-deletional HbH disease. Gastrointestinal iron absorption is increased, which leads to a mild iron overload in the 3^rd decade or later manifesting as elevation in serum ferritin, but with normal transferrin saturation [3].

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Patients with HbH disease can present with episodic exacerbation of haemolysis or transient aplastic events during infections. While haemolytic (or aplastic) episodes can occur in individuals with deletional HbH disease, various publications from different (more...)

Children with deletional HbH disease demonstrate normal growth and development based on their constitutional trajectory, and their physical activity is generally indistinguishable from peers [3]. Skeletal changes that are commonly seen in β-thalassaemia syndromes are not observed in deletional HbH disease. Splenomegaly is either absent or mild [2, 3].

In keeping with the benign disease course, cholelithiasis is observed in 15-20% of adults, though a significant increase in thrombotic and vascular complications is not reported [6]. Women can go through pregnancy without an increase in obstetrical complications or the need for regular transfusion support [6, 13]. An increase in adverse perinatal outcome and foetal growth restriction is reported by some groups [13], though this was not observed in a different series [6]. The risk of haemoglobin Bart’s hydrops foetalis must be considered if the partner has α⁰ thalassaemia trait. Some adults may develop fatigue, although quality of life has not been formally evaluated in HbH disease [6].

Management of deletional HbH disease

The aim is to provide comprehensive haematology care and follow up to patients with deletional HbH disease at all stages of life, while recognizing that the initial diagnosis may be made in different settings and at any age.

Routine care

The initial clinic visit is used to review complete blood count, electrophoresis, and genetic tests to ensure that results are consistent with deletional HbH disease. DNA testing is strongly recommended in all cases to exclude non-deletional mutants that make the disease course more severe. While routine testing for co-existing G6PD deficiency is not recommended, this should be considered when a patient experiences haemolytic crisis. The patient and family are counselled about the expected mild clinical course. Subsequent visits are conducted every three months for the first year and then every 12 months. A complete blood count with reticulocyte count is obtained at each visit, while bilirubin and ferritin are checked once a year. All childhood vaccinations are given according to the normal schedule and patients should receive the seasonal influenza vaccine. At each visit, height and weight percentiles are checked to document normal growth that is expected in deletional HbH. Folic acid 0.4 to 1 mg per day is recommended to all patients starting around 6 months. Vitamin D status is checked to maintain sufficiency, using supplements if needed. No dietary modifications are needed and there are no specific medications or foods to avoid. In particular, there is no evidence that oxidant drugs should be avoided in the absence of known G6PD deficiency. Adhering to a reduced-iron diet is not necessary, however, supplements containing iron are discouraged unless laboratory tests show presence of iron deficiency. Starting at 10 years of age, the child’s bone mineral density is evaluated by dual-energy X-ray absorptiometry (DXA) every 2–3 years, or more frequently if needed. Maintenance of physical activity and participation in sports is encouraged.

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Children with deletional HbH have similar incidences of common paediatric febrile illnesses compared with their peers. Patients with fever can be seen in the clinic on the next day unless an urgent visit is warranted by the reported symptoms. Checking (more...)

As severe anaemia is rare even during febrile illness, the need for transfusion should be assessed based on the clinical status of the patient. In otherwise uncomplicated situations, it is appropriate to observe the patient and transfuse if the haemoglobin drops <60 g/L in younger children, or <65 g/L in adults. Avoidance of transfusions is a desirable goal in the management of deletional HbH disease in view of the risk of alloimmunization and other complications. Chronic transfusion therapy or splenectomy is not recommended for patients with typical clinical course of deletional HbH disease (Please see Chapter 9: Blood transfusion and Chapter 10: Splenomegaly and splenectomy).

Iron overload

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Iron overload due to increased absorption of gastrointestinal iron develops with age in adults and can become significant (liver iron concentration >3 mg/d) in the fourth or fifth decade. Serum ferritin gradually increases, earlier in men than (more...)

Genetic counselling

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Reproductive counselling is very important and partner testing is routinely advised to identify the risk for transmission of a significant haemoglobin disorder. If the partner is carrier of the α⁰-thalassaemia trait, then there is a 25% risk of (more...)

Summary and recommendations

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