Prevalence in Germany is estimated to amount to approx. 1:2000 - 2500 [2]. Hereditary spherocytosis is by far the most common congenital hemolytic anemia in persons of northern or central European descent.

The common cause of the various forms of hereditary spherocytosis are membrane defects. These defects decrease the deformability of the erythrocytes and accelerate their degradation in the spleen. The genes encoding the membrane proteins ankyrin, band 3, and spectrin are most frequently affected [3]. Modifications of the genes encoding protein 4.2, the RH complex and cases with hitherto undefined defects are less frequent [4]. The disease follows an autosomal-dominant trait in about 70 percent of all persons affected, whereas autosomal-recessive inheritance prevails in only 15 percent. Other patients acquire the disease on account of new mutations. Table 1 shows a classification based on molecular features [3- 6].

The clinical spectrum of hereditary spherocytosis ranges from severe forms requiring transfusions in early childhood to asymptomatic patients with incidental diagnosis by laboratory analysis or other indication. Characteristic features and typical complications are compiled in Table 2 and 3.

Hemolytic crises reoccur particularly in the context of intercurrent infections. The course is mostly mild in young adults, and blood transfusion will not be necessary. The aplastic crisis mostly occurs only once. It might result in a strong decrease of the hemoglobin concentration, making a blood transfusion necessary. Of seldom occurrence are cardiovascular complications, extramedullary hematopoiesis, or secondary hemochromatosis [4].

In patients with a mild form of the disease - who did not undergo splenectomy - the condition of chronically enhanced hemolysis might also lead to extramedullary hematopoiesis with the clinical picture of intrathoracic, paravertebral tumors subsequent to a progression over decades. Varicose ulcers might appear in elderly patients. Whether the association between hereditary spherocytosis and spinocerebellar ataxia, rare cases of which have been reported, relies on the same genetic defect has not been elucidated yet.

A classification of hereditary spherocytosis based on clinical severity grades is shown in Table 4 [2, 7-10].

A special group are carriers of the genetic abnormality without clinical symptoms and without a positive family history, in whom incidentally conspicuous laboratory parameters were found. Laboratory findings indicative of hereditary spherocytosis are summarized in Table 5 [9]:

A combination of several parameters is needed to confirm the tentative diagnosis of a genetic predisposition. If no spherocytes are detected, if the erythrocyte indices remain unchanged, and if the reticulocytes are within normal range, hereditary spherocytosis cannot be ruled out, but it is unlikely that such person will ever show any symptoms. The differentiation between a clinically asymptomatic predisposition and a mild form of spherocytosis can be difficult. Mild forms may occasionally exacerbate due to splenomegaly of a different etiology (e.g. lymphomas) or due to viral infections (EBV, parvovirus).

The elevated MCHC (mean cellular hemoglobin concentration) value is of special relevance to identifying spherocytosis patients. It reports the concentration of hemoglobin in terms of hemoglobin per 100ml erythrocytes.

Increased MCHC values may be found in the following situations:

• Hemoglobin value is determined too high due to any kind of plasma turbidity

• RBC count is determined too low, e.g. in case of coagulated blood samples

• High cold agglutinin titers

• Hereditary RBC membrane disorders such as spherocytosis and variants, e.g. xerocytosis

• Hemoglobin CC anomaly

• Homozygous sickle-cell disease (occasional)

• Hemochromatosis patients with massive iron overload [11], also depending on the genotype

Meticulous medical history and physical examination provide the basis of rational diagnostics. Further diagnostic steps to be taken in adults are shown in Table 6 and 7 and as an algorithm presented in Figure 1.

There is no single test that identifies all forms of hereditary spherocytosis. For this reason it is recommended to combine two test procedures. A recent study with 150 patients even achieved a sensitivity of 100 percent by combination of AGLT and EMA test [12]. An examination of osmotic resistance with hypotonic salt solutions has a distinctly lower sensitivity than AGLT and EMA test.

Differential diagnostics of adult patients with hyperregenerative, normochromic anemia and spherocytes can be classified into congenital and acquired disorders:

Splenectomy often contributes to the elimination of anemia and to the regression of increased hemolysis parameters. However, the alterations discovered in blood smears will become more distinctive than they had been previously. Splenectomy is mostly indicated in childhood, but should, if possible, not performed before school age. Splenectomy also has to be considered in adults with symptomatic disease. Splenectomy is an option for adults with extramedullary hematopoiesis. It remains an open question whether extramedullary hematopoiesis recedes afterwards.

If hemolysis persists after splenectomy the diagnosis will have to be reconsidered. Accessory spleens must be searched for and, if they exist, they must be removed. The indication for splenectomy depends on the degree of clinical severity, see Table 9 [2].

The risk of splenectomy consists in the operation and in the life-long increased rate of severe infections, particularly due to pneumococci with a mortality of 0.1 – 0.4 % [2, 18]. The risk is reduced by a partial instead of a complete splenectomy [19, 20]. Subtotal splenectomy is recommended in patients with hereditary spherocytosis. A mild anemic condition might persist in patients with a severe variant of the disease, particularly in case of spectrin defects. Prior to and after splenectomy recommendations concerning vaccinations and/or antibiotic prophylaxis must be observed. [21, 22].