The coincidence of hemolysis with anemia, jaundice and splenomegaly is evident as it were in other pathophysiological entities. However, when the bone marrow is able to compensate with erythropoiesis 6 to 8-fold in about 30% of cases and as shown by increased reticulocyte counts, anemia is either mild or absent. Jaundice is more likely to occur when the marrow's capacity is jeopardized by intercurrent infection. On the other hand, marked splenomegaly is usually attributed to other medical conditions, In HS, an enlarged  spleen is not necessarily an indication for splenectomy nor for increased susceptibility to spleen rupture as with a  normal person.    

Hereditary spherocytosis can manifest at any age from birth to the 90s, with varying severity. Jaundice is common in neonates, sometimes requiring exchange transfusion. The parents should be informed that jaundice may persist for several days only and therefore, it is not a cause for apprehension.

Based on clinical features, HS in children may be categorized into: “severe”, “moderate”, or “mild.”  Intercurrent illness and other compounding factors must be ruled out for an accurate assessment of HS according to this classification. Severe hereditary spherocytosis is associated with persistent anemia in almost rare or about 5% of cases requiring transfusion especially in the first few years of life. Treatment with erythroladderpoietin is recommended to minimize the necessity for transfusion. Henceforth, most children can cope with a low hemoglobin level and live normally.

One of the consequences of hemolysis is increased red cell turnover and increased bilirubin, a breakdown product of heme. The liver has to excrete the bilirubin into the gallbladder leading to the formation of calcium bilirubinate or pigmented gallstones. This may occur during the first or second decade of life while the risk is increased with the co-inheritance of Gilbert syndrome. Increased reticulocyte count coincides with higher risk of gallstone formation. These events may appropriately guide the option for splenectomy.

Carriers of the HS trait with mild hemolysis may remain undiagnosed for years. The finding of enlarged spleen in routine physical examination and spherocytes in peripheral blood smears are incidental during consultation for pregnancy or other medical conditions. Concurrent infection with parvovirus B19 in HS carriers can precipitate aplastic crisis marked by a sudden decrease in hemoglobin level to as low as 20 to 30 g/l and reticulocyte count. Diagnosis of parvovirus is established by the presence of IGM antibody or viral DNA in the blood. Transfusion may be needed at least once. Following successful treatment, aplastic anemia and viral infection may not recur.

A newly developed recombinant parvovirus vaccine has shown seroconversion in phase 1 trials on adults. This is a highly contagious disease. Several members may be simultaneously infected. The family of HS carriers and others should be assessed of the dangers of parvovirus infection. 

The salient features of HS are spherocytes in stained peripheral blood smears and elevated reticulocyte count with or without anemia. Unconjugated bilirubin level is higher than normal [7] [8]. Mean corpuscular volume (MCV) is reduced and mean red cell hemoglobin concentration (MCHC) is increased. To differentiate from autoimmune haemolytic anaemia (AIHA), a direct antiglobulin test is negative in HS and usually positive in AIHA. People with HS are apparently well but often with a positive family history whereas AIHA is rare in children and frequently associated with an acute viral infection. These suffice to establish the diagnosis of HS.

The traditional osmotic fragility test (OF) is tedious and not helpful if spherocytes can not be demonstrated in blood films.  The fragility test does not distinguish among the causes of spherocytosis; it is also positive in AIHA. False negative is possible in the presence of iron deficiency in obstructive jaundice. It is difficult to interpret in neonates with variable normal range. To complicate diagnosis unaffect neonates may have spherocytes for some months.

EMA (eosin-5-maleimide) binding test, using flow cytometry is currently being introduced in many laboratories. EMA binds to a skeletal protein, band 3. Sensitivity is 92.7% and specificity is 99.1% for HS. The test uses a small sample of blood and results can be obtained within two hours. It can also help identify which gene is defective in the family for academic purposes but clinical management remains the same.

Genetic analysis is a concern of researchers. Except for unusual instances HS is readily diagnosed with routine methods. Some rare disorders of red blood cells may resemble HS requiring the services of a specialist in hematology or blood dyscrasia.

Parents and children afflicted by HS should be assured that the disorder is no cause for  alarm and that one may carry on with daily life without restrictions. They should however be informed about the health hazards associated with parvovirus infection within the family. Blood counts should be monitored periodically. Long term risk of infection in splenectomized patients should be considered. It  does not follow that every new case of HS in a child in the family should be considered for splenectomy with due regard to current stricter guidelines on splenectomy in HS [9]. 

Even with severe HS and anemia (i.e., Hb 60 g/l) children are able to survive well and do not usually require transfusion in which Hb should not be the only consideration. Once the child's status has been stabilized repeated blood tests may not be necessary unless there is pallor, jaundice or threat of intercurrent infection. Routine annual check up should suffice with continued vigilance for possible parvovirus infection or abdominal pain, indicating the presence of gallstones. 

Oral folate supplements are recommended for children with chronic hemolysis in severe to moderate HS, and for all patients during pregnancy. There is no standard regimen apart from the usual daily dose of 2.5 mg up to 5 years old and 5 mg daily thereafter.

Splenectomy

The critical issue in the management of HS is whether splenectomy is absolutely necessary and when should it be done [10]. It used to serve the purpose of eliminating the cause of hemolysis and its sequelae; it also renders the patient vulnerable to infection and sepsis which are potentially fatal. The risk is highest among children. When splenectomy can not be avoided, pre-operation vaccination is prescribed against pneumoccocus, haemophilus, and menigoccocus,, with life long postoperative prophylaxis with antibiotics such as penicillin. These measures raise more questions than answers as to how efficacious are immunization and prophylaxis, for that matter, short-term versus long-term treatment with antibiotics, in adults versus children.

The merits of splenectomy must be assessed vis-a-vis the perceived risks to the patient and moral responsibility of the family. While chronic anemia is undesirable young children can tolerate this deficiency in terms of normal activity; rarely, but it can, however lead to increased cardiac output with cardiomegaly, and leg ulcers, if at all. Children with chronic anemia may be underweight and grow slowly as they approach puberty. Chronic severe hemolysis may lead to gallstone formation as early  as the first or second decade of life. Splenectomy may normalize erythropoiesis or at least reduce deformed cell destruction, improving hemoglobin level. The longevity of erythrocytes is increased without change in morphology. Gallstone formation is prevented. If there is any indication of gallbladder disease, cholecystectomy may be considered.

Splenectomy should be deferred before the child is at least 6 years old. Partial splenectomy is recommended for the most severe transfusion- dependent children to remedy the hemolysis, but they may eventually have to undergo surgery again to complete the splenectomy. Elective surgery should be considered with caution and discussed extensively with both child and parents. There have been reports of improvement in patient's status following surgery. In any case, the choice of open laparotomy versus laparoscopic surgery rests upon the surgeon depending upon experience with the method and availability of specialized equipment.

Sonography of the gall bladder is best done towards the end of the first decade, since the presence of gall stones at this point in time, even without symptoms, is relevant to the decision for both splenectomy and cholecytectomy.

The platelet count in post-splenectomy sometimes reaches levels higher than 1000×109/l. This is not a risk factor per se for thrombosis in persons with HS and does not need to be treated. On the other hand, people with some forms of hereditary stomatocytosis are at risk of thrombosis after splenectomy, underscoring the importance of consulting a hematologist for cases with atypical red cell morphology. 

Patients afflicted with the mild pattern of HS disorder can survive without difficulty unless triggered by some predisposing factor or stress. Splenectomized patients can experience improvement in RBC status and and can maintain normal hemoglobin level. 

A study in The Netherlands of HS in 132 pediatric patients, reported that 48 who have undergone splenectomy were able to cope with the disorder [5]. The trade off is diminution of quality of life compared to unaffected peers, manifestations of fatigue, patients' apprehension of social stigma, and parents' concern of vulnerability of their child to health hazards and life-threatening consequences. 

Non-splenectomized HS patients are presumably thought to be at high risk to blunt splenic injury from trauma but it does not seem to  be the case. A review of a population-based data by Hsiao and colleagues showed that there is no significant difference in the rate of blunt splenic injury between non-splenectomized HS patients from those in the general populationi [6].

Hereditary spherocytosis is the result of gene mutations that lead to aberrations in cell proteins and membrane proteins of erythrocytes. HS is common, but not exclusively, among persons of northern European and northern American lineage. The defect is transmitted as an autosomal dominant or recessive trait, presumably, from heterozygous parents. Evidence has shown that 25% of newly recognized cases do not conform with a dominant Mendelian inheritance pattern because their parents do not manifest HS. Sporadic appearance of cases may be the result of de novo mutations.

Thus, an autosomal recessive mode of inheritance is possible as seen in families with more than one affected child from apparently non-HS parents.  This pattern of recessive inheritance may account for 20-25% of all HS cases and is compatible with the Mendelian law of dominance. In this case, individuals who are carrying both allelles (homozygous recessive) or (heterozygous dominant) are susceptible to severe hemolytic anemia [4].

Hereditary hemolytic anemia is common among persons of northern European or American origins; afterall the latter also descended from European migrants to the US. The incidence of hereditary spherocytosis (HS) in the United States is roughly 1:5000 individuals but which might well be underestimated. If the autosomal recessive inheritance pattern of 25% is observed, 1.4% of Americans would be inapparent carriers of HS. The prevalence of HS in other ethnic groups has not been studied extensively. 

The disorder in hereditary spherocytosis emanates from deficiencies in the biosynthesis of proteins needed for the structural integrity of red cell membranes. Underneath the bimolecular lipid layer of the membrane are horizontal alpha and beta spectrin molecules which form heterodimers with ankyrin, proteins 4.1 abd 4.2, and band 3 (a transmembrane protein) through vertical linkage elements. These are coded by different genes and deficiency in any of the component proteins will result in destabilization of the membrane leading to abnormal morhphology and shortening of  life span  of the erythrocyte (normally around 120 days).

Defect in the cell membrane causes the erythrocyte to change shape from the normal biconcave to spherical appearance. The spleen destroys deformed and old cells which are phagocytosed. Furthermore, the fragile cell membrane causes the spherocyte to lyse due to increased cellular permeability, releasing hemoglobin. Loss of hemoglobin causes iron deficiency anemia. Increased hemolysis will lead to increased bilirubin, a breakdown product of heme, thus, hyperbilirubinemia, manifested by jaundice. Concomitant infections especially parvovirus and influenza will lead to sepsis which is potentially fatal. Splenectomy per se which is a treatment procedure will render the patient susceptiblle to infections, henceforth, sepsis.

Shorter life span of red cell is linked to exacerbation of disease. The severity of symptoms varies within and among families with hemolytic crisis, anemia and jaundice as the principal manifestations. Inheritance pattern in heterogeneous dominant is 15%.

HS patients with low levels of chronic hemolysis should take folic acid supplements for life especially those who have not been through splenectomy. Before and after splenectomy, patients should be immunized against infections with parvovirus, pneumoccocus, hemophilus and meningoccocus. Postoperative prophylaxis with antibiotics is likewise recommended.

Hereditary spherocytosis (HS), an usually autosomal dominant abnormality of red blood cells is a major cause of hemolysis  among persons of northern European origin. It is usually a mild disease in children but a cause for concern when present with parvovirus B19 infection causing transient severe anemia. The traditional laboratory diagnosis of HS using the osmotic fragility test which is tedious and inconclusive is being replaced by the more recently developed EMA binding method. Since the spleen normally destroys deformed or old erythrocytes resulting in intravascular hemolysis, splenectomy is indicated to promote red cell survival in severe disease. Cholecystectomy may be needed if gallstones are present. The downside of splenectomy in HS patients is the possible risk of sepsis, despite preoperative vaccinations and prophylaxis with antibiotics.

Anemia in children is usually due to iron deficiency in the diet, infection with hookworms, or drug-induced hemolysis in G6PD (glucose-6-phosphate dehydrogenase) deficiency, a hereditary red cell enzyme disorder. G6PD deficiency is transient and self-limiting. On the other hand, hemolysis in hereditary spherocytosis, is chronic and subject to complications with intercurrent infections [1] [2] [3].

What is hereditary spherocytosis?

Hereditary spherocytosis (HS) is a genetic aberration in the red blood cells which predisposes the person affected with this disorder to chronic hemolysis. Normal red blood cells or erythrocytes are donut-shaped and can pass through small blood vessels. In HS the erythrocytes become deformed (actually, spherical) hence the term spherocytes. Spherocytes lack flexibility, are fragile and tend to break with physical pressure as when forced to pass through a small vessel, releasing hemoglobin, an essential component of iron. The process is called hemolysis and the result, hemolytic anemia and/or jaundice. The bone marrow has to produce more cells which are immature (reticulocytes) to prevent anemia. In HS, reticulocytes are in seen peripheral blood films in greater number than normal. HS is also manifested by the passage of "coke-colored" urine and formation of gallstones. 

Splenectomy and/or cholecystectomy may be needed in severe to moderate cases upon the discretion of the attending clinician. Otherwise, lifelong intake of folate supplements is prescribed to compensate for hemolytic anemia. Immunity to infection and prophylaxis with antibiotics are needed for pre-operative and post-operative treatment of cases. Hereditary spherocytosis is common in people of northern European and northern American origins. Affected persons have 50% probability of passing this gene to their offsprings. New mutations can occur in approximately 25% of cases. 

What are the signs and symptoms?

• Anemia – paleness (pallor), fatigue, dyspnea (shortness of  breath).
• Jaundice - yellow discoloration of the skin and white part of eyeball.
• Enlarged spleen (splenomegaly) - palpable on the left side of abdomen beneath the rib cage.
• Debilitated appearance, weakness, and inability to concentrate.
• Irritability, restlessness in children. 
• Abdominal pain – from splenomegaly and presence of gallstones.
• Underweight and slow growth in children.

What tests are needed? 

• Thorough physical examination and family history.
• Clinical laboratory – CBC (complete blood count), reticulocyte count, blood chemistry, and liver function tests. 

What treatments are available and what are their side effects?

• Usually no special is treatment is required. 
• Dietary folate supplements in children.
• Splenectomy, deferred until the child is 5 years old or older. This is to control destruction of abnormal and old erythrocytes, hemolysis and its sequelae. The morphology of the red blood cell remains unchanged but its life span returns to normal. However, splenectomy predisposes the patient to infections, hence. the need for preoperation and postoperation chemotherapy. 
• Prophylactic (preventative) antibiotics. 
• Blood transfusions, may have side effects rarely, if at all. allergic reaction and contaminants in the blood product.
• Immunodiagnostic tests for parvovirus infection.
• EMA binding test, using flow cytometry (in lieu of the osmotic fragility test).

Problems associated with spherocytosis 

Aplastic crisis may accompany the reduction in hemoglobin levels and reticulocyte counts. Viral infections may suppress bone marrow function and its capacity to compensate for cell loss, leading to severe anemia. Blood transfusion is often required in these instances. Hemolytic crisis results from rapid red cell destruction leading to jaundice, passage of dark urine and anemia. Blood transfusion is the immediate remedial measure. With supportive treatment and adequate nutrition, most pediatric  patients can cope well with the disorder and are able to lead normal lives.

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2. Comité Nacional de Hematología  Donato H, Crisp RL, Rapetti MC, García E, Attie M. Hereditary spherocytosis. Review. Part II. Symptomatology, outcome, complications, and treatment. Arch Argent Pediatr. 2015;113(2):168-76.
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