Hereditary spherocytosis and membrane disorders — formative SAQs

SAQ 1 (10 marks)

A seven-year-old girl is referred for investigation of chronic fatigue, pallor and intermittent yellowing of the eyes. Her mother had a splenectomy at age twelve and a cholecystectomy at twenty-eight. On examination she has scleral icterus and a spleen palpable four centimetres below the costal margin. Her haemoglobin is 84 g per litre, mean cell haemoglobin concentration is 370 g per litre, reticulocyte count is twelve per cent, unconjugated bilirubin is 42 micromoles per litre, and the blood film shows numerous small dense spherocytes. The direct antiglobulin test is negative. [1]

1. Give the diagnosis, explain the pathophysiology, and describe the confirmatory investigation of choice. (3) [1] [2]
2. Outline the definitive management, including the role and timing of splenectomy and the decision between total and partial splenectomy. (4) [2] [4]
3. Describe the pre-splenectomy preparation and the lifelong post-splenectomy precautions that this child must receive. (3) [2] [5]

Model answer — SAQ 1

(1) Diagnosis, pathophysiology and confirmation (3). The diagnosis is hereditary spherocytosis, supported by the family history of splenectomy and cholecystectomy, the triad of anaemia, jaundice and splenomegaly, the raised mean cell haemoglobin concentration, the reticulocytosis, the unconjugated hyperbilirubinaemia, the spherocytes on the blood film, and crucially the negative direct antiglobulin test excluding autoimmune haemolysis. The pathophysiology is a defect in the vertical protein linkages of the red cell membrane — most commonly ankyrin deficiency — that destabilises the lipid bilayer-to-cytoskeleton tether. The membrane blebs off, the cell loses surface area without losing volume, the surface-to-volume ratio falls, and the biconcave disc becomes a dense, rigid spherocyte that cannot deform through the splenic cords and is destroyed by splenic macrophages. The confirmatory investigation of choice is the eosin-5-maleimide binding test, a flow cytometric assay showing reduced fluorescence in hereditary spherocytosis due to reduced band 3 content, with a sensitivity of about ninety-three per cent and specificity of about ninety-eight per cent. [1] [2]

(2) Definitive management and splenectomy (4). Every child receives folic acid supplementation to support the expanded erythropoiesis, at a dose of 5 mg daily in this age group. For her moderate disease with symptomatic haemolysis and a haemoglobin of 84 g per litre, splenectomy is indicated. Splenectomy is the only curative treatment for the haemolysis: it removes the organ of red cell destruction, so the haemolysis resolves and the haemoglobin normalises, though the underlying membrane defect persists and the cells remain spherocytes. The splenectomy should be deferred until at least six years of age, which she has reached, and the laparoscopic approach is preferred. The choice between total and partial splenectomy is debated: total splenectomy provides superior haematological outcomes with complete elimination of the haemolysis, but it removes all splenic immune function and carries the full risk of overwhelming post-splenectomy infection. Partial splenectomy preserves some immune function but carries a higher rate of reoperation and recurrence. The recent systematic review and meta-analysis favours total splenectomy for definitive cure, with partial splenectomy reserved for younger children with severe disease who cannot wait until six years or for families who prioritise immune preservation. Concomitant cholecystectomy should be considered if gallstones are present. [2] [4]

(3) Pre-splenectomy preparation and lifelong precautions (3). At least two weeks before splenectomy she must complete the vaccination bundle against encapsulated organisms: pneumococcal (conjugate and polysaccharide as appropriate for age), meningococcal (ACWY and B), and Haemophilus influenzae type b. After splenectomy she requires lifelong antibiotic prophylaxis with penicillin V at 250 mg twice daily in this age group, or erythromycin if allergic. The family must receive a febrile-illness action plan: any fever is an emergency requiring immediate medical assessment and parenteral antibiotics, because the risk of overwhelming post-splenectomy infection is highest in the first two postoperative years and in young children. She should carry a medic alert device and a patient-held information card, and her vaccination schedule must be kept up to date through adolescence and into adulthood. [2] [5]

SAQ 2 (10 marks)

A three-year-old boy with known hereditary spherocytosis presents to the emergency department with four days of fever, coryza and increasing pallor. His haemoglobin is 42 g per litre, and his reticulocyte count is 0.5 per cent (previously 11 per cent). His mother is twenty weeks pregnant. [1] [6]

1. Interpret the presentation, give the diagnosis, and explain the pathophysiology of this complication. (3) [1] [6]
2. Outline the immediate management, including a specific public health precaution. (4) [1]
3. Describe how you would distinguish hereditary spherocytosis from hereditary stomatocytosis and explain why this distinction is critical before any future splenectomy. (3) [2] [3]

Model answer — SAQ 2

(1) Interpretation, diagnosis and pathophysiology (3). This child has a parvovirus B19 aplastic crisis. The diagnostic clue is the precipitous fall in haemoglobin to 42 g per litre accompanied by a collapse of the reticulocyte count from 11 per cent to 0.5 per cent, in a child with known hereditary spherocytosis and a febrile prodrome. Parvovirus B19 infects erythroid progenitor cells via the P antigen and transiently halts red cell production. In a child whose survival depends on a high reticulocyte count to compensate for ongoing haemolysis, this abrupt cessation of erythropoiesis causes a rapid and severe fall in haemoglobin over days, because the marrow stops producing while the haemolysis continues. [1] [6]

(2) Immediate management and public health precaution (4). The immediate management is urgent transfusion of packed red cells, because the child is severely anaemic with a haemoglobin of 42 g per litre and his marrow cannot produce red cells. Cardiovascular monitoring and supportive care are essential. Send parvovirus B19 serology or PCR to confirm the diagnosis. The recovery phase is heralded by a brisk reticulocytosis as the marrow recovers. The specific public health precaution is isolation from pregnant contacts: parvovirus B19 can cross the placenta and cause hydrops fetalis and fetal loss, and his mother is twenty weeks pregnant, so she must be informed, tested for parvovirus immunity, and referred for obstetric assessment. [1]

(3) Distinguishing hereditary spherocytosis from stomatocytosis (3). Hereditary spherocytosis and hereditary stomatocytosis can both present as chronic haemolytic anaemia, but they are distinguished by the blood film and specialised testing. Hereditary spherocytosis shows spherocytes (small dense cells without central pallor) and has a reduced eosin-5-maleimide binding test. Hereditary stomatocytosis shows stomatocytes (cells with a mouth-shaped central slit) and is confirmed by osmotic gradient ektacytometry or molecular testing for PIEZO1 or related mutations. The distinction is critical because splenectomy — the curative treatment for the haemolysis of hereditary spherocytosis — is dangerous and potentially fatal in hereditary stomatocytosis due to a high risk of thromboembolism, including fatal pulmonary hypertension and venous thrombosis. Before any splenectomy for a presumed membrane disorder, hereditary stomatocytosis must be excluded. [2] [3]