Hereditary spherocytosis and membrane disorders — branching viva

Examiner opening (Examiner)

You are the general paediatric registrar in the outpatient clinic. A seven-year-old girl is referred for 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. Talk me through your assessment and diagnostic plan. [1]

Exemplar opening (Candidate)

This child has a clinical picture strongly suggestive of hereditary spherocytosis, supported by the autosomal dominant family history of splenectomy and cholecystectomy and the triad of anaemia, jaundice and splenomegaly. I will confirm the diagnosis with a full blood count, reticulocyte count, unconjugated bilirubin, blood film, and a direct antiglobulin test to exclude autoimmune haemolysis. I expect to find a variable anaemia with a raised mean cell haemoglobin concentration, a raised reticulocyte count, unconjugated hyperbilirubinaemia, and spherocytes on the film with a negative direct antiglobulin test. I will then arrange the eosin-5-maleimide binding test as the first-line confirmatory investigation, and an abdominal ultrasound to document the spleen size and screen for gallstones. [1] [2]

Branch 1 — the disease and the pathophysiology (Examiner)

What is hereditary spherocytosis, and what is the mechanism by which the red cells are destroyed? [1]

Exemplar (Candidate)

Hereditary spherocytosis is the commonest inherited haemolytic anaemia in Northern European populations, caused by a quantitative or qualitative deficiency of one or more red cell membrane skeleton proteins. The defect is in the vertical interactions that link the lipid bilayer to the underlying spectrin-based cytoskeleton — most commonly ankyrin, but also beta-spectrin, band 3, alpha-spectrin and protein 4.2. When these linkages fail, the unsupported lipid bilayer blebs off in small vesicles, the cell loses surface area without losing volume, the surface-to-volume ratio falls, and the normal biconcave disc is forced into a sphere. The spherocyte is rigid and lacks the deformability to pass through the splenic cords, so it is trapped in the splenic red pulp and destroyed by splenic macrophages. This extravascular haemolysis is the engine of the anaemia, jaundice and splenomegaly, and it is why splenectomy is curative — removing the organ of destruction stops the haemolysis even though the membrane defect persists. [1]

Branch 2 — diagnosis and the EMA binding test (Examiner)

What is the eosin-5-maleimide binding test, and why has it replaced the osmotic fragility test? [2]

Exemplar (Candidate)

The eosin-5-maleimide binding test is a flow cytometric assay that is now the first-line confirmatory investigation for hereditary spherocytosis. Eosin-5-maleimide is a fluorescent dye that binds to band 3 and associated proteins on the red cell membrane. In hereditary spherocytosis, the reduced band 3 content means less dye binds, and flow cytometry shows reduced mean fluorescence compared with control cells. It has a sensitivity of about ninety-three per cent and a specificity of about ninety-eight per cent, it is rapid, requires only a small blood sample, and it can be performed on the same day as the blood film. It has largely replaced the osmotic fragility test because the osmotic fragility test is less sensitive, particularly in mild cases, and requires fresh blood. The EMA test cannot distinguish hereditary spherocytosis from hereditary pyropoikilocytosis or some cases of congenital dyserythropoietic anaemia, so the result must be interpreted alongside the blood film and clinical context. And I would always perform a direct antiglobulin test first, because autoimmune haemolysis produces identical spherocytes and is excluded only by a negative DAT. [2]

Branch 3 — management and splenectomy timing (Examiner)

How would you manage this girl, and at what point would you consider splenectomy? [2]

Exemplar (Candidate)

Every child with hereditary spherocytosis receives folic acid supplementation to support the expanded erythropoiesis, at a dose of 5 mg daily in this age group. For this girl with moderate disease — a haemoglobin of 84 g per litre with symptomatic haemolysis — I would plan splenectomy, because it is the only curative treatment for the haemolysis. I would defer the splenectomy until at least six years of age, which she has reached, because the risk of overwhelming post-splenectomy infection is highest in young children. The laparoscopic approach is preferred. I would also screen for gallstones with ultrasound and consider concomitant cholecystectomy if stones are present. [2] [4]

Branch 4 — total versus partial splenectomy (Examiner)

What are the arguments for and against partial splenectomy? [4]

Exemplar (Candidate)

The choice between total and partial splenectomy is the subject of ongoing debate. Total splenectomy eliminates the haemolysis completely and prevents recurrence, but it removes all splenic immune function and carries the full risk of overwhelming post-splenectomy infection. Partial splenectomy preserves some immune function and may reduce the infection risk, but a recent systematic review and meta-analysis found that it carries a higher rate of reoperation and recurrence of haemolysis. The current consensus favours total splenectomy for definitive cure, with partial splenectomy reserved for children under six years with severe disease who cannot wait until they are old enough, or for families who prioritise immune preservation after full counselling of the higher reoperation risk. [4] [6]

Branch 5 — pre-splenectomy bundle and lifelong precautions (Examiner)

What must you do before and after the splenectomy to protect this child? [5]

Exemplar (Candidate)

At least two weeks before the splenectomy she must complete the vaccination bundle against encapsulated organisms: pneumococcal, 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 she is allergic. The family must receive a febrile-illness action plan: any fever is an emergency requiring immediate medical assessment and parenteral antibiotics, because the asplenic child cannot clear encapsulated organisms such as Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type b, and overwhelming post-splenectomy infection can be fatal within hours. 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. [5]

Branch 6 — the stomatocytosis trap (Examiner)

Before you book the splenectomy, the blood film review notes some stomatocytes. What must you consider, and why is it critical? [3]

Exemplar (Candidate)

I must exclude hereditary stomatocytosis before proceeding with any splenectomy, because splenectomy in hereditary stomatocytosis carries a high risk of fatal thromboembolism, including fatal pulmonary hypertension and venous thrombosis. Hereditary stomatocytosis is a cation-leak disorder — mutations in transporters such as PIEZO1 in the dehydrated form — that produces chronic haemolysis with stomatocytes on the blood film, and it can clinically resemble hereditary spherocytosis. I would confirm the diagnosis with osmotic gradient ektacytometry or molecular testing for the relevant cation-leak mutations. If hereditary stomatocytosis is confirmed, splenectomy is contraindicated and I would manage her conservatively with folic acid and transfusion support. This is the single most important safety check before any splenectomy for a presumed membrane disorder. [3]

Examiner wrap-up (Examiner)

Thank you. Summarise the three points you most want the examiner to remember. [1]

Exemplar (Candidate)

First, hereditary spherocytosis is the commonest inherited haemolytic anaemia in Northern Europeans, autosomal dominant in about three-quarters of cases, with a vertical membrane protein defect producing spherocytes that the spleen traps and destroys. Second, the eosin-5-maleimide binding test is the first-line confirmatory investigation, and a direct antiglobulin test must always be performed first to exclude autoimmune haemolysis; splenectomy is the only curative treatment for the haemolysis, deferred until at least six years, with a mandatory pre-splenectomy vaccination bundle and lifelong antibiotic prophylaxis. Third, hereditary stomatocytosis must be excluded before any splenectomy, because splenectomy in that condition carries a high risk of fatal thromboembolism — this is the single most important safety check in the workup of any child with a presumed red cell membrane disorder. [1] [3]