HEREDITARY SPHEROCYTOSIS

Hereditary spherocytosis is the commonest intrinsic red cell membrane defect and fourth common cause of hemolytic anemia in childhood.

Etiology: Hereditary spherocytosis is predominantly an autosomal dominant disorder (~75%), characterized by a molecular defect in two RBC stromal proteins- spectrin and ankyrin.

Clinical manifestations vary according to the severity of defect, with most severe cases presenting with neonatal hyperbilirubinemia, requiring phototherapy or exchange transfusion.

However, most cases presents in early infancy with a clinical triad of—(i) mild/moderate pallor, (ii) pro­gressively severe splenomegaly, and (iii) persistent jaundice. Despite gross splenomegaly, anemia in hereditary spherocytosis is rarely severe enough to require transfusions except during intermittent aplastic crisis, often precipitated by viral (parvovirus) infections.

Formation of gallstones due to excessive bilirubin excretion, is a major complication of hereditary spherocytosis, seen in ~50% of older children/adults.

Laboratory diagnosis is based on:

• Presence of spherocytes in peripheral smear, i.e. small, round or biconvex RBCs with absent or reduced central pallor (Fig. 19.3).

• Osmotic fragility test, i.e. increased osmotic fragility on incubation of RBCs in progressive dilutions of normal saline. In doubtful cases, prior incubation of RBCs at 37°C for 24 hours (modified osmotic fragility test) accentuates this fragility.

• Demonstration of specific protein defect by Gel electro- phoresis/densitometric studies and RBC membrane studies are confirmative.

Other important laboratory abnormalities include: (a) moderate anemia (8-10 gm/dl) with low MCV but high MCHC, (b) high reticulocyte count (~ 5-20%), (c) indirect hyperbilirubinemia, (d) hypercellular bone marrow with erythroid hyperplasia (rarely needed), and (e) presence of gallstones on USG, which is indicated in all cases of hereditary spherocytosis with abdominal pain.

D/D includes other causes of spherocytes in peripheral smear, e.g. (a) Rh-hemolytic disease in newborn, (b) autoimmune hemolytic anemia, (c) Wilson disease,

(d) burns, and (e) septicemia.

Management: Since anemia in hereditary spherocytosis is mainly due to increased trapping and destruction of RBCs in the spleen, total or partial splenectomy is the treatment of choice. However, it is indicated only in cases with—(a) gross splenomegaly, (b) persistent moderate anemia lt;8 gm/dl, or (c) recurrent aplastic crisis. While peripheral smear abnormalities persist even after splenectomy, Hb levels usually return to normal. Splenectomy also reduces the risk of traumatic rupture of spleen.

Splenectomy should preferably be deferred till 5-6 years of age to cross the vulnerable age for infections. Till then, contact sports should be avoided to minimize risk of splenic injury. Preventive vaccines against

capsular organisms (pneumococcal, H. influenzae B and meningococcal) along with oral penicillin prophylaxis are recommended in splenectomized children.

Other interventions include blood transfusions during aplastic crisis, folic acid supplements (PO 1 mg/day), and treatment of complications, e.g. gallstones.

Other uncommon RBC membrane defects include:

Hereditary elliptocytosis/stomatocytosis may be either asymptomatic or present with mild hemolytic anemia. Diagnosis is established on smear examination. No treatment is necessary in asymptomatic cases, though symptomatic cases may require splenectomy and folic acid supplementation.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and RBC membrane defect, which renders them susceptible to damage by serum complement.

Clinically, these cases present with: (a) chronic hemolytic anemia with mild pancytopenia, (b) intermittent nocturnal paroxysms of intravascular hemolysis with hemoglobinuria, and (c) secondary complications, e.g. thromboembolic episodes, aplastic anemia and leukemia. Diagnosis usually rests on detection of hemosiderinuria during attacks and a positive Ham (acid serum) test or sucrose-lysis test, suggestive of complement lysis. Flow cytometry to detect deficiency of glycolipid-bound membrane proteins, identified by CD₅₉ expression, is currently the best diagnostic test for PNH.

Management includes: (a) glucocorticoids during acute hemolytic episodes, (b) prolonged anticoagulant therapy in thromboembolic episodes, and (c) bone marrow stimulants, e.g. ATG, cyclosporin, androgens, erythropoietin and GM-CSF, etc. Bone marrow transplant has been attempted in few cases as curative therapy.

19.5.2