hereditary elliptocytosis

**Pathophysiology:** HE results from mutations in genes encoding RBC cytoskeletal proteins that are responsible for horizontal interactions in the membrane skeleton: alpha-spectrin (SPTA1, most common), beta-spectrin (SPTB), and protein 4.1R (EPB41). Defective spectrin dimer-dimer self-association (tetramer formation) weakens the membrane skeleton. Cells are normal (biconcave) when newly released but become elliptical after repeated mechanical shear stress in the circulation, because the weakened skeleton can't recover its shape. Protein 4.1 deficiency (more common in some populations) can cause more severe disease. Glycophorin C deficiency also causes 4.1-related effects.

**Inheritance:** Autosomal dominant (mostly). Homozygous or compound heterozygous states cause severe disease. Hereditary pyropoikilocytosis (HPP) is a severe, often recessive/compound heterozygous variant with spectrin mutations: bizarre poikilocytes, fragmentation, microspherocytes; RBCs are abnormally thermally sensitive (fragment at ~45-46 °C rather than ~49 °C).

**Clinical features:** - Most (≈90%) are asymptomatic with normal or near-normal hemoglobin and compensated hemolysis, often found incidentally on smear. - Symptomatic patients: extravascular hemolytic anemia, jaundice, splenomegaly, pigmented gallstones (bilirubin), and possible aplastic crisis with parvovirus B19. - Neonates may have transient hemolysis (infantile poikilocytosis) that can resolve. - Hemolysis can worsen with infections, pregnancy, or hypersplenism.

**Diagnosis:** - Peripheral smear: elliptocytes (oval/cigar-shaped cells) in large numbers (often >25%, may be much higher). Contrast with the few elliptocytes seen in iron deficiency (pencil cells), thalassemia, megaloblastic anemia, and myelofibrosis. - Labs of hemolysis: elevated indirect bilirubin, LDH, and reticulocytes, low haptoglobin. - Normal or mildly abnormal osmotic fragility (unlike hereditary spherocytosis, in which fragility is increased). - Negative direct Coombs test. - Confirmatory: SDS-PAGE of membrane proteins, ektacytometry, or genetic testing.

**Treatment:** None for asymptomatic patients. Folic acid supplementation for chronic hemolysis. Transfusion for severe anemia. Splenectomy for severe symptomatic hemolysis (usually effective, particularly in HPP), ideally delayed until after age ~5 and with vaccination against encapsulated organisms (S. pneumoniae, H. influenzae type b, N. meningitidis). Cholecystectomy for symptomatic gallstones.

**Board-relevant comparisons:** - Hereditary spherocytosis: ankyrin (most common), band 3, spectrin, protein 4.2 defects (vertical interactions); spherocytes, increased MCHC, positive osmotic fragility/EMA binding test, Coombs negative. - Hereditary elliptocytosis: spectrin/4.1 defects (horizontal interactions); elliptocytes, usually mild. - Southeast Asian ovalocytosis (SAO): band 3 deletion; rigid stomatocytic ovalocytes, protective against malaria. - Both HE and HS are extravascular hemolysis (spleen), with similar complications (gallstones, aplastic crisis with parvovirus B19).

**High-yield mnemonics/associations:** "Horizontal = elliptocytes; vertical = spherocytes." Elliptocytes = defects in spectrin and protein 4.1.