Hereditary xerocytosis revisited

Abstract

A 21 year old male student presented in 1980 as an Olympic athlete with a 12 year history of jaundice, pallor, and darkened urine induced by the atraumatic exercise of swimming (1). Physical examination at that time was remarkable only for moderate scleral icterus without hepatosplenomegaly. Hematological examination revealed moderate macrocytosis (MCV 102 fL) without anemia (Hct 50%, Hb 17 g/dL, 9% reticulocytes). The peripheral blood smear showed occasional target cells. Red cell osmotic fragility was decreased. Red cell Na content was increased and K content was decreased, with reduced total monovalent ion content. Passive red cell permeability of both Na and K were increased. A supervised 2.5 hr swimming workout increased free plasma Hb from <5 to 45 mg/dL and decreased serum haptoglobin from 25 to 6 mg/dL. The post-exercise urine sediment was remarkable for hemosiderin-laden tubular epithelial cells, without frank hemoglobinuria. The circulating 15 day erythrocyte half-life measured after 6 days without exercise was further shortened to 12 days after resumption of twice-per-day swimming workouts for 1 week. The patient’s red cells were hypersensitive to in vitro shear stress applied by cone-plate viscometer.

Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis)

“…Biochemical data and T2* magnetic resonance indicate the presence of hepatic iron overload, previously described as an important complication of DHSt [6,7,39]. This feature in a splenectomized patient further supports the role of dyserythropoiesis as reported for PIEZO1 mutation-associated DHSt.…”

“…Several functional characterizations of identified PIEZO1 mutations in DHSt families have uniformly demonstrated gain-of-function properties consistent with the increased net ion fluxes leading to DHSt [7,[10][11][12][13].…”

“…The definitive diagnosis of DHSt is made by osmotic gradient ektacytometry, which shows a leftward shift of the bell-shaped curve [4,5]. Occasionally associated hepatosiderosis, beyond that expected from the mild hemolytic state, suggests a strong tendency to iron overload [6,7]. Unlike hereditary spherocytosis, in which splenectomy can be beneficial, splenectomy in DHSt is contraindicated due to increased risk of thromboembolic complications [8,9].…”

A mutation in the Gardos channel is associated with hereditary xerocytosis

“…For whole cell experiments, the bath solution was (in mM) NaCl 140, KCl 5, CaCl 2 All patch-clamp experiments were performed with a PC-controlled EPC 9 patch-clamp amplifier (HEKA, Lambrecht/Pfalz, Germany). Currents were acquired and analyzed with Pulse and Pulsefit software (HEKA).…”

“…1 In HX patients, red blood cells exhibit altered intracellular cation content and cellular dehydration, which are responsible for an increased erythrocyte mean corpuscular hemoglobin concentration (MCHC) and a decreased erythrocyte osmotic fragility. 2 Under the microscope, blood films show various cell shape abnormalities, the most characteristic being a central pallor, straight or crescent shaped. These cells are called stomatocytes, and HX is also known as dehydrated hereditary stomatocytosis.…”