Background
Abnormalities of red cell membrane cation permeability are seen in several hereditary disorders. These dominantly inherited conditions are collectively called the hereditary stomatocytoses and allied disorders. This class of hemolytic anemias is clinically diverse.
See image below.
Hereditary stomatocytosis. Courtesy of Jean A. Shafer, BS, MA, Assistant Professor of Hematology and Pathology at the University of Rochester School of Medicine and Dentistry.
Overhydrated hereditary stomatocytosis (OHSt), also called hydrocytosis, was the first of these disorders to be described.
An abnormally increased cation influx results in swollen erythrocytes, hemolysis, and stomatocytes. At the other end of the spectrum, net loss of cations and water results in the more common dehydrated hereditary stomatocytosis (DHSt), also called xerocytosis.
Intermediate syndromes that are asymptomatic or have mixed features, such as cryohydrocytosis (CHC) and familial pseudohyperkalemia (FP), have also been described.
OHSt has been linked to mutations in the erythroid ammonia channel Rh-associated glycoprotein (RhAG),
as well as, occasionally, to mutations in the band 3 chloride-bicarbonate exchanger AE1, regulated by SLC4A1. Decreases in stomatin are seen in OHSt.
The causative gene for DHSt was mapped to 16q23-24 and was identified with genome-wide sequencing as PIEZO1, with a few patients linked to KCCN4.
CHC has been linked to mutations in SLC4A1.
The causative gene for FP, mapped to 2q35-36, was identified as ABCB6.
Syndromic forms of hereditary stomatocytosis are rare but increasingly recognized and have improved our understanding of genetic mechanisms. Described syndromes including the following:
CHC with mental retardation, seizures, and hepatosplenomegaly (stomatin deficiency linked to
SLC4A1)
Nonleaky stomatocytosis with hypercholesterolemia, xanthomas, splenomegaly, and macrothrombocytopenia (severe phytosterolemia linked to
ABCG5 or
ABCG8)
DHSt with transient perinatal edema, including neonatal ascites (linked to
PIEZO1)