MedGen

Dehydrated hereditary stomatocytosis (DHS), also known as hereditary xerocytosis, is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. DHS erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. DHS patients typically exhibit mild to moderate compensated hemolytic anemia, with an increased erythrocyte mean corpuscular hemoglobin concentration and a decreased osmotic fragility, both of which reflect cellular dehydration (summary by Zarychanski et al., 2012). Patients may also show perinatal edema and pseudohyperkalemia due to loss of K+ from red cells stored at room temperature. A minor proportion of red cells appear as stomatocytes on blood films. Complications such as splenomegaly and cholelithiasis, resulting from increased red cell trapping in the spleen and elevated bilirubin levels, respectively, may occur. The course of DHS is frequently associated with iron overload, which may lead to hepatosiderosis (summary by Albuisson et al., 2013). Dehydrated red blood cells, including those from hereditary xerocytosis patients, show delayed infection rates to Plasmodium in vitro, suggesting a potential protective mechanism against malaria (Tiffert et al., 2005). A polymorphism in PIEZO1 that is enriched in populations of African descent and results in xerocytosis conferred resistance to Plasmodium infection in vitro (see 611184.0016). The 'leaky red blood cells' in familial pseudohyperkalemia show a temperature-dependent loss of potassium when stored at room temperature, manifesting as apparent hyperkalemia. The red blood cells show a reduced life span in vivo, but there is no frank hemolysis. Studies of cation content and transport show a marginal increase in permeability at 37 degrees C and a degree of cellular dehydration, qualitatively similar to the changes seen in dehydrated hereditary stomatocytosis. Physiologic studies show that the passive leak of potassium has an abnormal temperature dependence, such that the leak is less sensitive to temperature than that in normal cells (summary by Iolascon et al., 1999). Carella et al. (2004) noted that 3 clinical forms of pseudohyperkalemia unassociated with hematologic manifestations, based predominantly on the leak-temperature dependence curve, had been reported: (1) pseudohyperkalemia Edinburgh, in which the curve has a shallow slope; (2) pseudohyperkalemia Chiswick or Falkirk (see 609153), in which the curve is shouldered; and (3) pseudohyperkalemia Cardiff (see 609153), in which the temperature dependence of the leak shows a 'U-shaped' profile with a minimum at 23 degrees C. Gore et al. (2004) stated that potassium-flux temperature profiles are consistent both from year to year in an individual as well as consistent within affected members of a pedigree. Genetic Heterogeneity of Hereditary Stomatocytosis Dehydrated hereditary stomatocytosis-2 (DHS2; 616689) is caused by mutation in the KCNN4 gene (602754) on chromosome 19q13. Another form of stomatocytosis, involving familial pseudohyperkalemia with minimal hematologic abnormalities (PSHK2; 609153), is caused by mutation in the ABCB6 gene (605452) on chromosome 2q35. Cryohydrocytosis (CHC; 185020) is caused by mutation in the SLC4A1 gene (109270) on chromosome 17q21, and stomatin-deficient cryohydrocytosis with neurologic defects (SDCHCN; 608885) is caused by mutation in the SLC2A1 gene (138140) on chromosome 1p34. An overhydrated form of hereditary stomatocytosis (OHST; 185000) is caused by mutation in the RHAG gene (180297) on chromosome 6p12. See 137280 for a discussion of the association of familial stomatocytosis and hypertrophic gastritis in the dog, an autosomal recessive syndrome. Reviews Delaunay (2004) reviewed genetic disorders of red cell membrane permeability to monovalent cations, noting 'inevitable' overlap between entities based on clinical phenotype. Bruce (2009) provided a review of hereditary stomatocytosis and cation-leaky red cells, stating that consistent features include hemolytic anemia, a monovalent cation leak, and changes in red cell morphology that appear to follow a continuum, from normal discocyte to stomatocyte to echinocyte in DHS, and from discocyte to stomatocyte to spherocyte to fragmentation in OHST. Bruce (2009) suggested that the underlying pathologic mechanism might involve misfolded mutant proteins that escape the quality control system of the cell and reach the red cell membrane, where they disrupt the red cell membrane structure and cause a cation leak that alters the hydration of the red cell, thereby changing the morphology and viability of the cell. King and Zanella (2013) provided an overview of 2 groups of nonimmune hereditary red cell membrane disorders caused by defects in membrane proteins located in distinct layers of the red cell membrane: red cell cytoskeleton disorders, including hereditary spherocytosis (see 182900), hereditary elliptocytosis (see 611804), and hereditary pyropoikilocytosis (266140); and cation permeability disorders of the red cell membrane, or hereditary stomatocytoses, including DHS, OHST, CHC, and PSHK. The authors noted that because there is no specific screening test for the hereditary stomatocytoses, a preliminary diagnosis is based on the presence of a compensated hemolytic anemia, macrocytosis, and a temperature- or time-dependent pseudohyperkalemia in some patients. King et al. (2015) reported the International Council for Standardization in Haematology (ICSH) guidelines for laboratory diagnosis of nonimmune hereditary red cell membrane disorders. [from OMIM]

Platelets contain contractile proteins (actin and myosin) that induce clot retraction. As the platelets contract, they pull on the surrounding fibrin strands, squeezing serum form the mass, compacting the clot and drawing the ruptured edges of the blood vessel more closely together. Clot retraction is directly proportional to the platelet count and inversely proportional to the fibrinogen concentration. [from HPO]

The main cause of respiratory distress syndrome (RDS) in premature infants is a developmental deficiency of pulmonary surfactant. The frequency of RDS is inversely proportional to gestational age. However, not all infants born prematurely develop RDS, suggesting that there may be susceptibility factors. Because multiple factors can contribute to the pathogenesis of RDS specifically in premature infants, the etiology is considered to be multifactorial (summaries by Ramet et al., 2000; Clark and Clark, 2005). Pathogenic germline mutations in several genes involved in surfactant metabolism, including SFTPB (178640) and SFTPC (178620), can cause clinical features of respiratory distress syndrome in term neonates, children, and adults, disorders referred to as 'surfactant metabolism dysfunction' (see, e.g., SMDP1, 265120). Susceptibility to the development of RDS in premature infants may be associated with polymorphisms in surfactant genes, such as surfactant protein A1 (SFTPA1; 178630), SFTPB, and SFTPC (see MOLECULAR GENETICS). [from OMIM]

THPM2 is associated with severe hematopoietic toxicity when patients are treated with standard doses of thiopurines, a class of antineoplastic/immunosuppressant agents that consists of mercaptopurine, thioguanine, and azathioprine. Thiopurines are prodrugs that require extensive metabolism in order to exert their cytotoxic action. Thiopurines are converted into cytotoxic thioguanine nucleotides (TG), which are incorporated into DNA and cause cell death. NUDT15 inactivates thiopurine metabolites and negatively regulates cytotoxicity (summary by Moriyama et al., 2016). The NUDT15 deficiency trait follows an additive genetic mode of inheritance, with the severity of the phenotype proportional to the cumulative number of risk alleles in NUDT15. For a discussion of genetic heterogeneity of poor thiopurine metabolism, see THPM1 (610460). [from OMIM]

The Mulchandani-Bhoj-Conlin syndrome (MBCS) is characterized by prenatal growth restriction, severe short stature with proportional head circumference, and profound feeding difficulty (Mulchandani et al., 2016). [from OMIM]

A rare primary bone dysplasia with characteristics of proportional short stature, early cessation of bone growth, accelerated skeletal maturation, variable presence of early-onset osteoarthritis and osteochondritis dissecans and normal endocrine evaluation. The variable dysmorphic features include mild to relative macrocephaly, frontal bossing, midfacial hypoplasia, flat nasal bridge, brachydactyly, broad thumbs and lordosis. Caused by heterozygous mutation in the ACAN gene on chromosome 15q26. [from SNOMEDCT_US]

A rare genetic endocrine disease with characteristics of intrauterine growth restriction, failure of an adolescent growth spurt with proportional adult short stature, insulin resistance and early adulthood-onset diabetes. Minimal subluxation of the fifth metacarpal-phalangeal joint has been reported, while metaphyseal dysplasia is absent. Testicular volume is low, but fertility is normal. There is no evidence of primary adrenal insufficiency. [from SNOMEDCT_US]