#145260
ICD+
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| PSEUDOHYPOALDOSTERONISM, TYPE II; PHA2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HYPERPOTASSEMIA AND HYPERTENSION, FAMILIAL HYPERTENSIVE HYPERKALEMIA, FAMILIAL GORDON HYPERKALEMIA-HYPERTENSION SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PSEUDOHYPOALDOSTERONISM, TYPE IIA, INCLUDED; PHA2A, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PSEUDOHYPOALDOSTERONISM, TYPE IIB, INCLUDED; PHA2B, INCLUDED PSEUDOHYPOALDOSTERONISM, TYPE IIC, INCLUDED; PHA2C, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because PHA type II can be caused by mutations in the WNK4 gene on chromosome 17q21 (601844; PHA2B) or in the WNK1 gene on chromosome 12p (605232; PHA2C). An additional locus for PHA type II, referred to as PHA IIA, has been mapped to 1q. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pseudohypoaldosteronism type II, also known as Gordon hyperkalemia-hypertension syndrome, is characterized by hyperkalemia despite normal renal glomerular filtration, hypertension, and correction of physiologic abnormalities by thiazide diuretics. Mild hyperchloremia, metabolic acidosis, and suppressed plasma renin activity are variable associated findings. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Farfel et al. (1976, 1978) described an Ashkenazi Jewish family in which some members had hyperkalemia (6-7 mEq/L) evident in childhood and hypertension that developed later in life. The patients had mild acidosis of the proximal renal tubular acidosis type. Chlorothiazide administration promptly corrected all features. The syndrome affected 7 members of 3 generations with instances of male-to-male transmission, thus indicating autosomal dominant inheritance. Investigations showed normal renal and adrenal function. Aldosterone concentrations were normal, but probably inappropriately low for the level of hyperkalemia. Renin was low. A low-salt diet reduced blood pressure and urinary sodium (in contrast to the salt loss that occurs in pseudohypoaldosteronism) but serum potassium did not change. Aldosterone administration caused the expected decrease in urinary sodium but no increase in urinary potassium, supporting a mechanism of resistance to aldosterone regarding potassium but not sodium transport. Infusion of insulin produced hypoglycemia but no substantial reduction in serum potassium in 3 patients studied. Farfel et al. (1978) suggested the existence of a generalized cellular defect in transmembrane potassium transport (in which the kidneys, of course, participate) rather than an isolated renal tubular abnormality. In the family reported by Lee et al. (1979) and Lee and Morgan (1980), 2 generations were affected. In the family reported by Licht et al. (1985), as in the family reported by Farfel et al. (1978), 3 generations were affected. The disorder was sporadic in 14 cases. In some cases, short stature, intellectual impairment, and dental abnormalities have been noted. Gordon et al. (1970) studied an isolated case. Iitaka et al. (1980) observed affected brother and sister. Brautbar et al. (1978) described a 52-year-old man with hypertension, persistent hyperkalemia, and hyperchloremic metabolic acidosis. Four other members of the family, including the brother and son of the proband, were identically affected. Renal and adrenal functions were grossly normal. Plasma aldosterone was normal, although plasma renin (179820) activity was undetectable. Inability to increase potassium excretion when exogenous mineralocorticoid was given indicated a distal tubular defect in potassium handling. Reduction of the hyperkalemia with an ion exchange resin (polystyrene sodium sulfonate) given by mouth corrected the hyperchloremic acidosis. Type II pseudohypoaldosteronism was the designation used by Schambelan et al. (1981) for this syndrome of chronic mineralocorticoid-resistant hyperkalemia with hypertension. Whereas the primary defect in type I PHA (see 264350 and 177735) is a specific abnormality in renal response to mineralocorticoid hormone (a receptor disorder) leading to the coexistence of salt wasting and potassium retention, the primary abnormality in type II PHA is thought to be a specific defect of the renal secretory mechanism for potassium, which limits the kaliuretic response to, but not the sodium and chloride reabsorptive effect of, mineralocorticoid. Gordon et al. (1988) described an Australian family with 6 affected members in 2 generations and referred to the condition as Gordon syndrome or hyporeninemic hypoaldosteronism. (Gordon (1995) stated that de Wardener first termed it Gordon syndrome.) Studies suggested dysregulation of atrial natriuretic factor (ANP; 108780). Limal et al. (1978) reported 7 affected persons in 3 generations with no male-to-male transmission. Male-to-male transmission was observed by Roy (1977). Studies of a family by Hanukoglu et al. (1978) supported autosomal dominant inheritance with variable expression. The proposita was hospitalized at 3 months for failure to thrive and severe dehydration. Persistent hyperkalemia and elevated plasma aldosterone were found. The mother had been hospitalized during infancy because of vomiting and failure to thrive. The mother, maternal grandmother and 2 brothers had high aldosterone and renin values. Short stature was found in all affected persons except one of the brothers. A high-salt diet resulted in catch-up growth. (In a later report Hanukoglu (1991) interpreted this family as an example of type I PHA; see 177735.) Lee et al. (1979) emphasized the good response to bendrofluazide. Pasman et al. (1989) described a 14-year-old boy who had secondary hyperkalemic periodic paralysis caused by the Gordon syndrome. They suggested that in this disorder the kidney may lack sensitivity to ANP. After treatment with hydrochlorothiazide, serum potassium and plasma aldosterone values, plasma renin activity, and blood pressure became normal and the attacks of periodic paralysis disappeared. Take et al. (1991) described a 50-year-old Japanese man, his 24-year-old son and 21-year-old daughter with persistent hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular function with occasional elevation of blood pressure. The results of investigations supported the existence of sodium chloride shunting as the primary abnormality, as had been suggested by Schambelan et al. (1981), who found an abnormal increase in the reabsorption of chloride by the renal tubule. Throckmorton and Bia (1991) described an affected male who was 41 years old at the time that his disorder was first discovered. He complained of leg cramps and except for mild hypertension was otherwise found to be well. Hydrochlorothiazide controlled both his hyperkalemia and hypertension. At the other end of the age range were the infants with neonatal onset of Gordon syndrome described by Gereda et al. (1996). Two sisters developed Gordon syndrome within the first 2 weeks of life. The mother, who had been reported by Sanjad et al. (1982), also had Gordon syndrome. She had been seen at 13 years of age with severe hypertension, hyperkalemic metabolic acidosis, short stature, and pitted enamel hypoplasia of the teeth. Similar dental anomalies were observed in her father who did not have the metabolic abnormality. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| PHA IIA By analysis of linkage in 8 families in which PHA type II showed autosomal dominant transmission, Mansfield et al. (1997) demonstrated locus heterogeneity of the trait, with a multilocus lod score of 8.1 for linkage of the disorder to 1q31-q42 (PHA2A) and 17p11-q21 (PHA2B). PHA IIB By linkage analysis, Mansfield et al. (1997) demonstrated linkage of PHA II both to 1q31-q42 (PHA2A) and 17p11-q21 (PHA2B). Analysis of both chromosome regions together yielded a lod score of 8.1 for linkage of all families to either chromosome 1 (68% of families) or chromosome 17 (32% of families), with odds of 130 million:1 favoring linkage to 2 loci over the null hypothesis of no linkage. The lod score for linkage to only chromosome 1 with locus heterogeneity was 3.95 with 68% of the families linked. The lod score for linkage to only chromosome 17 with locus heterogeneity was 3.14 with 45% of families linked. The model specifying 2 linked loci had a likelihood 14,800-fold higher than the next most likely model of linkage only to chromosome 1, thus providing strong support for the 2-locus model. The chromosome 17 locus overlapped with the syntenic segment of rat chromosome 10 that contains a blood pressure quantitative trait locus (QTL). The segment of chromosome 17 to which the PHA2B locus was assigned contains the AE1 gene (109270), an ion exchanger. Analysis of all exons of the AE1 gene by SSCP in 15 PHAII index cases revealed no novel variants altering the encoded proteins. Wilson et al. (2001) identified the WNK4 gene (601844) between D17S250 and D17S579, within the minimum genetic interval containing the PHA IIB locus. They identified 4 missense mutations in PHA II kindreds that had previously been linked to chromosome 17. PHA IIC Disse-Nicodeme et al. (2000) analyzed a large French pedigree in which 12 affected members over 3 generations confirmed autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range, 5.2-6.2 mmol/liter), hyperchloremia (range, 100-109 mmol/liter), normal plasma creatinine, and low renin levels. Genetic linkage was excluded for the 2 previously mapped PHA II loci as well as for the thiazide-sensitive sodium-chloride cotransporter gene (SLC12A3; 600968) on 16q. A genomewide screen using 383 microsatellite markers showed strong linkage to 12p13 (PHA2C). Haplotype analysis using 10 additional polymorphic markers led to a minimal 13-cM interval. Analysis of 2 obvious candidate genes, SCNN1A (139130) and GNB3 (600228), located within the interval showed no deleterious mutation. Wilson et al. (2001) studied a new PHA II kindred that included 10 living members with typical features of PHA II, including hypertension, hyperkalemia (mean serum potassium, 6.2 mM), normal glomerular filtration rate, suppressed plasma renin activity, normal or elevated aldosterone levels, hyperchloremia (mean serum chloride, 112 mM), and reduced bicarbonate (mean serum bicarbonate, 17.5 mM). These features were absent in unaffected kindred members, and inheritance of the trait was consistent with autosomal dominant transmission with high penetrance. Genomic sequence analysis of linkage demonstrated complete linkage of the phenotype in this pedigree to the most telomeric 2-cM segment of chromosome 12p, with a multipoint lod score of 5.07. Affected family members were found to have a deletion in the interval between D12S341 and D12S91. Further evaluation indicated that affected family members had a 41-kb deletion within intron 1 of the WNK1 gene (605232.0001). Both deletion endpoints occur within Alu repetitive elements. Wilson et al. (2001) also identified a deletion in the WNK1 gene (605232.0002) in the family reported by Disse-Nicodeme et al. (2000). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Spitzer et al. (1973); Wehling et al. (1989); Weinstein et al. (1974) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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