Pseudohypoaldosteronism, Type Iia

Description

Pseudohypoaldosteronism type II (PHA2), 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 (179820) activity are variable associated findings (summary by Mansfield et al., 1997).

Genetic Heterogeneity of Pseudohypoaldosteronism Type II

PHA2A has been mapped to chromosome 1q31-q42. PHA2B (614491) is caused by mutations in the WNK4 gene on chromosome 17q21 (601844). PHA2C (614492) is caused by mutations in the WNK1 gene on chromosome 12p13 (605232). PHA2D (614495) is caused by mutations in the KLHL3 gene (605775) on chromosome 5q31. PHA2E (614496) is caused by mutations in the CUL3 gene (603136) on chromosome 2q36.

Boyden et al. (2012) observed that families with PHA type II due to mutation in the WNK1 gene (PHA2C) are significantly less severely affected than those with mutation in WNK4 (PHA2B) or dominant or recessive mutation in the KLHL3 gene (PHA2D), and all are less severely affected than those with dominant mutations in the CUL3 gene (PHA2E).

Clinical Features

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 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.

Gordon et al. (1970) studied an isolated case. Male-to-male transmission was observed by Roy (1977). Limal et al. (1978) reported 7 affected persons in 3 generations with no male-to-male transmission. Lee et al. (1979) emphasized the good response to bendrofluazide. Iitaka et al. (1980) observed affected brother and sister.

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 (600983) (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.

Licht et al. (1985) reported a 3-generation family. They noted that in some cases, short stature, intellectual impairment, and dental abnormalities had been observed.

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).

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.

Clinical Management

Thiazide diuretics correct abnormalities in virtually all PHA type II patients (Boyden et al., 2012).

Mapping

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; 614491). 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 including the family described by Throckmorton and Bia (1991). 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.