Hypertension, Early-Onset, Autosomal Dominant, With Severe Exacerbation In Pregnancy

A number sign (#) is used with this entry because of evidence that this disorder can be caused by mutation in the mineralocorticoid receptor gene (600983).

To determine if gain-of-function mutations in the mineralocorticoid receptor (MR) could cause increased renal reabsorption and hypertension, Geller et al. (2000) screened the mineralocorticoid receptor in 75 patients with early onset of severe hypertension. A 15-year-old boy with severe hypertension, suppressed plasma renin activity, low aldosterone, and no other underlying cause of hypertension was heterozygous for a missense mutation, resulting in substitution of a leucine for serine at codon 810 (600983.0005). The S810L mutation lies in the MR hormone-binding domain, altering an amino acid that is conserved in all MRs from Xenopus to human but not found in other nuclear receptors. Twenty-three relatives of the proband were evaluated. Remarkably, 11 had been diagnosed with severe hypertension before age 20, a rare trait in the general population, whereas the remaining 12 had unremarkable blood pressures. The MR S810L mutation precisely cosegregated with early-onset hypertension in this family, providing strong evidence of linkage, with a maximum lod score of 5.24 at a recombination fraction of 0.0. Comparison of the clinical features of carriers of the mutant allele (MR L810) and noncarriers revealed a marked increase in blood pressure among carriers even though they were taking antihypertensive medication, as well as suppression of aldosterone secretion. There was a nonsignificant trend toward lower serum potassium among carriers, and there were no significant effects of gender or age on phenotypic expression of MR L810. Of note, 3 deceased family members with early-onset hypertension died of heart failure before age 50. The MR S810L mutation resulted in constitutive MR activity and altered receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Spironolactone was also a potent agonist of MR L810, suggesting that this medication is contraindicated in MR L810 carriers.

That progesterone levels normally increase 100-fold in pregnancy, reaching concentrations of 500 nanomolar, suggested to Geller et al. (2000) that females with MR L810 might develop severe hypertension in pregnancy. Two MR L810 carriers had undergone 5 pregnancies; all had been complicated by marked exacerbation of hypertension. Blood pressure decreased early in the first pregnancy of 1 carrier, but then rose dramatically, reaching 170/130 mm Hg at 28 weeks despite antihypertensive therapy. This was accompanied by development of low serum potassium with marked renal potassium wasting. Aldosterone levels, which normally increase 10-fold in pregnancy, were undetectable. Of note, there were no proteinuria, edema, or neurologic changes, excluding preeclampsia. Because of still-worsening blood pressure (210/120 mm Hg), at 34 weeks' gestation a cesarean section was performed, and the patient gave birth to a healthy son. Two subsequent pregnancies followed similar courses, and the patient was advised to avoid further pregnancy. In the other carriers, 2 pregnancies were both complicated by severe exacerbation of hypertension, precipitating delivery in the sixth and seventh months of gestation, with advice to avoid further pregnancy. These findings strongly supported progesterone's in vivo agonism of MR L810.