A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism

Abstract

Context: Primary aldosteronism is a leading cause of secondary hypertension (HTN), but the mechanisms underlying the characteristic renin-independent secretion of aldosterone remain unknown in most patients.

Objectives: We report a new familial form of aldosteronism in a father and two daughters. All were diagnosed with severe HTN refractory to medical treatment by age 7 yr. We performed a variety of clinical, biochemical, and genetic studies to attempt to clarify the underlying molecular defect.

Results: Biochemical studies revealed hyporeninemia, hyperaldosteronism, and very high levels of 18-oxocortisol and 18-hydroxycortisol, steroids that reflect oxidation by both steroid 17-alpha hydroxylase and aldosterone synthase. These enzymes are normally compartmentalized in the adrenal fasciculata and glomerulosa, respectively. Administration of dexamethasone failed to suppress either aldosterone or cortisol secretion; these findings distinguish this clinical syndrome from glucocorticoid-remediable aldosteronism, another autosomal dominant form of HTN, and suggest a global defect in the regulation of adrenal steroid production. Genetic studies excluded mutation at the aldosterone synthase locus, further distinguishing this disorder from glucocorticoid-remediable aldosteronism. Because of unrelenting HTN, all three subjects underwent bilateral adrenalectomy, which in each case corrected the HTN. Adrenal glands showed dramatic enlargement, with paired adrenal weights as high as 82 g. Histology revealed massive hyperplasia and cellular hypertrophy of a single cortical compartment that had features of adrenal fasciculata or a transitional zone, with an atrophic glomerulosa.

Conclusion: These findings define a new inherited form of aldosteronism and suggest that identification of the underlying defect will provide insight into normal mechanisms regulating adrenal steroid biosynthesis.

Figure 1

Glucocorticoids fail to ameliorate aldosteronism or HTN in kindred HPA1. A, Serum aldosterone levels during the 23-d trial of dexamethasone. Serum aldosterone levels increased progressively during glucocorticoid therapy in these patients. B, A repeat 7-d trial of dexamethasone was attempted years later (see Results). Again, serum aldosterone levels increased steadily in the presence of administered glucocorticoid. C and D, Response of systolic and diastolic BP (SBP and DBP, respectively) to a 23-d trial of po dexamethasone in patients HPA1–2 and HPA1–3. There was no significant improvement in BP in either patient during glucocorticoid therapy.

Figure 2

Light microscopical analysis of adrenal glands from patient HPA1–2. A, Low-power magnification of the adrenal gland shows a thin, atrophic zona glomerulosa (ZG), a massive zona fasciculata (ZF), and a compressed, but present, zona reticularis (ZR). B, Higher-power magnification of the same gland shows evidence of diffuse hyperplasia without evidence of adenoma. The lipid-laden cytoplasm is indicative of high metabolic activity. Magnification (A), ×10; magnification (B), ×100.

Figure 3

Electron microscopical analysis of adrenal sections from patient HPA1–2. Electron micrographs of adrenal zona fasciculata from patient HPA1–2 demonstrate both platelike (PL) and tubulovesicular (T) cristae, consistent with transitional zone morphology. The presence of numerous lipid-laden vacuoles is suggestive of high metabolic activity. Magnification, ×4000.

Figure 4

Pedigree of kindred HPA1. The affected individuals are represented by filled symbols. The father of patient HPA1–1 died of HTN and heart failure at age 36 yr, and is the presumed source of the disease-causing mutation. His parents and siblings all lived beyond age 65 yr and are presumed unaffected. MI, Myocardial infarction.

Figure 5

Inheritance of aldosterone synthase polymorphisms in HPA1. Single stranded conformational polymorphism of Cyp11B2 (aldosterone synthase) exon 2 demonstrated that the index case (HPA1–1) is heterozygous for the G1279A polymorphism, as is HPA1–3, but not HPA1–2. The daughters’ mother, whose identity was confirmed by genotypical analysis, does not carry this allele. Thus, the affected father passed distinct Cyp11b2 alleles to each daughter, thus excluding this locus and the nearby Cyp11B1 locus as causes of this syndrome.