General review
Familial hyperaldosteronism

https://doi.org/10.1016/S0960-0760(01)00097-8Get rights and content

Abstract

Primary aldosteronism (PAL) may be as much as ten times more common than has been traditionally thought, with most patients normokalemic. The study of familial varieties has facilitated a fuller appreciation of the nature and diversity of its clinical, biochemical, morphological and molecular aspects. In familial hyperaldosteronism type I (FH-I), glucocorticoid-remediable PAL is caused by inheritance of an ACTH-regulated, hybrid CYP11B1/CYP11B2 gene. Genetic testing has greatly facilitated diagnosis. Hypertension severity varies widely, demonstrating relationships with gender, affected parent's gender, urinary kallikrein level, degree of biochemical disturbance and hybrid gene crossover point position. Analyses of aldosterone/PRA/cortisol ‘day-curves’ have revealed that (1) the hybrid gene dominates over wild type CYP11B2 in terms of aldosterone regulation and (2) correction of hypertension in FH-I requires only partial suppression of ACTH, and much smaller glucocorticoid doses than those previously recommended. Familial hyperaldosteronism type II is not glucocorticoid-remediable, and is clinically, biochemically and morphologically indistinguishable from apparently sporadic PAL. In one informative family available for linkage analysis, FH-II does not segregate with either the CYP11B2, AT1 or MEN1 genes, but a genome-wide search has revealed linkage with a locus in chromosome 7. As has already occurred in FH-I, elucidation of causative mutations is likely to facilitate earlier detection of PAL and other curable or specifically treatable forms of hypertension.

Section snippets

Introduction: the evolution of primary aldosteronism

Professor Jerome W. Conn, Head of the Endocrinology Division, Department of Medicine, University of Michigan, first described the syndrome of primary aldosteronism (PAL) in 1954 [1], the same year that the chemical structure of aldosterone was identified [2]. Conn's first patient was a 34-year-old hypertensive female who, for the 7 years preceding her presentation to his clinic, had suffered polydipsia, polyuria, nocturia, attacks of muscle weakness and episodic tetany due to severe hypokalemic

Familial hyperaldosteronism type I

In Sutherland's original family with FH-I [15], a 41-year-old Canadian man and his 16-year-old son exhibited hypertension, hypokalemia, increased aldosterone secretion rate and suppressed plasma renin activity (PRA), all of which normalized during the administration of dexamethasone 2 mg/day. Hypertension had been detected at an early age in both individuals (19 and 13-years old, respectively) and three of the father's 11 siblings had died prematurely (two in their 40s and one in his 60s) from

Original reports

In 1991, prior to the availability of genetic testing for FH-I, we were able to report the occurrence in three families of a familial variety of PAL that was not responsive to glucocorticoids; this was associated with either APA (four patients from two families) or BAH (two patients from one family) [43]. This represented the first description of the familial occurrence of APA, confirmed by pathological examination of removed adrenal tissue and cure (three patients) or marked improvement (one

Conclusions

The study of familial varieties has expanded the clinical, biochemical and genetic spectrum of PAL. Like FH-I, FH-II is associated with hyperaldosteronism and probable autosomal dominant inheritance. Unlike FH-I, hyperaldosteronism in FH-II is not glucocorticoid-remediable and FH-II is not associated with the hybrid gene mutation. In contrast to FH-I, FH-II is unlikely to be caused by a single genetic mutation, but by a variety of mutations, each predisposing to adrenal cortical hyperplasia and

Acknowledgements

The authors gratefully acknowledge the National Heart Foundation of Australia, National Health and Medical Research Council of Australia and the Commonwealth Department of Veterans’ Affairs for their support of studies conducted by the Greenslopes and Princess Alexandra Hospital Hypertension Units, which were described in this review.

References (122)

  • S.A. Simpson et al.

    Konstitution des aldosterons, des neuen mineralocorticoids

    Experientia

    (1954)
  • J.W. Conn et al.

    Primary aldosteronism, a new clinical entity

    Ann. Intern. Med.

    (1956)
  • J.W. Conn

    Aldosteronism and hypertension: primary aldosteronism versus hypertensive disease with secondary aldosteronism

    Arch. Intern. Med.

    (1961)
  • J.W. Conn

    The evolution of primary aldosteronism: 1954–1967

    Harvey Lect.

    (1968)
  • J.W. Gilbert et al.

    Primary aldosteronism: diagnosis and surgical treatment

    Ann. Surg.

    (1963)
  • R.K. Rhamy et al.

    Primary aldosteronism: experience with current diagnostic criteria and surgical treatment in fourteen patients

    Ann. Surg.

    (1968)
  • M.H. Weinberger et al.

    Primary aldosteronism: diagnosis, localization and treatment

    Ann. Intern. Med.

    (1979)
  • B. Therien et al.

    Primary aldosteronism due to adrenal hyperplasia: occurrence in a boy aged 10 years

    Am. J. Dis. Child

    (1959)
  • W.W. Davis et al.

    Bilateral adrenal hyperplasia as a cause of primary aldosteronism with hypertension, hypokalemia and suppressed renin activity

    Am. J. Med.

    (1967)
  • I.S. Salti et al.

    Non-tumorous ‘primary’ aldosteronism: II. Type not relieved by glucocorticoid

    Can. Med. Assoc. J.

    (1969)
  • J.B. Ferriss et al.

    Results of adrenal surgery in patients with hypertension, aldosterone excess, and low plasma renin concentration

    Br. Med. J.

    (1975)
  • D.J.A. Sutherland et al.

    Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone

    Can. Med. Assoc. J.

    (1966)
  • M.I. New et al.

    Evidence for an unidentified ACTH-induced steroid hormone causing hypertension

    J. Clin. Endocrinol. Metab.

    (1976)
  • C.E. Grim et al.

    Familial, dexamethasone-suppressible, normokalemic hyperaldosteronism

    Pediatrics

    (1980)
  • J.M.C. Connell et al.

    Dexamethasone-suppressible hyperaldosteronism: adrenal transitional cell hyperplasia?

    Hypertension

    (1986)
  • E. Woodland et al.

    Hypertension corrected and aldosterone responsiveness to renin-angiotensin restored by long-term dexamethasone in glucocorticoid-suppressible hyperaldosteronism

    Clin. Exp. Pharmacol. Physiol.

    (1985)
  • M. Stowasser et al.

    Clinical, biochemical and genetic approaches to the detection of Familial Hyperaldosteronism Type I

    J. Hypertens.

    (1995)
  • J.W. Conn

    Evolution of primary aldosteronism as a highly specific clinical entity

    J. Am. Med. Assoc.

    (1960)
  • J.H. Laragh et al.

    Patterns of adrenal secretion and urinary excretion of aldosterone and plasma renin activity in normal and hypertensive subjects

    Circ. Res.

    (1966)
  • L.M. Fishman et al.

    Incidence of primary aldosteronism uncomplicated ‘essential’ hypertension

    J. Am. Med. Assoc.

    (1968)
  • J.O. Lund et al.

    Prevalence of primary aldosteronism

    Act. Med. Scand.

    (1981)
  • G. Berglund et al.

    Prevalence of primary and secondary hypertension: studies in a random population

    Br. Med. J.

    (1976)
  • G.S. Anderson et al.

    The incidence rate of phaeochromocytoma and Conns syndrome in Denmark, 1977–1981

    J. Hum. Hypertens.

    (1988)
  • D.G. Beevers et al.

    The prevalence of hypertension in an unselected population, and the frequency of abnormalities of potassium, angiotensin II and aldosterone in hypertensive subjects

    Acta. Clin. Belg.

    (1974)
  • N.M. Kaplan
  • K. Hiramatsu et al.

    A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity

    Arch. Intern. Med.

    (1981)
  • T.J. McKenna et al.

    Diagnosis under random conditions of all disorders of the renin-angiotensin-aldosterone axis, including primary aldosteronism

    J. Clin. Endocrinol. Metab.

    (1991)
  • R.D. Gordon et al.

    High incidence of primary aldosteronism in 199 patients referred with hypertension

    Clin. Exp. Pharmacol. Physiol.

    (1994)
  • R.D. Gordon et al.

    Evidence that primary aldosteronism may not be uncommon-twelve percent incidence among antihypertensive drug trial volunteers

    Clin. Exp. Pharmacol. Physiol.

    (1993)
  • R.D. Gordon et al.

    Primary aldosteronism and other forms of mineralocorticoid hypertension

  • M. Stowasser, R.D. Gordon, Prevalence and diagnostic workup of primary aldosteronism, Nephrology 2001 (6)...
  • W.F. Young

    Primary aldosteronism: update on diagnosis and treatment

    The Endocrinologist

    (1997)
  • M.A. Brown et al.

    Primary aldosteronism: a missed diagnosis in ‘essential hypertensives’?

    Aust. NZ J. Med.

    (1996)
  • G.P. Rossi et al.

    Screening for primary aldosteronism with a logistic multivariate discriminant analysis

    Clin. Endocrinol.

    (1998)
  • B.L. Rayner et al.

    The aldosterone/renin ratio as a screening test for primary aldosteronism

    South African Med. J.

    (2000)
  • K.C. Loh et al.

    Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore

    J. Clin. Endocrinol. Metab.

    (2000)
  • C.E. Fardella et al.

    Primary aldosteronism in essential hypertensives: prevalence, biochemical profile and molecular biology

    J. Clin. Endocrinol. Metab.

    (2000)
  • R.D. Gordon et al.

    Clinical and pathological diversity of primary aldosteronism including a new familial variety

    Clin. Exp. Pharmacol. Physiol.

    (1991)
  • M. Stowasser et al.

    Familial hyperaldosteronism type II-five families with a new variety of primary aldosteronism

    Clin. Exp. Pharmacol. Physiol.

    (1992)
  • M.I. New et al.

    A new form of congenital adrenal hyperplasia

    J. Clin. Endocrinol. Metab.

    (1967)
  • Cited by (86)

    • Nutrigenomics of inward rectifier potassium channels

      2023, Biochimica et Biophysica Acta - Molecular Basis of Disease
    • Overview of endocrine hypertension in children

      2023, Progress in Pediatric Cardiology
    • Primary aldosteronism (Conn's syndrome)

      2022, Endocrine Hypertension: From Basic Science to Clinical Practice
    • Old and new genes in primary aldosteronism

      2020, Best Practice and Research: Clinical Endocrinology and Metabolism
      Citation Excerpt :

      These patients presented also high levels of 18-hydroxycortisol and 18-oxocortisol, their secretion being again under the control of ACTH and suppressible by glucocorticoids. FH-I is more often associated with bilateral adrenal hyperplasia rather than adrenocortical adenoma [32,33]. In 1992, the molecular basis of this autosomal dominant form of PA was elucidated by Lifton and coll [34,35].

    View all citing articles on Scopus
    View full text