Examination of Genotype and Phenotype Relationships in 14 Patients with Apparent Mineralocorticoid Excess<sup>1</sup>

Dave-Sharma, Swati; Wilson, Robert; Harbison, Madeleine D.; Newfield, Ron S.; Azar, Maryam Razzaghy; Krozowski, Zygmunt; Funder, John W.; Shackleton, Cedric; Bradlow, H. Leon; Wei, Ji-Qing; Hertecant, Jos; Moran, Antoinette; Neiberger, Richard E.; Balfe, J. Williamson; Fattah, Abduhl; Daneman, Denis; Akkurt, Halit Ilker; Santis, Carlo De; New, Maria I.

doi:10.1210/jcem.83.7.4986

Cited by 47 publications

(24 citation statements)

References 56 publications

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“…In our report (90), all 14 patients studied had characteristic signs of a severe 11␤-HSD2 defect, which were consistent with patients reported worldwide (56,57,59,75,(88)(89)(90)(91)(98)(99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111): birth weights were lower than in their unaffected sibs, and the patients were short, underweight, and hypertensive for age. Damage of one or more organs (kidneys, retina, heart, and central nervous system) because of hypertension was found in all of the patients except one.…”

Section: Biochemical Features Adrenal Steroidogenesis and Fetal Devesupporting

confidence: 90%

“…In our report in 1998 of 14 AME patients studied at our center, urinary metabolites of cortisol demonstrated an abnormal ratio of tetrahydrocortisone͞tetrahydrocortisone (THF͞THE) with a predominance of THF (90). The ratio of THFϩ5␣THF to THE was 6.7 to 33, whereas the normal ratio is 1.0.…”

Section: Biochemical Features Adrenal Steroidogenesis and Fetal Devementioning

confidence: 57%

“…to our primary role in the discovery and characterization of AME, we have been referred a large number of these patients and have been able to analyze the phenotype and genotype of these cases (90).…”

Section: Biochemical Features Adrenal Steroidogenesis and Fetal Devementioning

confidence: 99%

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Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

New

Wilson

1999

Proc. Natl. Acad. Sci. U.S.A.

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147

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Our research team and laboratories have concentrated on two inherited endocrine disorders, congenital adrenal hyperplasia (CAH) and apparent mineralocorticoid excess, in thier investigations of the pathophysiology of adrenal steroid hormone disorders in children. CAH refers to a family of inherited disorders in which defects occur in one of the enzymatic steps required to synthesize cortisol from cholesterol in the adrenal gland. Because of the impaired cortisol secretion, adrenocorticotropic hormone levels rise due to impairment of a negative feedback system, which results in hyperplasia of the adrenal cortex. The majority of cases is due to 21-hydroxylase deficiency (21-OHD). Owing to the blocked enzymatic step, cortisol precursors accumulate in excess and are converted to potent androgens, which are secreted and cause in utero virilization of the affected female fetus genitalia in the classical form of CAH. A mild form of the 21-OHD, termed nonclassical 21-OHD, is the most common autosomal recessive disorder in humans, and occurs in 1͞27 Ashkenazic Jews. Mutations in the CYP21 gene have been identified that cause both classical and nonclassical CAH. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre-and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11␤-hydroxysteroid dehydrogenase type 2. In 1998, we reported a mild form of this disease, which may represent an important cause of low-renin hypertension.

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Section: Biochemical Features Adrenal Steroidogenesis and Fetal Devesupporting

confidence: 90%

Section: Biochemical Features Adrenal Steroidogenesis and Fetal Devementioning

confidence: 57%

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Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

New

Wilson

1999

Proc. Natl. Acad. Sci. U.S.A.

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147

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“…Mutations in the HSD11B2 gene have been unequivocally shown to be the molecular basis of the syndrome of AME [46,[61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77] (Figure 3). Most of the known mutations are found in exons 3, 4 or 5 of the HSD11B2 gene, with the exception of the R74G and P75,∆1nt in exon 1 [76] and L114,∆6nt mutant in exon 2 [73].…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

The role of the 11β-hydroxysteroid dehydrogenase type 2 in human hypertension

Ferrari

Lovati

Frey

2000

Journal of Hypertension

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Please cite this article as: Paolo Ferrari, The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension, BBA -Molecular Basis of Disease (2009Disease ( ), doi:10.1016Disease ( /j.bbadis.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.A C C E P T E D M A N U S C R I P T A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPTSchoner: BBADIS-09-126, Revision 1 BBA-Series Molecular Basis of Disease, special issue on Hypertension: Chapter 4, Ferrari SUMMARYCortisol and aldosterone have the same in vitro affinity for the mineralocorticoid receptor (MR), although in vivo only aldosterone acts as a physiologic agonist of the MR, despite circulating levels of cortisol in humans and corticosterone in rodents being three orders of magnitude higher than aldosterone levels. In mineralocorticoid target organs the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) inactivates 11-hydroxy steroids, to their inactive keto-forms, thus protecting the nonselective MR from activation by glucocorticoids. The gene is highly expressed in all sodium-transporting epithelia, particularly in the kidney and colon, but also in human placenta and vascular wall. Mutations in the HSD11B2 gene cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, compromised 11ßHSD2enzyme activity results in activation of the MR by cortisol, causing sodium retention, hypokalaemia, and salt-dependent hypertension. Whereas mutations or inhibition of 11ßHSD2 by licorice have been clearly shown to produce a congenital or acquired syndrome of mineralocorticoid excess, the questions remaining are the extent to which subtle abnormalities in MR/11ßHSD2 mechanisms may contribute to essential hypertension. Studies in patients with essential hypertension showed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites, suggesting a deficient 11ßHSD2 activity. These abnormalities may be genetically determined, as suggested by the association of a microsatellite flanking the HSD11B2 gene with hypertension in black patients with end-stage kidney disease and with salt sensitivity of blood pressure in healthy subjects. These findings indicate that variants of the HSD11B2 gene may contribute to the enhanced blood pressure response to salt and possibly to hypertension in humans.

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“…Similar patients subsequently were described, all of whom had prominent clinical signs and symptoms, including low birth weight, polyuria and polydipsia, failure to thrive, severe hypertension, hypokalemia, hypoaldosteronemia, nephrocalcinosis, and suppressed plasma renin activity (PRA), and it has been associated with sudden fatality. The deficiency of 11␤-hydroxysteroid dehydrogenase type 2 enzyme has been demonstrated in patients with AME and explains the pathogenesis of the disease, which results from excess cortisol binding to the mineralocorticoid receptor (2). The cause of the disease was shown to be mutations in the HSD11B2 gene encoding the 11␤-HSD2 enzyme (3).…”

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confidence: 99%

A genetic defect resulting in mild low-renin hypertension

Wilson

Dave-Sharma

Wei

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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130

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Severe low-renin hypertension has few known causes. Apparent mineralocorticoid excess (AME) is a genetic disorder that results in severe juvenile low-renin hypertension, hyporeninemia, hypoaldosteronemia, hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. In 1995, it was shown that mutations in the gene (HSD11B2) encoding the 11␤-hydroxysteroid dehydrogenase type 2 enzyme (11␤-HSD2) cause AME. Typical patients with AME have defective 11␤-HSD2 activity, as evidenced by an abnormal ratio of cortisol to cortisone metabolites and by an exceedingly diminished ability to convert [11-3 H]cortisol to cortisone. Recently, we have studied an unusual patient with mild low-renin hypertension and a homozygous mutation in the HSD11B2 gene. The patient came from an inbred Mennonite family, and though the mutation identified her as a patient with AME, she did not demonstrate the typical features of AME. Biochemical analysis in this patient revealed a moderately elevated cortisol to cortisone metabolite ratio. The conversion of cortisol to cortisone was 58% compared with 0-6% in typical patients with AME whereas the normal conversion is 90-95%. Molecular analysis of the HSD11B2 gene of this patient showed a homozygous C3T transition in the second nucleotide of codon 227, resulting in a substitution of proline with leucine (P227L). The parents and sibs were heterozygous for this mutation. In vitro expression studies showed an increase in the K m (300 nM) over normal (54 nM). Because Ϸ40% of patients with essential hypertension demonstrate low renin, we suggest that such patients should undergo genetic analysis of the HSD11B2 gene.

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Examination of Genotype and Phenotype Relationships in 14 Patients with Apparent Mineralocorticoid Excess¹

Cited by 47 publications

References 56 publications

Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

The role of the 11β-hydroxysteroid dehydrogenase type 2 in human hypertension

A genetic defect resulting in mild low-renin hypertension

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Examination of Genotype and Phenotype Relationships in 14 Patients with Apparent Mineralocorticoid Excess1

Cited by 47 publications

References 56 publications

Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

The role of the 11β-hydroxysteroid dehydrogenase type 2 in human hypertension

A genetic defect resulting in mild low-renin hypertension

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Examination of Genotype and Phenotype Relationships in 14 Patients with Apparent Mineralocorticoid Excess¹