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Study Description

The objective of this project is to observe the natural history of apparent mineralocorticoid excess (AME). AME is a rare monogenic hypertensive disease first described by the Principal Investigator, Dr. Maria I. New, in 1977 [1], for which the first mutation in the causative HSD11B2 gene was reported by her group in 1995. [2]

Little is known about the progression of this rare hypertensive disorder, which is defined by the presence of hypertension in conjunction with low renin, low to absent levels of the mineralocorticoid aldosterone, elevated urinary cortisol/cortisone metabolite ratio 5β-tetrahydrocortisol (THF) + allo-THF/ tetrahydrocortisone (THE) (i.e., THF+αTHF/THE) and the presence of mutations in the HSD11B2 gene on both alleles. The range of symptoms reflecting progressive end-organ damage is wide in the small number of affected individuals studied to date. It is important to develop accurate information on the longitudinal pattern of progression (natural history) of AME not only because it may improve the care of affected individuals, but also because it may serve as a platform for understanding the role of mineralocorticoid excess in other forms of low-renin hypertension, which constitute 40% of all forms of hypertension. In this study, we will recruit as widely as possible through the Rare Diseases Clinical Research Network (RDCRN) to identify individuals with the triad of low renin, low aldosterone, and elevated urinary THF+αTHF/THE and confirm their disorder as AME by molecular genetic testing of the HSD11B2 gene.

We will gather clinical and biochemical data yearly for the duration of the grant. We will describe phenotype and genotype at diagnosis and follow the progression or regression of symptoms over time under standard treatment, with rigorous review of end organs potentially damaged by chronic hypertension.

Finally, we will study the natural history of the carriers of HSD11B2 mutations, i.e., the heterozygote relatives of the probands, in order to ascertain evidence of existing or developing hypertension and resulting end-organ damage. This will be the first rigorous study of AME heterozygotes. The participant accrual for AME-affected patients and the carriers of HSD11B2 mutations will be at least two years, but as long as seven years.

  • Study Design:
    • Case Set
  • Study Type:
    • Case Set
Authorized Access
Publicly Available Data (Public ftp)
Study Inclusion/Exclusion Criteria

Inclusion Criteria

Group 1 Participants: AME-affected

  • Low renin, low aldosterone hypertension
  • Elevated urinary (THF+ 5αTHF)/THE
  • Molecular genetic diagnosis of AME with two mutations of the HSD11B2 gene
  • Age range from 0-80 years old

Group 2 Participants: Family members

  • Heterozygote for an HSD11B2 mutation carried by the index AME case
  • Age range from 0-80 years old

In this research study, we shall not disclose results of genetic analysis to the participants (or the parents in case of a minor) or the referring physician, unless there is evidence to believe that the genetic status of either the probands or heterozygote family members will have an impact on the health outcome of those individuals. The family members will continue to receive medical care regardless of their mutational status, but his or her information will not be included in the data collection. This research study identifying natural history of both AME patients and heterozygote family members has a potential to reveal novel findings of the clinical outcomes of either group of participants. If the information is confirmed, we will discuss with DSMB prior to disclose the genetic information and the health risk to the participants.

Exclusion criteria

Any other illness that prevents compliance with study schedule. Physical illness such as any condition that prevents the participant from coming to the local participating site: altered consciousness, hemodynamically unstable conditions, bedridden vegetative states, mental illness that makes informed consent impossible.

Please note that end organ damage such as blindness, ambulatable chronic heart failure, chronic renal insufficiency or coinciding disorders (such as diabetes mellitus) does not exclude participation in the study.

Study Activated 04/18/2007
First Participant Enrolled 05/16/2007
Study Closed 08/01/2009

Molecular Data
TypeSourcePlatformNumber of Oligos/SNPsSNP Batch IdComment
Whole Genome Sequencing Complete Genomics Assembler Version 1.2.0; File Format Version: July 2009 N/A N/A
Whole Genome Genotyping Illumina HumanHap550v3.0 561466 51468
Study History

Apparent mineralocorticoid excess (AME) was first described in 1977 by the Principal Investigator in a Native American girl with severe hypertension. [1] Clinical manifestations of AME mimic those of excessive mineralocorticoid activity, but no elevation of known mineralocorticoids is present in the AME patients. The exploration and elucidation of this disease at our center opened a new area in receptor biology as a result of the demonstration that the specificity of the mineralocorticoid receptor (MR) function depends on a metabolic enzyme (11βHSD2) rather than the receptor itself. [3-7] This enzyme functions to protect the MR by inactivating cortisol to its inactive metabolite cortisone, thereby enabling the mineralocorticoid aldosterone to occupy the MR in vivo. [8, 9] Aldosterone is not metabolized by 11βHSD2 because it forms a C11-C18 hemi-ketal group in aqueous solution. The MR is non-selective in vitro and cannot distinguish between the glucocorticoid cortisol and its natural ligand, aldosterone. [10, 11] Therefore, lack of protection of the receptor owing to the enzyme defect allows cortisol, which has higher circulating levels than aldosterone, to bind to the MR and to act as a mineralocorticoid. This results in the clinical phenotype of excess mineralocorticoid activity. Thus, AME defined an important "pre-receptor" pathway in the analysis of corticosteroid hormone action. [12]

We subsequently determined that AME is an autosomal recessive monogenic disorder.

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