Natural History of Apparent Mineralocorticoid Excess Syndrome

AME is a rare genetic disorder that is caused by a mutated HSD11B2 gene, which encodes the
metabolic enzyme 11BHSD2. The altered gene interferes with the ability of 11BHSD2 to
inactivate the hormone cortisol. Above-normal cortisol activity then leads to a rise in
blood pressure and a reduction of potassium in the blood. It also leads to low levels of the
enzyme renin and the hormone aldosterone, both of which are involved in the regulation of
long-term blood pressure. Long-term high blood pressure and metabolic defects start at an
early age in children with severe AME. In others, AME may start later in life and cause less
serious side effects. Symptoms can include poor growth in childhood, delayed puberty, muscle
weakness, heart rate irregularity, frequent urination, and thirst. If left untreated, AME
can cause serious damage to the eyes, kidneys, heart, and other organs.

Current treatment with the synthetic steroid spironolactone usually improves symptoms;
however, despite treatment, some individuals with AME still experience disease progression
and even death within years of being diagnosed with AME. Understanding more about AME, how
it progresses, and how it affects people differently may help to improve treatment options.
The purpose of this study is to examine the genetic basis, natural history, disease
progression, and outcome of children and adults with AME. The study will also examine the
family members of study participants with AME for any genetic abnormalities and possible
mild forms of AME.

This study will last 2 to 7 years. Participants and their family members will attend yearly
study visits that will include interviews about medical history, symptoms, and hospital
stays; a physical exam; blood pressure testing; and blood and urine collection. Interim
reviews of medical records will occur as necessary. Children will undergo an x-ray of the
left hand. During the initial study visit, participants will be asked questions about family
members and birth size.

Inclusion Criteria for Participants with AME:

- High blood pressure characterized by low plasma renin and serum aldosterone levels

- Elevated urinary cortisol/cortisone metabolite ratio ([THF + 5aTHF]/THE)

- Molecular genetic diagnosis of AME with two mutations of the HSD11B2 gene

Inclusion Criteria for Family Members without Genetic Diagnosis of AME:

- Carrier of the HSD11B2 mutation that the AME participant has

Exclusion Criteria for All Participants:

- Any other illness or condition that might interfere with study participation