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Familial hyperaldosteronism type I
Familial hyperaldosteronism type I (FH-I) is a rare heritable, glucocorticoid remediable form of primary aldosteronism (PA) characterized by early-onset hypertension, hyperaldosteronism, variable hypokalemia, low plasma renin activity (PRA), and abnormal production of 18-oxocortisol and 18-hydroxycortisol.
ORPHA:403Classification level: Disorder
- Dexamethasone-sensitive hypertension
- Familial hyperaldosteronism type 1
- Glucocorticoid-remediable aldosteronism
- Glucocorticoid-sensitive hypertension
- Prevalence: 1-5 / 10 000
- Inheritance: Autosomal dominant
- Age of onset: Childhood, Adolescent, Adult
- ICD-10: E26.0
- OMIM: 103900
- UMLS: C1260386
- MeSH: -
- GARD: 2790
- MedDRA: -
PA is the most common form of secondary hypertension and is found in 10% of cases. However, familial forms are rare and represent 5% of adult PA cases. FH-I is estimated at 1% of all PA cases, but may attend 3% in the hypertensive pediatric population.
Hypertension, of varying severity even among members of the same family, manifests often before the age of 20. It can be accompanied with symptoms of severe hypertension such as headaches and nausea. Cardiovascular anomalies, such as fibrosis, left ventricular (LV) dysfunction, arrhythmias, and myocardial infarction, can be associated with the disease. In adults, a high risk of cerebrovascular aneurysms is observed that causes premature hemorrhagic stroke.
FH-I is due to an unequal crossing over on the long arm of chromosome 8 between the CYP11B2 gene (coding for cytochrome P450 aldosterone synthase), normally expressed in the zona glomerulosa (ZG), and the CYP11B1 gene (coding for the 11 beta-hydroxylase), normally expressed in the zona fasciculata (ZF), resulting in a chimeric gene composed of the adrenocorticotropic hormone (ACTH)-sensitive promoter of the CYP11B1 gene and the coding region of the CYP11B2gene. This leads to an excessive aldosterone synthase production in the zona fasciculata of the adrenal gland, regulated by the hypothalamo-pituitary axis rather than by the renin-angiotensin system. Excessive aldosterone synthesis leads to increased sodium reabsorption, loss of potassium and subsequent increased water reabsorption.
The diagnosis is suggested by the clinical picture and a family history of early-onset hypertension and/or stroke. Blood and urinary tests show biological signs of primary aldosteronism, i.e. an abnormal aldosterone/renin ratio with increased aldosterone levels and low plasma renin activity (tested after correction of potassium levels), associated or not with low serum potassium levels, and elevated urinary levels of the hybrid steroids 18-oxo- and 18-hydroxycortisol. Diagnosis is confirmed by genetic testing providing evidence of the hybrid gene by Southern blot and/or long-range PCR. Many patients are diagnosed during familial genetic screening in case of family history.
The clinical presentation closely resembles that of the other familial forms of hyperaldosteronism (FH-II, FH-III; see these terms).
Transmission is autosomal dominant.
Management and treatment
Once the diagnosis is ascertained, small doses of glucocorticoids (dexamethasoneat 0.125-0.250 mg/day or prednisone at 2.5 -5 mg/day) are given that reduce the production of aldosterone. Small doses are essential in order to maintain the circadian regulation of cortisol; complete suppression of ACTH-regulated hybrid 11β-hydroxylase-aldosterone synthase production is not necessary for controlling hypertension. In severe cases, dexamethasone can be combined with a mineralocorticoid receptor antagonist and other non-specific antihypertensive drugs. Because of the side effects of glucocorticoids, in children eplerenone can be given instead.
With treatment, hypertension can be controlled for many years, and echocardiographic parameters maintained in normal values.