Familial hyperaldosteronism type I (ORPHA:403)
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.
Epidemiology
PA is the most common form of secondary hypertension and is found in up to 10% of hypertensive patients. However, familial forms are rare and represent 6-7% of PA cases. Familial hyperaldosteronism type I (FH-I) is estimated at approximately 1% of all PA cases, but may reach 3% in the hypertensive pediatric population.
Clinical description
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. Exogenous glucocorticoids are effective in reducing hyperaldosteronism and normalizing blood pressure. Cardiovascular complications due to aldosterone excess, such as fibrosis, left ventricular (LV) dysfunction, arrhythmias, and myocardial infarction, can be associated with the disease; abnormal cardiac function may manifest even in young normotensive patients. In adults, FH-I is associated with high risk of hemorrhagic stroke and ruptured intracranial aneurysms occurring at a young age.
Etiology
FH-I is due to an unequal crossing over on the long arm of chromosome 8 between the CYP11B2 gene (coding for cytochrome P450 11B2 or aldosterone synthase), normally expressed in the zona glomerulosa (ZG), and the CYP11B1 gene (coding for the cytochrome P450 11B1 or steroid 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 cortex, regulated by ACTH rather than by the renin-angiotensin system. Excessive aldosterone synthesis leads to increased sodium reabsorption, loss of potassium and subsequent increased water reabsorption.
Diagnostic methods
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. increased aldosterone levels and low plasma renin activity (tested after correction of potassium levels) with an abnormal aldosterone/renin ratio, associated or not with low serum potassium levels, and elevated urinary levels of the hybrid steroids 18-oxocortisol 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.
Differential diagnosis
The clinical presentation resembles that of the other familial forms of hyperaldosteronism (FH-II, FH-III). Specific features of FH-I are the presence of hybrid steroids 18-hydroxycortisol and 18-oxocortisol in the urine and the suppression of aldosterone by dexamethasone.
Genetic counseling
Transmission is autosomal dominant and genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Once the diagnosis is ascertained, small doses of glucocorticoids (dexamethasone at 0.125-0.250 mg/day or prednisone at 2.5 -5 mg/day) are sufficient to correct hypertension and reduce the production of aldosterone. Small doses are essential in order to avoid side effects of glucocorticoid treatment; complete suppression of ACTH-regulated hybrid gene activity 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.
Prognosis
With treatment, hypertension can be controlled for many years, and echocardiographic parameters maintained at normal values.

                            Last update: 
                            September 2021


                            - Expert reviewer(s): 
                            Dr Maria-Christina ZENNARO