Getting the Right Diagnosis: Testing for FH-I

The diagnostic process for Familial Hyperaldosteronism Type I (FH-I) usually begins with a blood test to measure two key hormones: aldosterone and renin ^[1].

In a healthy body, renin is the “gas pedal” that tells the adrenal glands to make aldosterone ^[2]. In FH-I, the chimeric gene produces aldosterone regardless of what the body needs ^[3]. This creates a specific pattern:

• Suppressed Renin: The body tries to compensate by slamming on the brakes, causing renin levels to drop so low they may be undetectable ^[4][3].
• Variable Aldosterone: The adrenal glands are producing this salt-retaining hormone, though levels can vary ^[3].
• High ARR: Doctors look at the Aldosterone-to-Renin Ratio (ARR). A high ratio is an initial screening clue that suggests aldosterone production is inappropriate ^[1][5].

Important limitations of ARR: A high ARR is only a screening test, not a definitive diagnosis. The ratio can appear artificially high simply because renin is very low, even if aldosterone is not severely elevated. Furthermore, these tests are highly sensitive to posture, salt intake, time of day, your potassium levels, and especially the medications you take. Never stop or change your blood pressure medications on your own to prepare for a test; this can be dangerous. Your specialist will safely guide you on how to prepare.

Adjunctive Markers: “Hybrid” Steroids

Because the chimeric gene in FH-I combines parts of two different hormone-making pathways, the adrenal glands produce unusual “hybrid” steroids called 18-hydroxycortisol and 18-oxocortisol ^[6].

Finding high levels of these steroids in the blood or urine can suggest a genetic form of hyperaldosteronism ^[7]. However, these are adjunctive markers, not a reliable standalone diagnosis. They can also be elevated in sporadic (non-inherited) primary aldosteronism and in other rare familial types, such as FH-III ^[6].

The Genetic “Smoking Gun”

The only way to definitively confirm FH-I is through genetic testing ^[8]. This test looks specifically for the CYP11B1/CYP11B2 chimeric gene—the fusion of two genes that shouldn’t be joined ^[9].

Because this is a large structural rearrangement between genes, a standard sequencing panel might miss the fusion entirely. Testing typically requires a validated junction-specific assay or long-range PCR designed specifically to find the “seam” where the two genes fused ^[9][3]. Due to the complexity, genetic counseling is highly recommended to interpret the results and discuss the possibility of false negatives.

Who Should Be Tested?

Targeted genetic testing for FH-I is considered when specific “clues” are present:

1. Early Onset: High blood pressure or confirmed primary aldosteronism diagnosed before age 20 ^[8][10].
2. Family History: Having a close relative with primary aldosteronism or a history of early stroke (before age 40) ^[8][10].
3. Cascade Testing: First-degree relatives of someone who has tested positive for the chimeric gene ^[3].

Telling “Look-Alikes” Apart

Doctors must distinguish FH-I from other rare genetic conditions:

• Liddle Syndrome: A condition where patients also have early-onset high blood pressure. However, in Liddle syndrome, both renin and aldosterone are very low (suppressed) ^[11]. In FH-I, aldosterone is relatively higher while renin is low ^[12].
• FH-III: A very rare condition caused by mutations in the KCNJ5 gene that also involves high aldosterone and low renin. Genetic testing is the decisive way to distinguish these rare syndromes from one another ^[13][10].

Historically, doctors used the dexamethasone suppression test to see if giving a steroid would dramatically lower aldosterone, which pointed toward FH-I ^[3][14]. While it helps show if the disease is steroid-responsive, genetic testing has replaced it as the definitive way to confirm the condition ^[10].