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Difficulty: HardFormulating a Differential Diagnosis

A 22-year-old man presents to the clinic for a routine evaluation after a pre-employment physical revealed significantly elevated blood pressure. He reports experiencing occasional muscle cramping and generalized weakness, particularly after intense exercise, but is otherwise asymptomatic. He takes no medications, over-the-counter supplements, or herbal remedies. Family history is significant for severe, treatment-resistant hypertension in his father, paternal aunt, and paternal grandmother, all of whom were diagnosed in their early twenties.

Vital signs:
Temperature: 37.0°C (98.6°F)
Blood pressure: 178/112 mmHg
Pulse: 76/min
Respirations: 14/min

Physical examination is unremarkable, with no abdominal bruits, no striae, and normal secondary sexual characteristics.

Laboratory studies:
Serum sodium: 146 mEq/L
Serum potassium: 2.6 mEq/L
Serum chloride: 102 mEq/L
Serum bicarbonate: 31 mEq/L
Blood urea nitrogen: 14 mg/dL
Serum creatinine: 0.9 mg/dL
Plasma renin activity: Undetectable
Serum aldosterone: < 2 ng/dL (Reference: 3-16 ng/dL upright)
Serum morning cortisol: 14 mcg/dL (Reference: 5-25 mcg/dL)

Which of the following is the most likely diagnosis?

  1. Liddle syndromeAnswer
  2. B
    Fibromuscular dysplasia
  3. C
    Aldosterone-producing adenoma
  4. D
    11β11\beta-hydroxylase deficiency
  5. E
    Syndrome of apparent mineralocorticoid excess

Answer

Liddle syndrome is the most likely diagnosis due to the combination of early-onset hypertension, hypokalemic metabolic alkalosis, suppressed renin and aldosterone, and an autosomal dominant family history.
The correct answer accurately synthesizes the laboratory data and family history. The triad of early-onset hypertension, hypokalemia, and metabolic alkalosis indicates a mineralocorticoid effect. Because both renin and aldosterone are suppressed, the effect must be driven by a non-aldosterone mechanism or a primary renal tubular defect. The autosomal dominant family history strongly points to Liddle syndrome, an inherited gain-of-function mutation in the collecting tubule's epithelial sodium channels (ENaC) that leads to unregulated sodium reabsorption and subsequent potassium and hydrogen excretion.

Step-by-Step Solution

1
Analyze the patient's clinical and laboratory presentation.
The patient has severe early-onset hypertension, profound hypokalemia (2.62.6 mEq/L), and metabolic alkalosis.
This triad indicates a state of mineralocorticoid excess, prompting an evaluation of the renin-angiotensin-aldosterone system.
2
Interpret the plasma renin activity and serum aldosterone levels.
Both plasma renin activity (undetectable) and serum aldosterone (<2< 2 ng/dL) are suppressed.
Suppressed renin and aldosterone rule out primary hyperaldosteronism (where aldosterone would be high) and secondary hyperaldosteronism (where both renin and aldosterone would be high).
3
Formulate a differential diagnosis for 'low renin, low aldosterone' hypertension.
The differential includes Liddle syndrome, syndrome of apparent mineralocorticoid excess (SAME), licorice ingestion, and congenital adrenal hyperplasia (e.g., 11β11\beta-hydroxylase deficiency).
These conditions mimic aldosterone action via different mechanisms (e.g., unregulated ENaC channels, non-aldosterone mineralocorticoids, or impaired cortisol degradation).
4
Differentiate the remaining etiologies using historical and physical findings.
The patient takes no supplements (rules out licorice), has normal secondary sexual characteristics (makes CAH unlikely), and has a strong multi-generational autosomal dominant family history.
Liddle syndrome is an autosomal dominant condition caused by a gain-of-function mutation in the epithelial sodium channel (ENaC), perfectly matching the clinical picture and inheritance pattern.

Key Concept

Formulating a differential diagnosis for mineralocorticoid excess requires evaluating the renin and aldosterone levels. A 'low renin, low aldosterone' profile with an autosomal dominant inheritance pattern is highly specific for Liddle syndrome.
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Formulating a Differential Diagnosis

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