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Pediatr Nephrol (2004) 19:698–699 DOI 10.1007/s00467-004-1437-9

C L I N I C A L Q U I Z

F. Cachat · J. P. Guignard

Answer

Received: 29 August 2003 / Revised: 7 January 2004 / Accepted: 26 January 2004 / Published online: 9 March 2004  IPNA 2004

Answers

1. Reflux nephropathy could possibly explain the hyper-tension, but hypokalemia is unlikely in patients with reflux nephropathy.

2. A monogenic form of hypertension should be exclud-ed. Liddle syndrome, apparent mineralocorticoid excess, or glucocorticoid-remediable aldosteronism (GRA) would account for the hypertension and hypo-kalemia.

3. Increased urinary oxo-steroids or an abnormal ratio of urine oxo-steroids to cortisol would confirm the diagnosis of GRA. An abnormal ratio of urine cortisol to cortisone would confirm a diagnosis of the syn-drome of apparent mineralocorticoid excess.

4. The best treatment for GRA is oral dexamethasone and spironolactone.

Commentary

This patient presents with severe hypertension and hypo-kalemia. She also has a history of reflux nephropathy. Reflux nephropathy has been associated with abnormal-ities of the renin-angiotensin-aldosterone system [1, 2], but rarely causes severe hypertension [3]. In patients with duplex ureters and vesicoureteral reflux, the lower kidney poles are often dysplastic from the start, and these defects are not often associated with high blood pressure. Reflux nephropathy could therefore not be the sole cause of hypertension in our patient, unless associated with a renal artery stenosis. Given the normal findings on both duplex

Doppler sonography and 123I-Hippuran renal scan, renal

artery stenosis was unlikely. The strong family history suggests the presence of a monogenic form of hyperten-sion with hypokalemia. GRA is inherited as an autosomal dominant trait, and is associated with a high incidence of subarachnoid hemorrhages. GRA is due to gene chimer-ism. The hybrid, or chimeric gene, combines the 50 promoter sequence of the 11b-hydroxylase gene fused to the more-distal 30 aldosterone synthase coding sequence. As a result, aldosterone synthase is ectopically expressed in the cortisol-producing zone of adrenal cortex under the regulation of adrenocorticotropic hormone (ACTH) [4]. Hypertension is often early and may be of sufficient severity to result in death, commonly from intracerebral or subarachnoid hemorrhages [5]. The diagnosis is made by demonstrating the presence of an excessive production of 18-hydroxy- and 18-oxo-cortisol, as a result of aberrant expression of aldosterone synthase activity in the zona fasciculata, where cortisol is a substrate.

Apparent mineralocorticoid syndrome also causes severe hypertension with hypokalemia. It is secondary to the absence or inhibition of the 11-b-steroid dehydro-genase. This enzyme converts the hormonally active cortisol, which has a strong mineralocorticoid action, to the less active cortisone [6]. Liddle syndrome is caused by hyperactivity of the epithelial sodium channel (ENaC) secondary to mutations in the subunits [7]. This is transmitted as an autosomal dominant disorder, with early penetrance. Hypertension is severe, but hypokalemia is less marked than in GRA or apparent mineralocorticoid excess (Table 1). Measurements of plasma renin activity, plasma aldosterone, urinary 18-oxo-steroids, and urinary cortisol/cortisone ratio can lead to the correct diagnosis. Our patient and her father had a suppressed plasma renin activity (daughter 0.09 ng/ml per hour, normal 0.45–3.70, father <0.05 ng/ml per hour, normal 0.2–2.0) with elevated plasma aldosterone (daughter 320 pg/ml, normal 29–76, father 142 pg/ml, normal 29-76) (Professor J. Nussberger, personal communication; [8]). Although our patient had a normal urinary steroid profile, her father had an increased 18-oxo-steroid excretion (643 mg/day, nor-This refers to the article that can be found at http://dx.doi.org/

10.1007/s00467–004–1436-x F. Cachat (

)

) · J. P. Guignard

Department of Pediatrics, Division of Pediatric Nephrology, University Hospital,

1011 Lausanne, Switzerland e-mail: Francois.Cachat@hospvd.ch Tel.: +41-21-3141111

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mal 6–410). Treatment with 0.5 mg/day oral dexameth-asone and oral spironolactone 25 mg twice daily normal-ized her blood pressure within 2 weeks. More than a year later, she is still normotensive (110/70 to 120/80 mmHg) on the same drug treatment. Dexamethasone inhibits ACTH secretion (and secondary aldosterone production), whereas spironolactone blocks the aldosterone receptors in the distal tubules and collecting ducts (and decreases sodium reabsorption). The father declined dexamethasone therapy, and is still hypertensive on a b-blocker and an angiotensin converting enzyme inhibitor. Even without genetic analysis, we feel that the striking family history, biochemical findings, and response to specific therapy confirm the diagnosis of GRA in that family.

Acknowledgement The authors wish to thank P. Ferrari, MD, University of Bern, Switzerland, for performing the analysis of the urinary steroid profile of our patients, and J. Nussberger, MD, University of Lausanne, for performing the renin and aldosterone measurements.

References

1. Del Greco F, Huang CM, Quintanilla A, Krumlovsky F, Roxe DM, Santhanam S (1981) The renin-angiotensin-aldosterone system in primary and secondary hypertension. Ann Clin Lab Sci 11:497–505

2. Goonasekera CD, Dillon MJ (1998) Reflux nephropathy and hypertension. J Hum Hypertens 12:497–504

3. Wolfish NM, Delbrouck NF, Shanon A, Matzinger MA, Stentrom R, McLaine PN (1993) Prevalence of hypertension in children with primary vesicoureteral reflux. J Pediatr 123:559–563

4. Jackson RV (2002) New genetic insights in familial hyperal-dosteronism. Ann NY Acad Sci 970:77–88

5. Litchfield WR, Anderson BF, Weiss RJ, Lifton RP, Dluhy RG (1998) Intracranial aneurysm and hemorrhagic stroke in glu-cocorticoid remediable aldosteronism. Hypertension 31:445– 450

6. Morineau G (1999) Genetic, biochemical, and clinical studies of patients with A328V or R213C mutations in 11bHSD2 causing apparent mineralocorticoid excess. Hypertension 34:435–441

7. Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa P, Iwasaki T, Rossier B, Lifton RP (1995) Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet 11:76–82

8. Lentner C (ed) (1990) Geigy scientific tables, vol 5. Heart and circulation, 8th edn. Basel, pp 241–247 and 251–253

Table 1 Features of glucocorticoid-remediable aldosteronism (GRA), apparent mineralocorticoid excess (AME), and Liddle syndrome (AD autosomal dominant, AR autosomal recessive)

GRA AME Liddle

Hypertension 3+ 3+ 3+

Genetics AD AR AD

Hypokalemia 3+ 3+ +

Salt sensitivity 3+ 2+ 3+

Plasma renin activity # # #

Plasma aldosterone " # #

Urinary cortisol/cortisone ratio Normal " Normal Urinary 18-oxo-steroids " Absent Absent

Response to amiloride Yes Yes Yes

Response to spironolactone Yes No/poor No Response to dexamethasone Yes Yes No

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