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 Table of Contents  
Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 36-39

Apparent mineralocorticoid excess - A rare cause of endocrine hypertension

1 Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission12-Oct-2022
Date of Decision23-Jan-2022
Date of Acceptance23-Jan-2022
Date of Web Publication25-Feb-2022

Correspondence Address:
Dr. Preeti Dabadghao
Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_312_21

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Background: Endocrine causes of hypertension constitute a very small percentage of patients with secondary hypertension. Apparent mineralocorticoid excess (AME) is a rare genetic form of young-onset secondary hypertension. Clinical Description: We present a case of a 16-year-old boy who was diagnosed with hypertension at 5 years of age, had recurrent episodes of hypokalemic paralysis, and deranged renal function for 1 year. Hypertension was uncontrollable with multiple antihypertensive agents until an aldosterone antagonist (spironolactone) was added. Clinical history and evaluation could not identify any secondary causes of hypertension. There was no significant family history. Growth and puberty were age-appropriate. Management and Outcome: Endocrine workup was planned considering hypokalemia and metabolic alkalosis. This demonstrated hyporeninemic hypoaldosteronism and raised the possibility of AME and Liddle syndrome. Clinical exome sequencing revealed a probable diagnosis of AME due to a novel homozygous variant (c.911A>G) in HSD11B2 gene. Sanger sequencing confirmed heterozygosity of the same variant in both parents. Conclusion: A novel homozygous variant was found in HSD11B2 gene in a subject with early-onset hypertension associated with hypokalemic metabolic alkalosis, establishing the diagnosis of AME. The use of an algorithmic approach and individualized planning of genetic studies can help in early diagnosis. This helps clinicians to select the appropriate antihypertensive drug, attain good control, and prevent the development of end-organ damage. A high index of suspicion should be kept for AME and other hyporeninemic hypoaldosteronism conditions in the case of early-onset hypertension.

Keywords: Hypoaldosteronism, low renin, mineralocorticoid excess, pediatric, secondary hypertension

How to cite this article:
Verma S, Dabadghao P, Moirangthem A. Apparent mineralocorticoid excess - A rare cause of endocrine hypertension. Indian Pediatr Case Rep 2022;2:36-9

How to cite this URL:
Verma S, Dabadghao P, Moirangthem A. Apparent mineralocorticoid excess - A rare cause of endocrine hypertension. Indian Pediatr Case Rep [serial online] 2022 [cited 2022 May 27];2:36-9. Available from: http://www.ipcares.org/text.asp?2022/2/1/36/338487

Most guidelines such as of the American Academy of Pediatrics and European Society of Hypertension recommend mandatory annual blood pressure (BP) measurement in children and adolescents for the early detection of primary as well as asymptomatic secondary hypertension.[1] Primary hypertension can be differentiated from secondary hypertension by the absence of any identifiable secondary cause. [Table 1] lists various causes of secondary hypertension in children as well as their presenting features. Renal and renovascular causes are most common, constituting 34%–79% and 12%–13%, respectively, whereas endocrine disorders account for only 0.5%–6% causes of secondary hypertension.[2]
Table 1: Causes of secondary hypertension with their presenting features

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Elicitation of a detailed history, performance of a focused examination, and analysis of first-line investigation reports are invaluable steps that give direction to a clinical approach aimed at determining etiology. For instance, hypertension associated with metabolic alkalosis and hypokalemia warrants evaluation for increased mineralocorticoids. Apparent mineralocorticoid excess (AME) is a rare autosomal recessive monogenic disorder arising from deficiency of the renal isoenzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2).[3] It is characterized by severe hypertension (i.e., BP more than 95th centile + 12 mmHg, or the presence of target organ damage) that is early in onset (presenting before 40 years of age) and is due to hyporeninemic hypoaldosteronism. Normally, 11βHSD2 inactivates the glucocorticoid cortisol to a less active metabolite, cortisone. Mutations in the 11βHSD2 gene affect this step, leading to supraphysiological cortisol levels by binding and activating the mineralocorticoid receptor (MR) for aldosterone, thus behaving like an “apparent” mineralocorticoid. The spectrum of clinical phenotypes ranges from severe hypertension presenting in infancy to mild forms first seen in adulthood. Growth failure (prenatal and postnatal) may be seen in severe cases.

In AME, the renal damage that ensues from the untreated chronic hypertension makes the interpretation of biochemical and hormonal tests challenging, as well as control of hypertension difficult. The aim of presenting this case is to sensitize pediatricians to the clinical approach required for investigating secondary hypertension in young children.

  Clinical Description Top

A 16-year-old boy was referred to our center for the management of hypertension with deranged renal function. The child became symptomatic for the first time at the age of 5 years when he developed bilateral lower limb weakness. At that time, he had been diagnosed with hypertension and concurrent hypokalemia and metabolic alkalosis. Over the years, the child had visited multiple experts and had been prescribed various antihypertensive drugs. His hypertension remained uncontrolled despite good compliance to beta-blockers (metoprolol), calcium channel blocker (amlodipine), and an alpha-blocker (prazosin), until a mineralocorticoid antagonist (spironolactone) was added. During this period, there was a history of multiple episodes of weakness in the bilateral lower limbs associated with muscle cramps and pain. Each episode progressed to complete weakness over hours. These were attributed to severe hypokalemia (serum potassium <2.5 mEq/L) by his treating physician, with symptomatic relief on normalization of levels after the initiation of intravenous, followed by oral potassium. There was no history of decreased micturition or the passage of red or discolored urine, swelling of any part of the body, seizures, difficulty in breathing, or growth failure. There was no history suggestive of secondary causes of hypertension, as listed in [Table 1]. He was born out of nonconsanguineous marriage. No other family member had a history of hypertension, coronary artery disease, or any features suggestive of thyroid, parathyroid, or abdominal neoplasia, all causes of secondary hypertension.

On examination, all peripheral pulses were palpable, the heart rate was 90 beats per minute (min), and respiratory rate was 18 per min. However, the blood pressure was elevated on multiple occasions; 159/89 mmHg (>95th +12 mmHg in both diastolic and systolic BP). There was no significant difference between the upper and lower limbs. An abdominal bruit was not heard. The child's height was 164 cm (between 50th and 75th centile on Indian population charts) and weight 58 kg (25th–50th centile). The facies and body proportions appeared normal. Pubertal development was age-appropriate with Tanner's sexual maturity rating stage 4. There was no evidence of pallor, periorbital or pedal edema, labial and lingual nodular swellings, cushingoid features, neurocutaneous markers, rashes, or skin lesions, including acne. Thyroid examination was normal. Fundus examination revealed diffuse arteriolar narrowing with no constriction indicative of grade I hypertensive retinopathy. Respiratory, cardiovascular, abdominal, and central nervous system examinations were unremarkable. Thus, the clinical phenotype was early-onset hypertension with possible renal end-organ damage and intermittent episodes of symptomatic hypokalemia.

Significant biochemical abnormalities were identified; hypokalemia (K + 2.9 mEq/L) in the presence of normal serum sodium levels (149 mEq/L) and metabolic alkalosis (venous blood gas pH 7.45, bicarbonate level 24 mEq/L). Elevated serum creatinine (2.8 mg/dL) and decreased estimated glomerular filtration rate (eGFR) of 47 mL/min/1.73 m2 (normal >60 mL/min/1.73 m2) confirmed chronic kidney failure. The abdominal ultrasound revealed bilateral echogenic kidneys with loss of corticomedullary differentiation and a small-sized right kidney. Renal Doppler showed normal renal vasculature. Echocardiography detected left ventricular hypertrophy that was attributed to prolonged systemic hypertension.

The presence of hypokalemia and metabolic alkalosis suggested a hyperfunctioning mineralocorticoid axis. Thus, we decided to measure the plasma aldosterone levels and plasma renin activity. Plasma aldosterone level was 0.13 nmol/L (normal 0.19–0.83 nmol/L), while plasma renin activity was 0.2 ng/mL/h (normal 0.8–1.8 ng/mL/h). We had to stop spironolactone for 6 weeks before testing to avoid interference, and the BP was monitored strictly. During this period, there were episodes of elevation of systolic BP >160 mmHg that were managed by sublingual nicardipine (calcium channel blockers). The BP normalized as soon as spironolactone therapy was resumed. We also evaluated 17-OH-progesterone to rule out congenital adrenal hyperplasia secondary to 11 beta-hydroxylase deficiency, which was normal (10.48 nmol/L). Since the endocrinal phenotype of hyporeninemic hypoaldosteronism suggested overstimulation of the MR by cortisol or related precursors, the differential diagnoses of AME and Liddle syndrome were considered, and genetic testing was planned.

Clinical exome sequencing (ES) identified a homozygous missense variation c.911A>G in exon 5 of the HSD11B2 (ENST00000326152.6) gene. This variant results in substitution of arginine for histidine at codon 304. Sanger sequencing confirmed that the parents were heterozygous carriers for the same variant. The c.911A>C variant has not been reported in the 1000 genomes project (https://www.internationalgenome.org), gnomAD (https://gnomad. broadinstitute.org), database of Indian exomes, and internal databases of the laboratory. It is also not reported in disease databases such as Clinvar and human gene mutation database. The in silico prediction of the variant was inconsistent across various tools; Functional Analysis through Hidden Markov Models predicting a deleterious effect, while MutationTaster, scale-invariant feature transform, and polyphen-2 predicting a benign effect. This was classified as a variant of uncertain significance according to the American College of Medical Genetics criteria.[4] Protein structural modeling by EasyModeller and molecular dynamic simulation for determining the possible effect of change in the amino acid residue observed no significant perturbations in interaction as well as structure between the residues and ligand at the active site of both wild and mutant structures. The superimposition of both showed negligible root mean square deviation, which suggested that the mutation did not have any effect on structure or stability of the protein.

  Discussion Top

The differential diagnoses that need to be considered in children presenting with hypertension and hypokalemic metabolic alkalosis include heterogeneous causes; renovascular hypertension, AME, Cushing syndrome, Liddle syndrome, renal secreting tumors, 11β hydroxylase deficiency, and glucocorticoid remediable hypertension. Although the list appears daunting at first, an astute clinician can arrive at an etiological diagnosis in cases presenting with early-onset hypertension by following a stepwise algorithmic approach [Figure 1].
Figure 1: Algorithmic approach to early-onset hypertension. aTHF: Allo-tetrahydrocortisol; AME: Apparent mineralocorticoid excess; DOC: Deoxycortisol; MR: Mineralocorticoid receptor; PRA: Plasma renal activity; THE: Tetrahydrocortisone; THF: Tetrahydrocortisol; UFE: Urinary-free cortisone; UFF: Urinary-free cortisol

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Our patient had AME, a rare cause of severe early-onset hypertension characterized by hyporeninemic hypoaldosteronism that results in excessive water and sodium retention, hypokalemia, and hypertension. The severe, chronic, and difficult to control hypertension, as well as recurrent and/or chronic hypokalemia, may have been responsible for the end organ nephropathy seen in this case, as renal parenchyma is very sensitive to the effect of cortisol. The presence of renal failure confounds the interpretation of aldosterone and plasma renin levels in hyporeninemic hypoaldosteronism conditions. Aldosterone levels increase with a decrease in eGFR, and renal failure leads to hyperreninemic hyperaldosteronism. The Framingham Offspring study demonstrated a significant association between high serum aldosterone concentrations and eGFR less than 60 mL/min per 1.73 m2.[5] Our case showed suppressed renin and aldosterone levels even with low eGFR. The characteristic hormonal profile in AME is an increased ratio of urine-free cortisol to cortisone; 5–18 compared to <0.5 in normal individuals.[6] In this case, we were unable to test for urinary metabolites due to concurrent renal failure. The variability and overlapping nature of clinical and biochemical features with other differentials and aforementioned challenges in the interpretation of hormonal profiles highlight the importance of genetic evaluation in suspected cases of AME with end-organ renal failure.

Although the novel c.911A>G variant identified in this case is classified as a variant of uncertain significance, we believe that it is causative and offer two arguments to support this theory. First, the patient with hyporeninemic hypoaldosteronism responded very well to spironolactone, a mineralocorticoid antagonist. Second, none of the common variants usually associated with hyporeninemic hypertension (SCNN1A, SCNN1B, SCNN1G, CACNA1H, CLCN2, KCNJ5, or CYP11B1) were identified.

To conclude, a high index of suspicion for pediatric hypertension, routine and early BP monitoring, the use of an algorithmic approach, and individualized planning of genetic studies can not only help in ascertaining cause but can also guide the clinician to choose the most suitable antihypertensive drug, thereby preventing the development of end-organ damage.

Declaration of patient consent

The authors certify that they have obtained the appropriate consent from the parents. In the form, the patient's elder brother has given his consent for the images and other clinical information to be reported in the journal. The patient's elder brother understands that the name and initials will not be published, and due efforts have been made to conceal the same, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens 2016;34:1887-920.  Back to cited text no. 1
Flynn JT, Kaelber DC, Baker-Smith CM. Subcommittee on screening and management of high blood pressure in children. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 2017;140:e20171904.  Back to cited text no. 2
Razzaghy-Azar M, Yau M, Khattab A, et al. Apparent mineralocorticoid excess and the long term treatment of genetic hypertension. J Steroid Biochem Mol Biol 2017;165:145-50.  Back to cited text no. 3
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.  Back to cited text no. 4
Al-Harbi T, Al-Shaikh A. Apparent mineralocorticoid excess syndrome: Report of one family with three affected children. J Pediatr Endocrinol Metab 2012;25:1083-8.  Back to cited text no. 5
Funder JW. Apparent mineralocorticoid excess. J Steroid Biochem Mol Biol 2017;165:151-3.  Back to cited text no. 6


  [Figure 1]

  [Table 1]


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