The importance of genetic test for early detection of apparent mineralocorticoid excess: a case report

Introduction

Hypertension (HTN) in pediatrics is much more common of secondary cause than in adults, and it should always trigger an etiological investigation to determine its cause (1). The most frequent causes of HTN in children are renal, cardiac and endocrine (1). The syndrome of “apparent mineralocorticoid excess” (AME) has a number of causes but all are all related to increased physiologic mineralocorticoid activity, but in the absence of elevated aldosterone levels. This can occur with genetic mutations of the epithelial sodium channel (ENaC) such as seen in Liddle’s syndrome. It can also be seen in conditions in which the enzyme 11-beta-hydroxysteroid dehydrogenase (11β-HSD2 enzyme) is blocked or deficient. This enzyme converts cortisol which has mineralocorticoid activity to cortisone that lacks mineralocorticoid activity, and is found in tissues that have mineralocorticoid receptors, being particularly important in the kidney (2). This conversion serves to safeguard the mineralocorticoid receptor from the effects of excess inactivated cortisol (3). If this enzyme activity is deficient a patient can develop a state of mineralocorticoid excess with HTN and metabolic alkalosis from excessive cortisol mineralocorticoid activity. This will suppress both renin and aldosterone. The enzyme can be blocked by glycyrrhizic acid or the antifungal drugs posaconazole and itraconazole, and the enzyme can be overwhelmed in Cushing’s syndrome where the cortisol levels are higher than can be converted by the enzyme. Both of these conditions will present with HTN and metabolic alkalosis with suppressed renin and aldosterone. Finally, the rarest form of AME related to an extremely rare autosomal recessive form of monogenic HTN resulting from mutations in the HSD11B2 gene, which belongs to the short-chain alcohol dehydrogenase family (4). Those mutations cause a deficiency in the 11β-HSD2 enzyme (5). To date, a hundred cases have been reported in the literature and its incidence remains unknown (2). We report the case of an apparent excess of mineralocorticoids in a 3-year-old boy. We present this article in accordance with the CARE reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-25-29/rc).

Case presentation

A 3-year-old child was admitted to our pediatric department for epistaxis and weight loss. The child was born of a first-degree consanguineous marriage. He has two brothers who appear to be in good health, while his paternal grandfather is currently receiving treatment for urinary lithiasis. The patient was delivered by cesarean section at 36 weeks of gestation due to unexplained intrauterine growth retardation, with a birth weight of 1,600 grams. The parents reported that the child has been experiencing polyuria-polydipsia syndrome for the past 3 months, along with recurrent nosebleeds and a weight loss of 3 kg.

The clinical examination revealed that the child weighed 11 kg [−3 standard deviation (SD)], measured 90 cm in height (−2 SD), showed no dysmorphic features, had a heart rate of 135 beats per minute, and a blood pressure of 160/105 mmHg. Normal findings were observed during the examination of the heart and lungs. The external genitalia appeared normal for an infant male. The child was initiated on Nicardipine. Loading dose of 10 µg/kg was started, followed by continuous administration through a syringe pump. The patient’s laboratory tests revealed hypokalemia, metabolic alkalosis, suppressed plasma renin activity, and normal aldosterone levels. Detailed laboratory results are presented in Table 1. A chest X-ray indicated an enlarged heart with a cardiothoracic ratio of 0.6. Cardiac ultrasound revealed an enlargement of the left ventricle. Renal ultrasound showed that the kidneys were of normal size but exhibited grade 2 nephrocalcinosis. No renal artery stenosis or kidney or adrenal masses were detected.

Based on these findings, and after excluding differential diagnoses such as Liddle’s syndrome and 11β-hydroxylase deficiency through genetic testing, as well as ruling out primary glucocorticoid resistance based on a normal 24-hour urinary free cortisol level (Table 1), AME was suspected. The diagnosis was confirmed through molecular testing, which revealed a homozygous genetic variation in exon 2 of the HSD11B2 gene: c.478G>A, p.Gly160Ser. Indeed, the genetic test showed that the two parents carry the familial variation c.478G>A, p.Gly160Ser;[=] in a heterozygous state on exon 2 of the HSD11B2 gene.

The patient was prescribed spironolactone at a dose of 50 mg per day, along with potassium supplementation and a restricted sodium intake. Furthermore, a thiazide diuretic at 12.5 mg per day was administered to reduce nephrocalcinosis.

The patient’s clinical course was favorable, with resolution of left ventricular hypertrophy, stabilization of nephrocalcinosis, and no further end-organ damage, particularly no deterioration of renal function and no retinal involvement. Blood pressure was well controlled, with post-treatment values ranging from 90 to 105 mmHg systolic and 60 to 70 mmHg diastolic. Additionally, the polyuria-polydipsia syndrome resolved.

Ethical considerations

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Strengths and limitations

Our article highlights an extremely rare etiology of pediatric HTN, which is AME. Our case further enriches the literature, especially regarding the catalog of mutations described by it concerning the diagnosis of AME, and helps clinicians consider this rare diagnosis and the management of these patients to protect them from serious complications that could be fatal. The main limitation of our study is the report of a single case.

High blood pressure in children is defined as a blood pressure above the 95^th percentile according to the American Academy of Pediatrics (4). Diagnosing HTN in children requires a thorough diagnostic investigation to determine the cause. The most common causes are renal and renovascular conditions, which account for approximately 85% of pediatric HTN cases (6). Endocrine HTN is rare in children, physical examination findings can provide clues for diagnosis, but they are often absent in cases of pediatric HTN (7). The adrenals produce various hormones, including cortisol and aldosterone from the cortex, and catecholamines from the medulla. These hormones play a crucial role in regulating plasma volume and vascular resistance. Consequently, certain endocrine disorders associated with excessive hormone production, such as primary aldosteronism, Cushing syndrome, and pheochromocytoma, can lead to HTN. AME was first described in 1977 (8). It is particularly found in consanguineous families (9). In fact, the first HSD11B2 mutation was identified in 1995 in a consanguineous Iranian family (10).

The HSD11B2 gene is located in chromosome 16q22.1 and it has five exons (9,11). The 11β-HSD2 is expressed by this gene in many organs including the kidney (9,11,12).

11β-HSD2 is a nicotinamide adenine dinucleotide (NAD)-dependent dehydrogenase which has two major domains: the cofactor (NAD⁺) binding region and the substrate binding region (2). In vivo, mineralocorticoid receptors have more affinity for aldosterone compared to cortisol (13). When the coenzyme binding site binds to NAD⁺ and the substrate binding site binds to cortisol, 11β-HSD2 is functional and can convert cortisol to cortisone which is inactive on mineralocorticoid, therefore, it protects the mineralocorticoid receptor from activation by cortisol (2,14). When 11β-HSD2 is absent, excess cortisol can activate the mineralocorticoid receptor, resulting in HTN without increased levels of aldosterone or renin (15). In fact, cortisol levels in circulation are 100 to 1,000 times higher than aldosterone levels (3,16,17).

AME is caused by either homozygous or compound heterozygous HSD11B2 mutations (2,9). The mutations that could affect protein stability, the affinity to the substrate or cofactor, and the dimer interface are the main genetic mechanisms involved in a loss of enzymatic activity and cause AME (18-20). The most reported mutations are missense mutations occurring notably in exons 3, 4, and 5 and other mutations such as nonsense, splicing, insertion, frameshift and deletion mutations were less found (2,9,17,21).

The genetic testing of our patient showed a new missense homozygous variation in exon 2 of the HSD11B2 gene c.478G>A, p.Gly160Ser. This missense variation produced an amino acid change (Gly in ser at position 160). This genotype was considered responsible for the disease. In fact, a comprehensive search of major genetic databases revealed that this missense variant has not been previously reported or classified as pathogenic, indicating that this is a novel homozygous variant. To support its pathogenicity, in silico predictions suggest a functional impact. Sorting Intolerant From Tolerant (SIFT) predicts the variant to be deleterious, Polymorphism Phenotyping v2 (PolyPhen-2) classifies it as probably damaging, and a high PhyloP score indicates strong evolutionary conservation of the glycine residue at position 160. Conservation analysis further supports this, as glycine at this position is preserved across diverse species, underscoring its likely importance in protein function. The substitution of glycin which is critical for flexibility due to its small size with a larger, polar serine may disrupt local structural integrity. Clinically, the patient’s phenotype, characterized by HTN, hypokalemia, suppressed renin, and metabolic alkalosis, aligns closely with features AME, strengthening the genotype-phenotype correlation. Structural insights from the HSD11B2 model, as reported in the PNAS structural study, indicate that Gly160 lies within the substrate/NAD⁺-binding domain, a region known to be crucial for enzymatic activity. Although Gly160 is not directly annotated as part of the core binding sites in UniProt, it is located between annotated NAD⁺ (residues 82–111) and substrate (around residue 219) binding regions, possibly contributing to the structural scaffold necessary for enzymatic function. As a member of the short-chain dehydrogenase/reductase family, HSD11B2 relies on proper folding, dimerization, and cofactor/substrate binding for its catalytic activity. The substitution of glycine with serine may interfere with protein folding, substrate recognition, or NAD⁺ binding, or could destabilize dimer formation, each of which would result in reduced enzymatic activity. Furthermore, other reported missense mutations within these functional domains such as R337C are known to abolish enzyme activity and cause AME, supporting the conclusion that core missense variants like Gly160Ser are pathogenic. Collectively, these data strongly suggest that the novel c.478G>A, p.Gly160Ser variant is a disease-causing mutation contributing to the AME phenotype in our patient.

For AME, there is a genotype-phenotype correlations (18,22). Indeed, the clinical picture can vary from a severe, life-threatening form that presents the classic presentation of AME, appearing in early childhood, to a mild or non-classic forms that can be diagnosed in adolescents and adults (2,23).

This diversity and severity of clinical presentation essentially depends on the residual activity of the 11βHSD2 enzyme determined by the type of HSD11B2 mutations (5).

In fact, HSD11B2 homozygous mutations give rise to classic AME which are severe, causing an absent or minimal residual enzyme activity, however, heterozygous mutations are associated with mild forms of the disease (17,24).

In the classic form of AME, clinically, infants exhibit HTN, low birth weight, growth retardation and polyuria-polydipsia syndrome (5,25,26). Biologically, they presents with hypokalemia, hypernatremia, metabolic alkalosis, low renin, low or normal aldosterone levels and high cortisol to cortisone ratios (5,25). Kidney ultrasound may show typically nephrocalcinosis and renal cysts (27,28).

In the non-classic form of AME called also apparent mineralocorticoid excess type 2, patients present normal blood pressure levels or moderate HTN, high urinary cortisol/cortisone ratio and low cortisone level (26,29,30). Data of the clinical and biological characteristics of patients with AME in the literature are summarized in Table 2.

The genetic testing is mandatory, on the one hand, because of the variety of clinical presentation (9,31) and on the other hand because of serious consequences in the absence of an early diagnosis and appropriate management in time (32). In fact, severe HTN and chronic HTN can damage, central nervous system, the heart, kidneys and retina (9,32,33). Genetic evidence permits also to rule out differential diagnoses of AME that have similar clinical features such as Liddle syndrome, Bartter syndrome and primary glucocorticoid resistance (34-36). Genetic testing allows clinicians to confirm the specific diagnosis by identifying the exact genetic mutation, which helps differentiate between similar syndromes that often present with overlapping clinical and biochemical features. This distinction may not be possible based on clinical or biochemical data alone. Genetic testing also guides targeted therapy. For instance, in Liddle syndrome, treatment with ENaC inhibitors such as amiloride or triamterene is effective, whereas mineralocorticoid receptor antagonists are not beneficial. In contrast, in AME, treatment may include mineralocorticoid receptor antagonists and glucocorticoid therapy. Furthermore, genetic testing enables family screening and genetic counseling, as these conditions are inherited. Identifying the causative mutation allows for screening of at-risk family members, early diagnosis, and timely initiation of preventive treatment.

The goal of AME treatment is to control HTN and correct hypokalemia to prevent end-organ damages (33,37,38) and improve growth retardation.

Treatment is based on reduction of dietary sodium (39,40) and the blockade of mineralocorticoid receptor by spironolactone or eplerenone at doses ranging from 2 to 10 mg/kg/day in classic AME (33) combined with potassium supplementation (5) and/or ENaC inhibitors such as amiloride (2,33,41,42).

Thiazides can be added to help to normalize blood pressure and reduce hypercalciuria and nephrocalcinosis (23,33). Calcium channel blocker can be used if HTN remains uncontrolled (43). Low-dose dexamethasone (1.5–2 mg/day) can be prescribed to reduce the endogenous secretion of cortisol (23,42,44). Because long-term treatment with dexamethasone has adverse effects (42), careful monitoring is required (38). Kidney transplantation is suggested as a for patients with classic AME (38,39).

Regarding outcome of AME and long-term follow-up, Yau et al. (22) reported cardiovascular mortality (19%), persistence of nephrocalcinosis (89%) and kidney failure (15%).

Our patient has been prescribed spironolactone with potassium supplementation and restricted sodium intake. A thiazide diuretic has also been added. Our patient’s clinical course was favorable, with resolution of left ventricular hypertrophy, stabilization of nephrocalcinosis, and no further end-organ damage, particularly no deterioration of renal function and no retinal involvement. Blood pressure was well-controlled and the polyuria-polydipsia syndrome has resolved.

Conclusions

AME is an extremely rare cause of HTN with low renin in children, the diversity of clinical presentation and the serious complications that it can cause, implies the search for this disease at the slightest clinical suspicion. The genetic testing is the key element that ensures an exact diagnosis by specifying the responsible mutation and its severity. Early and adequate management ensures better outcomes by preventing end-organ damage and reducing mortality.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-25-29/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-25-29/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-25-29/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient’s parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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