Liddle syndrome caused by SCNN1B mutation presenting with severe early-onset hypertension and hypokalemia in an adolescent: a case report

Abstract

Background

Liddle syndrome is a rare autosomal dominant form of monogenic hypertension caused by gain-of-function mutations in genes encoding the epithelial sodium channel (ENaC). The disease is characterized by early-onset hypertension, hypokalemia, metabolic alkalosis, and suppression of the renin–angiotensin–aldosterone system (RAAS). Early diagnosis is essential because targeted therapy with ENaC inhibitors can effectively control blood pressure and prevent end-organ damage, whereas mineralocorticoid receptor antagonists are ineffective.

Case presentation

We report a 15-year-old Chinese male who presented with severe hypertension (196/143 mmHg) and profound hypokalemia (1.73 mmol/L) with a history of hypertension since the age of 10 years. Laboratory evaluation revealed suppressed plasma renin concentration (3.157 pg/mL), relatively normal aldosterone (61.784 pg/mL), and an aldosterone-to-renin ratio of 19.57. Arterial blood gas analysis demonstrated metabolic alkalosis (pH 7.48, HCO₃⁻ 28 mmol/L). A 24-hour urinary potassium excretion of 81.65 mmol/day confirmed renal potassium wasting. Serum cortisol and ACTH were within normal limits. Although definitive biochemical exclusion of apparent mineralocorticoid excess (AME) and glucocorticoid-remediable aldosteronism (GRA) was not performed, no pathogenic variants were identified in HSD11B2, CYP11B1, or CYP11B2 on the comprehensive genetic panel, providing molecular-level exclusion of these conditions. Echocardiography demonstrated ventricular wall thickening with mild valvular regurgitation. Brain MRI revealed bilateral basal ganglia and left corona radiata encephalomalacia with white-matter hyperintensity (Fazekas grade 1), indicating chronic hypertensive brain injury. Next-generation sequencing identified a heterozygous SCNN1B variant (NM_000336.3: c.1853 C > G; p.Pro618Arg; absent from gnomAD), classified as Likely Pathogenic per ACMG/AMP guidelines (criteria: PM1, PM2, PP3, PP4), confirming the diagnosis of Liddle syndrome. Treatment with compound amiloride tablets and potassium supplementation normalized serum potassium within 48 h and significantly improved blood pressure. At one-month follow-up, blood pressure was well controlled at 130/80 mmHg. Long-term follow-up is ongoing to assess sustained blood pressure control and end-organ recovery.

Conclusion

Although SCNN1B p.Pro618Arg is a recognized pathogenic hotspot variant, this case highlights the severe phenotypic consequences of delayed diagnosis in adolescents, and demonstrates that early genetic diagnosis and targeted ENaC inhibitor therapy are achievable even in resource-limited rural clinical settings. Early recognition and targeted therapy with ENaC inhibitors are critical to prevent serious cardiovascular and cerebrovascular complications. Genetic testing is essential for definitive diagnosis, particularly in resource-limited settings where misdiagnosis as primary aldosteronism (PA) may lead to ineffective treatment.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12902-026-02407-7.

Background

Liddle syndrome is a rare hereditary form of monogenic hypertension first described by Liddle et al. in 1963 [1]. The disorder is caused by gain-of-function mutations in the genes encoding the epithelial sodium channel (ENaC), most commonly SCNN1B and SCNN1G, though mutations in SCNN1A have also been reported [2]. ENaC mediates sodium reabsorption in the distal nephron and collecting duct, and its activity is tightly regulated by the ubiquitin ligase Nedd4-2, which promotes channel internalization and degradation [3, 4]. Mutations affecting the conserved PY motif (PPxY) in the C-terminal domain of ENaC subunits disrupt this interaction, resulting in constitutive channel overactivity, excessive sodium reabsorption, extracellular volume expansion, and hypertension independent of aldosterone signaling [3, 5].

Clinically, Liddle syndrome presents with early-onset hypertension, hypokalemia, metabolic alkalosis, suppressed plasma renin, and low or normal aldosterone levels. These features may overlap with primary aldosteronism (PA), apparent mineralocorticoid excess (AME), and congenital adrenal hyperplasia (CAH), making accurate diagnosis challenging [6, 7]. Crucially, mineralocorticoid receptor antagonists such as spironolactone are ineffective in Liddle syndrome, whereas direct ENaC inhibitors such as amiloride or triamterene provide targeted and effective therapy [8, 9].

In a study of young Chinese hypertensive patients of undetermined cause, Liddle syndrome was identified in approximately 1.5% of cases, suggesting it may be underdiagnosed in this population [10, 11]. Increasing availability of next-generation sequencing (NGS) has facilitated its identification in diverse populations, including East Asians, where SCNN1B mutations predominate [10, 12].Here we report an adolescent patient with severe early-onset hypertension, hypokalemia, and multiorgan end-organ damage who was definitively diagnosed with Liddle syndrome caused by a SCNN1B p.Pro618Arg variant, a recognized pathogenic hotspot previously reported in the literature (PMID: 15483078).

Case presentation

Patient history and presentation

A 15-year-old Chinese male (height 180 cm, weight 70 kg, BMI 21.6 kg/m²) was admitted to the Department of Internal Medicine at Shaoshan People’s Hospital in January 2026 with a one-day history of generalized weakness and difficulty ambulating. He had first been diagnosed with hypertension and hypokalemia at age 10 years at a neighboring institution, where systolic blood pressure had reached 180 mmHg. He was discharged on amlodipine and potassium chloride sustained-release tablets, but medication adherence was poor owing to limited access to specialized care in this rural region. The family pedigree is shown in Fig. 1. The patient’s maternal grandfather died young of unknown cause, and his maternal grandmother is also deceased. His mother had a history of hypertension with hypokalemia and died of intracerebral hemorrhage at approximately 30 years of age, a presentation highly consistent with autosomal dominant Liddle syndrome. His father is alive and normotensive. The patient is an only child, and no family members were available for genetic screening.

Fig. 1.

Pedigree of the proband’s family. Filled symbols indicate clinically affected individuals. The proband (arrow) is a 15-year-old male with genetically confirmed Liddle syndrome. His mother (deceased, †) had a history of hypertension with hypokalemia and died of intracerebral hemorrhage at approximately 30 years of age. His maternal grandfather (deceased, †) died young of unknown cause. His maternal grandmother (deceased, †) and father (alive, normotensive) are shown. No family members were available for genetic testing

Physical examination

On admission, vital signs were as follows: temperature 36.8 °C, pulse 110 beats/min, respiratory rate 23 breaths/min, and blood pressure 196/143 mmHg. Neurological examination revealed prominent generalized muscle weakness, with upper limb strength grade 4/5 and lower limb strength grade 2/5, consistent with hypokalemic myopathy.

Laboratory findings

Initial blood tests revealed severe hypokalemia (serum potassium 1.73 mmol/L) and serum sodium 142 mmol/L. Arterial blood gas analysis confirmed metabolic alkalosis (pH 7.48, HCO₃⁻ 28 mmol/L). Serial serum potassium measurements during hospitalization are shown in Table 1.

Table 1.

Serial serum potassium measurements during hospitalization

Date and Time	Serum Potassium (mmol/L)
10 Jan 2026, 17:39	1.73
10 Jan 2026, 20:44	1.95
11 Jan 2026, 00:54	2.43
11 Jan 2026, 09:44	3.90
11 Jan 2026, 16:17	3.87
14 Jan 2026	3.98

Reference range: 3.5–5.5 mmol/L. Intravenous and oral potassium supplementation initiated on admission

Hormonal evaluation demonstrated suppressed plasma renin concentration (PRC: 3.157 pg/mL; reference upright 5–40 pg/mL), with a relatively normal plasma aldosterone concentration (PAC: 61.784 pg/mL; reference upright 40–310 pg/mL) and an aldosterone-to-renin ratio (ARR) of 19.57. Plasma angiotensin II was 76.198 pg/mL. Notably, aldosterone was considered inappropriately normal relative to the degree of hypokalemia, which normally stimulates aldosterone secretion—a key feature distinguishing Liddle syndrome from PA. Serum cortisol was 15.65 µg/dL (reference 4.26–24.85 µg/dL) and ACTH was 53.4 pg/mL (reference 7.2–63.4 pg/mL), both within normal limits. Definitive exclusion of AME requires assessment of the urinary cortisol-to-cortisone metabolite ratio, and exclusion of glucocorticoid-remediable aldosteronism (GRA) requires measurement of urinary 18-hydroxycortisol and 18-oxocortisol or a dexamethasone suppression test; these investigations were not performed due to resource limitations. However, the comprehensive 347-gene panel included HSD11B2, CYP11B1, and CYP11B2, and no pathogenic variants were identified in these genes, providing molecular-level exclusion of AME and GRA. A 24-hour urinary potassium excretion of 81.65 mmol/day confirmed renal potassium wasting as the primary mechanism of hypokalemia. Aldosterone was measured on one occasion only; repeated measurements were not performed. It should be acknowledged that a single aldosterone measurement falling within the normal range does not definitively exclude PA, as intraindividual variability can result in values below diagnostic thresholds. However, the combination of suppressed plasma renin, normal aldosterone, and the identification of a pathogenic SCNN1B variant collectively supports the exclusion of PA.

Ancillary investigations

Blood pressure monitoring during hospitalization is summarized in Table 2. Peak blood pressure of 200/135 mmHg was recorded on the evening of admission.

Table 2.

Blood pressure monitoring during hospitalization

Date and Time	Blood Pressure (mmHg)
10 Jan 2026, 15:56 (admission)	196/143
10 Jan 2026, 19:56	200/135 (peak)
10 Jan 2026, 21:10	170/124
10 Jan 2026, 23:10	169/114
11 Jan 2026, 03:10	148/84
15 Jan 2026 (discharge)	152/94

Blood pressure declined progressively following initiation of potassium supplementation and amiloride therapy

Genetic testing

Electrocardiography showed sinus rhythm with ST-T wave changes and frequent atrial premature beats. Transthoracic echocardiography demonstrated left ventricular wall thickening consistent with hypertensive cardiomyopathy, mild aortic regurgitation, mild mitral regurgitation, and preserved systolic function. Brain MRI (axial T2-weighted and FLAIR sequences) revealed bilateral basal ganglia and left corona radiata encephalomalacia with white-matter hyperintensity (Fazekas grade 1; Fig. 2), indicating chronic hypertensive cerebrovascular injury.

Fig. 2.

Brain MRI (axial T2-weighted and FLAIR sequences) showing bilateral basal ganglia and left corona radiata encephalomalacia (arrows indicate areas of hyperintensity) and white-matter hyperintensities consistent with Fazekas grade 1, indicative of chronic hypertensive cerebrovascular injury

Genetic testing

Given the clinical constellation of early-onset severe hypertension, profound hypokalemia, suppressed RAAS, and a family history suggestive of hereditary hypertension, NGS of a validated 347-gene endocrine disease panel (covering SCNN1A, SCNN1B, SCNN1G, CYP11B1, CYP11B2, HSD11B2, and related genes) was performed at a reference laboratory. Sequencing identified a heterozygous missense variant in SCNN1B (NM_000336.3: c.1853 C > G; p.Pro618Arg; chromosomal position chr16:2339052; Fig. 3). The variant was absent from the gnomAD population database (PM2) and classified as Likely Pathogenic according to ACMG/AMP variant interpretation guidelines (criteria: PM1, PM2, PP3, PP4). This variant affects the conserved proline at position 618 within the PY motif of the β-ENaC subunit, a well-established mutational hotspot for Liddle syndrome [5, 13]. Based on the clinical findings and genetic results, a definitive diagnosis of Liddle syndrome was established.

Fig. 3.

Sanger sequencing chromatogram of SCNN1B exon 13 (c.1853 C > G; p.Pro618Arg) in the proband. The red arrow indicates the heterozygous variant site, with overlapping C and G peaks confirming a heterozygous substitution. The 347-gene endocrine disease panel confirmed this variant as Likely Pathogenic per ACMG/AMP guidelines (criteria: PM1, PM2, PP3, PP4)

Treatment and outcome

On admission, intravenous antihypertensive therapy was not initiated given the absence of hypertensive emergency with acute end-organ deterioration; instead, oral amlodipine 5 mg/day was continued, as the patient had been intermittently using this agent prior to admission. Intravenous and oral potassium chloride supplementation (up to 60 mmol/day) was commenced immediately to correct severe hypokalemia. Based on the clinical constellation of severe early-onset hypertension, profound hypokalemia, suppressed plasma renin, inappropriately normal aldosterone, and a family history of fatal hypertensive hemorrhagic stroke, a provisional clinical diagnosis of Liddle syndrome was established on January 12, 2026. Compound amiloride tablets (amiloride 2.5 mg / hydrochlorothiazide 25 mg per tablet; 1–2 tablets daily) were commenced empirically as targeted ENaC-inhibiting therapy prior to the availability of genetic results, given the high clinical probability of Liddle syndrome. Although pure amiloride monotherapy is preferred when available, compound amiloride tablets were selected given their superior availability in this resource-limited rural setting. Genetic testing subsequently confirmed the diagnosis of Liddle syndrome on January 30, 2026, validating the empirical treatment decision. Serum potassium normalized within 48 h, rising from 1.73 to 3.90 mmol/L (Table 1), and muscle weakness resolved in parallel. Blood pressure declined progressively over the first 12 h (Table 2) and was 152/94 mmHg at discharge on day 7. At one-month follow-up (office measurement), blood pressure was 130/80 mmHg and serum potassium remained within the normal range. The patient reported no recurrence of weakness or neurological symptoms. Spironolactone was not used at any point during this admission. Long-term follow-up has been recommended to assess sustained blood pressure control and potential end-organ recovery.

Discussion

This case illustrates several clinically important aspects of Liddle syndrome: the molecular basis of the p.Pro618Arg variant, differential diagnosis of hypokalemic hypertension, the severity of early-onset end-organ damage, and therapeutic implications.

Molecular pathogenesis: Liddle syndrome arises predominantly from mutations in the β (SCNN1B) or γ (SCNN1G) subunits of ENaC [2]. The PY motif (PPxY) in the C-terminal domain serves as the binding site for the E3 ubiquitin ligase Nedd4-2, which normally targets ENaC for internalization and proteasomal degradation [3, 14]. Disruption of this motif—as in the p.Pro618Arg substitution—abolishes Nedd4-2 binding, leading to constitutive ENaC surface expression and unregulated sodium reabsorption [5, 13]. The p.Pro618Arg variant identified in this patient has been previously reported as a pathogenic variant (PMID: 15483078), and the proline at position 618 represents a well-established mutational hotspot within the PPxY sequence, with substitutions at the same residue (p.Pro618Leu, p.Pro618Ser) reported across multiple independent families in both European and Asian cohorts [13, 15]. Its classification as Likely Pathogenic per ACMG criteria (PM1: located in well-established pathogenic domain; PM2: absent from gnomAD; PP3: damaging in silico predictions; PP4: phenotype highly specific for the disorder) is consistent with prior reports and provides robust support for the diagnosis.

Differential diagnosis: The differential diagnosis of hypertension with hypokalemia and suppressed renin encompasses PA, AME, CAH, and Liddle syndrome (Table 3). In our patient, several features were discriminating. Aldosterone was inappropriately normal despite severe hypokalemia, which typically stimulates aldosterone secretion—a pattern inconsistent with PA where aldosterone is elevated. Definitive exclusion of AME requires demonstration of an elevated urinary cortisol-to-cortisone metabolite ratio, reflecting impaired 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity, while exclusion of GRA requires measurement of urinary 18-hydroxycortisol and 18-oxocortisol or a dexamethasone suppression test [7]. These investigations were not performed in the present case due to resource constraints. Nevertheless, no pathogenic variants were identified in HSD11B2, CYP11B1, or CYP11B2 on the comprehensive 347-gene panel, providing molecular-level exclusion of AME and GRA. Regarding PA, aldosterone was measured on one occasion only, and while intraindividual variability means a single normal measurement cannot definitively exclude PA, the combination of suppressed plasma renin, normal aldosterone, and identification of a pathogenic SCNN1B variant collectively supports its exclusion [6, 7]. Confirmed renal potassium wasting (24-hour urinary potassium 81.65 mmol/day) excluded extrarenal causes. Together with the family history and genetic findings, these data fulfill robust diagnostic criteria for Liddle syndrome [6, 7].

Table 3.

Differential diagnosis of hypokalemic hypertension with suppressed renin

Condition	Plasma Renin	Aldosterone	Cortisol	Hypokalemia	Treatment
PA	Low	High	Normal	Yes	Spironolactone / Surgery
Liddle Syndrome	Low	Low/Normal*	Normal	Yes	Amiloride / Triamterene
AME	Low	Low	Normal; elevated urinary THF/THE ratio	Yes	Amiloride / Dexamethasone
CAH	Low	Low	Normal; elevated urinary 18-hydroxycortisol and 18-oxocortisol	Variable	Glucocorticoids

*Aldosterone is inappropriately normal relative to the degree of hypokalemia. THF: tetrahydrocortisol; THE: tetrahydrocortisone.*

End-organ damage: Our patient exhibited substantial multiorgan end-organ damage at only 15 years of age: MRI-confirmed bilateral hypertensive encephalomalacia, left ventricular hypertrophy, mild valvular regurgitation, and ECG abnormalities including ST-T changes and frequent atrial ectopy. Such severe cerebrovascular injury at a young age is rarely reported in pediatric Liddle syndrome patients and likely reflects five years of uncontrolled hypertension since age 10 [14]. The maternal history of fatal intracerebral hemorrhage at approximately 30 years is highly consistent with untreated autosomal dominant Liddle syndrome, highlighting the potentially lethal familial consequences of delayed diagnosis [6, 12]. Although cascade genetic screening of family members was not possible in the present case owing to the unavailability of first-degree relatives, this remains an important recommendation for future cases. As an autosomal dominant disorder, offspring of the index patient carry a 50% risk of inheriting the mutation, emphasizing the critical importance of cascade genetic screening of available family members.

Treatment: The cornerstone of Liddle syndrome management is direct ENaC blockade with amiloride or triamterene [8, 9]. Mineralocorticoid receptor antagonists such as spironolactone are ineffective because ENaC activation is aldosterone-independent. In our patient, compound amiloride tablets—selected for their availability in a resource-limited rural setting—achieved rapid normalization of serum potassium within 48 h and progressive blood pressure reduction, with office blood pressure 130/80 mmHg at one-month follow-up.

Limitations

This report has several limitations that should be acknowledged. First, the novelty of the genetic finding is limited, as SCNN1B p.Pro618Arg is a known pathogenic hotspot variant previously reported in the literature, and the clinical experience described reflects single-center observations from a medically underserved rural setting with limited generalizability. Second, the follow-up period of one month is relatively short, and long-term data on sustained blood pressure control and end-organ recovery are not yet available. Third, genetic confirmation in family members was not possible owing to the absence of available first-degree relatives for testing. Fourth, definitive biochemical exclusion of AME and GRA was not performed, as urinary cortisol-to-cortisone metabolite ratio measurement and dexamethasone suppression testing were unavailable at our institution; however, molecular exclusion was achieved through the comprehensive 347-gene panel. Fifth, compound amiloride tablets rather than pure amiloride monotherapy were used due to the limited availability of pure amiloride in this rural clinical setting. Sixth, functional characterization of the p.Pro618Arg variant in vitro was not performed, though its established pathogenicity in published literature provides adequate support for clinical management.

Conclusions

Liddle syndrome should be considered in adolescents presenting with severe early-onset hypertension, profound hypokalemia, and suppressed RAAS, particularly when a family history of hypertensive cerebrovascular events is present. Systematic biochemical evaluation—including 24-hour urinary potassium, serum cortisol, ACTH, and aldosterone-to-renin ratio—is essential for differential diagnosis and to exclude AME and CAH. Genetic testing with NGS enables definitive diagnosis and guides targeted therapy with ENaC inhibitors. Although SCNN1B p.Pro618Arg is a recognized pathogenic hotspot variant, this case underscores the severe phenotypic consequences of delayed diagnosis in adolescents and demonstrates that early genetic diagnosis and targeted ENaC inhibitor therapy are achievable even in resource-limited rural clinical settings in China. Clinicians in primary and county-level hospitals should maintain awareness of Liddle syndrome when encountering young patients with unexplained hypertension and hypokalemia.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

XM was responsible for patient clinical management, data collection, literature review, and manuscript drafting. YL contributed to genetic data interpretation, differential diagnosis analysis, and critical revision of the manuscript. Both authors read and approved the final manuscript.

Funding

The authors received no specific funding for this work.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This case report was conducted in accordance with the Declaration of Helsinki. Written informed consent to participate was obtained from the patient and his legal guardian prior to any data collection. Ethical approval was waived by the Ethics Committee of Shaoshan People’s Hospital, as this report involves a single patient with no experimental intervention beyond routine clinical care.

Consent for publication

Written informed consent for publication of clinical details, laboratory data, imaging findings, and genetic information was obtained from the patient and his legal guardian prior to submission.

Competing interests

The authors declare no competing interests.