Liddle Syndrome with a SCNN1A Mutation: A Case Report and Literature Review.

INTRODUCTION: Liddle syndrome is an autosomal dominant monogenic disease that mainly manifests as early-onset hypertension, hypokalaemia and metabolic alkalosis, as well as hyporeninaemia and hypoaldosteronism. The aetiology of Liddle syndrome is missense or frameshift mutations in the SCNN1A, SCNN1B or SCNN1G genes, which encode for the epithelial sodium channel subunits. Among these, mutations in the SCNN1A gene are very rare. Case Presentation Objective: A Liddle syndrome case caused by a SCNN1A mutation was reported from China. A 59-year-old proband had a 21-year history of chronic hypertension. His blood pressure was poorly controlled with various antihypertensive drugs, and hypokalaemia was found 8 years ago with no definite cause. At this visit, the patient presented with excessive renal potassium excretion and decreased renin activity in the postural stimulation test; however, his aldosterone level was normal. METHODS: Subsequent genetic testing identified a missense mutation in SCNN1A (c.1475G ＞ A), which encodes for a protein with an altered amino acid at position 492 (p.Arg492Gln). The pedigree investigation found that the older brother and son of the proband also have the same mutation. The patient's serum potassium returned to normal, and blood pressure control was significantly improved after being treated with triamterene. CONCLUSION: A middle-aged patient with Liddle syndrome was diagnosed. A new point mutation in the SCNN1A gene was detected in this patient, and the pathogenicity of this mutation was predicted using Alphafold software, expanding the genetic mutation spectrum of Liddle syndrome. Genetic testing should be improved to exclude monogenic hypertension in patients with hypertension complicated with hypokalaemia.

A frameshift mutation in the SCNN1B gene in a family with Liddle syndrome: A case report and systematic review.

Liddle syndrome is an autosomal dominant form of monogenic hypertension that is caused by mutations in SCNN1A, SCNN1B or SCNN1G, which respectively encode the α, ß and γ subunits of the epithelial sodium channel. In the present study, DNA was extracted from leukocytes in peripheral blood obtained from all members of a family with Liddle syndrome. Whole­exome sequencing and Sanger sequencing were performed to assess the candidate variant and a co­segregation analysis was conducted. A frameshift mutation in SCNN1B (NM_ 000336: c.1806dupG, p.Pro603Alafs*5) in the family was identified, characterized by early­onset hypertension and hypokalemia. The mutation led to the truncation of the ß subunit of the epithelial sodium channel and a lack of the conservative PY motif. Furthermore, a systematic review of follow­up data from patients with Liddle syndrome with SCNN1B mutations was performed. The follow­up data of 108 patients with pathogenic SCNN1B mutations from 47 families were summarized. Phenotypic heterogeneity was evident in patients with Liddle syndrome and early­onset hypertension was the most frequent symptom. Patients responded well to targeted amiloride therapy with significant improvements in blood pressure and serum potassium concentration. The present study demonstrates that confirmatory genetic testing and targeted therapy can prevent premature onset of clinical endpoint events in patients with Liddle syndrome.

Neonatal presentation of a patient with Liddle syndrome, South Africa.

Introduction: Liddle syndrome is an autosomal dominantly inherited disorder usually arising from single mutations of the genes that encode for the alpha, beta and gamma epithelial sodium channel (ENaC) subunits. This leads to refractory hypertension, hypokalaemia, metabolic alkalosis, hyporeninaemia and hypoaldosteronism, through over-activation of the ENaC. Case presentation: We describe a 5-day old neonate who presented with severe hypernatraemic dehydration requiring admission to Steve Biko Academic Hospital in South Africa in 2012. Further evaluation revealed features in keeping with Liddle syndrome. Two compound heterozygous mutations located at different subunits encoding the ENaC were detected following genetic sequencing done in 2020. The severe clinical phenotype observed here could be attributed to the synergistic effect of these known pathological mutations, but may also indicate that one of the other variants detected has hitherto undocumented pathological effects. Management and outcome: This child's treatment course was complicated by poor adherence to therapy, requiring numerous admissions over the years. Adequate blood pressure control was achieved only after the addition of amiloride at the end of 2018, which raised the suspicion of an ENaC abnormality. Conclusion: To our knowledge, this is the first Liddle syndrome case where a combined effect from mutations resulted in severe disease. This highlights the importance of early recognition and management of this highly treatable genetic disease to prevent the grave sequelae associated with long-standing hypertension. Whole exome sequencing may assist in the detection of known mutations, but may also unveil new potentially pathological variants. What this study adds: This study highlights the importance of developing a high index of suspicion of tubulopathy such as Liddle syndrome for any child presenting with persistent hypertension associated with hypokalaemic metabolic alkalosis.

The Epithelial Sodium Channel-An Underestimated Drug Target.

Epithelial sodium channels (ENaC) are part of a complex network of interacting biochemical pathways and as such are involved in several disease states. Dependent on site and type of mutation, gain- or loss-of-function generated symptoms occur which span from asymptomatic to life-threatening disorders such as Liddle syndrome, cystic fibrosis or generalized pseudohypoaldosteronism type 1. Variants of ENaC which are implicated in disease assist further understanding of their molecular mechanisms in order to create models for specific pharmacological targeting. Identification and characterization of ENaC modifiers not only furthers our basic understanding of how these regulatory processes interact, but also enables discovery of new therapeutic targets for the disease conditions caused by ENaC dysfunction. Numerous test compounds have revealed encouraging results in vitro and in animal models but less in clinical settings. The EMA- and FDA-designated orphan drug solnatide is currently being tested in phase 2 clinical trials in the setting of acute respiratory distress syndrome, and the NOX1/ NOX4 inhibitor setanaxib is undergoing clinical phase 2 and 3 trials for therapy of primary biliary cholangitis, liver stiffness, and carcinoma. The established ENaC blocker amiloride is mainly used as an add-on drug in the therapy of resistant hypertension and is being studied in ongoing clinical phase 3 and 4 trials for special applications. This review focuses on discussing some recent developments in the search for novel therapeutic agents.

Genetic diagnosis and treatment of hereditary renal tubular disease with hypokalemia and alkalosis.

Renal tubules play an important role in maintaining water, electrolyte, and acid-base balance. Renal tubule dysfunction can cause electrolyte disorders and acid-base imbalance. Clinically, hypokalemic renal tubular disease is the most common tubule disorder. With the development of molecular genetics and gene sequencing technology, hereditary renal tubular diseases have attracted attention, and an increasing number of pathogenic genes related to renal tubular diseases have been discovered and reported. Inherited renal tubular diseases mainly occur due to mutations in genes encoding various specific transporters or ion channels expressed on the tubular epithelial membrane, leading to dysfunctional renal tubular reabsorption, secretion, and excretion. An in-depth understanding of the molecular genetic basis of hereditary renal tubular disease will help to understand the physiological function of renal tubules, the mechanism by which the kidney maintains water, electrolyte, and acid-base balance, and the relationship between the kidney and other systems in the body. Meanwhile, understanding these diseases also improves our understanding of the pathogenesis of hypokalemia, alkalosis and other related diseases and ultimately promotes accurate diagnostics and effective disease treatment. The present review summarizes the most common hereditary renal tubular diseases (Bartter syndrome, Gitelman syndrome, EAST syndrome and Liddle syndrome) characterized by hypokalemia and alkalosis. Further detailed explanations are provided for pathogenic genes and functional proteins, clinical manifestations, intrinsic relationship between genotype and clinical phenotype, diagnostic clues, differential diagnosis, and treatment strategies for these diseases.

A case report of a young boy with low renin and high aldosterone levels induced by Liddle syndrome who was previously misdiagnosed with primary aldosteronism.

OBJECTIVES: Liddle syndrome is an autosomal dominant hereditary disease caused by a single gene mutation. Typical clinical manifestations are early-onset hypertension and hypokalemia. CASE PRESENTATION: This report describes a 17-year-old male with hypertension and hypokalemia. We performed Captopril inhibition and postural stimulation test to diagnose and type primary aldosteronism. The plasma renin activity was consistently low, and aldosterone levels were high, hence the patient was initially diagnosed with primary aldosteronism. After genetic analysis, a diagnosis of Liddle syndrome was made due to the presence of a p. Pro617Ser mutation in the SCNN1B gene. After diagnosis, the patient was prescribed one tablet of amiloride twice a day. The patient's blood pressure (average in 120-135/70-80 mmHg) and serum potassium levels (3.6-4.0 mmol/L) returned to normal and was well-controlled after treatment. CONCLUSIONS: Adolescent hypertension may be secondary to underlying medical conditions affecting the heart, kidneys, or endocrine system or primary with no known underlying disease process. Although in an adolescent with hypertension, hyperaldosteronism, and low plasma renin activity, the initial diagnosis suggested primary hyperaldosteronism, the failure of aldosterone receptor antagonist's therapy led to the diagnosis of Liddle syndrome. Increased aldosterone levels should always be evaluated with caution before a definitive diagnosis to prevent misdiagnosis. Genetic testing is the gold standard for the diagnosis of Liddle syndrome. Early diagnosis and early precise treatment can restore normal blood pressure and prevent severe sequelae of chronic hypertension in patients.

A case of Liddle syndrome and review of literature / 中华内分泌代谢杂志

The clinical data, laboratory test, and gene mutations were collected from a family with Liddle syndrome. Literatures on Liddle syndrome published in domestic and abroad since 1994 were reviewed and the types of gene mutations were summarized. The proband was diagnosed with hypertension at the age of 24. Laboratory test showed that serum potassium was 3.65 mmol/L, plasma renin was <0.5 mU/L, and plasma aldosterone was 1.5 ng/dL. Proband′s father was diagnosed with hypertension at the age of 34 with the serum potassium 3.34 mmol/L, plasma renin 3.72 mU/L, and plasma aldosterone 6.04 ng/dL. A nonsense mutation(1724G>A, p.Trp575*) in exon 13 of SCNN1G gene was detected in the proband and his father. In 288 cases from 107 families reported in the review of domestic and foreign literature, the incidence of hypertension, hypokalemia, and low renin/low aldosterone were 95.1%, 55.2%, and 49.6%, respectively. This case suggests that the clinical phenotype of Liddle syndrome is heterogeneous. Patients with early-onset hypertension, regardless of whether they are accompanied by hypokalemia, should be screened for renin-angiotensin-aldosterone and genetic testing related to Liddle syndrome should be further detected in patients with low plasma renin/aldosterone.

Liddle syndrome.

Liddle syndrome is an inherited form of arterial hypertension with autosomal dominant pattern of inheritance. It is caused by activating mutation of genes coding of the epithelial sodium channel in distal nephron. Mutation leads to excessive reabsorbtion of sodium ions and volume expansion resulting in arterial hypertension. Antoher typical laboratory findings are hypokalaemia, low levels of serum aldosteron and metabolic alkalosis. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, often resulting in misdiagnosis and severe complications at early age. Genetic studies should be done to confirm the diagnosis. Therapy of Liddle syndrome is based on administration of epithelial sodium channel blocker amilorid.

Clinical and genetic characteristics of the patients with hypertension and hypokalemia carrying a novel SCNN1A mutation.

The objective of this study was to clinically and genetically characterize a pedigree with Liddle syndrome (LS). A LS pedigree comprising with one proband and seven family members was enrolled. The subjects' symptoms, laboratory results and genotypes were analyzed. Peripheral venous samples were collected from the subjects, and genomic DNA was extracted. DNA library construction and exome capture were performed on an Illumina HiSeq 4000 platform. The selected variant sites were validated using Sanger sequencing. The mutation effects were investigated using prediction tools. The proband and her paternal male family members had mild hypertension, hypokalemia and muscle weakness, including the absence of low renin and low aldosterone. Genetic analysis revealed that the proband carried a compound heterozygous mutation in SCNN1A, a novel heterozygous mutation, c.1130T > G (p.Ile377Ser) and a previously characterized polymorphism, c.1987A > G (p.Thr633Ala). The novel mutation site was inherited in an autosomal dominant manner and was predicted by in silico tools to exert a damaging effect. Alterations in the SCNN1A domain were also predicted by protein structure modeling. After six months of follow-up, treatment had significantly improved the patient's limb weakness and electrolyte levels. The novel mutation c.1130T > G of the SCNN1A gene was detected in the pedigree with LS. The clinical manifestations of the pedigree were described, which expand the phenotypic spectrum of LS. This result of this study also emphasizes the value of genetic testing for diagnosing LS.

Promise of Physiological Profiling to Prevent Stroke in People of African Ancestry: Prototyping Ghana.

PURPOSE OF REVIEW: Worldwide, compared to other racial/ethnic groups, individuals of African ancestry have an excessively higher burden of hypertension-related morbidities, especially stroke. Identifying modifiable biological targets that contribute to these disparities could improve global stroke outcomes. In this scoping review, we discuss how pathological perturbations in the renin-angiotensin-aldosterone pathways could be harnessed via physiological profiling for the purposes of improving blood pressure control for stroke prevention among people of African ancestry. RECENT FINDINGS: Transcontinental comparative data from the USA and Ghana show that the prevalence of treatment-resistant hypertension among stroke survivors is 42.7% among indigenous Africans, 16.1% among African Americans, and 6.9% among non-Hispanic Whites, p < 0.0001. A multicenter clinical trial of patients without stroke in 3 African countries (Nigeria, Kenya, and South Africa) demonstrated that physiological profiling using plasma renin activity and aldosterone to individualize selection of antihypertensive medications compared with usual care resulted in better blood pressure control with fewer medications over 12 months. Among Ghanaian ischemic stroke survivors treated without renin-aldosterone profiling data, an analysis revealed that those with low renin phenotypes did not achieve any meaningful reduction in blood pressure over 12 months on 3-4 antihypertensive medications despite excellent adherence. For a polygenic condition such as hypertension, individualized therapy based on plasma renin-aldosterone-guided selection of therapy for uncontrolled BP following precision medicine principles may be a viable strategy for primary and secondary stroke prevention with the potential to reduce disparities in the poor outcomes of stroke disproportionately shared by individuals of African ancestry. A dedicated clinical trial to test this hypothesis is warranted.

A Novel Frame-Shift Mutation in SCNN1B Identified in a Chinese Family Characterized by Early-Onset Hypertension.

Background: Liddle syndrome is a form of monogenic hypertension caused by mutations in the three homologous subunits of the epithelial sodium channels (ENaCs), α, ß, and γ. It is characterized by early-onset refractory hypertension, hypokalemia, low renin activity, and hypoaldosteronism. In this study, we report a novel frame-shift mutation in SCNN1B responsible for Liddle syndrome in a Chinese family. Methods: DNA samples were collected from all participants. Whole-exome sequencing was performed in the proband to detect possible causative variants. Sanger sequencing was then conducted in the other family members to verify the candidate variant, and in 100 patients with hypertension and 100 normotensive controls to exclude population genetic polymorphism. Results: We identified a novel frame-shift mutation (c.1691_1693delinsG) in SCNN1B that was responsible for Liddle syndrome in this family. This mutation leads to the substitution of Arg in place of Gln at codon site 564 and generates a new stop codon at 592, influencing the crucial PY motif and resulting in reduced inactivation of the ENaCs. Aside from the proband, eight family members carried the mutation. Intra-familial phenotypic heterogeneity was observed in the blood pressure and serum potassium levels. Amiloride therapy combined with a low sodium diet is effective to alleviate the symptoms of patients with Liddle syndrome. Conclusion: c.1691_1693delinsG, a novel frame-shift mutation in the ß subunit of ENaC, was identified in a Chinese family with Liddle syndrome by whole-exome sequencing. Phenotypic heterogeneity can make diagnosis of Liddle syndrome difficult on the basis of clinical or biochemical characteristics alone. Genetic analysis is a useful tool allowing timely and accurate diagnosis of Liddle syndrome and playing a guiding role in precise treatment of the disease.

Geller Syndrome: A Rare Cause of Persistent Hypokalemia During Pregnancy.

Geller syndrome is a rare disease and part of Mendelian forms of hypertension. This syndrome is caused by a mutation in the mineralocorticoid receptor with a resultant gain of function. It is characterized by hypertension and hypokalemia, which is exacerbated by the effect of progesterone and thereby presenting during pregnancy. Our patient is a 22-year-old female diagnosed with preeclampsia who presented with hypokalemia, refractory to treatment toward the end of her third trimester. The patient's hypokalemia resolved once she delivered her infant. Genetic testing is available, which can confirm the diagnosis of Geller syndrome. The management is supportive therapy and requires close monitoring of the patient and her fetus. Delivery of the fetus results in the resolution of both hypertension and hypokalemia.

Chronic activation of vasopressin-2 receptors induces hypertension in Liddle mice by promoting Na+ and water retention.

The renin-angiotensin-aldosterone and arginine vasopressin-V2 receptor-aquaporin-2 (AQP2) systems converge on the epithelial Na+ channel (ENaC) to regulate blood pressure and plasma tonicity. Although it is established that V2 receptors initiate renal water reabsorption through AQP2, whether V2 receptors can also induce renal Na+ retention through ENaC and raise blood pressure remains an open question. We hypothesized that a specific increase in V2 receptor-mediated ENaC activity can lead to high blood pressure. Our approach was to test effects of chronic activation of V2 receptors in Liddle mice, a genetic mouse model of high ENaC activity, and compare differences in ENaC activity, urine Na+ excretion, and blood pressure with control mice. We found that ENaC activity was elevated in Liddle mice and could not be stimulated further by administration of desmopressin (dDAVP), a V2 receptor-specific agonist. In contrast, Liddle mice showed higher levels of expression of AQP2 and aquaporin-3, but they could still respond to dDAVP infusion by increasing phospho-AQP2 expression. With dDAVP infusion, Liddle mice excreted smaller urine volume and less urine Na+ and developed higher blood pressure compared with control mice; this hypertension was attenuated with administration of the ENaC inhibitor benzamil. We conclude that V2 receptors contribute to hypertension in the Liddle mouse model by promoting primary Na+ and concomitant water retention.NEW & NOTEWORTHY Liddle syndrome is a classic model for hypertension from high epithelial Na+ channel (ENaC) activity. In the Liddle mouse model, vasopressin-2 receptors stimulate both ENaC and aquaporin-2, which increases Na+ and water retention to such an extent that hypertension ensues. Liddle mice will preserve plasma tonicity at the expense of a higher blood pressure; these data highlight the inherent limitation in which the kidney must use ENaC as a pathway to regulate both plasma tonicity and blood pressure.

Corrigendum: Pathogenicity and Long-Term Outcomes of Liddle Syndrome Caused by a Nonsense Mutation of SCNN1G in a Chinese Family.

[This corrects the article DOI: 10.3389/fped.2022.887214.].

Liddle syndrome misdiagnosed as primary aldosteronism is caused by inaccurate aldosterone-rennin detection while a novel SCNN1G mutation is discovered.

PURPOSE: Through describing the confusing misdiagnosis process of Liddle syndrome, we try to reveal the importance of accurate aldosterone-renin detection and a genetic test for Liddle syndrome. METHODS: We found a family of hypertension and hypokalaemia with the proband of a 21-year-old female who had been misdiagnosed as primary aldosteronism (PA). She presented with high aldosterone and low renin levels. Aldosterone is not suppressed in the saline infusion test and captopril challenge test. However, treatment with a standard dose of spironolactone has no blood pressure improvement effect. A heterozygous variant of SCNN1G was found with whole exome sequencing and Liddle syndrome is indicated. Treatment with amiloride was effective. We rechecked aldosterone-renin levels with two different aldosterone and renin test kits. Clinical features and the mutant gene SCNN1G of each family member were determined by the Sanger method. RESULTS: The two kits had nearly opposite results. Among those Liddle syndrome patients confirmed by a genetic test, for Test kit A all ARR were screened positive while for test kit B negative. It seems Test kit B is consistent with the diagnosis while test kit A misleads the diagnosis. A novel SCNN1G mutation, c.1729 C > T, was found in this family, which introduce a premature stop codon in the γ subunit in the epithelial Na+ channel (ENaC) and resulted in a deletion of 72 amino acids at the carboxyl end. CONCLUSION: inaccurate ARR detection might misdiagnose Liddle syndrome. A Gene test is an important method for the diagnosis of Liddle syndrome. A novel SCNN1G missense mutation, c.1729 C > T, is found in a Chinese family.

Pathogenicity and Long-Term Outcomes of Liddle Syndrome Caused by a Nonsense Mutation of SCNN1G in a Chinese Family.

Objective: Liddle syndrome (LS) is a monogenic hypertension consistent with autosomal dominant inheritance, often with early onset high blood pressure in childhood or adolescence. This study aimed to identify the pathogenicity of a nonsense mutation in SCNN1G in a Chinese family with LS and the long-term outcomes of tailored treatment with amiloride. Methods: To explore the pathogenicity of candidate variant reported in 2015 by our team, we constructed mutant and wild-type models in vitro and measured amiloride-sensitive current in Chinese Hamster Ovary (CHO) cells using patch clamp technique. Participants were followed up for 7 years after tailored treatment with amiloride. Results: A nonsense variant was detected in six members, two of whom were pediatric patients. This mutation resulted in a termination codon at codon 572, truncating the Pro-Pro-Pro-X-Tyr motif. The mutant epithelial sodium channels displayed higher amiloride-sensitive currents than the wild-type channels (P < 0.05). Tailored treatment with amiloride achieved ideal blood pressure control in all patients with normal cardiorenal function, and no adverse events occurred during follow-up. Conclusion: We found the pathogenicity of a nonsense SCNN1G mutation (p.Glu571*) with enhanced amiloride-sensitive currents in a LS family with young patients. Tailored treatment with amiloride may be an effective strategy for the long-term control of blood pressure and protection from target organ damage or cardiovascular events, including children and youth patients with LS.

A Family with Liddle Syndrome Caused by a Novel Stop-Gain Mutation in the γ Subunit of Epithelial Sodium Channels.

Liddle syndrome (OMIM #177200) is an autosomal dominant disorder caused by gain-of-function pathogenic variants in the genes encoding epithelial sodium channel subunits, including α (SCNN1A), ß (SCNN1B), and γ (SCNN1G). The majority of the reported cases carry SCNN1B variants (∼90%), and SCNN1A/G variants are relatively infrequent. Here, we report a 24-year-old Chinese male patient diagnosed with early-onset hypertension. Laboratory tests revealed hypokalemia with a low level of plasma renin activity. Liddle syndrome was confirmed by high-throughput sequencing, which identified a novel nonsense variant Q591X in the SCNN1G gene, resulting in the PY motif's deletion. The patient's father has the same mutation, and his mother and sister are normal. All eleven variants in the SCNN1G gene were summarized. Liddle syndrome usually presents with early onset of hypertension with hypokalemia and low-renin activity, but it can be clinically heterogeneous. It is necessary to utilize next-generation sequencing to clarify the diagnosis to identify Liddle syndrome in young patients with hypertension and to perform early treatment and prevent a series of adverse outcomes caused by hypertension.

A novel nonsense mutation in the ß-subunit of the epithelial sodium channel causing Liddle syndrome.

PURPOSE: Liddle syndrome is a hereditary form of arterial hypertension caused by mutations in the genes coding of the epithelial sodium channel - SCNN1A, SCNN1B and SCNN1G. It is characterised by early onset of hypertension and variable biochemical features such as hypokalaemia and low plasma concentrations of renin and aldosterone. Phenotypic variability is large and, therefore, LS is probably underdiagnosed. Our objective was to examine a family suspected from Liddle syndrome including genetic testing and evaluate clinical and biochemical features of affected family members. MATERIALS AND METHODS: Thirteen probands from the Czech family, related by blood, underwent physical examination, laboratory tests, and genetic testing. Alleles of SCNN1B and SCNN1G genes were examined by PCR amplification and Sanger sequencing of amplicons. RESULTS: We identified a novel mutation in the ß-subunit of an epithelial sodium channel coded by the SCNN1B gene, causing the nonsense mutation in the protein sequence p.Tyr604*. This mutation was detected in 7 members of the family. The mutation carriers differed in the severity of hypertension and hypokalaemia which appeared only after diuretics in most of them; low aldosterone level (< 0.12 nmol/l) was, however, present in all. CONCLUSIONS: This finding expands the spectrum of known mutations causing Liddle syndrome. Hypoaldosteronemia was 100% sensitive sign in the mutation carriers. Low levels are observed especially in the Caucasian population reaching 96% sensitivity. Assessment of plasma aldosterone concentration is helpful for differential diagnosis of arterial hypertension. CONDENSED ABSTRACT: Liddle syndrome is a hereditary form of arterial hypertension caused by mutations in the genes encoding the epithelial sodium channel's α-, ß- and γ-subunit. It is usually manifested by early onset of hypertension accompanied by low potassium and aldosterone levels. We performed a physical examination, laboratory tests and genetic screening in 13 members of a Czech family. We found a new mutation of the SCNN1B gene which encodes the ß-subunit of the epithelial sodium channel. We describe the variability of each family member phenotype and point out the relevance of using aldosterone levels as a high sensitivity marker of Liddle syndrome in Caucasians.

Tubulopathy meets Sherlock Holmes: biochemical fingerprinting of disorders of altered kidney tubular salt handling.

Evolution moves in mysterious ways. Excretion of waste products by glomerular filtration made perfect sense when life evolved in the ocean. Yet, the associated loss of water and solutes became a problem when life moved onto land: a serious design change was needed and this occurred in the form of ever more powerful tubules that attached to the glomerulus. By reabsorbing typically more than 99% of the glomerular filtrate, the tubules not only minimise urinary losses, but, crucially, also maintain homeostasis: tubular reabsorption and secretion are adjusted so as to maintain an overall balance, in which urine volume and composition matches intake and environmental stressors. A whole orchestra of highly specialised tubular transport proteins is involved in this process and dysfunction of one or more of these results in the so-called kidney tubulopathies, characterised by specific patterns of clinical and biochemical abnormalities. In turn, recognition of these patterns helps establish a specific diagnosis and pinpoints the defective transport pathway. In this review, we will discuss these clinical and biochemical "fingerprints" of tubular disorders of salt-handling and how sodium handling affects volume homeostasis but also handling of other solutes.

Liddle syndrome: A case report.

INTRODUCTION: Liddle syndrome is an autosomal dominant hereditary disease caused by a single gene mutation. Typical clinical manifestations are early-onset hypertension and hypokalaemia and can be treated using ENaC blockers (amiloride and aminopterin). PATIENTS AND METHODS: This report describes a 17-year-old male with hypertension and hypokalaemia. We performed a Captopril inhibition test and a postural stimulation test for the diagnosis and typing of primary aldosteronism. RESULTS: The serum renin was low, and aldosterone was high, so the patient was initially misdiagnosed as primary aldosteronism. After a genetic analysis, a diagnosis of Liddle syndrome was made due to the presence of an SCNN1B p.Pro617Ser mutation. After diagnosis, the patient was administered one tablet of amiloride twice a day (each tablet contains 2.5mg of amiloride hydrochloride and 25mg of hydrochlorothiazide 25mg). The patient's blood pressure (average of 120-135/70-80mmHg) and serum potassium levels (3.6-4.0mmol/L) returned to normal and were well-controlled after treatment. DISCUSSION: The patient is an atypical case of Liddle syndrome; genetic analysis is helpful and essential for diagnosis.