Pseudohypoaldosteronism Type Research Articles

A case report of pseudohypoaldosteronism type II with a homozygous KLHL3 variant accompanied by hyperthyroidism

BackgroundPseudohypoaldosteronism type II (PHAII), also called Gordon syndrome, is a rare hereditary disease caused by variants in the WNK1, WNK4, KLHL3 and CUL3 genes. The combination of PHAII with hyperthyroidism and secondary hyperparathyroidism has not been reported previously.Case presentationA 54-year-old female with recently diagnosed Graves’ disease presented hyperkalemia, hypertension, hypercalciuria, elevated levels of parathyroid hormone (PTH) and normal renal function. PHAII was established based on the finding of a homozygous variant (c.328 A > G, T110A) in the KLHL3 gene. Low-dose thiazide diuretics normalized her potassium, calcium and PTH.ConclusionsPHAII caused by a KLHL3 variant can affect adults later in life. This diagnosis should be considered in patients with hypertension, consistent hyperkalemia, and normal eGFR and can be corrected by thiazides. The patient also had hyperthyroidism and secondary hyperparathyroidism. The latter was also corrected by thiazide treatment. The hyperthyroidism was assumed to be unrelated to PHAII.

Hypercalcemia in an Infant With Pseudohypoaldosteronism Type 1

Background: Pseudohypoaldosteronism type 1 (PHA1) is an aldosterone resistance syndrome due to insensitivity of target tissues to aldosterone action, with supraphysiologic aldosterone and renin levels. PHA1 presents usually in infancy and is divided into autosomal dominant (AD) and autosomal recessive (AR) form. A secondary form of PHA1 associated with UTI and/or renal malformations was described. In AD PHA1, salt loss is due to renal mineralocorticoid resistance while hyponatremia in AR PHA1 is caused by multi-organ salt loss. PHA1 has variable signs/symptoms associated with hyponatremia and hyperkalemia; thus, this clinical picture can be attributed to more common conditions such as dehydration, poor feeding, congenital adrenal hyperplasia. Clinical Case: A 5-month old male was admitted for airway evaluation. He was a 23-week gestation preemie, with chronic lung disease, failure to thrive. Patient was found to have hyponatremia, hyperkalemia, high FeNa of 1.3% (intrinsic renal disease) and elevated BUN/Cr (92/1.15). Renal US found echogenic kidneys with poor cortical medullary differentiation suggesting renal disease. Further evaluation noted high aldosterone (1700 ng/dL) and renin (400 ng/mL/hr) levels. He was placed on low protein formula to help optimize BUN level. Baby was diagnosed with secondary PHA1 due to renal disease and started on NaCl supplementation. This led to normalization of BUN, creatinine and improvement in electrolytes. Patient also had high serum calcium ranging from 11.1 to 12.0 mg/dL. Hyponatremia, hyperkalemia, hypercalcemia could be attributed to possible CAH, however state screen and ACTH stimulation test were normal. Further workup showed high 25-OH-vitamin D > 99 ng/mL, PTH 46.9 pg/mL, phosphorous 5.4 mg/dL and 1,25-OH-vitamin D 63.1 pg/mL. Urine Ca/cr ratio was 0.522. Vitamin D supplementation was stopped and daily total fluids increased. Subsequently, there was improvement in serum Ca at 10.9 mg/dL and 25-OH Vitamin D of 74 pg/mL. Next Generation Sequencing (NGS) was carried out, with a focus on the etiology of persisting hypercalcemia, including familial forms of hypercalcemia and Williams Syndrome. NGS revealed a likely pathogenic variant, c.2365 + 2T>C (p.?), in NR3C2, consistent with a diagnosis of AD PHA 1. Conclusion: This is a case of AD PHA1, marked by renal mineralocorticoid receptor resistance associated with persisting hypercalcemia. Initial hypercalcemia could be explained by hypervitaminosis D. It is important to note that electrolyte abnormalities, including persistent hypercalcemia, could be also secondary to the kidney disease found on renal US. There are only few reports of hypercalcemia in patients with PHA1 in the literature. In children with electrolyte abnormalities and failure to thrive, monitoring of serum and urine electrolytes would facilitate early accurate diagnosis and timely treatment.

A Rare Case of Pseudohypoaldosteronism Type II or Gordon Syndrome

Introduction: Pseudohypoaldosteronism type II (PHA II) or Gordon Syndrome is a rare, autosomally inherited disease with unknown prevalence. It is caused by mutations in the WNK1, WNK4, CUL3, or KLHL3 gene. It is characterized by hypertension, hyperkalemia, hyperchloremic metabolic acidosis and low plasma aldosterone levels, but otherwise normal kidney function. The age of onset of PHA2 is variable, ranging from infancy or childhood to adolescence and adultdood. The electrolyte and blood pressure abnormalities of PHA II is often managed with salt restriction and hydrochlorthiazide (HCTZ). Here we report a rare case of Pseudohypoaldosteronism type II in an adolescent patient.Case Presentation: A 16-yo female with past medical history of asthma and anemia presented to the emergency department with acute severe abdominal/suprapubic pain, associated with diaphoresis, non bloody diarrhea and non bilious non bloody vomiting. The patient also reported daily headaches relieved with Tylenol. In the ED, she was found to be hypertensive at 190/118 mmHg. Blood count showed mild anemia but normal white count and platelets. Comprehensive metabolic panel showed sodium 140, potassium 6.6, chloride 115, bicarbonate 16, creatinine 0.5, and normal liver enzymes. Urine electrolytes were as follows: sodium 189, potassium 20.8 and chloride 140. Arterial Blood Gas ahowed pH of 7.32. Plasma renin activity was low normal at 0.34 and aldosterone level was 2. CT scan of abdomen and pelvis was unremarkable. The blood work was consistent with pseudohypoaldosteronism type II or Gordon syndrome. The patient was adopted so there was no family history. She was started on hydrochlorothiazide. Later, she developed severe itching reaction with hydrochlorthiazide. She is currently being treated with Indapamide, with well controlled blood pressure and normal electrolytes.Conclusion: Pseudohypoaldosteronism type II or Gordon’s Syndrome is a rare disease, with usually autosomal dominant inheritance, with no specific diagnostic criteria for diagnosis. It should be suspected in adolescent or adult patients with hyperkalemia with normal glomerular filtartion, accompanied by hypertension (can be absent), metabolic acidosis, hyperchloremia, decreased plasma renin, relatively suppressed aldosteronism and family history of similar findings.

A Novel SCNN1A Variation in a Patient with Autosomal-recessive Pseudohypoaldosteronism Type 1

Pseudohypoaldosteronism type 1 (PHA1) is an autosomal-recessive disorder characterized by defective regulation of body sodium (Na) levels. The abnormality results from mutations in the genes encoding subunits of the epithelial Na channel. Patients with PHA1 present in infancy as being in adrenal crisis. A 41-day-old female who presented with recurrent adrenal crisis did not adequately respond to hydrocortisone and required mineralocorticoid therapy. The patient’s demographic data and clinical features were recorded. Blood samples were collected and tested for endocrine and metabolic characteristics and for use in genetic studies. Bidirectional Sanger sequencing of SCNN1A was conducted. The entire coding region of 12 exons and 20 bp of flanking intron were sequenced. Genetic analyses revealed a new mutation - c.729_730delAG (p.Val245Glyfs*65) - in SCNN1A exon four. Adrenal crisis during the neonatal period highlights the importance of early screening for PHA1. Genetic testing could help to anticipate the prognosis, severity, onset of the disease, and the mode of inheritance, especially given its extensive phenotype.

Il neonato che “sa di sale”

Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disease due to the peripheral resistance to aldosterone. Clinical spectrum with neonatal onset includes salt loss, hyponatremia, hypochloraemia, hyperkalaemia, metabolic acidosis and increased plasmatic levels of aldosterone. Two forms of the disease - renal and systemic – have been described, which are genetically distinct and with wide clinical expressivity. The most severe generalized PHA1 is caused by mutations in the genes encoding for the subunits of the epithelial sodium channels (ENaC). The paper reports the case of a newborn of the first pregnancy of healthy and consanguineous Sicilian parents, with a clinical and hormonal picture compatible with the diagnosis of generalized PHA1. A novel SCNN1A gene mutation, inherited from both heterozygous, was identified by next generation sequencing (NGS) in the homozygous child. The neonatologist should consider a diagnosis of PHA1 in case of hyponatremia, hyperkalaemia and metabolic acidosis. The diagnostic suspicion was confirmed by the increased plasmatic levels of aldosterone and aldosterone/renin ratio, associated to a poor response to steroid administration. The treatment is based on high doses of sodium chloride, fludrocortisone and glucocorticoids, insulin and ion exchange resins. It may be useful to reduce potassium intake with the use of special formulas. The clinician must gradually balance the doses of drugs on the basis of electrolyte and hormone levels. A multi-disciplinary team and close follow-up evaluations are needed for optimal management of such patients. The present report may broaden the knowledge of the genetic and molecular bases of disease, by improving its clinical characterization and providing useful indications for the treatment of patients. Clinical approach must be personalized, also in relation to long survival and potential multi-organ complications.

Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice.

Familial hyperkalemic hypertension (FHHt; also called pseudohypoaldosteronism type II) is a hereditary hypertensive disease which can be caused by mutations in four genes: WNK1 [with no lysine (K) 1], WNK4, Kelch-like3 (KLHL3), and cullin3 (CUL3). Decreased KLHL3 expression was identified as being involved in the pathogenesis of FHHt caused by cullin 3 disease mutations. Recent studies have revealed an increased WNK4 and hence Na-Cl cotransporter (NCC) activity in the db/db mice, resulting from PKC-mediated KLHL3 phosphorylation, which impairs the degradation of its substrate, WNK4. However, whether WNK4 and NCC were activated in type 1 diabetes still remains unclear. We created streptozotocin-induced type 1 diabetic mice and revealed that renal WNK-oxidative stress response kinase-1/STE20/SPS1-related proline alanine-rich kinase (OSR1/SPAK)-NCC cascade was activated, whereas KLHL3 expression was markedly decreased and CUL3 was heavily neddylated. Moreover, decreased KLHL3 was reversed and WNK1 and WNK4 abundance increased by MLN4924, a neddylation inhibitor. In vitro, our study also showed decreased KLHL3 abundance without any significant change in phosphorylated KLHL3 under high glucose exposure. These results indicate that decreased KLHL3 likely plays a role in the pathogenesis of renal sodium reabsorption in hyperglycemic conditions.

Clinical and Genetic Analysis of Multi-System Pseudohypoaldosteronism Type 1 Caused by a Novel Splice Site Mutation of the Beta Subunit Gene of Epithelial Sodium Channel (Enac)

This article aims to provide a comprehensive review of the clinical features and genetics basis of multi-system pseudohypoaldosteronism type 1 caused by SCNN1B gene mutations.

A comparative study of structural and conformational properties of WNK kinase isoforms bound to an inhibitor: insights from molecular dynamic simulations

The with-no-lysine (WNK) kinase causes pseudohypoaldosteronism type II, a genetic form of hypertension. Due to ∼80% similarity among four isoforms (WNK1/2/3/4) of the WNK protein family, the discovery of an ATP-competitive inhibitor renders a significant challenge. Here, we combined molecular modeling and molecular dynamics simulations to study the structural and conformational properties of the WNK kinase isoforms bound to an ATP competitive inhibitor (WNK463). We have also investigated the effect of phosphorylation on the conformational properties of each isoform. The largest deviation of Cα atoms is observed for the unphosphorylated uWNK4 complex, while the least deviation is obtained for uWNK3. The G-loop and αC-helix regions are also more flexible in uWNK4 compared to the other three unphosphorylated isoforms. However, in uWNK1, the A-loop region is the most flexible compared to other complexes. In all cases, phosphorylation stabilizes different regions of the protein–inhibitor complexes. In the case of uWNK4, relatively higher anti-correlated motions are observed compared to the other three unphosphorylated complexes. Furthermore, in the case of uWNK4, the distance between N- and C-lobes is found to be slightly higher than other complexes. This distance is reduced in all four complexes after the phosphorylation. Principal component analyses suggest that the phosphorylation leads to structural stabilization in WNK1 and WNK4, while it causes more flexibility in WNK2 and WNK3. Overall, our study provides comprehensive and comparative information on the structural dynamics of the WNK isoform family with the known competitive inhibitor that would aid in the development of a new inhibitor. Communicated by Ramaswamy H. Sarma

Clinical and Molecular Perspectives of Monogenic Hypertension.

Advances in molecular research techniques have enabled a new frontier in discerning the mechanisms responsible for monogenic diseases. In this review, we discuss the current research on the molecular pathways governing blood pressure disorders with a Mendelian inheritance pattern, each presenting with a unique pathophysiology. Glucocorticoid Remediable Aldosteronism (GRA) and Apparent Mineralocorticoid Excess (AME) are caused by mutations in regulatory enzymes that induce increased production of mineralocorticoids or inhibit degradation of glucocorticoids, respectively. Geller syndrome is due to a point mutation in the hormone responsive element of the promotor for the mineralocorticoid receptor, rendering the receptor susceptible to activation by progesterone, leading to hypertension during pregnancy. Pseudohypoaldosteronism type II (PHA-II), also known as Gordon’s syndrome or familial hyperkalemic hypertension, is a more variable disorder typically characterized by hypertension, high plasma potassium and metabolic acidosis. Mutations in a variety of intracellular enzymes that lead to enhanced sodium reabsorption have been identified. In contrast, hypertension in Liddle’s syndrome, which results from mutations in the Epithelial sodium Channel (ENaC), is associated with low plasma potassium and metabolic alkalosis. In Liddle’s syndrome, truncation of one the ENaC protein subunits removes a binding site necessary protein for ubiquitination and degradation, thereby promoting accumulation along the apical membrane and enhanced sodium reabsorption. The myriad effects due to mutation in phosphodiesterase 3A (PDE3A) lead to severe hypertension underlying sodium-independent autosomal dominant hypertension with brachydactyly. How mutations in PDE3A result in the phenotypic features of this disorder are discussed. Understanding the pathologies of these monogenic hypertensive disorders may provide insight into the causes of the more prevalent essential hypertension and new avenues to unravel the complexities of blood pressure regulation.

A case worth its salt: an abnormal presentation of pseudohypoaldosteronism type 1 in an infant

Introduction Pseudohypoaldosteronism type 1 (PHA1) is a rare genetic disorder characterized by resistance to aldosterone. Infants often present with weight loss, emesis, and dehydration, and expected lab values include hyponatremia, hyperkalemia, elevated aldosterone, and elevated urinary sodium excretion. However, there can be wide phenotypic variability with PHA1, which this case highlights. Case Report An 18 day-old male term, appropriate for gestational age infant with a history of a normal newborn screen presented to the Emergency Department with lethargy, poor feeding, and weight loss of 1lb 10oz since birth. Initial exam …

A case worth its salt: an abnormal presentation of pseudohypoaldosteronism type 1 in an infant

A case worth its salt: an abnormal presentation of pseudohypoaldosteronism type 1 in an infant

Pseudohypoaldosteronism Type 1 with a Novel Mutation in the NR3C2 Gene: A Case Report

Pseudohypoaldosteronism type 1 (PHA1) is a rare salt-wasting disorder caused by resistance to mineralocorticoid action. PHA1 is of two types with different levels of disease severity and phenotype as follows: systemic type with an autosomal recessive inheritance (caused by mutations of the epithelial sodium channel) and renal type with an autosomal dominant inheritance (caused by mutations in the mineralocorticoid receptor). The clinical manifestations of PHA1 vary widely; however, PHA1 commonly involves hyponatremia, hyperkalemia, metabolic acidosis and elevated levels of renin and aldosterone. The earliest signs of both type of PAH1 also comprise insufficiency weight gain due to chronic dehydration and failure to thrive during infancy. Here, we report a case of renal PAH1 in a 28-day-old male infant harboring a novel heterozygous mutation in NR3C2 gene (c.1341_1345dupAAACC in exon 2), showing only failure to thrive without the characteristic of dehydration. Key words: Pseudohypoaldosteronism; Mineralocorticoid receptors; NR3C2 gene; Hyponatremia; Hyperkalemia

The WNK signaling pathway and salt-sensitive hypertension

The distal nephron of the kidney has a central role in sodium and fluid homeostasis, and disruption of this homeostasis due to mutations of with-no-lysine kinase 1 (WNK1), WNK4, Kelch-like 3 (KLHL3), or Cullin 3 (CUL3) causes pseudohypoaldosteronism type II (PHAII), an inherited hypertensive disease. WNK1 and WNK4 activate the NaCl cotransporter (NCC) at the distal convoluted tubule through oxidative stress-responsive gene 1 (OSR1)/Ste20-related proline-alanine-rich kinase (SPAK), constituting the WNK-OSR1/SPAK-NCC phosphorylation cascade. The level of WNK protein is regulated through degradation by the CUL3-KLHL3 E3 ligase complex. In the normal state, the activity of WNK signaling in the kidney is physiologically regulated by sodium intake to maintain sodium homeostasis in the body. In patients with PHAII, however, because of the defective degradation of WNK kinases, NCC is constitutively active and not properly suppressed by a high salt diet, leading to abnormally increased salt reabsorption and salt-sensitive hypertension. Importantly, recent studies have demonstrated that potassium intake, insulin, and TNFα are also physiological regulators of WNK signaling, suggesting that they contribute to the salt-sensitive hypertension associated with a low potassium diet, metabolic syndrome, and chronic kidney disease, respectively. Moreover, emerging evidence suggests that WNK signaling also has some unique roles in metabolic, cardiovascular, and immunological organs. Here, we review the recent literature and discuss the molecular mechanisms of the WNK signaling pathway and its potential as a therapeutic target.

Sorting Nexins 1, 2, 3 and 17 Regulate Epithelial Sodium Channel Trafficking

The epithelial sodium channel (ENaC) facilitates sodium absorption of polarized epithelia and therefore, is required for regulation of salt and water homeostasis. ENaC’s apical membrane population is strictly controlled, with loss of this control leading to hyper‐ or hypotensive disorders such as Liddle’s Syndrome, or Pseudohypoaldosteronism type 1, respectively. Retromer and retriever are conserved endosome‐localized protein trafficking complexes that mediate recycling of membrane proteins back to the cell surface either directly, via recycling endosomes or via the trans‐Golgi network. Both retromer and retriever associate with accessory proteins including sorting nexins (SNX) proteins which play a role in the establishment of a tubulation complex leading to the formation of endosomal tubule‐shaped extensions which contain the cargo selected for recycling. We hypothesized that retromer and/or retriever are required for ENaC recycling. Using three epithelial cell lines (Fischer rat thyroid (FRT), mouse cortical collecting duct (mCCD) or human embryonic kidney cells (HEK293), we found that siRNA knockdown of retromer and retriever associated SNX proteins reduced ENaC amiloride‐sensitive short circuit current (Isc‐Amil). SNX1 and SNX2 are reported to be essential for cargo recycling through retromer. Individually, knockdown of SNX1 (n=6) or SNX2 (n=8) reduced Isc‐Amil by 38±9% and 39±8% compared with control FRT epithelia, respectively. Double‐knockdown of those SNXs reduced Isc‐Amil by 47±1% (n=6) compared with control FRT epithelia. SNX3 is known to bind directly with the retromer complex. Knockdown of SNX3 decreased Isc‐Amil by 47±5% FRT (n=9) and 35±4% in mCCD (n=9) epithelia compared with control epithelia. Additionally, it is known that SNX17 mediates cargo retrieval via the retriever complex. Knockdown of SNX17 lowered Isc‐Amil by 56±1% (n=9) in FRT and 35±6% (n=9) in mCCD epithelia compared with control epithelia. With cell surface biotinylation experiments and using FRT cells, knockdown of SNX3 and SNX17 reduced the ENaC cell surface population by 68±25% (n=3) and 77±17% (n=3), respectively, thus, attributing to the reduced Isc‐Amil. Furthermore, co‐immunoprecipitation experiments of αβHAγENaC overexpressed in HEK293 cells, demonstrated a protein‐protein interaction between retriever associated SNX17 and ENaC (n=3) suggesting SNX17 may act as a cargo binding protein between ENaC and the retriever complex. However, there was no evidence for an interaction between SNX3 and ENaC (n=3). Together, our findings suggest that SNX protein complexes play a role in ENaC recycling to the plasma membrane in polarized epithelia. Additionally, these data suggest that both the retromer and retriever recycling complexes may aid in the trafficking of ENaC to the plasma membrane.Support or Funding InformationThis work was supported by a grant from the New Zealand Lottery Health Board. Further support was provided by the School of Biomedical Sciences and the Department of Physiology of the University of Otago.

Hereditary causes of primary aldosteronism and other disorders of apparent excess mineralocorticoid activity.

Secondary hypertension is a common condition with a broad differential diagnosis. Identification of the true cause of hypertension can be critical for guiding appropriate management. Here, we review hereditary conditions underlying the most common cause of secondary hypertension, primary aldosteronism, as well as other disorders impacting various levels of mineralocorticoid action. Recently, several pathogenic variants of ion channels have been described as etiologies of familial aldosteronism. Defects in steroid hormone synthesis cause hypertension in 11β-hydroxylase deficiency and 17α-hydroxylase deficiency, two types of congenital adrenal hyperplasia. Inappropriate activation of mineralocorticoid receptors underlies the syndrome of apparent mineralocorticoid excess and constitutive activation of the mineralocorticoid receptor. Finally, Liddle syndrome and pseudohypoaldosteronism type 2 are disorders impacting the function of renal sodium channels, the endpoint of mineralocorticoid action. We discuss the pathophysiology, clinical presentation, diagnosis and management of these low renin hypertension states that ultimately result in apparent excess mineralocorticoid activity.

An infantile case of pseudohypoaldosteronism type 1 (PHA1) caused by a novel mutation of NR3C2.

An infantile case of pseudohypoaldosteronism type 1 (PHA1) caused by a novel mutation of NR3C2.

Failure to Thrive, Hyponatremia, Hyperkalemia - Differential Diagnostic Reflections of a Rare Genetic Disease.

Pseudohypoaldosteronism type I is a rare genetic disease of mineralocorticoid resistance that typically manifests in neonatal age. The patients are diagnosed with failure to thrive, dehydration, polyuria, vomiting, hyperkalemia, hyponatremia as well as potential metabolic acidosis accompanied by elevated values for serum aldosterone and renin. The disease is subdivided into a systemic and a renal type. Considering the renal type symptoms disappear in the toddler age group. The systemic type can -apart from the kidneys - affect colon, lungs, salivary and sweat glands. In that case symptoms persist until adulthood.

Interstitial 4q Deletion Syndrome Including NR3C2 Causing Pseudohypoaldosteronism

Interstitial and terminal deletions of chromosome 4q have been described for many years and have variable phenotypes depending on the size of the deletion present. Clinical features can include developmental delay, growth difficulty, digital differences, dysmorphic features, and cardiac anomalies. Here, we present an infant with pseudohypoaldosteronism found to have a deletion of 4q31.21q31.23, including NR3C2. Heterozygous mutations in NR3C2 have been reported to cause autosomal dominant pseudohypoaldosteronism type 1 (PHA1A). This represents a rare case of PHA1A due to a contiguous interstitial deletion and highlights the importance of evaluating patients with overlapping deletions for PHA1A.

One-month-old girl presenting with pseudohypoaldosteronism leading to the diagnosis of CDK13-related disorder: a\xa0case report and review of the literature

BackgroundIt is not uncommon that an infant with a disease of unknown etiology is presented to a physician. Facial dysmorphic features lead to a different diagnosis. It is a challenge to link the presentation to the newfound diagnosis.Case presentationA 37-day-old Yemenite Jewish girl was presented to our institution with a clinical picture of pseudohypoaldosteronism due to abnormal facial features and a psychomotor developmental delay. Further investigation led to the diagnosis of CDK13-related disorder. According to the literature, CDK13 has a key role in the cell cycle, but no interference with the aldosterone signaling pathway or electrolyte balance was described. No mutations in the previously described gene NR3C2 (cytogenetic location 4q31.23), encoding the mineralocorticoid receptor, were found. Although the clinical presentation corresponded to pseudohypoaldosteronism type 1, we could not genetically confirm this.ConclusionsProbably pseudohypoaldosteronism was a coincidental finding in this girl with a CDK13 mutation, but because only limited information is known about CDK13-related disorders, further investigation could be more informative to clarify this presentation.

Pseudo hypoaldosteronism type 1B due to novel deletion mutation in SCNN1A gene

Pseudo hypoaldosteronism type 1B (PHA1B) is a systemic form of salt wasting. Children present after the first week of life with typical symptoms of an adrenal crisis. PHA1B is caused by autosomal recessive homozygous mutations in genes encoding epithelial sodium channels (ENaC) subunits α, β and γ. ENaC are widespread and present in renal tubules, airways, colon, sweat and salivary glands. Electrolyte imbalance is significant with severe hyponatremia, hyperkalemia and metabolic acidosis. In early life until approximately one year of age electrolytes remain unstable despite active management but then gradually improve. The mainstay of treatment is high dose salt replacement, sodium bicarbonate and sodium polystyrene therapy. The adequate treatment and monitoring can result in normal physical and psychomotor development. We present a case of PHA1B with severe intractable electrolyte imbalances in neonatal period. The genetic sequence revealed a novel homozygous deletion mutation in exon 4 of the SCNN1A gene (c.942delC, p.N315Tfs*16).