Insights into the diverse mechanisms and effects of variant CUL3-induced familial hyperkalemic hypertension.

Familial hyperkalemic hypertension (FHHt), also known as Pseudohypoaldosteronism type II (PHAII) or Gordon syndrome is a rare Mendelian disease classically characterized by hyperkalemia, hyperchloremic metabolic acidosis, and high systolic blood pressure. The most severe form of the disease is caused by autosomal dominant variants in CUL3 (Cullin 3), a critical subunit of the multimeric CUL3-RING ubiquitin ligase complex. The recent identification of a novel FHHt disease variant of CUL3 revealed intricacies within the underlying disease mechanism. When combined with studies on canonical CUL3 variant-induced FHHt, these findings further support CUL3's role in regulating renal electrolyte transport and maintaining systemic vascular tone. However, the pathophysiological effects of CUL3 variants are often accompanied by diverse systemic disturbances in addition to classical FHHt symptoms. Recent global proteomic analyses provide a rationale for these systemic disturbances, paving the way for future mechanistic studies to reveal how CUL3 variants dysregulate processes outside of the renovascular axis. Video Abstract.

[Neonatal systemic pseudohypoaldosteronism type I]. / æ–°ç”Ÿå„¿å¤šè„å™¨åž‹å‡æ€§é†›å›ºé ®å‡å°‘ç—‡â 型.

An 18-day-old male infant was admitted to the hospital due to recurrent hyperkalemia for more than 10 days. The neonate had milk refusal and dyspnea. The blood gas analysis revealed recurrent hyperkalemia, hyponatremia and metabolic acidosis. Adrenocortical hormone replacement therapy was ineffective. Additional tests showed a significant increase in aldosterone levels. Family whole exome sequencing revealed that the infant had compound heterozygous in the SCNNIA gene, inherited from both parents. The infant was diagnosed with neonatal systemic pseudohypoaldosteronism type I. The infant's electrolyte levels were stabilized through treatment with sodium polystyrene sulfonate and sodium supplement. The infant was discharged upon clinical recovery. This study provides a focused description of differential diagnosis of salt-losing syndrome in infants and introduces the multidisciplinary management of neonatal systemic pseudohypoaldosteronism type I.

Brugada syndrome uncovered in patient with pseudohypoaldosteronism due to hyperkalaemia.

Brugada syndrome is a rare sodium channelopathy that predisposes to an increased risk of malignant arrythmias and sudden cardiac death. Previous studies have reported that metabolic disturbances can uncover a Brugada ECG pattern. Given the risk of malignant arrhythmias, it is important to correctly diagnose and treat Brugada syndrome. We report a case of Brugada syndrome uncovered by hyperkalaemia precipitated in a patient with pseudohypoaldosteronism.

Classification of pseudohypoaldosteronism type II as type IV renal tubular acidosis: results of a literature review.

Pseudohypoaldosteronism (PHA) type II (PHA2) is a genetic disorder that leads to volume overload and hyperkalemic metabolic acidosis. PHA2 and PHA type I (PHA1) have been considered to be genetic and pediatric counterparts to type IV renal tubular acidosis (RTA). Type IV RTA is frequently found in adults with chronic kidney disease and is characterized by hyperchloremic hyperkalemic acidosis with normal anion gap (AG). However, we recently observed that PHA1 was not always identical to type IV RTA. In this study, we focused on the acid-base balance in PHA2. Through a literature search published between 2008-2020, 46 molecularly diagnosed cases with PHA2 were identified (median age of 14 years). They comprised 11 sets of familial and 16 sporadic cases and the pathology was associated with mutations in WNK 4 (n = 1), KLHL3 (n = 17), and CUL3 (n = 9). The mean potassium (K+) level was 6.2 ± 0.9 mEq/L (n = 46, range 4.0-8.6 mEq/L), whereas that of chloride (Cl-) was 110 ± 3.5 mEq/L (n = 41, 100-119 mEq/L), with 28 of 41 cases identified as hyperchloremic. More than half of the cases (18/35) presented with metabolic acidosis. Although AG data was obtained only in 16 cases, all but one cases were within normal AG range. Both Cl- and HCO3- levels showed significant correlations with K+ levels, which suggested that the degree of hyperchloremia and acidosis reflect the clinical severity, and is closely related to the fundamental pathophysiology of PHA2. In conclusion, our study confirmed that PHA2 is compatible with type IV RTA based on laboratory findings.

Case report: Early molecular confirmation and sodium polystyrene sulfonate management of systemic pseudohypoaldosteronism type I.

Introduction: Type 1 pseudohypoaldosteronism (PHA) consists of resistance to aldosterone. Neonatal presentation is characterized by salt wasting, hyperkalemia, and metabolic acidosis with high risk of mortality. Type 1 PHA can be autosomal dominant (renal type 1) or autosomal recessive (systemic type 1). Renal PHA type 1 can be feasibly managed with salt supplementation; however, systemic PHA type 1 tends to have more severe electrolyte imbalance and can be more refractory to treatment. Case Presentation: We present a case of a 3-year-old girl with systemic PHA type 1, diagnosed and confirmed molecularly in infancy, who has been successfully managed with sodium polystyrene sulfonate decanted into feeds along with sodium supplementation. On day 5 of life, a full-term female infant presented to the ED for 2 days of non-bloody, non-bilious emesis, along with hypothermia to 94°F. Laboratory results were notable for hyponatremia (Na) of 127, hyperkalemia (K) of 7.9, and acidosis with bicarbonate level of 11.2. Genetic testing ordered within a week of life confirmed PHA type 1 with a homozygous pathogenic frameshift variant in SCNN1A c.575delA (p.Arg192GlyfsX57). Sodium polystyrene sulfonate and feeds were decanted until the age of 16 months, and she was also continued on NaCl supplementation. She was gradually transitioned to directly administered sodium polystyrene sulfonate without any electrolyte issues. She has overall done well after gastrostomy-tube (G-tube) placement without severe hyperkalemia even with several hospitalizations for gastrointestinal or respiratory illnesses. Discussion/Conclusion: A treatment approach to systemic PHA and sodium polystyrene sulfonate administration in neonates and infants is described.

Salt-Losing Syndrome in a Girl with Type I and II Pseudohypoaldosteronism.

BACKGROUND Pseudohypoaldosteronism (PHA) is characterized by renal tubular resistance to aldosterone and leads to hyponatremia, hyperkalemia, and metabolic acidosis. PHA is divided into 2 types: PHAI and PHAII. PHAI can be dominant (systemic disease) or recessive (renal form). PHAII causes hypertension with hyperkalemia and is recognized mostly in adults. PHA can be a life-threatening disease due to salt-wasting syndrome and severe hypovolemia. CASE REPORT We describe the case of a 2-month-old girl who was admitted to our hospital with hypovolemic shock due to salt-wasting syndrome. Laboratory tests revealed severe electrolyte abnormalities: hyponatremia (Na-116 mmol/L), hyperkalemia (K-10 mmol/L) and metabolic acidosis (pH-7.27; HCO3-12 mmol/L). Serum aldosterone was >100 ng/dL. Genetic analysis confirmed mutations in SCNN1A and CUL3 gene responsible for PHAI and PHAII. Supplementation with NaCl, pharmacological treatment of hyperkalemia, and restriction of potassium in the diet resulted in the normalization of serum electrolytes and proper future development. CONCLUSIONS Pseudohypoaldosteronism should always be considered in the differential diagnosis of hyponatremia and hyperkalemia in children. Salt loss syndrome can lead to hypovolemic shock and, when unrecognized and untreated, to death of a child due to arrythmias and brain edema. The presence of 2 types of PHA in the same patient increases the risk of salt loss and at the same time significantly increases the risk of hypertension because of genetic predisposition and regular diet. Increased salt concentration in sweat and saliva may suggest pseudohypoaldosteronism.

Difficulties in the diagnosis and management of eight infants with secondary pseudohypoaldosteronism.

BACKGROUND: Type 1 pseudohypoaldosteronism (PHA1) is a rare condition characterized by the resistance of the kidney to the effect of aldosterone. Secondary PHA1 is a syndrome that is most often related to urinary tract anomalies (UTAs) and/or urinary tract infections (UTIs). A similar pattern of electrolyte impairment is seen in congenital adrenal hyperplasia (CAH) and secondary PHA1, and CAH is a condition that requires urgent treatment. In our study, eight patients aged between 15 days and 8 months (seven males and one female) were included in the evaluation. It was aimed to evaluate cases of secondary PHA1 in our clinic and to identify the problems encountered in diagnosis and follow-up. METHODS: The records of the patients who presented to our hospital between February 2010 and 2021 were retrieved and retrospectively scanned. RESULTS: In all cases, hyponatremia, hyperkalemia, hyperaldosteronism, and hyperreninemia were detected. Other biochemical and hormonal tests were normal. Leukocytosis was detected in urine analysis, and urine cultures were productive. UTA was detected in five cases. Nine episodes of PHA1 occurred in eight patients and fungal infections were responsible for causing two episodes. Four episodes of PHA1 needed mineralocorticoid treatment. On the third day, serum electrolytes normalized. Fludrocortisone treatment was continued for 1 week. In one case, UTIs were repeated with PHA1, but in the follow-up, there were no additional problems. CONCLUSIONS: Secondary PHA1 should be kept in mind when hyponatremia and hyperkalemia are seen, especially in infants aged under 3 months or older, up to 8 months, who present with non-specific symptoms. Fungal infections should not be forgotten in UTI etiology because PHA1 episodes can be initiated. If CAH is suspected, mineralocorticoid treatment should be rapidly initiated.

A case of novel mutation of Cullin 3 gene in pseudohypoaldosteronism type II.

Pseudohypoaldosteronism type II (PHA II) is a rare inherited disease characterized by hypertension, hyperkalemia and metabolic acidosis. With the development of gene sequencing technology, more genetic mutations underlying PHA II were reported and the understanding of its pathogenesis has gone deep into the molecular level. Here, we present a juvenile case of PHA II. A novel missense mutation (c.1376 A>T) located in exon 9 of Cullin 3 (CUL3) was found by whole-exome sequencing. The clinical manifestations were significantly improved after oral hydrochlorothiazide. This case enriches the genetic and clinical phenotype spectrum of PHA II and provides experience for diagnosing and treating the disease.

Diagnostic and management considerations in pseudohypoaldosteronism type 1b.

Pseudohypoaldosteronism type 1B is a rare autosomal recessive disorder caused by dysfunction of amiloride-sensitive epithelial sodium channels (ENaCs). We present the case of a neonate with cardiogenic shock after cardiac arrest due to profound hyperkalaemia. Genetic testing revealed a novel homozygous variant in SCNNIA We review diagnostic considerations including the molecular mechanisms of disease, discuss treatment approaches and highlight the possible significance of the diversity of pulmonary ENaCs.

TRANSIENT PSEUDOHYPOALDOSTERONISM SECONDARY TO URINARY TRACT INFECTION IN A MALE INFANT WITH UNILATERAL HYDRONEPHROSIS DUE TO PRIMARY OBSTRUCTIVE MEGAURETER: A CASE REPORT.

We present a case of transient form of type 1 pseudohypoaldosteronism (S-PHA) in a 1.5-month-old male infant who presented with lethargy, failure to thrive, severe hyponatremia (Na=118 mmol/L), hypochloremia (Cl=93 mmol/L) and fever due to urinary tract infection. Potassium levels were normal. Markedly elevated serum aldosterone level and elevated serum renin confirmed the diagnosis of pseudohypoaldosteronism. Renal ultrasound showed grade III hydronephrosis on the left kidney while contrast-enhanced voiding urosonography excluded the existence of vesicoureteral reflux, which raised suspicion of obstructive uropathy at the level of vesicoureteral junction. Serum sodium normalized after several days of intravenous fluids and antibiotic therapy, after which oral supplementation of sodium was introduced. The levels of 17-hydroxyprogesterone, adrenocorticotropic hormone, cortisol and thyroid-stimulating hormone were normal. Functional magnetic resonance urography conducted at the age of 3 months confirmed the diagnosis of primary congenital obstructive megaureter and the infant was referred to a pediatric surgeon. Although a rare occurrence, S-PHA can be a potentially life-threatening condition in infants if not recognized and treated appropriately. Therefore, serum concentrations of electrolytes should be obtained in every child diagnosed with obstructive anomaly of the urinary tract and/or acute cystopyelonephritis. On the other hand, every child diagnosed with S-PHA should be evaluated for obstructive anomaly of the urinary tract.

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.

Genotype-phenotype correlation in Gordon's syndrome: report of two cases carrying novel heterozygous mutations.

Gordon's syndrome, known also as Pseudohypoaldosteronism type II is a rare inherited dominant form of low-renin hypertension associated with hyperkalemia and metabolic acidosis. Four genes related to the regulation of the NaCl co-symporter NCC have been discovered associated to Gordon phenotypes: WINK 1 and WINK4, which, along with WNK2 and WNK3, encode a family of WNK-kinases, and KLHL3 and CUL3 encoding respectively, Kelch-like 3 protein and cullin. Heterozygous mutations in these genes constitutively activate NCC leading to abnormally increased salt reabsorption and salt-sensitive hypertension. Thiazide diuretic is the recognized treatment for this condition. We report and discuss phenotypic and genetic heterogeneity of two patients with Gordon's syndrome carrying novel heterozygous mutations in the WNK1 and KLHL3 genes. A very rare variant in the SCNN1G gene encoding the γ subunit of epithelial sodium channel ENaC was also identified in one patient.

A late diagnosis of Pseudohypoaldosteronism type I in an infant with hypoplastic left heart syndrome presenting with failure to thrive.

Pseudohypoaldosteronism type I is caused by a peripheral resistance to aldosterone and can present with electrolyte abnormalities, poor growth, or dehydration. Although a rare disease, several case reports have been published regarding Pseudohypoaldosteronism type I in neonates and infants. We report a case of failure to thrive and hyponatremia in an infant with hypoplastic left heart syndrome who was subsequently found to have Pseudohypoaldosteronism type I.

[A Case of Pseudohypoaldosteronism Type â ¡ (PHA2) Caused by a Novel Mutation of KLHL3].

The patient, a 41-year-old woman, was admitted because "it was found out she had elevated serum potassium levels for 18 days". Eighteen days prior to admission at our hospital, the patient was found to have elevated serum potassium during hospitalization at another hospital, where the patient received symptomatic treatment and was discharged after her serum potassium returned to a normal level. However, the patient still had elevated serum potassium repeatedly and was referred to our hospital for further examination. The patient had a history of acute nephritis and gestational hypertension. Six months prior to admission at our hospital, it was found out that the patient had slightly elevated blood pressure, but no intervention was done. The patient's father has a history of hypertension and diabetes. After admission, laboratory results showed that the patient had hyperkalemia, hyperchloremia and metabolic acidosis. The level of plasma renin was obviously below the normal range, but the concentration of plasma aldosterone was within the normal range. A new mutation locus (c.1115delG) in KLHL3 (Kelch like family member 3) gene was revealed by genetic testing, leading to the diagnosis of pseudoaldosteronism type Ⅱ (PHA2). The patient was given regular treatment of oral hydrochlorothiazide hydrochloride at set intervals. Subsequently, her blood electrolyte level, blood pH, BE and BEB have returned to normal levels. The patient was followed up for 12 months and did not feel unwell during the follow-up period.