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.

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.

Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism.

INTRODUCTION: Autosomal recessive forms of pseudohypoaldosteronism are caused by genetic defects in the epithelial sodium channel. Little is known about the long-term outcome and medication needs during childhood and adolescence. OBJECTIVE: This study reports a single-centre experience of children affected with this ultra-rare condition over a 37-year period. METHODS: We report the clinical presentation, growth, neuro-development, associated conditions, mortality and medication dosing and administration for 12 affected children from eight families. RESULTS: All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia. All parents were consanguineous and of South Asian, Middle Eastern or African ethnic origin. Eight children had homozygous mutations in the SCNN1A and SCNN1G genes, encoding the epithelial sodium channel subunits alpha and gamma, respectively, including one novel mutation. Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia. One affected female had a successful pregnancy at the age of 28 years. CONCLUSION: Despite high mortality and morbidity in this condition, survival with normal physical and neurological outcome is possible, justifying intensive management to prevent electrolyte imbalance.

Clinical Management in Systemic Type Pseudohypoaldosteronism Due to SCNN1B Variant and Literature Review

Systemic pseudohypoaldosteronism (PHA) is a rare, salt-wasting syndrome that is caused by inactivating variants in genes encoding epithelial sodium channel subunits. Hyponatremia, hyperkalemia, metabolic acidosis, increased aldosterone and renin levels are expected findings in PHA. Clinical management is challenging due to high dose oral replacement therapy. Furthermore, patients with systemic PHA require life-long therapy. Here we report a patient with systemic PHA due to SCNN1B variant whose hyponatremia and hyperkalemia was detected at the 24th hour of life. Hyperkalemia did not improve with conventional treatments and dialysis was required. He also developed myocarditis and hypertension in follow-up. Challenges for diagnosis and treatment in this patient are discussed herein. In addition, published evidence concerning common features of patients with SCNN1B variant are reviewed.

A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4.

BACKGROUND: There have been still few case reports of pseudohypoaldosteronism type II (PHA2), also known as Gordon's syndrome, genetically diagnosed, and this is the first report of familial PHA2 case in Japan with a novel D564N mutation in WNK4. METHODS: A 29-year-old woman was admitted to our hospital due to hyperkalemia (serum potassium: 6.4 mmol/L). She had mild hypertension (135/91 mm Hg), a bicarbonate level at the lower limit of the normal range (HCO3 : 22 mmol/L) with a normal anion gap, low plasma renin activity (0.2 ng ml-1  hr-1 ), and high urinary calcium excretion (505.4 mg/g Cre). A hereditary condition was suspected because her mother also had the same symptoms. We performed a comprehensive genetic analysis for major inherited kidney diseases with next-generation sequencing including the genes responsible for PHA2 (WNK1, WNK4, KLHL3, and CUL3). RESULTS: Genetic analysis revealed that the patient and her mother had a novel missense mutation (D564N) in the acidic motif in WNK4, which leads to the diagnosis of PHA2. Administration of trichlormethiazide (1 mg/day) effectively ameliorated her blood pressure (114/69 mm Hg), plasma bicarbonate (25 mmol/L), serum potassium (4.3 mmol/L), and urinary calcium excretion (27.2 mg/g Cre). CONCLUSION: We report the first Japanese familial case of PHA2 with WNK4 mutation. D564N mutation in WNK4 is a novel genetic cause of PHA2 with a relatively mild phenotype.

Transient pseudohypoaldosteronism: a potentially severe condition affecting infants with urinary tract malformation.

BACKGROUND: Secondary pseudohypoaldosteronism (S-PHA) is a life-threatening condition affecting young children with urinary tract malformation (UTM). OBJECTIVE: The aim of the study was to highlight the diagnosis of S-PHA in children with UTM and propose appropriate management. STUDY DESIGN: The authors retrospectively reviewed cases of S-PHA related to UTM observed at the institution and searched the PubMed® database to review the literature. RESULTS: A total of 116 cases of S-PHA associated with UTM, including the four cases from the institution, were reviewed. One hundred six cases (92.2%) were younger than 6 months, and 95 cases (81.9%) occurred in boys. Urinary tract infection was associated in 105 cases (90.5%). All types of UTM were observed. In the absence of urinary tract infection, S-PHA was related to bilateral UTM or solitary kidney. In 89 cases (76.5%), S-PHA resolved with medical treatment only. In cases of UTM requiring immediate surgery, electrolyte imbalance related to S-PHA also resolved after surgery. Children with associated urinary tract infection and bilateral UTM are at higher risk of developing S-PHA. DISCUSSION: The pathogenesis of S-PHA has not been fully elucidated. Renal tubular immaturity may be one of the factors involved, in view of the young age of the population being affected. A high rate of bilateral UTM (or UTM on solitary kidney) was observed (50.9%), suggesting an association with S-PHA. In the absence of urinary tract infection (UTI), S-PHA appeared to occur more frequently in the presence of bilateral UTM. Although the indication for early surgery remains unclear, it may have a role in the prevention of UTI and prevention of recurrence of S-PHA. Serum electrolytes should be checked in children with UTM before urological surgery, and/or presenting urinary tract infection, before the age of 6 months. The results of this study must be interpreted cautiously because of its retrospective nature and the fact that data were derived from various articles. Few articles on S-PHA related to UTM have been published in the literature. To the best of the authors' knowledge, the study constitutes the largest series published to date. CONCLUSIONS: S-PHA results in potentially severe electrolyte imbalance and affects children younger than 6 months with UTI and/or UTM. Electrolyte abnormalities related to S-PHA often resolve after administration of appropriate intravenous electrolyte solution and treatment of UTI and/or surgery.

A potential serious complication in infants with congenital obstructive uropathy: Secondary pseudohypoaldosteronism.

Patients who have secondary pseudohypoaldosteronism (PHA) in addition to hyponatraemia, hyperpotassaemia and high serum aldosterone levels for the age were included in this retrospective study.Among eight patients, seven patients were diagnosed with PHA secondary to obstructive uropathy (OUP), whereas one patient had PHA secondary to ileostomy. Six patients with OUP had simultaneous urinary tract infection (UTI) and in all except one patient, secondary PHA recovered with only UTI treatment before applying surgical correction. All the patients were younger than 3 months age. In three patients with PUV diagnosis, salt wasting recurred in an UTI episode under 3 months of age.

Pseudohypoaldosteronism type-I: a rare cause of hyperkalemia in neonates.

Pseudohypoaldosteronism type I (PHA-I) is a rare disorder with only a few cases reported worldwide. It appears early in life with salt-wasting, failure to thrive, dehydration, hypotension, hyperkalaemia and metabolic acidosis. There is a resistance to aldosterone by the mineralocorticoid receptors. We describe one such case of a 14-day-old female neonate who presented with frequent episodes of dehydration, hyperkalaemia and hyponatraemia. On further workup, she proved to be a case of PHA-I. The aim of this report is to discuss the evaluation and to highlight the difficulties associated with the management of this rare disorder.

Genetic disorders of potassium homeostasis.

Hereditary disorders of potassium homeostasis are an interesting group of disorders, affecting people from the newborn period to adults of all ages. The clinical presentation varies from severe hypotension at birth to uncontrolled hypertension in adults, often associated with abnormal potassium values, although many patients may have a normal serum potassium concentration despite being affected by the genetic disorder. A basic understanding of these disorders and their underlying mechanisms has significant clinical implications, especially in the few patients with subtle clinical signs and symptoms. We present a summary of these disorders, with emphasis on the clinical presentation and genetic mechanisms of these disorders.

CUL3 gene analysis enables early intervention for pediatric pseudohypoaldosteronism type II in infancy.

BACKGROUND: Four genes responsible for pseudohypoaldosteronism type II (PHA-II) have been identified, thereby facilitating molecular diagnostic testing. CASE-DIAGNOSIS/TREATMENT: A 1-year-old boy with prolonged hyperkalemia, metabolic acidosis, hyperchloremia, growth delay, and mild hypertension was diagnosed with PHA-II based on the detection of exon 9 skipping in CUL3 mRNA. The impaired splicing was the result of a de novo, previously unreported single nucleotide substitution in the splice acceptor site of CUL3 intron 8. Among the four genes reported to be involved in PHA-II, CUL3 was the primary suspect in our patient because in patients with the CUL3 mutation, the onset of disease is often early in infancy and the phenotypes of PHA-II are more severe. Our patient was treated with trichlormethiazide, which inhibits the function of the sodium-chloride co-transporter (NCC), and the outcome was favorable, with correction of body fluids and blood electrolyte homeostasis. CONCLUSION: Since chronic acidosis and hypertension associated with PHA-II can result in delayed growth and development in pediatric patients, genetic analysis to detect the CUL3 mutation and to enable intervention early in the disease course would be beneficial for infants with suspected PHA-II.

Pseudohypoaldosteronism type 1: management issues.

We report a newborn girl with life-threatening hyperkalemia and salt wasting crisis due to severe autosomal recessive multiple target organ dysfunction pseudohypoaldosteronism type 1 (MTOD PHA1). She was aggressively managed with intravenous fluids, potassium-lowering agents, high-dose sodium chloride supplementation and peritoneal dialysis. Genetic analysis revealed a homozygous mutation of the α- ENaC (epithelial Na(+) channel) gene. She had a stormy clinical course with refractory hyperkalemia and prolonged hospitalization. Eventually, she succumbed to pneumonia and septicemia at 4 months of age. This is probably the first case of PHA1 confirmed by genetic analysis from India.

Colitis isquémica secundaria a poliestireno sulfonato cálcico (Kalimato) no asociado a sorbitol / Colonic necrosis due to calcium polystyrene sulfonate (Kalimate) not suspended in sorbitol

Las resinas de intercambio iónico forman parte del tratamiento habitual de la hiperkaliemia, especialmente en pacientes con insuficiencia renal crónica. Estas resinas se han asociado en muchas ocasiones a lesiones del tracto digestivo, especialmente en el caso del poliestireno sulfonato sódico (Kayexalato) asociado a sorbitol. Presentamos el caso de un paciente con una hemorragia digestiva secundaria a colitis isquémica asociada a cristales de poliestireno sulfonato cálcico (Kalimato) sin sorbitol (AU)

Cation-exchange resins are used in the management of hyperkalemia, particularly in patients with end-stage renal disease. These resins were associated with gastrointestinal tract lesions, especially sodium polystyrene sulfonate (Kayexalate) mixed with sorbitol. We present a case of colonic necrosis after the administration of calcium polystyrene sulfonate (Kalimate) not suspended in sorbitol (AU)

Clinical and molecular analysis of six Japanese patients with a renal form of pseudohypoaldosteronism type 1.

Pseudohypoaldosteronism type 1 (PHA1) is a rare condition characterized by neonatal salt loss with elevated plasma aldosterone and renin levels. Two types of PHA1 have been described: an autosomal recessive systemic form and an autosomal dominant renal form, in which the target organ defect is confined to the renal tubules. The dominant renal form of PHA1 is caused by heterozygous mutations in the NR3C2 gene, which encodes the mineralocorticoid receptor (MR). We determined clinical and biochemical parameters in two familial and four sporadic Japanese patient and analyzed the status of the NR3C2 gene. Failure to thrive was noted in five of the six patients. In one of the familial cases, the mother had an episode of failure to thrive when she was a toddler, but received no medical treatment. NaCl supplementation was discontinued in four of the six patients after they reached one year of age and they have grown normally thereafter. However, in one patient, 9 g/day of salt has been required to maintain serum Na concentration after 1 year of age. Analysis of NR3C2 identified three novel mutations [c. C1951T (p.R651X), c.304_305delGC (p.A102fsX103), c.del 603A (p.T201fsX34)] and one previously reported mutation [c.A2839G (p.947X)]. p.R651X was identified in one familial case and one unrelated sporadic patient. The patient who has been supplemented with large amount of salt was heterozygous for c.del 603A in exon 2. In conclusion, our study expands the spectrum of phenotypes, and characterized mutations of NR3C2 in the renal form of PHA1.

Life threatening hyperkalemia in a neonate with pseudo-hypoaldosteronism.

Pseudohypoaldosteronism type 1 is a rare disorder characterized by renal resistance to aldosterone which may present with a salt wasting crisis in infancy. We report a neonate with hyponatremia, severe dehydration and refractory life threatening hyperkalemia who was treated with dietary sodium chloride supplementation, potassium binding resins and fluid replacement therapy which proved to be lifesaving.

Critical points in the management of pseudohypoaldosteronism type 1.

Pseudohypoaldosteronism type 1 (PHA-1, MIM #264350) is caused by defective transepithelial sodium transport. Affected patients develop life-threatening neonatal-onset salt loss, hyperkalemia, acidosis, and elevated aldosterone levels due to end-organ resistance to aldosterone. In this report, we present a patient diagnosed as PHA-1 who had clinical and laboratory findings compatible with the diagnosis and had genetically proven autosomal recessive PHA-1. The patient received high doses of sodium supplementation and potassium-lowering therapies; however, several difficulties were encountered in the management of this case. The aim of this presentation was to point out the potential pitfalls in the treatment of such patients in the clinical practice and to recommend solutions.