Systemic Pseudohypoaldosteronism Research Articles

Neonatal systemic pseudohypoaldosteronism type I

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.

Epithelial sodium channel (ENaC) in GtoPdb v.2023.1

Epithelial sodium channel (ENaC) in GtoPdb v.2023.1

Cutaneous and Ocular Findings in Systemic Pseudohypoaldosteronism I: Early Clinical Pointers

Systemic Pseudohypoaldosteronism type I (PHA I) is an uncommon and an often missed cause of salt wasting crisis in the neonatal period. In addition to dyselectrolytemia, cutaneous findings in the form of miliaria rubra, and ophthalmic findings secondary to abnormal sebum accumulation in the eye may also be present in patients with systemic PHA I. This article is about systemic PHA in a female neonate (birth weight 2.040 Kg, delivered at 34 weeks of gestation), who presented with life-threatening hyperkalemia, along with characteristic cutaneous and ophthalmic manifestations. Normal female genitalia, history of hyperkalemia with similar cutaneous and ophthalmic manifestations leading to death in the previous sibling, provided clue to the diagnosis. All relevant investigations were performed. Blood chemistry in this neonate revealed hyponatremia and hyperkalemia with metabolic acidosis. Plasma renin and serum aldosterone levels were reportedly high. Neonate was followed and electrolytes were monitored twice weekly on outpatient basis. But the life-threatening hyperkalemia led to multiple episodes of vomiting and, refusal to feed for few hours and the baby succumbed to death at age of 2.5 months. Hence, it was concluded that systemic PHA I should be considered in the differential diagnosis of neonates presenting with hyponatremic dehydration, hyperkalemia, and metabolic acidosis. Timely and appropriate electrolyte correction is pivotal for favourable outcome.

Systemic Pseudohypoaldosteronism Type 1 due to 3 Novel Mutations in SCNN1Aand SCNN1BGenes

Objective: The systemic form of pseudohypoaldosteronism type 1 (PHA1) is an autosomal recessive disorder characterized by defective sodium transport in multi-organ systems. Mutations in the genes encoding the amiloride-sensitive epithelial sodium channel, ENaC, account for genetic causes of systemic PHA1. We describe systemic PHA1 due to 4 novel variants detected in SCNN1A and SCNN1B in 3 cases from 3 unrelated consanguineous families. Patients and Methods: We evaluated the clinical presentations, biochemical and hormonal characteristics, and molecular genetic analysis results of 3 patients from 3 unrelated consanguineous families and parents from whom samples were available. Results: The ages at presentation were postnatal days 9, 10, and 5. The main presentation symptoms were vomiting, poor feeding, weakness, weight loss, and skin rash. All patients exhibited laboratory characteristics including severe hyponatremia, hyperkalemia, metabolic acidosis, elevated plasma renin, elevated aldosterone, and positive sweat tests, suggesting a diagnosis of systemic PHA1. Molecular genetic analysis revealed 2 novel pathogenic variants [c.87C>A(p.Tyr29*)/IVS9 + 1G>A (c.1346 + 1G>A)] in SCNN1Bin case 1, a novel homozygous pathogenic variant [p.His69Arg(c.206A>G] in SCNN1Ain case 2, and a homozygous one-base duplication, p.A200Gfs*6 (c.598dupG), in SCNN1A in case 3. Conclusion: PHA1 should be considered at differential diagnosis in patients presenting with hyponatremia, hyperkalemia, and metabolic acidosis. The cases in this report involving 4 novel variants will add valuable insights into the phenotype-genotype relationship and will expand the mutation database.

Systemic Pseudohypoaldosteronism Type I: A Case Report and Review of the Literature

Systemic pseudohypoaldosteronism (PHA) type I is a rare genetic disorder resulting from mutations in the subunits of the epithelial sodium channel that manifests as severe salt wasting, hyperkalemia, and metabolic acidosis in infancy. In this article we report a patient with systemic PHA type I presenting with severe dehydration due to salt wasting at 6 days of life. She was found to have a known mutation in the SCNN1A gene and subsequently required treatment with sodium supplementation. We also review the clinical presentation, differential diagnosis, and treatment of systemic PHA type I and summarize data from 27 cases with follow-up data.

Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit.

Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal life-threatening hypovolemia and hyperkalemia. The very high plasma aldosterone levels detected under hypovolemic or hyperkalemic challenge can lead to increased or decreased sodium reabsorption, respectively, through the Na(+)/Cl(-) cotransporter (NCC). However, the role of ENaC deficiency remains incompletely defined, because constitutive inactivation of individual ENaC subunits is neonatally lethal in mice. We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1. Compared with control mice fed a regular-salt diet, knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC protein, despite high plasma aldosterone levels. In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized. Finally, shift to a regular diet after the rescue diet reinstated the symptoms of severe PHA-1 syndrome and significantly reduced NCC phosphorylation. In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet. We further conclude that hyperkalemia becomes the determining factor in regulating NCC activity, regardless of sodium loss, in the ENaC-mediated salt-losing PHA-1 phenotype.

A case of systemic pseudohypoaldosteronism with a novel mutation in the SCNN1A gene

We report a neonatal case of systemic pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene (homozygous c.1052 + 2dupT in intron 3) in which the patient presented with life-threatening hyperkalemia, hyponatremia and metabolic acidosis. It remains uncertain if there is genotype–phenotype correlation, due to the rarity of the disease. This mutation, which to our best knowledge has not been described before, was associated with a very severe phenotype requiring aggressive therapy. Se presenta un caso neonatal de pseudohipoaldosteronismo sistémico tipo 1 causado por una nueva mutación en el gen SCNN1A (homocigotos C.1052 2 dupT en el intrón 3) en el que el se evidenció hiperpotasemia potencialmente mortal, hiponatremia y acidosis metabólica. Continúa sin saberse con certeza si hay correlación genotipo-fenotipo, debido a la rareza de la enfermedad. Esta mutación, que no ha sido previamente descrita, se asoció con un fenotipo muy grave por lo que requirió un abordaje terapéutico agresivo.

A case of SCNN1A splicing mutation presenting as mild systemic pseudohypoaldosteronism type 1

Systemic pseudohypoaldosteronism type 1 (PHA1) is characterized by excessive salt loss from the renal tubulus, colon, sweat and salivary glands. Here we present a case of systemic PHA1 whose genetic analysis revealed a homozygous splicing mutation in intron 4 of SCNN1A (c.684+2 T>A) and discuss with the patient's phenotype. Previously described systemic PHA cases show varying degrees of severity dependent on the mutation. Most of the SCNN1A gene mutations present with a severe phenotype. The long-term follow-up and phenotype of the two reported cases with splicing mutation of the SCNN1A gene are unknown. Our case, with a new splicing mutation of SCNN1A, presented with a severe phenotype in the neonatal period. Since then she has been well without any hospitalization and respiratory illness. Her requirement for medication also decreased gradually. After early infancy she presented a mild systemic PHA1 phenotype up to the age of 39 months. In conclusion, the mutation in the patient is located at the splicing site and is definitely a new and pathogenic one, and the phenotype of the patient was milder as observed in a patient with missense mutation.

A case of systemic pseudohypoaldosteronism with a novel mutation in the SCNN1A gene

We report a neonatal case of systemic pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene (homozygous c.1052+2dupT in intron 3) in which the patient presented with life-threatening hyperkalemia, hyponatremia and metabolic acidosis. It remains uncertain if there is genotype-phenotype correlation, due to the rarity of the disease. This mutation, which to our best knowledge has not been described before, was associated with a very severe phenotype requiring aggressive therapy.

Miliaire rouge et pseudo hypoaldostéronémisme de type 1b de révélation néonatale

The term "miliaria" is used to describe a group of highly transient skin disorders in the newborn characterized by eccrine duct obstruction and the passage of sweat into the epidermis and papillary dermis. This rash in the susceptible skin of the neonate is brought on by heat and confined environments. Our paper reports several episodes of pustular miliaria rubra associated with salt loss crises in a newborn with systemic pseudohypoaldosteronism type 1b (PHA). Since the first days of life, the child presented severe and diffuse miliaria comprising many disseminated pustules associated with salt loss syndrome. Pseudohypoaldosteronism type 1b was readily diagnosed on the basis of aldosterone, sodium and chloride levels in sweat, saliva and in feces. The course was characterized by chronicity and flares simultaneously with salt loss. Associated pseudohypoaldosteronism type 1b/red miliaria is not fortuitous with this in fact being the second case reported in the literature. Obstruction of the eccrine ducts and pustular exanthema were probably due to abnormal Na+ levels in sweat.

Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome

Cystic fibrosis (CF) is an autosomal recessive disorder of Cl(-) and Na(+) transport. The vast majority of CF patients have deleterious mutations in an epithelial Cl(-) channel called the CF transmembrane conductance regulator (CFTR). In contrast, defects in the epithelial Na(+) channel (SCNN1) have been associated with phenotypes dominated by renal disease (systemic pseudohypoaldosteronism type I and Liddle syndrome). We report two non-classic CF patients without CFTR mutations who have novel deleterious mutations in the beta-subunits of SCNN1 in the absence of overt renal disease.

Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism.

Active sodium absorption is the dominant mechanism of ion transport in airway epithelium, but its role in pulmonary physiology and airway host defense is unknown. To address this question, we studied the function of airway epithelial cells and determined the frequency of pulmonary symptoms in patients with systemic pseudohypoaldosteronism, a salt-losing disorder caused by loss-of-function mutations in the genes for the epithelial sodium channel. In nine patients 1.5 to 22 years of age who had systemic pseudohypoaldosteronism, we tested for mutations in the genes for the epithelial sodium channel, estimated the rate of sodium transport in the airway, determined the volume and ion composition of airway surface liquid, reviewed clinical features, collected laboratory data pertinent to pulmonary function, and, in three adults, measured mucociliary clearance. The patients with systemic pseudohypoaldosteronism had loss-of-function mutations in the genes for the epithelial sodium-channel subunits, no sodium absorption from airway surfaces, and a volume of airway surface liquid that was more than twice the normal value. The mean (+/-SE) mucociliary transport rate was higher in the 3 adult patients than in 12 normal subjects (2.0+/-0.7 vs. 0.5+/-0.3 percent per minute, P=0.009). Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa. Older patients (those more than five years of age) had less frequent respiratory symptoms. Patients with systemic pseudohypoaldosteronism fail to absorb liquid from airway surfaces; the result is an increased volume of liquid in the airways. These results demonstrate that sodium transport has a role in regulating the volume of liquid on airway surfaces.