Pseudohypoaldosteronism Type IB3 Autosomal Recessive

Mendelian MONDO:0859318 Pathograph 30 Show in embeddings browser Pseudohypoaldosteronism type 1 Autosomal recessive disease

Pseudohypoaldosteronism type IB3 (PHA1B3) is the SCNN1G-related form of autosomal recessive, systemic (multi-organ) pseudohypoaldosteronism type 1. Biallelic loss-of-function variants in SCNN1G, which encodes the gamma subunit of the amiloride-sensitive epithelial sodium channel (ENaC), abolish or reduce channel activity in aldosterone-responsive epithelia. Failure of ENaC-mediated sodium reabsorption in the distal nephron causes renal salt wasting, volume depletion and failure of potassium and hydrogen ion secretion, so affected infants present in the first weeks of life with vomiting, poor feeding, dehydration, life-threatening hyperkalemia and metabolic acidosis despite high renin and aldosterone and no response to mineralocorticoid therapy. Extra-renal ENaC loss adds salt loss through sweat and colon, and skin and airway manifestations are reported in systemic PHA1. Severe disease follows splice-site, frameshift and gross-deletion alleles, while at least one hypomorphic missense allele (p.Gly532Ser) produced a mild, salt-responsive course. Treatment is lifelong sodium chloride, alkali and potassium control; dietary potassium restriction reduces urinary sodium loss. The SCNN1A (PHA1B1) and SCNN1B (PHA1B2) forms share the mechanism and are separate MONDO concepts.

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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic (homozygous or compound heterozygous) SCNN1G loss-of-function variants. Most reported families are consanguineous, and a 318-1G>A splice-site allele shared by three families from the Indian subcontinent sits on a common haplotype consistent with a founder variant.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:41275343 SUPPORT Human clinical
"Systemic pseudohypoaldosteronism type 1(PHA1) is a rare, autosomal recessive disorder resulting from loss-of-function mutations in epithelial sodium channel subunit genes."
States the autosomal recessive inheritance of systemic PHA1, in a report of a homozygous SCNN1G deletion.
PMID:27485500 SUPPORT Human clinical
"One girl showed autosomal recessive PHA1 related to compound heterozygosity for two variants in intron eight of the SCNN1G gene (c.1294 + 5G > A e c.1295-10 T > A)."
Compound heterozygous SCNN1G splice variants in a girl with autosomal recessive PHA1.
PMID:8640238 SUPPORT Human clinical
"They share a common haplotype which suggests the presence of a founder mutation in this sub-population."
The three families carrying the SCNN1G 318-1G>A allele share a haplotype, consistent with a founder variant.
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Pathophysiology

8
Biallelic SCNN1G loss of function
Biallelic splice-site, frameshift, deletion or missense SCNN1G variants remove or impair the ENaC gamma subunit. The 318-1G>A allele produces two aberrant transcripts, one predicting a protein truncated from 649 to 134 amino acids. The hypomorphic p.Gly532Ser allele reduces but does not abolish channel expression and activity, which matches its milder phenotype.
SCNN1G hgnc:10602 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCNN1G (hgnc:10602). hgnc:10602 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
epithelial sodium channel activity GO:0005272 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased epithelial sodium channel activity, annotated with sodium channel activity (GO:0005272). GO:0005272 is a molecular function from the Gene Ontology.
Downstream
Distal nephron ENaC sodium reabsorption failure
Sweat duct sodium reabsorption failure
Airway epithelial sodium absorption failure
Colonic sodium absorption failure
Show evidence (2 references)
PMID:8640238 SUPPORT Human clinical
"Abnormal splicing results with the production of two messenger RNAs, one arising from activation of an adjacent cryptic splice site and the other from skipping of the downstream exon."
The founding SCNN1G splice variant disrupts normal splicing of the gamma subunit transcript.
PMID:40969802 SUPPORT In vitro / ex vivo
"This analysis showed that the γG532S mutation reduced, but did not suppress ENaC expression and activity."
Heterologous expression shows the gamma G532S variant lowers ENaC expression and current.
Distal nephron ENaC sodium reabsorption failure
In principal cells of the aldosterone-sensitive distal nephron and collecting duct, ENaC provides the rate-limiting apical step of sodium reabsorption. Without a functional gamma subunit, aldosterone cannot drive sodium reabsorption, producing end-organ mineralocorticoid resistance and urinary salt wasting.
kidney collecting duct principal cell CL:1001431 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney collecting duct principal cell (CL:1001431). CL:1001431 is a cell type from the Cell Ontology.
renal sodium ion absorption GO:0070294 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased renal sodium ion absorption (GO:0070294). GO:0070294 is a biological process from the Gene Ontology.
collecting duct UBERON:0001232 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in collecting duct, annotated with collecting duct of renal tubule (UBERON:0001232). UBERON:0001232 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
gammaENaC-deficient mouse Mouse recapitulates Reproduces renal sodium wasting and hyperkalemia of human neonatal PHA1.
Downstream
Renal salt wasting
Extracellular volume depletion
Impaired distal potassium and hydrogen ion secretion
Show evidence (2 references)
PMID:9788978 SUPPORT Model organism
"died between 24 and 36 h, probably from hyperkalemia (gammaENaC -/- 18.3 mEq/l, control littermates 9.7 mEq/l)."
gammaENaC-null mice waste sodium and retain potassium in urine.
PMID:29371419 SUPPORT Model organism
"Nephron-specific γENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia."
Renal gammaENaC deletion alone is sufficient for salt wasting and hyperkalemia.
Impaired distal potassium and hydrogen ion secretion
Loss of electrogenic sodium entry through ENaC removes the lumen-negative driving force for potassium and hydrogen ion secretion in the distal nephron, so potassium and acid are retained. In nephron-specific gammaENaC knockout mice hyperkalemia is severe and, unlike alpha or beta subunit deletion, is not corrected by a high-sodium low-potassium diet, only by removing potassium from the diet.
kidney collecting duct principal cell CL:1001431 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney collecting duct principal cell (CL:1001431). CL:1001431 is a cell type from the Cell Ontology.
renal potassium excretion GO:0036359 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased renal potassium excretion (GO:0036359). GO:0036359 is a biological process from the Gene Ontology.
Animal models
Adult nephron-specific gammaENaC knockout mouse Mouse recapitulates Reproduces severe hyperkalemia from loss of renal gammaENaC.
Downstream
Hyperkalemia
Metabolic acidosis
Show evidence (2 references)
PMID:19571553 SUPPORT REVIEW SYNTHESIS Other
"Pseudohypoaldosteronism (PHA) is a rare heterogeneous syndrome of mineralocorticoid resistance causing insufficient potassium and hydrogen secretion."
Mineralocorticoid resistance in PHA causes insufficient potassium and hydrogen secretion.
PMID:29371419 SUPPORT Model organism
"Unlike mice lacking αENaC or βΕΝaC, an HNa+/LK+ diet did not normalize plasma potassium (K+) concentration or increase NCC activation."
Hyperkalemia after renal gammaENaC loss resists the dietary rescue that works for the other subunits.
Extracellular volume depletion
Renal, colonic and sweat sodium loss depletes the extracellular fluid compartment, causing hyponatremic dehydration, hypovolemia and, in severe crises, hypotension and shock.
sodium ion homeostasis GO:0055078 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal sodium ion homeostasis (GO:0055078). GO:0055078 is a biological process from the Gene Ontology.
Downstream
Hyponatremia
Dehydration
Hypotension
Compensatory renin-angiotensin-aldosterone activation
Failure to thrive in infancy
Show evidence (2 references)
PMID:40969802 SUPPORT Human clinical
"Pseudohypoaldosteronism type 1 (PHA-1) is a rare genetic disease caused by aldosterone resistance, characterized by severe sodium loss, hyperkalemia, dehydration, and vomiting."
Sodium loss with dehydration characterizes PHA1.
PMID:31900739 SUPPORT Human clinical
"reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity."
Documents volume depletion with raised renin in a patient with SCNN1G variants, reversed when urinary sodium loss fell.
Compensatory renin-angiotensin-aldosterone activation
Volume depletion strongly stimulates renin secretion and aldosterone synthesis, but the elevated aldosterone cannot act through the defective channel, so plasma renin and aldosterone remain high.
regulation of blood volume by renin-angiotensin GO:0002016 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased regulation of blood volume by renin-angiotensin (GO:0002016). GO:0002016 is a biological process from the Gene Ontology.
Downstream
Increased circulating renin concentration
Increased circulating aldosterone concentration
Show evidence (1 reference)
ORPHA:171876 SUPPORT Other
"Presentation is in the first few weeks of life with severe dehydration, vomiting and failure to thrive in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels."
Elevated renin and aldosterone are part of the presenting picture of generalized PHA1.
Sweat duct sodium reabsorption failure
ENaC in the eccrine sweat duct reabsorbs sodium from primary sweat. In systemic PHA1 the ducts lack ENaC conductance, so sweat salt absorption is blocked although CFTR chloride conductance is preserved, giving high sweat sodium and chloride.
epithelial cell of sweat gland CL:1000448 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epithelial cell of sweat gland (CL:1000448). CL:1000448 is a cell type from the Cell Ontology.
sodium ion transmembrane transport GO:0035725 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sodium ion transmembrane transport (GO:0035725). GO:0035725 is a biological process from the Gene Ontology.
sweat gland UBERON:0001820 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in sweat gland (UBERON:0001820). UBERON:0001820 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Elevated sweat chloride
Extracellular volume depletion
Show evidence (1 reference)
PMID:15986094 SUPPORT INDIRECT In vitro / ex vivo
"Lack of gENaC completely blocked salt absorption and caused dramatic reversal of skin potentials associated with pilocarpine-induced sweat secretion"
Ex vivo sweat ducts from systemic PHA1 patients show no ENaC conductance and no salt absorption; the study does not report which subunit gene was affected.
Colonic sodium absorption failure
ENaC mediates amiloride-sensitive sodium absorption in distal colon epithelium; its loss adds intestinal salt loss to the renal deficit.
colon epithelial cell CL:0011108 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves colon epithelial cell (CL:0011108). CL:0011108 is a cell type from the Cell Ontology.
sodium ion transmembrane transport GO:0035725 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sodium ion transmembrane transport (GO:0035725). GO:0035725 is a biological process from the Gene Ontology.
colon UBERON:0001155 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in colon (UBERON:0001155). UBERON:0001155 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Extracellular volume depletion
Show evidence (1 reference)
ORPHA:171876 SUPPORT Other
"A severe form of pseudohypoaldosteronism type 1 characterized by salt wasting in multiple organs including the kidney, colon, and sweat and salivary glands."
Orphanet defines generalized PHA1 by salt wasting from kidney, colon, sweat and salivary glands.
Airway epithelial sodium absorption failure
Airway ENaC absorbs sodium and liquid from the airway surface. Patients with systemic PHA1 have no airway sodium absorption, more than double the normal airway surface liquid volume, and recurrent chest congestion, coughing and wheezing in early childhood. These data come from cohorts with ENaC subunit mutations generally. gammaENaC-null mice clear neonatal lung liquid more slowly than controls but reach nearly normal lung water, so the gamma subunit facilitates but is not essential for perinatal lung liquid clearance.
bronchial epithelial cell CL:0002328 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves bronchial epithelial cell (CL:0002328). CL:0002328 is a cell type from the Cell Ontology.
sodium ion transmembrane transport GO:0035725 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sodium ion transmembrane transport (GO:0035725). GO:0035725 is a biological process from the Gene Ontology.
respiratory airway UBERON:0001005 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in respiratory airway (UBERON:0001005). UBERON:0001005 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
gammaENaC-deficient mouse Mouse partially recapitulates Neonatal lung liquid clearance is slowed but lung water nearly normalizes by 12 hours.
Downstream
Wheezing
Cough
Recurrent upper and lower respiratory tract infections
Show evidence (2 references)
PMID:10403853 SUPPORT INDIRECT Human clinical
"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."
Systemic PHA1 patients lack airway sodium absorption and have excess airway surface liquid; the cohort is not restricted to SCNN1G.
PMID:9788978 SUPPORT Model organism
"Newborn gammaENaC (-/-) mice cleared lung liquid more slowly than control littermates, but lung water at 12 h (wet/dry = 5.5) was nearly normal (wet/dry = 5.3)."
Loss of gammaENaC slows neonatal lung liquid clearance in mice, though lung water nearly normalizes.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Pseudohypoaldosteronism Type IB3 Autosomal Recessive Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

17
Cardiovascular 2
Hypotension HP:0002615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotension (HP:0002615). HP:0002615 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34258491 SUPPORT Human clinical
"All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension."
Hypotension at presentation in a PHA1B cohort that included SCNN1G siblings.
Cardiac arrest HP:0001695 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac arrest (HP:0001695). HP:0001695 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33690157 SUPPORT Human clinical
"Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia."
Hyperkalemic cardiac arrest in a series of SCNN1A and SCNN1G patients.
Digestive 1
Vomiting FREQUENT HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34258491 SUPPORT Human clinical
"All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension."
Vomiting at presentation in a PHA1B cohort that included SCNN1G siblings.
ORPHA:171876 SUPPORT Other
"HP:0002013 | Vomiting | Frequent (79-30%)"
Orphanet records vomiting as frequent.
Endocrine 2
Increased circulating renin concentration VERY_FREQUENT HP:0000848 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating renin concentration (HP:0000848). HP:0000848 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:171876 SUPPORT Other
"HP:0000848 | Increased circulating renin level | Very frequent (99-80%)"
Orphanet records elevated renin as very frequent.
Increased circulating aldosterone concentration HP:0000859 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating aldosterone concentration (HP:0000859). HP:0000859 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:171876 SUPPORT Other
"Presentation is in the first few weeks of life with severe dehydration, vomiting and failure to thrive in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels."
Elevated aldosterone is part of the presenting picture of generalized PHA1.
Genitourinary 1
Renal salt wasting HP:0000127 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal salt wasting (HP:0000127). HP:0000127 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31900739 SUPPORT Human clinical
"reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity."
Urinary sodium wasting in a patient with SCNN1G variants, reduced by potassium restriction.
Head and Neck 1
Recurrent upper and lower respiratory tract infections FREQUENT HP:0200117 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent upper and lower respiratory tract infections (HP:0200117). HP:0200117 is a phenotype from the Human Phenotype Ontology.
The Orphanet frequency applies to generalized PHA1 across ENaC genes.
Show evidence (1 reference)
ORPHA:171876 SUPPORT Other
"HP:0200117 | Recurrent upper and lower respiratory tract infections | Frequent (79-30%)"
Orphanet records recurrent respiratory tract infections as frequent in generalized PHA1.
Immune 1
Eczematous skin lesions Eczematoid dermatitis HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eczematous skin lesions, annotated with Eczematoid dermatitis (HP:0000964). HP:0000964 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41275343 SUPPORT Human clinical
"The case presented to our center with persistent electrolyte imbalances and treatment-resistant eczematous skin lesions."
Persistent eczematous lesions in a homozygous SCNN1G deletion patient.
Metabolism 5
Hyponatremia VERY_FREQUENT HP:0002902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyponatremia (HP:0002902). HP:0002902 is a phenotype from the Human Phenotype Ontology.
Sequelae: Seizure
Show evidence (3 references)
PMID:33690157 SUPPORT Human clinical
"All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia."
All patients in a series including SCNN1G cases presented with hyponatremia.
PMID:40969802 SUPPORT Human clinical
"The child presented with failure to thrive, accompanied by mild hyponatremia and hyperkalemia, together with a normal anion gap metabolic acidosis."
Hyponatremia was present even in the mild missense case.
ORPHA:171876 SUPPORT Other
"HP:0002902 | Hyponatremia | Very frequent (99-80%)"
Orphanet records hyponatremia as very frequent.
Hyperkalemia VERY_FREQUENT HP:0002153 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperkalemia (HP:0002153). HP:0002153 is a phenotype from the Human Phenotype Ontology.
Sequelae: Cardiac arrest
Show evidence (3 references)
PMID:33690157 SUPPORT Human clinical
"All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia."
Severe hyperkalemia at presentation in a series including SCNN1G cases.
PMID:9788978 SUPPORT Model organism
"died between 24 and 36 h, probably from hyperkalemia (gammaENaC -/- 18.3 mEq/l, control littermates 9.7 mEq/l)."
gammaENaC-null mice develop lethal hyperkalemia.
ORPHA:171876 SUPPORT Other
"HP:0002153 | Hyperkalemia | Very frequent (99-80%)"
Orphanet records hyperkalemia as very frequent.
Metabolic acidosis VERY_FREQUENT HP:0001942 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metabolic acidosis (HP:0001942). HP:0001942 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40969802 SUPPORT Human clinical
"The child presented with failure to thrive, accompanied by mild hyponatremia and hyperkalemia, together with a normal anion gap metabolic acidosis."
Normal anion gap metabolic acidosis in an SCNN1G missense case.
ORPHA:171876 SUPPORT Other
"HP:0001942 | Metabolic acidosis | Very frequent (99-80%)"
Orphanet records metabolic acidosis as very frequent.
Dehydration FREQUENT HP:0001944 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dehydration (HP:0001944). HP:0001944 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:171876 SUPPORT Other
"HP:0001944 | Dehydration | Frequent (79-30%)"
Orphanet records dehydration as frequent.
PMID:40969802 SUPPORT Human clinical
"Pseudohypoaldosteronism type 1 (PHA-1) is a rare genetic disease caused by aldosterone resistance, characterized by severe sodium loss, hyperkalemia, dehydration, and vomiting."
Dehydration is a characteristic feature of PHA1.
Elevated sweat chloride HP:0012236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated sweat electrolytes (positive sweat test), annotated with Elevated sweat chloride (HP:0012236). HP:0012236 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15986094 SUPPORT INDIRECT In vitro / ex vivo
"Lack of gENaC completely blocked salt absorption and caused dramatic reversal of skin potentials associated with pilocarpine-induced sweat secretion"
Absent sweat duct ENaC conductance in systemic PHA1 raises sweat electrolytes; the study does not name the subunit gene.
Nervous System 1
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyponatremic seizure, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41275343 SUPPORT Human clinical
"At the age of five, the case experienced a febrile seizure, during which laboratory related biochemical tests showed isolated hyponatremia with normokalemia."
Seizure during a hyponatremic episode in an SCNN1G patient.
Respiratory 2
Wheezing OCCASIONAL HP:0030828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wheezing (HP:0030828). HP:0030828 is a phenotype from the Human Phenotype Ontology.
Reported in systemic PHA1 cohorts not restricted to SCNN1G; Orphanet lists it as occasional for generalized PHA1.
Show evidence (2 references)
PMID:10403853 SUPPORT INDIRECT Human clinical
"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."
Recurrent wheezing in young patients with systemic PHA1 from ENaC subunit mutations.
ORPHA:171876 SUPPORT Other
"HP:0030828 | Wheezing | Occasional (29-5%)"
Orphanet records wheezing as occasional.
Cough OCCASIONAL HP:0012735 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cough (HP:0012735). HP:0012735 is a phenotype from the Human Phenotype Ontology.
Reported in systemic PHA1 cohorts not restricted to SCNN1G.
Show evidence (2 references)
PMID:10403853 SUPPORT INDIRECT Human clinical
"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."
Recurrent coughing in young patients with systemic PHA1 from ENaC subunit mutations.
ORPHA:171876 SUPPORT Other
"HP:0012735 | Cough | Occasional (29-5%)"
Orphanet records cough as occasional.
Growth 1
Failure to thrive in infancy FREQUENT HP:0001531 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive in infancy (HP:0001531). HP:0001531 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40969802 SUPPORT Human clinical
"The child presented with failure to thrive, accompanied by mild hyponatremia and hyperkalemia, together with a normal anion gap metabolic acidosis."
Failure to thrive was the presenting feature in an SCNN1G missense case.
ORPHA:171876 SUPPORT Other
"HP:0001531 | Failure to thrive in infancy | Frequent (79-30%)"
Orphanet records failure to thrive in infancy as frequent.
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Genetic Associations

1
SCNN1G (Causative (biallelic loss of function))
Gene: SCNN1G hgnc:10602 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCNN1G (hgnc:10602). hgnc:10602 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (6 references)
PMID:8640238 SUPPORT Human clinical
"We now report the identification of a 3' splice site mutation in SCNN1G (318-1 G-->A) in three families showing linkage to 16p."
First identification of an SCNN1G variant in recessive PHA1.
ORPHA:171876 SUPPORT Other
"SCNN1G | sodium channel epithelial 1 subunit gamma | hgnc:10602 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists germline loss-of-function SCNN1G variants as disease-causing.
PMID:34258491 SUPPORT Human clinical
"an SCNN1G deletion mutation c.527_528 delCA, p.T176Rfs*9 (novel) in 2 siblings from another Omani family."
Homozygous SCNN1G frameshift variant in two siblings with PHA1B.
+ 3 more references
💊

Medical Actions

5
High-dose sodium chloride supplementation
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium chloride CHEBI:26710 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium chloride (CHEBI:26710). CHEBI:26710 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Lifelong oral sodium chloride replacement is the mainstay of therapy for the systemic form. The hypomorphic p.Gly532Ser patient responded to sodium chloride alone.
Mechanism Target:
Extracellular volume depletion — Replaces renal and extra-renal sodium losses.
Show evidence (3 references)
PMID:40969802 SUPPORT Human clinical
"In our case, the patient showed a positive clinical response to sodium chloride supplementation alone."
Sodium chloride supplementation alone controlled the mild SCNN1G missense case.
PMID:42549990 SUPPORT Human clinical
"Six patients (67%) died, mainly due to sepsis (n = 2) or treatment discontinuation (n = 4), while three remain stable on oral sodium supplementation."
Survivors in a PHA1B series including SCNN1G patients remain stable on oral sodium, and stopping treatment was a major cause of death.
PMID:17546235 SUPPORT REVIEW SYNTHESIS Other
"The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary."
Review states that systemic PHA1 requires high-dose salt supplementation.
Dietary potassium restriction
Category: Therapeutic Action: Dietary potassium restrictionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary potassium restriction, annotated with Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
Lowering dietary potassium reduces urinary sodium loss and restores volume. The proposed explanation is that low plasma potassium activates WNK signalling in the distal convoluted tubule, so the thiazide-sensitive NaCl cotransporter and pendrin take over sodium reabsorption from the non-functional ENaC. In nephron-specific gammaENaC knockout mice only removal of dietary potassium prevented hyperkalemia and weight loss.
Mechanism Target:
Impaired distal potassium and hydrogen ion secretion — Limits the potassium load the distal nephron cannot excrete.
Extracellular volume depletion — Recruits compensatory distal convoluted tubule sodium reabsorption.
Show evidence (3 references)
PMID:31900739 SUPPORT Human clinical
"reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity."
Potassium restriction corrected volume depletion and sodium wasting in a patient with SCNN1G variants.
PMID:31900739 SUPPORT Human clinical
"Thus, potassium restriction causes NCC and pendrin to compensate for the non-functional ENaC in the collecting duct."
Proposed mechanism by which potassium restriction compensates for absent ENaC.
PMID:29371419 SUPPORT Model organism
"However, when K+ was eliminated from the diet at the time that γENaC was deleted, plasma K+ concentration and NCC activity remained normal, and progressive weight loss was prevented."
Removing dietary potassium prevents the PHA1 phenotype after renal gammaENaC deletion in mice.
Sodium bicarbonate
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium bicarbonate NCIT:C29457 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses sodium bicarbonate (NCIT:C29457). NCIT:C29457 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Alkali therapy to correct metabolic acidosis while also supplying sodium.
Mechanism Target:
Metabolic acidosis — Buffers retained acid.
Show evidence (1 reference)
PMID:26807262 SUPPORT INDIRECT Human clinical
"High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
Sodium bicarbonate is part of symptomatic treatment of systemic PHA1; this report concerns the SCNN1B form, which shares the mechanism.
Potassium-binding resin
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium polystyrene sulfonate NCIT:C29461 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses sodium polystyrene sulfonate (NCIT:C29461). NCIT:C29461 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Cation-exchange resins such as sodium polystyrene sulfonate increase fecal potassium excretion to control chronic hyperkalemia.
Mechanism Target:
Hyperkalemia — Removes retained potassium through the gut.
Show evidence (1 reference)
PMID:26807262 SUPPORT INDIRECT Human clinical
"High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
Sodium polystyrene sulfonate is part of symptomatic treatment of systemic PHA1; this report concerns the SCNN1B form, which shares the mechanism.
Mineralocorticoid and glucocorticoid replacement
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: fludrocortisone CHEBI:50885 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses fludrocortisone (CHEBI:50885). CHEBI:50885 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Hydrocortisone and fludrocortisone are often started empirically for suspected salt-wasting adrenal disease but do not correct the electrolyte disturbance, because the defect lies in the target channel rather than in hormone supply. Failure to respond helps distinguish PHA1 from congenital adrenal hyperplasia.
Show evidence (1 reference)
PMID:34165441 REFUTE Human clinical
"A child presenting with features that mimic salt-losing congenital adrenal hyperplasia (CAH) crises that do not respond to glucocorticoid and mineralocorticoid therapy should alert the pediatricians to the possibility of end-organ resistance to aldosterone."
Salt-losing crises in end-organ aldosterone resistance do not respond to glucocorticoid and mineralocorticoid therapy.
🔬

Diagnosis

2
Biochemical and hormonal profile
Neonatal hyponatremia, hyperkalemia and metabolic acidosis with high plasma renin and aldosterone, after exclusion of congenital adrenal hyperplasia and other adrenal causes, suggest PHA1. The renal and systemic forms cannot be told apart by early presentation or by this profile.
Show evidence (2 references)
PMID:27485500 SUPPORT Human clinical
"PHA is characterised by the renal tubular unresponsiveness to aldosterone and presents with hyponatremia, hyperkalaemia and metabolic acidosis with elevated plasma aldosterone and renin concentrations, but normal levels of ACTH and cortisol [3]."
The biochemical and hormonal profile that points to PHA among infant salt-wasting disorders.
PMID:31301676 SUPPORT Human clinical
"It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile."
The biochemical profile does not separate renal from systemic PHA1.
Molecular genetic testing of ENaC subunit genes
Sequencing of SCNN1A, SCNN1B and SCNN1G (with NR3C2 for the renal form), usually by exome sequencing, confirms the diagnosis and assigns the subtype; biallelic SCNN1G variants define PHA1B3. Copy-number analysis is needed when sequencing is negative, because an intragenic SCNN1G deletion was missed by sequencing and found by chromosomal microarray.
Genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:31301676 SUPPORT Human clinical
"We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b."
Genetic testing is needed to distinguish PHA1A from PHA1B.
PMID:41275343 SUPPORT Human clinical
"Initial sequencing of PHA1-associated genes (SCNN1A, SCNN1B, and SCNN1G) did not reveal any pathogenic variants."
Sequencing alone missed a homozygous SCNN1G exon deletion.
PMID:41275343 SUPPORT Human clinical
"This case expands the phenotypic and genotypic spectrum of systemic PHA1 and emphasizes the importance of considering copy number variants in genetically unresolved cases of PHA1, especially those presenting with atypical electrolyte profiles and extrarenal manifestations such as persistent eczema."
Copy-number analysis should be considered when sequencing is unrevealing.
📈

Progression

2
Neonatal salt-wasting presentation
Age: First weeks of life
Presentation is typically within the first two weeks of life with vomiting, poor feeding, weight loss and dehydration, accompanied by hyponatremia, hyperkalemia and metabolic acidosis. A hypomorphic missense allele presented later, at four months, with failure to gain weight and mild electrolyte changes.
Show evidence (3 references)
ORPHA:171876 SUPPORT Other
"Presentation is in the first few weeks of life with severe dehydration, vomiting and failure to thrive in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels."
Orphanet describes neonatal onset of the salt-wasting presentation.
PMID:33690157 SUPPORT Human clinical
"All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia."
In a series of SCNN1A and SCNN1G patients, all presented within two weeks of birth.
PMID:40969802 SUPPORT Human clinical
"The present investigation is a case study of a 4-month-old female born to consanguineous parents with symptoms suggestive of a form of PHA-1."
A hypomorphic SCNN1G missense allele presented at four months rather than in the neonatal period.
Chronic course with recurrent salt-losing crises
Age: Infancy to adulthood
The systemic form does not remit; lifelong treatment is needed and salt-losing crises recur, especially with intercurrent illness. Mortality and post-arrest neurological injury are substantial in case series, but survival into adulthood with a successful pregnancy has been reported. A homozygous SCNN1G deletion patient had a seizure with hyponatremia in the fifth year of treatment.
Show evidence (5 references)
ORPHA:171876 SUPPORT Other
"No remission is reported and patients suffer from recurrent life-threatening episodes of salt loss."
Orphanet describes a non-remitting course with recurrent crises.
PMID:17546235 SUPPORT REVIEW SYNTHESIS Other
"The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent."
Review describes the lifelong recurrent course of systemic PHA1.
PMID:33690157 SUPPORT Human clinical
"Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia."
High mortality and post-arrest morbidity in a series of SCNN1A and SCNN1G patients.
+ 2 more references
📊

Prevalence

1
United Kingdom
Prevalence at birth 1–9 per 1,000,000 (births)
Orphanet birth-prevalence class 1-9 / 1,000,000 for generalized PHA1 across all ENaC subunit genes. No SCNN1G-specific figure is available; SCNN1G accounts for a minority of systemic PHA1 families.
Show evidence (3 references)
ORPHA:171876 SUPPORT Other
"1-9 / 1 000 000 | United Kingdom | Prevalence at birth | PMID:24616761"
Orphanet epidemiology row for generalized PHA1.
PMID:15853823 SUPPORT Human clinical
"Most of the PHA-causing mutations appear in the alphaENaC gene located on chromosome 12 rather than in the beta and gammaENaC genes located tandemly on chromosome 16."
Gamma subunit variants account for fewer multisystem PHA cases than alpha subunit variants.
PMID:34258491 SUPPORT Human clinical
"We found a total of 8 mutations in 13 families as follows: 6 mutations in SCNN1A, 1 in SCNN1B, and 1 in SCNN1G."
In a Gulf PHA1B series only one of 13 families carried an SCNN1G variant.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Pseudohypoaldosteronism Type IB3 Autosomal Recessive:

Congenital adrenal hyperplasia
Overlapping Features Salt-wasting congenital adrenal hyperplasia produces the same neonatal hyponatremia, hyperkalemia and acidosis and is often considered first.
Distinguishing Features
  • Normal cortisol and 17-hydroxyprogesterone with high aldosterone in PHA1
  • No response to glucocorticoid and mineralocorticoid replacement in PHA1
Show evidence (2 references)
PMID:34165441 SUPPORT Human clinical
"The classical presentation is life-threatening neonatal/infantile salt-losing crises that mimic congenital adrenal hyperplasia (CAH)."
Systemic PHA1 crises mimic salt-wasting CAH.
PMID:27485500 SUPPORT Human clinical
"PHA is characterised by the renal tubular unresponsiveness to aldosterone and presents with hyponatremia, hyperkalaemia and metabolic acidosis with elevated plasma aldosterone and renin concentrations, but normal levels of ACTH and cortisol [3]."
Normal ACTH and cortisol separate PHA from adrenal causes of infant salt wasting.
Autosomal dominant pseudohypoaldosteronism type 1 Not Yet Curated MONDO:0008329
Overlapping Features Renal PHA1A from heterozygous NR3C2 variants causes a milder kidney-limited salt-wasting syndrome that remits with age. The mild SCNN1G p.Gly532Ser phenotype was reminiscent of PHA1A, so genotype is needed to separate them.
Distinguishing Features
  • Kidney-limited salt loss with normal sweat electrolytes in renal PHA1A
  • Improvement with age in renal PHA1A versus lifelong treatment in systemic PHA1B
Show evidence (2 references)
PMID:31301676 SUPPORT Human clinical
"Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA."
Prognosis is worse in multisystem PHA1B than in NR3C2-related renal PHA1A.
PMID:40969802 SUPPORT Human clinical
"The mild phenotype exhibited by the infant was reminiscent of PHA-1A, with the symptoms easily managed with low-dose salt supplementation."
A hypomorphic SCNN1G allele can mimic the renal form clinically.
Pseudohypoaldosteronism type IB2 autosomal recessive MONDO:0859317
Overlapping Features The SCNN1B form of systemic PHA1 is clinically indistinguishable and is separated only by molecular testing.
Distinguishing Features
  • Biallelic SCNN1B rather than SCNN1G variants
Show evidence (1 reference)
PMID:19571553 SUPPORT REVIEW SYNTHESIS Other
"This review provides an overview on transepithelial sodium reabsorption and on clinical features and the underlying molecular pathology of systemic and renal PHA1 caused by mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G) of the epithelial sodium channel (ENaC) and the mineralocorticoid..."
Systemic PHA1 arises from variants in any of the three ENaC subunit genes.
Early-onset familial hypoaldosteronism MONDO:0035320
Overlapping Features Aldosterone synthase deficiency also causes infantile salt wasting with hyponatremia, hyperkalemia and high renin, but aldosterone is low to normal.
Distinguishing Features
  • Low to normal aldosterone in aldosterone synthase deficiency versus high aldosterone in PHA1
  • Response to fludrocortisone in aldosterone synthase deficiency
Show evidence (1 reference)
PMID:41905953 SUPPORT REVIEW SYNTHESIS Other
"ASD must also be differentiated from another disease, pseudohypoaldosteronism type 1 (PHA1), which involves resistance to aldosterone."
Names PHA1 and aldosterone synthase deficiency as mutual differential diagnoses.
Secondary (transient) pseudohypoaldosteronism
Overlapping Features Transient renal aldosterone resistance from urinary tract infection or urinary tract anomalies produces renal salt loss, hyponatremia, hyperkalemia and high aldosterone in early infancy.
Distinguishing Features
  • Urinary tract infection or obstructive anomaly on urine culture and renal imaging
  • Resolution after treatment of the underlying cause
Show evidence (1 reference)
PMID:22397047 SUPPORT Human clinical
"Secondary pseudohypoaldosteronism type 1 develops due to transient aldosterone resistance in renal tubules and is characterized by renal sodium loss, hyponatremia, hyperkalemia and high plasma aldosterone levels."
Secondary PHA reproduces the biochemical picture of PHA1.
🐁

Animal Models

2
gammaENaC-deficient mouse
Germline disruption of the gamma subunit gene produces urinary sodium loss and potassium retention with lethal hyperkalemia between 24 and 36 hours after birth, and slower but largely completed neonatal lung liquid clearance.
Species
Mouse
Genotype
Scnn1g-/- (germline targeted disruption)
Publication
PMID:9788978
Pathograph links
Distal nephron ENaC sodium reabsorption failure recapitulates fidelity: high observes: organism Reproduces renal sodium wasting and hyperkalemia of human neonatal PHA1.
Limitations: Mice die within 36 hours of birth, so the chronic course, extra-renal salt loss and response to salt supplementation cannot be studied in this germline model.
Show evidence (1 reference)
PMID:9788978 SUPPORT Model organism
"The gammaENaC (-/-) newborn exhibits a phenotype that resembles the clinical manifestations of human neonatal PHA1."
The authors state the knockout phenotype resembles human neonatal PHA1.
Airway epithelial sodium absorption failure partially recapitulates fidelity: low observes: organism Neonatal lung liquid clearance is slowed but lung water nearly normalizes by 12 hours.
Limitations: Only the neonatal transition to air breathing was assessed; chronic airway surface liquid and mucociliary function, which carry the human airway phenotype, could not be measured because the mice die within 36 hours.
Show evidence (1 reference)
PMID:9788978 SUPPORT Model organism
"Newborn gammaENaC (-/-) mice cleared lung liquid more slowly than control littermates, but lung water at 12 h (wet/dry = 5.5) was nearly normal (wet/dry = 5.3)."
Lung liquid clearance is slowed but nearly completed without gammaENaC.
Adult nephron-specific gammaENaC knockout mouse
Inducible deletion of gammaENaC in the adult nephron produces salt wasting with severe hyperkalemia that, unlike alpha or beta subunit deletion, is not corrected by a high-sodium low-potassium diet but is prevented by a potassium-free diet.
Species
Mouse
Genotype
Scnn1g inducible nephron-specific knockout
Publication
PMID:29371419
Pathograph links
Impaired distal potassium and hydrogen ion secretion recapitulates fidelity: moderate observes: organism Reproduces severe hyperkalemia from loss of renal gammaENaC.
Limitations: Adult induction bypasses the neonatal presentation of the human disease, and the model lacks the extra-renal ENaC loss of systemic PHA1B3.
Show evidence (1 reference)
PMID:29371419 SUPPORT Model organism
"Nephron-specific γENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia."
Renal gammaENaC deletion causes salt wasting and severe hyperkalemia.
{ }

Source YAML

click to show 
name: Pseudohypoaldosteronism Type IB3 Autosomal Recessive
category: Mendelian
creation_date: "2026-10-30T10:37:47Z"
synonyms:
- PHA1B3
- Autosomal recessive pseudohypoaldosteronism type 1B3
- SCNN1G-related systemic pseudohypoaldosteronism type 1
- Systemic pseudohypoaldosteronism type 1 due to SCNN1G deficiency
description: >-
  Pseudohypoaldosteronism type IB3 (PHA1B3) is the SCNN1G-related form of
  autosomal recessive, systemic (multi-organ) pseudohypoaldosteronism type 1.
  Biallelic loss-of-function variants in SCNN1G, which encodes the gamma
  subunit of the amiloride-sensitive epithelial sodium channel (ENaC), abolish
  or reduce channel activity in aldosterone-responsive epithelia. Failure of
  ENaC-mediated sodium reabsorption in the distal nephron causes renal salt
  wasting, volume depletion and failure of potassium and hydrogen ion
  secretion, so affected infants present in the first weeks of life with
  vomiting, poor feeding, dehydration, life-threatening hyperkalemia and
  metabolic acidosis despite high renin and aldosterone and no response to
  mineralocorticoid therapy. Extra-renal ENaC loss adds salt loss through sweat
  and colon, and skin and airway manifestations are reported in systemic PHA1.
  Severe disease follows splice-site, frameshift and gross-deletion alleles,
  while at least one hypomorphic missense allele (p.Gly532Ser) produced a mild,
  salt-responsive course. Treatment is lifelong sodium chloride, alkali and
  potassium control; dietary potassium restriction reduces urinary sodium loss.
  The SCNN1A (PHA1B1) and SCNN1B (PHA1B2) forms share the mechanism and are
  separate MONDO concepts.
disease_term:
  preferred_term: pseudohypoaldosteronism, type IB3, autosomal recessive
  term:
    id: MONDO:0859318
    label: pseudohypoaldosteronism, type IB3, autosomal recessive
parents:
- Pseudohypoaldosteronism type 1
- Autosomal recessive disease
notes: >-
  SCNN1G is the least often mutated of the three ENaC subunit genes in systemic
  PHA1, and the published SCNN1G cases are scattered single families. The
  Orphanet record cited here (ORPHA:171876, generalized pseudohypoaldosteronism
  type 1) covers all three ENaC genes, so its phenotype frequencies describe
  systemic PHA1 as a whole rather than the SCNN1G form alone, and the
  frequencies on the phenotypes below are taken from it. Respiratory and sweat
  findings are documented for systemic PHA1 cohorts not restricted to SCNN1G.
  No GeneReviews chapter covers this disorder or systemic PHA1, so case reports,
  case series and Orphanet form the phenotype baseline.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Biallelic (homozygous or compound heterozygous) SCNN1G loss-of-function
    variants. Most reported families are consanguineous, and a 318-1G>A
    splice-site allele shared by three families from the Indian subcontinent
    sits on a common haplotype consistent with a founder variant.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:41275343
    reference_title: "The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Systemic pseudohypoaldosteronism type 1(PHA1) is a rare, autosomal recessive disorder resulting from loss-of-function mutations in epithelial sodium channel subunit genes."
    explanation: States the autosomal recessive inheritance of systemic PHA1, in a report of a homozygous SCNN1G deletion.
  - reference: PMID:27485500
    reference_title: "Congenital primary adrenal insufficiency and selective aldosterone defects presenting as salt-wasting in infancy: a single center 10-year experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One girl showed autosomal recessive PHA1 related to compound heterozygosity for two variants in intron eight of the SCNN1G gene (c.1294 + 5G > A e c.1295-10 T > A)."
    explanation: Compound heterozygous SCNN1G splice variants in a girl with autosomal recessive PHA1.
  - reference: PMID:8640238
    reference_title: "A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They share a common haplotype which suggests the presence of a founder mutation in this sub-population."
    explanation: The three families carrying the SCNN1G 318-1G>A allele share a haplotype, consistent with a founder variant.
prevalence:
- population: United Kingdom
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  notes: >-
    Orphanet birth-prevalence class 1-9 / 1,000,000 for generalized PHA1 across
    all ENaC subunit genes. No SCNN1G-specific figure is available; SCNN1G
    accounts for a minority of systemic PHA1 families.
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | United Kingdom | Prevalence at birth | PMID:24616761"
    explanation: Orphanet epidemiology row for generalized PHA1.
  - reference: PMID:15853823
    reference_title: "Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the PHA-causing mutations appear in the alphaENaC gene located on chromosome 12 rather than in the beta and gammaENaC genes located tandemly on chromosome 16."
    explanation: Gamma subunit variants account for fewer multisystem PHA cases than alpha subunit variants.
  - reference: PMID:34258491
    reference_title: "A Unique Genotype of Pseudohypoaldosteronism Type 1b in a Highly Consanguineous Population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a total of 8 mutations in 13 families as follows: 6 mutations in SCNN1A, 1 in SCNN1B, and 1 in SCNN1G."
    explanation: In a Gulf PHA1B series only one of 13 families carried an SCNN1G variant.
progression:
- phase: Neonatal salt-wasting presentation
  age_range: First weeks of life
  notes: >-
    Presentation is typically within the first two weeks of life with vomiting,
    poor feeding, weight loss and dehydration, accompanied by hyponatremia,
    hyperkalemia and metabolic acidosis. A hypomorphic missense allele presented
    later, at four months, with failure to gain weight and mild electrolyte
    changes.
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Presentation is in the first few weeks of life with severe dehydration, vomiting and failure to thrive in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels."
    explanation: Orphanet describes neonatal onset of the salt-wasting presentation.
  - reference: PMID:33690157
    reference_title: "Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia."
    explanation: In a series of SCNN1A and SCNN1G patients, all presented within two weeks of birth.
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The present investigation is a case study of a 4-month-old female born to consanguineous parents with symptoms suggestive of a form of PHA-1."
    explanation: A hypomorphic SCNN1G missense allele presented at four months rather than in the neonatal period.
- phase: Chronic course with recurrent salt-losing crises
  age_range: Infancy to adulthood
  notes: >-
    The systemic form does not remit; lifelong treatment is needed and
    salt-losing crises recur, especially with intercurrent illness. Mortality
    and post-arrest neurological injury are substantial in case series, but
    survival into adulthood with a successful pregnancy has been reported. A
    homozygous SCNN1G deletion patient had a seizure with hyponatremia in the
    fifth year of treatment.
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "No remission is reported and patients suffer from recurrent life-threatening episodes of salt loss."
    explanation: Orphanet describes a non-remitting course with recurrent crises.
  - reference: PMID:17546235
    reference_title: "[Mineralocorticoid resistance: pseudohypoaldosteronism type 1]."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent."
    explanation: Review describes the lifelong recurrent course of systemic PHA1.
  - reference: PMID:33690157
    reference_title: "Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia."
    explanation: High mortality and post-arrest morbidity in a series of SCNN1A and SCNN1G patients.
  - reference: PMID:33690157
    reference_title: "Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One affected female had a successful pregnancy at the age of 28 years."
    explanation: Survival to adulthood with a successful pregnancy is possible.
  - reference: PMID:41275343
    reference_title: "The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of five, the case experienced a febrile seizure, during which laboratory related biochemical tests showed isolated hyponatremia with normokalemia."
    explanation: A hyponatremic crisis with seizure occurred years into treatment in a homozygous SCNN1G deletion patient.
genetic:
- name: SCNN1G
  association: Causative (biallelic loss of function)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SCNN1G
    term:
      id: hgnc:10602
      label: SCNN1G
  notes: >-
    Reported PHA1B3 alleles include the splice-site variants 318-1G>A (the
    founding report), c.1294+5G>A and c.1295-10T>A, the frameshift
    c.527_528delCA, a homozygous six-base deletion, a homozygous deletion of
    exons 2-3 found only by chromosomal microarray after normal sequencing, and
    the hypomorphic missense p.Gly532Ser. Gain-of-function SCNN1G variants that
    disrupt the C-terminal PY motif cause the opposite disorder, Liddle
    syndrome.
  evidence:
  - reference: PMID:8640238
    reference_title: "A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now report the identification of a 3' splice site mutation in SCNN1G (318-1 G-->A) in three families showing linkage to 16p."
    explanation: First identification of an SCNN1G variant in recessive PHA1.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCNN1G | sodium channel epithelial 1 subunit gamma | hgnc:10602 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists germline loss-of-function SCNN1G variants as disease-causing.
  - reference: PMID:34258491
    reference_title: "A Unique Genotype of Pseudohypoaldosteronism Type 1b in a Highly Consanguineous Population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an SCNN1G deletion mutation c.527_528 delCA, p.T176Rfs*9 (novel) in 2 siblings from another Omani family."
    explanation: Homozygous SCNN1G frameshift variant in two siblings with PHA1B.
  - reference: PMID:41275343
    reference_title: "The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further genetic work-up with high-resolution chromosomal microarray analysis was performed, revealing a novel homozygous gross deletion involving exons 2-3 of the SCNN1G gene."
    explanation: A homozygous intragenic SCNN1G deletion causes systemic PHA1.
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed a variant of uncertain significance, the homozygous missense mutation c.1594G > A, p. Gly532Ser in the SCNN1G gene, associated with PHA-1B3."
    explanation: Homozygous SCNN1G missense variant in an infant with a mild PHA1B3 phenotype.
  - reference: PMID:42549990
    reference_title: "Clinical, Biochemical, and Molecular Spectrum of Pseudohypoaldosteronism Type 1B in Indian Children: A Multicentric Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight (pathogenic/likely-pathogenic: 4, supporting: 4) homozygous variants were identified in SCNN1A (n = 2), SCNN1B (n = 3), and SCNN1G (n = 3); all were novel."
    explanation: Three novel homozygous SCNN1G variants in a South Indian PHA1B series.
pathophysiology:
- name: Biallelic SCNN1G loss of function
  description: >-
    Biallelic splice-site, frameshift, deletion or missense SCNN1G variants
    remove or impair the ENaC gamma subunit. The 318-1G>A allele produces two
    aberrant transcripts, one predicting a protein truncated from 649 to 134
    amino acids. The hypomorphic p.Gly532Ser allele reduces but does not
    abolish channel expression and activity, which matches its milder
    phenotype.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SCNN1G
    term:
      id: hgnc:10602
      label: SCNN1G
  molecular_functions:
  - preferred_term: epithelial sodium channel activity
    modifier: DECREASED
    term:
      id: GO:0005272
      label: sodium channel activity
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:8640238
    reference_title: "A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal splicing results with the production of two messenger RNAs, one arising from activation of an adjacent cryptic splice site and the other from skipping of the downstream exon."
    explanation: The founding SCNN1G splice variant disrupts normal splicing of the gamma subunit transcript.
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This analysis showed that the γG532S mutation reduced, but did not suppress ENaC expression and activity."
    explanation: Heterologous expression shows the gamma G532S variant lowers ENaC expression and current.
  downstream:
  - target: Distal nephron ENaC sodium reabsorption failure
    causal_link_type: DIRECT
  - target: Sweat duct sodium reabsorption failure
    causal_link_type: DIRECT
  - target: Airway epithelial sodium absorption failure
    causal_link_type: DIRECT
  - target: Colonic sodium absorption failure
    causal_link_type: DIRECT
- name: Distal nephron ENaC sodium reabsorption failure
  description: >-
    In principal cells of the aldosterone-sensitive distal nephron and
    collecting duct, ENaC provides the rate-limiting apical step of sodium
    reabsorption. Without a functional gamma subunit, aldosterone cannot drive
    sodium reabsorption, producing end-organ mineralocorticoid resistance and
    urinary salt wasting.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: kidney collecting duct principal cell
    term:
      id: CL:1001431
      label: kidney collecting duct principal cell
  locations:
  - preferred_term: collecting duct
    term:
      id: UBERON:0001232
      label: collecting duct of renal tubule
  biological_processes:
  - preferred_term: renal sodium ion absorption
    modifier: DECREASED
    term:
      id: GO:0070294
      label: renal sodium ion absorption
  evidence:
  - reference: PMID:9788978
    reference_title: "Role of gammaENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "died between 24 and 36 h, probably from hyperkalemia (gammaENaC -/- 18.3 mEq/l, control littermates 9.7 mEq/l)."
    explanation: gammaENaC-null mice waste sodium and retain potassium in urine.
  - reference: PMID:29371419
    reference_title: "Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Nephron-specific γENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia."
    explanation: Renal gammaENaC deletion alone is sufficient for salt wasting and hyperkalemia.
  downstream:
  - target: Renal salt wasting
    causal_link_type: DIRECT
  - target: Extracellular volume depletion
    causal_link_type: DIRECT
  - target: Impaired distal potassium and hydrogen ion secretion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19571553
      reference_title: "Clinical and molecular features of type 1 pseudohypoaldosteronism."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Pseudohypoaldosteronism (PHA) is a rare heterogeneous syndrome of mineralocorticoid resistance causing insufficient potassium and hydrogen secretion."
      explanation: Review links mineralocorticoid resistance to insufficient distal potassium and hydrogen ion secretion.
- name: Impaired distal potassium and hydrogen ion secretion
  description: >-
    Loss of electrogenic sodium entry through ENaC removes the lumen-negative
    driving force for potassium and hydrogen ion secretion in the distal
    nephron, so potassium and acid are retained. In nephron-specific gammaENaC
    knockout mice hyperkalemia is severe and, unlike alpha or beta subunit
    deletion, is not corrected by a high-sodium low-potassium diet, only by
    removing potassium from the diet.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: kidney collecting duct principal cell
    term:
      id: CL:1001431
      label: kidney collecting duct principal cell
  biological_processes:
  - preferred_term: renal potassium excretion
    modifier: DECREASED
    term:
      id: GO:0036359
      label: renal potassium excretion
  evidence:
  - reference: PMID:19571553
    reference_title: "Clinical and molecular features of type 1 pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pseudohypoaldosteronism (PHA) is a rare heterogeneous syndrome of mineralocorticoid resistance causing insufficient potassium and hydrogen secretion."
    explanation: Mineralocorticoid resistance in PHA causes insufficient potassium and hydrogen secretion.
  - reference: PMID:29371419
    reference_title: "Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Unlike mice lacking αENaC or βΕΝaC, an HNa+/LK+ diet did not normalize plasma potassium (K+) concentration or increase NCC activation."
    explanation: Hyperkalemia after renal gammaENaC loss resists the dietary rescue that works for the other subunits.
  downstream:
  - target: Hyperkalemia
    causal_link_type: DIRECT
  - target: Metabolic acidosis
    causal_link_type: DIRECT
- name: Extracellular volume depletion
  description: >-
    Renal, colonic and sweat sodium loss depletes the extracellular fluid
    compartment, causing hyponatremic dehydration, hypovolemia and, in severe
    crises, hypotension and shock.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: sodium ion homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0055078
      label: sodium ion homeostasis
  evidence:
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pseudohypoaldosteronism type 1 (PHA-1) is a rare genetic disease caused by aldosterone resistance, characterized by severe sodium loss, hyperkalemia, dehydration, and vomiting."
    explanation: Sodium loss with dehydration characterizes PHA1.
  - reference: PMID:31900739
    reference_title: "Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity."
    explanation: Documents volume depletion with raised renin in a patient with SCNN1G variants, reversed when urinary sodium loss fell.
  downstream:
  - target: Hyponatremia
    causal_link_type: DIRECT
  - target: Dehydration
    causal_link_type: DIRECT
  - target: Hypotension
    causal_link_type: DIRECT
  - target: Compensatory renin-angiotensin-aldosterone activation
    causal_link_type: DIRECT
  - target: Failure to thrive in infancy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Compensatory renin-angiotensin-aldosterone activation
  description: >-
    Volume depletion strongly stimulates renin secretion and aldosterone
    synthesis, but the elevated aldosterone cannot act through the defective
    channel, so plasma renin and aldosterone remain high.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: regulation of blood volume by renin-angiotensin
    modifier: INCREASED
    term:
      id: GO:0002016
      label: regulation of blood volume by renin-angiotensin
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Presentation is in the first few weeks of life with severe dehydration, vomiting and failure to thrive in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels."
    explanation: Elevated renin and aldosterone are part of the presenting picture of generalized PHA1.
  downstream:
  - target: Increased circulating renin concentration
    causal_link_type: DIRECT
  - target: Increased circulating aldosterone concentration
    causal_link_type: DIRECT
- name: Sweat duct sodium reabsorption failure
  description: >-
    ENaC in the eccrine sweat duct reabsorbs sodium from primary sweat. In
    systemic PHA1 the ducts lack ENaC conductance, so sweat salt absorption is
    blocked although CFTR chloride conductance is preserved, giving high sweat
    sodium and chloride.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: epithelial cell of sweat gland
    term:
      id: CL:1000448
      label: epithelial cell of sweat gland
  locations:
  - preferred_term: sweat gland
    term:
      id: UBERON:0001820
      label: sweat gland
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
  evidence:
  - reference: PMID:15986094
    reference_title: "Normal CFTR Activity and Reversed Skin Potentials in Pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Lack of gENaC completely blocked salt absorption and caused dramatic reversal of skin potentials associated with pilocarpine-induced sweat secretion"
    explanation: Ex vivo sweat ducts from systemic PHA1 patients show no ENaC conductance and no salt absorption; the study does not report which subunit gene was affected.
  downstream:
  - target: Elevated sweat chloride
    causal_link_type: DIRECT
  - target: Extracellular volume depletion
    causal_link_type: DIRECT
- name: Colonic sodium absorption failure
  description: >-
    ENaC mediates amiloride-sensitive sodium absorption in distal colon
    epithelium; its loss adds intestinal salt loss to the renal deficit.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: colon epithelial cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A severe form of pseudohypoaldosteronism type 1 characterized by salt wasting in multiple organs including the kidney, colon, and sweat and salivary glands."
    explanation: Orphanet defines generalized PHA1 by salt wasting from kidney, colon, sweat and salivary glands.
  downstream:
  - target: Extracellular volume depletion
    causal_link_type: DIRECT
- name: Airway epithelial sodium absorption failure
  description: >-
    Airway ENaC absorbs sodium and liquid from the airway surface. Patients
    with systemic PHA1 have no airway sodium absorption, more than double the
    normal airway surface liquid volume, and recurrent chest congestion,
    coughing and wheezing in early childhood. These data come from cohorts with
    ENaC subunit mutations generally. gammaENaC-null mice clear neonatal lung
    liquid more slowly than controls but reach nearly normal lung water, so the
    gamma subunit facilitates but is not essential for perinatal lung liquid
    clearance.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  locations:
  - preferred_term: respiratory airway
    term:
      id: UBERON:0001005
      label: respiratory airway
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
  evidence:
  - reference: PMID:10403853
    reference_title: "Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "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."
    explanation: Systemic PHA1 patients lack airway sodium absorption and have excess airway surface liquid; the cohort is not restricted to SCNN1G.
  - reference: PMID:9788978
    reference_title: "Role of gammaENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Newborn gammaENaC (-/-) mice cleared lung liquid more slowly than control littermates, but lung water at 12 h (wet/dry = 5.5) was nearly normal (wet/dry = 5.3)."
    explanation: Loss of gammaENaC slows neonatal lung liquid clearance in mice, though lung water nearly normalizes.
  downstream:
  - target: Wheezing
    causal_link_type: DIRECT
  - target: Cough
    causal_link_type: DIRECT
  - target: Recurrent upper and lower respiratory tract infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Metabolic/Laboratory
  name: Hyponatremia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  sequelae:
  - target: Seizure
    description: Hyponatremic crises can provoke seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41275343
      reference_title: "The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At the age of five, the case experienced a febrile seizure, during which laboratory related biochemical tests showed isolated hyponatremia with normokalemia."
      explanation: A seizure occurred with isolated hyponatremia in a homozygous SCNN1G deletion patient.
  evidence:
  - reference: PMID:33690157
    reference_title: "Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia."
    explanation: All patients in a series including SCNN1G cases presented with hyponatremia.
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The child presented with failure to thrive, accompanied by mild hyponatremia and hyperkalemia, together with a normal anion gap metabolic acidosis."
    explanation: Hyponatremia was present even in the mild missense case.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002902 | Hyponatremia | Very frequent (99-80%)"
    explanation: Orphanet records hyponatremia as very frequent.
- category: Metabolic/Laboratory
  name: Hyperkalemia
  frequency: VERY_FREQUENT
  description: >-
    Often severe and life-threatening in the neonatal period; hyperkalemic
    cardiac arrest with neurological injury is reported.
  phenotype_term:
    preferred_term: Hyperkalemia
    term:
      id: HP:0002153
      label: Hyperkalemia
  sequelae:
  - target: Cardiac arrest
    description: Severe hyperkalemia can cause cardiac arrest.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33690157
      reference_title: "Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia."
      explanation: Hyperkalemia caused cardiac arrest in a series of SCNN1A and SCNN1G patients.
  evidence:
  - reference: PMID:33690157
    reference_title: "Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia."
    explanation: Severe hyperkalemia at presentation in a series including SCNN1G cases.
  - reference: PMID:9788978
    reference_title: "Role of gammaENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "died between 24 and 36 h, probably from hyperkalemia (gammaENaC -/- 18.3 mEq/l, control littermates 9.7 mEq/l)."
    explanation: gammaENaC-null mice develop lethal hyperkalemia.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002153 | Hyperkalemia | Very frequent (99-80%)"
    explanation: Orphanet records hyperkalemia as very frequent.
- category: Metabolic/Laboratory
  name: Metabolic acidosis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The child presented with failure to thrive, accompanied by mild hyponatremia and hyperkalemia, together with a normal anion gap metabolic acidosis."
    explanation: Normal anion gap metabolic acidosis in an SCNN1G missense case.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001942 | Metabolic acidosis | Very frequent (99-80%)"
    explanation: Orphanet records metabolic acidosis as very frequent.
- category: Renal
  name: Renal salt wasting
  phenotype_term:
    preferred_term: Renal salt wasting
    term:
      id: HP:0000127
      label: Renal salt wasting
  evidence:
  - reference: PMID:31900739
    reference_title: "Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity."
    explanation: Urinary sodium wasting in a patient with SCNN1G variants, reduced by potassium restriction.
- category: Metabolic/Laboratory
  name: Increased circulating renin concentration
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Increased circulating renin concentration
    term:
      id: HP:0000848
      label: Increased circulating renin concentration
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000848 | Increased circulating renin level | Very frequent (99-80%)"
    explanation: Orphanet records elevated renin as very frequent.
- category: Metabolic/Laboratory
  name: Increased circulating aldosterone concentration
  phenotype_term:
    preferred_term: Increased circulating aldosterone concentration
    term:
      id: HP:0000859
      label: Increased circulating aldosterone concentration
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Presentation is in the first few weeks of life with severe dehydration, vomiting and failure to thrive in association with hyponatremia, hyperkalemia and metabolic acidosis as well as elevated aldosterone and renin levels."
    explanation: Elevated aldosterone is part of the presenting picture of generalized PHA1.
- category: Systemic
  name: Dehydration
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001944 | Dehydration | Frequent (79-30%)"
    explanation: Orphanet records dehydration as frequent.
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pseudohypoaldosteronism type 1 (PHA-1) is a rare genetic disease caused by aldosterone resistance, characterized by severe sodium loss, hyperkalemia, dehydration, and vomiting."
    explanation: Dehydration is a characteristic feature of PHA1.
- category: Cardiovascular
  name: Hypotension
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  evidence:
  - reference: PMID:34258491
    reference_title: "A Unique Genotype of Pseudohypoaldosteronism Type 1b in a Highly Consanguineous Population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension."
    explanation: Hypotension at presentation in a PHA1B cohort that included SCNN1G siblings.
- category: Gastrointestinal
  name: Vomiting
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:34258491
    reference_title: "A Unique Genotype of Pseudohypoaldosteronism Type 1b in a Highly Consanguineous Population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension."
    explanation: Vomiting at presentation in a PHA1B cohort that included SCNN1G siblings.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002013 | Vomiting | Frequent (79-30%)"
    explanation: Orphanet records vomiting as frequent.
- category: Growth
  name: Failure to thrive in infancy
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive in infancy
    term:
      id: HP:0001531
      label: Failure to thrive in infancy
  evidence:
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The child presented with failure to thrive, accompanied by mild hyponatremia and hyperkalemia, together with a normal anion gap metabolic acidosis."
    explanation: Failure to thrive was the presenting feature in an SCNN1G missense case.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001531 | Failure to thrive in infancy | Frequent (79-30%)"
    explanation: Orphanet records failure to thrive in infancy as frequent.
- category: Cardiovascular
  name: Cardiac arrest
  description: >-
    Hyperkalemic cardiac arrest, with severe neurological impairment in
    survivors, is reported in autosomal recessive PHA1 series.
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
  evidence:
  - reference: PMID:33690157
    reference_title: "Clinical characteristics and treatment requirements of children with autosomal recessive pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia."
    explanation: Hyperkalemic cardiac arrest in a series of SCNN1A and SCNN1G patients.
- category: Neurological
  name: Seizure
  description: >-
    Seizures occur with hyponatremic crises; a homozygous SCNN1G deletion
    patient had a febrile seizure with isolated hyponatremia at five years.
  phenotype_term:
    preferred_term: Hyponatremic seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41275343
    reference_title: "The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of five, the case experienced a febrile seizure, during which laboratory related biochemical tests showed isolated hyponatremia with normokalemia."
    explanation: Seizure during a hyponatremic episode in an SCNN1G patient.
- category: Integument
  name: Elevated sweat chloride
  phenotype_term:
    preferred_term: Elevated sweat electrolytes (positive sweat test)
    term:
      id: HP:0012236
      label: Elevated sweat chloride
  evidence:
  - reference: PMID:15986094
    reference_title: "Normal CFTR Activity and Reversed Skin Potentials in Pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Lack of gENaC completely blocked salt absorption and caused dramatic reversal of skin potentials associated with pilocarpine-induced sweat secretion"
    explanation: Absent sweat duct ENaC conductance in systemic PHA1 raises sweat electrolytes; the study does not name the subunit gene.
- category: Integument
  name: Eczematous skin lesions
  description: >-
    Treatment-resistant eczematous lesions were the prominent extra-renal
    finding in a homozygous SCNN1G deletion patient.
  phenotype_term:
    preferred_term: Eczematous skin lesions
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:41275343
    reference_title: "The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The case presented to our center with persistent electrolyte imbalances and treatment-resistant eczematous skin lesions."
    explanation: Persistent eczematous lesions in a homozygous SCNN1G deletion patient.
- category: Respiratory
  name: Wheezing
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Wheezing
    term:
      id: HP:0030828
      label: Wheezing
  notes: >-
    Reported in systemic PHA1 cohorts not restricted to SCNN1G; Orphanet lists
    it as occasional for generalized PHA1.
  evidence:
  - reference: PMID:10403853
    reference_title: "Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "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."
    explanation: Recurrent wheezing in young patients with systemic PHA1 from ENaC subunit mutations.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030828 | Wheezing | Occasional (29-5%)"
    explanation: Orphanet records wheezing as occasional.
- category: Respiratory
  name: Cough
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  notes: Reported in systemic PHA1 cohorts not restricted to SCNN1G.
  evidence:
  - reference: PMID:10403853
    reference_title: "Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "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."
    explanation: Recurrent coughing in young patients with systemic PHA1 from ENaC subunit mutations.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012735 | Cough | Occasional (29-5%)"
    explanation: Orphanet records cough as occasional.
- category: Respiratory
  name: Recurrent upper and lower respiratory tract infections
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent upper and lower respiratory tract infections
    term:
      id: HP:0200117
      label: Recurrent upper and lower respiratory tract infections
  notes: The Orphanet frequency applies to generalized PHA1 across ENaC genes.
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200117 | Recurrent upper and lower respiratory tract infections | Frequent (79-30%)"
    explanation: Orphanet records recurrent respiratory tract infections as frequent in generalized PHA1.
diagnosis:
- name: Biochemical and hormonal profile
  description: >-
    Neonatal hyponatremia, hyperkalemia and metabolic acidosis with high plasma
    renin and aldosterone, after exclusion of congenital adrenal hyperplasia
    and other adrenal causes, suggest PHA1. The renal and systemic forms cannot
    be told apart by early presentation or by this profile.
  evidence:
  - reference: PMID:27485500
    reference_title: "Congenital primary adrenal insufficiency and selective aldosterone defects presenting as salt-wasting in infancy: a single center 10-year experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PHA is characterised by the renal tubular unresponsiveness to aldosterone and presents with hyponatremia, hyperkalaemia and metabolic acidosis with elevated plasma aldosterone and renin concentrations, but normal levels of ACTH and cortisol [3]."
    explanation: The biochemical and hormonal profile that points to PHA among infant salt-wasting disorders.
  - reference: PMID:31301676
    reference_title: "Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile."
    explanation: The biochemical profile does not separate renal from systemic PHA1.
- name: Molecular genetic testing of ENaC subunit genes
  description: >-
    Sequencing of SCNN1A, SCNN1B and SCNN1G (with NR3C2 for the renal form),
    usually by exome sequencing, confirms the diagnosis and assigns the
    subtype; biallelic SCNN1G variants define PHA1B3. Copy-number analysis is
    needed when sequencing is negative, because an intragenic SCNN1G deletion
    was missed by sequencing and found by chromosomal microarray.
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:31301676
    reference_title: "Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b."
    explanation: Genetic testing is needed to distinguish PHA1A from PHA1B.
  - reference: PMID:41275343
    reference_title: "The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial sequencing of PHA1-associated genes (SCNN1A, SCNN1B, and SCNN1G) did not reveal any pathogenic variants."
    explanation: Sequencing alone missed a homozygous SCNN1G exon deletion.
  - reference: PMID:41275343
    reference_title: "The first report of a gross deletion in the SCNN1G gene in a case presenting with hyponatremic convulsion at fifth year of treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case expands the phenotypic and genotypic spectrum of systemic PHA1 and emphasizes the importance of considering copy number variants in genetically unresolved cases of PHA1, especially those presenting with atypical electrolyte profiles and extrarenal manifestations such as persistent eczema."
    explanation: Copy-number analysis should be considered when sequencing is unrevealing.
treatments:
- name: High-dose sodium chloride supplementation
  description: >-
    Lifelong oral sodium chloride replacement is the mainstay of therapy for the
    systemic form. The hypomorphic p.Gly532Ser patient responded to sodium
    chloride alone.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium chloride
      term:
        id: CHEBI:26710
        label: sodium chloride
  target_mechanisms:
  - target: Extracellular volume depletion
    description: Replaces renal and extra-renal sodium losses.
  evidence:
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our case, the patient showed a positive clinical response to sodium chloride supplementation alone."
    explanation: Sodium chloride supplementation alone controlled the mild SCNN1G missense case.
  - reference: PMID:42549990
    reference_title: "Clinical, Biochemical, and Molecular Spectrum of Pseudohypoaldosteronism Type 1B in Indian Children: A Multicentric Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients (67%) died, mainly due to sepsis (n = 2) or treatment discontinuation (n = 4), while three remain stable on oral sodium supplementation."
    explanation: Survivors in a PHA1B series including SCNN1G patients remain stable on oral sodium, and stopping treatment was a major cause of death.
  - reference: PMID:17546235
    reference_title: "[Mineralocorticoid resistance: pseudohypoaldosteronism type 1]."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary."
    explanation: Review states that systemic PHA1 requires high-dose salt supplementation.
- name: Dietary potassium restriction
  description: >-
    Lowering dietary potassium reduces urinary sodium loss and restores volume.
    The proposed explanation is that low plasma potassium activates WNK
    signalling in the distal convoluted tubule, so the thiazide-sensitive NaCl
    cotransporter and pendrin take over sodium reabsorption from the
    non-functional ENaC. In nephron-specific gammaENaC knockout mice only
    removal of dietary potassium prevented hyperkalemia and weight loss.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary potassium restriction
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Impaired distal potassium and hydrogen ion secretion
    description: Limits the potassium load the distal nephron cannot excrete.
  - target: Extracellular volume depletion
    description: Recruits compensatory distal convoluted tubule sodium reabsorption.
  evidence:
  - reference: PMID:31900739
    reference_title: "Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity."
    explanation: Potassium restriction corrected volume depletion and sodium wasting in a patient with SCNN1G variants.
  - reference: PMID:31900739
    reference_title: "Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, potassium restriction causes NCC and pendrin to compensate for the non-functional ENaC in the collecting duct."
    explanation: Proposed mechanism by which potassium restriction compensates for absent ENaC.
  - reference: PMID:29371419
    reference_title: "Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, when K+ was eliminated from the diet at the time that γENaC was deleted, plasma K+ concentration and NCC activity remained normal, and progressive weight loss was prevented."
    explanation: Removing dietary potassium prevents the PHA1 phenotype after renal gammaENaC deletion in mice.
- name: Sodium bicarbonate
  description: Alkali therapy to correct metabolic acidosis while also supplying sodium.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium bicarbonate
      term:
        id: NCIT:C29457
        label: Sodium Bicarbonate
  target_mechanisms:
  - target: Metabolic acidosis
    description: Buffers retained acid.
  evidence:
  - reference: PMID:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
    explanation: Sodium bicarbonate is part of symptomatic treatment of systemic PHA1; this report concerns the SCNN1B form, which shares the mechanism.
- name: Potassium-binding resin
  description: >-
    Cation-exchange resins such as sodium polystyrene sulfonate increase fecal
    potassium excretion to control chronic hyperkalemia.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium polystyrene sulfonate
      term:
        id: NCIT:C29461
        label: Sodium Polystyrene Sulfonate
  target_mechanisms:
  - target: Hyperkalemia
    description: Removes retained potassium through the gut.
  evidence:
  - reference: PMID:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
    explanation: Sodium polystyrene sulfonate is part of symptomatic treatment of systemic PHA1; this report concerns the SCNN1B form, which shares the mechanism.
- name: Mineralocorticoid and glucocorticoid replacement
  description: >-
    Hydrocortisone and fludrocortisone are often started empirically for
    suspected salt-wasting adrenal disease but do not correct the electrolyte
    disturbance, because the defect lies in the target channel rather than in
    hormone supply. Failure to respond helps distinguish PHA1 from congenital
    adrenal hyperplasia.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fludrocortisone
      term:
        id: CHEBI:50885
        label: fludrocortisone
  evidence:
  - reference: PMID:34165441
    reference_title: "Systemic pseudohypoaldosteronism-1 with episodic dyslipidemia in a Sudanese child."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "A child presenting with features that mimic salt-losing congenital adrenal hyperplasia (CAH) crises that do not respond to glucocorticoid and mineralocorticoid therapy should alert the pediatricians to the possibility of end-organ resistance to aldosterone."
    explanation: Salt-losing crises in end-organ aldosterone resistance do not respond to glucocorticoid and mineralocorticoid therapy.
differential_diagnoses:
- name: Congenital adrenal hyperplasia
  description: >-
    Salt-wasting congenital adrenal hyperplasia produces the same neonatal
    hyponatremia, hyperkalemia and acidosis and is often considered first.
  distinguishing_features:
  - Normal cortisol and 17-hydroxyprogesterone with high aldosterone in PHA1
  - No response to glucocorticoid and mineralocorticoid replacement in PHA1
  evidence:
  - reference: PMID:34165441
    reference_title: "Systemic pseudohypoaldosteronism-1 with episodic dyslipidemia in a Sudanese child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The classical presentation is life-threatening neonatal/infantile salt-losing crises that mimic congenital adrenal hyperplasia (CAH)."
    explanation: Systemic PHA1 crises mimic salt-wasting CAH.
  - reference: PMID:27485500
    reference_title: "Congenital primary adrenal insufficiency and selective aldosterone defects presenting as salt-wasting in infancy: a single center 10-year experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PHA is characterised by the renal tubular unresponsiveness to aldosterone and presents with hyponatremia, hyperkalaemia and metabolic acidosis with elevated plasma aldosterone and renin concentrations, but normal levels of ACTH and cortisol [3]."
    explanation: Normal ACTH and cortisol separate PHA from adrenal causes of infant salt wasting.
- name: Autosomal dominant pseudohypoaldosteronism type 1
  disease_term:
    preferred_term: autosomal dominant pseudohypoaldosteronism type 1
    term:
      id: MONDO:0008329
      label: autosomal dominant pseudohypoaldosteronism type 1
  description: >-
    Renal PHA1A from heterozygous NR3C2 variants causes a milder kidney-limited
    salt-wasting syndrome that remits with age. The mild SCNN1G p.Gly532Ser
    phenotype was reminiscent of PHA1A, so genotype is needed to separate them.
  distinguishing_features:
  - Kidney-limited salt loss with normal sweat electrolytes in renal PHA1A
  - Improvement with age in renal PHA1A versus lifelong treatment in systemic PHA1B
  evidence:
  - reference: PMID:31301676
    reference_title: "Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA."
    explanation: Prognosis is worse in multisystem PHA1B than in NR3C2-related renal PHA1A.
  - reference: PMID:40969802
    reference_title: "Case Report: Functional investigation of the γENaC G532S mutation presenting as mild PHA-1B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mild phenotype exhibited by the infant was reminiscent of PHA-1A, with the symptoms easily managed with low-dose salt supplementation."
    explanation: A hypomorphic SCNN1G allele can mimic the renal form clinically.
- name: Pseudohypoaldosteronism type IB2 autosomal recessive
  disease_term:
    preferred_term: pseudohypoaldosteronism, type IB2, autosomal recessive
    term:
      id: MONDO:0859317
      label: pseudohypoaldosteronism, type IB2, autosomal recessive
  description: >-
    The SCNN1B form of systemic PHA1 is clinically indistinguishable and is
    separated only by molecular testing.
  distinguishing_features:
  - Biallelic SCNN1B rather than SCNN1G variants
  evidence:
  - reference: PMID:19571553
    reference_title: "Clinical and molecular features of type 1 pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "This review provides an overview on transepithelial sodium reabsorption and on clinical features and the underlying molecular pathology of systemic and renal PHA1 caused by mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G) of the epithelial sodium channel (ENaC) and the mineralocorticoid receptor coding gene NR3C2."
    explanation: Systemic PHA1 arises from variants in any of the three ENaC subunit genes.
- name: Early-onset familial hypoaldosteronism
  disease_term:
    preferred_term: early-onset familial hypoaldosteronism
    term:
      id: MONDO:0035320
      label: early-onset familial hypoaldosteronism
  description: >-
    Aldosterone synthase deficiency also causes infantile salt wasting with
    hyponatremia, hyperkalemia and high renin, but aldosterone is low to normal.
  distinguishing_features:
  - Low to normal aldosterone in aldosterone synthase deficiency versus high aldosterone in PHA1
  - Response to fludrocortisone in aldosterone synthase deficiency
  evidence:
  - reference: PMID:41905953
    reference_title: "Congenital aldosterone deficiency and its resistance."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "ASD must also be differentiated from another disease, pseudohypoaldosteronism type 1 (PHA1), which involves resistance to aldosterone."
    explanation: Names PHA1 and aldosterone synthase deficiency as mutual differential diagnoses.
- name: Secondary (transient) pseudohypoaldosteronism
  description: >-
    Transient renal aldosterone resistance from urinary tract infection or
    urinary tract anomalies produces renal salt loss, hyponatremia,
    hyperkalemia and high aldosterone in early infancy.
  distinguishing_features:
  - Urinary tract infection or obstructive anomaly on urine culture and renal imaging
  - Resolution after treatment of the underlying cause
  evidence:
  - reference: PMID:22397047
    reference_title: "Secondary pseudohypoaldosteronism caused by urinary tract infection associated with urinary tract anomalies: case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary pseudohypoaldosteronism type 1 develops due to transient aldosterone resistance in renal tubules and is characterized by renal sodium loss, hyponatremia, hyperkalemia and high plasma aldosterone levels."
    explanation: Secondary PHA reproduces the biochemical picture of PHA1.
animal_models:
- name: gammaENaC-deficient mouse
  species: Mouse
  genotype: Scnn1g-/- (germline targeted disruption)
  publication: PMID:9788978
  description: >-
    Germline disruption of the gamma subunit gene produces urinary sodium loss
    and potassium retention with lethal hyperkalemia between 24 and 36 hours
    after birth, and slower but largely completed neonatal lung liquid
    clearance.
  modeled_mechanisms:
  - target: Distal nephron ENaC sodium reabsorption failure
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: Reproduces renal sodium wasting and hyperkalemia of human neonatal PHA1.
    limitations: >-
      Mice die within 36 hours of birth, so the chronic course, extra-renal
      salt loss and response to salt supplementation cannot be studied in this
      germline model.
    evidence:
    - reference: PMID:9788978
      reference_title: "Role of gammaENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The gammaENaC (-/-) newborn exhibits a phenotype that resembles the clinical manifestations of human neonatal PHA1."
      explanation: The authors state the knockout phenotype resembles human neonatal PHA1.
  - target: Airway epithelial sodium absorption failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Neonatal lung liquid clearance is slowed but lung water nearly normalizes by 12 hours.
    limitations: >-
      Only the neonatal transition to air breathing was assessed; chronic airway
      surface liquid and mucociliary function, which carry the human airway
      phenotype, could not be measured because the mice die within 36 hours.
    evidence:
    - reference: PMID:9788978
      reference_title: "Role of gammaENaC subunit in lung liquid clearance and electrolyte balance in newborn mice. Insights into perinatal adaptation and pseudohypoaldosteronism."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Newborn gammaENaC (-/-) mice cleared lung liquid more slowly than control littermates, but lung water at 12 h (wet/dry = 5.5) was nearly normal (wet/dry = 5.3)."
      explanation: Lung liquid clearance is slowed but nearly completed without gammaENaC.
- name: Adult nephron-specific gammaENaC knockout mouse
  species: Mouse
  genotype: Scnn1g inducible nephron-specific knockout
  publication: PMID:29371419
  description: >-
    Inducible deletion of gammaENaC in the adult nephron produces salt wasting
    with severe hyperkalemia that, unlike alpha or beta subunit deletion, is not
    corrected by a high-sodium low-potassium diet but is prevented by a
    potassium-free diet.
  modeled_mechanisms:
  - target: Impaired distal potassium and hydrogen ion secretion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reproduces severe hyperkalemia from loss of renal gammaENaC.
    limitations: >-
      Adult induction bypasses the neonatal presentation of the human disease,
      and the model lacks the extra-renal ENaC loss of systemic PHA1B3.
    evidence:
    - reference: PMID:29371419
      reference_title: "Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Nephron-specific γENaC knockout mice also presented with salt-wasting syndrome and severe hyperkalemia."
      explanation: Renal gammaENaC deletion causes salt wasting and severe hyperkalemia.
references:
- reference: ORPHA:171876
  title: "Generalized pseudohypoaldosteronism type 1"
📚

References & Deep Research

References

1
ORPHA:171876
Generalized pseudohypoaldosteronism type 1
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Pseudohypoaldosteronism Type IB3 Autosomal Recessive (SCNN1G) · 2026-10-30T10:54:55Z · View source

De novo curation of SCNN1G-related systemic PHA1 (PHA1B3). Deep research: openscientist (25/25 refs verified, 0 confabulation). Evidence from primary literature fetched directly (PMID:8640238 founding SCNN1G splice variant, PMID:40969802 mild G532S functional study, PMID:41275343 gross-deletion case, PMID:34258491/42549990 PHA1B series, PMID:9788978/29371419 gammaENaC mouse models, ORPHA:171876 generalized PHA1). preflight-dr flagged that the DR report gave HGNC:10601 beside SCNN1G; entry uses the correct hgnc:10602 from the term cache, not the report. Validated with just validate (0 issues), entity-refs, causal-targets, coarse-phenotypes, qualifier-terms, delivery-system, duplicate-keys, block-scalar-comments, logical-rules.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 2026-10-30T10:52:25.268533

1. Disease Information

  • What it is: A rare hereditary channelopathy of aldosterone resistance (pseudohypoaldosteronism) in its severe systemic form, caused by defective ENaC. "Pseudo"-hypoaldosteronism because aldosterone levels are normal/high but its downstream effect (ENaC-mediated Na⁺ reabsorption) is absent. PMID 42549990: "Pseudohypoaldosteronism type 1 (PHA1) is a rare hereditary disorder characterised by aldosterone resistance leading to salt wasting, hyperkalaemia, and metabolic acidosis… a severe systemic form (PHA1B) caused by biallelic mutations in epithelial sodium channel (ENaC) subunit genes."
  • Key identifiers:
  • OMIM: 620126 (Pseudohypoaldosteronism, type IB3, autosomal recessive)
  • MONDO: MONDO:0859318
  • Gene: SCNN1G (HGNC:10601; NCBI Gene 6340; Ensembl ENSG00000166828; UniProt P51170), chromosome 16p12.2
  • Orphanet: PHA type 1 (ORPHA:171876 generalized/systemic PHA1; parent ORPHA:171871 for PHA1)
  • ICD-10: E27.4 (other and unspecified adrenocortical insufficiency; PHA has no dedicated ICD-10 code); ICD-11: 5A71.Z/5A7Y adrenal-related; often coded under disorders of mineralocorticoid action
  • MeSH: D011546 "Pseudohypoaldosteronism"
  • Synonyms / alternative names: Systemic pseudohypoaldosteronism type 1; generalized PHA1; multiple-target-organ defect PHA1; autosomal recessive PHA type 1 (γ-ENaC type); PHA1B3; gamma-ENaC–related systemic PHA.
  • Information source type: Derived chiefly from disease-level aggregated resources (OMIM, Orphanet) and individual-patient case reports/small case series (ultra-rare disease; no large EHR cohorts).

2. Etiology

  • Primary cause — genetic: Biallelic (homozygous or compound-heterozygous) loss-of-function variants in SCNN1G. Inheritance is autosomal recessive. This is a monogenic Mendelian disease; there are no infectious or acquired primary causes of this specific (inherited) subtype. (A phenotypically similar but genetically distinct entity, secondary/transient PHA, is acquired — see §10 differentials.)
  • Genetic risk factors:
  • Causal variants: biallelic SCNN1G null/hypomorphic alleles (see §4).
  • Parental consanguinity is a major risk factor (homozygosity for founder/private alleles). PMID 42549990: "parental consanguinity was present in seven (78%)." PMID 33690157: "All parents were consanguineous and of South Asian, Middle Eastern or African ethnic origin."
  • Family history of an affected sib (25% recurrence risk per pregnancy).
  • Environmental risk factors: None cause the disease. However, salt loss, intercurrent illness, vomiting/diarrhea, heat, and poor sodium intake precipitate or worsen salt-wasting crises in genetically affected individuals (gene–environment interaction: dietary sodium availability modulates crisis frequency). Mouse data directly demonstrate diet dependence — a high-Na/low-K "rescue diet" normalizes the phenotype and reverting to regular diet reinstates severe disease (PMID 26701978).
  • Protective factors: No genetic protective alleles described. Aggressive dietary sodium supplementation and potassium restriction are protective against crises (environmental/therapeutic). Residual ENaC function from hypomorphic missense alleles is "protective" relative to null alleles (milder disease; see §4/§9).
  • Gene–environment interaction: Dietary Na⁺/K⁺ intake is the dominant modifiable factor interacting with the fixed genetic defect to set clinical severity and crisis risk.

3. Phenotypes

Onset is neonatal (congenital functional defect); presentation typically within the first 2 weeks of life (median ~14 days; PMID 42549990, 33690157). Severity is usually severe in the classic systemic form; variable/milder with partial-function alleles. Course is episodic/crisis-prone on a chronic lifelong baseline (systemic form does not remit).

Phenotype Type HPO term Onset / severity / frequency
Hyponatremia Lab abnormality HP:0002902 Neonatal; severe (median Na⁺ 124 mEq/L); ~100%
Hyperkalemia Lab abnormality HP:0002153 Neonatal; severe/life-threatening (median K⁺ 8.0 mEq/L); ~100%
Metabolic acidosis (hyperchloremic) Lab abnormality HP:0001942 Neonatal; moderate–severe; very frequent
Elevated plasma renin activity Lab abnormality HP:0000848 (hyperaldosteronism); renin ↑ ~100%
Hyperaldosteronism (secondary) Lab abnormality HP:0000859 ~100%
Salt wasting / renal sodium wasting Clinical sign HP:0000127/HP:0012605 (natriuria) ~100%
Dehydration / hypovolemia Clinical sign HP:0001944 Frequent during crises
Vomiting Symptom HP:0002013 Common presenting symptom
Failure to thrive / poor feeding / weight loss Clinical sign HP:0001508 / HP:0011471 Common
Lethargy Symptom HP:0001254 Common at presentation
Cardiac arrhythmia / cardiac arrest (hyperkalemic) Clinical sign HP:0011675 / HP:0001695 Life-threatening; drives mortality
Skin lesions (miliaria rubra–like, eczematous/seborrheic, folliculitis, generalized rash) Physical manifestation HP:0011123 (inflammatory abnormality of the skin) / HP:0000964 (eczema) Occur during salt-depletion crises (PMID 3654220, 41275343)
Elevated sweat chloride / salivary sodium Lab abnormality HP:0012236 (↑ sweat chloride) Characteristic; CF-like
Recurrent respiratory symptoms / lower-airway disease Clinical sign HP:0002783 (recurrent LRTI) Reported; airway ENaC involvement
Intestinal salt wasting (diarrhea) Clinical sign HP:0002028 Reported (PMID 40398899)
  • Quality-of-life impact: High treatment burden (frequent oral medication/dose titration, salt supplements, resins, repeated electrolyte monitoring, risk of acute crises). PMID 42569709: "This condition requires a lifelong close follow-up and treatment process." Survivors with good control can achieve normal physical/neurological development and even pregnancy (PMID 33690157). No formal EQ-5D/SF-36 data for this ultra-rare disease.

4. Genetic / Molecular Information

  • Causal gene: SCNN1G (sodium channel epithelial 1 gamma subunit), chromosome 16p12.2 (historically mapped 16p12.2–13.11 alongside SCNN1B). HGNC:10601; OMIM gene 600761; disease OMIM 620126. Encodes γ-ENaC (~649 aa; UniProt P51170).
  • Pathogenic variants (germline; this disease has no somatic basis):
  • Variant classes: splice-site, nonsense, framesh4ift (frameshift), missense, and large/gross deletions — all converging on loss of function. Landmark: PMID 8640238 — SCNN1G 3′ splice-site 318-1 G→A, truncating γ-ENaC from 649→134 aa. Recent: first homozygous gross deletion in a PHA1 ENaC gene (PMID 41275343); novel homozygous SCNN1G variants across case series (PMID 42549990).
  • Classification: per ACMG/AMP — pathogenic/likely pathogenic for null alleles; some novel variants remain VUS pending functional/segregation data (PMID 42549990).
  • Allele frequency: Pathogenic alleles are extremely rare in gnomAD (private/founder); loss-of-function constraint for SCNN1G is modest (recessive gene).
  • Functional consequence: Loss of function — reduced channel number and/or reduced open probability. Example: γ-ENaC A635V (c.1904C>T) reduced amiloride-sensitive current ~30% with lower open probability (PMID 40153144); G532S → mild PHA-1B3 (PMID 40969802).
  • Modifier genes: The other ENaC subunits (SCNN1A, SCNN1B) and regulators (NEDD4L, SGK1, CAP serine proteases, kallikrein-1) plausibly modify residual channel activity; co-expression/digenic contributions have been proposed in a network-medicine analysis (PMID 41569463). No validated clinical modifier locus specific to PHA1B3.
  • Epigenetic information: No disease-specific DNA-methylation/histone data reported for PHA1B3. (Aldosterone/MR signaling epigenetically regulates ENaC transcription physiologically, but this is not altered as the primary lesion.)
  • Chromosomal abnormalities: Point mutations and intragenic deletions predominate; a homozygous gross (multi-exon) deletion of an ENaC gene has been reported (PMID 41275343). No recurrent aneuploidy/translocation.
  • Allelic contrast: Gain-of-function SCNN1G (PY-motif loss, e.g., Q591X) → Liddle syndrome (PMID 35661050) — demonstrating ENaC activity as the salt-retention↔salt-wasting axis.

Ontology: gene product GO:0034765 (regulation of ion transmembrane transport); protein class CHEBI/ion channel; variant effect "loss_of_function."

5. Environmental Information

  • Environmental/toxic/occupational factors: None cause PHA1B3 (purely genetic).
  • Lifestyle/dietary factors: Dietary sodium and potassium intake are the key modifiable determinants of crisis frequency and severity (see §2 gene–environment interaction). Heat exposure → sweat Na⁺ loss can precipitate crises (sweat gland ENaC defect).
  • Infectious agents: Not causal. Intercurrent infections (and, for the acquired mimic, urinary tract infection/obstruction in secondary PHA) can precipitate salt-wasting episodes but are not the cause of the inherited disease.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic loss-of-function variant in SCNN1G → produces a non-functional or hypomorphic γ-ENaC subunit (truncation, misassembly, or reduced open probability). (Demonstrated: in-vitro electrophysiology, PMID 40153144.)
  2. Defective γ-subunit → impaired assembly/proteolytic activation of the αβγ-ENaC heterotrimer at the apical membrane (γ-ENaC GRIP-domain cleavage is required to relieve autoinhibition and open the channel). (Demonstrated mechanism of ENaC gating, PMID 42463047.)
  3. Non-functional ENaC → loss of amiloride-sensitive apical Na⁺ reabsorption in principal/epithelial cells of ENaC-expressing tissues. (Demonstrated.)
  4. In the distal nephron (connecting tubule/collecting duct) → reduced Na⁺ reabsorption → renal salt wasting → hyponatremia and hypovolemia. Loss of the lumen-negative transepithelial potential → reduced K⁺ and H⁺ secretion → hyperkalemia and metabolic acidosis. (Demonstrated; mirrored in conditional αENaC-KO mice, PMID 26701978.)
  5. Hypovolemia + hyperkalemia → marked activation of renin–angiotensin–aldosterone system → very high plasma renin and aldosterone, which cannot act because the effector channel is defective ("pseudo"-hypoaldosteronism). (Demonstrated.)
  6. Branch A (kidney/colon): ongoing Na⁺ wasting via gut (intestinal salt wasting/diarrhea) compounds hyponatremia.
  7. Branch B (sweat/salivary glands): failure of ductal Na⁺ reabsorption → elevated sweat/saliva Na⁺/Cl⁻ (CF-like); hypertonic sweat → sweat-gland inflammation and skin lesions (miliaria-like, eczematous). (Demonstrated histologically, PMID 3654220.)
  8. Branch C (airway): loss of ENaC-mediated airway surface liquid absorption → impaired mucus clearance / fluid handling → recurrent respiratory symptoms; neonatally, failure to clear fetal lung liquid is lethal in constitutive KO mice (PMID 9326675) — an inferred contributor to neonatal respiratory vulnerability in humans.
  9. Severe hyponatremia + hyperkalemia → cardiac arrhythmia/arrest, dehydration, shock → neonatal death or hypoxic-ischemic neurological injury if untreated. (Demonstrated clinically, PMID 33690157.)

Supporting detail

  • Molecular pathways: Aldosterone–mineralocorticoid-receptor → ENaC Na⁺ transport pathway (Reactome R-HSA-1799339 "ENaC"; KEGG "aldosterone-regulated sodium reabsorption" hsa04960). Proteolytic activation by furin/CAPs/kallikrein-1 (PMID 42463047, 41671061).
  • Protein dysfunction: Loss-of-function of a trimeric ion channel; cryo-EM structure of human αβγ-ENaC available (PMID 30251954) supports structural interpretation of variants.
  • Cellular processes: Defective transepithelial Na⁺ transport; secondary sweat-gland inflammation (destructive inflammatory reaction, PMID 3654220).
  • Biochemical abnormality: Ion-channel defect (not an enzyme deficiency) → electrolyte/acid-base derangement.
  • Immune/metabolic/epigenetic: No primary autoimmune or metabolic component; skin inflammation is secondary to hypertonic sweat.
  • Molecular profiling: No disease-specific transcriptomic/proteomic/metabolomic datasets; a systems-medicine interactome highlights sodium-ion-transport and aldosterone-regulated reabsorption processes (PMID 41569463).

Ontology: GO:0006814 (sodium ion transport), GO:0035725 (sodium ion transmembrane transport), GO:0050891 (multicellular organismal water homeostasis), GO:0003051 (angiotensin-mediated regulation of ECF volume); CL:1000714 (kidney collecting duct principal cell), CL:1000454 (kidney collecting duct epithelial cell), CL:0002254 (epithelial cell of distal tubule), CL:0000078 (epithelial cell of sweat gland duct / CL:1000296), CL:0002633 (respiratory epithelial cell).

7. Anatomical Structures Affected

  • Organ level (primary): Kidney (distal nephron: connecting tubule, cortical/medullary collecting duct) — UBERON:0001232 (collecting duct), UBERON:0004135 (connecting tubule). Distal colon (UBERON:0001157). Sweat glands (UBERON:0001820) and salivary glands (UBERON:0001044). Lung/airway (UBERON:0001005 respiratory airway; UBERON:0002186 bronchiole).
  • Secondary/complication organs: Heart (hyperkalemic arrhythmia; UBERON:0000948), brain (hypoxic-ischemic injury post-arrest; UBERON:0000955), skin (UBERON:0002097) with sweat-gland inflammation.
  • Body systems: Endocrine (mineralocorticoid signaling), renal/urinary, gastrointestinal, integumentary, respiratory; cardiovascular and nervous secondarily.
  • Tissue/cell level: Epithelial tissue — Na⁺-reabsorbing principal cells of the collecting duct, distal colonic enterocytes, sweat/salivary duct epithelial cells, airway epithelial cells. CL terms as in §6.
  • Subcellular level: Apical plasma membrane (GO:0016324) — ENaC resides on the apical membrane of multiciliated/epithelial cells (and in cilia; PMID 26772908); trafficking involves ER/Golgi (furin cleavage) and membrane recycling (NEDD4L/ubiquitin). GO CC: GO:0016324 (apical plasma membrane), GO:0034707 (chloride channel complex – N/A), GO:0005886 (plasma membrane).
  • Localization/lateralization: Systemic and bilateral/symmetric (both kidneys, generalized skin/gland involvement).

8. Temporal Development

  • Onset: Congenital/neonatal, typically acute salt-wasting crisis in the first days–2 weeks of life (median ~14 days; PMID 42549990). Milder hypomorphic alleles may present later or more insidiously (PMID 40153144).
  • Progression: No formal staging. Natural history = chronic lifelong disease with recurrent episodic crises superimposed on a persistent requirement for sodium/potassium management. The most dangerous window is the neonatal/infantile period (highest mortality). Symptoms/medication needs often ease but do not disappear with age (PMID 41569463: "symptoms tend to improve with age") — in contrast to renal PHA1A, which can remit in childhood.
  • Patterns: No spontaneous remission in the systemic form; "improvement" reflects maturation of compensatory mechanisms and better tolerance, not cure. Critical period / window of opportunity: rapid neonatal recognition and correction of hyperkalemia/hyponatremia is life-saving (PMID 42569709).

9. Inheritance and Population

  • Epidemiology: Ultra-rare. Orphanet classifies PHA type 1 as a rare disease (point prevalence <1/1,000,000); the systemic (ENaC) form is rarer than the renal (NR3C2) form, and PHA1B3 (SCNN1G) is one of three systemic subtypes. Precise incidence/prevalence figures are unavailable; data come from case reports/small series. Neonatal hyponatremia series find genetic hypo-/pseudo-hypoaldosteronism in a few percent of referred cases (PMID 31300884).
  • Inheritance: Autosomal recessive. 25% recurrence risk for sibs of an affected child.
  • Penetrance / expressivity: Essentially complete penetrance of the biochemical phenotype with biallelic null alleles; variable expressivity with partial-function alleles (§4).
  • Anticipation / mosaicism: Not applicable (not a repeat disorder; no reported germline mosaicism relevant to AR transmission).
  • Founder effects: Yes — a shared SCNN1G 318-1 G→A haplotype in Indian-subcontinent families (PMID 8640238).
  • Consanguinity: Strong driver (78%–100% of reported families; PMID 42549990, 33690157).
  • Carrier frequency: Not formally established; carriers (parents) are asymptomatic.
  • Population demographics: Higher among South Asian, Middle Eastern, and African / consanguineous populations (PMID 33690157). Sex ratio ≈ 1:1 (autosomal). Age distribution: overwhelmingly neonates/infants at diagnosis.

10. Diagnostics

  • Laboratory (LOINC-codable): Serum Na⁺ (LOINC 2951-2) ↓, K⁺ (2823-3) ↑, bicarbonate/CO₂ ↓ with hyperchloremic metabolic acidosis; plasma renin activity ↑↑ and serum/plasma aldosterone ↑↑ (hyperreninemic hyperaldosteronism); inappropriately high urine sodium; elevated sweat chloride (LOINC 2075-0) and salivary Na⁺. Normal 17-hydroxyprogesterone (LOINC 1668-3) and cortisol help exclude CAH/adrenal insufficiency (PMID 42549990).
  • Biomarkers: Aldosterone and renin (markedly elevated); sweat/salivary electrolytes; SCNN1G genotype is the definitive marker.
  • Imaging: Non-specific; used to exclude adrenal pathology (adrenal ultrasound) and renal tract anomalies (to exclude secondary PHA from obstruction/reflux).
  • Electrophysiology: ECG for hyperkalemic changes (peaked T waves, widened QRS) — critical acute monitoring. Research: Ussing-chamber/two-electrode voltage clamp confirm reduced amiloride-sensitive current for VUS (PMID 40153144).
  • Biopsy/pathology: Not required for diagnosis; sweat-gland biopsy historically showed peri-ductal destructive inflammation (PMID 3654220).
  • Genetic testing (definitive): Clinical/whole-exome sequencing or targeted ENaC/PHA gene panels covering SCNN1A, SCNN1B, SCNN1G + NR3C2 (± secondary genes); single-gene or deletion/duplication (CNV/MLPA) analysis for gross deletions (PMID 41275343). PMID 42549990: "Genetic testing was performed using clinical exome sequencing, and variants were classified according to… (ACMG) guidelines." Early genetic testing is advocated because PHA1A vs PHA1B cannot be distinguished clinically/biochemically at presentation (PMID 31301676).
  • Clinical criteria: No formal consensus criteria; diagnosis = neonatal salt wasting + hyperreninemic hyperaldosteronism + ENaC-gene biallelic variants.
  • Differential diagnosis: salt-wasting CAH (21-hydroxylase deficiency — high 17-OHP; PMID 27485500); aldosterone synthase deficiency (CYP11B2); primary adrenal insufficiency / adrenal hypoplasia congenita (NR0B1); familial glucocorticoid deficiency (MC2R); Bartter syndrome type II (transient neonatal hyperkalemia then hypokalemic alkalosis; PMID 40630717); renal PHA1A (NR3C2, milder/remitting); secondary/transient PHA (UTI/obstructive uropathy).
  • Screening: Not on routine newborn screening. Cascade/carrier testing for consanguineous families; prenatal/preimplantation testing possible once the familial variant is known.

11. Outcome / Prognosis

  • Mortality: High in the neonatal/infantile period. 25% mortality (3/12) with 16% severe neurological impairment post-hyperkalemic cardiac arrest in a UK cohort (PMID 33690157); 67% (6/9) died in an Indian series with limited resources (PMID 42549990). Deaths are driven by hyperkalemic cardiac arrest and crises.
  • Life expectancy / survival: With early diagnosis and intensive lifelong management, normal survival and development are achievable; PMID 33690157: "survival with normal physical and neurological outcome is possible, justifying intensive management." One survivor had a successful pregnancy at age 28.
  • Morbidity / disability: Recurrent electrolyte crises, growth faltering, skin disease, respiratory symptoms; neurodevelopmental sequelae mainly from hypoxic-ischemic events during crises.
  • Complications: Hyperkalemic arrhythmia/arrest, hypovolemic shock, failure to thrive, recurrent infections/respiratory disease, nephrocalcinosis (from therapy) and treatment burden.
  • Prognostic factors: Residual ENaC function (allele type) — null/truncating = severe; hypomorphic missense = milder (§4/§9); speed of neonatal recognition and adequacy of electrolyte control; access to care. No validated molecular prognostic biomarker beyond genotype.

12. Treatment

No cure or disease-modifying/gene therapy exists; management is supportive and lifelong. Mineralocorticoids (fludrocortisone) are ineffective because the defect is downstream of the receptor.

  • Acute crisis: IV normal saline/volume resuscitation; aggressive hyperkalemia management (calcium gluconate for cardioprotection; insulin-glucose, β-agonists to shift K⁺; cation-exchange resins to remove K⁺); correction of acidosis with sodium bicarbonate/citrate. (NCIT: fluid resuscitation; electrolyte management.)
  • Chronic maintenance (mainstays):
  • High-dose oral sodium chloride (salt) supplementation — CHEBI:26710 (sodium chloride); NCIT:C83164 (sodium chloride). Doses are high and require frequent titration (PMID 42569709).
  • Sodium bicarbonate / sodium citrate for metabolic acidosis (CHEBI:32139; NCIT sodium bicarbonate).
  • Potassium-lowering therapy: sodium polystyrene sulfonate (Kayexalate) or calcium polystyrene sulfonate resins, often decanted into feeds for infants (PMID 38288475: "successfully managed with sodium polystyrene sulfonate decanted into feeds along with sodium supplementation"). Newer K⁺ binders (patiromer, sodium zirconium cyclosilicate) are options in principle.
  • Dietary potassium restriction.
  • Pharmacogenomics: Not applicable (no genotype-directed drug metabolism issue). Treatment is genotype-informed in that systemic (ENaC) disease mandates lifelong therapy vs potential weaning in renal PHA1A.
  • Advanced/experimental therapeutics: No approved gene/cell/RNA therapy. ENaC biology is an active drug target in the opposite direction (ENaC inhibitors for cystic fibrosis; PMID 42184559) — not applicable to loss-of-function PHA. No disease-specific clinical trials (no NCT identifiers specific to PHA1B3).
  • Surgical/rehabilitative: None specific; supportive nutrition/growth support; respiratory care as needed.
  • Treatment strategy: Early molecular diagnosis → lifelong high-sodium + K⁺-binder regimen with frequent electrolyte-guided dose adjustment; multidisciplinary team (endocrinology, nephrology, dietetics) (PMID 35918792).

13. Prevention

  • Primary prevention: Not possible for an inherited monogenic disease. Genetic counseling for consanguineous couples and families with an affected child; carrier testing, and where desired prenatal diagnosis / preimplantation genetic testing once the familial SCNN1G variant is known (25% recurrence risk).
  • Secondary prevention (early detection): High index of suspicion for any neonate with hyponatremia + hyperkalemia + acidosis; rapid genetic testing to subtype and guide therapy (PMID 31301676). Not part of standard newborn blood-spot screening.
  • Tertiary prevention (complication avoidance): Strict electrolyte control, written sick-day/crisis plans, prompt management of intercurrent illness, avoidance of K⁺-raising drugs and excessive heat/sweat losses, regular cardiac (ECG) and growth monitoring.
  • Immunization / public-health / environmental interventions: Not applicable (non-infectious, non-environmental cause); routine childhood immunization and infection prevention reduce crisis triggers.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: ENaC subunits are conserved across tetrapods (PMID 26772908: four ENaC paralogs in most Sarcopterygii). Human SCNN1G orthologs: mouse Scnn1g (NCBI Gene 20278; Mus musculus, NCBI:txid10090), rat Scnn1g (Rattus norvegicus, NCBI:txid10116).
  • Natural disease in animals: No well-characterized spontaneous SCNN1G-PHA described in companion animals (not a recognized OMIA entry for γ-ENaC PHA). Disease knowledge is from engineered models, not natural occurrence.
  • Comparative biology: ENaC's dual role in renal salt handling and airway/lung-liquid clearance is conserved; mouse knockouts reveal the lung-liquid role that is harder to observe clinically in humans. Evolutionary conservation of the αβγ architecture underpins model validity.
  • Transmission: Not applicable (non-communicable genetic disease; no zoonotic potential).

15. Model Organisms

  • Mouse (primary model; Mus musculus, MGI):
  • Constitutive αENaC (Scnn1a) knockout — neonatal lethal from failure to clear fetal lung liquid (PMID 9326675): "inactivation of alphaENaC results in failure to clear fetal lung liquid at birth and in early neonatal death."
  • Transgenically rescued αENaC⁻/⁻Tg — reproduces systemic PHA-1: "alphaENaC(−/−)Tg mice showed clinical features of severe PHA-1 with metabolic acidosis, urinary salt-wasting, growth retardation, and 50% mortality"; adults show compensated PHA-1 with 6-fold elevated aldosterone (PMID 9326675). This is the classic mouse model for PHA-1.
  • Conditional, adult nephron-specific αENaC knockout (Scnn1a^Pax8/LC1) — hyperkalemia and weight loss on normal diet, rescued by high-Na/low-K diet, "thus mimicking PHA-1" (PMID 26701978) — isolates the renal phenotype and demonstrates diet dependence.
  • αENaC-deficient (rescued) mice — impaired respiratory Na⁺ transport predisposing to pulmonary oedema (PMID 15308680) — models the airway dimension.
  • γENaC-specific mouse mutants (e.g., distal polybasic-tract/cleavage-site mutants) illuminate γ-subunit proteolytic activation and sodium conservation (PMID 42037165).
  • In-vitro / heterologous systems: Xenopus oocytes and mammalian cells with two-electrode/patch-clamp electrophysiology are the standard for functionally classifying SCNN1G variants (PMID 40153144, 40969802); cryo-EM of human ENaC provides structural context (PMID 30251954).
  • Phenotype recapitulation: Mouse models reproduce salt wasting, hyperkalemia, acidosis, hyperaldosteronism (renal/systemic PHA) and the neonatal lung-liquid phenotype. Limitations: constitutive KO lethality necessitates transgenic/conditional strategies; models are predominantly αENaC-based (direct biallelic Scnn1g-null disease models are less commonly reported); species differences in ENaC proteolysis exist.
  • Resources: MGI (Scnn1g MGI gene), IMPC/KOMP, IMSR for strain availability.

Supported vs Refuted Hypotheses

Supported (evidence-based): - PHA1B3 is caused by biallelic LoF SCNN1G (γ-ENaC) variants → systemic aldosterone resistance. ✔ (PMID 42549990, 40969802, 8640238) - Neonatal salt-wasting triad with hyperreninemic hyperaldosteronism. ✔ (PMID 42549990, 33690157) - Multi-organ (systemic) involvement incl. sweat/salivary/skin/airway. ✔ (PMID 3654220, 26772908) - Loss-of-function mechanism with genotype-severity correlation. ✔ (PMID 40153144, 31301676) - Mouse ENaC-KO recapitulates PHA-1. ✔ (PMID 9326675, 26701978) - Ultra-rare AR disease, consanguinity/founder effects. ✔ (PMID 33690157, 8640238)

Refuted / excluded: - Mineralocorticoid (fludrocortisone) therapy is effective — refuted; defect is downstream of MR. - Disease is renal-limited — refuted; systemic multi-organ disease (distinguishes from PHA1A/NR3C2). - Caused by gain-of-function — refuted; GoF SCNN1G causes Liddle syndrome instead (PMID 35661050).

Limitations & Future Directions

  • Ultra-rarity → no large cohorts, no formal prevalence/QoL/natural-history statistics; evidence skewed to case reports.
  • Most mechanistic/model data are αENaC-centric; γENaC(Scnn1g)-null disease models and SCNN1G-specific genotype-phenotype datasets are limited.
  • No approved targeted therapy; LoF channelopathies are not yet correctable — potential future directions: read-through/ASO for specific alleles, channel-activating small molecules, or gene/base-editing (all pre-clinical).

Evidence source types: human clinical (case series/reports, functional patient studies), model organism (mouse), in vitro (heterologous electrophysiology), computational/structural (cryo-EM, network medicine).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 25
On topic 16
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 50
Resolved 47
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 28
Terms named correctly 9
Terms named as a different term 9
Terms whose name is worth a second look 10

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0002902 (1 mention) - the report calls it "Lab abnormality"; HP calls it Hyponatremia
  • HP:0002153 (1 mention) - the report calls it "Lab abnormality"; HP calls it Hyperkalemia
  • HP:0001942 (1 mention) - the report calls it "Lab abnormality"; HP calls it Metabolic acidosis
  • HP:0000859 (1 mention) - the report calls it "Lab abnormality"; HP calls it Increased circulating aldosterone concentration
  • HP:0001944 (1 mention) - the report calls it "Clinical sign"; HP calls it Dehydration
  • HP:0002013 (1 mention) - the report calls it "Symptom"; HP calls it Vomiting
  • HP:0001254 (1 mention) - the report calls it "Symptom"; HP calls it Lethargy
  • HP:0002028 (1 mention) - the report calls it "Clinical sign"; HP calls it Chronic diarrhea
  • NCIT:C83164 (1 mention) - the report calls it "sodium chloride"; NCIT calls it Birth Year

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0050891 (1 mention) - the report calls it "multicellular organismal water homeostasis"; GO calls it multicellular organismal-level water homeostasis, and lists "multicellular organismal water homeostasis" among its other names
  • GO:0003051 (1 mention) - the report calls it "angiotensin-mediated regulation of ECF volume"; GO calls it angiotensin-mediated drinking behavior
  • CL:1000714 (1 mention) - the report calls it "kidney collecting duct principal cell"; CL calls it kidney cortex collecting duct principal cell
  • CL:0002254 (1 mention) - the report calls it "epithelial cell of distal tubule"; CL calls it epithelial cell of small intestine
  • CL:0002633 (1 mention) - the report calls it "respiratory epithelial cell"; CL calls it respiratory basal cell
  • UBERON:0004135 (1 mention) - the report calls it "connecting tubule"; UBERON calls it distal tubule, and lists "kidney distal tubule" among its other names
  • UBERON:0001157 (1 mention) - the report calls it "Distal colon"; UBERON calls it transverse colon
  • UBERON:0002097 (1 mention) - the report calls it "skin"; UBERON calls it skin of body, and lists "skin" among its other names
  • GO:0016324 (2 mentions) - the report calls it "Apical plasma membrane", "apical plasma membrane", "Subcellular level: Apical plasma membrane"; GO calls it apical plasma membrane
  • GO:0034707 (1 mention) - the report calls it "chloride channel complex – N/A"; GO calls it chloride channel complex

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0016324 - called "Apical plasma membrane", "apical plasma membrane", "Subcellular level: Apical plasma membrane"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.