Pseudohypoaldosteronism Type IB1 Autosomal Recessive

Mendelian MONDO:0009917 Pathograph 30 Show in embeddings browser Pseudohypoaldosteronism type 1 Autosomal recessive disease

Pseudohypoaldosteronism type IB1 (PHA1B1) is the SCNN1A-related form of autosomal recessive, systemic (multi-organ) pseudohypoaldosteronism type 1, and the most frequently genotyped of the three ENaC subunit forms. Biallelic loss-of-function variants in SCNN1A, which encodes the alpha subunit of the amiloride-sensitive epithelial sodium channel (ENaC), remove the subunit the channel cannot function without. Failure of ENaC-mediated sodium reabsorption in the aldosterone-sensitive 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, hyperkalemia and metabolic acidosis despite high renin and aldosterone. ENaC loss in the colon and sweat glands adds extra-renal salt loss, and loss in the airway leaves excess airway surface liquid with recurrent chest symptoms. Truncating alleles cause a lifelong course; missense alleles that leave partial channel activity can cause a mild or transient one. Treatment is lifelong sodium chloride with potassium control. The SCNN1B (PHA1B2) and SCNN1G (PHA1B3) 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) SCNN1A variants. Most reported families are consanguineous and parents are usually asymptomatic, although carriers of the p.Ser562Pro allele had raised sweat sodium and chloride with no clinical or hormonal abnormality.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:23416952 SUPPORT Human clinical
"All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance."
Asymptomatic heterozygous parents of seven SCNN1A-homozygous children confirm recessive inheritance.
PMID:18547339 SUPPORT Human clinical
"In heterozygote carriers, sweat sodium and chloride concentrations were increased without additional hormonal or clinical phenotypes."
Carriers of one SCNN1A S562P allele show only a subclinical sweat electrolyte change.
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Discussions and Knowledge Gaps

1
Why do alphaENaC-null mice die from retained lung liquid at birth when a preterm infant homozygous for an SCNN1A loss-of-function variant adapted to air breathing normally?
HUMAN MODEL MISMATCH OPEN alpha_enac_lung_liquid_mismatch
Attached to
pathophysiology#Airway epithelial sodium absorption failure
The mouse knockout made ENaC look essential for clearing fetal lung liquid, but the human SCNN1A case shows that postnatal alveolar fluid clearance does not critically depend on ENaC in humans. Airway ENaC loss in patients instead shows up later as excess airway surface liquid and recurrent chest symptoms. The mouse is therefore a poor guide to the timing and severity of the respiratory phenotype, and the species difference in fetal lung liquid clearance is unexplained.
Show evidence (2 references)
PMID:8589728 SUPPORT Model organism
"Alpha-ENaC(-/-) neonates developed respiratory distress and died within 40 h of birth from failure to clear their lungs of liquid."
The mouse knockout is lethal through failed lung liquid clearance.
PMID:22124517 SUPPORT Human clinical
"We conclude that clearance of alveolar fluid after birth in humans does not critically depend on ENaC."
A human SCNN1A-null infant did not reproduce the mouse lung phenotype.
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Pathophysiology

8
Biallelic SCNN1A loss of function
Biallelic SCNN1A variants remove or impair the ENaC alpha subunit. In heterologous expression the beta and gamma subunits cannot produce an amiloride-sensitive current without alpha, which may explain why SCNN1A is the gene most often affected. Missense alleles such as p.Phe226Cys reduce channel activity and expression only partly, matching their milder course.
SCNN1A hgnc:10599 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCNN1A (hgnc:10599). hgnc:10599 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 (3 references)
PMID:8589714 SUPPORT Human clinical
"These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of channel activity."
Recessive PHA1 alleles in the alpha and beta subunits abolish channel activity.
PMID:23416952 SUPPORT Human clinical
"The α subunit is essential for ENaC function and mutations truncating the pore-forming part of the protein leading to systemic PHA1."
Truncation of the pore-forming alpha subunit causes systemic PHA1.
PMID:37134141 SUPPORT In vitro / ex vivo
"In functional studies in X. laevis oocytes, p.Phe226Cys caused a significant reduction of ENaC activity (83% reduction), reduced the number of active ENαC mutant channels, and reduced the basal open probability compared with wt."
A mild-phenotype SCNN1A missense allele leaves partial channel activity in oocytes.
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 it aldosterone cannot drive sodium reabsorption, producing end-organ mineralocorticoid resistance and urinary salt wasting. Adult nephron-specific alphaENaC deletion in mice reproduces the syndrome, which no other transporter compensates except under a high-sodium, low-potassium 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 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
Adult nephron-specific alphaENaC knockout mouse Mouse recapitulates Reproduces renal salt loss and hyperkalemia from loss of nephron alphaENaC.
Downstream
Renal salt wasting
Extracellular volume depletion
Impaired distal potassium and hydrogen ion secretion
Show evidence (2 references)
PMID:26701978 SUPPORT Model organism
"We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1."
Renal alphaENaC deletion alone reproduces the salt-losing, hyperkalemic syndrome.
PMID:26701978 SUPPORT Model organism
"In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet."
Other nephron transporters do not compensate for absent alphaENaC.
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.
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.
Downstream
Hyperkalemia
Metabolic acidosis
Show evidence (1 reference)
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.
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.
Animal models
Adult nephron-specific alphaENaC knockout mouse Mouse rescues A high-sodium, reduced-potassium diet normalizes weight and electrolytes.
Downstream
Hyponatremia
Dehydration
Hypotension
Hypovolemic shock
Compensatory renin-angiotensin-aldosterone activation
Failure to thrive in infancy
Show evidence (1 reference)
PMID:26701978 SUPPORT BACKGROUND Human clinical
"Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal life-threatening hypovolemia and hyperkalemia."
Background statement from a mouse study describing the human hypovolemic salt-losing syndrome.
Compensatory renin-angiotensin-aldosterone activation
Volume depletion stimulates renin secretion and aldosterone synthesis, but aldosterone cannot act through the absent channel, so plasma renin and aldosterone stay 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)
PMID:22124517 SUPPORT Human clinical
"At nine days of life, he became lethargic and hyperthermic, displaying low Na(+) (126 mmol l(-1)), high K(+) (8.9 mmol l(-1)), high aldosterone (3000 ng l(-1))and high renin (1000 ng l(-1)) plasma concentrations, commensurate with pseudohypoaldosteronism type I."
High renin and aldosterone alongside hyponatremia and hyperkalemia in an SCNN1A-homozygous infant.
Sweat duct sodium reabsorption failure
ENaC on the apical membrane of the eccrine sweat duct reabsorbs sodium from primary sweat. Without it sweat sodium and chloride are high, as a positive sweat test.
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 (2 references)
PMID:28130590 SUPPORT In vitro / ex vivo
"In the eccrine glands and ducts, ENaC and CFTR are located on the apical side of the membrane."
Human skin immunostaining places ENaC at the apical membrane of the sweat duct, where salt is reabsorbed.
PMID:31018202 SUPPORT Human clinical
"All patients exhibited laboratory characteristics including severe hyponatremia, hyperkalemia, metabolic acidosis, elevated plasma renin, elevated aldosterone, and positive sweat tests, suggesting a diagnosis of systemic PHA1."
Positive sweat tests in a series that includes two SCNN1A patients.
Colonic sodium absorption failure
ENaC mediates amiloride-sensitive sodium absorption in the surface epithelium of the distal colon. Its loss adds fecal sodium loss and a colonic form of aldosterone resistance 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)
PMID:24480829 SUPPORT Model organism
"However, Scnn1a(KO) mice fed a low-salt diet lost significant amounts of sodium in their feces and exhibited high plasma aldosterone and increased urinary sodium retention."
Colon-specific alphaENaC deletion causes fecal sodium loss under salt restriction.
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 twice the normal airway surface liquid volume, and recurrent chest congestion, cough and wheeze in early childhood. In alphaENaC-null mice airway sodium transport is abolished and neonates die from retained lung liquid, but a preterm SCNN1A-homozygous infant breathed normally after birth.
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
alphaENaC-null mouse Mouse recapitulates Reproduces loss of amiloride-sensitive airway sodium transport.
Downstream
Wheezing
Cough
Recurrent respiratory 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 SCNN1A.
PMID:8589728 SUPPORT Model organism
"Amiloride-sensitive electrogenic Na+ transport was abolished in airway epithelia from alpha-ENaC(-/-) mice."
Loss of alphaENaC abolishes airway sodium transport in mice.
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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 IB1 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

19
Cardiovascular 3
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 was mostly SCNN1A.
Hypovolemic shock FREQUENT HP:0031274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypovolemic shock (HP:0031274). HP:0031274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:171876 SUPPORT Other
"HP:0031274 | Hypovolemic shock | Frequent (79-30%)"
Orphanet records hypovolemic shock as frequent.
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:38963175 SUPPORT Human clinical
"We report a boy with PHA1B, who presented with vomiting, lethargy, and poor feeding due to salt wasting six days after birth."
Vomiting at presentation in an SCNN1A-homozygous neonate.
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)
PMID:22124517 SUPPORT Human clinical
"At nine days of life, he became lethargic and hyperthermic, displaying low Na(+) (126 mmol l(-1)), high K(+) (8.9 mmol l(-1)), high aldosterone (3000 ng l(-1))and high renin (1000 ng l(-1)) plasma concentrations, commensurate with pseudohypoaldosteronism type I."
Plasma aldosterone of 3000 ng/l in an SCNN1A-homozygous infant.
Genitourinary 2
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:23813355 SUPPORT BACKGROUND Human clinical
"Systemic pseudohypoaldosteronism type 1 (PHA1) is characterized by excessive salt loss from the renal tubulus, colon, sweat and salivary glands."
Renal salt loss is a defining feature of systemic PHA1, stated in an SCNN1A case report.
Female infertility HP:0008222 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Female infertility (HP:0008222). HP:0008222 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29885352 SUPPORT Human clinical
"Our results support the hypothesis that lack of expression of ENaC on the endometrial surface may be responsible for the infertility of the PHA patient."
Infertility with absent endometrial ENaC in a patient with an SCNN1A nonsense variant.
Immune 2
Atopic dermatitis OCCASIONAL HP:0001047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atopic dermatitis-like skin lesions, annotated with Atopic dermatitis (HP:0001047). HP:0001047 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:0001047 | Atopic dermatitis | Occasional (29-5%)"
Orphanet records atopic dermatitis as occasional in generalized PHA1.
Recurrent respiratory infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Sequelae: Bronchiectasis
Show evidence (2 references)
PMID:23416952 SUPPORT Human clinical
"Five out of seven patients exhibited pulmonary symptoms in the neonatal period."
Most SCNN1A-homozygous children had neonatal pulmonary symptoms.
PMID:39419738 SUPPORT REVIEW SYNTHESIS Human clinical
"Lower respiratory tract infections caused by Pseudomonas aeruginosa and Staphylococcus aureus were reported in 3 cases each, while 2 patients developed bronchiectasis."
Bacterial lower respiratory infections are reported in PHA1B, most of whose genotyped cases are SCNN1A.
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.
Show evidence (2 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 SCNN1A cases presented with hyponatremia.
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 (2 references)
PMID:22124517 SUPPORT Human clinical
"At nine days of life, he became lethargic and hyperthermic, displaying low Na(+) (126 mmol l(-1)), high K(+) (8.9 mmol l(-1)), high aldosterone (3000 ng l(-1))and high renin (1000 ng l(-1)) plasma concentrations, commensurate with pseudohypoaldosteronism type I."
Plasma potassium of 8.9 mmol/l in an SCNN1A-homozygous infant.
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:23031435 SUPPORT Human clinical
"We report a neonatal case of systemic pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene (homozygous c.1052+2dupT in intron 3) in which the patient presented with life-threatening hyperkalemia, hyponatremia and metabolic acidosis."
Metabolic acidosis at presentation in an SCNN1A-homozygous neonate.
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 (1 reference)
ORPHA:171876 SUPPORT Other
"HP:0001944 | Dehydration | Frequent (79-30%)"
Orphanet records dehydration as frequent.
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 (2 references)
PMID:31018202 SUPPORT Human clinical
"All patients exhibited laboratory characteristics including severe hyponatremia, hyperkalemia, metabolic acidosis, elevated plasma renin, elevated aldosterone, and positive sweat tests, suggesting a diagnosis of systemic PHA1."
Positive sweat tests in a series including two SCNN1A patients.
PMID:39419738 SUPPORT REVIEW SYNTHESIS Human clinical
"Pathological sweat test results were recorded in all 34 patients with available data."
Every PHA1B case with a reported sweat test was abnormal in a systematic review where most cases were SCNN1A.
Respiratory 3
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.
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.
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.
Bronchiectasis VERY_RARE HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39419738 SUPPORT REVIEW SYNTHESIS Human clinical
"Lower respiratory tract infections caused by Pseudomonas aeruginosa and Staphylococcus aureus were reported in 3 cases each, while 2 patients developed bronchiectasis."
Two of 62 reviewed PHA1B cases with respiratory symptoms developed bronchiectasis.
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 (1 reference)
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
SCNN1A (Causative (biallelic loss of function))
Gene: SCNN1A hgnc:10599 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCNN1A (hgnc:10599). hgnc:10599 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (6 references)
PMID:8589714 SUPPORT Human clinical
"Investigation of affected offspring of consanguineous union reveals mutations in either the alpha or beta subunits of the amiloride-sensitive epithelial sodium channel in five kindreds."
First identification of alpha subunit (SCNN1A) mutations in recessive PHA1.
PMID:8824886 SUPPORT Human clinical
"The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families."
Homozygosity mapping placed one PHA1 locus at 12p13, where SCNN1A lies.
ORPHA:171876 SUPPORT Other
"SCNN1A | sodium channel epithelial 1 subunit alpha | hgnc:10599 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists germline loss-of-function SCNN1A variants as disease-causing.
+ 3 more references
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Medical Actions

4
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
Oral sodium chloride, often in large and frequent doses, replaces renal and extra-renal sodium losses. Systemic PHA1 is harder to manage than the renal form, with recurrent electrolyte crises despite treatment. Infants with the transient missense form have been able to stop supplementation.
Mechanism Target:
Extracellular volume depletion — Replaces renal, sweat and colonic sodium losses.
Show evidence (3 references)
PMID:23762408 SUPPORT Human clinical
"After increasing doses of oral 10%NaCl to 30 mEq/kg/d and doses of ion-exchange resins to 1g/kg/d, the serum potassium level was controlled at 4.5 to 5.5 mmol/L."
High-dose oral sodium chloride with a resin controlled the electrolytes of an SCNN1A patient.
PMID:24616761 SUPPORT Human clinical
"Renal PHA type 1 responds well to salt supplementation, whereas management of patients with systemic PHA type 1 proves more difficult as they are likely to get frequent episodes of electrolyte imbalance requiring urgent correction."
Systemic PHA1 needs salt supplementation but remains prone to recurrent electrolyte crises.
PMID:21653223 SUPPORT Human clinical
"The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo."
In the transient SCNN1A missense form, salt supplementation could be withdrawn.
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 that corrects metabolic acidosis while also supplying sodium.
Mechanism Target:
Metabolic acidosis — Buffers retained acid.
Show evidence (1 reference)
PMID:34134742 SUPPORT Human clinical
"Intravenous (IV) rehydration therapy with sodium chloride and sodium bicarbonate was started, for correction of hyponatremia and metabolic acidosis, respectively."
Sodium bicarbonate was used to correct metabolic acidosis in an SCNN1A patient.
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
Platform: Small molecule
Oral or rectal cation-exchange resins increase fecal potassium excretion to control chronic hyperkalemia.
Mechanism Target:
Hyperkalemia — Removes retained potassium through the gut.
Show evidence (2 references)
PMID:23762408 SUPPORT Human clinical
"After increasing doses of oral 10%NaCl to 30 mEq/kg/d and doses of ion-exchange resins to 1g/kg/d, the serum potassium level was controlled at 4.5 to 5.5 mmol/L."
Ion-exchange resin contributed to potassium control in an SCNN1A patient.
PMID:39295704 SUPPORT Human clinical
"The discharge medication regimen consisted of 3% sodium chloride solution 7 mL administered orally via the nasogastric tube every 4 h, calcium resonium 1 gram orally twice daily, and fludrocortisone 0.3 mg orally once daily."
Maintenance therapy of an SCNN1A infant combined oral sodium chloride with a potassium-binding resin.
Mineralocorticoid 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
Fludrocortisone is often started while salt-wasting adrenal disease is still suspected. It does not correct the electrolyte disturbance, because the defect lies in the channel aldosterone acts on rather than in hormone supply, and it is usually stopped once PHA1 is recognized. Some patients are nonetheless kept on it.
Show evidence (2 references)
PMID:23762408 REFUTE Human clinical
"However, 9α-fluorohydrocortisone (9α-FHC) supplement therapy was ineffective."
Fludrocortisone did not work in an SCNN1A patient.
PMID:24616761 REFUTE Human clinical
"After the diagnosis of PHA was made, the hydrocortisone and fludrocortisone were stopped, and calcium resonium was gradually decreased."
Steroid replacement was withdrawn once PHA1 was diagnosed.
🔬

Diagnosis

3
Biochemical and hormonal profile
Neonatal hyponatremia, hyperkalemia and metabolic acidosis with high plasma renin and aldosterone suggest PHA1. Normal cortisol and 17-hydroxyprogesterone exclude congenital adrenal hyperplasia, the usual first working diagnosis.
Show evidence (2 references)
PMID:24616761 SUPPORT Human clinical
"The differential diagnosis of type 1 PHA includes adrenal disorders such as adrenal hypoplasia and congenital adrenal hyperplasia; thus, adrenal function including cortisol levels, 17-hydroxyprogesterone and a urinary steroid profile are required."
Adrenal function testing is required to exclude adrenal causes before PHA1 is diagnosed.
PMID:39295704 SUPPORT Human clinical
"Initial evaluation for congenital adrenal hyperplasia was unremarkable."
In an SCNN1A-confirmed infant, congenital adrenal hyperplasia was excluded before the genetic diagnosis.
Sweat test
Raised sweat (or saliva) sodium and chloride reflect extra-renal ENaC loss and support the systemic rather than the renal form of PHA1. Missense alleles that leave residual channel function can give a normal sweat test.
sweat chloride and sodium LOINC:74993-7 Logical Observation Identifiers Names and Codes (LOINC)
The sweat chloride and sodium panel is bound because the cited sources report both electrolytes as raised. No reference range is bound: the cited sources give no SCNN1A-specific decision limit, and the cystic fibrosis sweat chloride thresholds belong to a different disease.
Show evidence (2 references)
PMID:24616761 SUPPORT Human clinical
"A positive saliva or sweat test showing increased sodium and chloride levels helps to complete the diagnostic picture for AR PHA"
A positive sweat or saliva test supports autosomal recessive (systemic) PHA1.
PMID:24616761 SUPPORT Human clinical
"A differentiation between renal and systemic PHA type 1 may be made based on sodium requirements, ease of management of electrolyte imbalance, sweat test results and genetic testing."
Sweat test results help separate systemic from renal PHA1.
Molecular genetic testing of SCNN1A
Sequencing, usually by a next-generation sequencing panel or exome, finds biallelic SCNN1A variants and confirms PHA1B1. It also identifies heterozygous carriers in the family.
Genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:34134742 SUPPORT Human clinical
"Next generation sequencing (NGS) techniques allowed the identification of the SCNN1A gene mutation either in both patients or in other heterozygous family members, enabling also primary prevention of disease."
NGS identified the SCNN1A variant in patients and carriers.
PMID:23762408 SUPPORT Human clinical
"The results of hormone levels and TTKG value tests provided further evidence of PHA1 and the clinical diagnosis was confirmed by molecular genetic testing."
Molecular genetic testing confirmed the clinical diagnosis in an SCNN1A patient.
📈

Progression

3
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.
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:31018202 SUPPORT Human clinical
"The ages at presentation were postnatal days 9, 10, and 5."
Presentation in the first ten days of life in a series including two SCNN1A patients.
Chronic course with recurrent salt-losing crises
Age: Infancy to adulthood
With truncating alleles the systemic form does not remit and salt-losing crises recur. Mortality and post-arrest neurological injury are substantial in case series, but survival into adulthood with a successful pregnancy has been reported.
Show evidence (3 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: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.
PMID:33690157 SUPPORT Human clinical
"One affected female had a successful pregnancy at the age of 28 years."
Survival to adulthood with a successful pregnancy is possible.
Mild or transient course with partial-function missense alleles
Age: Neonatal period to early childhood
Some SCNN1A missense alleles leave partial channel activity and give a mild or transient course, with variable expressivity and incomplete penetrance within families.
Show evidence (2 references)
PMID:21653223 SUPPORT Human clinical
"The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo."
A homozygous SCNN1A missense allele produced a transient neonatal course in a preterm infant.
PMID:37134141 SUPPORT Human clinical
"We present 12 patients from four different families with a mild and transient autosomal recessive PHA1 due to a novel homozygous missense mutation in the SCNN1A gene."
A homozygous SCNN1A missense allele causes mild, transient disease across four families.
📊

Prevalence

2
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 SCNN1A-specific figure is available.
Show evidence (1 reference)
ORPHA:171876 SUPPORT Other
"1-9 / 1 000 000 | United Kingdom | Prevalence at birth | PMID:24616761"
Orphanet epidemiology row for generalized PHA1.
Published PHA1B cases with respiratory symptoms and an identified variant
Cases/families reported in the literature
In a systematic review of PHA1B cases with respiratory symptoms, 36 of 47 patients with an identified variant carried it in SCNN1A. This is the share of SCNN1A among genotyped cases, not a population rate.
Show evidence (3 references)
PMID:39419738 SUPPORT REVIEW SYNTHESIS Human clinical
"In 36/47 patients the underlying pathogenic variant was identified in SCNN1A gene."
SCNN1A is the predominant gene among genotyped PHA1B cases in a systematic review.
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."
Alpha subunit variants account for most multisystem PHA cases.
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 most mutations were in SCNN1A.
🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Pseudohypoaldosteronism Type IB1 Autosomal Recessive:

Congenital adrenal hyperplasia
Overlapping Features Salt-wasting congenital adrenal hyperplasia (21-hydroxylase or 3-beta-hydroxysteroid dehydrogenase deficiency) produces the same neonatal hyponatremia, hyperkalemia and acidosis.
Distinguishing Features
  • Normal cortisol and 17-hydroxyprogesterone with high aldosterone in PHA1
  • No response to mineralocorticoid replacement in PHA1
Show evidence (2 references)
PMID:23762408 SUPPORT Human clinical
"The symptoms of PHA1 are easily confused with the symptoms of congenital adrenal hyperplasia (CAH) associated with 21-hydroxylase deficiency or 3-beta-hydroxysteroid dehydrogenase deficiency; and the symptoms of hypoaldosteronism (HA) due to aldosterone deficiency, antenatal or infantile Bartter..."
Names CAH, aldosterone deficiency and Bartter syndrome as conditions confused with PHA1.
PMID:39295704 SUPPORT Human clinical
"These findings helped to rule out congenital adrenal hyperplasia."
Hormonal studies excluded CAH in an SCNN1A infant.
Autosomal dominant pseudohypoaldosteronism type 1 MONDO:0008329
Overlapping Features Renal PHA1 from heterozygous NR3C2 variants causes kidney-limited salt wasting that responds well to salt and improves with age.
Distinguishing Features
  • Normal sweat electrolytes in renal PHA1
  • Lower sodium requirement and easier electrolyte control in renal PHA1
Show evidence (2 references)
PMID:24616761 SUPPORT Human clinical
"A differentiation between renal and systemic PHA type 1 may be made based on sodium requirements, ease of management of electrolyte imbalance, sweat test results and genetic testing."
Lists the features that separate renal from systemic PHA1.
PMID:23762408 SUPPORT Human clinical
"Mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G) of the epithelial sodium channel (ENaC) and the NR3C2 gene encoding the mineralocorticoid receptor, result in systemic PHA1 and renal PHA1 respectively."
Renal PHA1 is the NR3C2 form, distinct from the ENaC-related systemic form.
Hypoaldosteronism due to aldosterone deficiency
Overlapping Features Aldosterone deficiency causes infantile salt wasting with hyponatremia and hyperkalemia, but aldosterone is low rather than high.
Distinguishing Features
  • Low aldosterone in aldosterone deficiency versus high aldosterone in PHA1
Show evidence (1 reference)
PMID:34134742 SUPPORT Human clinical
"Congenital adrenal hyperplasia (CAH) due to 21-β-hydroxylase or 3-β-hydroxysteroid dehydrogenase deficiency, hypoaldosteronism due to aldosterone deficiency, and Bartter syndrome should be considered as possible differential diagnosis in affected newborns"
Lists aldosterone deficiency among the neonatal differential diagnoses of SCNN1A-related PHA1.
Bartter syndrome
Overlapping Features Antenatal or infantile Bartter syndrome causes neonatal renal salt wasting.
Distinguishing Features
  • Hypokalemic alkalosis in Bartter syndrome versus hyperkalemic acidosis in PHA1
Show evidence (1 reference)
PMID:34134742 SUPPORT Human clinical
"Congenital adrenal hyperplasia (CAH) due to 21-β-hydroxylase or 3-β-hydroxysteroid dehydrogenase deficiency, hypoaldosteronism due to aldosterone deficiency, and Bartter syndrome should be considered as possible differential diagnosis in affected newborns"
Lists Bartter syndrome among the neonatal differential diagnoses.
Secondary (transient) pseudohypoaldosteronism
Overlapping Features Transient renal aldosterone resistance from urinary tract infection or a renal anomaly reproduces the biochemical picture in early infancy.
Distinguishing Features
  • Urinary tract infection on urine culture or anomaly on renal ultrasound
Show evidence (1 reference)
PMID:24616761 SUPPORT Human clinical
"Secondary (transient) causes of PHA may be due to urinary tract infections or renal anomalies; thus, urine culture and renal ultrasound scan are required respectively."
Secondary PHA must be excluded with urine culture and renal ultrasound.
Cystic fibrosis MONDO:0009061
Overlapping Features Raised sweat electrolytes and recurrent lower respiratory infections make systemic PHA1 resemble cystic fibrosis.
Distinguishing Features
  • Hyperkalemia with high renin and aldosterone in PHA1
  • No CFTR variants on mutation analysis
Show evidence (1 reference)
PMID:22208790 SUPPORT REVIEW SYNTHESIS Other
"Pseudohypoaldosteronism type 1 may be indistinguishable from cystic fibrosis (CF) unless serum aldosterone, plasma renin activity, and urinary electrolytes are measured and mutation analysis rules out CF."
Review names cystic fibrosis as a differential and lists the tests that separate it.
🐁

Animal Models

2
alphaENaC-null mouse
Germline inactivation of the alpha subunit abolishes airway sodium transport, and neonates die within 40 hours from failure to clear lung liquid.
Species
Mouse
Genotype
Scnn1a-/- (germline targeted disruption)
Publication
PMID:8589728
Pathograph links
Airway epithelial sodium absorption failure recapitulates fidelity: moderate observes: organism Reproduces loss of amiloride-sensitive airway sodium transport.
Limitations: Neonatal death from retained lung liquid is not seen in human SCNN1A loss of function, so the mouse overstates the role of ENaC in postnatal lung adaptation, and its early death prevents study of the chronic airway phenotype.
Show evidence (1 reference)
PMID:8589728 SUPPORT Model organism
"Amiloride-sensitive electrogenic Na+ transport was abolished in airway epithelia from alpha-ENaC(-/-) mice."
Germline alphaENaC loss abolishes airway sodium transport.
Adult nephron-specific alphaENaC knockout mouse
Inducible deletion of alphaENaC in the adult nephron causes hyperkalemia and weight loss on a regular-salt diet, mimicking PHA1, and a high-sodium, low-potassium diet rescues it.
Species
Mouse
Genotype
Scnn1a Pax8/LC1 inducible nephron-specific knockout
Publication
PMID:26701978
Pathograph links
Distal nephron ENaC sodium reabsorption failure recapitulates fidelity: moderate observes: organism Reproduces renal salt loss and hyperkalemia from loss of nephron alphaENaC.
Limitations: Adult induction bypasses the neonatal presentation of the human disease, and the kidney-restricted deletion leaves sweat gland, colon and airway ENaC intact.
Show evidence (1 reference)
PMID:26701978 SUPPORT Model organism
"We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1."
Nephron alphaENaC deletion reproduces the PHA1 renal phenotype.
Extracellular volume depletion rescues fidelity: moderate observes: organism A high-sodium, reduced-potassium diet normalizes weight and electrolytes.
Limitations: Dietary rescue in adult mice does not test the large, frequent sodium doses that infants need.
Show evidence (1 reference)
PMID:26701978 SUPPORT Model organism
"In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized."
Salt loading with potassium restriction rescues the renal phenotype.
{ }

Source YAML

click to show 
name: Pseudohypoaldosteronism Type IB1 Autosomal Recessive
category: Mendelian
creation_date: "2026-11-01T07:35:18Z"
synonyms:
- PHA1B1
- SCNN1A-related systemic pseudohypoaldosteronism type 1
- Autosomal recessive pseudohypoaldosteronism type 1B1
description: >-
  Pseudohypoaldosteronism type IB1 (PHA1B1) is the SCNN1A-related form of
  autosomal recessive, systemic (multi-organ) pseudohypoaldosteronism type 1,
  and the most frequently genotyped of the three ENaC subunit forms. Biallelic
  loss-of-function variants in SCNN1A, which encodes the alpha subunit of the
  amiloride-sensitive epithelial sodium channel (ENaC), remove the subunit the
  channel cannot function without. Failure of ENaC-mediated sodium reabsorption
  in the aldosterone-sensitive 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, hyperkalemia and metabolic acidosis despite high renin and
  aldosterone. ENaC loss in the colon and sweat glands adds extra-renal salt
  loss, and loss in the airway leaves excess airway surface liquid with
  recurrent chest symptoms. Truncating alleles cause a lifelong course;
  missense alleles that leave partial channel activity can cause a mild or
  transient one. Treatment is lifelong sodium chloride with potassium control.
  The SCNN1B (PHA1B2) and SCNN1G (PHA1B3) forms share the mechanism and are
  separate MONDO concepts.
disease_term:
  preferred_term: pseudohypoaldosteronism, type IB1, autosomal recessive
  term:
    id: MONDO:0009917
    label: pseudohypoaldosteronism, type IB1, autosomal recessive
parents:
- Pseudohypoaldosteronism type 1
- Autosomal recessive disease
notes: >-
  The Orphanet record cited here (ORPHA:171876, generalized
  pseudohypoaldosteronism type 1) covers all three ENaC subunit genes, so its
  phenotype frequencies describe systemic PHA1 as a whole rather than the
  SCNN1A form alone. The airway surface liquid study cited for the respiratory
  phenotype (PMID:10403853) reports ENaC subunit mutations without restricting
  itself to SCNN1A. No GeneReviews chapter covers this disorder or systemic
  PHA1, so case reports, case series, a systematic review of pulmonary cases
  and Orphanet form the phenotype baseline.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Biallelic (homozygous or compound heterozygous) SCNN1A variants. Most
    reported families are consanguineous and parents are usually
    asymptomatic, although carriers of the p.Ser562Pro allele had raised sweat
    sodium and chloride with no clinical or hormonal abnormality.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23416952
    reference_title: "Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance."
    explanation: Asymptomatic heterozygous parents of seven SCNN1A-homozygous children confirm recessive inheritance.
  - reference: PMID:18547339
    reference_title: "Revealing a subclinical salt-losing phenotype in heterozygous carriers of the novel S562P mutation in the alpha subunit of the epithelial sodium channel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In heterozygote carriers, sweat sodium and chloride concentrations were increased without additional hormonal or clinical phenotypes."
    explanation: Carriers of one SCNN1A S562P allele show only a subclinical sweat electrolyte change.
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 SCNN1A-specific figure is available.
  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.
- population: Published PHA1B cases with respiratory symptoms and an identified variant
  measure_type: CASES_IN_LITERATURE
  notes: >-
    In a systematic review of PHA1B cases with respiratory symptoms, 36 of 47
    patients with an identified variant carried it in SCNN1A. This is the share
    of SCNN1A among genotyped cases, not a population rate.
  evidence:
  - reference: PMID:39419738
    reference_title: "Pulmonary manifestations of Pseudohypoaldosteronism type 1b: A systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In 36/47 patients the underlying pathogenic variant was identified in SCNN1A gene."
    explanation: SCNN1A is the predominant gene among genotyped PHA1B cases in a systematic review.
  - 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: Alpha subunit variants account for most multisystem PHA cases.
  - 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 most mutations were in SCNN1A.
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.
  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:31018202
    reference_title: "Systemic Pseudohypoaldosteronism Type 1 due to 3 Novel Mutations in SCNN1Aand SCNN1BGenes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ages at presentation were postnatal days 9, 10, and 5."
    explanation: Presentation in the first ten days of life in a series including two SCNN1A patients.
- phase: Chronic course with recurrent salt-losing crises
  age_range: Infancy to adulthood
  notes: >-
    With truncating alleles the systemic form does not remit and salt-losing
    crises recur. Mortality and post-arrest neurological injury are substantial
    in case series, but survival into adulthood with a successful pregnancy has
    been reported.
  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: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.
- phase: Mild or transient course with partial-function missense alleles
  age_range: Neonatal period to early childhood
  notes: >-
    Some SCNN1A missense alleles leave partial channel activity and give a mild
    or transient course, with variable expressivity and incomplete penetrance
    within families.
  evidence:
  - reference: PMID:21653223
    reference_title: "A homozygous missense mutation in SCNN1A is responsible for a transient neonatal form of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo."
    explanation: A homozygous SCNN1A missense allele produced a transient neonatal course in a preterm infant.
  - reference: PMID:37134141
    reference_title: "A mild and transient form of autosomal recessive pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present 12 patients from four different families with a mild and transient autosomal recessive PHA1 due to a novel homozygous missense mutation in the SCNN1A gene."
    explanation: A homozygous SCNN1A missense allele causes mild, transient disease across four families.
genetic:
- name: SCNN1A
  association: Causative (biallelic loss of function)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SCNN1A
    term:
      id: hgnc:10599
      label: SCNN1A
  gene_disease_validity:
  - validity_classification: STRONG
    classified_by: CLINGEN
    external_id: CGGV:assertion_38f18fef-1443-4005-a358-31f7d3a96ee0-2021-11-18T013000.000Z
    evidence:
    - reference: CGGV:assertion_38f18fef-1443-4005-a358-31f7d3a96ee0-2021-11-18T013000.000Z
      reference_title: "SCNN1A / pseudohypoaldosteronism, type IB1, autosomal recessive (Strong)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SCNN1A | HGNC:10599 | pseudohypoaldosteronism, type IB1, autosomal recessive | MONDO:0009917 | AR | Strong"
      explanation: ClinGen Tubulopathy GCEP classifies SCNN1A for this disease as Strong, autosomal recessive.
  notes: >-
    Reported alleles are mostly truncating: frameshifts (c.203_204delTC,
    recurrent in Gulf families; c.587_588insC), nonsense, splice-site variants
    and whole-gene deletions. Missense alleles (p.Ser243Pro, p.Phe226Cys,
    p.Gly327Cys, p.Ser562Pro) reduce rather than abolish channel activity, and
    the first three gave mild or transient disease.
  evidence:
  - reference: PMID:8589714
    reference_title: "Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Investigation of affected offspring of consanguineous union reveals mutations in either the alpha or beta subunits of the amiloride-sensitive epithelial sodium channel in five kindreds."
    explanation: First identification of alpha subunit (SCNN1A) mutations in recessive PHA1.
  - reference: PMID:8824886
    reference_title: "Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families."
    explanation: Homozygosity mapping placed one PHA1 locus at 12p13, where SCNN1A lies.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCNN1A | sodium channel epithelial 1 subunit alpha | hgnc:10599 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists germline loss-of-function SCNN1A variants as disease-causing.
  - reference: PMID:23416952
    reference_title: "Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Amplification of the SCNN1A gene and sequencing of all 13 coding exons unraveled mutations in all of our patients."
    explanation: SCNN1A mutations were found in all seven children with systemic PHA1 studied.
  - reference: PMID:34258491
    reference_title: "A Unique Genotype of Pseudohypoaldosteronism Type 1b in a Highly Consanguineous Population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "c.203_204 delTC, p.I68Tfs*76 (a known mutation) in 8 patients of 5 families; and whole SCNN1A gene deletion (novel) in 2 patients of 2 families."
    explanation: A recurrent SCNN1A frameshift and whole-gene deletions in Gulf PHA1B families.
  - reference: PMID:18547339
    reference_title: "Revealing a subclinical salt-losing phenotype in heterozygous carriers of the novel S562P mutation in the alpha subunit of the epithelial sodium channel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hence, the novel mutation S562P is causing systemic PHA1 in the homozygous state."
    explanation: A homozygous SCNN1A missense variant causes systemic PHA1.
pathophysiology:
- name: Biallelic SCNN1A loss of function
  description: >-
    Biallelic SCNN1A variants remove or impair the ENaC alpha subunit. In
    heterologous expression the beta and gamma subunits cannot produce an
    amiloride-sensitive current without alpha, which may explain why SCNN1A is
    the gene most often affected. Missense alleles such as p.Phe226Cys reduce
    channel activity and expression only partly, matching their milder course.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SCNN1A
    term:
      id: hgnc:10599
      label: SCNN1A
  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:8589714
    reference_title: "Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of channel activity."
    explanation: Recessive PHA1 alleles in the alpha and beta subunits abolish channel activity.
  - reference: PMID:23416952
    reference_title: "Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The α subunit is essential for ENaC function and mutations truncating the pore-forming part of the protein leading to systemic PHA1."
    explanation: Truncation of the pore-forming alpha subunit causes systemic PHA1.
  - reference: PMID:37134141
    reference_title: "A mild and transient form of autosomal recessive pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In functional studies in X. laevis oocytes, p.Phe226Cys caused a significant reduction of ENaC activity (83% reduction), reduced the number of active ENαC mutant channels, and reduced the basal open probability compared with wt."
    explanation: A mild-phenotype SCNN1A missense allele leaves partial channel activity in oocytes.
  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 it aldosterone cannot drive sodium reabsorption,
    producing end-organ mineralocorticoid resistance and urinary salt wasting.
    Adult nephron-specific alphaENaC deletion in mice reproduces the syndrome,
    which no other transporter compensates except under a high-sodium,
    low-potassium diet.
  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:26701978
    reference_title: "Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1."
    explanation: Renal alphaENaC deletion alone reproduces the salt-losing, hyperkalemic syndrome.
  - reference: PMID:26701978
    reference_title: "Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet."
    explanation: Other nephron transporters do not compensate for absent alphaENaC.
  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
- 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.
  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.
  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:26701978
    reference_title: "Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal life-threatening hypovolemia and hyperkalemia."
    explanation: Background statement from a mouse study describing the human hypovolemic salt-losing syndrome.
  downstream:
  - target: Hyponatremia
    causal_link_type: DIRECT
  - target: Dehydration
    causal_link_type: DIRECT
  - target: Hypotension
    causal_link_type: DIRECT
  - target: Hypovolemic shock
    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 stimulates renin secretion and aldosterone synthesis, but
    aldosterone cannot act through the absent channel, so plasma renin and
    aldosterone stay 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: PMID:22124517
    reference_title: "Unimpaired postnatal respiratory adaptation in a preterm human infant with a homozygous ENaC-α unit loss-of-function mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At nine days of life, he became lethargic and hyperthermic, displaying low Na(+) (126  mmol l(-1)), high K(+) (8.9  mmol l(-1)), high aldosterone (3000  ng l(-1))and high renin (1000  ng l(-1)) plasma concentrations, commensurate with pseudohypoaldosteronism type I."
    explanation: High renin and aldosterone alongside hyponatremia and hyperkalemia in an SCNN1A-homozygous infant.
  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 on the apical membrane of the eccrine sweat duct reabsorbs sodium from
    primary sweat. Without it sweat sodium and chloride are high, as a positive
    sweat test.
  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:28130590
    reference_title: "Expression of epithelial sodium channel (ENaC) and CFTR in the human epidermis and epidermal appendages."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the eccrine glands and ducts, ENaC and CFTR are located on the apical side of the membrane."
    explanation: Human skin immunostaining places ENaC at the apical membrane of the sweat duct, where salt is reabsorbed.
  - reference: PMID:31018202
    reference_title: "Systemic Pseudohypoaldosteronism Type 1 due to 3 Novel Mutations in SCNN1Aand SCNN1BGenes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients exhibited laboratory characteristics including severe hyponatremia, hyperkalemia, metabolic acidosis, elevated plasma renin, elevated aldosterone, and positive sweat tests, suggesting a diagnosis of systemic PHA1."
    explanation: Positive sweat tests in a series that includes two SCNN1A patients.
  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 the surface
    epithelium of the distal colon. Its loss adds fecal sodium loss and a
    colonic form of aldosterone resistance 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: PMID:24480829
    reference_title: "Colon-specific deletion of epithelial sodium channel causes sodium loss and aldosterone resistance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, Scnn1a(KO) mice fed a low-salt diet lost significant amounts of sodium in their feces and exhibited high plasma aldosterone and increased urinary sodium retention."
    explanation: Colon-specific alphaENaC deletion causes fecal sodium loss under salt restriction.
  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 twice the
    normal airway surface liquid volume, and recurrent chest congestion,
    cough and wheeze in early childhood. In alphaENaC-null mice airway sodium
    transport is abolished and neonates die from retained lung liquid, but a
    preterm SCNN1A-homozygous infant breathed normally after birth.
  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 SCNN1A.
  - reference: PMID:8589728
    reference_title: "Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Amiloride-sensitive electrogenic Na+ transport was abolished in airway epithelia from alpha-ENaC(-/-) mice."
    explanation: Loss of alphaENaC abolishes airway sodium transport in mice.
  downstream:
  - target: Wheezing
    causal_link_type: DIRECT
  - target: Cough
    causal_link_type: DIRECT
  - target: Recurrent respiratory 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
  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 SCNN1A cases presented with hyponatremia.
  - 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:22124517
    reference_title: "Unimpaired postnatal respiratory adaptation in a preterm human infant with a homozygous ENaC-α unit loss-of-function mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At nine days of life, he became lethargic and hyperthermic, displaying low Na(+) (126  mmol l(-1)), high K(+) (8.9  mmol l(-1)), high aldosterone (3000  ng l(-1))and high renin (1000  ng l(-1)) plasma concentrations, commensurate with pseudohypoaldosteronism type I."
    explanation: Plasma potassium of 8.9 mmol/l in an SCNN1A-homozygous infant.
  - 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:23031435
    reference_title: "A case of systemic pseudohypoaldosteronism with a novel mutation in the SCNN1A gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a neonatal case of systemic pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene (homozygous c.1052+2dupT in intron 3) in which the patient presented with life-threatening hyperkalemia, hyponatremia and metabolic acidosis."
    explanation: Metabolic acidosis at presentation in an SCNN1A-homozygous neonate.
  - 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:23813355
    reference_title: "A case of SCNN1A splicing mutation presenting as mild systemic pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Systemic pseudohypoaldosteronism type 1 (PHA1) is characterized by excessive salt loss from the renal tubulus, colon, sweat and salivary glands."
    explanation: Renal salt loss is a defining feature of systemic PHA1, stated in an SCNN1A case report.
- 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: PMID:22124517
    reference_title: "Unimpaired postnatal respiratory adaptation in a preterm human infant with a homozygous ENaC-α unit loss-of-function mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At nine days of life, he became lethargic and hyperthermic, displaying low Na(+) (126  mmol l(-1)), high K(+) (8.9  mmol l(-1)), high aldosterone (3000  ng l(-1))and high renin (1000  ng l(-1)) plasma concentrations, commensurate with pseudohypoaldosteronism type I."
    explanation: Plasma aldosterone of 3000 ng/l in an SCNN1A-homozygous infant.
- 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.
- 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 was mostly SCNN1A.
- category: Cardiovascular
  name: Hypovolemic shock
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypovolemic shock
    term:
      id: HP:0031274
      label: Hypovolemic shock
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031274 | Hypovolemic shock | Frequent (79-30%)"
    explanation: Orphanet records hypovolemic shock as frequent.
- category: Gastrointestinal
  name: Vomiting
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:38963175
    reference_title: "Novel homozygous mutation in SCNN1A gene in an Iranian boy with PHA1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a boy with PHA1B, who presented with vomiting, lethargy, and poor feeding due to salt wasting six days after birth."
    explanation: Vomiting at presentation in an SCNN1A-homozygous neonate.
  - 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: 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: 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:31018202
    reference_title: "Systemic Pseudohypoaldosteronism Type 1 due to 3 Novel Mutations in SCNN1Aand SCNN1BGenes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients exhibited laboratory characteristics including severe hyponatremia, hyperkalemia, metabolic acidosis, elevated plasma renin, elevated aldosterone, and positive sweat tests, suggesting a diagnosis of systemic PHA1."
    explanation: Positive sweat tests in a series including two SCNN1A patients.
  - reference: PMID:39419738
    reference_title: "Pulmonary manifestations of Pseudohypoaldosteronism type 1b: A systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pathological sweat test results were recorded in all 34 patients with available data."
    explanation: Every PHA1B case with a reported sweat test was abnormal in a systematic review where most cases were SCNN1A.
- category: Integument
  name: Atopic dermatitis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Atopic dermatitis-like skin lesions
    term:
      id: HP:0001047
      label: Atopic dermatitis
  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:0001047 | Atopic dermatitis | Occasional (29-5%)"
    explanation: Orphanet records atopic dermatitis as occasional in generalized PHA1.
- category: Respiratory
  name: Wheezing
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Wheezing
    term:
      id: HP:0030828
      label: Wheezing
  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
  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 respiratory infections
  description: >-
    Neonatal respiratory symptoms are common in SCNN1A cases. Infections with
    Pseudomonas aeruginosa or Staphylococcus aureus, and bronchiectasis, are
    reported in a minority, mimicking cystic fibrosis.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  sequelae:
  - target: Bronchiectasis
    description: Recurrent lower respiratory infection can progress to bronchiectasis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39419738
      reference_title: "Pulmonary manifestations of Pseudohypoaldosteronism type 1b: A systematic review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Lower respiratory tract infections caused by Pseudomonas aeruginosa and Staphylococcus aureus were reported in 3 cases each, while 2 patients developed bronchiectasis."
      explanation: Bronchiectasis developed in a minority of PHA1B cases with respiratory involvement.
  evidence:
  - reference: PMID:23416952
    reference_title: "Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five out of seven patients exhibited pulmonary symptoms in the neonatal period."
    explanation: Most SCNN1A-homozygous children had neonatal pulmonary symptoms.
  - reference: PMID:39419738
    reference_title: "Pulmonary manifestations of Pseudohypoaldosteronism type 1b: A systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Lower respiratory tract infections caused by Pseudomonas aeruginosa and Staphylococcus aureus were reported in 3 cases each, while 2 patients developed bronchiectasis."
    explanation: Bacterial lower respiratory infections are reported in PHA1B, most of whose genotyped cases are SCNN1A.
- category: Respiratory
  name: Bronchiectasis
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:39419738
    reference_title: "Pulmonary manifestations of Pseudohypoaldosteronism type 1b: A systematic review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Lower respiratory tract infections caused by Pseudomonas aeruginosa and Staphylococcus aureus were reported in 3 cases each, while 2 patients developed bronchiectasis."
    explanation: Two of 62 reviewed PHA1B cases with respiratory symptoms developed bronchiectasis.
- category: Reproductive
  name: Female infertility
  description: >-
    One woman homozygous for SCNN1A p.Arg508Ter failed to conceive despite
    repeated IVF, and her endometrium lacked apical ENaC staining. A single
    case; another SCNN1A or SCNN1G patient had a successful pregnancy.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:29885352
    reference_title: "Expression of the epithelial sodium channel (ENaC) in the endometrium - Implications for fertility in a patient with pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results support the hypothesis that lack of expression of ENaC on the endometrial surface may be responsible for the infertility of the PHA patient."
    explanation: Infertility with absent endometrial ENaC in a patient with an SCNN1A nonsense variant.
diagnosis:
- name: Biochemical and hormonal profile
  description: >-
    Neonatal hyponatremia, hyperkalemia and metabolic acidosis with high plasma
    renin and aldosterone suggest PHA1. Normal cortisol and
    17-hydroxyprogesterone exclude congenital adrenal hyperplasia, the usual
    first working diagnosis.
  evidence:
  - reference: PMID:24616761
    reference_title: "Pseudohypoaldosteronism type 1: clinical features and management in infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The differential diagnosis of type 1 PHA includes adrenal disorders such as adrenal hypoplasia and congenital adrenal hyperplasia; thus, adrenal function including cortisol levels, 17-hydroxyprogesterone and a urinary steroid profile are required."
    explanation: Adrenal function testing is required to exclude adrenal causes before PHA1 is diagnosed.
  - reference: PMID:39295704
    reference_title: "Pseudohypoaldosteronism Type 1b in a Saudi Female Infant Due to Homozygous Variant Gene Mutation in SCNN1A: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial evaluation for congenital adrenal hyperplasia was unremarkable."
    explanation: In an SCNN1A-confirmed infant, congenital adrenal hyperplasia was excluded before the genetic diagnosis.
- name: Sweat test
  description: >-
    Raised sweat (or saliva) sodium and chloride reflect extra-renal ENaC loss
    and support the systemic rather than the renal form of PHA1. Missense
    alleles that leave residual channel function can give a normal sweat test.
  measurements:
  - preferred_term: sweat chloride and sodium
    term:
      id: LOINC:74993-7
      label: Chloride and sodium panel [Moles/volume] - Sweat
  notes: >-
    The sweat chloride and sodium panel is bound because the cited sources
    report both electrolytes as raised. No reference range is bound: the cited
    sources give no SCNN1A-specific decision limit, and the cystic fibrosis
    sweat chloride thresholds belong to a different disease.
  evidence:
  - reference: PMID:24616761
    reference_title: "Pseudohypoaldosteronism type 1: clinical features and management in infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A positive saliva or sweat test showing increased sodium and chloride levels helps to complete the diagnostic picture for AR PHA"
    explanation: A positive sweat or saliva test supports autosomal recessive (systemic) PHA1.
  - reference: PMID:24616761
    reference_title: "Pseudohypoaldosteronism type 1: clinical features and management in infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A differentiation between renal and systemic PHA type 1 may be made based on sodium requirements, ease of management of electrolyte imbalance, sweat test results and genetic testing."
    explanation: Sweat test results help separate systemic from renal PHA1.
- name: Molecular genetic testing of SCNN1A
  description: >-
    Sequencing, usually by a next-generation sequencing panel or exome, finds
    biallelic SCNN1A variants and confirms PHA1B1. It also identifies
    heterozygous carriers in the family.
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:34134742
    reference_title: "Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Next generation sequencing (NGS) techniques allowed the identification of the SCNN1A gene mutation either in both patients or in other heterozygous family members, enabling also primary prevention of disease."
    explanation: NGS identified the SCNN1A variant in patients and carriers.
  - reference: PMID:23762408
    reference_title: "Novel mutations in the SCNN1A gene causing Pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results of hormone levels and TTKG value tests provided further evidence of PHA1 and the clinical diagnosis was confirmed by molecular genetic testing."
    explanation: Molecular genetic testing confirmed the clinical diagnosis in an SCNN1A patient.
treatments:
- name: High-dose sodium chloride supplementation
  description: >-
    Oral sodium chloride, often in large and frequent doses, replaces renal and
    extra-renal sodium losses. Systemic PHA1 is harder to manage than the renal
    form, with recurrent electrolyte crises despite treatment. Infants with the
    transient missense form have been able to stop supplementation.
  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, sweat and colonic sodium losses.
  evidence:
  - reference: PMID:23762408
    reference_title: "Novel mutations in the SCNN1A gene causing Pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After increasing doses of oral 10%NaCl to 30 mEq/kg/d and doses of ion-exchange resins to 1g/kg/d, the serum potassium level was controlled at 4.5 to 5.5 mmol/L."
    explanation: High-dose oral sodium chloride with a resin controlled the electrolytes of an SCNN1A patient.
  - reference: PMID:24616761
    reference_title: "Pseudohypoaldosteronism type 1: clinical features and management in infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal PHA type 1 responds well to salt supplementation, whereas management of patients with systemic PHA type 1 proves more difficult as they are likely to get frequent episodes of electrolyte imbalance requiring urgent correction."
    explanation: Systemic PHA1 needs salt supplementation but remains prone to recurrent electrolyte crises.
  - reference: PMID:21653223
    reference_title: "A homozygous missense mutation in SCNN1A is responsible for a transient neonatal form of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo."
    explanation: In the transient SCNN1A missense form, salt supplementation could be withdrawn.
- name: Sodium bicarbonate
  description: Alkali therapy that corrects 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:34134742
    reference_title: "Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intravenous (IV) rehydration therapy with sodium chloride and sodium bicarbonate was started, for correction of hyponatremia and metabolic acidosis, respectively."
    explanation: Sodium bicarbonate was used to correct metabolic acidosis in an SCNN1A patient.
- name: Potassium-binding resin
  description: >-
    Oral or rectal cation-exchange resins 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
  notes: >-
    No therapeutic_agent is bound because the SCNN1A reports cited here use
    different resins (sodium polystyrene sulfonate in PMID:34134742, calcium
    resonium in PMID:39295704, an unnamed ion-exchange resin in
    PMID:23762408).
  target_mechanisms:
  - target: Hyperkalemia
    description: Removes retained potassium through the gut.
  evidence:
  - reference: PMID:23762408
    reference_title: "Novel mutations in the SCNN1A gene causing Pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After increasing doses of oral 10%NaCl to 30 mEq/kg/d and doses of ion-exchange resins to 1g/kg/d, the serum potassium level was controlled at 4.5 to 5.5 mmol/L."
    explanation: Ion-exchange resin contributed to potassium control in an SCNN1A patient.
  - reference: PMID:39295704
    reference_title: "Pseudohypoaldosteronism Type 1b in a Saudi Female Infant Due to Homozygous Variant Gene Mutation in SCNN1A: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The discharge medication regimen consisted of 3% sodium chloride solution 7 mL administered orally via the nasogastric tube every 4 h, calcium resonium 1 gram orally twice daily, and fludrocortisone 0.3 mg orally once daily."
    explanation: Maintenance therapy of an SCNN1A infant combined oral sodium chloride with a potassium-binding resin.
- name: Mineralocorticoid replacement
  description: >-
    Fludrocortisone is often started while salt-wasting adrenal disease is
    still suspected. It does not correct the electrolyte disturbance, because
    the defect lies in the channel aldosterone acts on rather than in hormone
    supply, and it is usually stopped once PHA1 is recognized. Some patients
    are nonetheless kept on it.
  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:23762408
    reference_title: "Novel mutations in the SCNN1A gene causing Pseudohypoaldosteronism type 1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, 9α-fluorohydrocortisone (9α-FHC) supplement therapy was ineffective."
    explanation: Fludrocortisone did not work in an SCNN1A patient.
  - reference: PMID:24616761
    reference_title: "Pseudohypoaldosteronism type 1: clinical features and management in infancy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "After the diagnosis of PHA was made, the hydrocortisone and fludrocortisone were stopped, and calcium resonium was gradually decreased."
    explanation: Steroid replacement was withdrawn once PHA1 was diagnosed.
differential_diagnoses:
- name: Congenital adrenal hyperplasia
  description: >-
    Salt-wasting congenital adrenal hyperplasia (21-hydroxylase or
    3-beta-hydroxysteroid dehydrogenase deficiency) produces the same neonatal
    hyponatremia, hyperkalemia and acidosis.
  distinguishing_features:
  - Normal cortisol and 17-hydroxyprogesterone with high aldosterone in PHA1
  - No response to mineralocorticoid replacement in PHA1
  evidence:
  - reference: PMID:23762408
    reference_title: "Novel mutations in the SCNN1A gene causing Pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The symptoms of PHA1 are easily confused with the symptoms of congenital adrenal hyperplasia (CAH) associated with 21-hydroxylase deficiency or 3-beta-hydroxysteroid dehydrogenase deficiency; and the symptoms of hypoaldosteronism (HA) due to aldosterone deficiency, antenatal or infantile Bartter syndrome."
    explanation: Names CAH, aldosterone deficiency and Bartter syndrome as conditions confused with PHA1.
  - reference: PMID:39295704
    reference_title: "Pseudohypoaldosteronism Type 1b in a Saudi Female Infant Due to Homozygous Variant Gene Mutation in SCNN1A: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings helped to rule out congenital adrenal hyperplasia."
    explanation: Hormonal studies excluded CAH in an SCNN1A infant.
- 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 PHA1 from heterozygous NR3C2 variants causes kidney-limited salt
    wasting that responds well to salt and improves with age.
  distinguishing_features:
  - Normal sweat electrolytes in renal PHA1
  - Lower sodium requirement and easier electrolyte control in renal PHA1
  evidence:
  - reference: PMID:24616761
    reference_title: "Pseudohypoaldosteronism type 1: clinical features and management in infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A differentiation between renal and systemic PHA type 1 may be made based on sodium requirements, ease of management of electrolyte imbalance, sweat test results and genetic testing."
    explanation: Lists the features that separate renal from systemic PHA1.
  - reference: PMID:23762408
    reference_title: "Novel mutations in the SCNN1A gene causing Pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G) of the epithelial sodium channel (ENaC) and the NR3C2 gene encoding the mineralocorticoid receptor, result in systemic PHA1 and renal PHA1 respectively."
    explanation: Renal PHA1 is the NR3C2 form, distinct from the ENaC-related systemic form.
- name: Hypoaldosteronism due to aldosterone deficiency
  description: >-
    Aldosterone deficiency causes infantile salt wasting with hyponatremia and
    hyperkalemia, but aldosterone is low rather than high.
  distinguishing_features:
  - Low aldosterone in aldosterone deficiency versus high aldosterone in PHA1
  evidence:
  - reference: PMID:34134742
    reference_title: "Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital adrenal hyperplasia (CAH) due to 21-β-hydroxylase or 3-β-hydroxysteroid dehydrogenase deficiency, hypoaldosteronism due to aldosterone deficiency, and Bartter syndrome should be considered as possible differential diagnosis in affected newborns"
    explanation: Lists aldosterone deficiency among the neonatal differential diagnoses of SCNN1A-related PHA1.
- name: Bartter syndrome
  description: >-
    Antenatal or infantile Bartter syndrome causes neonatal renal salt
    wasting.
  distinguishing_features:
  - Hypokalemic alkalosis in Bartter syndrome versus hyperkalemic acidosis in PHA1
  evidence:
  - reference: PMID:34134742
    reference_title: "Novel SCNN1A gene splicing-site mutation causing autosomal recessive pseudohypoaldosteronism type 1 (PHA1) in two Italian patients belonging to the same small town."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital adrenal hyperplasia (CAH) due to 21-β-hydroxylase or 3-β-hydroxysteroid dehydrogenase deficiency, hypoaldosteronism due to aldosterone deficiency, and Bartter syndrome should be considered as possible differential diagnosis in affected newborns"
    explanation: Lists Bartter syndrome among the neonatal differential diagnoses.
- name: Secondary (transient) pseudohypoaldosteronism
  description: >-
    Transient renal aldosterone resistance from urinary tract infection or a
    renal anomaly reproduces the biochemical picture in early infancy.
  distinguishing_features:
  - Urinary tract infection on urine culture or anomaly on renal ultrasound
  evidence:
  - reference: PMID:24616761
    reference_title: "Pseudohypoaldosteronism type 1: clinical features and management in infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary (transient) causes of PHA may be due to urinary tract infections or renal anomalies; thus, urine culture and renal ultrasound scan are required respectively."
    explanation: Secondary PHA must be excluded with urine culture and renal ultrasound.
- name: Cystic fibrosis
  disease_term:
    preferred_term: cystic fibrosis
    term:
      id: MONDO:0009061
      label: cystic fibrosis
  description: >-
    Raised sweat electrolytes and recurrent lower respiratory infections make
    systemic PHA1 resemble cystic fibrosis.
  distinguishing_features:
  - Hyperkalemia with high renin and aldosterone in PHA1
  - No CFTR variants on mutation analysis
  evidence:
  - reference: PMID:22208790
    reference_title: "Pulmonary complications of endocrine and metabolic disorders."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pseudohypoaldosteronism type 1 may be indistinguishable from cystic fibrosis (CF) unless serum aldosterone, plasma renin activity, and urinary electrolytes are measured and mutation analysis rules out CF."
    explanation: Review names cystic fibrosis as a differential and lists the tests that separate it.
animal_models:
- name: alphaENaC-null mouse
  species: Mouse
  genotype: Scnn1a-/- (germline targeted disruption)
  publication: PMID:8589728
  description: >-
    Germline inactivation of the alpha subunit abolishes airway sodium
    transport, and neonates die within 40 hours from failure to clear lung
    liquid.
  modeled_mechanisms:
  - target: Airway epithelial sodium absorption failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reproduces loss of amiloride-sensitive airway sodium transport.
    limitations: >-
      Neonatal death from retained lung liquid is not seen in human SCNN1A
      loss of function, so the mouse overstates the role of ENaC in
      postnatal lung adaptation, and its early death prevents study of the
      chronic airway phenotype.
    evidence:
    - reference: PMID:8589728
      reference_title: "Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Amiloride-sensitive electrogenic Na+ transport was abolished in airway epithelia from alpha-ENaC(-/-) mice."
      explanation: Germline alphaENaC loss abolishes airway sodium transport.
- name: Adult nephron-specific alphaENaC knockout mouse
  species: Mouse
  genotype: Scnn1a Pax8/LC1 inducible nephron-specific knockout
  publication: PMID:26701978
  description: >-
    Inducible deletion of alphaENaC in the adult nephron causes hyperkalemia
    and weight loss on a regular-salt diet, mimicking PHA1, and a high-sodium,
    low-potassium diet rescues it.
  modeled_mechanisms:
  - target: Distal nephron ENaC sodium reabsorption failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reproduces renal salt loss and hyperkalemia from loss of nephron alphaENaC.
    limitations: >-
      Adult induction bypasses the neonatal presentation of the human disease,
      and the kidney-restricted deletion leaves sweat gland, colon and airway
      ENaC intact.
    evidence:
    - reference: PMID:26701978
      reference_title: "Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1."
      explanation: Nephron alphaENaC deletion reproduces the PHA1 renal phenotype.
  - target: Extracellular volume depletion
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: A high-sodium, reduced-potassium diet normalizes weight and electrolytes.
    limitations: >-
      Dietary rescue in adult mice does not test the large, frequent sodium
      doses that infants need.
    evidence:
    - reference: PMID:26701978
      reference_title: "Severe Salt-Losing Syndrome and Hyperkalemia Induced by Adult Nephron-Specific Knockout of the Epithelial Sodium Channel α-Subunit."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized."
      explanation: Salt loading with potassium restriction rescues the renal phenotype.
discussions:
- discussion_id: alpha_enac_lung_liquid_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Airway epithelial sodium absorption failure
  prompt: >-
    Why do alphaENaC-null mice die from retained lung liquid at birth when a
    preterm infant homozygous for an SCNN1A loss-of-function variant adapted
    to air breathing normally?
  rationale: >-
    The mouse knockout made ENaC look essential for clearing fetal lung liquid,
    but the human SCNN1A case shows that postnatal alveolar fluid clearance
    does not critically depend on ENaC in humans. Airway ENaC loss in patients
    instead shows up later as excess airway surface liquid and recurrent chest
    symptoms. The mouse is therefore a poor guide to the timing and severity of
    the respiratory phenotype, and the species difference in fetal lung liquid
    clearance is unexplained.
  evidence:
  - reference: PMID:8589728
    reference_title: "Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Alpha-ENaC(-/-) neonates developed respiratory distress and died within 40 h of birth from failure to clear their lungs of liquid."
    explanation: The mouse knockout is lethal through failed lung liquid clearance.
  - reference: PMID:22124517
    reference_title: "Unimpaired postnatal respiratory adaptation in a preterm human infant with a homozygous ENaC-α unit loss-of-function mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that clearance of alveolar fluid after birth in humans does not critically depend on ENaC."
    explanation: A human SCNN1A-null infant did not reproduce the mouse lung phenotype.
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)

Add diagnosis, treatments, differential diagnoses, animal models and model-mismatch discussion · 2026-11-04T12:08:38Z · View source

Answered the third review round of PR 16324. Added three diagnosis rows (biochemical and hormonal profile, sweat test bound to LOINC:74993-7, SCNN1A genetic testing), four treatments (sodium chloride, sodium bicarbonate, potassium-binding resin, fludrocortisone graded REFUTE), six differential diagnoses (congenital adrenal hyperplasia, renal PHA1 MONDO:0008329, aldosterone deficiency, Bartter syndrome, secondary PHA, cystic fibrosis MONDO:0009061), two alphaENaC mouse models (germline null PMID:8589728, adult nephron-specific PMID:26701978), and a HUMAN_MODEL_MISMATCH discussion contrasting mouse neonatal lung-liquid lethality with the SCNN1A-null preterm infant in PMID:22124517. All evidence quotes SCNN1A case reports or case series already cached on the branch; no new references were fetched. The potassium-binding resin row carries no therapeutic_agent because the SCNN1A reports use different resins. Removed the uncited PMID_26582762 cache; the other uncited caches back the deep-research report's citations and were kept. Deleted the curated stub. just validate passed with 90 snippets and 0 issues; entity-ref, causal-target, enum, duplicate-key and logical-rule gates pass.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 28 citations 2026-11-03T04:49:41.082482

1. Disease Information

PHA1B1 is the autosomal recessive, generalized (systemic / multisystem) form of pseudohypoaldosteronism type 1, a condition of end-organ resistance to aldosterone. "Pseudo" denotes that the biochemical picture mimics aldosterone deficiency (salt wasting, hyperkalemia, acidosis) while aldosterone is in fact high — the defect lies downstream of the hormone, in the ENaC effector channel itself.

Key identifiers: - OMIM: 264350 (Pseudohypoaldosteronism type I, autosomal recessive) - MONDO: MONDO:0009917 - Orphanet: systemic/generalized PHA1 (ORPHA:171876); PHA1 parent ORPHA:79168 - ICD-10: E27.4 (other and unspecified adrenocortical insufficiency); ICD-11: mineralocorticoid-resistance endocrine disorders - MeSH: D011546 (Pseudohypoaldosteronism) - Gene: SCNN1A, HGNC:10599, NCBI Gene 6337, Ensembl ENSG00000111319, UniProt P37088 (SCNNA_HUMAN), locus 12p13.31

Synonyms: autosomal recessive PHA 1; PHA1B; autosomal recessive pseudohypoaldosteronism type 1; generalized/generalised PHA1; generalized/generalised pseudohypoaldosteronism type 1; multisystem/systemic PHA1.

Nomenclature note: "PHA1B" is used in OMIM for the recessive ENaC-subunit form as a whole. More granular subtyping assigns PHA1B1 to SCNN1A, PHA1B2 to SCNN1B, and PHA1B3 to SCNN1G. This report concerns the SCNN1A-driven subtype but necessarily draws on the shared ENaC biology, because most mechanistic and clinical literature treats the three subunit genes together.

Source of information: Derived almost entirely from aggregated disease-level resources (OMIM, Orphanet, reviews) and published case reports / small single-center cohorts rather than large EHR datasets, reflecting the disorder's rarity.

2. Etiology

Primary cause — genetic. PHA1B1 is caused by biallelic (homozygous or compound-heterozygous) loss-of-function mutations in SCNN1A. Of the three ENaC subunit genes, SCNN1A-related cases are the most frequent cause of systemic PHA1.

PMID: 41457049: "The autosomal recessive systemic form (PHA1B), caused by mutations in SCNN1A, SCNN1B, or SCNN1G, is particularly severe and typically manifests in the neonatal period. Among these, SCNN1B-related cases occur less frequently than SCNN1A-related cases."

Genetic risk factors. - Causal variants: biallelic LoF variants in SCNN1A (frameshift, nonsense/premature-termination, splice-site; also hypomorphic missense). - Consanguinity is the dominant risk amplifier: it raises the chance of homozygosity for a recessive allele. A 37-year single-center cohort found all affected children had consanguineous parents (South Asian, Middle Eastern, or African origin) (PMID: 33690157). - Founder effects exist for specific alleles (e.g., a SCNN1G splice variant shared on a common haplotype across Indian-subcontinent families) (PMID: 8640238).

Environmental risk factors: None are causal. The disease is fully genetically determined. However, environmental/physiologic stressors (intercurrent illness, gastroenteritis, heat, salt restriction, dehydration) precipitate acute salt-wasting crises in already-affected individuals.

Protective factors. - Genetic: residual channel activity is protective in the sense of attenuating severity — missense/hypomorphic alleles that retain partial ENaC function yield milder or transient disease (PMID: 31301676; PMID: 20064610). Compensatory NCC (SLC12A3) upregulation mitigates renal salt loss over time (PMID: 20376516). - Environmental: generous dietary sodium supplementation functionally rescues the salt-losing phenotype; this is therapeutic rather than preventive of the underlying disorder.

Gene–environment interaction: The principal interaction is between the fixed genetic defect and sodium/potassium intake and physiologic stress — a high-sodium, potassium-managing diet counteracts the channel defect, whereas salt restriction or illness unmasks crises.

3. Phenotypes

PHA1B1 phenotypes fall into laboratory abnormalities, clinical signs/symptoms, and extrarenal manifestations. Onset is overwhelmingly neonatal (first days–weeks of life). Severity in systemic disease is severe and persistent (lifelong), contrasting with renal PHA1.

Phenotype Type Onset Frequency HPO term
Hyponatremia Lab abnormality Neonatal ~Universal HP:0002902
Hyperkalemia Lab abnormality Neonatal ~Universal HP:0002153
Metabolic acidosis Lab abnormality Neonatal ~Universal HP:0001942
Elevated plasma renin Lab abnormality Neonatal ~Universal HP:0000848 (hyperreninemia)
Elevated aldosterone (hyperaldosteronism) Lab abnormality Neonatal ~Universal HP:0000859
Renal salt wasting Clinical sign Neonatal ~Universal HP:0000127 (renal salt wasting)
Failure to thrive Clinical sign Neonatal/infancy Common HP:0001508
Dehydration / volume depletion Clinical sign Neonatal (crises) Common HP:0001944
Vomiting / feeding difficulty Symptom Neonatal/infancy Common HP:0002013
Recurrent respiratory infection / CF-like lung disease Clinical sign Infancy/childhood Common in systemic form HP:0002783 / HP:0006532
Cough / wheeze / chest congestion Symptom Early childhood (≤5 y) Frequent in young systemic patients HP:0012735 / HP:0030828
Elevated sweat chloride / sweat electrolytes Lab abnormality Congenital Characteristic of systemic form HP:0012236
Skin lesions / eczematous dermatitis / miliaria Physical manifestation Infancy Reported (salt deposition) HP:0000964 (eczema)
Cardiac arrhythmia / arrest (hyperkalemia) Clinical sign Neonatal crises Minority but life-threatening HP:0011675
Neurodevelopmental impairment (post-arrest) Clinical sign After crisis ~16% in one cohort HP:0012759

Severity and progression: Systemic PHA1B1 is typically severe and lifelong, with episodic salt-wasting crises superimposed on a chronic course. Hypomorphic variants produce milder, sometimes transient disease that can improve with age.

Quality-of-life impact: Substantial. Affected children require lifelong oral salt and potassium-lowering medication, frequent electrolyte monitoring, and hospital admissions for crises; respiratory involvement adds CF-like morbidity. Survivors of hyperkalemic cardiac arrest may have permanent neurological disability. No disease-specific QoL instrument (EQ-5D/SF-36/PROMIS) data exist for this rare disorder.

4. Genetic / Molecular Information

Causal gene. SCNN1A (sodium channel epithelial 1 subunit alpha), 12p13.31; HGNC:10599; OMIM gene 600228; disease OMIM 264350. The gene encodes the α-ENaC subunit, which is obligatory for channel assembly, trafficking, and Na⁺ conduction. ENaC is a heterotrimer of α (SCNN1A), β (SCNN1B, 16p12), and γ (SCNN1G, 16p12) subunits in 1:1:1 stoichiometry.

PMID: 38963175: "Systemic PHA type I (PHA1B) has varying degrees of clinical presentation and results from mutations in genes encoding subunits of the epithelial sodium channel (ENaC) including the alpha, beta, and gamma subunits. To date, about 45 variants of PHA1B have been identified."

Pathogenic variants. - Variant types: frameshift (including gross deletions, insertions/deletions), nonsense/premature termination, canonical splice-site, and missense. Truncating/null variants predominate in severe systemic disease; a gross deletion of SCNN1A has also been reported (PMID: 41275343). - Classification (ACMG/AMP): most reported SCNN1A LoF variants are pathogenic/likely pathogenic; novel missense variants are sometimes initially VUS pending functional testing. - Allele frequency: causal alleles are very rare in gnomAD (private/family-specific or founder); LoF constraint on SCNN1A means null alleles are uncommon in the general population. - Origin: germline; no somatic involvement. - Functional consequence: loss of function — abolished or markedly reduced amiloride-sensitive Na⁺ current. Truncating variants remove pore/gating elements; missense variants reduce open probability (e.g., a γ-ENaC A635V example reduced amiloride-sensitive current by ~30%, illustrating the residual-activity principle) (PMID: 40153144).

PMID: 8589714: "Investigation of affected offspring of consanguineous union reveals mutations in either the alpha or beta subunits of the amiloride-sensitive epithelial sodium channel in five kindreds. These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of channel activity."

Modifier genes. NCC/SLC12A3 (thiazide-sensitive Na-Cl cotransporter) acts as a physiologic modifier — its upregulation partially compensates for ENaC loss. Broader aldosterone-pathway regulators (WNK kinases, Nedd4L/NEDD4L ubiquitin ligase, channel-activating proteases such as CAP1/Prss8, CAP3/St14, kallikrein-1) influence ENaC abundance/activity and are candidate modulators but are not established clinical modifiers in PHA1B1.

Epigenetic information: No disease-specific DNA-methylation or histone-modification findings are established for PHA1B1.

Chromosomal abnormalities: Point mutations and small indels dominate; gross intragenic deletions of SCNN1A occur but large cytogenetic rearrangements are not characteristic.

5. Environmental Information

PHA1B1 is a monogenic disorder with no environmental cause. There are no toxins, radiation, pollution, occupational exposures, lifestyle factors, or infectious agents that cause the disease.

Environmental factors are relevant only as modulators of the established disease: - Dietary sodium/potassium — the key modifiable factor (therapeutic high-salt intake; potassium restriction). - Heat/sweating — excess sodium loss through defective sweat glands can worsen salt depletion. - Intercurrent infection/gastroenteritis — precipitates acute crises.

Infectious agents: none cause PHA1B1. Notably, recurrent lower-respiratory infections occur as a consequence of airway ENaC dysfunction, but — unlike cystic fibrosis — typically without characteristic S. aureus / P. aeruginosa colonization early on (PMID: 10403853).

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function mutation in SCNN1A (frameshift/nonsense/splice/missense) → leads to absent or non-functional α-ENaC protein.
  2. Loss of the obligatory α-subunit → results in failure of ENaC heterotrimer assembly/trafficking and/or absent pore conduction → abolished amiloride-sensitive Na⁺ current at the apical membrane of sodium-absorbing epithelia. (Demonstrated in Xenopus oocyte expression studies.)
  3. In the distal nephron (connecting tubule/collecting duct): loss of apical Na⁺ entry → leads to reduced electrogenic Na⁺ reabsorption → impaired lumen-negative transepithelial voltage → reduced driving force for K⁺ and H⁺ secretion.
  4. Branch → renal salt wasting (natriuresis, volume depletion) and impaired K⁺/H⁺ excretion → hyponatremia + hyperkalemia + metabolic acidosis.
  5. Volume depletion and hyperkalemia → stimulate renin and aldosterone → very high plasma renin activity and aldosterone, but because the effector (ENaC) is defective → target-organ resistance → biochemical picture mimics aldosterone deficiency ("pseudo").
  6. Extrarenal branch — ENaC loss in colon (fecal Na⁺ loss), sweat glands (→ high sweat Na⁺/Cl⁻), salivary glands (→ high saliva electrolytes), and airway → multisystem phenotype.
  7. Airway branch: loss of ENaC-mediated Na⁺ (and fluid) absorption from airway surfaces → excess airway surface liquid (>2× normal) → altered mucociliary clearance and recurrent chest congestion/cough/wheeze (CF-like). (Demonstrated by in vivo airway measurements.)
  8. Severe hyperkalemia → can cause cardiac arrhythmia/arrest → in survivors, hypoxic-ischemic injury → neurodevelopmental impairment. (Observed clinically.)
  9. Compensatory branch (partial): over time, NCC (SLC12A3) upregulation in the distal nephron → partially restores Na⁺ reabsorption → clinical improvement in some patients. (Inferred from human urinary NCC protein and mouse models.)

Mechanistic detail

Molecular pathway: the aldosterone–mineralocorticoid receptor (MR)–ENaC axis (renin-angiotensin-aldosterone system, RAAS). Aldosterone normally binds MR (NR3C2), inducing transcription/activity of ENaC and Na⁺/K⁺-ATPase in principal cells. PHA1B1 disables the terminal effector (ENaC) rather than the receptor, so RAAS output is high but ineffective (PMID: 24840884).

Protein dysfunction: Cryo-EM established ENaC as a heterotrimeric α:β:γ channel with large extracellular "hand"-like domains (PDB 6BQN), with defined principles of assembly, proteolytic activation, and inhibition (PMID: 30251954; PMID: 32729833). Loss-of-function truncations remove pore/gating elements and abolish current; missense variants lower open probability. Truncated β-ENaC subunits can still support partial channel activity, explaining milder phenotypes (PMID: 20064610).

Cellular processes: defective transepithelial ion transport (sodium reabsorption, potassium/proton secretion) in epithelial principal cells; secondary fluid homeostasis dysregulation at airway surfaces.

Biochemical abnormality: an ion-channel defect (amiloride-sensitive Na⁺ channel) — the defining lesion.

Suggested GO terms: sodium ion transmembrane transport (GO:0035725); regulation of sodium ion transport (GO:0002028); sodium channel activity (GO:0005272); cellular response to aldosterone (GO:1904045); potassium ion homeostasis (GO:0055075); renal sodium ion absorption (GO:0070294). Suggested CL terms: kidney collecting duct principal cell (CL:1000714); kidney connecting tubule epithelial cell (CL:1000768); eccrine sweat gland cell; respiratory multiciliated epithelial cell (CL:0002145); colonic epithelial cell (CL:0011108). Suggested CHEBI terms: sodium(1+) (CHEBI:29101); potassium(1+) (CHEBI:29103); aldosterone (CHEBI:27584); amiloride (CHEBI:2639).

Molecular profiling: No large transcriptomic/proteomic/metabolomic datasets exist for human PHA1B1; mechanistic evidence comes from targeted electrophysiology (oocyte expression) and mouse knockouts.

7. Anatomical Structures Affected

Organ level (primary): - Kidney (distal nephron: connecting tubule, cortical collecting duct) — UBERON:0002113; primary site of salt wasting. - Colon / distal large intestine — UBERON:0001155; fecal sodium loss. - Sweat glands (eccrine) — UBERON:0001820; elevated sweat electrolytes. - Salivary glands — UBERON:0001044; elevated saliva electrolytes. - Lung / airway epithelium — UBERON:0002048; excess airway surface liquid, CF-like disease.

Secondary/organ systems: endocrine (RAAS activation), cardiovascular (hyperkalemic arrhythmia), nervous system (post-arrest injury), skin (salt-related dermatitis/eczema).

Body systems: renal/urinary, gastrointestinal, integumentary, respiratory, cardiovascular, endocrine.

Tissue and cell level: epithelial tissue throughout; specifically Na⁺-absorbing principal cells of the collecting duct, surface colonocytes, eccrine gland ductal cells, and airway multiciliated epithelial cells (ENaC localizes to cilia and regulates surface-liquid volume) (PMID: 26772908). ENaC (with CFTR) is expressed in human epidermis and epidermal appendages including eccrine sweat glands (PMID: 28130590).

Subcellular level: apical plasma membrane of epithelial cells (GO:0016324, apical plasma membrane); the channel traffics through ER/Golgi and is regulated at the membrane by proteases and Nedd4L-mediated ubiquitination.

Localization / lateralization: bilateral / systemic — all paired and unpaired target organs are affected symmetrically; this is not a focal or lateralized disorder.

8. Temporal Development

Onset: Congenital/neonatal. Essentially all systemic (SCNN1A) cases present within the first days to two weeks of life.

PMID: 33690157: "All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia. All parents were consanguineous and of South Asian, Middle Eastern or African ethnic origin."

Onset pattern: acute presentation (salt-wasting crisis / adrenal-crisis-like picture: dehydration, failure to thrive, shock) superimposed on a congenital defect.

Progression: - Course: chronic, lifelong for severe (truncating) systemic disease, punctuated by episodic crises triggered by illness, heat, or salt restriction. - Rate: variable; crises are acute, baseline disease is persistent. - Milder variants: some hypomorphic SCNN1A/SCNN1B cases show transient disease that improves/remits with age, partly via NCC compensation and reduced dependence on ENaC for salt homeostasis with growth (PMID: 23426840; PMID: 37134141).

Remission patterns: No spontaneous cure for severe disease; treatment-controlled stability is achievable. Partial, age-related improvement occurs with hypomorphic alleles.

Critical period: The neonatal period is the window of maximal vulnerability (hyperkalemic cardiac arrest) and the critical window for diagnosis and electrolyte stabilization to prevent death and neurological injury.

9. Inheritance and Population

Inheritance: Autosomal recessive. Both SCNN1A alleles must be non-functional (homozygous or compound heterozygous).

Epidemiology: Very rare; systemic PHA1 prevalence is not precisely established (orders of magnitude rarer than the autosomal dominant renal form). Overall PHA1 is estimated at roughly 1 in 80,000 newborns (all forms), with the recessive systemic form being a minority.

Penetrance: Complete for biallelic LoF genotypes (all homozygotes manifest). Expressivity: Variable, driven chiefly by residual channel activity (genotype–phenotype correlation).

PMID: 31301676: "Patients presenting with missense mutations of SCNN1A and SCNN1B had a less marked rise in serum aldosterone suggesting preservation in sodium epithelial channel function."

Genetic anticipation: Not applicable (not a repeat-expansion disorder). Germline mosaicism: Not a described feature. Consanguinity: Major contributing factor — nearly all recessive systemic cases arise in consanguineous unions. Founder effects: Documented for specific ENaC alleles (e.g., shared SCNN1G splice haplotype in Indian-subcontinent families; clustered SCNN1A variants in defined geographic populations such as a Sicilian town) (PMID: 8640238; PMID: 34134742). Carrier frequency: Low; not precisely quantified for SCNN1A; heterozygous carriers are asymptomatic.

Population demographics: Reported disproportionately in populations with high consanguinity — South Asian, Middle Eastern, North/Sub-Saharan African, and certain Mediterranean communities (PMID: 33690157). Sex ratio: ~1:1 (autosomal recessive; no sex predilection). Age distribution: Diagnosed in neonates; affected individuals survive into childhood/adulthood with treatment.

10. Diagnostics

Laboratory tests (core): - Serum electrolytes: hyponatremia, hyperkalemia (LOINC 2951-2 sodium; 2823-3 potassium). - Metabolic acidosis (low bicarbonate; LOINC 1963-8). - Plasma renin activity — markedly elevated (LOINC 2915-7). - Plasma/serum aldosterone — markedly elevated; elevated aldosterone:renin ratio (LOINC 1763-2). - Urinary electrolytes: high urine sodium, inappropriately low urine K⁺ excretion for the degree of hyperkalemia. - Normal cortisol and normal 17-hydroxyprogesterone — essential to exclude salt-wasting congenital adrenal hyperplasia (21-hydroxylase deficiency).

Extrarenal / differentiating tests: - Sweat chloride test — elevated in systemic PHA1, overlapping with cystic fibrosis. - Saliva electrolytes — elevated.

PMID: 7965429: "Four patients with severe pseudohypoaldosteronism caused by multiple end-organ resistance to aldosterone had frequently recurring lower respiratory tract infections and persistently elevated sweat and saliva electrolyte values."

Genetic testing (confirmatory): - Single-gene / gene-panel sequencing of SCNN1A, SCNN1B, SCNN1G (systemic form) and NR3C2 (renal form) is the definitive approach. - Whole-exome sequencing (WES) is widely used and has identified novel SCNN1A variants; whole-genome sequencing (WGS) or deletion/duplication analysis (MLPA/CMA) is needed to detect gross deletions missed by standard sequencing (PMID: 41275343). - Functional confirmation (Xenopus oocyte amiloride-sensitive current) resolves VUS, especially missense variants.

Clinical diagnostic criteria: Neonatal salt-wasting (hyponatremia + hyperkalemia + metabolic acidosis) with high renin and aldosterone and poor/absent response to mineralocorticoid (fludrocortisone), after excluding adrenal insufficiency/CAH, plus confirmatory genetics.

Differential diagnosis: - Salt-wasting congenital adrenal hyperplasia (21-OH deficiency) — distinguished by elevated 17-OHP, low aldosterone, response to steroid. - Primary adrenal insufficiency / aldosterone synthase deficiency — low aldosterone (vs high in PHA). - Autosomal dominant renal PHA1 (NR3C2) — milder, kidney-restricted, normal sweat electrolytes, often improves with age (PMID: 26817011). - Secondary (transient) PHA — e.g., urinary tract infection/obstructive uropathy in infants. - Cystic fibrosis — overlapping high sweat chloride and respiratory disease; PHA1 may be clinically indistinguishable until hormonal/genetic testing.

PMID: 22208790: "Pseudohypoaldosteronism type 1 may be indistinguishable from cystic fibrosis (CF) unless serum aldosterone, plasma renin activity, and urinary electrolytes are measured and mutation analysis rules out CF."

Notably, PHA1 and CF can rarely coexist (PMID: 38914525).

Screening: No routine newborn screen for PHA1B1; cascade/carrier testing and prenatal/preimplantation diagnosis are available for families with a known SCNN1A variant.

11. Outcome / Prognosis

Mortality: Significant in severe systemic disease, driven by hyperkalemic cardiac arrest in the neonatal/infant period.

PMID: 33690157: "Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia."

Morbidity / disability: Neurological impairment in survivors of cardiac arrest (~16% in the cited cohort); chronic burden of electrolyte management; CF-like respiratory morbidity in systemic cases.

Life expectancy: With intensive lifelong electrolyte management, survival with normal neurodevelopment is achievable. Growth is often normal with adequate salt replacement (PMID: 8865238).

Disease course / complications: Recurrent dehydration/crises, failure to thrive, recurrent respiratory infections, and (in a minority) cardiac/neurological catastrophe. Systemic (SCNN1A) disease has a poorer prognosis than renal (NR3C2) disease and generally does not remit with age when the variant is a true null.

Prognostic factors: - Genotype / residual channel activity — the dominant prognostic determinant (truncating = severe/persistent; missense/hypomorphic = milder/transient). - Severity of initial hyperkalemia and timeliness of neonatal stabilization (predicts arrest/neurological outcome).

12. Treatment

There is no curative or disease-modifying therapy. Management is lifelong, supportive, and electrolyte-directed.

Pharmacotherapy / supportive care (NCIT suggestions in parentheses): - Oral sodium chloride supplementation, high-dose (often up to ~10–45 mmol/kg/day), the cornerstone of therapy (NCIT:C692 Sodium Chloride). - Sodium bicarbonate to correct metabolic acidosis (NCIT:C29141 Sodium Bicarbonate). - Potassium-lowering measures: cation-exchange resins — sodium polystyrene sulfonate (Kayexalate) — and newer potassium binders (patiromer, sodium zirconium cyclosilicate) (NCIT:C47704 Polystyrene Sulfonate). Dietary potassium restriction. - Acute hyperkalemia management: insulin/glucose, beta-agonists, calcium gluconate (cardioprotection), and dialysis in refractory cases. - Mineralocorticoids (fludrocortisone) are INEFFECTIVE — the defect is downstream of the receptor — and do not form part of definitive therapy (useful diagnostically by their lack of effect). - Indomethacin has been used empirically in some historical cases to reduce salt loss, with reported benefit, but is not standard (PMID: 6395746).

Respiratory care: For systemic patients with CF-like airway disease, CF-style airway clearance and infection management may be required.

PMID: 7965429: "Patients with pseudohypoaldosteronism may require treatment similar to that for cystic fibrosis to prevent long-term respiratory complications."

Advanced/experimental therapeutics: No approved gene, cell, RNA-based, or targeted therapy exists. Proof-of-concept laboratory work shows pharmacological rescue of channel function — e.g., the TNF lectin-like domain (AP301/solnatide) restored ENaC function in PHA1B frameshift mutants in vitro (PMID: 28611771) — but this is not a clinical therapy for PHA1B1.

Treatment strategy: Individualized titration of sodium supplementation, acidosis correction, and potassium control to normalize electrolytes and support growth; multidisciplinary follow-up (endocrinology, nephrology, pulmonology, genetics). Personalized intensity is guided by genotype/residual activity — milder variants may need less and may be weaned as the child grows.

Treatment outcomes: With adherence, electrolytes and renin/aldosterone can normalize and growth proceeds normally; however, severe cases demand large daily supplement doses and remain at risk of crises.

13. Prevention

The disease itself cannot be prevented (congenital genetic cause); prevention focuses on avoiding complications and reproductive risk reduction.

  • Primary prevention: Not applicable for disease occurrence. Genetic counseling for consanguineous couples and families with a known variant; carrier testing, prenatal diagnosis, and preimplantation genetic diagnosis allow informed reproductive choices and early preparedness (PMID: 34134742).
  • Secondary prevention: Early recognition of neonatal salt-wasting and prompt genetic confirmation to start therapy before a catastrophic hyperkalemic event; cascade screening of at-risk siblings.
  • Tertiary prevention: Rigorous electrolyte management, sick-day rules (increased salt, early medical review during illness/heat), and respiratory surveillance to prevent crises, cardiac arrest, neurological injury, and chronic lung disease.
  • Immunization / public health / environmental interventions: Not applicable to the genetic cause; routine childhood immunization and respiratory-infection precautions are prudent given airway involvement.

14. Other Species / Natural Disease

  • Taxonomy: Human disease (Homo sapiens, NCBI Taxon 9606). Naturally occurring PHA1B1 is not a recognized spontaneous disease in companion animals or wildlife (no OMIA entry for a natural SCNN1A-PHA phenotype of veterinary importance).
  • Orthologous genes: Scnn1a in mouse (NCBI Gene 20276, chr 6) and rat (Scnn1a, NCBI Gene 25122). ENaC subunit genes are deeply conserved across vertebrates — orthologs appear from jawless fish onward, and most tetrapods carry four ENaC paralogs (PMID: 26772908).
  • Comparative biology: The aldosterone–ENaC axis is evolutionarily conserved, making rodent models highly informative. Complete α-ENaC knockout in mice is neonatally lethal from defective lung fluid clearance, underscoring the channel's conserved role in airway as well as renal sodium/fluid handling.
  • Transmission: None — non-infectious, non-zoonotic genetic disorder.

15. Model Organisms

Mouse (Mus musculus) — the principal model. - Constitutive α-ENaC (Scnn1a) knockout: dies within ~40 h of birth from failure to clear lung fluid — demonstrating ENaC's essential role in perinatal airway fluid absorption and modeling the respiratory dimension of systemic PHA1. - Inducible, nephron-specific α-ENaC knockout (Scnn1a^Pax8/LC1): recapitulates renal PHA-1 in adults — hyperkalemia and body-weight loss on a regular diet, rescued by a high-Na⁺/low-K⁺ diet.

PMID: 26701978: "We generated adult inducible nephron-specific αENaC-knockout mice (Scnn1a(Pax8/LC1)) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1."

  • Importantly, these mice reveal a compensatory mechanism: on a regular diet NCC is paradoxically downregulated despite high aldosterone, and a rescue diet normalizes electrolytes and restores NCC — dovetailing with the human finding of NCC-mediated compensation (PMID: 20376516).
  • Conditional (floxed) alleles for Scnn1b and Scnn1g exist to dissect β- and γ-subunit roles, since their constitutive knockouts are also perinatally lethal (PMID: 19036848).

In vitro / cellular models: - Xenopus laevis oocyte expression of mutant ENaC subunits is the standard functional assay for pathogenicity and residual activity (e.g., truncated β-ENaC retains partial activity; γ-A635V reduces current ~30%) (PMID: 20064610; PMID: 40153144).

Model characteristics: Inducible nephron-specific knockouts faithfully reproduce the renal electrolyte phenotype and the diet-dependent compensation; constitutive knockouts capture the lethal pulmonary phenotype. Limitations: no single mouse fully reproduces the complete human multisystem spectrum simultaneously (renal + sweat/saliva + chronic survivable lung disease), and perinatal lethality of global knockouts necessitates conditional/inducible strategies.

Resources: MGI (Scnn1a, Scnn1b, Scnn1g), IMPC/KOMP conditional alleles, IMSR.

Mechanistic Model (Synthesis)

   Biallelic LoF mutation in SCNN1A (12p13)
 │
 ▼
   Absent / non-functional α-ENaC subunit
 │   (α is obligatory for assembly + conduction)
 ▼
   No functional α:β:γ ENaC heterotrimer at apical membrane
 │
     ┌───────────┼─────────────┬──────────────┬───────────────┐
     ▼           ▼             ▼              ▼               ▼
  Kidney      Colon        Sweat gland    Saliva gland      Airway
 (CD/CNT)   (Na⁺ loss)   (↑sweat Na/Cl)  (↑saliva e-lytes) (↓Na⁺+fluid
     │                                                      absorption)
     ▼                                                         ▼
 ↓Na⁺ reabsorption → ↓lumen-negative voltage            Airway surface
 → ↓K⁺/H⁺ secretion                                     liquid >2× normal
     │                                                         ▼
     ▼                                                 CF-like cough/
 HYPONATREMIA + HYPERKALEMIA + METABOLIC ACIDOSIS      wheeze/infection
     │                               │
     ▼                               ▼
 RAAS activation →            Severe hyperkalemia →
 ↑↑renin, ↑↑aldosterone       cardiac arrhythmia/arrest →
 (ineffective = "pseudo")     neurological injury (survivors)
     │
     ▼
 Partial compensation over time: ↑NCC (SLC12A3) → mild/transient improvement

Upstream vs downstream: The mutation and loss of ENaC conduction are upstream; renal/colonic salt wasting and the electrolyte triad are proximal downstream effects; RAAS activation, crises, cardiac/neurological events, and respiratory disease are distal downstream consequences. NCC upregulation is a compensatory feedback branch.

Evidence Base

PMID Title (abbrev.) Evidence type Supports
8589714 ENaC subunit mutations cause PHA1 Human genetics (landmark) Causal LoF in α/β ENaC; recessive inheritance
8640238 Homozygosity mapping of PHA1 Human genetics (landmark) Loci at 12p (SCNN1A) & 16p; founder haplotype
38963175 Novel SCNN1A mutation, PHA1B Human case / review PHA1B from ENaC subunits; ~45 variants
41457049 PHA1B2 twins (SCNN1B) Human case Gene triad; severity; SCNN1A most common
33690157 AR-PHA1 clinical cohort Human cohort (12 pts, 37 y) Neonatal onset, consanguinity, 25% mortality
31301676 Genotype–phenotype in PHA1 Human cohort Missense → residual activity, milder disease
10403853 Airway ENaC dysfunction in PHA1 Human physiology Abolished airway Na⁺ absorption; 2× ASL
22208790 Pulmonary complications review Review PHA1 vs CF differentiation
7965429 Sweat/saliva electrolytes in PHA Human case series Elevated sweat/saliva; CF-like respiratory care
28130590 ENaC/CFTR in epidermis Human expression Molecular basis of sweat phenotype
20376516 NCC upregulation in AR-PHA1 Human Compensatory NCC mechanism
26701978 Nephron-specific αENaC KO mouse Mouse model Recapitulates renal PHA-1
19036848 Conditional Scnn1b/Scnn1g Mouse model Tools for subunit dissection
20064610 Truncated β-ENaC partial activity In vitro (oocyte) Residual-activity genotype–phenotype
40153144 γ-ENaC A635V function In vitro + human Missense reduces current ~30%
30251954 Cryo-EM ENaC structure Structural Heterotrimeric architecture
32729833 ENaC assembly/activation Structural Assembly, proteolytic activation
26772908 ENaC family review Review Tissue distribution, phylogeny, disease
24840884 Aldosterone function disorders Review RAAS–ENaC axis, PHA genetics
28611771 TNF lectin-like domain rescue In vitro Experimental channel rescue
41275343 Gross deletion in SCNN1A Human case Deletion-detection diagnostic gap
34134742 SCNN1A splice mutation, Sicily Human case Founder clustering; prevention via NGS
37134141 Mild/transient AR-PHA1 Human cohort Milder phenotype spectrum
23426840 SCNN1B splice mutation, Turkey Human case Age-related improvement mechanism
8865238 Severe PHA twins Human case Lifelong management; normal growth achievable
6395746 PHA review / indomethacin Human case Historical salt/indomethacin therapy
26817011 Renal PHA1 (NR3C2) Human case Distinguishes renal vs systemic PHA1
38914525 PHA1 coexisting with CF Human case PHA1/CF overlap and coexistence

Limitations and Knowledge Gaps

  1. SCNN1A-specific vs pooled data. Much of the clinical and mechanistic literature pools the three ENaC subunit genes under "PHA1B." Pure SCNN1A-only cohorts are small, and some cited cohorts include SCNN1G/SCNN1B patients.
  2. No large-scale omics. No transcriptomic, proteomic, metabolomic, or single-cell datasets exist specifically for human PHA1B1; mechanism rests on targeted electrophysiology and mouse genetics.
  3. Epidemiology imprecise. True prevalence/incidence and carrier frequency of SCNN1A-PHA1B1 are not well quantified; estimates are extrapolated from all-PHA1 figures.
  4. Structure–function for specific variants. Only a minority of reported SCNN1A variants have functional characterization; many remain inferred LoF.
  5. No disease-modifying therapy. Promising in vitro channel-rescue approaches (e.g., solnatide/AP301) have not been translated to PHA1B1 clinical trials.
  6. Quality-of-life data absent. No validated QoL instrument data for this rare disorder.
  7. Deletion detection gap. Standard sequencing can miss gross SCNN1A deletions, risking under-diagnosis.

Proposed Follow-up Experiments / Actions

  1. Assemble an SCNN1A-only genotype–phenotype registry correlating variant class (null vs hypomorphic) and functional residual activity with mortality, salt-requirement, and respiratory outcomes.
  2. Systematic functional assays (oocyte/mammalian electrophysiology + cryo-EM-guided modeling) for all reported SCNN1A VUS to firm up ACMG classification and residual-activity predictions.
  3. Ensure deletion/duplication analysis (MLPA/CMA/WGS) in genetically unconfirmed clinically typical cases to close the gross-deletion diagnostic gap.
  4. Translate channel-rescue pharmacology (e.g., solnatide/AP301, small-molecule ENaC potentiators) toward preclinical PHA1B1 models and, if promising, early-phase trials.
  5. Characterize the extrarenal burden (longitudinal sweat/saliva electrolytes, pulmonary function, airway microbiome) to define when CF-style respiratory care improves outcomes.
  6. Investigate NCC-targeted or dietary strategies that exploit the compensatory NCC branch to reduce salt-supplement burden.
  7. Develop a humanized/hypomorphic knock-in mouse reproducing the survivable multisystem phenotype for therapeutic testing.

Report compiled from 7 confirmed findings and 36 reviewed papers across a 5-iteration autonomous investigation. Evidence source types are indicated throughout (human clinical, model organism, in vitro, structural/computational).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 28
Resolved 28
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 28
On topic 18
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 44
Resolved 41
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 13
Terms named correctly 2
Terms named as a different term 10
Terms whose name is worth a second look 1

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 "~Universal"; HP calls it Hyponatremia
  • HP:0002153 (1 mention) - the report calls it "~Universal"; HP calls it Hyperkalemia
  • HP:0001942 (1 mention) - the report calls it "~Universal"; HP calls it Metabolic acidosis
  • HP:0000859 (1 mention) - the report calls it "~Universal"; HP calls it Increased circulating aldosterone concentration
  • HP:0001508 (1 mention) - the report calls it "Common"; HP calls it Failure to thrive
  • HP:0001944 (1 mention) - the report calls it "Common"; HP calls it Dehydration
  • HP:0002013 (1 mention) - the report calls it "Common"; HP calls it Vomiting
  • HP:0012236 (1 mention) - the report calls it "Characteristic of systemic form"; HP calls it Elevated sweat chloride
  • HP:0011675 (1 mention) - the report calls it "Minority but life-threatening"; HP calls it Arrhythmia
  • HP:0012759 (1 mention) - the report calls it "~16% in one cohort"; HP calls it Neurodevelopmental abnormality

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:

  • HP:0000848 (1 mention) - the report calls it "hyperreninemia"; HP calls it Increased circulating renin concentration, and lists "Hyperreninemia" among its other names

Terms named inconsistently

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

  • ORPHA:171876 - called "systemic PHA1", "Orphanet:** systemic/generalized PHA1"

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.