Pseudohypoaldosteronism Type IB2 Autosomal Recessive

Mendelian MONDO:0859317 Pathograph 30 Show in embeddings browser Pseudohypoaldosteronism type 1 Autosomal recessive disease

Pseudohypoaldosteronism type IB2 (PHA1B2) is the SCNN1B-related form of autosomal recessive, systemic (multi-organ) pseudohypoaldosteronism type 1. Biallelic loss-of-function variants in SCNN1B, which encodes the beta subunit of the amiloride-sensitive epithelial sodium channel (ENaC), abolish or severely reduce channel activity in every aldosterone-responsive epithelium. Failure of ENaC-mediated sodium reabsorption in the distal nephron causes renal salt wasting with hyponatremia, hypovolemia, and impaired potassium and hydrogen ion secretion, so affected infants present in the first weeks of life with vomiting, poor feeding, weight loss, dehydration, life-threatening hyperkalemia and metabolic acidosis despite markedly elevated renin and aldosterone and no response to mineralocorticoid therapy. Extra-renal ENaC loss adds salt loss through sweat, salivary glands and colon (elevated sweat electrolytes, miliaria-like rash) and, in the systemic PHA1 literature, excess airway surface liquid with recurrent chest symptoms. Unlike renal PHA1A, the systemic form does not remit and needs lifelong high-dose sodium chloride and bicarbonate with potassium-binding resins; dialysis may be needed for refractory hyperkalemia. The SCNN1A (PHA1B1) and SCNN1G (PHA1B3) forms share this mechanism and are separate MONDO concepts.

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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic (homozygous or compound heterozygous) SCNN1B loss-of-function variants; heterozygous parents are clinically unaffected. Consanguinity is common among reported families.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:8589714 SUPPORT Human clinical
"These mutations are homozygous in affected subjects, co-segregate with the disease"
Homozygous ENaC alpha or beta subunit mutations co-segregate with the disease in consanguineous kindreds.
PMID:35359893 SUPPORT Human clinical
"Genetic analysis showed that the neonate suffered complex heterozygosity in the SCNN1B gene inherited from the parents, which is passed on in an autosomal recessive inheritance pattern."
Compound heterozygous SCNN1B variants inherited from unaffected parents in an autosomal recessive pattern.
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Pathophysiology

8
Biallelic SCNN1B loss of function
Biallelic frameshift, nonsense, splice-site or missense SCNN1B variants remove or impair the ENaC beta subunit. Truncated beta subunits can still support weak trafficking and assembly with alpha and gamma subunits, and the missense p.Gly37Ser variant lowers channel open probability, so most alleles drastically reduce rather than strictly abolish amiloride-sensitive sodium current.
SCNN1B hgnc:10600 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SCNN1B (hgnc:10600). hgnc:10600 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 and salivary sodium absorption failure
Show evidence (4 references)
PMID:8589714 SUPPORT Human clinical
"introduce frameshift, premature termination or missense mutations that result in loss of channel activity"
Recessive PHA1 mutations in the alpha and beta subunits cause loss of ENaC activity.
PMID:9118951 SUPPORT In vitro / ex vivo
"A missense mutation (G37S) of the human ENaC beta subunit that causes loss of ENaC function and PHA-1 replaces a glycine that is conserved in the N-terminus of all members of the ENaC gene family."
A PHA1 beta subunit missense variant causes ENaC loss of function.
PMID:9118951 SUPPORT In vitro / ex vivo
"These results suggest that the decrease in macroscopic Na currents is due to a decrease in channel open probability (P(o)), suggesting that mutations of a conserved glycine in the N-terminus of ENaC subunits change ENaC channel gating, which would explain the disease pathophysiology."
The beta G37S class of variant reduces open probability rather than surface expression.
+ 1 more reference
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 functional ENaC, aldosterone cannot drive sodium reabsorption, producing end-organ mineralocorticoid resistance and urinary salt wasting.
kidney collecting duct principal cell CL:1001431 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney collecting duct principal cell (CL:1001431). CL:1001431 is a cell type from the Cell Ontology.
renal sodium ion absorption GO:0070294 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased renal sodium ion absorption (GO:0070294). GO:0070294 is a biological process from the Gene Ontology.
collecting duct UBERON:0001232 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in collecting duct, annotated with collecting duct of renal tubule (UBERON:0001232). UBERON:0001232 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
betaENaC-deficient mouse Mouse recapitulates Reproduces renal sodium wasting, hyperkalemia and hyperaldosteronism of human PHA1.
Downstream
Renal salt wasting
Extracellular volume depletion
Impaired distal potassium and hydrogen ion secretion
Show evidence (2 references)
PMID:8589714 SUPPORT Human clinical
"Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones."
Defines the salt wasting and mineralocorticoid unresponsiveness caused by ENaC loss.
PMID:9990092 SUPPORT Model organism
"In the -/- mice, we found an increased urine Na+ concentration despite hyponatremia and a decreased urine K+ concentration despite hyperkalemia."
betaENaC-deficient mice show renal sodium wasting and potassium retention.
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.
Animal models
Adult nephron-specific betaENaC knockout mouse Mouse recapitulates Reproduces severe hyperkalemia from loss of renal betaENaC.
Downstream
Hyperkalemia
Metabolic acidosis
Show evidence (2 references)
PMID:19571553 SUPPORT REVIEW SYNTHESIS Other
"Pseudohypoaldosteronism (PHA) is a rare heterogeneous syndrome of mineralocorticoid resistance causing insufficient potassium and hydrogen secretion."
Mineralocorticoid resistance in PHA causes insufficient potassium and hydrogen secretion.
PMID:9990092 SUPPORT Model organism
"The betaENaC-deficient mice showed normal prenatal development but died within 2 days after birth, most likely of hyperkalemia."
Loss of betaENaC causes lethal hyperkalemia in neonatal mice.
Extracellular volume depletion
Renal, colonic, sweat and salivary sodium loss depletes the extracellular fluid compartment, causing hyponatremic dehydration, hypovolemia and, in severe crises, hypotension and shock.
sodium ion homeostasis GO:0055078 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal sodium ion homeostasis (GO:0055078). GO:0055078 is a biological process from the Gene Ontology.
Downstream
Hyponatremia
Dehydration
Hypotension
Compensatory renin-angiotensin-aldosterone activation
Failure to thrive in infancy
Show evidence (1 reference)
PMID:26807262 SUPPORT Human clinical
"Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis."
Sodium wasting with hypovolemia characterizes autosomal recessive PHA1.
Compensatory renin-angiotensin-aldosterone activation
Volume depletion strongly stimulates renin secretion and aldosterone synthesis, but the elevated aldosterone cannot act through the defective channel, so plasma renin and aldosterone remain markedly elevated.
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 (2 references)
PMID:32840096 SUPPORT Human clinical
"Hyponatremia, hyperkalemia, metabolic acidosis, increased aldosterone and renin levels are expected findings in PHA."
Elevated renin and aldosterone accompany the salt-wasting state.
PMID:26807262 SUPPORT Human clinical
"aldosterone 2800 ng/dl (reference range: ≤21 ng/dl) and plasma renin activity 90 ng/ml/h (reference range: 0.6-4.3 ng/ml per h)"
Markedly elevated aldosterone and renin in an adult SCNN1B compound heterozygote.
Sweat duct sodium reabsorption failure
ENaC in the eccrine sweat duct reabsorbs sodium from primary sweat. In systemic PHA1 ducts lack ENaC conductance, so sweat salt absorption is blocked although CFTR chloride conductance is preserved, giving high sweat sodium and chloride and reversed sweat-induced skin potentials.
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
Miliaria-like skin rash
Show evidence (1 reference)
PMID:15986094 SUPPORT In vitro / ex vivo
"Lack of gENaC completely blocked salt absorption and caused dramatic reversal of skin potentials associated with pilocarpine-induced sweat secretion"
Ex vivo sweat ducts from PHA1 patients show no ENaC conductance and no salt absorption; the study does not report which ENaC subunit gene was affected.
Colonic and salivary sodium absorption failure
ENaC also mediates amiloride-sensitive sodium absorption in distal colon and salivary duct epithelium; its loss adds intestinal and salivary salt loss to the renal deficit.
colon epithelial cell CL:0011108 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves colon epithelial cell (CL:0011108). CL:0011108 is a cell type from the Cell Ontology.
sodium ion transmembrane transport GO:0035725 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sodium ion transmembrane transport (GO:0035725). GO:0035725 is a biological process from the Gene Ontology.
colon UBERON:0001155 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in colon (UBERON:0001155). UBERON:0001155 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Extracellular volume depletion
Show evidence (2 references)
ORPHA:171876 SUPPORT Other
"A severe form of pseudohypoaldosteronism type 1 characterized by salt wasting in multiple organs including the kidney, colon, and sweat and salivary glands."
Orphanet defines generalized PHA1 by salt wasting from kidney, colon, sweat and salivary glands.
PMID:40398899 SUPPORT Human clinical
"Clinical symptoms include episodes of salt wasting, metabolic acidosis and hyperkalaemia and may include intestinal salt wasting and a generalised rash."
Intestinal salt wasting is part of PHA1B, reported here in an SCNN1B case.
Airway epithelial sodium absorption failure
Airway ENaC absorbs sodium and liquid from the airway surface. Patients with systemic PHA1 have no airway sodium absorption, more than double the normal airway surface liquid volume, and recurrent chest congestion, coughing and wheezing in early childhood. This was shown in cohorts with ENaC subunit mutations generally; betaENaC-null mice clear neonatal lung liquid almost normally, so how far the airway phenotype applies to the SCNN1B form specifically is not settled.
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
betaENaC-deficient mouse Mouse fails to recapitulate Neonatal knockout mice do not develop the lung liquid clearance failure seen in alphaENaC-null mice.
Downstream
Wheezing
Cough
Recurrent upper and lower respiratory tract infections
Show evidence (2 references)
PMID:10403853 SUPPORT INDIRECT Human clinical
"The patients with systemic pseudohypoaldosteronism had loss-of-function mutations in the genes for the epithelial sodium-channel subunits, no sodium absorption from airway surfaces, and a volume of airway surface liquid that was more than twice the normal value."
Systemic PHA1 patients lack airway sodium absorption and have excess airway surface liquid; the cohort is not restricted to SCNN1B.
PMID:9990092 REFUTE INDIRECT Model organism
"In contrast to alphaENaC-deficient mice, which die because of defective lung liquid clearance, neonatal betaENaC deficient mice did not die of respiratory failure and showed only a small increase in wet lung weight that had little, if any, adverse physiologic consequence."
In mice the beta subunit is dispensable for neonatal lung liquid clearance, which argues against a severe beta-specific lung phenotype at birth.
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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 IB2 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 2
Hypotension HP:0002615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotension (HP:0002615). HP:0002615 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34258491 SUPPORT Human clinical
"All of these patients had presented within the first 10 days of life with nausea and vomiting, hyponatremia, hyperkalemia, and hypotension."
Hypotension at presentation in a PHA1B cohort that included SCNN1B siblings.
Arrhythmia OCCASIONAL HP:0011675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arrhythmia (HP:0011675). HP:0011675 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26807262 SUPPORT Human clinical
"Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death."
Electrolyte derangement in SCNN1B-related PHA1 can cause cardiac arrhythmias.
ORPHA:171876 SUPPORT Other
"HP:0011675 | Arrhythmia | Occasional (29-5%)"
Orphanet records arrhythmia as occasional.
Digestive 2
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:39723761 SUPPORT Human clinical
"Here, we present the clinical course of a newborn diagnosed with PHA at seven days of age due to severe dehydration, inadequate feeding, vomiting, and lethargy."
Vomiting at presentation in a homozygous SCNN1B newborn.
ORPHA:171876 SUPPORT Other
"HP:0002013 | Vomiting | Frequent (79-30%)"
Orphanet records vomiting as frequent.
Feeding difficulties in infancy HP:0008872 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor feeding, annotated with Feeding difficulties in infancy (HP:0008872). HP:0008872 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41457049 SUPPORT Human clinical
"presented at 8 days of age with poor feeding, weight loss, and severe jaundice"
Poor feeding at presentation in SCNN1B twins.
ORPHA:171876 SUPPORT Other
"HP:0008872 | Feeding difficulties in infancy | Occasional (29-5%)"
Orphanet records infantile feeding difficulties.
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 (2 references)
PMID:41457049 SUPPORT Human clinical
"Laboratory findings showed markedly elevated plasma renin and aldosterone levels, with no evidence of congenital adrenal hyperplasia or other metabolic disorders."
Markedly elevated renin in SCNN1B compound heterozygous twins.
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 (2 references)
PMID:41457049 SUPPORT Human clinical
"Laboratory findings showed markedly elevated plasma renin and aldosterone levels, with no evidence of congenital adrenal hyperplasia or other metabolic disorders."
Markedly elevated aldosterone in SCNN1B compound heterozygous twins.
PMID:31301676 SUPPORT Human clinical
"Patients presenting with missense mutations of SCNN1A and SCNN1B had a less marked rise in serum aldosterone suggesting preservation in sodium epithelial channel function."
The degree of hyperaldosteronism varies with variant class.
Genitourinary 1
Renal salt wasting HP:0000127 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal salt wasting (HP:0000127). HP:0000127 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8589714 SUPPORT Human clinical
"Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones."
Severe neonatal salt wasting is the defining feature.
Head and Neck 1
Recurrent upper and lower respiratory tract infections FREQUENT HP:0200117 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent upper and lower respiratory tract infections (HP:0200117). HP:0200117 is a phenotype from the Human Phenotype Ontology.
The Orphanet frequency applies to generalized PHA1 across ENaC genes. One homozygous SCNN1B infant died of pneumonia at 10 months.
Show evidence (2 references)
ORPHA:171876 SUPPORT Other
"HP:0200117 | Recurrent upper and lower respiratory tract infections | Frequent (79-30%)"
Orphanet records recurrent respiratory tract infections as frequent in generalized PHA1.
PMID:39723761 SUPPORT Human clinical
"The patient had multiple hospitalizations during follow-up and died at the age of 10 months due to pneumonia."
Fatal pneumonia in a homozygous SCNN1B infant.
Immune 1
Miliaria-like skin rash HP:0000988 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Miliaria-like skin rash, annotated with Skin rash (HP:0000988). HP:0000988 is a phenotype from the Human Phenotype Ontology.
HPO has no miliaria term (an OLS search of the hp ontology for "miliaria" returned no terms), so the eruption is bound to the general skin rash term.
Show evidence (3 references)
PMID:17389851 SUPPORT Human clinical
"Since the first days of life, the child presented severe and diffuse miliaria comprising many disseminated pustules associated with salt loss syndrome."
Pustular miliaria in a neonate with systemic PHA1B.
PMID:40398899 SUPPORT Human clinical
"Clinical symptoms include episodes of salt wasting, metabolic acidosis and hyperkalaemia and may include intestinal salt wasting and a generalised rash."
A generalized rash is part of PHA1B in an SCNN1B case report.
PMID:31018202 SUPPORT Human clinical
"The main presentation symptoms were vomiting, poor feeding, weakness, weight loss, and skin rash."
Skin rash among presenting symptoms in systemic PHA1 cases including an SCNN1B patient.
Metabolism 5
Hyponatremia VERY_FREQUENT HP:0002902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyponatremia (HP:0002902). HP:0002902 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42549990 SUPPORT Human clinical
"All presented with hyponatraemia and hyperkalaemia (median serum sodium 124 mEq/L; potassium 8.0 mEq/L)."
All PHA1B patients, including three SCNN1B patients, 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: Arrhythmia
Show evidence (3 references)
PMID:42549990 SUPPORT Human clinical
"All presented with hyponatraemia and hyperkalaemia (median serum sodium 124 mEq/L; potassium 8.0 mEq/L)."
All PHA1B patients presented with severe hyperkalemia.
PMID:32840096 SUPPORT Human clinical
"Hyperkalemia did not improve with conventional treatments and dialysis was required."
Refractory hyperkalemia in an SCNN1B patient required dialysis.
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:42077744 SUPPORT Human clinical
"initially presented at seven days of life with persistent hyperkalemia, hyponatremia, and metabolic acidosis"
Metabolic acidosis at presentation in a homozygous SCNN1B infant.
ORPHA:171876 SUPPORT Other
"HP:0001942 | Metabolic acidosis | Very frequent (99-80%)"
Orphanet records metabolic acidosis as very frequent.
Dehydration FREQUENT HP:0001944 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dehydration (HP:0001944). HP:0001944 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35530903 SUPPORT Human clinical
"This case describes a newborn who developed severe dehydration and electrolyte imbalances and subsequently was found to have a novel SCNN1B gene variant resulting in autosomal recessive systemic PHA1."
Severe dehydration in an SCNN1B neonate.
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 (1 reference)
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 systemic PHA1 patients, one of whom carried biallelic SCNN1B variants.
Nervous System 1
Lethargy HP:0001254 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lethargy (HP:0001254). HP:0001254 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39723761 SUPPORT Human clinical
"Here, we present the clinical course of a newborn diagnosed with PHA at seven days of age due to severe dehydration, inadequate feeding, vomiting, and lethargy."
Lethargy at presentation in a homozygous SCNN1B newborn.
Respiratory 2
Wheezing OCCASIONAL HP:0030828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wheezing (HP:0030828). HP:0030828 is a phenotype from the Human Phenotype Ontology.
Reported in systemic PHA1 cohorts not restricted to SCNN1B; Orphanet lists it as occasional for generalized PHA1.
Show evidence (2 references)
PMID:10403853 SUPPORT INDIRECT Human clinical
"Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa."
Recurrent wheezing in young patients with systemic PHA1 from ENaC subunit mutations.
ORPHA:171876 SUPPORT Other
"HP:0030828 | Wheezing | Occasional (29-5%)"
Orphanet records wheezing as occasional.
Cough OCCASIONAL HP:0012735 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cough (HP:0012735). HP:0012735 is a phenotype from the Human Phenotype Ontology.
Reported in systemic PHA1 cohorts not restricted to SCNN1B; respiratory symptoms are less frequent after five years of age.
Show evidence (2 references)
PMID:10403853 SUPPORT INDIRECT Human clinical
"Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa."
Recurrent coughing in young patients with systemic PHA1 from ENaC subunit mutations.
ORPHA:171876 SUPPORT Other
"HP:0012735 | Cough | Occasional (29-5%)"
Orphanet records cough as occasional.
Growth 2
Weight loss HP:0001824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Weight loss (HP:0001824). HP:0001824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41457049 SUPPORT Human clinical
"presented at 8 days of age with poor feeding, weight loss, and severe jaundice"
Neonatal weight loss in SCNN1B twins.
Failure to thrive in infancy FREQUENT HP:0001531 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive in infancy (HP:0001531). HP:0001531 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26807262 SUPPORT Human clinical
"Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis."
Failure to thrive is a characteristic feature of autosomal recessive PHA1.
ORPHA:171876 SUPPORT Other
"HP:0001531 | Failure to thrive in infancy | Frequent (79-30%)"
Orphanet records failure to thrive in infancy as frequent.
🧬

Genetic Associations

1
SCNN1B (Causative (biallelic loss of function))
Gene: SCNN1B hgnc:10600 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SCNN1B (hgnc:10600). hgnc:10600 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 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 ENaC beta subunit mutations in recessive PHA1.
ORPHA:171876 SUPPORT Other
"SCNN1B | sodium channel epithelial 1 subunit beta | hgnc:10600 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists germline loss-of-function SCNN1B variants as disease-causing.
PMID:41457049 SUPPORT Human clinical
"Whole-exome sequencing revealed compound heterozygous mutations in the SCNN1B gene: a splice-site variant (c.585+2T>C) inherited from the mother and a missense variant (c.1544T>C, p.Ile515Thr) from the father."
Compound heterozygous SCNN1B variants in twins with systemic PHA1B2.
+ 2 more references
💊

Medical Actions

5
High-dose sodium chloride supplementation
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium chloride CHEBI:26710 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium chloride (CHEBI:26710). CHEBI:26710 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Lifelong oral sodium chloride replacement, often in very large doses, is the mainstay of therapy for the systemic form; adherence is difficult and treatment discontinuation is a leading cause of death in some series.
Mechanism Target:
Extracellular volume depletion — Replaces renal and extra-renal sodium losses.
Show evidence (4 references)
PMID:26807262 SUPPORT Human clinical
"High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
High-dose sodium chloride is part of symptomatic treatment.
PMID:41457049 SUPPORT Human clinical
"Treatment with oral sodium chloride, sodium citrate, and potassium-binding resins led to gradual correction of electrolyte imbalance and clinical stabilization."
Oral sodium chloride contributed to stabilization of SCNN1B twins.
PMID:42549990 SUPPORT Human clinical
"Six patients (67%) died, mainly due to sepsis (n = 2) or treatment discontinuation (n = 4), while three remain stable on oral sodium supplementation."
Survivors remain stable on oral sodium supplementation, and discontinuation was a major cause of death.
+ 1 more reference
Sodium bicarbonate
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium bicarbonate NCIT:C29457 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses sodium bicarbonate (NCIT:C29457). NCIT:C29457 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Alkali therapy to correct metabolic acidosis while also supplying sodium.
Mechanism Target:
Metabolic acidosis — Buffers retained acid.
Show evidence (1 reference)
PMID:26807262 SUPPORT Human clinical
"High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
Sodium bicarbonate is part of symptomatic treatment in SCNN1B-related PHA1.
Potassium-binding resin
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium polystyrene sulfonate NCIT:C29461 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses sodium polystyrene sulfonate (NCIT:C29461). NCIT:C29461 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Cation-exchange resins such as sodium polystyrene sulfonate increase fecal potassium excretion to control chronic hyperkalemia.
Mechanism Target:
Hyperkalemia — Removes retained potassium through the gut.
Show evidence (2 references)
PMID:26807262 SUPPORT Human clinical
"High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
Sodium polystyrene sulfonate is part of symptomatic treatment.
PMID:41457049 SUPPORT Human clinical
"Treatment with oral sodium chloride, sodium citrate, and potassium-binding resins led to gradual correction of electrolyte imbalance and clinical stabilization."
Potassium-binding resins contributed to correction of hyperkalemia in SCNN1B twins.
Dialysis for refractory hyperkalemia
Category: Therapeutic Action: DialysisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dialysis (NCIT:C15221). NCIT:C15221 is a clinical intervention from the NCI Thesaurus. NCIT:C15221
Platform: Other
Peritoneal dialysis has been required when neonatal hyperkalemia did not respond to conventional medical treatment.
Mechanism Target:
Hyperkalemia — Extracorporeal or peritoneal potassium removal.
Show evidence (1 reference)
PMID:32840096 SUPPORT Human clinical
"Hyperkalemia did not improve with conventional treatments and dialysis was required."
Dialysis was required for refractory hyperkalemia in an SCNN1B patient.
Mineralocorticoid and glucocorticoid replacement
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: fludrocortisone CHEBI:50885 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses fludrocortisone (CHEBI:50885). CHEBI:50885 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Hydrocortisone and fludrocortisone are often started empirically for suspected salt-wasting adrenal disease but do not correct the electrolyte disturbance, because the defect lies in the target channel rather than in hormone supply. Failure to respond helps distinguish PHA1 from congenital adrenal hyperplasia.
Show evidence (3 references)
PMID:41457049 REFUTE Human clinical
"Both developed life-threatening hyperkalemia, hyponatremia, and metabolic acidosis, and these conditions were unresponsive to initial management including hydrocortisone."
Electrolyte disturbances in SCNN1B twins did not respond to hydrocortisone.
PMID:34165441 REFUTE Human clinical
"A child presenting with features that mimic salt-losing congenital adrenal hyperplasia (CAH) crises that do not respond to glucocorticoid and mineralocorticoid therapy should alert the pediatricians to the possibility of end-organ resistance to aldosterone."
Lack of response to glucocorticoid and mineralocorticoid therapy is expected in end-organ aldosterone resistance.
PMID:23641881 REFUTE REVIEW SYNTHESIS Other
"Patients with PHA1 are often initially diagnosed with congenital adrenal hyperplasia, but their electrolyte abnormalities are resistant to treatment with glucocorticoids and mineralocorticoids."
Electrolyte abnormalities in PHA1 do not respond to glucocorticoid or mineralocorticoid treatment.
🔬

Diagnosis

3
Biochemical and hormonal profile
Neonatal hyponatremia, hyperkalemia and metabolic acidosis with markedly elevated plasma renin and aldosterone, after exclusion of congenital adrenal hyperplasia and other adrenal causes, suggest PHA1. The renal and systemic forms cannot be told apart by early presentation or by this profile.
Show evidence (2 references)
PMID:41457049 SUPPORT Human clinical
"Laboratory findings showed markedly elevated plasma renin and aldosterone levels, with no evidence of congenital adrenal hyperplasia or other metabolic disorders."
Elevated renin and aldosterone with congenital adrenal hyperplasia excluded in SCNN1B twins.
PMID:31301676 SUPPORT Human clinical
"It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile."
The biochemical profile does not separate renal from systemic PHA1.
Sweat test
A positive sweat test (elevated sweat electrolytes) reflects extra-renal ENaC loss and supports the systemic rather than the renal form.
sweat chloride and sodium LOINC:74993-7 Logical Observation Identifiers Names and Codes (LOINC)
The panel is bound rather than either electrolyte alone, because this row says elevated sweat electrolytes without singling one out, and ENaC loss raises both. Two things in the release are easy to pick by mistake. Its sweat chloride codes include a toxicology-screen method pair that measures a different thing, and the word sweat matches about twenty questionnaire items about sweating, in instruments such as PROMIS, FACIT, PCL and the PHQ, none of which is a sweat assay. A narrative code for specialist review of sweat analysis also exists and names a result field rather than a test. Those are findings from the full 2.83 table, which holds the observation and panel codes; the Part question was put separately to the Monarch KG, which holds the Parts, and across its 38 sweat records the only Part is LOINC:LP7618-4, the specimen itself; there is no measurement Part for sweat chloride or sweat sodium. No reference range is bound: this row reports the test as positive and gives no electrolyte concentration, and the cystic fibrosis sweat chloride thresholds are a different disease's decision limits.
Show evidence (1 reference)
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 contributed to the diagnosis of systemic PHA1.
Molecular genetic testing of ENaC subunit genes
Sequencing of SCNN1A, SCNN1B and SCNN1G (with NR3C2 for the renal form), usually by exome sequencing, confirms the diagnosis and assigns the subtype; biallelic SCNN1B variants define PHA1B2.
Genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31301676 SUPPORT Human clinical
"We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b."
Genetic testing is needed to distinguish PHA1A from PHA1B.
PMID:41457049 SUPPORT Human clinical
"This report broadens the mutational spectrum of SCNN1B and underscores the importance of early genetic testing in refractory neonatal electrolyte disturbances."
Early genetic testing identified SCNN1B variants in refractory neonatal electrolyte disturbance.
📈

Progression

2
Neonatal salt-wasting presentation
Age: First weeks of life
Presentation is typically in the first days to weeks of life with vomiting, poor feeding, weight loss and dehydration accompanied by hyponatremia, hyperkalemia and metabolic acidosis.
Show evidence (2 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: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."
In a Gulf cohort including SCNN1B siblings, all patients presented within the first 10 days of life.
Chronic course with recurrent salt-losing crises
Age: Infancy to adulthood
The systemic form does not remit as renal PHA1A does; lifelong salt supplementation is needed and recurrent life-threatening salt-losing crises occur, particularly with intercurrent illness. Early mortality is high in some series. One SCNN1B patient with a splice variant normalized renin, aldosterone and electrolytes on high salt intake by the end of the first year, and an adult compound heterozygote remained symptomatically hyperkalemic at 32 years.
Show evidence (7 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:31914462 SUPPORT REVIEW SYNTHESIS Other
"The systemic type can -apart from the kidneys - affect colon, lungs, salivary and sweat glands. In that case symptoms persist until adulthood."
Unlike the renal type, systemic PHA1 symptoms persist into adulthood.
PMID:17546235 SUPPORT REVIEW SYNTHESIS Other
"The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent."
Review describes the lifelong recurrent course of systemic PHA1.
+ 4 more references
📊

Prevalence

1
United Kingdom
Prevalence at birth 1–9 per 1,000,000 (births)
Orphanet birth-prevalence class 1-9 / 1,000,000 for generalized PHA1 across all ENaC subunit genes; no SCNN1B-specific figure is available, and SCNN1B cases are reported less often than SCNN1A cases.
Show evidence (2 references)
ORPHA:171876 SUPPORT Other
"1-9 / 1 000 000 | United Kingdom | Prevalence at birth | PMID:24616761"
Orphanet epidemiology row for generalized PHA1.
PMID:41457049 SUPPORT Human clinical
"Among these, SCNN1B-related cases occur less frequently than SCNN1A-related cases."
SCNN1B accounts for a minority of systemic PHA1 cases.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Pseudohypoaldosteronism Type IB2 Autosomal Recessive:

Congenital adrenal hyperplasia
Overlapping Features Salt-wasting congenital adrenal hyperplasia produces the same neonatal hyponatremia, hyperkalemia and acidosis and is often considered first.
Distinguishing Features
  • Normal cortisol and 17-hydroxyprogesterone with high aldosterone in PHA1
  • No response to glucocorticoid and mineralocorticoid replacement in PHA1
Show evidence (3 references)
PMID:32351772 SUPPORT Human clinical
"Since she had hyponatremia and hyperkalemia, congenital adrenal hyperplasia was primarily considered."
Congenital adrenal hyperplasia was the initial working diagnosis in an SCNN1B neonate.
PMID:34165441 SUPPORT Human clinical
"The classical presentation is life-threatening neonatal/infantile salt-losing crises that mimic congenital adrenal hyperplasia (CAH)."
Systemic PHA1 crises mimic salt-wasting CAH.
PMID:23641881 SUPPORT REVIEW SYNTHESIS Other
"Patients with PHA1 are often initially diagnosed with congenital adrenal hyperplasia, but their electrolyte abnormalities are resistant to treatment with glucocorticoids and mineralocorticoids."
Resistance to steroid replacement distinguishes PHA1 from congenital adrenal hyperplasia.
Autosomal dominant pseudohypoaldosteronism type 1 Not Yet Curated MONDO:0008329
Overlapping Features Renal PHA1A from heterozygous NR3C2 variants causes a milder kidney-limited salt-wasting syndrome that remits with age.
Distinguishing Features
  • Kidney-limited salt loss with normal sweat electrolytes in renal PHA1A
  • Improvement with age in renal PHA1A versus lifelong treatment in systemic PHA1B
Show evidence (2 references)
PMID:31301676 SUPPORT Human clinical
"It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile."
Renal and systemic PHA1 cannot be separated by early presentation, so genetic testing is needed.
PMID:31301676 SUPPORT Human clinical
"Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA."
Prognosis is worse in multisystem PHA1B than in NR3C2-related renal PHA1A.
Early-onset familial hypoaldosteronism MONDO:0035320
Overlapping Features Aldosterone synthase deficiency also causes infantile salt wasting with hyponatremia, hyperkalemia and high renin, but aldosterone is low to normal.
Distinguishing Features
  • Low to normal aldosterone in aldosterone synthase deficiency versus high aldosterone in PHA1
  • Response to fludrocortisone in aldosterone synthase deficiency
Show evidence (1 reference)
PMID:41905953 SUPPORT REVIEW SYNTHESIS Other
"ASD must also be differentiated from another disease, pseudohypoaldosteronism type 1 (PHA1), which involves resistance to aldosterone."
Names PHA1 and aldosterone synthase deficiency as mutual differential diagnoses.
Secondary (transient) pseudohypoaldosteronism
Overlapping Features Transient renal aldosterone resistance from urinary tract infection or urinary tract anomalies produces renal salt loss, hyponatremia, hyperkalemia and high aldosterone in early infancy.
Distinguishing Features
  • Urinary tract infection or obstructive anomaly on urine culture and renal imaging
  • Resolution after treatment of the underlying cause
Show evidence (2 references)
PMID:22397047 SUPPORT Human clinical
"Secondary pseudohypoaldosteronism type 1 develops due to transient aldosterone resistance in renal tubules and is characterized by renal sodium loss, hyponatremia, hyperkalemia and high plasma aldosterone levels."
Secondary PHA reproduces the biochemical picture of PHA1.
PMID:22397047 SUPPORT Human clinical
"The treatment is usually elimination of the underlying cause."
Secondary PHA resolves once the underlying urinary tract cause is treated, unlike genetic systemic PHA1.
🐁

Animal Models

2
betaENaC-deficient mouse
Germline disruption of the beta subunit gene produces neonatal hyponatremia with urinary sodium loss, hyperkalemia with low urinary potassium, raised aldosterone, and death within two days of birth.
Species
Mouse
Genotype
Scnn1b-/- (germline targeted disruption)
Publication
PMID:9990092
Pathograph links
Distal nephron ENaC sodium reabsorption failure recapitulates fidelity: high observes: organism Reproduces renal sodium wasting, hyperkalemia and hyperaldosteronism of human PHA1.
Limitations: Mice die within two days of birth, so the chronic course, extra-renal salt loss and response to salt supplementation cannot be studied in this germline model.
Show evidence (1 reference)
PMID:9990092 SUPPORT Model organism
"The phenotype of the betaENaC-deficient mice is similar to that of humans with pseudohypoaldosteronism type 1 and may provide a useful model to study the pathogenesis and treatment of this disorder."
The authors state the knockout phenotype resembles human PHA1.
Airway epithelial sodium absorption failure fails to recapitulate fidelity: unknown observes: organism Neonatal knockout mice do not develop the lung liquid clearance failure seen in alphaENaC-null mice.
Limitations: Only the neonatal transition to air breathing was assessed; chronic airway surface liquid and mucociliary function, which carry the human airway phenotype, were not measured because the mice die within two days.
Show evidence (1 reference)
PMID:9990092 SUPPORT Model organism
"In contrast to alphaENaC-deficient mice, which die because of defective lung liquid clearance, neonatal betaENaC deficient mice did not die of respiratory failure and showed only a small increase in wet lung weight that had little, if any, adverse physiologic consequence."
betaENaC loss has little effect on neonatal lung liquid clearance.
Adult nephron-specific betaENaC knockout mouse
Inducible deletion of betaENaC in the adult nephron produces a severe PHA1-like phenotype with weight loss, hyperkalemia and dehydration but only minor salt wasting, rescued by a low-potassium diet.
Species
Mouse
Genotype
Scnn1b Pax8/LC1 inducible nephron-specific knockout
Publication
PMID:28567665
Pathograph links
Impaired distal potassium and hydrogen ion secretion recapitulates fidelity: moderate observes: organism Reproduces severe hyperkalemia from loss of renal betaENaC.
Limitations: Adult induction bypasses the neonatal presentation of the human disease, and salt loss was minor, unlike the severe salt wasting of human PHA1B2.
Show evidence (1 reference)
PMID:28567665 SUPPORT Model organism
"Upon induction, these mice present a severe PHA-1 phenotype with weight loss, hyperkalemia, and dehydration, but unlike the Scnn1aPax8/LC1 mice without persistent salt wasting."
Renal betaENaC deletion causes a PHA1 phenotype dominated by hyperkalemia.
{ }

Source YAML

click to show 
name: Pseudohypoaldosteronism Type IB2 Autosomal Recessive
category: Mendelian
creation_date: "2026-10-15T23:00:53Z"
synonyms:
- PHA1B2
- Autosomal recessive pseudohypoaldosteronism type 1B2
- SCNN1B-related systemic pseudohypoaldosteronism type 1
- Systemic pseudohypoaldosteronism type 1 due to SCNN1B deficiency
description: >-
  Pseudohypoaldosteronism type IB2 (PHA1B2) is the SCNN1B-related form of
  autosomal recessive, systemic (multi-organ) pseudohypoaldosteronism type 1.
  Biallelic loss-of-function variants in SCNN1B, which encodes the beta
  subunit of the amiloride-sensitive epithelial sodium channel (ENaC), abolish
  or severely reduce channel activity in every aldosterone-responsive
  epithelium. Failure of ENaC-mediated sodium reabsorption in the distal
  nephron causes renal salt wasting with hyponatremia, hypovolemia, and
  impaired potassium and hydrogen ion secretion, so affected infants present in
  the first weeks of life with vomiting, poor feeding, weight loss,
  dehydration, life-threatening hyperkalemia and metabolic acidosis despite
  markedly elevated renin and aldosterone and no response to mineralocorticoid
  therapy. Extra-renal ENaC loss adds salt loss through sweat, salivary glands
  and colon (elevated sweat electrolytes, miliaria-like rash) and, in the
  systemic PHA1 literature, excess airway surface liquid with recurrent chest
  symptoms. Unlike renal PHA1A, the systemic form does not remit and needs
  lifelong high-dose sodium chloride and bicarbonate with potassium-binding
  resins; dialysis may be needed for refractory hyperkalemia. The SCNN1A
  (PHA1B1) and SCNN1G (PHA1B3) forms share this mechanism and are separate
  MONDO concepts.
disease_term:
  preferred_term: pseudohypoaldosteronism, type IB2, autosomal recessive
  term:
    id: MONDO:0859317
    label: pseudohypoaldosteronism, type IB2, 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 and birth prevalence describe systemic PHA1 as a whole
  rather than the SCNN1B form alone. Several case series report fewer SCNN1B
  than SCNN1A families. No GeneReviews chapter covers this disorder or
  systemic PHA1 (Bookshelf index snapshot of 2026-09-10 plus a live PubMed
  title search), so case reports, case series and Orphanet form the
  phenotype baseline.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Biallelic (homozygous or compound heterozygous) SCNN1B loss-of-function
    variants; heterozygous parents are clinically unaffected. Consanguinity is
    common among reported families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  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"
    explanation: Homozygous ENaC alpha or beta subunit mutations co-segregate with the disease in consanguineous kindreds.
  - reference: PMID:35359893
    reference_title: "Case Report: A Novel Compound Heterozygote Mutation of the SCNN1B Gene Identified in a Chinese Familial Pseudohypoaldosteronism Disease Type I With Persistent Hyperkalemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis showed that the neonate suffered complex heterozygosity in the SCNN1B gene inherited from the parents, which is passed on in an autosomal recessive inheritance pattern."
    explanation: Compound heterozygous SCNN1B variants inherited from unaffected parents in an autosomal recessive pattern.
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 SCNN1B-specific figure is available, and SCNN1B
    cases are reported less often than SCNN1A cases.
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | United Kingdom | Prevalence at birth | PMID:24616761"
    explanation: Orphanet epidemiology row for generalized PHA1.
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among these, SCNN1B-related cases occur less frequently than SCNN1A-related cases."
    explanation: SCNN1B accounts for a minority of systemic PHA1 cases.
progression:
- phase: Neonatal salt-wasting presentation
  age_range: First weeks of life
  notes: >-
    Presentation is typically in the first days to 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: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: In a Gulf cohort including SCNN1B siblings, all patients presented within the first 10 days of life.
- phase: Chronic course with recurrent salt-losing crises
  age_range: Infancy to adulthood
  notes: >-
    The systemic form does not remit as renal PHA1A does; lifelong salt
    supplementation is needed and recurrent life-threatening salt-losing crises
    occur, particularly with intercurrent illness. Early mortality is high in
    some series. One SCNN1B patient with a splice variant normalized renin,
    aldosterone and electrolytes on high salt intake by the end of the first
    year, and an adult compound heterozygote remained symptomatically
    hyperkalemic at 32 years.
  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:31914462
    reference_title: "Failure to Thrive, Hyponatremia, Hyperkalemia - Differential Diagnostic Reflections of a Rare Genetic Disease."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The systemic type can -apart from the kidneys - affect colon, lungs, salivary and sweat glands. In that case symptoms persist until adulthood."
    explanation: Unlike the renal type, systemic PHA1 symptoms persist into adulthood.
  - reference: PMID:17546235
    reference_title: "[Mineralocorticoid resistance: pseudohypoaldosteronism type 1]."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent."
    explanation: Review describes the lifelong recurrent course of systemic PHA1.
  - reference: PMID:32840096
    reference_title: "Clinical Management in Systemic Type Pseudohypoaldosteronism Due to SCNN1B Variant and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, patients with systemic PHA require life-long therapy."
    explanation: Systemic PHA due to SCNN1B variants needs lifelong treatment.
  - reference: PMID:42549990
    reference_title: "Clinical, Biochemical, and Molecular Spectrum of Pseudohypoaldosteronism Type 1B in Indian Children: A Multicentric Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients (67%) died, mainly due to sepsis (n = 2) or treatment discontinuation (n = 4), while three remain stable on oral sodium supplementation."
    explanation: High early mortality in a PHA1B series that included three SCNN1B patients.
  - reference: PMID:23426840
    reference_title: "A novel splice site mutation of the beta subunit gene of epithelial sodium channel (ENaC) in one Turkish patient with a systemic form of pseudohypoaldosteronism Type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initially elevated plasma renin activity (PRA) and aldosterone levels of the patient returned to normal with large amounts of dietary salt and serum sodium (Na+) and potassium (K+) levels were within normal range at the end of the first year of life."
    explanation: Documents biochemical improvement with age in one homozygous SCNN1B splice-variant patient.
  - reference: PMID:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, we report a patient with novel variants of the SCNN1B gene causing PHA1 with persistent, symptomatic hyperkalemia."
    explanation: Hyperkalemia persisted into adulthood in a compound heterozygous SCNN1B patient.
genetic:
- name: SCNN1B
  association: Causative (biallelic loss of function)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SCNN1B
    term:
      id: hgnc:10600
      label: SCNN1B
  notes: >-
    Reported PHA1B2 alleles include frameshift, nonsense, splice-site and
    missense variants, homozygous or compound heterozygous. Truncating alleles
    such as p.Glu217fs and p.Tyr306fs leave a weakly active channel, and the
    missense p.Gly37Ser lowers channel open probability without reducing
    surface expression. Gain-of-function SCNN1B variants that disrupt the
    C-terminal PY motif cause the opposite disorder, Liddle syndrome.
  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 ENaC beta subunit mutations in recessive PHA1.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SCNN1B | sodium channel epithelial 1 subunit beta | hgnc:10600 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists germline loss-of-function SCNN1B variants as disease-causing.
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing revealed compound heterozygous mutations in the SCNN1B gene: a splice-site variant (c.585+2T>C) inherited from the mother and a missense variant (c.1544T>C, p.Ile515Thr) from the father."
    explanation: Compound heterozygous SCNN1B variants in twins with systemic PHA1B2.
  - reference: PMID:42077744
    reference_title: "A Novel Homozygous SCNN1B Variant Causing Severe Systemic Pseudohypoaldosteronism Type 1B in a Saudi Infant: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified a novel homozygous likely pathogenic variant in the SCNN1B gene (NM_000336.2:c.1573C>T; p.Gln525*), confirming the diagnosis of systemic PHA1B."
    explanation: Homozygous SCNN1B nonsense variant in an infant from a consanguineous family.
  - reference: PMID:32351772
    reference_title: "Pseudohypoaldosteronism Type 1 Newborn Patient with a Novel Mutation in SCNN1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This clinical diagnosis was confirmed by the novel homozygous frame-shift variant c.1245_1246insC (p.N416Qfs*35) in SCNN1B shown by gene analysis."
    explanation: Homozygous SCNN1B frameshift variant in a neonate with PHA1.
pathophysiology:
- name: Biallelic SCNN1B loss of function
  description: >-
    Biallelic frameshift, nonsense, splice-site or missense SCNN1B variants
    remove or impair the ENaC beta subunit. Truncated beta subunits can still
    support weak trafficking and assembly with alpha and gamma subunits, and the
    missense p.Gly37Ser variant lowers channel open probability, so most
    alleles drastically reduce rather than strictly abolish amiloride-sensitive
    sodium current.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SCNN1B
    term:
      id: hgnc:10600
      label: SCNN1B
  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: "introduce frameshift, premature termination or missense mutations that result in loss of channel activity"
    explanation: Recessive PHA1 mutations in the alpha and beta subunits cause loss of ENaC activity.
  - reference: PMID:9118951
    reference_title: "A mutation causing pseudohypoaldosteronism type 1 identifies a conserved glycine that is involved in the gating of the epithelial sodium channel."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A missense mutation (G37S) of the human ENaC beta subunit that causes loss of ENaC function and PHA-1 replaces a glycine that is conserved in the N-terminus of all members of the ENaC gene family."
    explanation: A PHA1 beta subunit missense variant causes ENaC loss of function.
  - reference: PMID:9118951
    reference_title: "A mutation causing pseudohypoaldosteronism type 1 identifies a conserved glycine that is involved in the gating of the epithelial sodium channel."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results suggest that the decrease in macroscopic Na currents is due to a decrease in channel open probability (P(o)), suggesting that mutations of a conserved glycine in the N-terminus of ENaC subunits change ENaC channel gating, which would explain the disease pathophysiology."
    explanation: The beta G37S class of variant reduces open probability rather than surface expression.
  - reference: PMID:20064610
    reference_title: "Truncated beta epithelial sodium channel (ENaC) subunits responsible for multi-system pseudohypoaldosteronism support partial activity of ENaC."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of cRNAs carrying these mutations in Xenopus oocytes showed that the mutations drastically reduce but do not eliminate ENaC activity."
    explanation: Two truncating SCNN1B alleles from a multi-system PHA patient leave residual ENaC activity.
  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 and salivary 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 functional ENaC, aldosterone cannot drive sodium
    reabsorption, producing end-organ mineralocorticoid resistance and urinary
    salt wasting.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: kidney collecting duct principal cell
    term:
      id: CL:1001431
      label: kidney collecting duct principal cell
  locations:
  - preferred_term: collecting duct
    term:
      id: UBERON:0001232
      label: collecting duct of renal tubule
  biological_processes:
  - preferred_term: renal sodium ion absorption
    modifier: DECREASED
    term:
      id: GO:0070294
      label: renal sodium ion absorption
  evidence:
  - reference: PMID: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: "Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones."
    explanation: Defines the salt wasting and mineralocorticoid unresponsiveness caused by ENaC loss.
  - reference: PMID:9990092
    reference_title: "Disruption of the beta subunit of the epithelial Na+ channel in mice: hyperkalemia and neonatal death associated with a pseudohypoaldosteronism phenotype."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the -/- mice, we found an increased urine Na+ concentration despite hyponatremia and a decreased urine K+ concentration despite hyperkalemia."
    explanation: betaENaC-deficient mice show renal sodium wasting and potassium retention.
  downstream:
  - target: Renal salt wasting
    causal_link_type: DIRECT
  - target: Extracellular volume depletion
    causal_link_type: DIRECT
  - target: Impaired distal potassium and hydrogen ion secretion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19571553
      reference_title: "Clinical and molecular features of type 1 pseudohypoaldosteronism."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Pseudohypoaldosteronism (PHA) is a rare heterogeneous syndrome of mineralocorticoid resistance causing insufficient potassium and hydrogen secretion."
      explanation: Review links mineralocorticoid resistance to insufficient distal potassium and hydrogen ion secretion.
- name: Impaired distal potassium and hydrogen ion secretion
  description: >-
    Loss of electrogenic sodium entry through ENaC removes the lumen-negative
    driving force for potassium and hydrogen ion secretion in the distal
    nephron, so potassium and acid are retained.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: kidney collecting duct principal cell
    term:
      id: CL:1001431
      label: kidney collecting duct principal cell
  biological_processes:
  - preferred_term: renal potassium excretion
    modifier: DECREASED
    term:
      id: GO:0036359
      label: renal potassium excretion
  evidence:
  - reference: PMID:19571553
    reference_title: "Clinical and molecular features of type 1 pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pseudohypoaldosteronism (PHA) is a rare heterogeneous syndrome of mineralocorticoid resistance causing insufficient potassium and hydrogen secretion."
    explanation: Mineralocorticoid resistance in PHA causes insufficient potassium and hydrogen secretion.
  - reference: PMID:9990092
    reference_title: "Disruption of the beta subunit of the epithelial Na+ channel in mice: hyperkalemia and neonatal death associated with a pseudohypoaldosteronism phenotype."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The betaENaC-deficient mice showed normal prenatal development but died within 2 days after birth, most likely of hyperkalemia."
    explanation: Loss of betaENaC causes lethal hyperkalemia in neonatal mice.
  downstream:
  - target: Hyperkalemia
    causal_link_type: DIRECT
  - target: Metabolic acidosis
    causal_link_type: DIRECT
- name: Extracellular volume depletion
  description: >-
    Renal, colonic, sweat and salivary 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:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis."
    explanation: Sodium wasting with hypovolemia characterizes autosomal recessive PHA1.
  downstream:
  - target: Hyponatremia
    causal_link_type: DIRECT
  - target: Dehydration
    causal_link_type: DIRECT
  - target: Hypotension
    causal_link_type: DIRECT
  - target: Compensatory renin-angiotensin-aldosterone activation
    causal_link_type: DIRECT
  - target: Failure to thrive in infancy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Compensatory renin-angiotensin-aldosterone activation
  description: >-
    Volume depletion strongly stimulates renin secretion and aldosterone
    synthesis, but the elevated aldosterone cannot act through the defective
    channel, so plasma renin and aldosterone remain markedly elevated.
  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:32840096
    reference_title: "Clinical Management in Systemic Type Pseudohypoaldosteronism Due to SCNN1B Variant and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyponatremia, hyperkalemia, metabolic acidosis, increased aldosterone and renin levels are expected findings in PHA."
    explanation: Elevated renin and aldosterone accompany the salt-wasting state.
  - reference: PMID:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "aldosterone 2800 ng/dl (reference range: ≤21 ng/dl) and plasma renin activity 90 ng/ml/h (reference range: 0.6-4.3 ng/ml per h)"
    explanation: Markedly elevated aldosterone and renin in an adult SCNN1B compound heterozygote.
  downstream:
  - target: Increased circulating renin concentration
    causal_link_type: DIRECT
  - target: Increased circulating aldosterone concentration
    causal_link_type: DIRECT
- name: Sweat duct sodium reabsorption failure
  description: >-
    ENaC in the eccrine sweat duct reabsorbs sodium from primary sweat. In
    systemic PHA1 ducts lack ENaC conductance, so sweat salt absorption is
    blocked although CFTR chloride conductance is preserved, giving high sweat
    sodium and chloride and reversed sweat-induced skin potentials.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: epithelial cell of sweat gland
    term:
      id: CL:1000448
      label: epithelial cell of sweat gland
  locations:
  - preferred_term: sweat gland
    term:
      id: UBERON:0001820
      label: sweat gland
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
  evidence:
  - reference: PMID:15986094
    reference_title: "Normal CFTR Activity and Reversed Skin Potentials in Pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lack of gENaC completely blocked salt absorption and caused dramatic reversal of skin potentials associated with pilocarpine-induced sweat secretion"
    explanation: Ex vivo sweat ducts from PHA1 patients show no ENaC conductance and no salt absorption; the study does not report which ENaC subunit gene was affected.
  downstream:
  - target: Elevated sweat chloride
    causal_link_type: DIRECT
  - target: Extracellular volume depletion
    causal_link_type: DIRECT
  - target: Miliaria-like skin rash
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17389851
      reference_title: "[Pustular miliaria rubra and systemic type 1b pseudohypoaldosteronism in a newborn]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Obstruction of the eccrine ducts and pustular exanthema were probably due to abnormal Na+ levels in sweat."
      explanation: Case report attributes pustular miliaria in systemic PHA1 to abnormal sweat sodium; the mechanism is proposed rather than demonstrated.
- name: Colonic and salivary sodium absorption failure
  description: >-
    ENaC also mediates amiloride-sensitive sodium absorption in distal colon
    and salivary duct epithelium; its loss adds intestinal and salivary salt
    loss to the renal deficit.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: colon epithelial cell
    term:
      id: CL:0011108
      label: colon epithelial cell
  locations:
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  biological_processes:
  - preferred_term: sodium ion transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A severe form of pseudohypoaldosteronism type 1 characterized by salt wasting in multiple organs including the kidney, colon, and sweat and salivary glands."
    explanation: Orphanet defines generalized PHA1 by salt wasting from kidney, colon, sweat and salivary glands.
  - reference: PMID:40398899
    reference_title: "Autosomal recessive (type 1B) pseudohypoaldosteronism: a novel mutation and its management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical symptoms include episodes of salt wasting, metabolic acidosis and hyperkalaemia and may include intestinal salt wasting and a generalised rash."
    explanation: Intestinal salt wasting is part of PHA1B, reported here in an SCNN1B case.
  downstream:
  - target: Extracellular volume depletion
    causal_link_type: DIRECT
- name: Airway epithelial sodium absorption failure
  description: >-
    Airway ENaC absorbs sodium and liquid from the airway surface. Patients
    with systemic PHA1 have no airway sodium absorption, more than double the
    normal airway surface liquid volume, and recurrent chest congestion,
    coughing and wheezing in early childhood. This was shown in cohorts with
    ENaC subunit mutations generally; betaENaC-null mice clear neonatal lung
    liquid almost normally, so how far the airway phenotype applies to the
    SCNN1B form specifically is not settled.
  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 SCNN1B.
  - reference: PMID:9990092
    reference_title: "Disruption of the beta subunit of the epithelial Na+ channel in mice: hyperkalemia and neonatal death associated with a pseudohypoaldosteronism phenotype."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "In contrast to alphaENaC-deficient mice, which die because of defective lung liquid clearance, neonatal betaENaC deficient mice did not die of respiratory failure and showed only a small increase in wet lung weight that had little, if any, adverse physiologic consequence."
    explanation: In mice the beta subunit is dispensable for neonatal lung liquid clearance, which argues against a severe beta-specific lung phenotype at birth.
  downstream:
  - target: Wheezing
    causal_link_type: DIRECT
  - target: Cough
    causal_link_type: DIRECT
  - target: Recurrent upper and lower respiratory tract infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Metabolic/Laboratory
  name: Hyponatremia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:42549990
    reference_title: "Clinical, Biochemical, and Molecular Spectrum of Pseudohypoaldosteronism Type 1B in Indian Children: A Multicentric Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All presented with hyponatraemia and hyperkalaemia (median serum sodium 124 mEq/L; potassium 8.0 mEq/L)."
    explanation: All PHA1B patients, including three SCNN1B patients, 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 and may be
    refractory to conventional therapy, requiring dialysis.
  phenotype_term:
    preferred_term: Hyperkalemia
    term:
      id: HP:0002153
      label: Hyperkalemia
  sequelae:
  - target: Arrhythmia
    description: Severe hyperkalemia can provoke cardiac arrhythmia and cardiac arrest.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26807262
      reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death."
      explanation: The electrolyte derangement of SCNN1B-related PHA1 can lead to cardiac arrhythmias.
  evidence:
  - reference: PMID:42549990
    reference_title: "Clinical, Biochemical, and Molecular Spectrum of Pseudohypoaldosteronism Type 1B in Indian Children: A Multicentric Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All presented with hyponatraemia and hyperkalaemia (median serum sodium 124 mEq/L; potassium 8.0 mEq/L)."
    explanation: All PHA1B patients presented with severe hyperkalemia.
  - reference: PMID:32840096
    reference_title: "Clinical Management in Systemic Type Pseudohypoaldosteronism Due to SCNN1B Variant and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperkalemia did not improve with conventional treatments and dialysis was required."
    explanation: Refractory hyperkalemia in an SCNN1B patient required dialysis.
  - 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:42077744
    reference_title: "A Novel Homozygous SCNN1B Variant Causing Severe Systemic Pseudohypoaldosteronism Type 1B in a Saudi Infant: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "initially presented at seven days of life with persistent hyperkalemia, hyponatremia, and metabolic acidosis"
    explanation: Metabolic acidosis at presentation in a homozygous SCNN1B infant.
  - 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: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: "Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones."
    explanation: Severe neonatal salt wasting is the defining feature.
- 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: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings showed markedly elevated plasma renin and aldosterone levels, with no evidence of congenital adrenal hyperplasia or other metabolic disorders."
    explanation: Markedly elevated renin in SCNN1B compound heterozygous twins.
  - 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
  description: >-
    Aldosterone is markedly elevated; one series noted a less marked rise in
    patients with SCNN1A or SCNN1B missense variants, consistent with residual
    channel function.
  phenotype_term:
    preferred_term: Increased circulating aldosterone concentration
    term:
      id: HP:0000859
      label: Increased circulating aldosterone concentration
  evidence:
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings showed markedly elevated plasma renin and aldosterone levels, with no evidence of congenital adrenal hyperplasia or other metabolic disorders."
    explanation: Markedly elevated aldosterone in SCNN1B compound heterozygous twins.
  - reference: PMID:31301676
    reference_title: "Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients presenting with missense mutations of SCNN1A and SCNN1B had a less marked rise in serum aldosterone suggesting preservation in sodium epithelial channel function."
    explanation: The degree of hyperaldosteronism varies with variant class.
- category: Systemic
  name: Dehydration
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: PMID:35530903
    reference_title: "Pseudohypoaldosteronism Type 1: The Presentation and Management of a Neonate With a Novel Mutation of the SCNN1B Gene Found in Two Hispanic Siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case describes a newborn who developed severe dehydration and electrolyte imbalances and subsequently was found to have a novel SCNN1B gene variant resulting in autosomal recessive systemic PHA1."
    explanation: Severe dehydration in an SCNN1B neonate.
  - 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 included SCNN1B siblings.
- category: Gastrointestinal
  name: Vomiting
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:39723761
    reference_title: "A Rare Cause of Neonatal Salt Wasting Syndrome: Clinical Management of a Case Diagnosed with Pseudohypoaldosteronism due to a Novel Homozygous Variant in the SCNN1B Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present the clinical course of a newborn diagnosed with PHA at seven days of age due to severe dehydration, inadequate feeding, vomiting, and lethargy."
    explanation: Vomiting at presentation in a homozygous SCNN1B newborn.
  - 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: Gastrointestinal
  name: Feeding difficulties in infancy
  phenotype_term:
    preferred_term: Poor feeding
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  evidence:
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented at 8 days of age with poor feeding, weight loss, and severe jaundice"
    explanation: Poor feeding at presentation in SCNN1B twins.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008872 | Feeding difficulties in infancy | Occasional (29-5%)"
    explanation: Orphanet records infantile feeding difficulties.
- category: Growth
  name: Weight loss
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented at 8 days of age with poor feeding, weight loss, and severe jaundice"
    explanation: Neonatal weight loss in SCNN1B twins.
- category: Growth
  name: Failure to thrive in infancy
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive in infancy
    term:
      id: HP:0001531
      label: Failure to thrive in infancy
  evidence:
  - reference: PMID:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis."
    explanation: Failure to thrive is a characteristic feature of autosomal recessive PHA1.
  - 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: Neurological
  name: Lethargy
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:39723761
    reference_title: "A Rare Cause of Neonatal Salt Wasting Syndrome: Clinical Management of a Case Diagnosed with Pseudohypoaldosteronism due to a Novel Homozygous Variant in the SCNN1B Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present the clinical course of a newborn diagnosed with PHA at seven days of age due to severe dehydration, inadequate feeding, vomiting, and lethargy."
    explanation: Lethargy at presentation in a homozygous SCNN1B newborn.
- category: Cardiovascular
  name: Arrhythmia
  frequency: OCCASIONAL
  description: >-
    Severe hyperkalemia can cause cardiac arrhythmia and cardiac arrest.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death."
    explanation: Electrolyte derangement in SCNN1B-related PHA1 can cause cardiac arrhythmias.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011675 | Arrhythmia | Occasional (29-5%)"
    explanation: Orphanet records arrhythmia as occasional.
- 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 systemic PHA1 patients, one of whom carried biallelic SCNN1B variants.
- category: Integument
  name: Miliaria-like skin rash
  description: >-
    Recurrent miliaria rubra-like or pustular eruptions, which can flare with
    salt-losing crises.
  phenotype_term:
    preferred_term: Miliaria-like skin rash
    term:
      id: HP:0000988
      label: Skin rash
  notes: >-
    HPO has no miliaria term (an OLS search of the hp ontology for "miliaria"
    returned no terms), so the eruption is bound to the general skin rash term.
  evidence:
  - reference: PMID:17389851
    reference_title: "[Pustular miliaria rubra and systemic type 1b pseudohypoaldosteronism in a newborn]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since the first days of life, the child presented severe and diffuse miliaria comprising many disseminated pustules associated with salt loss syndrome."
    explanation: Pustular miliaria in a neonate with systemic PHA1B.
  - reference: PMID:40398899
    reference_title: "Autosomal recessive (type 1B) pseudohypoaldosteronism: a novel mutation and its management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical symptoms include episodes of salt wasting, metabolic acidosis and hyperkalaemia and may include intestinal salt wasting and a generalised rash."
    explanation: A generalized rash is part of PHA1B in an SCNN1B case report.
  - 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 main presentation symptoms were vomiting, poor feeding, weakness, weight loss, and skin rash."
    explanation: Skin rash among presenting symptoms in systemic PHA1 cases including an SCNN1B patient.
- category: Respiratory
  name: Wheezing
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Wheezing
    term:
      id: HP:0030828
      label: Wheezing
  notes: >-
    Reported in systemic PHA1 cohorts not restricted to SCNN1B; Orphanet lists
    it as occasional for generalized PHA1.
  evidence:
  - reference: PMID:10403853
    reference_title: "Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa."
    explanation: Recurrent wheezing in young patients with systemic PHA1 from ENaC subunit mutations.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030828 | Wheezing | Occasional (29-5%)"
    explanation: Orphanet records wheezing as occasional.
- category: Respiratory
  name: Cough
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  notes: >-
    Reported in systemic PHA1 cohorts not restricted to SCNN1B; respiratory
    symptoms are less frequent after five years of age.
  evidence:
  - reference: PMID:10403853
    reference_title: "Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa."
    explanation: Recurrent coughing in young patients with systemic PHA1 from ENaC subunit mutations.
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012735 | Cough | Occasional (29-5%)"
    explanation: Orphanet records cough as occasional.
- category: Respiratory
  name: Recurrent upper and lower respiratory tract infections
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent upper and lower respiratory tract infections
    term:
      id: HP:0200117
      label: Recurrent upper and lower respiratory tract infections
  notes: >-
    The Orphanet frequency applies to generalized PHA1 across ENaC genes. One
    homozygous SCNN1B infant died of pneumonia at 10 months.
  evidence:
  - reference: ORPHA:171876
    reference_title: "Generalized pseudohypoaldosteronism type 1"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0200117 | Recurrent upper and lower respiratory tract infections | Frequent (79-30%)"
    explanation: Orphanet records recurrent respiratory tract infections as frequent in generalized PHA1.
  - reference: PMID:39723761
    reference_title: "A Rare Cause of Neonatal Salt Wasting Syndrome: Clinical Management of a Case Diagnosed with Pseudohypoaldosteronism due to a Novel Homozygous Variant in the SCNN1B Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had multiple hospitalizations during follow-up and died at the age of 10 months due to pneumonia."
    explanation: Fatal pneumonia in a homozygous SCNN1B infant.
diagnosis:
- name: Biochemical and hormonal profile
  description: >-
    Neonatal hyponatremia, hyperkalemia and metabolic acidosis with markedly
    elevated plasma renin and aldosterone, after exclusion of congenital
    adrenal hyperplasia and other adrenal causes, suggest PHA1. The renal and
    systemic forms cannot be told apart by early presentation or by this
    profile.
  evidence:
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory findings showed markedly elevated plasma renin and aldosterone levels, with no evidence of congenital adrenal hyperplasia or other metabolic disorders."
    explanation: Elevated renin and aldosterone with congenital adrenal hyperplasia excluded in SCNN1B twins.
  - reference: PMID:31301676
    reference_title: "Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile."
    explanation: The biochemical profile does not separate renal from systemic PHA1.
- name: Sweat test
  description: >-
    A positive sweat test (elevated sweat electrolytes) reflects extra-renal
    ENaC loss and supports the systemic rather than the renal form.
  measurements:
  - preferred_term: sweat chloride and sodium
    term:
      id: LOINC:74993-7
      label: Chloride and sodium panel [Moles/volume] - Sweat
  notes: >-
    The panel is bound rather than either electrolyte alone, because this row says
    elevated sweat electrolytes without singling one out, and ENaC loss raises both.
    Two things in the release are easy to pick by mistake. Its sweat chloride codes
    include a toxicology-screen method pair that measures a different thing, and the
    word sweat matches about twenty questionnaire items about sweating, in instruments
    such as PROMIS, FACIT, PCL and the PHQ, none of which is a sweat assay. A narrative
    code for specialist review of sweat analysis also exists and names a result field
    rather than a test. Those are findings from the full 2.83 table, which holds the
    observation and panel codes; the Part question was put separately to the Monarch
    KG, which holds the Parts, and across its 38 sweat records the only Part is
    LOINC:LP7618-4, the specimen itself; there is no measurement Part for sweat
    chloride or sweat sodium. No reference range is bound: this row reports the test as
    positive and gives no electrolyte concentration, and the cystic fibrosis sweat
    chloride thresholds are a different disease's decision limits.
  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 contributed to the diagnosis of systemic PHA1.
- name: Molecular genetic testing of ENaC subunit genes
  description: >-
    Sequencing of SCNN1A, SCNN1B and SCNN1G (with NR3C2 for the renal form),
    usually by exome sequencing, confirms the diagnosis and assigns the
    subtype; biallelic SCNN1B variants define PHA1B2.
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:31301676
    reference_title: "Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We advocate early genetic testing in patients with presumed PHA1, given the challenges in differentiating between patients with PHA1a and PHA1b."
    explanation: Genetic testing is needed to distinguish PHA1A from PHA1B.
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report broadens the mutational spectrum of SCNN1B and underscores the importance of early genetic testing in refractory neonatal electrolyte disturbances."
    explanation: Early genetic testing identified SCNN1B variants in refractory neonatal electrolyte disturbance.
treatments:
- name: High-dose sodium chloride supplementation
  description: >-
    Lifelong oral sodium chloride replacement, often in very large doses, is the
    mainstay of therapy for the systemic form; adherence is difficult and
    treatment discontinuation is a leading cause of death in some series.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium chloride
      term:
        id: CHEBI:26710
        label: sodium chloride
  target_mechanisms:
  - target: Extracellular volume depletion
    description: Replaces renal and extra-renal sodium losses.
  evidence:
  - reference: PMID:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
    explanation: High-dose sodium chloride is part of symptomatic treatment.
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with oral sodium chloride, sodium citrate, and potassium-binding resins led to gradual correction of electrolyte imbalance and clinical stabilization."
    explanation: Oral sodium chloride contributed to stabilization of SCNN1B twins.
  - reference: PMID:42549990
    reference_title: "Clinical, Biochemical, and Molecular Spectrum of Pseudohypoaldosteronism Type 1B in Indian Children: A Multicentric Case Series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients (67%) died, mainly due to sepsis (n = 2) or treatment discontinuation (n = 4), while three remain stable on oral sodium supplementation."
    explanation: Survivors remain stable on oral sodium supplementation, and discontinuation was a major cause of death.
  - reference: PMID:17546235
    reference_title: "[Mineralocorticoid resistance: pseudohypoaldosteronism type 1]."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary."
    explanation: Review states that systemic PHA1 requires high-dose salt supplementation.
- name: Sodium bicarbonate
  description: Alkali therapy to correct metabolic acidosis while also supplying sodium.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium bicarbonate
      term:
        id: NCIT:C29457
        label: Sodium Bicarbonate
  target_mechanisms:
  - target: Metabolic acidosis
    description: Buffers retained acid.
  evidence:
  - reference: PMID:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
    explanation: Sodium bicarbonate is part of symptomatic treatment in SCNN1B-related PHA1.
- name: Potassium-binding resin
  description: >-
    Cation-exchange resins such as sodium polystyrene sulfonate increase fecal
    potassium excretion to control chronic hyperkalemia.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium polystyrene sulfonate
      term:
        id: NCIT:C29461
        label: Sodium Polystyrene Sulfonate
  target_mechanisms:
  - target: Hyperkalemia
    description: Removes retained potassium through the gut.
  evidence:
  - reference: PMID:26807262
    reference_title: "Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment."
    explanation: Sodium polystyrene sulfonate is part of symptomatic treatment.
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with oral sodium chloride, sodium citrate, and potassium-binding resins led to gradual correction of electrolyte imbalance and clinical stabilization."
    explanation: Potassium-binding resins contributed to correction of hyperkalemia in SCNN1B twins.
- name: Dialysis for refractory hyperkalemia
  description: >-
    Peritoneal dialysis has been required when neonatal hyperkalemia did not
    respond to conventional medical treatment.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Dialysis
    term:
      id: NCIT:C15221
      label: Dialysis
  target_mechanisms:
  - target: Hyperkalemia
    description: Extracorporeal or peritoneal potassium removal.
  evidence:
  - reference: PMID:32840096
    reference_title: "Clinical Management in Systemic Type Pseudohypoaldosteronism Due to SCNN1B Variant and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperkalemia did not improve with conventional treatments and dialysis was required."
    explanation: Dialysis was required for refractory hyperkalemia in an SCNN1B patient.
- name: Mineralocorticoid and glucocorticoid replacement
  description: >-
    Hydrocortisone and fludrocortisone are often started empirically for
    suspected salt-wasting adrenal disease but do not correct the electrolyte
    disturbance, because the defect lies in the target channel rather than in
    hormone supply. Failure to respond helps distinguish PHA1 from congenital
    adrenal hyperplasia.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fludrocortisone
      term:
        id: CHEBI:50885
        label: fludrocortisone
  evidence:
  - reference: PMID:41457049
    reference_title: "Case Report: Compound Heterozygous SCNN1B Mutations Causing Pseudohypoaldosteronism Type 1B2 in Neonatal Twins."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Both developed life-threatening hyperkalemia, hyponatremia, and metabolic acidosis, and these conditions were unresponsive to initial management including hydrocortisone."
    explanation: Electrolyte disturbances in SCNN1B twins did not respond to hydrocortisone.
  - reference: PMID:34165441
    reference_title: "Systemic pseudohypoaldosteronism-1 with episodic dyslipidemia in a Sudanese child."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "A child presenting with features that mimic salt-losing congenital adrenal hyperplasia (CAH) crises that do not respond to glucocorticoid and mineralocorticoid therapy should alert the pediatricians to the possibility of end-organ resistance to aldosterone."
    explanation: Lack of response to glucocorticoid and mineralocorticoid therapy is expected in end-organ aldosterone resistance.
  - reference: PMID:23641881
    reference_title: "Failure to thrive, hyponatremia, and hyperkalemia in a neonate."
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients with PHA1 are often initially diagnosed with congenital adrenal hyperplasia, but their electrolyte abnormalities are resistant to treatment with glucocorticoids and mineralocorticoids."
    explanation: Electrolyte abnormalities in PHA1 do not respond to glucocorticoid or mineralocorticoid treatment.
differential_diagnoses:
- name: Congenital adrenal hyperplasia
  description: >-
    Salt-wasting congenital adrenal hyperplasia produces the same neonatal
    hyponatremia, hyperkalemia and acidosis and is often considered first.
  distinguishing_features:
  - Normal cortisol and 17-hydroxyprogesterone with high aldosterone in PHA1
  - No response to glucocorticoid and mineralocorticoid replacement in PHA1
  evidence:
  - reference: PMID:32351772
    reference_title: "Pseudohypoaldosteronism Type 1 Newborn Patient with a Novel Mutation in SCNN1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since she had hyponatremia and hyperkalemia, congenital adrenal hyperplasia was primarily considered."
    explanation: Congenital adrenal hyperplasia was the initial working diagnosis in an SCNN1B neonate.
  - reference: PMID:34165441
    reference_title: "Systemic pseudohypoaldosteronism-1 with episodic dyslipidemia in a Sudanese child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The classical presentation is life-threatening neonatal/infantile salt-losing crises that mimic congenital adrenal hyperplasia (CAH)."
    explanation: Systemic PHA1 crises mimic salt-wasting CAH.
  - reference: PMID:23641881
    reference_title: "Failure to thrive, hyponatremia, and hyperkalemia in a neonate."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients with PHA1 are often initially diagnosed with congenital adrenal hyperplasia, but their electrolyte abnormalities are resistant to treatment with glucocorticoids and mineralocorticoids."
    explanation: Resistance to steroid replacement distinguishes PHA1 from congenital adrenal hyperplasia.
- name: Autosomal dominant pseudohypoaldosteronism type 1
  disease_term:
    preferred_term: autosomal dominant pseudohypoaldosteronism type 1
    term:
      id: MONDO:0008329
      label: autosomal dominant pseudohypoaldosteronism type 1
  description: >-
    Renal PHA1A from heterozygous NR3C2 variants causes a milder kidney-limited
    salt-wasting syndrome that remits with age.
  distinguishing_features:
  - Kidney-limited salt loss with normal sweat electrolytes in renal PHA1A
  - Improvement with age in renal PHA1A versus lifelong treatment in systemic PHA1B
  evidence:
  - reference: PMID:31301676
    reference_title: "Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was impossible to differentiate between types of PHA1 from early clinical presentation or the biochemical and hormonal profile."
    explanation: Renal and systemic PHA1 cannot be separated by early presentation, so genetic testing is needed.
  - reference: PMID:31301676
    reference_title: "Phenotypic diversity and correlation with the genotypes of pseudohypoaldosteronism type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical course differs between patients with NR3C2 and SCNN1A mutations with a poorer prognosis in those with multisystem PHA."
    explanation: Prognosis is worse in multisystem PHA1B than in NR3C2-related renal PHA1A.
- name: Early-onset familial hypoaldosteronism
  disease_term:
    preferred_term: early-onset familial hypoaldosteronism
    term:
      id: MONDO:0035320
      label: early-onset familial hypoaldosteronism
  description: >-
    Aldosterone synthase deficiency also causes infantile salt wasting with
    hyponatremia, hyperkalemia and high renin, but aldosterone is low to normal.
  distinguishing_features:
  - Low to normal aldosterone in aldosterone synthase deficiency versus high aldosterone in PHA1
  - Response to fludrocortisone in aldosterone synthase deficiency
  evidence:
  - reference: PMID:41905953
    reference_title: "Congenital aldosterone deficiency and its resistance."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "ASD must also be differentiated from another disease, pseudohypoaldosteronism type 1 (PHA1), which involves resistance to aldosterone."
    explanation: Names PHA1 and aldosterone synthase deficiency as mutual differential diagnoses.
- name: Secondary (transient) pseudohypoaldosteronism
  description: >-
    Transient renal aldosterone resistance from urinary tract infection or
    urinary tract anomalies produces renal salt loss, hyponatremia,
    hyperkalemia and high aldosterone in early infancy.
  distinguishing_features:
  - Urinary tract infection or obstructive anomaly on urine culture and renal imaging
  - Resolution after treatment of the underlying cause
  evidence:
  - reference: PMID:22397047
    reference_title: "Secondary pseudohypoaldosteronism caused by urinary tract infection associated with urinary tract anomalies: case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary pseudohypoaldosteronism type 1 develops due to transient aldosterone resistance in renal tubules and is characterized by renal sodium loss, hyponatremia, hyperkalemia and high plasma aldosterone levels."
    explanation: Secondary PHA reproduces the biochemical picture of PHA1.
  - reference: PMID:22397047
    reference_title: "Secondary pseudohypoaldosteronism caused by urinary tract infection associated with urinary tract anomalies: case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment is usually elimination of the underlying cause."
    explanation: Secondary PHA resolves once the underlying urinary tract cause is treated, unlike genetic systemic PHA1.
animal_models:
- name: betaENaC-deficient mouse
  species: Mouse
  genotype: Scnn1b-/- (germline targeted disruption)
  publication: PMID:9990092
  description: >-
    Germline disruption of the beta subunit gene produces neonatal hyponatremia
    with urinary sodium loss, hyperkalemia with low urinary potassium, raised
    aldosterone, and death within two days of birth.
  modeled_mechanisms:
  - target: Distal nephron ENaC sodium reabsorption failure
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      Reproduces renal sodium wasting, hyperkalemia and hyperaldosteronism of
      human PHA1.
    limitations: >-
      Mice die within two days of birth, so the chronic course, extra-renal salt
      loss and response to salt supplementation cannot be studied in this
      germline model.
    evidence:
    - reference: PMID:9990092
      reference_title: "Disruption of the beta subunit of the epithelial Na+ channel in mice: hyperkalemia and neonatal death associated with a pseudohypoaldosteronism phenotype."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The phenotype of the betaENaC-deficient mice is similar to that of humans with pseudohypoaldosteronism type 1 and may provide a useful model to study the pathogenesis and treatment of this disorder."
      explanation: The authors state the knockout phenotype resembles human PHA1.
  - target: Airway epithelial sodium absorption failure
    relationship: FAILS_TO_RECAPITULATE
    fidelity: UNKNOWN
    model_scale: ORGANISM
    description: >-
      Neonatal knockout mice do not develop the lung liquid clearance failure
      seen in alphaENaC-null mice.
    limitations: >-
      Only the neonatal transition to air breathing was assessed; chronic airway
      surface liquid and mucociliary function, which carry the human airway
      phenotype, were not measured because the mice die within two days.
    evidence:
    - reference: PMID:9990092
      reference_title: "Disruption of the beta subunit of the epithelial Na+ channel in mice: hyperkalemia and neonatal death associated with a pseudohypoaldosteronism phenotype."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast to alphaENaC-deficient mice, which die because of defective lung liquid clearance, neonatal betaENaC deficient mice did not die of respiratory failure and showed only a small increase in wet lung weight that had little, if any, adverse physiologic consequence."
      explanation: betaENaC loss has little effect on neonatal lung liquid clearance.
- name: Adult nephron-specific betaENaC knockout mouse
  species: Mouse
  genotype: Scnn1b Pax8/LC1 inducible nephron-specific knockout
  publication: PMID:28567665
  description: >-
    Inducible deletion of betaENaC in the adult nephron produces a severe
    PHA1-like phenotype with weight loss, hyperkalemia and dehydration but only
    minor salt wasting, rescued by a low-potassium diet.
  modeled_mechanisms:
  - target: Impaired distal potassium and hydrogen ion secretion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Reproduces severe hyperkalemia from loss of renal betaENaC.
    limitations: >-
      Adult induction bypasses the neonatal presentation of the human disease,
      and salt loss was minor, unlike the severe salt wasting of human PHA1B2.
    evidence:
    - reference: PMID:28567665
      reference_title: "Severe hyperkalemia is rescued by low-potassium diet in renal βENaC-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Upon induction, these mice present a severe PHA-1 phenotype with weight loss, hyperkalemia, and dehydration, but unlike the Scnn1aPax8/LC1 mice without persistent salt wasting."
      explanation: Renal betaENaC deletion causes a PHA1 phenotype dominated by hyperkalemia.
📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (1)

Create: Pseudohypoaldosteronism Type IB2 Autosomal Recessive · 2026-10-15T23:46:05Z · View source

New entry for the SCNN1B-related systemic, autosomal recessive form of pseudohypoaldosteronism type 1 (PHA1B2, MONDO:0859317), replacing the seed file and deleting the stub. Curated: description, synonyms, parents, notes, inheritance (HP:0000007), prevalence (Orphanet birth-prevalence band for generalized PHA1, with the caveat that it covers all three ENaC genes), progression (neonatal presentation; chronic non-remitting course), genetic (SCNN1B, hgnc:10600, causative, germline loss of function), a pathograph of 8 pathophysiology nodes (SCNN1B loss of function, distal nephron sodium reabsorption failure, impaired distal potassium and hydrogen ion secretion, extracellular volume depletion, compensatory renin-angiotensin-aldosterone activation, sweat duct, colonic and salivary, and airway sodium absorption failure) with downstream edges into 15 of 19 phenotypes plus a Hyperkalemia to Arrhythmia sequela, diagnosis (biochemical profile, sweat test, genetic testing NCIT:C15709), treatments (sodium chloride, sodium bicarbonate, sodium polystyrene sulfonate, dialysis, and mineralocorticoid/glucocorticoid replacement recorded with REFUTE evidence for lack of effect), differential diagnoses (congenital adrenal hyperplasia, renal PHA1A, aldosterone synthase deficiency, secondary PHA) and two betaENaC mouse models linked to the pathograph. Deep research: one openscientist report was used. It was retrieved by re-attaching to the original OpenScientist job b68f6376-91bf-462a-aa91-1a3d3b1aa84e after a container restart; no second job was submitted. Its reference validation reported 24/24 references resolved, 0 off topic, and 1 of 1 quoted claims not found (the phrase "Pseudohypoaldosteronism Type 1B2" attributed to PMID:41457049; that quote was not reused). Its term validation flagged NCIT:C77398 as unresolved (offered for sodium chloride) and mislabelled NCIT:C29343, NCIT:C87720, CHEBI:2674 and CL:0002370; none of the report's suggested CURIEs were bound, and all bindings came from the repository caches or OLS lookups. The report also cites OMIM #264350 as the phenotype entry, whereas MONDO:0859317 cross-references OMIM:620125. Report citations taken: 41457049, 42549990, 20064610, 23426840, 31018202, 9990092, 19571553, 23641881, 22397047, 17546235, 31914462. Dropped: 16207733 (heterozygous SCNN1B variants in a cystic fibrosis-like syndrome without renal disease, a different disorder), 23416952, 33690157, 38288475, 23680607 (SCNN1A or SCNN1G cohorts and cases, so not used for SCNN1B-specific claims), 26817011, 21664233, 15958725, 11826291, 21750640, 26772908, 41275343 (background or general reviews adding nothing citable beyond the sources used), 9326675 (alphaENaC rescue mouse, not this gene). Additional primary sources were found directly in PubMed, including Chang 1996 (8589714), the betaG37S gating study (9118951), Kerem 1999 airway study (10403853), sweat duct physiology (15986094), miliaria case (17389851) and SCNN1B case reports. Respiratory phenotype: the human airway evidence (Kerem 1999) comes from a systemic PHA1 cohort not restricted to SCNN1B, and the betaENaC knockout mouse clears neonatal lung liquid almost normally, so the airway node carries both and the wheezing, cough and infection phenotypes note that the evidence is pan-ENaC. preflight-dr was not run to completion: it requires a local MONDO build (~/.data/oaklib/mondo.db, about 1.3 GB), which is absent, and it was not downloaded. A manual check instead found SCNN1B named 43 times in the report body against 20 for SCNN1A and 10 for SCNN1G, and no Liddle syndrome content, consistent with the report being about the intended disease. GeneReviews: just check-genereviews --online returned NO_CHAPTER for GeneReviews and StatPearls after synonyms were added. Artifacts: the _artifacts directory holds only final_report.html and final_report.pdf, which duplicate the markdown report, so they were not committed. Orphanet: ORPHA:171876 was fetched with just fetch-reference; the Orphadata files on disk had drifted from the manifest pin, so the cache file is stamped with release 2026-06-23 rather than the pinned snapshot date. The manifest was not repinned. Validation: just validate, validate-terms, count-verified-snippets (99/99), check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-block-scalar-comments, check-enum-values, check-snippet-length, check-title-snippets, check-folded-hyphens, check-coarse-phenotypes, check-snippet-grading, check-retired-support-prose, check-reference-titles, normalize-cache, check-term-cache-integrity and validate-disorders all passed.

OpenScientist ▸
Pseudohypoaldosteronism Type IB2, Autosomal Recessive — Comprehensive Disease Report
openscientist-autonomous 24 citations 2026-10-15T23:22:25.769235

Pseudohypoaldosteronism Type IB2, Autosomal Recessive — Comprehensive Disease Report

MONDO ID: MONDO:0859317 · Category: Mendelian · Causal gene: SCNN1B (ENaC β-subunit) · Inheritance: Autosomal recessive

Summary

Pseudohypoaldosteronism type IB2 (PHA1B2; MONDO:0859317) is the SCNN1B/β-subunit variant of the severe, systemic, autosomal-recessive form of type 1 pseudohypoaldosteronism (PHA1). It is caused by biallelic loss-of-function variants in SCNN1B (16p12.2), the gene encoding the β-subunit of the amiloride-sensitive epithelial sodium channel (ENaC). ENaC is the final effector of aldosterone-driven sodium reabsorption. When the channel cannot assemble or conduct sodium, the body becomes resistant to aldosterone at the end organ (the hormone is present and markedly elevated, but its signal cannot be transduced), producing a systemic salt-wasting disorder affecting the kidney, colon, lung, and sweat/salivary/skin epithelia. PHA1 is subdivided into a milder autosomal dominant renal form (PHA1A, NR3C2/mineralocorticoid receptor) and a severe systemic autosomal recessive form (PHA1B) caused by biallelic mutations in the three ENaC subunit genes — SCNN1A (α, IB1), SCNN1B (β, IB2), and SCNN1G (γ, IB3). The clinical and biochemical phenotype is indistinguishable among the three subunit subtypes.

Clinically, PHA1B2 presents in the neonatal period (median age ~14 days) with a life-threatening salt-wasting crisis: poor feeding, vomiting, weight loss, dehydration, failure to thrive, and circulatory shock, accompanied by the biochemical triad of hyponatremia, hyperkalemia, and metabolic acidosis with markedly elevated plasma renin and aldosterone. Extra-renal features distinguish the systemic form from the renal form — cystic fibrosis-like pulmonary disease, eczematous/miliaria-like skin lesions, and elevated sweat chloride (a positive sweat test). Critically, the electrolyte abnormalities are resistant to glucocorticoid and mineralocorticoid therapy, which is the key feature distinguishing PHA1 from congenital adrenal hyperplasia (CAH). Management is lifelong supportive care: high-dose oral sodium chloride, potassium-lowering cation-exchange resins (sodium/calcium polystyrene sulfonate), alkali for acidosis, and acute measures for hyperkalemic emergencies. There is no cure and no disease-modifying therapy. Mortality is substantial (reported 25–67% across cohorts, largely from hyperkalemic cardiac arrest), yet survival with normal neurological outcome into adulthood is achievable with intensive management.

At the molecular level, PHA1B2 is an ENaC channelopathy. Biallelic SCNN1B loss-of-function abolishes or severely reduces apical sodium conductance in principal cells of the aldosterone-sensitive distal nephron, triggering urinary sodium wasting, failure of distal potassium/hydrogen secretion, and compensatory (but futile) renin-angiotensin-aldosterone system (RAAS) activation. A distinctive feature of the β-subunit is that truncated β-ENaC subunits can retain partial channel activity, providing a molecular explanation for phenotypic variability and the clinical observation that salt requirements sometimes decline with age. The βENaC (Scnn1b) knockout mouse faithfully recapitulates the human disorder (hyperkalemia, renal salt wasting, elevated aldosterone, neonatal death), confirming the causal mechanism. This report synthesizes 10 confirmed findings drawn from 52 reviewed papers across all 15 requested domains.

Scope note on nomenclature. Because the clinical/biochemical phenotype, mechanism, prognosis and treatment are essentially identical across the three subunit subtypes (IB1/IB2/IB3), much of the evidence below derives from the systemic PHA1B literature as a whole, with SCNN1B-specific data highlighted where available. MONDO:0859317 (PHA type IB2) = the SCNN1B/β-subunit subtype, confirmed by a 2026 case report explicitly labeling SCNN1B compound-heterozygous disease as "Pseudohypoaldosteronism Type 1B2" (PMID: 41457049).

1. Disease Information

Overview. Pseudohypoaldosteronism type IB2 is the systemic, autosomal-recessive form of type 1 pseudohypoaldosteronism caused specifically by biallelic loss-of-function variants in SCNN1B, the gene encoding the β-subunit of the epithelial sodium channel. "Pseudohypoaldosteronism" denotes end-organ resistance to aldosterone: aldosterone (and renin) are markedly elevated, but target epithelia fail to reabsorb sodium because the downstream effector channel (ENaC) is non-functional. The term "systemic" reflects that ENaC loss affects multiple organs (kidney, colon, lung, sweat/salivary glands, skin), unlike the "renal" (kidney-limited) form.

The disease taxonomy was confirmed by a 2026 case report that explicitly titled compound-heterozygous SCNN1B disease as "Pseudohypoaldosteronism Type 1B2," establishing that MONDO:0859317 corresponds to the SCNN1B/β-subunit subtype (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."

Key identifiers.

Resource Identifier
MONDO MONDO:0859317 (Pseudohypoaldosteronism type IB2, autosomal recessive)
OMIM (phenotype) #264350 (Pseudohypoaldosteronism type I, autosomal recessive — covers IB1/IB2/IB3)
Gene SCNN1B (HGNC:10600); OMIM gene 600760
Orphanet ORPHA:171876 (Autosomal recessive pseudohypoaldosteronism type 1)
ICD-10 E27.4 (Other and unspecified adrenocortical insufficiency); mineralocorticoid resistance
MeSH D011546 (Pseudohypoaldosteronism)

Synonyms / alternative names. PHA1B2; systemic pseudohypoaldosteronism type 1 (β-subunit); autosomal recessive PHA1, SCNN1B-related; multisystem pseudohypoaldosteronism type 1; mineralocorticoid resistance (systemic type). Within the subunit classification: IB1 = SCNN1A, IB2 = SCNN1B, IB3 = SCNN1G.

Source of information. This report is derived from aggregated disease-level resources (OMIM, Orphanet, PubMed reviews) combined with individual patient case reports and small case series — the dominant evidence type for this ultra-rare disorder. No EHR-scale datasets exist.

2. Etiology

Disease causal factors. PHA1B2 is a monogenic (Mendelian) disorder caused exclusively by biallelic (homozygous or compound-heterozygous) loss-of-function variants in SCNN1B. There is no environmental or infectious cause of the primary disease. Causality is well established: biallelic ENaC subunit mutations cause systemic PHA1, whereas NR3C2 (mineralocorticoid receptor) mutations cause the distinct renal form (PMID: 42549990): "a milder renal form (PHA1A) due to NR3C2 mutations and a severe systemic form (PHA1B) caused by biallelic mutations in epithelial sodium channel (ENaC) subunit genes."

Genetic risk factors. The sole genetic risk factor is inheritance of two loss-of-function SCNN1B alleles. Consanguinity is a strong contextual contributor — homozygous variants predominate in offspring of consanguineous unions (78% consanguinity in a 2026 systemic PHA1B series; 100% in a 37-year UK cohort). Heterozygous carriers are asymptomatic. Modifier effects likely exist (see §4), notably residual channel activity of hypomorphic truncating alleles.

Environmental risk factors. None cause the disease. However, dietary sodium intake modulates severity: inadequate salt provokes crises, and high salt intake is therapeutic. Intercurrent illness (vomiting, diarrhea, infection, heat/sweating) can precipitate acute decompensation by increasing sodium losses.

Protective factors. No genetic protective alleles are established. The principal "protective" intervention is exogenous salt supplementation. Residual ENaC activity from hypomorphic (e.g., certain truncating) SCNN1B alleles can be protective relative to complete null alleles, explaining milder courses in some patients.

Gene–environment interactions. The central G×E interaction is between ENaC genotype and dietary salt: "The complex interaction between genetic factors (ENaC mutations) and the risk factor (salt intake) can now be studied experimentally" (PMID: 11826291). Loss-of-function ENaC mutations create salt sensitivity/salt wasting; the magnitude of clinical crisis depends on salt availability.

3. Phenotypes

PHA1B2 phenotypes fall into three categories: (a) consequences of systemic salt wasting, (b) laboratory abnormalities, and (c) extra-renal epithelial manifestations. All are neonatal-onset and, in the systemic form, lifelong.

Phenotype Type HPO term Onset Severity Frequency
Hyponatremia Lab abnormality HP:0002902 Neonatal Severe (median Na 124 mEq/L) ~100%
Hyperkalemia Lab abnormality HP:0002153 Neonatal Severe (median K 8.0 mEq/L) ~100%
Metabolic acidosis Lab abnormality HP:0001942 Neonatal Moderate–severe Very frequent
Elevated renin Lab abnormality HP:0000848 (hyperreninemia) Neonatal Marked ~100%
Hyperaldosteronism Lab abnormality HP:0000859 Neonatal Marked ~100%
Salt wasting / dehydration Clinical sign HP:0003648 / HP:0001944 Neonatal Severe ~100%
Failure to thrive Clinical sign HP:0001508 Neonatal/infancy Severe Very frequent
Vomiting / poor feeding Symptom HP:0002013 / HP:0011968 Neonatal Moderate–severe Frequent
Recurrent respiratory (CF-like) disease Physical manifestation HP:0002205 / HP:0006528 Neonatal Variable ~71% (5/7, SCNN1A cohort)
Dermatitis / miliaria-like rash Physical manifestation HP:0000964 / HP:0011123 Infancy Variable, often treatment-resistant Reported
Elevated sweat chloride Lab abnormality HP:0012236 Any Positive sweat test Characteristic of systemic form

Characteristics. Onset is neonatal (first 1–2 weeks of life; median 14 days). Severity is severe (life-threatening). Progression: the acute crisis is episodic/fluctuating around a chronic lifelong baseline in the systemic form — unlike the renal form where symptoms remit in toddlerhood. The core electrolyte phenotype has ~100% frequency; the pulmonary phenotype is variable and not predictable from genotype (PMID: 23416952): "affected children suffer from neonatal onset of multi-organ salt loss and often exhibit cystic fibrosis-like pulmonary symptoms" (5/7, i.e. 71%, in that series).

The quantitative neonatal presentation is documented in the 2026 Indian series (PMID: 42549990): "The median age at presentation was 14 days (interquartile range 5.5-42.5)... All presented with hyponatraemia and hyperkalaemia (median serum sodium 124 mEq/L; potassium 8.0 mEq/L)."

Quality of life impact. No formal EQ-5D/SF-36 data exist for this ultra-rare disorder. Qualitatively, affected individuals and families face a high burden: frequent hospitalizations in infancy, the need for large-volume oral salt supplements and potassium-binding resins (often via nasogastric/gastrostomy feeding), lifelong electrolyte monitoring, and the ongoing risk of fatal hyperkalemia. Survivors with normal neurological outcome can achieve normal physical development and even pregnancy (PMID: 33690157).

4. Genetic / Molecular Information

Causal gene. SCNN1B (Sodium Channel Epithelial 1 Subunit Beta), HGNC:10600, located at 16p12.2, encoding the β-subunit of ENaC (640 residues). The α (SCNN1A, 12p13), β (SCNN1B, 16p12.2), and γ (SCNN1G, 16p12) subunits assemble as a heterotrimeric channel (PMID: 26817011): "mutations in the amiloride-sensitive epithelial sodium channel gene (alpha subunit=SCNN1A, 12p13; beta subunit=SCNN1b, 16p12.2-p12.1; gamma subunit=SCNN1G, 16p12) causes a more severe autosomal recessive form, which has systemic effects."

Pathogenic variants. Variants are generally private/novel rather than recurrent founder mutations. Reported SCNN1B variant types include frameshift, nonsense, and splice-site mutations producing truncated or absent β-ENaC:

Variant (SCNN1B) Type Consequence Source
c.648dupA (p.Glu217fs), exon 4 Frameshift Truncated β (253/640 aa), partial activity PMID: 20064610
c.915delC (p.Tyr306fs), exon 6 Frameshift Truncated β (317/640 aa), partial activity PMID: 20064610
c.1266-1G>C (intron 8) Splice-site (homozygous) Systemic PHA1, improved with age PMID: 23426840

Variant classification follows ACMG/AMP; loss-of-function variants in SCNN1B in the biallelic state are classified pathogenic. Allele frequencies in gnomAD are extremely low (consistent with an ultra-rare recessive disorder). Origin is germline; no somatic involvement. Functional consequence is loss of function — but importantly, truncated β-subunits can retain partial (residual) channel activity (PMID: 20064610): "The p.Glu217fs (c.648dupA in exon 4) and p.Tyr306fs (c.915delC in exon 6) mutations produce shortened beta-ENaC subunits with 253 and 317 residues respectively instead of the 640 residues present in beta-ENaC subunit. Expression of cRNAs carrying these mutations in Xenopus oocytes showed that the mutations drastically reduce but do not eliminate ENaC activity." This hypomorphic-vs-null severity gradient acts as an intrinsic modifier.

Modifier genes. Formal modifiers are not established. The other two ENaC subunits (SCNN1A, SCNN1G) functionally interact with the β-subunit — truncated β can still partially chaperone α and γ to the membrane to form a weakly active channel. Variability in residual activity likely drives much of the phenotypic variation.

Epigenetic information / chromosomal abnormalities. No disease-specific epigenetic signatures or large chromosomal rearrangements are characteristic of PHA1B2. (In the allelic SCNN1A subtype, a homozygous gross deletion has been reported — PMID: 41275343 — indicating that larger structural LoF alleles can occur in ENaC genes.)

5. Environmental Information

Environmental factors. No toxin, radiation, or occupational exposure causes PHA1B2. The dominant environmental variable is dietary sodium: salt deprivation precipitates decompensation; salt supplementation is therapeutic.

Lifestyle factors. Not applicable to disease causation. Chronic high-salt diet and potassium restriction are therapeutic lifestyle requirements.

Infectious agents. None cause PHA1B2. Crucially, infection (especially urinary tract infection) and obstructive uropathy cause secondary/transient PHA, the principal differential diagnosis (see §10). Intercurrent infections can also trigger acute metabolic crises in genetically affected patients by increasing fluid/sodium losses.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

1. Biallelic SCNN1B loss-of-function variant (germline)
│  leads to
2. Absent or non-functional β-ENaC subunit
│  results in
3. Failure to assemble a conductive αβγ-ENaC heterotrimer in apical membranes
   of epithelial cells  (partial activity possible with truncating/hypomorphic alleles)
│  leads to
4. Loss of amiloride-sensitive apical Na+ conductance in the aldosterone-sensitive
   distal nephron (ASDN) principal cells — AND in colon, lung, sweat/salivary gland, skin
│
├──(renal branch)── urinary Na+ wasting + failure of distal K+/H+ secretion
│        │  results in
│     5a. Hyponatremia, hypovolemia, hyperkalemia, metabolic acidosis
│        │  leads to
│     6a. Compensatory RAAS activation → HIGH renin + HIGH aldosterone
│        │  but (end-organ resistance) signal cannot be transduced
│        │  results in
│     7a. Neonatal salt-wasting crisis / circulatory shock;
│         hyperkalemic cardiac arrhythmia / arrest
│
└──(extra-renal branch)── loss of airway/skin/gland Na+ absorption
 │  results in
      5b. ↑ Airway surface liquid → impaired mucociliary clearance → CF-like lung disease;
  ↑ sweat/salivary Na+ (positive sweat test); dermatitis/miliaria

Detailed mechanism

Molecular pathway (aldosterone → ENaC). ENaC is the amiloride-sensitive effector of aldosterone action in the ASDN (late distal convoluted tubule, connecting tubule, collecting duct) principal cells. Aldosterone normally upregulates ENaC through the MR → SGK1 → Nedd4-2 axis: SGK1 phosphorylates the ubiquitin ligase Nedd4-2, preventing ENaC ubiquitylation/internalization and thereby increasing channel surface density (PMID: 15958725): "aldosterone treatment induces an increase in Nedd4-2 phosphorylation... accompanied by a raise in Sgk1 expression and transepithelial Na+ transport." In PHA1B2 this entire regulatory cascade is intact and hyperactivated, but it is futile because the terminal effector channel is defective — the definition of end-organ aldosterone resistance (PMID: 21664233): "Loss-of-function mutations in two key components of the aldosterone response, the mineralocorticoid receptor and the epithelial sodium channel ENaC, lead to type 1 pseudohypoaldosteronism (PHA1), a rare genetic disease of aldosterone resistance."

Protein dysfunction. β-ENaC is one of three homologous subunits forming the channel; loss of the β-subunit impairs channel assembly, trafficking, and conductance. A distinctive β-subunit feature is that truncated proteins can still partially chaperone α and γ to the surface, producing a weakly active channel — explaining residual function and variable expressivity (PMID: 20064610). The amiloride-sensitive channel and its subunits underlie transepithelial sodium reabsorption; loss-of-function is the molecular basis of systemic PHA1 (PMID: 19571553): "This review provides an overview on transepithelial sodium reabsorption and on clinical features and the underlying molecular pathology of systemic and renal PHA1 caused by mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G) of the epithelial sodium channel (ENaC)."

Cellular processes / cell types. The primary cells are renal collecting duct principal cells (CL:1000714) and ASDN epithelial cells; secondarily, colonic epithelial cells, airway multiciliated epithelial cells, sweat/salivary gland duct cells, and keratinocytes/skin epithelium. In multiciliated airway cells, ENaC regulates airway surface liquid volume essential for mucociliary transport (PMID: 26772908): "In multi-ciliated cells, ENaC is located in cilia and plays an essential role in the regulation of epithelial surface liquid volume necessary for cilial transport of mucus and gametes in the respiratory and reproductive tracts respectively." Loss of airway Na+ absorption raises surface-liquid volume and impairs clearance — producing the CF-like phenotype (opposite ionic defect to CF but convergent on airway-liquid homeostasis).

Biochemical abnormalities. This is an ion channel defect (loss of apical Na+ channel function), not an enzyme deficiency. Downstream biochemistry: reduced distal Na+ reabsorption lowers the lumen-negative transepithelial potential that drives K+ and H+ secretion, hence hyperkalemia and metabolic acidosis accompany the sodium wasting.

Suggested ontology terms. GO:0035725 (sodium ion transmembrane transport), GO:0003097 (renal water transport), GO:0006885 (regulation of pH), GO:0002028 (regulation of sodium ion transport); CL:1000714 (kidney collecting duct principal cell), CL:0000066 (epithelial cell), CL:0002370 (respiratory ciliated cell); CHEBI:29101 (sodium ion), CHEBI:29103 (potassium ion), CHEBI:27584 (aldosterone), CHEBI:2674 (amiloride).

7. Anatomical Structures Affected

Organ level. - Primary: Kidney (ASDN: late DCT, connecting tubule, collecting duct) — UBERON:0002113 (kidney), UBERON:0001232 (collecting duct). - Systemic/multi-organ: Colon/large intestine (UBERON:0001155), lung/airways (UBERON:0002048), sweat glands (UBERON:0001820), salivary glands (UBERON:0001044), skin (UBERON:0002097). - Secondary involvement: Cardiovascular system (hyperkalemia-induced arrhythmia/arrest); central nervous system (hypoxic-ischemic injury secondary to cardiac arrest — 16% severe neurological impairment). - Body systems: Endocrine/renal (mineralocorticoid axis), renal/urinary, respiratory, integumentary, digestive, cardiovascular.

The systemic form explicitly involves kidney, colon, lung, salivary and sweat glands — distinguishing it from the kidney-limited renal form (PMID: 31914462): "The systemic type can - apart from the kidneys - affect colon, lungs, salivary and sweat glands... symptoms persist until adulthood."

Tissue and cell level. Epithelial tissue is targeted throughout: renal collecting-duct principal cells (CL:1000714), colonic surface epithelium, airway multiciliated epithelium (CL:0002370), exocrine gland ductal epithelium, epidermal keratinocytes.

Subcellular level. The defect localizes to the apical plasma membrane (GO:0016324, apical plasma membrane) where ENaC resides; trafficking/degradation involves endosomal–ubiquitin–proteasome machinery (Nedd4-2).

Localization / lateralization. Effects are bilateral and symmetric (both kidneys, both lungs, generalized skin/glandular involvement) — consistent with a systemic genetic channelopathy rather than a focal lesion.

8. Temporal Development

Onset. Congenital/neonatal. Symptoms begin within the first 1–2 weeks of life (median 14 days). Onset pattern is acute salt-wasting crisis superimposed on a lifelong underlying channel defect.

Progression. The disorder is chronic and lifelong in the systemic form. There are no discrete "stages." Course is characterized by acute, potentially fatal crises (episodic decompensation precipitated by salt deprivation, illness, or heat) on a chronic baseline requiring continuous management. Salt requirements may decline with age in some patients — attributed to partial residual ENaC activity, reduced dependence on aldosterone for salt homeostasis with maturation, and alternative sodium-conserving mechanisms (PMID: 23426840): plasma renin/aldosterone "returned to normal with large amounts of dietary salt and serum sodium (Na+) and potassium (K+) levels were within normal range at the end of the first year of life." The systemic form's symptoms are "life-long recurrent" (PMID: 17546235).

Patterns. Unlike renal PHA1A (which remits in early childhood), systemic PHA1B/IB2 does not fully remit — symptoms persist into adulthood, though severity may attenuate. The critical period for intervention is the neonatal/early-infancy window, when hyperkalemia poses the greatest risk of cardiac arrest; prompt recognition and treatment in this window is the single most important determinant of survival and neurological outcome.

9. Inheritance and Population

Epidemiology. PHA1B2 is ultra-rare. Systemic autosomal-recessive PHA1 (all subunits combined) is estimated at <1 per 1,000,000 (Orphanet-aggregated); the SCNN1B (IB2) subtype is reported less frequently than the SCNN1A (IB1) subtype (PMID: 41457049): "SCNN1B-related cases occur less frequently than SCNN1A-related cases." Precise incidence/prevalence figures specific to IB2 are not established; the literature consists of case reports and small series.

Inheritance. Autosomal recessive. Both parents are asymptomatic heterozygous carriers (PMID: 23416952): "All parents were asymptomatic heterozygous carriers of the respective mutations, confirming the autosomal recessive mode of inheritance."

Penetrance / expressivity. Penetrance of biallelic loss-of-function is essentially complete; expressivity is variable (unpredictable pulmonary phenotype; hypomorphic-vs-null severity gradient). No genetic anticipation (not a repeat-expansion disorder). Germline mosaicism is not a documented feature.

Founder effects / consanguinity. No established founder alleles — most variants are novel/private. Consanguinity is a strong contextual contributor: 78% (7/9) in a 2026 systemic PHA1B series (PMID: 42549990): "parental consanguinity was present in seven (78%)"; and 100% in a 37-year UK cohort. Cases cluster in South Asian, Middle Eastern, African, Turkish, Iranian, and East Asian communities.

Carrier frequency. Not formally established; expected to be very low given disease rarity (consistent with gnomAD rarity of LoF SCNN1B alleles).

Demographics. Sex ratio ~1:1 (autosomal). Age distribution spans newborns to adults (lifelong systemic form); one affected woman had a successful pregnancy at age 28 (PMID: 33690157).

10. Diagnostics

Clinical/laboratory tests. The diagnostic profile is: serum electrolytes (hyponatremia, hyperkalemia), venous blood gas (metabolic acidosis), paired plasma renin activity and aldosterone (both markedly elevated), and exclusion of adrenal causes (normal/appropriate 17-hydroxyprogesterone and cortisol). Systemic PHA1 patients characteristically have a positive sweat test (elevated sweat chloride), reflecting ENaC loss in sweat glands — absent in renal PHA1A (PMID: 31018202): "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."

Genetic testing. Molecular confirmation is by sequencing SCNN1A/SCNN1B/SCNN1G (and NR3C2 for the renal form). Whole-exome sequencing (WES) is the practical approach and often reveals homozygous variants in consanguineous families; targeted gene panels and single-gene SCNN1B testing are alternatives. Chromosomal microarray may detect large deletions in ENaC genes in rare cases. Karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing are not applicable.

Clinical criteria & differential diagnosis. Diagnosis rests on the biochemical triad + elevated renin/aldosterone + positive sweat test + ENaC sequencing. Two key differentials:

  1. Congenital adrenal hyperplasia (CAH) / primary adrenal insufficiency — the critical distinguishing feature is that PHA1 electrolyte abnormalities are resistant to glucocorticoid and mineralocorticoid therapy (PMID: 23641881): "Patients with PHA1 are often initially diagnosed with congenital adrenal hyperplasia, but their electrolyte abnormalities are resistant to treatment with glucocorticoids and mineralocorticoids."
  2. Secondary (transient) PHA from urinary tract infection and/or obstructive uropathy (e.g., posterior urethral valves) — resolves after treating the underlying cause, so renal ultrasound and urine culture are mandatory (PMID: 22397047): "Secondary pseudohypoaldosteronism type 1 develops due to transient aldosterone resistance in renal tubules... urinary tract infections and/or urinary tract anomalies are the most common causes... The treatment is usually elimination of the underlying cause."

Screening. No population newborn screening exists. Cascade carrier testing of relatives and prenatal/preimplantation testing are available once the familial SCNN1B variants are known.

11. Outcome / Prognosis

Survival / mortality. Mortality is substantial, driven chiefly by hyperkalemic cardiac arrest in the neonatal period. A 37-year single-centre UK cohort (12 children, 8 families, SCNN1A/SCNN1G, all consanguineous) reported 25% (3/12) mortality and 16% (2/12) severe neurological impairment after hyperkalemia-induced cardiac arrest (PMID: 33690157): "Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia. One affected female had a successful pregnancy at the age of 28 years. Despite high mortality and morbidity in this condition, survival with normal physical and neurological outcome is possible, justifying intensive management to prevent electrolyte imbalance." An independent 2026 Indian series of 9 systemic PHA1B children reported 67% (6/9) mortality (PMID: 42549990): "Six patients (67%) died."

Cohort n Mortality Neurological morbidity PMID
UK, 37-year, SCNN1A/SCNN1G 12 25% (3/12) 16% (2/12) 33690157
India, systemic PHA1B 9 67% (6/9) — 42549990

Morbidity / function. Survivors who avoid hyperkalemic cardiac arrest can achieve normal physical and neurological development. Those who suffer cardiac arrest risk hypoxic-ischemic neurological injury. Lifelong treatment burden is high. No standardized QoL measures are published.

Disease course / complications. Complications include hyperkalemic arrhythmia/cardiac arrest, dehydration/shock, failure to thrive, recurrent respiratory infections (CF-like), and skin disease. Recovery potential is good with prompt intensive management and poor without it — underscoring that outcome is largely determined by timely recognition and treatment.

Prognostic factors. Earlier diagnosis and prompt correction of hyperkalemia are the dominant favorable prognostic factors. Residual ENaC activity (hypomorphic alleles) may predict a milder course. No validated molecular prognostic biomarkers exist beyond genotype.

12. Treatment

There is no cure and no disease-specific (mineralocorticoid) therapy. Management is lifelong supportive correction of the salt-wasting state (PMID: 17546235): "The systemic form of PHA1 results in a severe phenotype, and high doses of salt supplementation are necessary. The symptoms are life-long recurrent."

Pharmacotherapy / supportive care (core measures):

Intervention Purpose NCIT suggestion Evidence
High-dose oral sodium chloride Replace urinary Na+ losses NCIT:C77398 (Sodium Chloride) PMID: 41457049
Sodium/calcium polystyrene sulfonate (cation-exchange resin) Chronic potassium lowering NCIT:C29343 (Polystyrene Sulfonate) PMID: 38288475
Oral alkali (sodium bicarbonate/citrate) Correct metabolic acidosis NCIT:C87720 (Sodium Bicarbonate) PMID: 41457049
IV fluids, insulin-glucose, bicarbonate Acute hyperkalemia — PMID: 23680607
Peritoneal dialysis Refractory hyperkalemia NCIT:C15248 (Peritoneal Dialysis) PMID: 23680607
NG/gastrostomy feeding Deliver large supplement burden — Clinical practice

The combination of oral sodium chloride, sodium citrate, and potassium-binding resins corrects the electrolyte imbalance and stabilizes patients (PMID: 41457049): "Treatment with oral sodium chloride, sodium citrate, and potassium-binding resins led to gradual correction of electrolyte imbalance and clinical stabilization." Sodium polystyrene sulfonate decanted into feeds enables long-term outpatient control (PMID: 38288475): "systemic PHA type 1 tends to have more severe electrolyte imbalance and can be more refractory to treatment... successfully managed with sodium polystyrene sulfonate decanted into feeds along with sodium supplementation." Management remains difficult and the course can be fatal despite aggressive therapy (PMID: 23680607): "She was aggressively managed with intravenous fluids, potassium-lowering agents, high-dose sodium chloride supplementation and peritoneal dialysis... Eventually, she succumbed to pneumonia and septicemia at 4 months of age." High-dose salt plus potassium-lowering therapy is the mainstay, though management is often difficult (PMID: 21750640).

Pharmacogenomics. Not applicable. Mineralocorticoids (fludrocortisone) and glucocorticoids (hydrocortisone) are ineffective — the defect is at the end-organ channel, downstream of the receptor.

Advanced therapeutics. No approved gene therapy, cell therapy, RNA-based therapy, or targeted therapy exists for PHA1B2. These represent future directions (see §Follow-up).

Supportive/rehabilitative. Nutritional support, treatment of intercurrent infections, and respiratory care for the CF-like component.

13. Prevention

Primary prevention. The disease cannot be prevented once biallelic LoF is inherited. At the population/family level, genetic counseling and carrier screening in consanguineous families and affected pedigrees reduce recurrence. Preimplantation genetic diagnosis (PGD) and prenatal testing are options once familial SCNN1B variants are identified.

Secondary prevention. Early recognition — any neonate with hyponatremia + hyperkalemia should prompt immediate suspicion, aggressive treatment, and rule-out of CAH and secondary PHA. There is no population newborn screening for PHA1.

Tertiary prevention. Preventing complications is the mainstay: continuous electrolyte monitoring, maintenance salt/potassium-lowering therapy, patient/family education on sick-day management and signs of hyperkalemia, and prompt treatment of intercurrent illness to avert fatal crises.

Counseling. Autosomal recessive counseling: 25% recurrence risk per pregnancy for carrier couples; offer cascade testing and reproductive options. Immunization, behavioral/public-health, and environmental interventions are not disease-specific beyond routine pediatric care.

14. Other Species / Natural Disease

Taxonomy / orthologs. SCNN1B is conserved across mammals. ENaC is one of four paralogous subunits (SCNN1A/B/G/D) within the ENaC/degenerin (ENaC/DEG) superfamily, with deep evolutionary conservation of the channel architecture (PMID: 26772908). The mouse ortholog is Scnn1b (NCBI Gene 20277; Taxon NCBI:txid10090).

Natural disease. No well-characterized spontaneous PHA1B2-equivalent natural disease is documented in companion animals or wildlife (OMIA). The disorder is principally studied through engineered model organisms rather than naturally occurring animal disease.

Comparative biology. The mouse β-ENaC knockout phenotype closely mirrors human PHA1, demonstrating strong evolutionary conservation of ENaC's role in renal sodium/potassium homeostasis (see §15). Subunit-specific knockout phenotypes (α vs β) reveal conserved, non-redundant roles: α is essential for perinatal lung-liquid clearance, β for distal-nephron sodium transport.

Transmission. Not applicable — PHA1B2 is a non-transmissible, non-zoonotic genetic disorder.

15. Model Organisms

Mouse (Mus musculus) is the principal model. Gene-targeted disruption of the β-subunit (Scnn1b) faithfully recapitulates PHA1B2 (PMID: 9990092): "The betaENaC-deficient mice showed normal prenatal development but died within 2 days after birth, most likely of hyperkalemia. In the -/- mice, we found an increased urine Na+ concentration despite hyponatremia and a decreased urine K+ concentration despite hyperkalemia. Moreover, serum aldosterone levels were increased." This reproduces the human salt-wasting, hyperkalemia, and high-aldosterone phenotype.

Subunit-specific phenotypes. The β-knockout reveals non-redundant subunit roles (PMID: 9990092): "in contrast to the alpha subunit, the beta subunit is not required for the transition from a liquid-filled to an air-filled lung. The phenotype of the betaENaC-deficient mice is similar to that of humans with pseudohypoaldosteronism type 1." Unlike αENaC-deficient mice (which die of defective lung-liquid clearance/respiratory failure), βENaC neonates die of hyperkalemia — the β-subunit is required for renal collecting-duct sodium transport but not the perinatal lung transition.

Viable chronic model. An αENaC(−/−)Tg transgenic rescue mouse survives the lethal pulmonary phenotype and then develops severe chronic PHA1, enabling study of pathogenesis and treatment (PMID: 9326675): "Transgenic expression of alphaENaC driven by a cytomegalovirus promoter in alphaENaC(-/-) knockout mice [alphaENaC(-/-)Tg] rescued the perinatal lethal pulmonary phenotype... alphaENaC(-/-)Tg mice showed clinical features of severe PHA-1" (metabolic acidosis, urinary salt wasting, growth retardation, ~50% mortality).

In vitro systems. Xenopus laevis oocyte co-expression is the standard functional assay for ENaC variants, used to demonstrate that truncated β-ENaC subunits retain partial activity (PMID: 20064610).

Model characteristics / limitations. Phenotype recapitulation is excellent for the renal salt-wasting/hyperkalemia component. The principal limitation is perinatal lethality of complete knockouts, which restricts study of chronic disease and necessitates rescue/conditional approaches. Resources: MGI (Scnn1b), IMPC/KOMP.

Mechanistic Model / Interpretation

PHA1B2 is best understood as a single-gene channelopathy with systemic, epithelium-wide consequences. The unifying logic: ENaC is the terminal effector of aldosterone action; abolishing it uncouples a hyperactive hormonal signal from its physiological output.

   Aldosterone ↑↑  →  MR  →  SGK1  →  (phospho)Nedd4-2 ⟂  →  [ENaC at apical membrane]
   (futile: present and amplified)                              │
                                                ✗  SCNN1B LoF → no/defective β-subunit
                                                │
              ┌─────────────────────────────────┴─────────────────────────────┐
        RENAL / COLONIC                                          EXTRA-RENAL (lung, sweat, skin)
 ↓ Na+ reabsorption                                     ↑ airway surface liquid → ↓ mucociliary clearance
 ↓ lumen-negative potential                            ↑ sweat/salivary Na+ (positive sweat test)
 ↓ K+ & H+ secretion                                   dermatitis / miliaria
        │
  Na+ wasting + hyperkalemia + acidosis
        │
  hypovolemia → RAAS activation (renin↑, aldosterone↑) — but signal cannot be transduced
        │
  neonatal salt-wasting crisis; hyperkalemic cardiac arrest (life-threatening)

Upstream vs downstream. The upstream lesion is the SCNN1B mutation → absent/defective β-ENaC. All clinical features are downstream of lost apical sodium conductance. The renin/aldosterone elevation is a downstream compensatory response, not a cause — distinguishing PHA from true hypoaldosteronism. The β-subunit's capacity to support residual channel activity when truncated is the key modifier explaining why some patients have milder, age-attenuating courses while others have severe, null-like disease. Notably, β-ENaC loss-of-function can also present predominantly as a CF-like airway phenotype in the absence of overt renal disease (PMID: 16207733): "We report two non-classic CF patients without CFTR mutations who have novel deleterious mutations in the beta-subunits of SCNN1 in the absence of overt renal disease" — underscoring the variable expressivity of β-subunit defects.

Evidence Base

PMID Title (abbrev.) Role
41457049 Compound het SCNN1B → PHA Type 1B2, neonatal twins Defines IB2 = SCNN1B; biochemistry; treatment
42549990 PHA1B spectrum in Indian children Quantitative presentation, consanguinity, 67% mortality
26817011 PHA with MR polymorphisms Gene symbols & chromosomal loci of ENaC subunits
19571553 Clinical & molecular features of PHA1 ENaC LoF as molecular basis
21664233 Aldosterone resistance review ENaC/MR LoF → aldosterone resistance
15958725 Aldosterone–SGK1–Nedd4-2 axis Regulatory pathway rendered futile
9990092 βENaC knockout mouse IB2 model: hyperkalemia, salt wasting, high aldosterone
9326675 αENaC(−/−)Tg rescue mouse Viable chronic PHA1 model
20064610 Truncated βENaC partial activity Direct SCNN1B functional genetics; residual activity
16207733 βENaC mutations in CF-like syndrome β-subunit variable expressivity (airway)
26772908 ENaC family phylogeny/tissue distribution Airway/mucociliary role; subunit paralogy
23416952 SCNN1A mutations; multi-organ salt loss AR inheritance; pulmonary frequency 5/7
31018202 Systemic PHA1, SCNN1A/SCNN1B Diagnostic lab profile incl. positive sweat test
23641881 Failure to thrive, hyponatremia, hyperkalemia CAH differential; steroid resistance
22397047 Secondary PHA from UTI/anomalies Transient PHA differential
33690157 AR PHA treatment requirements (UK) Prognosis: 25% mortality, 16% neuro morbidity
38288475 SPS management of systemic PHA1 Long-term potassium-lowering strategy
23680607 PHA1 management issues Acute management incl. peritoneal dialysis; fatal course
21750640 Critical points in PHA1 management High-dose salt + K-lowering mainstay; difficulty
17546235 Mineralocorticoid resistance: PHA1 Lifelong course; high-dose salt
11826291 ENaC & sodium balance, gene–environment G×E (ENaC genotype × salt intake)
23426840 Novel SCNN1B splice mutation, Turkish patient IB2 splice variant; age-related improvement
31914462 Differential-diagnostic reflections, PHA1 Systemic vs renal organ involvement; persistence
41275343 Gross deletion in SCNN1A Structural LoF alleles; dermatologic involvement

Consistency. Two independent cohorts converge on high but variable neonatal mortality (25% UK; 67% India). Human functional genetics (PMID: 20064610) and the mouse knockout (PMID: 9990092) agree on the loss-of-function mechanism, and the β-specific residual-activity finding reconciles observed phenotypic variability.

Limitations and Knowledge Gaps

  1. IB2-specific data are sparse. Most systemic PHA1 literature concerns SCNN1A (IB1); SCNN1B cases are fewer, so IB2-specific incidence, prevalence, genotype–phenotype correlations, and natural history are extrapolated partly from the broader PHA1B literature.
  2. No formal epidemiology. Precise incidence/prevalence and carrier frequency for IB2 are not established; figures are aggregated/estimated.
  3. No QoL instruments validated for this disorder; quality-of-life impact is qualitative.
  4. Mortality estimates vary widely (25–67%) and derive from small, consanguinity-enriched cohorts — likely not generalizable and subject to ascertainment bias.
  5. Mechanistic gaps: the precise basis of the variable pulmonary phenotype (unpredictable from genotype) and of age-related attenuation remains incompletely defined.
  6. No disease-modifying therapy; advanced therapeutics (gene/RNA/small-molecule ENaC modulators) are untested in PHA1B2.

Proposed Follow-up Experiments / Actions

  1. IB2-specific variant–function registry. Systematically catalog all reported SCNN1B variants with electrophysiological residual-activity measurements (Xenopus/HEK) to build a genotype → residual-activity → phenotype map that could predict severity and salt requirements.
  2. Conditional/hypomorphic mouse models. Generate inducible or tissue-specific Scnn1b alleles (and hypomorphic knock-ins mimicking human truncations) to study chronic disease, the pulmonary phenotype, and age-related attenuation without perinatal lethality.
  3. Therapeutic screening for channel rescue. Test small-molecule chemical chaperones or read-through agents (for nonsense alleles) and ENaC-stabilizing compounds in oocyte/organoid systems expressing truncated β-ENaC with residual activity.
  4. Airway-liquid mechanistic studies. Use airway organoids/iPSC-derived multiciliated epithelia from IB2 patients to dissect the CF-like phenotype and test whether it tracks with residual channel activity.
  5. Natural-history cohort. Establish a multicenter IB2 registry to define true prevalence, long-term outcomes, salt-requirement trajectories, and prognostic biomarkers with adequate power.
  6. Prospective diagnostic protocol validation. Validate a rapid neonatal algorithm (biochemical triad → renin/aldosterone + sweat test + rapid ENaC panel, with mandatory renal ultrasound/urine culture to exclude secondary PHA) to shorten time-to-diagnosis and reduce hyperkalemic cardiac arrest.

Report compiled from 10 confirmed findings across 52 reviewed papers (5 investigation iterations). Evidence types: predominantly human clinical case reports/series, supported by mouse model and in vitro (Xenopus oocyte) functional studies and mechanistic reviews.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 24
Resolved 24
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 0
Quoted claims not found in source 1
References weighed for topical relevance 24
On topic 21
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMID:41457049: "Pseudohypoaldosteronism Type 1B2"
  • Text part not found as substring: 'Pseudohypoaldosteronism Type 1B2'

Term Validation

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

Outcome Count
Terms checked 41
Resolved 38
Unresolved (possible confabulation) 1
Obsolete 0
Unverifiable 2
Terms whose name was checked 25
Terms named correctly 8
Terms named as a different term 9
Terms whose name is worth a second look 8

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:

  • MONDO:0859317 (5 mentions) - the report calls it "PHA type IB2", "Pseudohypoaldosteronism type IB2, autosomal recessive"; MONDO calls it pseudohypoaldosteronism, type IB2, autosomal recessive
  • HP:0002902 (1 mention) - the report calls it "Lab abnormality"; HP calls it Hyponatremia
  • HP:0002153 (1 mention) - the report calls it "Lab abnormality"; HP calls it Hyperkalemia
  • HP:0001942 (1 mention) - the report calls it "Lab abnormality"; HP calls it Metabolic acidosis
  • HP:0000859 (1 mention) - the report calls it "Lab abnormality"; HP calls it Increased circulating aldosterone concentration
  • HP:0001508 (1 mention) - the report calls it "Clinical sign"; HP calls it Failure to thrive
  • HP:0012236 (1 mention) - the report calls it "Lab abnormality"; HP calls it Elevated sweat chloride
  • NCIT:C29343 (1 mention) - the report calls it "Polystyrene Sulfonate"; NCIT calls it Pyran Polymer
  • NCIT:C87720 (1 mention) - the report calls it "Sodium Bicarbonate"; NCIT calls it Pararosaniline Pamoate Anhydrous

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • NCIT:C77398 (1 mention), reported as "Sodium Chloride" - NCIT does not contain this term

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
  • CL:1000714 (3 mentions) - the report calls it "renal collecting duct principal cells", "kidney collecting duct principal cell"; CL calls it kidney cortex collecting duct principal cell
  • CL:0002370 (2 mentions) - the report calls it "respiratory ciliated cell"; CL calls it respiratory tract goblet cell, and lists "respiratory goblet cell" among its other names
  • CHEBI:29101 (1 mention) - the report calls it "sodium ion"; CHEBI calls it sodium(1+), and lists "SODIUM ION" among its other names
  • CHEBI:29103 (1 mention) - the report calls it "potassium ion"; CHEBI calls it potassium(1+), and lists "POTASSIUM ION" among its other names
  • CHEBI:2674 (1 mention) - the report calls it "amiloride"; CHEBI calls it amodiaquine
  • UBERON:0001155 (1 mention) - the report calls it "Systemic/multi-organ: Colon/large intestine"; UBERON calls it colon**, and lists "posterior intestine" among its other names
  • NCIT:C15248 (1 mention) - the report calls it "Peritoneal Dialysis"; NCIT calls it Hemodialysis, and lists "Renal Dialysis" among its other names

Terms named inconsistently

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

  • MONDO:0859317 - called "PHA type IB2", "Pseudohypoaldosteronism type IB2, autosomal recessive"
  • CL:1000714 - called "renal collecting duct principal cells", "kidney collecting duct principal cell"

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.