Early-onset Familial Hypoaldosteronism

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic (homozygous or compound heterozygous) CYP11B2 variants; carrier parents are unaffected.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:33098647 SUPPORT Human Clinical

"The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency."

States the autosomal recessive inheritance of aldosterone synthase deficiency.

PMID:7852500 SUPPORT Human Clinical

"both parents were heterozygous carriers for R384P, whereas the patient appeared homozygous"

Family segregation consistent with recessive inheritance.

◆

Subtypes

2

Corticosterone methyloxidase type I deficiency MONDO:0008751

CYP11B2 hgnc:2592

Biochemical type in which aldosterone and 18-hydroxycorticosterone are both decreased while corticosterone and 11-deoxycorticosterone are elevated, reflecting loss of the 18-hydroxylase step; typically caused by truncating or fully inactivating CYP11B2 variants (for example E255X, R384P).

Show evidence (2 references)

PMID:9360501 SUPPORT Human Clinical

"Aldosterone and 18-OH-corticosterone were decreased, whereas corticosterone and 11-deoxycorticosterone were elevated, thus confirming the diagnosis of corticosterone methyl oxidase deficiency type I."

Defines the CMO I steroid profile in the original Visser and Cost patients.

PMID:7852500 SUPPORT In Vitro

"R384P leads to complete loss of 11 beta- and 18-hydroxylase activities of P450aldo"

A CMO I allele abolishes both 11beta- and 18-hydroxylase activities in expression studies.

Corticosterone methyloxidase type II deficiency MONDO:0012524

CYP11B2 hgnc:2592

Biochemical type characterized by an elevated ratio of 18-hydroxycorticosterone to aldosterone, reflecting selective loss of the 18-oxidase step with retained 18-hydroxylase activity. Highly prevalent in Iranian Jews homozygous for the combined R181W and V386A alleles.

Show evidence (2 references)

PMID:1594605 SUPPORT Human Clinical

"Corticosterone methyloxidase II (CMO-II) deficiency is an autosomal recessive disorder of aldosterone biosynthesis, characterized by an elevated ratio of 18-hydroxycorticosterone to aldosterone in serum."

Defines CMO II by its steroid ratio.

PMID:1594605 SUPPORT In Vitro

"R181W reduced 18-hydroxylase and abolished 18-oxidase activities but left 11 beta-hydroxylase activity intact"

Expression of the CMO II allele shows the selective loss of 18-oxidase activity underlying the subtype.

⚙

Pathophysiology

4

Biallelic CYP11B2 loss of function

Biallelic inactivating CYP11B2 variants reduce or abolish aldosterone synthase (P450c11AS) activity. Enzymatic activity generally has to fall below about 1% of normal before aldosterone synthesis is impaired; the pattern of residual 11beta-hydroxylase, 18-hydroxylase and 18-oxidase activity determines the CMO I versus CMO II steroid profile.

CYP11B2 hgnc:2592

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

aldosterone synthase 18-hydroxylase activity GO:0047783 ↓ DECREASED

Downstream

Impaired zona glomerulosa aldosterone biosynthesis

Show evidence (2 references)

PMID:15134805 SUPPORT Other

"Many mutations have been documented in each of these genes; in general enzymatic activity must be reduced to <1% of normal for aldosterone biosynthesis to be impaired."

Review states the residual-activity threshold for disease.

PMID:20494601 SUPPORT In Vitro

"The expression studies of the mutant proteins in COS-1 cells showed a complete absence of CYP11B2 activity of p.S315R and p.R374W mutants for the conversion of 11-deoxycorticosterone to aldosterone."

Patient missense variants abolish aldosterone synthase activity in vitro.

Impaired zona glomerulosa aldosterone biosynthesis

Aldosterone synthase catalyzes the terminal 11beta-hydroxylation, 18-hydroxylation and 18-oxidation steps converting 11-deoxycorticosterone to aldosterone in zona glomerulosa cells. Its loss produces isolated aldosterone deficiency with intact cortisol synthesis, which is CYP11B1-dependent.

zona glomerulosa cell CL:0002099

aldosterone biosynthetic process GO:0032342 ↓ DECREASED

zona glomerulosa of adrenal gland UBERON:0002053

Downstream

Renal sodium wasting and potassium retention

Decreased circulating aldosterone

Show evidence (2 references)

PMID:1594605 SUPPORT Human Clinical

"P450XIB2 catalyzes the synthesis of aldosterone from deoxycorticosterone, a process that successively requires hydroxylation at positions 11 beta and 18 and oxidation at position 18."

Describes the three terminal steps performed by aldosterone synthase.

PMID:38262861 SUPPORT Human Clinical

"Aldosterone synthase deficiency (ASD) is a rare autosomal recessive disorder involving isolated aldosterone deficiency without any compromise of other adrenal hormones."

Aldosterone deficiency is isolated, with other adrenal steroids preserved.

Renal sodium wasting and potassium retention

Without aldosterone, distal nephron and collecting duct principal cells fail to reabsorb sodium and secrete potassium, producing urinary sodium loss, hypovolemia, hyponatremia, hyperkalemia and metabolic acidosis.

kidney collecting duct principal cell CL:1001431

renal sodium ion absorption GO:0070294 ↓ DECREASED potassium ion homeostasis GO:0055075 ⚠ ABNORMAL

Downstream

Hyponatremia

Hyperkalemia

Dehydration

Metabolic acidosis

Renal salt wasting

Compensatory renin-angiotensin system activation

Failure to thrive

Show evidence (1 reference)

PMID:15134805 SUPPORT Other

"Aldosterone's main actions are to regulate intravascular volume and serum electrolytes by controlling sodium absorbtion and potassium excretion in the distal nephron."

Establishes the renal sodium and potassium handling disrupted by aldosterone deficiency.

Compensatory renin-angiotensin system activation

Volume depletion drives renin secretion; plasma renin activity is markedly elevated in affected infants and young children but may be normal in adults.

Downstream

Increased circulating renin

Show evidence (1 reference)

PMID:32539318 SUPPORT Human Clinical

"Plasma renin activity is significantly increased in affected infants and young children (up to 100-fold normal) but can be normal in adults."

Describes the magnitude and age dependence of hyperreninemia.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

9

Digestive 1

Vomiting HP:0002013

Show evidence (1 reference)

PMID:32539318 SUPPORT Human Clinical

"All of the patients presented with vomiting, failure to thrive and severe dehydration, except one patient with only failure to thrive."

Vomiting was a presenting feature in most reported patients.

Endocrine 2

Increased circulating renin Increased circulating renin concentration HP:0000848

Show evidence (1 reference)

PMID:32539318 SUPPORT Human Clinical

"All patients had normal cortisol response to adrenocorticotropic hormone stimulation test and had elevated plasma renin activity with low aldosterone levels."

Elevated renin with low aldosterone and preserved cortisol response.

Decreased circulating aldosterone Decreased circulating aldosterone concentration HP:0004319

Show evidence (2 references)

PMID:32539318 SUPPORT Human Clinical

"All patients had normal cortisol response to adrenocorticotropic hormone stimulation test and had elevated plasma renin activity with low aldosterone levels."

Low aldosterone levels in affected patients.

PMID:9360501 SUPPORT Human Clinical

"Aldosterone and 18-OH-corticosterone were decreased"

Decreased aldosterone in untreated adult CMO I patients.

Genitourinary 1

Renal salt wasting HP:0000127

Show evidence (2 references)

PMID:38262861 SUPPORT Human Clinical

"This condition manifests mainly in the neonatal period and in infants as a salt wasting syndrome with vomiting and failure to thrive."

Salt wasting is the characteristic neonatal presentation.

PMID:9838244 SUPPORT Human Clinical

"Salt wasting was caused by an enzymatic defect in the terminal aldosterone biosynthesis."

Attributes salt wasting to the aldosterone synthesis defect.

Metabolism 4

Hyponatremia HP:0002902

Show evidence (2 references)

PMID:32539318 SUPPORT Human Clinical

"Biochemical studies showed hyponatremia, hyperkalemia and acidosis."

Hyponatremia was present in the reported patients.

PMID:9838244 SUPPORT Human Clinical

"Important laboratory findings were low plasma sodium and elevated potassium and renin."

Case report documents hyponatremia, hyperkalemia and elevated renin.

Hyperkalemia HP:0002153

Show evidence (2 references)

PMID:32539318 SUPPORT Human Clinical

"In untreated infants with CMOD, serum sodium level is generally between 120-130 mmol/L and serum potassium level is between 6.0-8.5 mmol/L"

Gives the typical range of hyperkalemia (and hyponatremia) in untreated infants.

PMID:31302112 SUPPORT Human Clinical

"Aldosterone synthase deficiency (ASD) is a rare autosomal recessive disorder characterized by severe hyperkalemia, salt loss, vomiting, severe dehydration and failure to thrive."

Lists hyperkalemia among the defining features.

Metabolic acidosis HP:0001942

Show evidence (1 reference)

PMID:32539318 SUPPORT Human Clinical

"These findings may include vomiting, dehydration, hypovolemia, hyponatremia, hyperkalemia and metabolic acidosis."

Metabolic acidosis is part of the neonatal salt-wasting presentation.

Dehydration HP:0001944

Show evidence (1 reference)

PMID:33098647 SUPPORT Human Clinical

"Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive."

Severe dehydration is a presenting symptom.

Growth 1

Failure to thrive HP:0001508

Show evidence (2 references)

PMID:34415991 SUPPORT Human Clinical

"The most common symptom was poor weight gain (56.3%)."

Poor weight gain was the most common presenting symptom in a 16-patient cohort.

PMID:9838244 SUPPORT Human Clinical

"The first child of consanguineous parents presented with failure to thrive and feeding problems at age 6 weeks."

Failure to thrive was the presenting complaint.

🧬

Genetic Associations

1

CYP11B2 (Causative)

Gene: CYP11B2 hgnc:2592 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:33098647 SUPPORT Human Clinical

"Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant."

Largest cohort identifies biallelic CYP11B2 variants and a recurrent founder allele.

PMID:34415991 SUPPORT Human Clinical

"The most common variant (40%) was p.T185I."

Independent cohort confirms p.T185I as a common pathogenic allele.

PMID:16733366 SUPPORT Human Clinical

"We could not find a molecular defect in 2 patients: one was a carrier of the D335G mutation and the other had no detectable molecular change in the coding and promoter regions."

Some clinically typical patients lack identified biallelic CYP11B2 variants, indicating incomplete molecular yield.

💊

Medical Actions

2

Fludrocortisone mineralocorticoid replacement

Action: Pharmacotherapy NCIT:C15986

Agent: fludrocortisone CHEBI:50885

Platform: Small molecule

Oral fludrocortisone replaces mineralocorticoid action, correcting electrolyte disturbances and producing rapid catch-up growth. The dose requirement wanes with age and therapy can be discontinued in many children, but long-term surveillance is advised because the enzymatic defect persists.

Mechanism Target:

INHIBITS Renal sodium wasting and potassium retention — Mineralocorticoid replacement restores renal sodium retention and potassium excretion.

Target Phenotypes: Hyponatremia HP:0002902 Hyperkalemia HP:0002153 Failure to thrive HP:0001508

Show evidence (2 references)

PMID:34415991 SUPPORT Human Clinical

"Fludrocortisone could be stopped in 5 patients at a median age of 6.0 years (range: 2.2 to 7.6)."

Treatment can be withdrawn in a subset of children.

PMID:31302112 SUPPORT Human Clinical

"Fludrocortisone treatment is essential for ASD, and the need for mineralocorticoid replacement wanes with age; eventually, therapy can be discontinued for many affected children."

Fludrocortisone is the essential treatment, with waning requirement.

Sodium chloride supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: sodium chloride CHEBI:26710

Platform: Small molecule

Oral salt supplementation, together with rehydration in acute presentations, is used alongside fludrocortisone, particularly in infancy.

Target Phenotypes: Hyponatremia HP:0002902 Dehydration HP:0001944

Show evidence (1 reference)

PMID:38262861 SUPPORT Human Clinical

"rehydration as well as salt and fludrocortisone supplementation"

Management combines rehydration with salt and fludrocortisone supplementation.

🔬

Biochemical Markers

2

18-hydroxycorticosterone to aldosterone ratio (INCREASED)

Show evidence (1 reference)

PMID:32539318 SUPPORT Human Clinical

"Type 2 deficiency can be easily diagnosed by a marked increase in the ratio of 18-OHB to aldosterone in urine or serum (usually 100-fold)."

States the diagnostic CMO II steroid ratio.

18-hydroxycorticosterone (DECREASED)

Show evidence (1 reference)

PMID:9360501 SUPPORT Human Clinical

"Aldosterone and 18-OH-corticosterone were decreased, whereas corticosterone and 11-deoxycorticosterone were elevated, thus confirming the diagnosis of corticosterone methyl oxidase deficiency type I."

CMO I steroid profile.

🔬

Diagnosis

3

Clinical and laboratory diagnostic criteria

Japanese national diagnostic criteria for aldosterone synthase deficiency require salt-wasting symptoms without skin pigmentation, together with hyponatremia and hyperkalemia, low to normal plasma aldosterone with high renin, and no low cortisol. PHA1, 21-hydroxylase deficiency, congenital lipoid adrenal hyperplasia and congenital adrenal hypoplasia must be excluded.

clinical and biochemical diagnostic criteria NCIT:C124351

Because 18-hydroxycorticosterone cannot be measured in routine practice in Japan, these criteria do not separate CMO I from CMO II.

Show evidence (3 references)

PMID:41905953 SUPPORT REVIEW SYNTHESIS Other

"1) Presents with salt-wasting symptoms (poor feeding, vomiting, dehydration, poor weight gain). 2) No skin pigmentation."

Clinical arm of the published diagnostic criteria.

PMID:41905953 SUPPORT REVIEW SYNTHESIS Other

"1) Low serum sodium and high serum potassium. 2) Low to normal plasma aldosterone and high plasma renin activity or high plasma active renin concentration. 3) No low blood cortisol level."

Laboratory arm of the published diagnostic criteria.

PMID:41905953 SUPPORT REVIEW SYNTHESIS Other

"Since 18-hydroxycorticosterone measurements are not possible in clinical practice, the current diagnostic criteria do not classify ASD1 or ASD2."

States the limitation recorded in notes.

Multisteroid profiling

Plasma or urine steroid profiling showing a highly elevated 18-hydroxycorticosterone to aldosterone ratio establishes the biochemical diagnosis of CMO II; normal aldosterone against highly elevated renin points to impaired aldosterone biosynthesis.

multisteroid analysis NCIT:C25294

Show evidence (2 references)

PMID:22931312 SUPPORT Human Clinical

"The biochemical diagnosis of corticosterone methyl oxidase deficiency type II was established by multisteroid analysis, revealing a pathognomonic pattern with a highly elevated ratio of 18-OH-corticosterone to aldosterone."

Multisteroid analysis with the 18-OH-corticosterone to aldosterone ratio is diagnostic for CMO II.

PMID:22931312 SUPPORT Human Clinical

"Normal levels of plasma aldosterone compared with highly elevated levels of plasma renin indicate an impaired aldosterone biosynthesis and suggest the disorder."

The aldosterone to renin relationship is the first biochemical clue.

CYP11B2 genetic testing

Sequencing of CYP11B2 confirms the diagnosis after hormonal work-up. The high homology between CYP11B2 and the neighbouring CYP11B1 gene is a recognised source of sequencing pitfalls.

CYP11B2 sequencing NCIT:C15709

Show evidence (3 references)

PMID:39700478 SUPPORT Human Clinical

"a comprehensive hormonal investigation followed by genetic confirmation is essential for the clinical management of offspring"

Recommends hormonal work-up followed by genetic confirmation.

PMID:39700478 SUPPORT Human Clinical

"describe potential pitfalls in CYP11B2 sequencing due to its homology to CYP11B1"

Names CYP11B1 homology as a source of sequencing pitfalls. The abstract does not detail the pitfalls.

PMID:22931312 SUPPORT Human Clinical

"Molecular genetic analysis supported the diagnosis revealing homozygosity for a pathogenic c.554C>T (p.T185I) variation in exon 3 of the CYP11B2 gene encoding aldosterone synthase."

CYP11B2 sequencing confirmed the biochemical diagnosis.

📈

Progression

2

Infantile salt-wasting presentation

Age: Neonatal period to early infancy

Symptoms usually begin in the first weeks to months of life; in a Turkish cohort the median age at presentation was 3.1 months.

Show evidence (1 reference)

PMID:34415991 SUPPORT Human Clinical

"Sixteen patients from 12 families were included (8 females; median age at presentation: 3.1 months, range: 0.4 to 8.1)."

Age at presentation in a multicenter cohort.

Childhood amelioration

Age: Childhood to adulthood

Mineralocorticoid requirement decreases with age and treatment can often be stopped in childhood, although the biochemical defect persists; adults are usually asymptomatic.

Show evidence (2 references)

PMID:34415991 SUPPORT Human Clinical

"Decreased mineralocorticoid requirement over time can be explained by the development of physiological adaptation mechanisms rather than improved aldosterone synthase activity."

Clinical amelioration with age reflects adaptation, not recovery of enzyme activity.

PMID:32539318 SUPPORT Human Clinical

"The signs and symptoms of the disorder typically become milder or disappear by adulthood."

Symptoms typically wane by adulthood.

📊

Prevalence

1

Jews of Iranian origin

Birth Prevalence 25.0 per 100,000 1–9 per 10,000 (births) CMO II

Source wording: "CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births)". A founder-population figure; affected individuals are homozygous for both CYP11B2 R181W and V386A. No general-population estimate was found.

Show evidence (2 references)

PMID:8481357 SUPPORT REVIEW SYNTHESIS Human Clinical

"CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births)"

Gives the birth frequency of CMO II deficiency in Iranian Jews.

PMID:8481357 SUPPORT REVIEW SYNTHESIS Human Clinical

"all individuals affected were homozygous for two missense mutations in CYP11B2"

The high frequency in this population reflects a founder CYP11B2 haplotype.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Early-onset Familial Hypoaldosteronism:

Pseudohypoaldosteronism type 1 Not Yet Curated MONDO:0019161

Overlapping Features Aldosterone resistance (renal PHA1a from NR3C2 defects, systemic PHA1b from ENaC subunit defects, or secondary PHA1) produces the same infantile salt wasting with hyponatremia, hyperkalemia and high renin.

Distinguishing Features

Aldosterone is markedly elevated in PHA1a, whereas it is low to normal in aldosterone synthase deficiency

Show evidence (2 references)

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 as the key differential diagnosis.

PMID:41905953 SUPPORT REVIEW SYNTHESIS Other

"Endocrine testing typically reveals significantly elevated aldosterone and elevated serum renin levels."

Describes the high-aldosterone profile of PHA1a that separates it from ASD.

Salt-wasting 21-hydroxylase deficiency Not Yet Curated MONDO:0017839

Overlapping Features Salt-wasting congenital adrenal hyperplasia presents with similar neonatal salt-wasting symptoms and is one of the listed diagnoses of exclusion.

Distinguishing Features

Cortisol deficiency with raised ACTH and skin pigmentation
Atypical external genitalia in affected females

Show evidence (1 reference)

PMID:41905953 SUPPORT REVIEW SYNTHESIS Other

"In females with 21-hydroxylase deficiency, differentiation of the disorders is possible based on external genital findings. Males with 21-hydroxylase deficiency, congenital lipoid adrenal hyperplasia, and congenital adrenal hypoplasia also exhibit cortisol deficiency, resulting in elevated..."

States the features that separate 21-hydroxylase deficiency from ASD.

{ }

Source YAML

click to show

name: Early-onset Familial Hypoaldosteronism
creation_date: "2026-10-15T12:00:00Z"
category: Mendelian
synonyms:
- Aldosterone synthase deficiency
- Congenital hyperreninemic hypoaldosteronism
- Corticosterone methyloxidase deficiency
- Early-onset familial hyperreninemic hypoaldosteronism
- Severe aldosterone synthase deficiency
description: >-
  Early-onset familial hypoaldosteronism (aldosterone synthase deficiency) is an
  autosomal recessive isolated defect of the terminal steps of aldosterone
  biosynthesis caused by biallelic loss-of-function variants in CYP11B2, which
  encodes aldosterone synthase in the adrenal zona glomerulosa. Cortisol
  synthesis is preserved. Lack of aldosterone causes renal sodium wasting and
  potassium retention, so affected infants present in the first weeks to months
  of life with vomiting, dehydration, failure to thrive, hyponatremia,
  hyperkalemia and markedly elevated renin. Two biochemical types are
  distinguished by the steroid profile: corticosterone methyloxidase type I
  (CMO I), with low 18-hydroxycorticosterone, and type II (CMO II), with an
  elevated 18-hydroxycorticosterone to aldosterone ratio. Treatment is
  fludrocortisone with sodium supplementation; mineralocorticoid requirement
  usually wanes in childhood and adults are often asymptomatic.
disease_term:
  preferred_term: Early-onset familial hypoaldosteronism
  term:
    id: MONDO:0035320
    label: early-onset familial hypoaldosteronism
parents:
- familial hypoaldosteronism
- hypoaldosteronism disease
has_subtypes:
- name: CMO I
  display_name: Corticosterone methyloxidase type I deficiency
  subtype_term:
    preferred_term: corticosterone methyloxidase type 1 deficiency
    term:
      id: MONDO:0008751
      label: corticosterone methyloxidase type 1 deficiency
  genes:
  - preferred_term: CYP11B2
    term:
      id: hgnc:2592
      label: CYP11B2
  description: >-
    Biochemical type in which aldosterone and 18-hydroxycorticosterone are both
    decreased while corticosterone and 11-deoxycorticosterone are elevated,
    reflecting loss of the 18-hydroxylase step; typically caused by truncating
    or fully inactivating CYP11B2 variants (for example E255X, R384P).
  evidence:
  - reference: PMID:9360501
    reference_title: "Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aldosterone and 18-OH-corticosterone were decreased, whereas corticosterone and 11-deoxycorticosterone were elevated, thus confirming the diagnosis of corticosterone methyl oxidase deficiency type I."
    explanation: Defines the CMO I steroid profile in the original Visser and Cost patients.
  - reference: PMID:7852500
    reference_title: "Amino acid substitution R384P in aldosterone synthase causes corticosterone methyloxidase type I deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "R384P leads to complete loss of 11 beta- and 18-hydroxylase activities of P450aldo"
    explanation: A CMO I allele abolishes both 11beta- and 18-hydroxylase activities in expression studies.
- name: CMO II
  display_name: Corticosterone methyloxidase type II deficiency
  subtype_term:
    preferred_term: corticosterone methyloxidase type 2 deficiency
    term:
      id: MONDO:0012524
      label: corticosterone methyloxidase type 2 deficiency
  genes:
  - preferred_term: CYP11B2
    term:
      id: hgnc:2592
      label: CYP11B2
  description: >-
    Biochemical type characterized by an elevated ratio of
    18-hydroxycorticosterone to aldosterone, reflecting selective loss of the
    18-oxidase step with retained 18-hydroxylase activity. Highly prevalent in
    Iranian Jews homozygous for the combined R181W and V386A alleles.
  evidence:
  - reference: PMID:1594605
    reference_title: Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Corticosterone methyloxidase II (CMO-II) deficiency is an autosomal recessive disorder of aldosterone biosynthesis, characterized by an elevated ratio of 18-hydroxycorticosterone to aldosterone in serum."
    explanation: Defines CMO II by its steroid ratio.
  - reference: PMID:1594605
    reference_title: Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "R181W reduced 18-hydroxylase and abolished 18-oxidase activities but left 11 beta-hydroxylase activity intact"
    explanation: Expression of the CMO II allele shows the selective loss of 18-oxidase activity underlying the subtype.
inheritance:
- name: Autosomal recessive inheritance
  description: Biallelic (homozygous or compound heterozygous) CYP11B2 variants; carrier parents are unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33098647
    reference_title: Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency."
    explanation: States the autosomal recessive inheritance of aldosterone synthase deficiency.
  - reference: PMID:7852500
    reference_title: "Amino acid substitution R384P in aldosterone synthase causes corticosterone methyloxidase type I deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both parents were heterozygous carriers for R384P, whereas the patient appeared homozygous"
    explanation: Family segregation consistent with recessive inheritance.
genetic:
- name: CYP11B2
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CYP11B2
    term:
      id: hgnc:2592
      label: CYP11B2
  notes: >-
    Biallelic missense, nonsense, frameshift, splice and in-frame deletion
    variants are reported. In a Greek cohort of 62 patients, p.T185I was present
    in 96% of unrelated patients; it was also the most common variant (40%) in a
    Turkish multicenter series. A minority of clinically typical patients carry
    no identifiable CYP11B2 defect.
  evidence:
  - reference: PMID:33098647
    reference_title: Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant."
    explanation: Largest cohort identifies biallelic CYP11B2 variants and a recurrent founder allele.
  - reference: PMID:34415991
    reference_title: Catch-up Growth and Discontinuation of Fludrocortisone Treatment in Aldosterone Synthase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common variant (40%) was p.T185I."
    explanation: Independent cohort confirms p.T185I as a common pathogenic allele.
  - reference: PMID:16733366
    reference_title: "Congenital hyperreninemic hypoaldosteronism in Israel: sequence analysis of CYP11B2 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We could not find a molecular defect in 2 patients: one was a carrier of the D335G mutation and the other had no detectable molecular change in the coding and promoter regions."
    explanation: Some clinically typical patients lack identified biallelic CYP11B2 variants, indicating incomplete molecular yield.
pathophysiology:
- name: Biallelic CYP11B2 loss of function
  description: >-
    Biallelic inactivating CYP11B2 variants reduce or abolish aldosterone
    synthase (P450c11AS) activity. Enzymatic activity generally has to fall
    below about 1% of normal before aldosterone synthesis is impaired; the
    pattern of residual 11beta-hydroxylase, 18-hydroxylase and 18-oxidase
    activity determines the CMO I versus CMO II steroid profile.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CYP11B2
    term:
      id: hgnc:2592
      label: CYP11B2
  molecular_functions:
  - preferred_term: aldosterone synthase 18-hydroxylase activity
    term:
      id: GO:0047783
      label: corticosterone 18-monooxygenase activity
    modifier: DECREASED
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:15134805
    reference_title: Aldosterone synthase deficiency and related disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Many mutations have been documented in each of these genes; in general enzymatic activity must be reduced to <1% of normal for aldosterone biosynthesis to be impaired."
    explanation: Review states the residual-activity threshold for disease.
  - reference: PMID:20494601
    reference_title: "Five novel mutations in CYP11B2 gene detected in patients with aldosterone synthase deficiency type I: Functional characterization and structural analyses."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The expression studies of the mutant proteins in COS-1 cells showed a complete absence of CYP11B2 activity of p.S315R and p.R374W mutants for the conversion of 11-deoxycorticosterone to aldosterone."
    explanation: Patient missense variants abolish aldosterone synthase activity in vitro.
  downstream:
  - target: Impaired zona glomerulosa aldosterone biosynthesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31302112
      reference_title: Analysis of novel heterozygous mutations in the CYP11B2 gene causing congenital aldosterone synthase deficiency and literature review.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The HEK-293T expression system was used to investigate the variants, demonstrating negligible aldosterone synthesis compared with WT CYP11B2."
      explanation: Patient CYP11B2 variants produce negligible aldosterone in a cellular expression system.
- name: Impaired zona glomerulosa aldosterone biosynthesis
  description: >-
    Aldosterone synthase catalyzes the terminal 11beta-hydroxylation,
    18-hydroxylation and 18-oxidation steps converting 11-deoxycorticosterone to
    aldosterone in zona glomerulosa cells. Its loss produces isolated aldosterone
    deficiency with intact cortisol synthesis, which is CYP11B1-dependent.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: zona glomerulosa cell
    term:
      id: CL:0002099
      label: type I cell of adrenal cortex
  locations:
  - preferred_term: zona glomerulosa of adrenal gland
    term:
      id: UBERON:0002053
      label: zona glomerulosa of adrenal gland
  biological_processes:
  - preferred_term: aldosterone biosynthetic process
    term:
      id: GO:0032342
      label: aldosterone biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:1594605
    reference_title: Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P450XIB2 catalyzes the synthesis of aldosterone from deoxycorticosterone, a process that successively requires hydroxylation at positions 11 beta and 18 and oxidation at position 18."
    explanation: Describes the three terminal steps performed by aldosterone synthase.
  - reference: PMID:38262861
    reference_title: "Neonatal salt wasting syndrome: Aldosterone synthase deficiency caused by a new splicing variant in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aldosterone synthase deficiency (ASD) is a rare autosomal recessive disorder involving isolated aldosterone deficiency without any compromise of other adrenal hormones."
    explanation: Aldosterone deficiency is isolated, with other adrenal steroids preserved.
  downstream:
  - target: Renal sodium wasting and potassium retention
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15134805
      reference_title: Aldosterone synthase deficiency and related disorders.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Inherited defects in aldosterone biosynthesis thus cause hypovolemia, hyponatremia and hyperkalemia."
      explanation: Review states that loss of aldosterone biosynthesis causes the renal electrolyte disturbance.
  - target: Decreased circulating aldosterone
- name: Renal sodium wasting and potassium retention
  description: >-
    Without aldosterone, distal nephron and collecting duct principal cells fail
    to reabsorb sodium and secrete potassium, producing urinary sodium loss,
    hypovolemia, hyponatremia, hyperkalemia and metabolic acidosis.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: kidney collecting duct principal cell
    term:
      id: CL:1001431
      label: kidney collecting duct principal cell
  biological_processes:
  - preferred_term: renal sodium ion absorption
    term:
      id: GO:0070294
      label: renal sodium ion absorption
    modifier: DECREASED
  - preferred_term: potassium ion homeostasis
    term:
      id: GO:0055075
      label: potassium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15134805
    reference_title: Aldosterone synthase deficiency and related disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Aldosterone's main actions are to regulate intravascular volume and serum electrolytes by controlling sodium absorbtion and potassium excretion in the distal nephron."
    explanation: Establishes the renal sodium and potassium handling disrupted by aldosterone deficiency.
  downstream:
  - target: Hyponatremia
  - target: Hyperkalemia
  - target: Dehydration
  - target: Metabolic acidosis
  - target: Renal salt wasting
  - target: Compensatory renin-angiotensin system activation
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34415991
      reference_title: Catch-up Growth and Discontinuation of Fludrocortisone Treatment in Aldosterone Synthase Deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Fludrocortisone treatment is associated with a rapid catch-up growth and control of electrolyte imbalances in ASD."
      explanation: Correction of mineralocorticoid deficiency restores growth, linking salt wasting to growth failure through a treatment-response inference.
- name: Compensatory renin-angiotensin system activation
  description: >-
    Volume depletion drives renin secretion; plasma renin activity is markedly
    elevated in affected infants and young children but may be normal in adults.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:32539318
    reference_title: "Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma renin activity is significantly increased in affected infants and young children (up to 100-fold normal) but can be normal in adults."
    explanation: Describes the magnitude and age dependence of hyperreninemia.
  downstream:
  - target: Increased circulating renin
phenotypes:
- category: Metabolic/Laboratory
  name: Hyponatremia
  description: Low serum sodium, typically 120-130 mmol/L in untreated infants.
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:32539318
    reference_title: "Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical studies showed hyponatremia, hyperkalemia and acidosis."
    explanation: Hyponatremia was present in the reported patients.
  - reference: PMID:9838244
    reference_title: Homozygous deletion of arginine-173 in the CYP11B2 gene in a girl with congenital hypoaldosteronism. Corticosterone methyloxidase deficiency type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Important laboratory findings were low plasma sodium and elevated potassium and renin."
    explanation: Case report documents hyponatremia, hyperkalemia and elevated renin.
- category: Metabolic/Laboratory
  name: Hyperkalemia
  description: Elevated serum potassium, typically 6.0-8.5 mmol/L in untreated infants.
  phenotype_term:
    preferred_term: Hyperkalemia
    term:
      id: HP:0002153
      label: Hyperkalemia
  evidence:
  - reference: PMID:32539318
    reference_title: "Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In untreated infants with CMOD, serum sodium level is generally between 120-130 mmol/L and serum potassium level is between 6.0-8.5 mmol/L"
    explanation: Gives the typical range of hyperkalemia (and hyponatremia) in untreated infants.
  - reference: PMID:31302112
    reference_title: Analysis of novel heterozygous mutations in the CYP11B2 gene causing congenital aldosterone synthase deficiency and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aldosterone synthase deficiency (ASD) is a rare autosomal recessive disorder characterized by severe hyperkalemia, salt loss, vomiting, severe dehydration and failure to thrive."
    explanation: Lists hyperkalemia among the defining features.
- category: Metabolic/Laboratory
  name: Metabolic acidosis
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:32539318
    reference_title: "Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings may include vomiting, dehydration, hypovolemia, hyponatremia, hyperkalemia and metabolic acidosis."
    explanation: Metabolic acidosis is part of the neonatal salt-wasting presentation.
- category: Renal
  name: Renal salt wasting
  description: Urinary sodium loss caused by absent aldosterone action, presenting as a neonatal salt-wasting syndrome.
  phenotype_term:
    preferred_term: Renal salt wasting
    term:
      id: HP:0000127
      label: Renal salt wasting
  evidence:
  - reference: PMID:38262861
    reference_title: "Neonatal salt wasting syndrome: Aldosterone synthase deficiency caused by a new splicing variant in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This condition manifests mainly in the neonatal period and in infants as a salt wasting syndrome with vomiting and failure to thrive."
    explanation: Salt wasting is the characteristic neonatal presentation.
  - reference: PMID:9838244
    reference_title: Homozygous deletion of arginine-173 in the CYP11B2 gene in a girl with congenital hypoaldosteronism. Corticosterone methyloxidase deficiency type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Salt wasting was caused by an enzymatic defect in the terminal aldosterone biosynthesis."
    explanation: Attributes salt wasting to the aldosterone synthesis defect.
- category: Systemic
  name: Dehydration
  description: Hypovolemic dehydration, sometimes severe, in the first weeks or months of life.
  phenotype_term:
    preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: PMID:33098647
    reference_title: Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive."
    explanation: Severe dehydration is a presenting symptom.
- category: Gastrointestinal
  name: Vomiting
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:32539318
    reference_title: "Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients presented with vomiting, failure to thrive and severe dehydration, except one patient with only failure to thrive."
    explanation: Vomiting was a presenting feature in most reported patients.
- category: Growth
  name: Failure to thrive
  description: >-
    Poor weight gain is the most common presenting symptom; growth delay can be
    the only sign in milder or later-diagnosed cases, and catch-up growth follows
    treatment.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:34415991
    reference_title: Catch-up Growth and Discontinuation of Fludrocortisone Treatment in Aldosterone Synthase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common symptom was poor weight gain (56.3%)."
    explanation: Poor weight gain was the most common presenting symptom in a 16-patient cohort.
  - reference: PMID:9838244
    reference_title: Homozygous deletion of arginine-173 in the CYP11B2 gene in a girl with congenital hypoaldosteronism. Corticosterone methyloxidase deficiency type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first child of consanguineous parents presented with failure to thrive and feeding problems at age 6 weeks."
    explanation: Failure to thrive was the presenting complaint.
- category: Endocrine
  name: Increased circulating renin
  description: Markedly elevated plasma renin activity (hyperreninemia), most pronounced in infancy.
  phenotype_term:
    preferred_term: Increased circulating renin concentration
    term:
      id: HP:0000848
      label: Increased circulating renin concentration
  evidence:
  - reference: PMID:32539318
    reference_title: "Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had normal cortisol response to adrenocorticotropic hormone stimulation test and had elevated plasma renin activity with low aldosterone levels."
    explanation: Elevated renin with low aldosterone and preserved cortisol response.
- category: Endocrine
  name: Decreased circulating aldosterone
  description: >-
    Aldosterone is low, or inappropriately normal relative to the elevated renin
    (particularly in CMO II).
  phenotype_term:
    preferred_term: Decreased circulating aldosterone concentration
    term:
      id: HP:0004319
      label: Decreased circulating aldosterone concentration
  evidence:
  - reference: PMID:32539318
    reference_title: "Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had normal cortisol response to adrenocorticotropic hormone stimulation test and had elevated plasma renin activity with low aldosterone levels."
    explanation: Low aldosterone levels in affected patients.
  - reference: PMID:9360501
    reference_title: "Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aldosterone and 18-OH-corticosterone were decreased"
    explanation: Decreased aldosterone in untreated adult CMO I patients.
biochemical:
- name: 18-hydroxycorticosterone to aldosterone ratio
  presence: INCREASED
  subtype: CMO II
  notes: Diagnostic for CMO II; the ratio is usually raised about 100-fold and does not change with age.
  evidence:
  - reference: PMID:32539318
    reference_title: "Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type 2 deficiency can be easily diagnosed by a marked increase in the ratio of 18-OHB to aldosterone in urine or serum (usually 100-fold)."
    explanation: States the diagnostic CMO II steroid ratio.
- name: 18-hydroxycorticosterone
  presence: DECREASED
  subtype: CMO I
  notes: Low in CMO I, with elevated corticosterone and 11-deoxycorticosterone.
  evidence:
  - reference: PMID:9360501
    reference_title: "Hereditary defect in biosynthesis of aldosterone: aldosterone synthase deficiency 1964-1997."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aldosterone and 18-OH-corticosterone were decreased, whereas corticosterone and 11-deoxycorticosterone were elevated, thus confirming the diagnosis of corticosterone methyl oxidase deficiency type I."
    explanation: CMO I steroid profile.
prevalence:
- population: Jews of Iranian origin
  subtype: CMO II
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 25.0
  notes: >-
    Source wording: "CMO-II deficiency is frequent among Jews from Iran (1 in
    4000 births)". A founder-population figure; affected individuals are
    homozygous for both CYP11B2 R181W and V386A. No general-population estimate
    was found.
  evidence:
  - reference: PMID:8481357
    reference_title: "Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births)"
    explanation: Gives the birth frequency of CMO II deficiency in Iranian Jews.
  - reference: PMID:8481357
    reference_title: "Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "all individuals affected were homozygous for two missense mutations in CYP11B2"
    explanation: The high frequency in this population reflects a founder CYP11B2 haplotype.
diagnosis:
- name: Clinical and laboratory diagnostic criteria
  description: >-
    Japanese national diagnostic criteria for aldosterone synthase deficiency
    require salt-wasting symptoms without skin pigmentation, together with
    hyponatremia and hyperkalemia, low to normal plasma aldosterone with high
    renin, and no low cortisol. PHA1, 21-hydroxylase deficiency, congenital
    lipoid adrenal hyperplasia and congenital adrenal hypoplasia must be
    excluded.
  diagnosis_term:
    preferred_term: clinical and biochemical diagnostic criteria
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  notes: >-
    Because 18-hydroxycorticosterone cannot be measured in routine practice in
    Japan, these criteria do not separate CMO I from CMO II.
  evidence:
  - reference: PMID:41905953
    reference_title: Congenital aldosterone deficiency and its resistance.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "1) Presents with salt-wasting symptoms (poor feeding, vomiting, dehydration, poor weight gain). 2) No skin pigmentation."
    explanation: Clinical arm of the published diagnostic criteria.
  - reference: PMID:41905953
    reference_title: Congenital aldosterone deficiency and its resistance.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "1) Low serum sodium and high serum potassium. 2) Low to normal plasma aldosterone and high plasma renin activity or high plasma active renin concentration. 3) No low blood cortisol level."
    explanation: Laboratory arm of the published diagnostic criteria.
  - reference: PMID:41905953
    reference_title: Congenital aldosterone deficiency and its resistance.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Since 18-hydroxycorticosterone measurements are not possible in clinical practice, the current diagnostic criteria do not classify ASD1 or ASD2."
    explanation: States the limitation recorded in notes.
- name: Multisteroid profiling
  description: >-
    Plasma or urine steroid profiling showing a highly elevated
    18-hydroxycorticosterone to aldosterone ratio establishes the biochemical
    diagnosis of CMO II; normal aldosterone against highly elevated renin points
    to impaired aldosterone biosynthesis.
  diagnosis_term:
    preferred_term: multisteroid analysis
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:22931312
    reference_title: Homozygosity for a mutation in the CYP11B2 gene in an infant with congenital corticosterone methyl oxidase deficiency type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The biochemical diagnosis of corticosterone methyl oxidase deficiency type II was established by multisteroid analysis, revealing a pathognomonic pattern with a highly elevated ratio of 18-OH-corticosterone to aldosterone."
    explanation: Multisteroid analysis with the 18-OH-corticosterone to aldosterone ratio is diagnostic for CMO II.
  - reference: PMID:22931312
    reference_title: Homozygosity for a mutation in the CYP11B2 gene in an infant with congenital corticosterone methyl oxidase deficiency type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Normal levels of plasma aldosterone compared with highly elevated levels of plasma renin indicate an impaired aldosterone biosynthesis and suggest the disorder."
    explanation: The aldosterone to renin relationship is the first biochemical clue.
- name: CYP11B2 genetic testing
  description: >-
    Sequencing of CYP11B2 confirms the diagnosis after hormonal work-up. The
    high homology between CYP11B2 and the neighbouring CYP11B1 gene is a
    recognised source of sequencing pitfalls.
  diagnosis_term:
    preferred_term: CYP11B2 sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:39700478
    reference_title: "Cracking the code of aldosterone synthase deficiency: bridging genetics and biochemistry: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a comprehensive hormonal investigation followed by genetic confirmation is essential for the clinical management of offspring"
    explanation: Recommends hormonal work-up followed by genetic confirmation.
  - reference: PMID:39700478
    reference_title: "Cracking the code of aldosterone synthase deficiency: bridging genetics and biochemistry: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "describe potential pitfalls in CYP11B2 sequencing due to its homology to CYP11B1"
    explanation: Names CYP11B1 homology as a source of sequencing pitfalls. The abstract does not detail the pitfalls.
  - reference: PMID:22931312
    reference_title: Homozygosity for a mutation in the CYP11B2 gene in an infant with congenital corticosterone methyl oxidase deficiency type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular genetic analysis supported the diagnosis revealing homozygosity for a pathogenic c.554C>T (p.T185I) variation in exon 3 of the CYP11B2 gene encoding aldosterone synthase."
    explanation: CYP11B2 sequencing confirmed the biochemical diagnosis.
differential_diagnoses:
- name: Pseudohypoaldosteronism type 1
  disease_term:
    preferred_term: pseudohypoaldosteronism type 1
    term:
      id: MONDO:0019161
      label: pseudohypoaldosteronism type 1
  description: >-
    Aldosterone resistance (renal PHA1a from NR3C2 defects, systemic PHA1b from
    ENaC subunit defects, or secondary PHA1) produces the same infantile salt
    wasting with hyponatremia, hyperkalemia and high renin.
  distinguishing_features:
  - Aldosterone is markedly elevated in PHA1a, whereas it is low to normal 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 as the key differential diagnosis.
  - reference: PMID:41905953
    reference_title: Congenital aldosterone deficiency and its resistance.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "Endocrine testing typically reveals significantly elevated aldosterone and elevated serum renin levels."
    explanation: Describes the high-aldosterone profile of PHA1a that separates it from ASD.
- name: Salt-wasting 21-hydroxylase deficiency
  disease_term:
    preferred_term: salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency
    term:
      id: MONDO:0017839
      label: classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
  description: >-
    Salt-wasting congenital adrenal hyperplasia presents with similar neonatal
    salt-wasting symptoms and is one of the listed diagnoses of exclusion.
  distinguishing_features:
  - Cortisol deficiency with raised ACTH and skin pigmentation
  - Atypical external genitalia in affected females
  evidence:
  - reference: PMID:41905953
    reference_title: Congenital aldosterone deficiency and its resistance.
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: "In females with 21-hydroxylase deficiency, differentiation of the disorders is possible based on external genital findings. Males with 21-hydroxylase deficiency, congenital lipoid adrenal hyperplasia, and congenital adrenal hypoplasia also exhibit cortisol deficiency, resulting in elevated adrenocorticotropic hormone levels and skin pigmentation."
    explanation: States the features that separate 21-hydroxylase deficiency from ASD.
progression:
- phase: Infantile salt-wasting presentation
  age_range: Neonatal period to early infancy
  notes: >-
    Symptoms usually begin in the first weeks to months of life; in a Turkish
    cohort the median age at presentation was 3.1 months.
  evidence:
  - reference: PMID:34415991
    reference_title: Catch-up Growth and Discontinuation of Fludrocortisone Treatment in Aldosterone Synthase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixteen patients from 12 families were included (8 females; median age at presentation: 3.1 months, range: 0.4 to 8.1)."
    explanation: Age at presentation in a multicenter cohort.
- phase: Childhood amelioration
  age_range: Childhood to adulthood
  notes: >-
    Mineralocorticoid requirement decreases with age and treatment can often be
    stopped in childhood, although the biochemical defect persists; adults are
    usually asymptomatic.
  evidence:
  - reference: PMID:34415991
    reference_title: Catch-up Growth and Discontinuation of Fludrocortisone Treatment in Aldosterone Synthase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased mineralocorticoid requirement over time can be explained by the development of physiological adaptation mechanisms rather than improved aldosterone synthase activity."
    explanation: Clinical amelioration with age reflects adaptation, not recovery of enzyme activity.
  - reference: PMID:32539318
    reference_title: "Clinical and Genetic Characteristics of Patients with Corticosterone Methyloxidase Deficiency Type 2: Novel Mutations in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The signs and symptoms of the disorder typically become milder or disappear by adulthood."
    explanation: Symptoms typically wane by adulthood.
treatments:
- name: Fludrocortisone mineralocorticoid replacement
  description: >-
    Oral fludrocortisone replaces mineralocorticoid action, correcting
    electrolyte disturbances and producing rapid catch-up growth. The dose
    requirement wanes with age and therapy can be discontinued in many children,
    but long-term surveillance is advised because the enzymatic defect persists.
  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
  target_mechanisms:
  - target: Renal sodium wasting and potassium retention
    treatment_effect: INHIBITS
    description: Mineralocorticoid replacement restores renal sodium retention and potassium excretion.
  target_phenotypes:
  - preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  - preferred_term: Hyperkalemia
    term:
      id: HP:0002153
      label: Hyperkalemia
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:34415991
    reference_title: Catch-up Growth and Discontinuation of Fludrocortisone Treatment in Aldosterone Synthase Deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fludrocortisone could be stopped in 5 patients at a median age of 6.0 years (range: 2.2 to 7.6)."
    explanation: Treatment can be withdrawn in a subset of children.
  - reference: PMID:31302112
    reference_title: Analysis of novel heterozygous mutations in the CYP11B2 gene causing congenital aldosterone synthase deficiency and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fludrocortisone treatment is essential for ASD, and the need for mineralocorticoid replacement wanes with age; eventually, therapy can be discontinued for many affected children."
    explanation: Fludrocortisone is the essential treatment, with waning requirement.
- name: Sodium chloride supplementation
  description: >-
    Oral salt supplementation, together with rehydration in acute presentations,
    is used alongside fludrocortisone, particularly in infancy.
  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_phenotypes:
  - preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  - preferred_term: Dehydration
    term:
      id: HP:0001944
      label: Dehydration
  evidence:
  - reference: PMID:38262861
    reference_title: "Neonatal salt wasting syndrome: Aldosterone synthase deficiency caused by a new splicing variant in CYP11B2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rehydration as well as salt and fludrocortisone supplementation"
    explanation: Management combines rehydration with salt and fludrocortisone supplementation.
notes: >-
  MONDO places the CMO I and CMO II terms (MONDO:0008751, MONDO:0012524) as
  siblings of MONDO:0035320 under familial hypoaldosteronism rather than as its
  children. They are recorded here as has_subtypes because both are the
  early-onset CYP11B2 aldosterone synthase deficiency described by this entry
  and differ only in steroid profile.
  No GeneReviews chapter covers aldosterone synthase deficiency (Bookshelf
  index check). Vomiting is recorded as a presenting feature but is not wired
  to a mechanism node because the cited sources do not state its cause.

📚

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 (2)

Reconcile OpenScientist deep research; add prevalence, diagnosis and differential diagnoses · 2026-10-15T04:12:21Z · View source

Deep research for this entry: a first OpenScientist run timed out and produced no report; an Asta run was off-topic and was not committed. A second OpenScientist run (15/15 references resolved) is committed under research/ and was cross-checked against the entry. Added from it: (1) a BIRTH_PREVALENCE record for CMO II in Jews of Iranian origin, 1 in 4000 births (rate_per_100000 25.0, BAND_1_5_PER_10000), PMID:8481357; (2) three diagnosis rows: the Japanese national clinical and laboratory diagnostic criteria (PMID:41905953), multisteroid profiling with the 18-OH-corticosterone to aldosterone ratio (PMID:22931312), and CYP11B2 genetic testing with the CYP11B1 homology caveat (PMID:39700478, PMID:22931312); (3) differential diagnoses for pseudohypoaldosteronism type 1 (MONDO:0019161) and salt-wasting 21-hydroxylase deficiency (MONDO:0017839), quoted from the full text of PMID:41905953. Not taken: the report's HP:0011046 and UBERON:0001228 suggestions, which the report's own term validation shows resolve to unrelated terms (incisor agenesis, renal papilla); the under-1-percent residual activity threshold (PMID:15134805, already cited elsewhere in the entry) and enzyme structure, dexfadrostat and fission-yeast assay papers (PMID:37827219, PMID:21237269), which add no disease-level claim the entry lacks; the aldosterone synthase-deficient mouse (PMID:20624970), whose cited use is renal kallikrein physiology rather than a model of this disease; and the report's inferred mineralocorticoid receptor to ENaC step, which it flags as inferred and which the entry already covers. All 53 snippets verified; validate-disorders passed.

Create: Early-onset_Familial_Hypoaldosteronism · 2026-10-15T02:27:59Z · View source

New entry for early-onset familial hypoaldosteronism (aldosterone synthase deficiency, MONDO:0035320), CYP11B2 (hgnc:2592), claim issue #14253. Deep research was attempted with the falcon provider (with --fallback) but failed with an Edison authentication error, so the literature was searched directly in PubMed. Twelve PMIDs were fetched into references_cache and cited with exact abstract snippets (40/40 verified). CMO I (MONDO:0008751) and CMO II (MONDO:0012524) are recorded as has_subtypes; MONDO models them as siblings of MONDO:0035320 under familial hypoaldosteronism, which the entry notes. Pathograph: CYP11B2 loss of function -> impaired zona glomerulosa aldosterone biosynthesis -> renal sodium wasting and potassium retention -> hyponatremia, hyperkalemia, dehydration, metabolic acidosis, renal salt wasting, failure to thrive and compensatory renin elevation; 8 of 9 phenotypes connected (vomiting left unwired). Treatments: fludrocortisone (CHEBI:50885) and sodium chloride (CHEBI:26710) under NCIT Pharmacotherapy. No GeneReviews chapter exists (check-genereviews NO_CHAPTER). Validated with just validate, validate-terms, count-verified-snippets, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and validate-disorders, all passing. The stubs for this disease and for the two CMO subtypes were removed.

OpenScientist ▸

Key Findings

openscientist-autonomous 13 citations 2026-10-15T04:06:14.406217

Key Findings

Finding 1 — CYP11B2 loss of function causes isolated aldosterone deficiency

Biallelic inactivating mutations in CYP11B2 (chr8q24.3, encoding the mitochondrial cytochrome P450 aldosterone synthase) cause an isolated defect in aldosterone biosynthesis. The two clinical forms, CMO I (OMIM 203400) and CMO II (OMIM 610600), are distinguished by residual terminal enzyme activity. A critical quantitative principle is that enzymatic activity must generally fall below ~1% of normal before aldosterone biosynthesis is measurably impaired, reflecting substantial functional reserve in the pathway. Documented pathogenic variants include p.Gly452Arg, p.Thr185Ile, the compound R173K+E198D+V386A allele, and in-frame deletion of Arg173.

"Pathogenic variants in CYP11B2 result in corticosterone methyloxidase type I deficiency (CMO I), an orphan condition with a potentially lethal electrolyte imbalance in infancy." — PMID: 41229259

"Many mutations have been documented in each of these genes; in general enzymatic activity must be reduced to <1% of normal for aldosterone biosynthesis to be impaired." — PMID: 15134805

"The first, corticosterone methyloxidase type I (CMO I or type 1 deficiency), is characterized by no detectable aldosterone secretion, a low or normal secretion of the steroid 18OHB" — PMID: 9814506

Finding 2 — Clinical presentation: neonatal/infantile salt wasting with a high-renin, low-aldosterone profile

Patients present in the neonatal period or early infancy with failure to thrive, feeding problems, recurrent vomiting and dehydration, severe hyponatremia, hyperkalemia, and metabolic acidosis. The laboratory hallmark is markedly elevated plasma renin activity with low (CMO I) or inappropriately normal (CMO II) plasma aldosterone. Because cortisol synthesis is unaffected, this is an isolated mineralocorticoid defect. The pathognomonic biochemical signature of CMO II is an elevated 18-hydroxycorticosterone/aldosterone ratio.

"We studied an infant with failure to thrive and persistent hyponatremia despite oral sodium supplementation. Initial analyses revealed highly elevated plasma renin but normal values of plasma aldosterone." — PMID: 22931312

"diagnosed initially in the neonatal period because of severe hyponatremia, hyperkalemia, metabolic acidosis, and failure to thrive" — PMID: 41229259

"presented with failure to thrive and feeding problems at age 6 weeks. Important laboratory findings were low plasma sodium and elevated potassium and renin." — PMID: 9838244

Finding 3 — Diagnosis by steroid profiling and CYP11B2 sequencing; treatment with fludrocortisone is highly effective and often discontinuable

Biochemical diagnosis rests on multisteroid analysis demonstrating the pathognomonic elevation of the 18-hydroxycorticosterone/aldosterone ratio (CMO II) together with elevated precursors (11-deoxycorticosterone [DOC], corticosterone, 18-OHDOC). Molecular confirmation is by CYP11B2 sequencing. Mineralocorticoid replacement with fludrocortisone (± sodium chloride supplementation in infancy) corrects the electrolyte disturbance and produces catch-up growth. Because distal-tubular aldosterone responsiveness matures with age and dietary salt intake rises, treatment can frequently be discontinued in later childhood without deterioration — in one documented case, stopped at age 9 years without relapse.

"revealing a pathognomonic pattern with a highly elevated ratio of 18-OH-corticosterone to aldosterone" — PMID: 22931312

"Treatment with fludrocortisone resulted in catch-up growth. Discontinuation of treatment at the age of 9 years was later possible without any clinical or biochemical deterioration." — PMID: 22931312

"secrete increased amounts of the steroid precursors DOC, corticosterone, and 18OHDOC, and are subject to salt wasting and poor growth" — PMID: 9814506

Finding 4 — Pathophysiology and differential diagnosis

The isolated nature of the defect (normal cortisol, no hyperpigmentation) is the central clinical discriminator from aldosterone-resistance disorders and from CAH. ASD must be separated from pseudohypoaldosteronism type 1 (PHA1) — a resistance disorder in which aldosterone is HIGH — and from 21-hydroxylase deficiency CAH (low cortisol, ambiguous genitalia, hyperpigmentation).

"Aldosterone synthase deficiency (ASD), which is caused by a genetic defect in CYP11B2, involves a deficiency in aldosterone alone." — PMID: 41905953

"ASD must also be differentiated from another disease, pseudohypoaldosteronism type 1 (PHA1), which involves resistance to aldosterone. PHA1a is caused by a heterozygous defect in NR3C2, which encodes the mineralocorticoid receptor. PHA1b is an autosomal recessive disorder caused by defects in the 3 epithelial sodium channel subunits" — PMID: 41905953

"Aldosterone is synthesized in the adrenal zona glomerulosa via the action of the mitochondrial cytochrome P450 enzyme aldosterone synthase (CYP11B2) through sequential enzyme reactions." — PMID: 41229259

Finding 5 — Epidemiology and founder mutations (Jews of Iranian origin, ~1/4,000)

CMO II deficiency is relatively frequent among Jews of Iranian origin, with an estimated incidence of 1 in 4,000 births. Affected individuals are homozygous for two CYP11B2 missense variants, p.R181W and p.V386A, inherited together on a founder haplotype. Functional expression showed that R181W reduces 18-hydroxylase and abolishes 18-oxidase activity while leaving 11β-hydroxylase intact, whereas V386A causes a small reduction in 18-hydroxycorticosterone production. Critically, individuals homozygous for R181W alone (n=8) or V386A alone (n=3) were asymptomatic, demonstrating that the two variants act additively to produce disease. Globally the disorder is ultra-rare; most other reports are single consanguineous kindreds, consistent with autosomal recessive inheritance.

"CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births)" — PMID: 8481357

"two candidate mutations, R181W and V386A, were found in the CYP11B2 genes" — PMID: 1594605

"R181W reduced 18-hydroxylase and abolished 18-oxidase activities but left 11 beta-hydroxylase activity intact, whereas V386A caused a small but consistent reduction in the production of 18-hydroxycorticosterone" — PMID: 1594605

"All individuals affected with CMO-II deficiency were homozygous for both mutations, whereas eight asymptomatic subjects were homozygous for R181W alone and three were homozygous for V386A alone" — PMID: 1594605

Finding 6 — Enzyme biochemistry: a three-step mitochondrial P450 reaction

Aldosterone synthase (CYP11B2, UniProt P19099) is a mitochondrial cytochrome P450 that converts 11-deoxycorticosterone to aldosterone via three sequential reactions: 11β-hydroxylation (→ corticosterone), 18-hydroxylation (→ 18-hydroxycorticosterone), and 18-oxidation (→ aldosterone). The enzyme coordinates its substrate at a catalytic heme moiety in the substrate-binding pocket (demonstrated structurally with the inhibitor dexfadrostat). Disease variants are characterized functionally in heterologous expression systems (cultured mammalian cells; fission yeast Schizosaccharomyces pombe) by measuring residual 11β-/18-hydroxylase and 18-oxidase activity. CMO I variants abolish all terminal activity (no aldosterone, low 18-OHB), whereas CMO II variants retain 18-hydroxylase but lose 18-oxidase (normal/low aldosterone, high 18-OHB).

"The aldosterone synthase, CYP11B2, catalyses the conversion of 11-deoxycorticosterone to aldosterone, a process that requires three steps: a hydroxylation at position 11β to form corticosterone, another one at position 18 to produce 18-hydroxycorticosterone, and, finally, an oxidation at position 18 to form aldosterone." — PMID: 21237269

"precisely coordinates with the catalytic heme moiety in the space of the CYP11B2 substrate binding pocket forming a tight and stable complex" — PMID: 37827219

"the heterologous expression of the mutants of CYP11B2 in fission yeast (Schizosaccharomyces pombe) followed by steroid bioconversion assays for the enzymatic characterisation of the investigated mutants" — PMID: 21237269

Relevant CHEBI entities: aldosterone (CHEBI:27584), corticosterone (CHEBI:16827), 11-deoxycorticosterone (CHEBI:16973), 18-hydroxycorticosterone, potassium(1+) (CHEBI:29103), sodium(1+) (CHEBI:29101).

Finding 7 — Natural history and prognosis (multicenter cohort data)

A multicenter cohort of 16 patients from 12 families (8 female) quantified the natural history: median age at presentation 3.1 months (range 0.4–8.1), with poor weight gain the most common presenting symptom (56.3%). Median age at starting fludrocortisone was 3.6 months, and catch-up growth was achieved a median of 2 months after treatment began. Fludrocortisone was successfully discontinued in 5/16 patients at a median age of 6.0 years (range 2.2–7.6). Importantly, reduced aldosterone synthase activity persisted biochemically even after discontinuation, confirming that clinical remission reflects compensatory maturation (increasing dietary salt, maturing renal mineralocorticoid sensitivity) rather than resolution of the enzyme defect.

"Catch-up growth was achieved at median 2 months (range: 0.5 to 14.5) after treatment. Fludrocortisone could be stopped in 5 patients at a median age of 6.0 years (range: 2.2 to 7.6)." — PMID: 34415991

"Sixteen patients from 12 families were included (8 females; median age at presentation: 3.1 months, range: 0.4 to 8.1). The most common symptom was poor weight gain (56.3%)." — PMID: 34415991

"Plasma steroid profiles revealed reduced aldosterone synthase activity both at diagnosis and after discontinuation of treatment compared to age-matched controls." — PMID: 34415991

Finding 8 — Variant spectrum and the CYP11B1 homology pitfall

Pathogenic CYP11B2 variants span all molecular classes and are enriched in consanguineous populations: missense (p.T185I — most common at 40% in a Turkish cohort; also p.Y195H, p.F130L, p.G452W, p.G288S, p.G452R, p.R181W, p.V386A, p.E198D), nonsense (p.Q338stop), frameshift (p.Ser344Profs9), splice-site (c.1200+1G>A, c.1122-18G>A), and in-frame deletions (p.E198del, p.I339_E343del, p.K175del, deletion of Arg173). Novel variants continue to be reported in Palestinian, Turkish, Arab, Chinese, Indian, and Polish patients from consanguineous or founder backgrounds. Variants are germline, biallelic (homozygous or compound heterozygous), and loss-of-function, classified pathogenic/likely pathogenic under ACMG criteria with functional/structural support. A key diagnostic caveat: CYP11B2 shares ~95% sequence identity with the neighboring CYP11B1 gene*, creating sequencing pitfalls and risk of chimeric/unequal-crossover alleles.

"We identified 6 novel (p.Y195H, c.1200 + 1G > A, p.F130L, p.E198del, c.1122-18G > A, p.I339_E343del) and 4 previously described CYP11B2 variants. The most common variant (40%) was p.T185I." — PMID: 34415991

"revealed three homozygous pathogenic variants: p.Ser344Profs9, p.G452W in two patients from an extended family, and p.Q338stop"* — PMID: 33438832

"describe potential pitfalls in CYP11B2 sequencing due to its homology to CYP11B1" — PMID: 39700478

Finding 9 — Formal diagnostic criteria separate ASD from PHA1 and CAH

A consensus diagnostic framework (Japanese Intractable Adrenal Disorders Research) defines ASD by: (clinical) salt-wasting symptoms — poor feeding, vomiting, dehydration, poor weight gain — AND absence of skin pigmentation; plus (laboratory) low serum sodium with high serum potassium; low-to-normal plasma aldosterone with high plasma renin activity/active renin concentration; and no low blood cortisol. Diagnoses of exclusion include PHA1 and 21-hydroxylase deficiency. This operationalizes the key discriminators: aldosterone is LOW/normal in ASD (deficiency) vs HIGH in PHA1 (resistance); cortisol is normal in ASD vs low in salt-wasting CAH; and there is no hyperpigmentation.

"1) Presents with salt-wasting symptoms (poor feeding, vomiting, dehydration, poor weight gain). 2) No skin pigmentation." — PMID: 41905953

"2) Low to normal plasma aldosterone and high plasma renin activity or high plasma active renin concentration. 3) No low blood cortisol level." — PMID: 41905953

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

A biallelic loss-of-function CYP11B2 mutation (germline, homozygous or compound heterozygous) leads to deficient or absent aldosterone synthase protein/activity in the adrenal zona glomerulosa.
Deficient aldosterone synthase activity results in failure of the terminal reactions of aldosterone biosynthesis — specifically 18-hydroxylation and/or 18-oxidation of corticosterone.
This leads to profound aldosterone deficiency (CMO I: no aldosterone; CMO II: low/inappropriately normal aldosterone with accumulated 18-hydroxycorticosterone — hence the diagnostic high 18-OHB/aldosterone ratio).
Loss of circulating aldosterone results in loss of mineralocorticoid-receptor–driven ENaC and Na⁺/K⁺ transport in the aldosterone-sensitive distal nephron (inferred from the known physiology of MR/ENaC signaling).
Impaired distal sodium reabsorption and potassium/H⁺ secretion lead to renal sodium wasting with impaired potassium and acid excretion.
This results in hyponatremia, hyperkalemia, metabolic acidosis, and hypovolemia.
Hypovolemia and hyponatremia lead to compensatory activation of the renin–angiotensin system (hyperreninemia), which cannot be translated into aldosterone because the enzymatic block is downstream.
The net effect results in a neonatal/infantile salt-wasting crisis with dehydration, vomiting, and failure to thrive — potentially lethal if untreated.

Branch point (preserved pathway): Because the lesion is specific to the terminal zona-glomerulosa enzyme, cortisol and sex-steroid synthesis are unaffected. This branch explains the two defining clinical negatives — normal cortisol and no hyperpigmentation — which separate ASD from salt-wasting CAH and from primary adrenal insufficiency.

Age-dependent amelioration branch: Over time, increasing dietary salt intake and maturing renal tubular mineralocorticoid sensitivity compensate for the persistent enzyme deficit, allowing clinical (but not biochemical) remission and discontinuation of therapy by mid-childhood.

Compact pathway diagram

CYP11B2 biallelic LOF mutation
│
▼
↓ Aldosterone synthase activity (zona glomerulosa mitochondria)
│
▼
Block of 18-hydroxylation / 18-oxidation of corticosterone
│
├── CMO I  → no aldosterone, low/normal 18-OHB
└── CMO II → low/normal aldosterone, HIGH 18-OHB  ⇒ ↑18-OHB/aldo ratio
│
▼
Aldosterone deficiency        ╌╌╌╌╌  Cortisol/sex steroids PRESERVED
│                             (⇒ normal cortisol, NO hyperpigmentation)
▼
↓ MR→ENaC / Na-K transport in distal nephron  (inferred)
│
▼
Renal Na⁺ wasting + impaired K⁺/H⁺ excretion
│
▼
Hyponatremia + Hyperkalemia + Metabolic acidosis + Hypovolemia
│
▼
Compensatory RAAS activation → HIGH renin (aldosterone cannot rise)
│
▼
Salt-wasting crisis, failure to thrive (lethal if untreated)
│
▼
Fludrocortisone ± NaCl → electrolyte correction + catch-up growth
│
▼
Age-dependent amelioration (↑dietary salt, ↑tubular MR sensitivity)
   → therapy often discontinuable by mid-childhood

Ontology term suggestions

Domain	Term(s)
Disease (MONDO)	MONDO:0035320 (Early-onset Familial Hypoaldosteronism)
Gene (HGNC)	CYP11B2
Phenotype (HPO)	Hyponatremia (HP:0002902); Hyperkalemia (HP:0002153); Metabolic acidosis (HP:0001942); Failure to thrive (HP:0001508); Dehydration (HP:0001944); Vomiting (HP:0002013); Hypoaldosteronism (HP:0011046); Increased circulating renin level (HP:0000848); Salt craving (HP:0003108)
Biological process (GO)	Aldosterone biosynthetic process (GO:0032342); steroid biosynthetic process (GO:0006694); sodium ion transport (GO:0006814); potassium ion homeostasis (GO:0055075)
Cellular component (GO)	Mitochondrion (GO:0005739); mitochondrial inner membrane (GO:0005743)
Cell type (CL)	Adrenal cortex zona glomerulosa cell; (kidney) principal cell of the collecting duct
Anatomy (UBERON)	Adrenal gland / adrenal cortex (UBERON:0001235); zona glomerulosa (UBERON:0001228); kidney (UBERON:0002113); distal convoluted tubule / collecting duct
Chemical (CHEBI)	Aldosterone (CHEBI:27584); corticosterone (CHEBI:16827); 11-deoxycorticosterone (CHEBI:16973); sodium(1+) (CHEBI:29101); potassium(1+) (CHEBI:29103)
Treatment (NCIT)	Fludrocortisone; sodium chloride supplementation

Section-by-Section Characterization

1. Disease Information

Isolated aldosterone synthase deficiency (CMO I/II), an autosomal recessive inborn error of adrenal steroidogenesis. Identifiers: MONDO:0035320; OMIM 203400 (CMO I) and 610600 (CMO II); gene CYP11B2 (8q24.3); protein UniProt P19099. Synonyms as listed above. Information derived from aggregated disease-level resources and primary clinical literature.

2. Etiology

Causal factor: purely genetic — biallelic loss-of-function CYP11B2 variants. Genetic risk factors: founder/consanguineous backgrounds dramatically raise risk (e.g., Iranian-Jewish R181W+V386A haplotype). No established environmental causes; the disease is monogenic. Protective/modifier factors: none proven genetically, but dietary salt intake and maturation of renal mineralocorticoid sensitivity act as powerful acquired modifiers of clinical severity with age. Gene–environment interaction: the principal interaction is between the fixed enzymatic deficit and dietary sodium availability — high salt intake offsets renal sodium wasting and underlies age-dependent remission.

3. Phenotypes

Phenotype	Type	HPO	Onset	Frequency / notes
Hyponatremia	Lab abnormality	HP:0002902	Neonatal/infantile	Core feature
Hyperkalemia	Lab abnormality	HP:0002153	Neonatal/infantile	Core feature
Metabolic acidosis	Lab abnormality	HP:0001942	Neonatal/infantile	Common
Failure to thrive / poor weight gain	Clinical sign	HP:0001508	Infantile	56.3% most common presenting symptom (PMID 34415991)
Recurrent vomiting	Symptom	HP:0002013	Infantile	Common
Dehydration	Clinical sign	HP:0001944	Infantile	Common, can be severe
Elevated plasma renin	Lab abnormality	HP:0000848	Neonatal/infantile	Diagnostic hallmark
Low/inappropriately normal aldosterone	Lab abnormality	HP:0011046	Neonatal/infantile	Core; defines deficiency

Severity: severe in infancy (potentially lethal salt-wasting crises), self-ameliorating with age. Progression: episodic crises early; overall course improves (clinical remission by mid-childhood). Quality of life: major in untreated infancy; excellent with timely treatment and after age-related remission.

4. Genetic / Molecular Information

Causal gene: CYP11B2 (8q24.3). Variant classes: missense, nonsense, frameshift, splice-site, and in-frame deletions — all germline, biallelic, loss-of-function (see Finding 8). Allele frequencies: pathogenic alleles are rare globally but locally common on founder haplotypes (e.g., R181W+V386A in Iranian Jews). Functional consequence: loss of function (reduced/absent 18-hydroxylase and/or 18-oxidase activity). Diagnostic caveat: ~95% homology with CYP11B1 risks mis-mapping and chimeric alleles. No epigenetic or large chromosomal mechanisms are established for this disorder.

5. Environmental Information

No toxic, infectious, or occupational cause. The one environmentally modifiable factor is dietary sodium: low intake unmasks/worsens salt wasting; higher intake (and salt supplementation) mitigates it.

6. Mechanism / Pathophysiology

See the ordered causal chain and diagram above. Upstream: CYP11B2 LOF → zona glomerulosa mitochondrial enzyme failure. Downstream: aldosterone deficiency → distal-nephron sodium wasting → electrolyte derangement → RAAS activation. Preserved branch: intact cortisol/androgen synthesis.

7. Anatomical Structures Affected

Primary organ: adrenal gland, specifically the adrenal cortex zona glomerulosa (UBERON:0001228), site of the enzymatic defect.
Secondary (functionally affected) organ: kidney — aldosterone-sensitive distal nephron (distal convoluted tubule, connecting tubule, collecting duct principal cells), where mineralocorticoid action is lost.
Body system: endocrine (adrenal steroidogenesis) and renal/electrolyte-regulatory.
Subcellular compartment: mitochondrion (GO:0005739) — aldosterone synthase is a mitochondrial inner-membrane P450.
Lateralization: bilateral (systemic hormonal deficiency).

8. Temporal Development

Onset: neonatal to early infancy (median presentation ~3.1 months; range 0.4–8.1). Pattern: acute salt-wasting crises on a chronic genetic background. Course: severe early, then progressive clinical amelioration with age. Remission: treatment can be discontinued in a substantial fraction (5/16; median 6.0 years) — a treatment-withdrawable clinical remission despite persistent biochemical deficit. Critical period: infancy is the window of vulnerability (crisis risk) and of therapeutic opportunity.

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: essentially complete for biallelic LOF genotypes, though expressivity varies (CMO I vs II; allele-dependent). Epidemiology: ultra-rare globally; ~1/4,000 births among Jews of Iranian origin (founder effect). Founder effect: R181W+V386A compound haplotype. Consanguinity: major driver — most non-founder cases arise in consanguineous Palestinian, Turkish, Arab, Chinese, Indian kindreds. Sex ratio: no strong sex bias (cohort 8/16 female). Carrier frequency: elevated in founder/consanguineous populations; heterozygotes are asymptomatic.

10. Diagnostics

Laboratory: serum electrolytes (↓Na⁺, ↑K⁺, acidosis); plasma renin activity (high); plasma aldosterone (low/inappropriately normal); multisteroid profiling showing elevated DOC, corticosterone, 18-OHDOC, and the pathognomonic high 18-OHB/aldosterone ratio (CMO II); normal cortisol. Genetic testing: CYP11B2 single-gene sequencing or targeted adrenal/steroidogenesis gene panels; WES/WGS for atypical cases — with careful handling of CYP11B1 homology. Clinical criteria: salt-wasting symptoms + no skin pigmentation + the laboratory profile above (Finding 9). Differential diagnosis: PHA1 (high aldosterone, resistance), salt-wasting CAH / 21-hydroxylase deficiency (low cortisol, virilization, hyperpigmentation), secondary PHA (renal/urologic disease, UTI/reflux). Screening: cascade/carrier testing in affected families and founder populations.

11. Outcome / Prognosis

Excellent with early recognition and mineralocorticoid replacement: normal growth and development, catch-up growth within ~2 months. Mortality: untreated infantile salt-wasting crises can be fatal. Morbidity: minimal once treated. Prognostic factors: timeliness of diagnosis and treatment; CMO subtype. Long-term, many patients achieve treatment-free clinical remission while retaining a subclinical enzyme defect.

12. Treatment

Mainstay: fludrocortisone (synthetic mineralocorticoid; NCIT: Fludrocortisone), ± sodium chloride supplementation in infancy. Corrects electrolytes, restores volume, enables catch-up growth. Pharmacogenomics / advanced/gene/cell/RNA therapies: none established or required — the disorder is managed effectively by hormone replacement. Treatment strategy: initiate in infancy, titrate to electrolytes/renin/growth, and attempt supervised discontinuation in mid-childhood once salt tolerance and renal sensitivity mature. Adverse events: standard mineralocorticoid excess risks (hypertension, hypokalemia) if overdosed — monitored by electrolytes and blood pressure.

13. Prevention

No primary prevention (monogenic). Secondary prevention: early detection and prompt fludrocortisone prevent crises and failure to thrive. Genetic counseling / screening: autosomal recessive counseling, carrier and cascade testing in founder/consanguineous families; prenatal/preimplantation options where a familial variant is known. Tertiary prevention: electrolyte monitoring and salt management to prevent recurrent crises.

14. Other Species / Natural Disease

Human disease (NCBI Taxon 9606). Murine models of aldosterone synthase deficiency (aldosterone synthase-deficient mice) are used experimentally to study renal potassium/sodium handling (e.g., tissue-kallikrein and NCC studies). Orthologous gene: mouse Cyp11b2. No prominent naturally occurring companion-animal counterpart is established in the reviewed literature.

15. Model Organisms

Mouse is the principal model: aldosterone synthase (Cyp11b2)-deficient mice recapitulate aldosterone-independent physiology and have been used to dissect distal-nephron potassium handling and renal adaptation (e.g., PMID 20624970 used aldosterone synthase-deficient mice to show aldosterone-independent control of tissue kallikrein). In vitro: heterologous expression in cultured mammalian cells and fission yeast (S. pombe) enables steroid-bioconversion assays to functionally classify CYP11B2 variants (PMID 21237269). Applications: variant functional characterization, steroidogenesis pathway dissection, renal electrolyte physiology. Limitations: rodent adrenal zonation and steroid profiles differ from humans; in vitro systems isolate enzymatic activity but not whole-organism salt handling.

Evidence Base

PMID	Title (abbrev.)	Supports
15134805	Aldosterone synthase deficiency and related disorders	<1% residual activity threshold; overview
9814506	Isolated ASD caused by E198D and V386A	CMO I vs II biochemistry; elevated precursors
41229259	ASD with coexisting celiac disease	Orphan, lethal infantile electrolyte imbalance; zona glomerulosa mitochondrial synthesis
22931312	Homozygous CYP11B2 in infant with CMO II	High renin/normal aldosterone; 18-OHB/aldo ratio; fludrocortisone + discontinuation at 9y
9838244	Homozygous deletion of Arg-173, CMO II	Infantile onset; hyponatremia, hyperkalemia, high renin
41905953	Congenital aldosterone deficiency and its resistance	Isolated deficiency; PHA1 differential; formal diagnostic criteria
8481357	11β-hydroxylase/CMO-II in Jews of Morocco/Iran	1/4,000 incidence in Iranian Jews
1594605	CYP11B2 mutations causing CMO II	R181W + V386A founder variants; additive two-variant requirement; functional data
21237269	S. pombe system for CMO-causing mutations	Three-step enzymatic mechanism; yeast functional assay
37827219	CYP11B2 inhibition by dexfadrostat	Heme/substrate-pocket active-site structure
34415991	Catch-up growth and discontinuation of fludrocortisone in ASD	Cohort demographics; catch-up growth; discontinuation; persistent biochemical defect; variant spectrum
33438832	CYP11B2 deficiency in Palestinian infants	Frameshift/missense/nonsense variants; consanguinity; genetic heterogeneity
39700478	Cracking the code of ASD: genetics and biochemistry	CYP11B1 homology sequencing pitfall

Supporting/contextual literature also reviewed: PMID 32539318 (CMO II novel mutations), 41426917 (ASD type I novel variant, neonate), 37332400 (CMO1 case reports), 35848593 (novel CYP11B2 variant), 15179565 and 22764468 (differential diagnosis: selective hypoaldosteronism vs PHA1), 38324138 and 38027139 (chimeric CYP11B1/CYP11B2 alleles), 41709876 (rare CAH subtypes including ASD), 6507399 (Iranian-Jewish CMO II child). Several RAAS/renal-physiology and mouse-model papers (e.g., 20624970, 23447069, 20049674) provide mechanistic context for aldosterone action and model-organism applications.

Limitations and Knowledge Gaps

Small evidence base. The disorder is ultra-rare; most data come from single kindreds, founder cohorts, and one 16-patient multicenter series. There are no large-scale prevalence, incidence, or outcome datasets outside founder populations.
Downstream nephron step is inferred. The loss of MR→ENaC signaling in the distal nephron is drawn from general mineralocorticoid physiology rather than disease-specific tissue studies in ASD patients.
Genotype–phenotype relationships are incompletely resolved. The boundary between CMO I and CMO II is biochemical and allele-dependent, and some variants produce intermediate phenotypes; residual-activity thresholds are approximate.
Quality-of-life and long-term outcome data are sparse. Formal QoL instruments (EQ-5D, SF-36, PROMIS) have not been applied; long-term adult outcomes after childhood remission are under-characterized.
No omics-scale molecular profiling (transcriptomic/proteomic/metabolomic) specific to ASD adrenal tissue was identified; mechanism rests on enzymology and steroid biochemistry.
Diagnostic homology pitfall (CYP11B2/CYP11B1 ~95% identity) may cause under- or mis-diagnosis in laboratories not using homology-aware methods.

Proposed Follow-up Experiments / Actions

Build an international ASD registry capturing genotype, steroid profiles (including 18-OHB/aldosterone ratio), treatment course, age at discontinuation, and long-term adult outcomes to firm up natural history and penetrance/expressivity.
Systematic functional classification of all reported CYP11B2 variants in a standardized assay (e.g., S. pombe or mammalian expression) to produce a quantitative residual-activity ladder predicting CMO I vs II vs intermediate phenotypes.
Homology-aware diagnostic protocols (long-read sequencing, MLPA/CNV analysis) to resolve CYP11B1/CYP11B2 chimeras and prevent misclassification; validate against known founder haplotypes.
Prospective QoL and growth outcome study using standardized instruments, including after treatment discontinuation, to document remission durability and any late relapse risk.
Mechanistic confirmation of the distal-nephron step in patient-derived or model systems (e.g., renal organoids/iPSC-derived tubular cells) to move the MR→ENaC step from inferred to demonstrated.
Carrier-screening evaluation in founder/consanguineous populations (Iranian-Jewish, Palestinian, Turkish, Arab cohorts) to quantify carrier frequency and inform genetic counseling and prenatal/preimplantation options.

Report compiled from 9 confirmed findings and 38 reviewed papers over 5 investigation iterations. Evidence types span human clinical case reports/series, in vitro functional expression assays, structural biology, and model-organism studies.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	14
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	24
Resolved	24
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	11
Terms named correctly	1
Terms named as a different term	9
Terms whose name is worth a second look	1

Terms the report names something else

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

HP:0002902 (2 mentions) - the report calls it "Lab abnormality"; HP calls it Hyponatremia
HP:0002153 (2 mentions) - the report calls it "Lab abnormality"; HP calls it Hyperkalemia
HP:0001942 (2 mentions) - the report calls it "Lab abnormality"; HP calls it Metabolic acidosis
HP:0001508 (2 mentions) - the report calls it "Clinical sign"; HP calls it Failure to thrive
HP:0001944 (2 mentions) - the report calls it "Clinical sign"; HP calls it Dehydration
HP:0002013 (2 mentions) - the report calls it "Symptom"; HP calls it Vomiting
HP:0011046 (2 mentions) - the report calls it "Lab abnormality"; HP calls it Agenesis of primary maxillary central incisor
HP:0000848 (2 mentions) - the report calls it "Lab abnormality"; HP calls it Increased circulating renin concentration
UBERON:0001228 (2 mentions) - the report calls it "adrenal cortex zona glomerulosa"; UBERON calls it renal papilla

Terms whose name is worth a second look

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

GO:0005739 (2 mentions) - the report calls it "mitochondrion", "Subcellular compartment: mitochondrion"; GO calls it mitochondrion

Terms named inconsistently

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

GO:0005739 - called "mitochondrion", "Subcellular compartment: mitochondrion"

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Source YAML

References & Deep Research

Deep Research

Key Findings

Finding 1 — CYP11B2 loss of function causes isolated aldosterone deficiency

Finding 2 — Clinical presentation: neonatal/infantile salt wasting with a high-renin, low-aldosterone profile

Finding 3 — Diagnosis by steroid profiling and CYP11B2 sequencing; treatment with fludrocortisone is highly effective and often discontinuable

Finding 4 — Pathophysiology and differential diagnosis

Finding 5 — Epidemiology and founder mutations (Jews of Iranian origin, ~1/4,000)

Finding 6 — Enzyme biochemistry: a three-step mitochondrial P450 reaction

Finding 7 — Natural history and prognosis (multicenter cohort data)

Finding 8 — Variant spectrum and the CYP11B1 homology pitfall

Finding 9 — Formal diagnostic criteria separate ASD from PHA1 and CAH

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

Compact pathway diagram

Ontology term suggestions

Section-by-Section Characterization

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently