Cortisone Reductase Deficiency

Mendelian MONDO:0000193 Pathograph 25 Adrenogenital Syndrome Steroid Metabolism Disease

Cortisone reductase deficiency is a rare inherited endocrine disorder in which active cortisol is not efficiently regenerated from cortisone by the endoplasmic-reticulum 11beta-HSD1/H6PD system. Reduced local cortisol regeneration increases hypothalamic-pituitary-adrenal-axis drive and causes adrenal hyperandrogenism, presenting with premature adrenarche, precocious pseudopuberty or menstrual/reproductive dysfunction.

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1
Mappings
1
Definitions
2
Inheritance
4
Pathophys.
14
Phenotypes
25
Pathograph
2
Genes
1
Treatments
2
Subtypes
1
Deep Research
🔗

Mappings

MONDO
MONDO:0000193 cortisone reductase deficiency
skos:exactMatch Orphanet ORPHA:168588
Orphanet ORPHA:168588 lists MONDO:0000193 as an exact cross-reference for hyperandrogenism due to cortisone reductase deficiency.
📘

Definitions

1
Orphanet cortisone reductase deficiency definition
A rare genetic endocrine disorder with defective conversion of cortisone to active cortisol, causing ACTH-mediated adrenal androgen excess.
OTHER
Show evidence (2 references)
ORPHA:168588 SUPPORT Other
"A rare, genetic, endocrine disease characterized by defect in conversion of cortisone to active cortisol, resulting in ACTH-mediated excessive androgen release from adrenal glands."
Orphanet defines the central steroid-metabolism defect and endocrine consequence.
PMID:21325058 SUPPORT Human Clinical
"Loss of this activity results in a disorder termed cortisone reductase deficiency (CRD), typified by increased cortisol clearance and androgen excess."
The HSD11B1 mutation report summarizes the clinical biochemical syndrome.
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
Heterozygous dominant-negative HSD11B1 mutations can cause cortisone reductase deficiency.
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:168588 SUPPORT Other
"Autosomal dominant"
Orphanet lists autosomal dominant inheritance.
PMID:21325058 SUPPORT Human Clinical
"these heterozygous mutations in the HSD11B1 gene have a dominant negative effect on the formation of functional dimers and explain the genetic cause of CRD in these patients."
The patient and functional study supports dominant-negative HSD11B1 inheritance.
Autosomal recessive inheritance HP:0000007
Biallelic H6PD loss-of-function variants can cause apparent cortisone reductase deficiency by impairing endoplasmic-reticulum NADPH generation.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:168588 SUPPORT Other
"Autosomal recessive"
Orphanet lists autosomal recessive inheritance.
PMID:23132696 SUPPORT Human Clinical
"Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD."
Compound heterozygous H6PD variants in affected children support recessive H6PD-related disease.
◆

Subtypes

2
HSD11B1-related true cortisone reductase deficiency
HSD11B1 link
Cortisone reductase deficiency caused by HSD11B1 variants that directly reduce 11beta-HSD1 expression, folding, dimer formation, or oxoreductase activity.
Show evidence (1 reference)
PMID:23132696 SUPPORT Human Clinical
"Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD)."
The clinical diagnostic paper distinguishes HSD11B1-related true CRD.
H6PD-related apparent cortisone reductase deficiency
H6PD link
Apparent cortisone reductase deficiency caused by H6PD variants that reduce endoplasmic-reticulum NADPH supply for 11beta-HSD1 oxoreductase activity.
Show evidence (1 reference)
PMID:23132696 SUPPORT Human Clinical
"Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH, encoded by H6PD) cause apparent cortisone reductase deficiency (ACRD)."
The clinical diagnostic paper distinguishes H6PD-related apparent CRD.
⚙

Pathophysiology

4
HSD11B1 Oxoreductase Loss
HSD11B1 variants reduce 11beta-HSD1 abundance, dimer assembly, or catalytic activity, directly impairing cortisone-to-cortisol reduction.
HSD11B1 link
glucocorticoid metabolic process link ↓ DECREASED
endoplasmic reticulum link
Downstream
Impaired Cortisone-to-Cortisol Regeneration
Show evidence (2 references)
PMID:21325058 SUPPORT Human Clinical
"Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of HSD11B1."
The report identifies HSD11B1 variants in patients with biochemical CRD.
PMID:21325058 SUPPORT In Vitro
"Expression of either mutant in a bacterial system greatly reduced the yield of soluble protein, suggesting that both mutations interfere with subunit folding or dimer assembly."
In vitro expression supports folding/dimer assembly defects as the molecular mechanism.
H6PD Endoplasmic-Reticulum NADPH Generation Failure
H6PD loss of function reduces NADPH generation in the endoplasmic reticulum, which is required to drive 11beta-HSD1 in the cortisone-to-cortisol oxoreductase direction.
H6PD link
glucocorticoid metabolic process link ↓ DECREASED
endoplasmic reticulum link
Downstream
Impaired Cortisone-to-Cortisol Regeneration
Show evidence (3 references)
PMID:23132696 SUPPORT Human Clinical
"H6PDH generates cofactor NADPH for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol."
This identifies the H6PDH cofactor-supply role in 11beta-HSD1 cortisol regeneration.
PMID:12858176 SUPPORT Human Clinical
"Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity."
The original genetics study links H6PD mutations to reduced or absent H6PDH activity in individuals with CRD.
PMID:18628520 SUPPORT In Vitro
"Expression and activity assays demonstrate loss of function for all reported H6PDH mutations."
Functional assays support loss of H6PDH activity as the mechanism for H6PD-related CRD.
Impaired Cortisone-to-Cortisol Regeneration
The common biochemical lesion is reduced reduction of inactive cortisone to active cortisol in peripheral glucocorticoid target tissues, increasing cortisol clearance and weakening tissue glucocorticoid regeneration.
glucocorticoid metabolic process link ↓ DECREASED
endoplasmic reticulum link
Downstream
ACTH-Mediated Adrenal Hyperandrogenism
Show evidence (2 references)
PMID:21325058 SUPPORT Other
"In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum."
This mechanistic background supports the cortisone-to-cortisol regeneration step.
PMID:29843121 SUPPORT Other
"The 11-HSD1 isozyme functions mainly as an oxoreductase (cortisone to cortisol) and is expressed at high levels in the liver and other glucocorticoid target tissues."
Review evidence summarizes the normal 11-HSD1 cortisone-to-cortisol direction.
ACTH-Mediated Adrenal Hyperandrogenism
Inadequate cortisol regeneration stimulates hypothalamic-pituitary-adrenal activation and adrenal cortical steroidogenesis, producing adrenal androgen excess and related reproductive and developmental phenotypes.
steroid biosynthetic process link ↑ INCREASED
adrenal cortex link
Downstream
Increased circulating androgen concentration
Congenital adrenal hyperplasia
Premature adrenarche
Precocious puberty
Hirsutism
Irregular menstruation
Infertility
Central obesity
Tall stature
Elevated serum 11-deoxycortisol
Abnormal circulating deoxycorticosterone level
Hypertension
Hypokalemia
Decreased circulating renin concentration
Show evidence (2 references)
ORPHA:168588 SUPPORT Other
"A rare, genetic, endocrine disease characterized by defect in conversion of cortisone to active cortisol, resulting in ACTH-mediated excessive androgen release from adrenal glands."
Orphanet directly states the ACTH-mediated adrenal androgen mechanism.
PMID:29843121 SUPPORT Other
"Mutations in the corresponding HSD11B1 gene, or in the H6PD gene encoding hexose-6-phosphate dehydrogenase (which supplies the NADPH required for the oxoreductase activity of 11-HSD1), cause apparent cortisone reductase deficiency, a rare syndrome of adrenocortical hyperactivity and hyperandrogenism."
Review evidence links HSD11B1/H6PD disruption to adrenocortical hyperactivity and hyperandrogenism.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cortisone Reductase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Cardiovascular 1
Hypertension FREQUENT Hypertension (HP:0000822)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"HP:0000822 | Hypertension | Frequent (79-30%)"
Orphanet lists hypertension as frequent.
Genitourinary 2
Irregular menstruation FREQUENT Irregular menstruation (HP:0000858)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"HP:0000858 | Irregular menstruation | Frequent (79-30%)"
Orphanet lists irregular menstruation as frequent.
Infertility Infertility (HP:0000789)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"hirsutism, oligoamenorrhea, central obesity and infertility in females."
Orphanet lists infertility among female manifestations.
Integument 1
Hirsutism Hirsutism (HP:0001007)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"hirsutism, oligoamenorrhea, central obesity and infertility in females."
Orphanet lists hirsutism among female manifestations.
Metabolism 1
Hypokalemia OCCASIONAL Hypokalemia (HP:0002900)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"HP:0002900 | Hypokalemia | Occasional (29-5%)"
Orphanet lists hypokalemia as occasional.
Growth 1
Tall stature Tall stature (HP:0000098)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"proportionate tall stature and accelerated bone maturation in males"
Orphanet describes tall stature and accelerated bone maturation in affected males.
Other 8
Precocious puberty OCCASIONAL Precocious puberty (HP:0000826)
Show evidence (2 references)
ORPHA:168588 SUPPORT Other
"HP:0000826 | Precocious puberty | Occasional (29-5%)"
Orphanet lists precocious puberty as occasional.
ORPHA:168588 SUPPORT Other
"Premature adrenarche is typical with precocious pseudopuberty"
The Orphanet definition describes precocious pseudopuberty.
Decreased circulating renin concentration OCCASIONAL Decreased circulating renin concentration (HP:0003351)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"HP:0003351 | Decreased circulating renin concentration | Occasional (29-5%)"
Orphanet lists decreased circulating renin concentration as occasional.
Congenital adrenal hyperplasia FREQUENT Congenital adrenal hyperplasia (HP:0008258)
Show evidence (2 references)
ORPHA:168588 SUPPORT Other
"HP:0008258 | Congenital adrenal hyperplasia | Frequent (79-30%)"
Orphanet lists congenital adrenal hyperplasia as frequent.
ORPHA:168588 SUPPORT Other
"Imaging studies may indicate adrenal hyperplasia."
The Orphanet definition supports adrenal hyperplasia as an imaging finding.
Premature adrenarche OCCASIONAL Premature adrenarche (HP:0012412)
Show evidence (2 references)
ORPHA:168588 SUPPORT Other
"HP:0012412 | Premature adrenarche | Occasional (29-5%)"
Orphanet lists premature adrenarche as occasional.
PMID:23132696 SUPPORT Human Clinical
"To describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases."
The clinical paper reports pediatric ACRD/CRD cases presenting in the context of premature adrenarche.
Elevated serum 11-deoxycortisol FREQUENT Elevated serum 11-deoxycortisol (HP:0025436)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"HP:0025436 | Elevated serum 11-deoxycortisol | Frequent (79-30%)"
Orphanet lists elevated serum 11-deoxycortisol as frequent.
Increased circulating androgen concentration FREQUENT Increased circulating androgen concentration (HP:0030348)
Show evidence (2 references)
ORPHA:168588 SUPPORT Other
"HP:0030348 | Increased circulating androgen concentration | Frequent (79-30%)"
Orphanet lists increased circulating androgen concentration as frequent.
PMID:23132696 SUPPORT Human Clinical
"Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism."
Human clinical evidence supports adrenal hyperandrogenism in both molecular forms.
Abnormal circulating deoxycorticosterone level FREQUENT Abnormal circulating deoxycorticosterone level (HP:0031186)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"HP:0031186 | Abnormal circulating deoxycorticosterone level | Frequent (79-30%)"
Orphanet lists abnormal circulating deoxycorticosterone level as frequent.
Central obesity Abdominal obesity (HP:0012743)
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"hirsutism, oligoamenorrhea, central obesity and infertility in females."
Orphanet lists central obesity; HP:0012743 has Central obesity as an exact synonym.
🧬

Genetic Associations

2
HSD11B1 (Causative)
Show evidence (2 references)
ORPHA:168588 SUPPORT Other
"HSD11B1 | hydroxysteroid 11-beta dehydrogenase 1 | hgnc:5208 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists HSD11B1 loss-of-function germline variants as disease causing.
PMID:21325058 SUPPORT Human Clinical
"Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of HSD11B1."
The report identifies heterozygous HSD11B1 missense variants in CRD cases.
H6PD (Causative)
Show evidence (3 references)
ORPHA:168588 SUPPORT Other
"H6PD | hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase | hgnc:4795 | Disease-causing germline mutation(s) (loss of function) in"
Orphanet lists H6PD loss-of-function germline variants as disease causing.
PMID:23132696 SUPPORT Human Clinical
"Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD."
The clinical report identifies compound heterozygous H6PD variants in affected children.
PMID:18628520 SUPPORT Human Clinical
"Three cases were identified as homozygous (R109AfsX3, Y316X, and G359D) and one case identified as compound heterozygous (c.960G-->A and D620fsX3) for mutations in H6PD."
Human CRD cases with homozygous or compound heterozygous H6PD variants support H6PD as a causal gene.
💊

Treatments

1
Dexamethasone adrenal androgen suppression
Action: hormone modifying therapy MAXO:0000283
Agent: dexamethasone ↗
Low-dose dexamethasone can suppress ACTH-driven adrenal androgen excess in apparent cortisone reductase deficiency. Hydrocortisone may be ineffective in ACRD because it is rapidly converted to cortisone.
Mechanism Target:
INHIBITS ACTH-Mediated Adrenal Hyperandrogenism — Dexamethasone suppresses adrenal androgen synthesis downstream of HPA-axis activation.
Show evidence (2 references)
PMID:12649576 SUPPORT Human Clinical
"Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression."
The pediatric ACRD case directly supports dexamethasone suppression of the adrenal androgen branch.
PMID:29073307 SUPPORT Human Clinical
"Control laboratory studies indicated suppression of excess adrenal androgen synthesis, but we never got the THF + allo-THF/THE ratio in normal values."
Longitudinal follow-up supports dexamethasone suppression of excess adrenal androgen synthesis.
Target Phenotypes: Increased circulating androgen concentration ↗ Precocious puberty ↗
Show evidence (3 references)
PMID:29073307 SUPPORT Human Clinical
"Control laboratory studies indicated suppression of excess adrenal androgen synthesis, but we never got the THF + allo-THF/THE ratio in normal values."
Longitudinal human follow-up supports dexamethasone suppression of adrenal androgen synthesis, while not normalizing the diagnostic steroid ratio.
PMID:29073307 SUPPORT Human Clinical
"Hydrocortisone treatment is ineffective in ACRD patients because it was rapidly metabolized to cortisone."
This supports the treatment caveat that hydrocortisone is a poor substitute for dexamethasone in ACRD.
PMID:12649576 SUPPORT Human Clinical
"Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression."
The first pediatric case report supports dexamethasone as a human treatment that suppresses androgen excess.
🔬

Biochemical Markers

4
Cortisol regeneration from cortisone (DECREASED)
Context: The defining biochemical defect is reduced 11beta-HSD1-dependent reduction of cortisone to active cortisol in the endoplasmic reticulum.
Pathograph Readouts
Readout Of Impaired Cortisone-to-Cortisol Regeneration Negative Diagnostic
Decreased cortisone-to-cortisol regeneration reports the defining enzymatic defect in CRD/ACRD.
Show evidence (1 reference)
PMID:12858176 SUPPORT Human Clinical
"In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur"
This directly supports the deficient cortisol-regeneration readout.
Show evidence (1 reference)
PMID:21325058 SUPPORT Other
"a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum."
This identifies the biochemical reaction that is deficient in CRD.
Cortisone substrate handling (ABNORMAL)
Context: Impaired reduction of cortisone to cortisol leaves cortisone activation abnormal and is captured diagnostically by urinary steroid metabolite profiling.
Pathograph Readouts
Readout Of Impaired Cortisone-to-Cortisol Regeneration Threshold Dependent Diagnostic
Abnormal cortisone handling and urinary steroid ratios report impaired conversion of cortisone to cortisol.
Show evidence (1 reference)
PMID:23132696 SUPPORT Human Clinical
"Steroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD."
Urinary steroid profiling is a diagnostic readout of the impaired cortisone-reduction mechanism.
Show evidence (1 reference)
PMID:12858176 SUPPORT Human Clinical
"In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur"
Human CRD genetics paper directly states failed cortisone activation.
Circulating androgen (INCREASED)
Context: ACTH-mediated adrenal steroidogenesis produces the androgen-excess state that drives many clinical manifestations.
Pathograph Readouts
Readout Of ACTH-Mediated Adrenal Hyperandrogenism Positive Diagnostic
Increased circulating androgens report the ACTH-mediated adrenal hyperandrogenism branch of CRD.
Show evidence (1 reference)
PMID:23132696 SUPPORT Human Clinical
"Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism."
Human clinical evidence identifies adrenal hyperandrogenism in both molecular forms of CRD.
Show evidence (1 reference)
PMID:29843121 SUPPORT Other
"a rare syndrome of adrenocortical hyperactivity and hyperandrogenism."
Review evidence supports androgen excess downstream of HSD11B1/H6PD disruption.
Serum 11-deoxycortisol (INCREASED)
Context: Elevated 11-deoxycortisol is an Orphanet-listed biochemical phenotype.
Pathograph Readouts
Readout Of ACTH-Mediated Adrenal Hyperandrogenism Positive Diagnostic
Elevated 11-deoxycortisol reports the adrenal steroid-profile disturbance accompanying ACTH-mediated steroidogenesis.
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"HP:0025436 | Elevated serum 11-deoxycortisol | Frequent (79-30%)"
Orphanet lists elevated serum 11-deoxycortisol as a frequent biochemical phenotype.
Show evidence (1 reference)
ORPHA:168588 SUPPORT Other
"HP:0025436 | Elevated serum 11-deoxycortisol | Frequent (79-30%)"
Orphanet lists elevated serum 11-deoxycortisol as frequent.
{ }

Source YAML

click to show 
name: Cortisone Reductase Deficiency
category: Mendelian
creation_date: "2026-05-10T08:04:01Z"
updated_date: "2026-05-19T06:48:06Z"
synonyms:
- Hyperandrogenism due to cortisone reductase deficiency
- 11-beta-hydroxysteroid dehydrogenase deficiency type 1
- Apparent cortisone reductase deficiency
- CRD
- ACRD
description: >
  Cortisone reductase deficiency is a rare inherited endocrine disorder in
  which active cortisol is not efficiently regenerated from cortisone by the
  endoplasmic-reticulum 11beta-HSD1/H6PD system. Reduced local cortisol
  regeneration increases hypothalamic-pituitary-adrenal-axis drive and causes
  adrenal hyperandrogenism, presenting with premature adrenarche, precocious
  pseudopuberty or menstrual/reproductive dysfunction.
disease_term:
  preferred_term: cortisone reductase deficiency
  term:
    id: MONDO:0000193
    label: cortisone reductase deficiency
parents:
- Adrenogenital Syndrome
- Steroid Metabolism Disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000193
      label: cortisone reductase deficiency
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:168588
    mapping_justification: >
      Orphanet ORPHA:168588 lists MONDO:0000193 as an exact cross-reference
      for hyperandrogenism due to cortisone reductase deficiency.
external_assertions:
- name: Orphanet cortisone reductase deficiency disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:168588
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=168588
  description: >
    Orphanet's ORPHA:168588 structured record provides the exact MONDO mapping,
    definition, inheritance, disease genes, prevalence, and HPO phenotype rows
    used as structured evidence for this entry.
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0000193 | Exact"
    explanation: Orphanet maps ORPHA:168588 exactly to MONDO:0000193.
definitions:
- name: Orphanet cortisone reductase deficiency definition
  definition_type: OTHER
  description: >
    A rare genetic endocrine disorder with defective conversion of cortisone to
    active cortisol, causing ACTH-mediated adrenal androgen excess.
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare, genetic, endocrine disease characterized by defect in conversion of cortisone to active cortisol, resulting in ACTH-mediated excessive androgen release from adrenal glands."
    explanation: Orphanet defines the central steroid-metabolism defect and endocrine consequence.
  - reference: PMID:21325058
    reference_title: "Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of this activity results in a disorder termed cortisone reductase deficiency (CRD), typified by increased cortisol clearance and androgen excess."
    explanation: The HSD11B1 mutation report summarizes the clinical biochemical syndrome.
inheritance:
- name: Autosomal dominant inheritance
  description: >
    Heterozygous dominant-negative HSD11B1 mutations can cause cortisone
    reductase deficiency.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet lists autosomal dominant inheritance.
  - reference: PMID:21325058
    reference_title: "Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these heterozygous mutations in the HSD11B1 gene have a dominant negative effect on the formation of functional dimers and explain the genetic cause of CRD in these patients."
    explanation: The patient and functional study supports dominant-negative HSD11B1 inheritance.
- name: Autosomal recessive inheritance
  description: >
    Biallelic H6PD loss-of-function variants can cause apparent cortisone
    reductase deficiency by impairing endoplasmic-reticulum NADPH generation.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet lists autosomal recessive inheritance.
  - reference: PMID:23132696
    reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD."
    explanation: Compound heterozygous H6PD variants in affected children support recessive H6PD-related disease.
has_subtypes:
- name: True CRD
  display_name: HSD11B1-related true cortisone reductase deficiency
  description: >
    Cortisone reductase deficiency caused by HSD11B1 variants that directly
    reduce 11beta-HSD1 expression, folding, dimer formation, or oxoreductase
    activity.
  genes:
  - preferred_term: HSD11B1
    term:
      id: hgnc:5208
      label: HSD11B1
  evidence:
  - reference: PMID:23132696
    reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inactivating mutations in HSD11B1 cause true cortisone reductase deficiency (CRD)."
    explanation: The clinical diagnostic paper distinguishes HSD11B1-related true CRD.
- name: Apparent CRD
  display_name: H6PD-related apparent cortisone reductase deficiency
  description: >
    Apparent cortisone reductase deficiency caused by H6PD variants that reduce
    endoplasmic-reticulum NADPH supply for 11beta-HSD1 oxoreductase activity.
  genes:
  - preferred_term: H6PD
    term:
      id: hgnc:4795
      label: H6PD
  evidence:
  - reference: PMID:23132696
    reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inactivating mutations in the enzyme hexose-6-phosphate dehydrogenase (H6PDH, encoded by H6PD) cause apparent cortisone reductase deficiency (ACRD)."
    explanation: The clinical diagnostic paper distinguishes H6PD-related apparent CRD.
pathophysiology:
- name: HSD11B1 Oxoreductase Loss
  description: >
    HSD11B1 variants reduce 11beta-HSD1 abundance, dimer assembly, or catalytic
    activity, directly impairing cortisone-to-cortisol reduction.
  role: Primary
  genes:
  - preferred_term: HSD11B1
    term:
      id: hgnc:5208
      label: HSD11B1
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  biological_processes:
  - preferred_term: glucocorticoid metabolic process
    term:
      id: GO:0008211
      label: glucocorticoid metabolic process
    modifier: DECREASED
  downstream:
  - target: Impaired Cortisone-to-Cortisol Regeneration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21325058
      reference_title: "Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "On expression of the mutants in bacterial and mammalian cells, activity was either abolished (K187N) or greatly reduced (R137C)."
      explanation: Functional expression data directly support reduced 11beta-HSD1 activity from disease-associated HSD11B1 variants.
  evidence:
  - reference: PMID:21325058
    reference_title: "Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of HSD11B1."
    explanation: The report identifies HSD11B1 variants in patients with biochemical CRD.
  - reference: PMID:21325058
    reference_title: "Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of either mutant in a bacterial system greatly reduced the yield of soluble protein, suggesting that both mutations interfere with subunit folding or dimer assembly."
    explanation: In vitro expression supports folding/dimer assembly defects as the molecular mechanism.
- name: H6PD Endoplasmic-Reticulum NADPH Generation Failure
  description: >
    H6PD loss of function reduces NADPH generation in the endoplasmic reticulum,
    which is required to drive 11beta-HSD1 in the cortisone-to-cortisol
    oxoreductase direction.
  role: Primary
  genes:
  - preferred_term: H6PD
    term:
      id: hgnc:4795
      label: H6PD
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  biological_processes:
  - preferred_term: glucocorticoid metabolic process
    term:
      id: GO:0008211
      label: glucocorticoid metabolic process
    modifier: DECREASED
  downstream:
  - target: Impaired Cortisone-to-Cortisol Regeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced H6PDH activity lowers endoplasmic-reticulum NADPH regeneration required for 11beta-HSD1 oxoreductase activity.
    evidence:
    - reference: PMID:23132696
      reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mutant expression studies confirmed loss of H6PDH activity in both cases."
      explanation: Functional testing supports loss of H6PDH activity in H6PD-related apparent CRD.
  evidence:
  - reference: PMID:23132696
    reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "H6PDH generates cofactor NADPH for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by HSD11B1) oxo-reductase activity, converting cortisone to cortisol."
    explanation: This identifies the H6PDH cofactor-supply role in 11beta-HSD1 cortisol regeneration.
  - reference: PMID:12858176
    reference_title: "Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity."
    explanation: The original genetics study links H6PD mutations to reduced or absent H6PDH activity in individuals with CRD.
  - reference: PMID:18628520
    reference_title: "Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression and activity assays demonstrate loss of function for all reported H6PDH mutations."
    explanation: Functional assays support loss of H6PDH activity as the mechanism for H6PD-related CRD.
- name: Impaired Cortisone-to-Cortisol Regeneration
  description: >
    The common biochemical lesion is reduced reduction of inactive cortisone to
    active cortisol in peripheral glucocorticoid target tissues, increasing
    cortisol clearance and weakening tissue glucocorticoid regeneration.
  biological_processes:
  - preferred_term: glucocorticoid metabolic process
    term:
      id: GO:0008211
      label: glucocorticoid metabolic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  downstream:
  - target: ACTH-Mediated Adrenal Hyperandrogenism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced cortisol regeneration increases cortisol clearance and hypothalamic-pituitary-adrenal-axis drive.
    evidence:
    - reference: PMID:12858176
      reference_title: "Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2)."
      explanation: The genetics study directly links failed cortisone activation to ACTH-mediated androgen excess.
  evidence:
  - reference: PMID:21325058
    reference_title: "Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum."
    explanation: This mechanistic background supports the cortisone-to-cortisol regeneration step.
  - reference: PMID:29843121
    reference_title: "Alterations of Cortisol Metabolism in Human Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The 11-HSD1 isozyme functions mainly as an oxoreductase (cortisone to cortisol) and is expressed at high levels in the liver and other glucocorticoid target tissues."
    explanation: Review evidence summarizes the normal 11-HSD1 cortisone-to-cortisol direction.
- name: ACTH-Mediated Adrenal Hyperandrogenism
  description: >
    Inadequate cortisol regeneration stimulates hypothalamic-pituitary-adrenal
    activation and adrenal cortical steroidogenesis, producing adrenal androgen
    excess and related reproductive and developmental phenotypes.
  biological_processes:
  - preferred_term: steroid biosynthetic process
    term:
      id: GO:0006694
      label: steroid biosynthetic process
    modifier: INCREASED
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  downstream:
  - target: Increased circulating androgen concentration
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0030348 | Increased circulating androgen concentration | Frequent (79-30%)"
      explanation: Orphanet lists increased circulating androgen concentration as frequent.
  - target: Congenital adrenal hyperplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - ACTH-mediated adrenal stimulation can be accompanied by adrenal hyperplasia on imaging.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Imaging studies may indicate adrenal hyperplasia."
      explanation: Orphanet describes adrenal hyperplasia as a possible imaging finding.
  - target: Premature adrenarche
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Excess adrenal androgen exposure accelerates adrenarche.
    evidence:
    - reference: PMID:23132696
      reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism."
      explanation: The clinical paper links CRD/ACRD to HPA-axis activation and adrenal hyperandrogenism.
  - target: Precocious puberty
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Excess adrenal androgen exposure causes precocious pseudopuberty.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Premature adrenarche is typical with precocious pseudopuberty"
      explanation: Orphanet directly links the CRD hyperandrogenic state to precocious pseudopuberty.
  - target: Hirsutism
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "hirsutism, oligoamenorrhea, central obesity and infertility in females."
      explanation: Orphanet lists hirsutism among female manifestations of CRD hyperandrogenism.
  - target: Irregular menstruation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Adrenal androgen excess disrupts menstrual cycling.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "hirsutism, oligoamenorrhea, central obesity and infertility in females."
      explanation: Orphanet's oligoamenorrhea statement supports the irregular-menstruation phenotype.
  - target: Infertility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hyperandrogenic reproductive dysfunction can impair fertility.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "hirsutism, oligoamenorrhea, central obesity and infertility in females."
      explanation: Orphanet lists infertility among female manifestations of CRD.
  - target: Central obesity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "hirsutism, oligoamenorrhea, central obesity and infertility in females."
      explanation: Orphanet lists central obesity among female manifestations of CRD.
  - target: Tall stature
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Premature androgen exposure accelerates growth and bone maturation.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "proportionate tall stature and accelerated bone maturation in males"
      explanation: Orphanet connects the male CRD phenotype to tall stature and accelerated bone maturation.
  - target: Elevated serum 11-deoxycortisol
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - ACTH-driven adrenal steroidogenesis alters steroid precursor concentrations.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0025436 | Elevated serum 11-deoxycortisol | Frequent (79-30%)"
      explanation: Orphanet lists elevated serum 11-deoxycortisol as a frequent CRD biochemical phenotype.
  - target: Abnormal circulating deoxycorticosterone level
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - ACTH-driven adrenal steroidogenesis alters mineralocorticoid precursor concentrations.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0031186 | Abnormal circulating deoxycorticosterone level | Frequent (79-30%)"
      explanation: Orphanet lists abnormal circulating deoxycorticosterone level as a frequent CRD phenotype.
  - target: Hypertension
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Abnormal deoxycorticosterone and mineralocorticoid precursor activity promote sodium retention and volume expansion.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000822 | Hypertension | Frequent (79-30%)"
      explanation: Orphanet lists hypertension as a frequent CRD phenotype.
  - target: Hypokalemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mineralocorticoid receptor activation promotes renal potassium wasting.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002900 | Hypokalemia | Occasional (29-5%)"
      explanation: Orphanet lists hypokalemia as an occasional CRD phenotype.
  - target: Decreased circulating renin concentration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mineralocorticoid-mediated volume expansion suppresses circulating renin.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003351 | Decreased circulating renin concentration | Occasional (29-5%)"
      explanation: Orphanet lists decreased circulating renin concentration as an occasional CRD phenotype.
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare, genetic, endocrine disease characterized by defect in conversion of cortisone to active cortisol, resulting in ACTH-mediated excessive androgen release from adrenal glands."
    explanation: Orphanet directly states the ACTH-mediated adrenal androgen mechanism.
  - reference: PMID:29843121
    reference_title: "Alterations of Cortisol Metabolism in Human Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in the corresponding HSD11B1 gene, or in the H6PD gene encoding hexose-6-phosphate dehydrogenase (which supplies the NADPH required for the oxoreductase activity of 11-HSD1), cause apparent cortisone reductase deficiency, a rare syndrome of adrenocortical hyperactivity and hyperandrogenism."
    explanation: Review evidence links HSD11B1/H6PD disruption to adrenocortical hyperactivity and hyperandrogenism.
phenotypes:
- category: Cardiovascular
  name: Hypertension
  description: Elevated blood pressure is listed by Orphanet among frequent CRD phenotypes.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000822 | Hypertension | Frequent (79-30%)"
    explanation: Orphanet lists hypertension as frequent.
- category: Endocrine
  name: Precocious puberty
  description: Premature androgen exposure can produce precocious pseudopuberty.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Precocious puberty
    term:
      id: HP:0000826
      label: Precocious puberty
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000826 | Precocious puberty | Occasional (29-5%)"
    explanation: Orphanet lists precocious puberty as occasional.
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Premature adrenarche is typical with precocious pseudopuberty"
    explanation: The Orphanet definition describes precocious pseudopuberty.
- category: Reproductive
  name: Irregular menstruation
  description: Oligoamenorrhea and irregular menstruation are part of the female hyperandrogenic phenotype.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Irregular menstruation
    term:
      id: HP:0000858
      label: Irregular menstruation
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000858 | Irregular menstruation | Frequent (79-30%)"
    explanation: Orphanet lists irregular menstruation as frequent.
- category: Metabolic
  name: Hypokalemia
  description: Hypokalemia is listed as an occasional CRD phenotype.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002900 | Hypokalemia | Occasional (29-5%)"
    explanation: Orphanet lists hypokalemia as occasional.
- category: Biochemical
  name: Decreased circulating renin concentration
  description: Suppressed circulating renin is listed as an occasional biochemical phenotype.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Decreased circulating renin concentration
    term:
      id: HP:0003351
      label: Decreased circulating renin concentration
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003351 | Decreased circulating renin concentration | Occasional (29-5%)"
    explanation: Orphanet lists decreased circulating renin concentration as occasional.
- category: Endocrine
  name: Congenital adrenal hyperplasia
  description: Adrenal hyperplasia can accompany ACTH-mediated adrenal stimulation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congenital adrenal hyperplasia
    term:
      id: HP:0008258
      label: Congenital adrenal hyperplasia
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008258 | Congenital adrenal hyperplasia | Frequent (79-30%)"
    explanation: Orphanet lists congenital adrenal hyperplasia as frequent.
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Imaging studies may indicate adrenal hyperplasia."
    explanation: The Orphanet definition supports adrenal hyperplasia as an imaging finding.
- category: Endocrine
  name: Premature adrenarche
  description: Premature adrenarche is a pediatric presentation of adrenal androgen excess.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Premature adrenarche
    term:
      id: HP:0012412
      label: Premature adrenarche
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012412 | Premature adrenarche | Occasional (29-5%)"
    explanation: Orphanet lists premature adrenarche as occasional.
  - reference: PMID:23132696
    reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To describe the clinical, biochemical and molecular characteristics of two additional female children with ACRD and to illustrate the diagnostic value of urinary steroid profiling in identifying and differentiating a total of six ACRD and four CRD cases."
    explanation: The clinical paper reports pediatric ACRD/CRD cases presenting in the context of premature adrenarche.
- category: Biochemical
  name: Elevated serum 11-deoxycortisol
  description: Elevated serum 11-deoxycortisol is listed as a frequent biochemical phenotype.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated serum 11-deoxycortisol
    term:
      id: HP:0025436
      label: Elevated serum 11-deoxycortisol
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025436 | Elevated serum 11-deoxycortisol | Frequent (79-30%)"
    explanation: Orphanet lists elevated serum 11-deoxycortisol as frequent.
- category: Biochemical
  name: Increased circulating androgen concentration
  description: Adrenal androgen excess is the central endocrine consequence of CRD.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Increased circulating androgen concentration
    term:
      id: HP:0030348
      label: Increased circulating androgen concentration
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030348 | Increased circulating androgen concentration | Frequent (79-30%)"
    explanation: Orphanet lists increased circulating androgen concentration as frequent.
  - reference: PMID:23132696
    reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism."
    explanation: Human clinical evidence supports adrenal hyperandrogenism in both molecular forms.
- category: Biochemical
  name: Abnormal circulating deoxycorticosterone level
  description: Altered deoxycorticosterone is listed as a frequent steroid-profile phenotype.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal circulating deoxycorticosterone level
    term:
      id: HP:0031186
      label: Abnormal circulating deoxycorticosterone level
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031186 | Abnormal circulating deoxycorticosterone level | Frequent (79-30%)"
    explanation: Orphanet lists abnormal circulating deoxycorticosterone level as frequent.
- category: Hair
  name: Hirsutism
  description: Female patients can present with hirsutism from adrenal hyperandrogenism.
  phenotype_term:
    preferred_term: Hirsutism
    term:
      id: HP:0001007
      label: Hirsutism
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "hirsutism, oligoamenorrhea, central obesity and infertility in females."
    explanation: Orphanet lists hirsutism among female manifestations.
- category: Reproductive
  name: Infertility
  description: Female infertility can occur as part of the hyperandrogenic reproductive phenotype.
  phenotype_term:
    preferred_term: Infertility
    term:
      id: HP:0000789
      label: Infertility
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "hirsutism, oligoamenorrhea, central obesity and infertility in females."
    explanation: Orphanet lists infertility among female manifestations.
- category: Growth
  name: Tall stature
  description: Proportionate tall stature may occur in affected males with premature androgen exposure.
  phenotype_term:
    preferred_term: Tall stature
    term:
      id: HP:0000098
      label: Tall stature
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "proportionate tall stature and accelerated bone maturation in males"
    explanation: Orphanet describes tall stature and accelerated bone maturation in affected males.
- category: Growth
  name: Central obesity
  description: Central obesity is reported among female manifestations in the Orphanet definition.
  phenotype_term:
    preferred_term: Central obesity
    term:
      id: HP:0012743
      label: Abdominal obesity
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "hirsutism, oligoamenorrhea, central obesity and infertility in females."
    explanation: Orphanet lists central obesity; HP:0012743 has Central obesity as an exact synonym.
biochemical:
- name: Cortisol regeneration from cortisone
  presence: DECREASED
  context: >
    The defining biochemical defect is reduced 11beta-HSD1-dependent reduction
    of cortisone to active cortisol in the endoplasmic reticulum.
  biomarker_term:
    preferred_term: cortisol
    term:
      id: CHEBI:17650
      label: cortisol
  readouts:
  - target: Impaired Cortisone-to-Cortisol Regeneration
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Decreased cortisone-to-cortisol regeneration reports the defining
      enzymatic defect in CRD/ACRD.
    evidence:
    - reference: PMID:12858176
      reference_title: "Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur"
      explanation: This directly supports the deficient cortisol-regeneration readout.
  evidence:
  - reference: PMID:21325058
    reference_title: "Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a dimeric enzyme that catalyzes the reduction of cortisone to cortisol within the endoplasmic reticulum."
    explanation: This identifies the biochemical reaction that is deficient in CRD.
- name: Cortisone substrate handling
  presence: ABNORMAL
  context: >
    Impaired reduction of cortisone to cortisol leaves cortisone activation
    abnormal and is captured diagnostically by urinary steroid metabolite
    profiling.
  biomarker_term:
    preferred_term: cortisone
    term:
      id: CHEBI:16962
      label: cortisone
  readouts:
  - target: Impaired Cortisone-to-Cortisol Regeneration
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Abnormal cortisone handling and urinary steroid ratios report impaired
      conversion of cortisone to cortisol.
    evidence:
    - reference: PMID:23132696
      reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Steroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD."
      explanation: Urinary steroid profiling is a diagnostic readout of the impaired cortisone-reduction mechanism.
  evidence:
  - reference: PMID:12858176
    reference_title: "Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur"
    explanation: Human CRD genetics paper directly states failed cortisone activation.
- name: Circulating androgen
  presence: INCREASED
  context: >
    ACTH-mediated adrenal steroidogenesis produces the androgen-excess state
    that drives many clinical manifestations.
  biomarker_term:
    preferred_term: androgen
    term:
      id: CHEBI:50113
      label: androgen
  readouts:
  - target: ACTH-Mediated Adrenal Hyperandrogenism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased circulating androgens report the ACTH-mediated adrenal
      hyperandrogenism branch of CRD.
    evidence:
    - reference: PMID:23132696
      reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both ACRD and CRD present with hypothalamic-pituitary-adrenal (HPA) axis activation and adrenal hyperandrogenism."
      explanation: Human clinical evidence identifies adrenal hyperandrogenism in both molecular forms of CRD.
  evidence:
  - reference: PMID:29843121
    reference_title: "Alterations of Cortisol Metabolism in Human Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a rare syndrome of adrenocortical hyperactivity and hyperandrogenism."
    explanation: Review evidence supports androgen excess downstream of HSD11B1/H6PD disruption.
- name: Serum 11-deoxycortisol
  presence: INCREASED
  context: Elevated 11-deoxycortisol is an Orphanet-listed biochemical phenotype.
  biomarker_term:
    preferred_term: 11-deoxycortisol
    term:
      id: CHEBI:28324
      label: 11-deoxycortisol
  readouts:
  - target: ACTH-Mediated Adrenal Hyperandrogenism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated 11-deoxycortisol reports the adrenal steroid-profile disturbance
      accompanying ACTH-mediated steroidogenesis.
    evidence:
    - reference: ORPHA:168588
      reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0025436 | Elevated serum 11-deoxycortisol | Frequent (79-30%)"
      explanation: Orphanet lists elevated serum 11-deoxycortisol as a frequent biochemical phenotype.
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025436 | Elevated serum 11-deoxycortisol | Frequent (79-30%)"
    explanation: Orphanet lists elevated serum 11-deoxycortisol as frequent.
genetic:
- name: HSD11B1
  gene_term:
    preferred_term: HSD11B1
    term:
      id: hgnc:5208
      label: HSD11B1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    HSD11B1 encodes 11beta-hydroxysteroid dehydrogenase type 1. Disease-linked
    variants include heterozygous dominant-negative missense variants that
    reduce dimer formation or catalytic activity.
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HSD11B1 | hydroxysteroid 11-beta dehydrogenase 1 | hgnc:5208 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists HSD11B1 loss-of-function germline variants as disease causing.
  - reference: PMID:21325058
    reference_title: "Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel heterozygous mutations (R137C or K187N) were found in the coding sequence of HSD11B1."
    explanation: The report identifies heterozygous HSD11B1 missense variants in CRD cases.
- name: H6PD
  gene_term:
    preferred_term: H6PD
    term:
      id: hgnc:4795
      label: H6PD
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    H6PD encodes endoplasmic-reticulum hexose-6-phosphate dehydrogenase, which
    supplies NADPH for 11beta-HSD1 oxoreductase activity. Loss-of-function H6PD
    variants cause apparent cortisone reductase deficiency.
  evidence:
  - reference: ORPHA:168588
    reference_title: "Hyperandrogenism due to cortisone reductase deficiency"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "H6PD | hexose-6-phosphate dehydrogenase/glucose 1-dehydrogenase | hgnc:4795 | Disease-causing germline mutation(s) (loss of function) in"
    explanation: Orphanet lists H6PD loss-of-function germline variants as disease causing.
  - reference: PMID:23132696
    reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case 1 was compound heterozygous for R109AfsX3 and a novel P146L missense mutation in H6PD. Case 2 was compound heterozygous for novel nonsense mutations Q325X and Y446X in H6PD."
    explanation: The clinical report identifies compound heterozygous H6PD variants in affected children.
  - reference: PMID:18628520
    reference_title: "Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three cases were identified as homozygous (R109AfsX3, Y316X, and G359D) and one case identified as compound heterozygous (c.960G-->A and D620fsX3) for mutations in H6PD."
    explanation: Human CRD cases with homozygous or compound heterozygous H6PD variants support H6PD as a causal gene.
diagnosis:
- name: Urinary steroid metabolite profiling
  description: >
    Gas chromatography/mass spectrometry-based urinary steroid profiling can
    identify the cortisone reductase defect and distinguish apparent H6PD-related
    CRD from true HSD11B1-related CRD.
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: MAXO:0000789
      label: urine chemistry measurement
  results: Steroid metabolite signatures can discriminate ACRD from true CRD.
  evidence:
  - reference: PMID:23132696
    reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Steroid profile analysis of a 24-h urine collection provides a diagnostic method for discriminating between ACRD and CRD."
    explanation: The study directly supports urine steroid profiling as a diagnostic discriminator.
  - reference: PMID:18628520
    reference_title: "Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gas chromatography/mass spectrometry identified steroid biomarkers that correlated with CRD in each case."
    explanation: This supports GC/MS urinary steroid biomarkers as a diagnostic approach in CRD.
  - reference: PMID:12649576
    reference_title: "11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') in a 6-year-old boy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis is based on determinations of urinary steroid metabolites."
    explanation: This pediatric ACRD case report supports urinary steroid metabolite testing for diagnosis.
- name: HSD11B1 and H6PD molecular genetic testing
  description: >
    Sequencing of HSD11B1 and H6PD helps confirm the molecular cause after a
    biochemical steroid-profile pattern suggests CRD or ACRD.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  results: Pathogenic HSD11B1 variants support true CRD; pathogenic H6PD variants support apparent CRD.
  evidence:
  - reference: PMID:23132696
    reference_title: "Novel H6PDH mutations in two girls with premature adrenarche: 'apparent' and 'true' CRD can be differentiated by urinary steroid profiling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we were able to establish a steroid metabolite signature differentiating ACRD and CRD, providing a basis for genetic diagnosis and future individualised management."
    explanation: The study links steroid profiles to subsequent molecular genetic diagnosis.
treatments:
- name: Dexamethasone adrenal androgen suppression
  description: >
    Low-dose dexamethasone can suppress ACTH-driven adrenal androgen excess in
    apparent cortisone reductase deficiency. Hydrocortisone may be ineffective
    in ACRD because it is rapidly converted to cortisone.
  treatment_term:
    preferred_term: hormone modifying therapy
    term:
      id: MAXO:0000283
      label: hormone modifying therapy
    therapeutic_agent:
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
  target_mechanisms:
  - target: ACTH-Mediated Adrenal Hyperandrogenism
    treatment_effect: INHIBITS
    description: Dexamethasone suppresses adrenal androgen synthesis downstream of HPA-axis activation.
    evidence:
    - reference: PMID:12649576
      reference_title: "11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') in a 6-year-old boy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression."
      explanation: The pediatric ACRD case directly supports dexamethasone suppression of the adrenal androgen branch.
    - reference: PMID:29073307
      reference_title: "A follow-up history of young man with apparent cortisone reductase deficiency (ACRD) - several years after diagnosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Control laboratory studies indicated suppression of excess adrenal androgen synthesis, but we never got the THF + allo-THF/THE ratio in normal values."
      explanation: Longitudinal follow-up supports dexamethasone suppression of excess adrenal androgen synthesis.
  target_phenotypes:
  - preferred_term: Increased circulating androgen concentration
    term:
      id: HP:0030348
      label: Increased circulating androgen concentration
  - preferred_term: Precocious puberty
    term:
      id: HP:0000826
      label: Precocious puberty
  evidence:
  - reference: PMID:29073307
    reference_title: "A follow-up history of young man with apparent cortisone reductase deficiency (ACRD) - several years after diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Control laboratory studies indicated suppression of excess adrenal androgen synthesis, but we never got the THF + allo-THF/THE ratio in normal values."
    explanation: Longitudinal human follow-up supports dexamethasone suppression of adrenal androgen synthesis, while not normalizing the diagnostic steroid ratio.
  - reference: PMID:29073307
    reference_title: "A follow-up history of young man with apparent cortisone reductase deficiency (ACRD) - several years after diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hydrocortisone treatment is ineffective in ACRD patients because it was rapidly metabolized to cortisone."
    explanation: This supports the treatment caveat that hydrocortisone is a poor substitute for dexamethasone in ACRD.
  - reference: PMID:12649576
    reference_title: "11beta-hydroxysteroid dehydrogenase type 1 deficiency ('apparent cortisone reductase deficiency') in a 6-year-old boy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression."
    explanation: The first pediatric case report supports dexamethasone as a human treatment that suppresses androgen excess.
notes: >-
  This entry emphasizes the disease-defining steroid-metabolism mechanism and
  the Orphanet very/frequent phenotype set. Falcon deep research was integrated
  for urinary steroid biomarker evidence and for case-report treatment evidence
  supporting dexamethasone adrenal androgen suppression; no CRD-specific
  interventional clinical trial was identified in the research output.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 27 citations 2026-05-10T01:31:06.562166

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Cortisone Reductase Deficiency
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Cortisone Reductase Deficiency covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Cortisone Reductase Deficiency (CRD): Comprehensive Disease Characteristics Report

Target disease

  • Disease name: Cortisone Reductase Deficiency (CRD)
  • Category: Mendelian endocrine/metabolic disorder (rare)

Important scope note: The retrieved evidence base contains strong primary literature for CRD/“apparent” CRD but did not include authoritative MONDO/Orphanet/ICD/MeSH identifiers in accessible full text. Where those identifiers are required, this report explicitly marks them as not available in the retrieved sources.

1. Disease information

1.1 Concise overview (current understanding)

Cortisone reductase deficiency (CRD) is a rare disorder of impaired regeneration of active cortisol from inactive cortisone due to deficient 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) reductase function in vivo, producing increased cortisol clearance and compensatory activation of the hypothalamic–pituitary–adrenal (HPA) axis with consequent ACTH-driven adrenal androgen excess. (g2008steroidbiomarkersand pages 1-2, draper2003mutationsinthe pages 1-2)

A clinically overlapping entity, apparent cortisone reductase deficiency (ACRD), results from defects in the cofactor system that supplies NADPH to 11β-HSD1 (notably H6PD in the endoplasmic reticulum), leading to a functional loss of 11β-HSD1 reductase directionality. (zajkowska2017afollowuphistory pages 1-2, white2018alterationsofcortisol pages 3-4)

1.2 Key identifiers (as available in retrieved sources)

  • OMIM/MIM (disease): CRD MIM #604931 (example cited in an OMIM/medical genetics context). (zajkowska2017afollowuphistory pages 1-2)
  • OMIM (genes): HSD11B1 (MIM *600713) and H6PD (MIM *138090) referenced in the same OMIM example context. (zajkowska2017afollowuphistory pages 1-2)
  • “Cortisone reductase type 2 deficiency / CRD2”: a 2024 case report cites MIM #614662 in association with HSD11B1 frameshift disease presentation. (almache2024migueldelos pages 2-5)
  • MONDO / Orphanet / ICD-10/ICD-11 / MeSH: Not identified in retrieved full-text evidence (cannot be asserted from current tool outputs).

1.3 Synonyms / alternative names

  • Cortisone reductase deficiency (CRD) (draper2003mutationsinthe pages 1-2, g2008steroidbiomarkersand pages 1-2)
  • Apparent cortisone reductase deficiency (ACRD) (zajkowska2017afollowuphistory pages 1-2, white2018alterationsofcortisol pages 3-4)
  • Apparent cortisone reductase deficiency / “AERD” (historical usage in early case literature) (biasonlauber2000apparentcortisonereductase pages 1-3)

1.4 Evidence source type

Most disease knowledge is derived from case reports/series, and mechanistic genetic studies, with synthesis in expert reviews. (draper2003mutationsinthe pages 1-2, g2008steroidbiomarkersand pages 1-2, biasonlauber2000apparentcortisonereductase pages 1-3)

2. Etiology

2.1 Disease causal factors

Primary causal mechanism: Reduced 11β-HSD1-dependent cortisone→cortisol regeneration in tissues, due to: 1) HSD11B1 variants that reduce 11β-HSD1 expression or activity, and/or (draper2003mutationsinthe pages 1-2, lawson2011cortisonereductasedeficiencyassociated pages 1-2) 2) H6PD loss-of-function variants impairing ER NADPH generation, shifting/abrogating 11β-HSD1 oxoreductase activity in vivo. (g2008steroidbiomarkersand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)

Mechanistic causal chain (human disease): impaired tissue cortisol regeneration → increased cortisol clearance → reduced negative feedback → increased ACTH drive → increased adrenal androgen (and cortisol) production → clinical hyperandrogenism/precocious puberty or PCOS-like phenotype. (g2008steroidbiomarkersand pages 1-2, white2018alterationsofcortisol pages 3-4)

2.2 Genetic risk factors / causal variants

Causal genes

  • HSD11B1 (encodes 11β-HSD1) (lawson2011cortisonereductasedeficiencyassociated pages 1-2)
  • H6PD (encodes hexose-6-phosphate dehydrogenase; provides NADPH in ER lumen) (g2008steroidbiomarkersand pages 1-2)

Pathogenic variants (examples explicitly stated in retrieved evidence)

  • H6PD inactivating variants identified in CRD cohorts include R109AfsX3, Y316X, G359D, and compound heterozygous combinations including D620fsX3 (as reported in the JCEM 2008 cohort). (g2008steroidbiomarkersand pages 1-2)
  • HSD11B1 coding variants reported in PNAS 2011: c.409C>T (R137C) and c.561G>T (K187N), heterozygous and maternally inherited in those families. (lawson2011cortisonereductasedeficiencyassociated pages 1-2, lawson2011cortisonereductasedeficiencyassociated pages 1-1)
  • HSD11B1 frameshift in a 2024 pediatric case: HSD11B1:c.513delG:p.(Ala172Leufs*47) identified by whole-exome sequencing. (almache2024migueldelos pages 2-5)

Inheritance patterns (as supported by retrieved sources)

  • A digenic/triallelic interaction model (HSD11B1 intronic variants + H6PD mutations) was proposed in the 2003 Nature Genetics report. (draper2003mutationsinthe pages 1-2)
  • A recessive pattern is strongly suggested in the 2008 JCEM series by homozygous and compound heterozygous H6PD loss-of-function genotypes. (g2008steroidbiomarkersand pages 1-2)
  • A heterozygous/maternal transmission pattern was described in PNAS 2011 for some HSD11B1 missense cases (mothers shared the biochemical phenotype). (lawson2011cortisonereductasedeficiencyassociated pages 1-2)

2.3 Environmental risk/protective factors and GxE

No disease-specific environmental risk/protective factors or gene–environment interactions were identified in the retrieved evidence; CRD/ACRD is primarily described as a genetic/cofactor-enzyme defect. (white2018alterationsofcortisol pages 3-4, g2008steroidbiomarkersand pages 1-2)

3. Phenotypes

3.1 Core phenotype spectrum

CRD/ACRD phenotypes cluster around ACTH-driven adrenal androgen excess and related reproductive/androgenic manifestations: - Females: hirsutism, acne, oligomenorrhea/oligo-amenorrhea, anovulation and infertility; androgenic alopecia in some cases. (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23, g2008steroidbiomarkersand pages 1-2) - Males/children: precocious puberty or precocious pseudopuberty, precocious pubarche, virilization, advanced bone age. (zajkowska2017afollowuphistory pages 1-2, almache2024migueldelos pages 1-2)

Additional reported findings/associations include adrenal hyperplasia in at least one adult case, and mild hypertension in that report. (biasonlauber2000apparentcortisonereductase pages 1-3)

3.2 Age of onset, severity, progression

  • Typical female presentation: adolescence or early adulthood (reviewed case aggregate), but also midlife presentations occur in case series (e.g., ages 44 and 55 in one report set). (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23, g2008steroidbiomarkersand pages 1-2)
  • Pediatric male presentation: childhood onset with precocious pubarche/pseudopuberty; a 2017 follow-up report describes diagnosis at ~7 years with advanced bone age and androgen excess. (zajkowska2017afollowuphistory pages 1-2)
  • A 2024 case report highlights progression from peripheral androgen excess to secondary central precocious puberty with sustained androgen exposure. (almache2024migueldelos pages 1-2)

3.3 Phenotype frequencies

Robust per-phenotype frequency percentages are not available because evidence is predominantly case-based. However, an endocrine review summarized that among 11 described cases (at that time) the majority were female. (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23)

3.4 Quality-of-life impact

Direct standardized QoL instruments were not reported in retrieved sources. Based on clinical phenotype, QoL impact is expected through infertility, hirsutism/acne/alopecia, and early puberty with psychosocial and growth consequences. (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23, almache2024migueldelos pages 5-5)

3.5 Suggested HPO terms (non-exhaustive; mapped from retrieved phenotypes)

  • Hyperandrogenism (HP:0000843)
  • Hirsutism (HP:0001007)
  • Acne (HP:0001061)
  • Oligomenorrhea / Amenorrhea (HP:0000876 / HP:0000869)
  • Infertility (HP:0000789)
  • Androgenic alopecia (HP:0002210)
  • Precocious puberty (HP:0000826)
  • Precocious pubarche (HP:0008080)
  • Advanced bone age (HP:0002808)

(These HPO IDs are standard ontology mappings; the underlying clinical features are supported by the cited sources.) (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23, zajkowska2017afollowuphistory pages 1-2)

4. Genetic / molecular information

4.1 Core molecular concept

11β-HSD1 is an ER-localized enzyme that predominantly acts as a reductase in vivo to regenerate cortisol from cortisone. A key modern concept emphasized by Seckl (2024) is that the directionality of 11β-HSD1 is governed by co-localized H6PDH, which generates luminal NADPH; without sufficient NADPH, 11β-HSD1 can lose reductase directionality. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)

4.2 Protein dysfunction and functional consequence

  • Loss of H6PD function reduces NADPH, impairing 11β-HSD1 reductase activity; in vivo this manifests as markedly low urinary cortisol-derived metabolites relative to cortisone-derived metabolites. (g2008steroidbiomarkersand pages 1-2, draper2003mutationsinthe media 390e56cf)
  • HSD11B1 missense variants can reduce enzyme activity and show dominant-negative behavior in co-expression (reported in PNAS 2011). (lawson2011cortisonereductasedeficiencyassociated pages 1-1)

4.3 Suggested GO biological process terms (examples)

  • Glucocorticoid metabolic process (GO:0008211)
  • Steroid metabolic process (GO:0008202)
  • Cortisol biosynthetic/metabolic process (general mapping; supported mechanistically by tissue regeneration described) (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)

4.4 Suggested GO cellular component terms

  • Endoplasmic reticulum lumen (GO:0005788) (H6PDH NADPH generation locale)
  • Endoplasmic reticulum membrane (GO:0005789) (11β-HSD1 localization concept)

4.5 Suggested Cell Ontology (CL) terms (inferred from expression sites discussed in 2024 expert review)

Seckl (2024) emphasizes 11β-HSD1 abundance in liver, adipose, vasculature, muscle, inflammatory cells, gonads and brain. Candidate CL terms include: - Hepatocyte (CL:0000182) - Adipocyte (CL:0000136) - Macrophage (CL:0000235) - Neuron (CL:0000540)

(These are plausible mechanistic cell types; clinical disease manifestations are primarily adrenal axis-driven.) (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)

5. Environmental information

No specific environmental or infectious contributors were identified in retrieved sources. CRD/ACRD is described as a genetic/cofactor-enzyme defect with endocrine downstream consequences. (white2018alterationsofcortisol pages 3-4)

6. Mechanism / pathophysiology

6.1 Molecular pathway summary

  • Upstream defect: HSD11B1 loss-of-function and/or H6PD loss-of-function → reduced 11β-HSD1 oxoreductase activity (cortisone→cortisol). (g2008steroidbiomarkersand pages 1-2, seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)
  • Intermediate: increased metabolic clearance of cortisol; reduced tissue cortisol regeneration. (g2008steroidbiomarkersand pages 1-2)
  • Downstream endocrine compensation: increased ACTH drive → adrenal hyperandrogenism → PCOS-like phenotype (women) or precocious puberty/pubarche (children). (g2008steroidbiomarkersand pages 1-2, tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23)

6.2 Biochemical abnormalities (key measurable signature)

A defining biochemical feature is a markedly reduced urinary tetrahydrocortisol (THF + allo-THF or THF + 5α-THF) to tetrahydrocortisone (THE) ratio, often around 0.03–0.05 compared with reference ~0.7–1.2. (draper2003mutationsinthe pages 1-2, g2008steroidbiomarkersand pages 1-2, draper2003mutationsinthe media 390e56cf)

The key diagnostic table in Draper et al. shows affected ratios 0.03–0.04 vs reference 0.7–1.1. (draper2003mutationsinthe media 390e56cf)

7. Anatomical structures affected

7.1 Organ/system level

  • Endocrine system: HPA axis (hypothalamus/pituitary signaling), adrenal androgen production (functional outcome). (g2008steroidbiomarkersand pages 1-2)
  • Reproductive system: ovulatory dysfunction/infertility in females; pubertal development axis in children. (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23, almache2024migueldelos pages 5-5)

7.2 Suggested UBERON terms (examples)

  • Adrenal gland (UBERON:0002369)
  • Pituitary gland (UBERON:0000007)
  • Ovary (UBERON:0000992)
  • Testis (UBERON:0000473)

8. Temporal development

  • Onset: childhood (boys with precocious pubarche/pseudopuberty) or adolescence/early adulthood (women with hyperandrogenism/infertility). (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23, zajkowska2017afollowuphistory pages 1-2)
  • Course: chronic endocrine imbalance; androgen excess can drive progression (e.g., peripheral → central precocious puberty in sustained pediatric cases). (almache2024migueldelos pages 1-2)

9. Inheritance and population

9.1 Epidemiology

CRD/ACRD is described as extremely rare; case-based counts include: - ~11 cases described as of an Endocrine Reviews synthesis (majority female). (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23) - A later case report review states “around 16 cases” in literature. (zajkowska2017afollowuphistory pages 1-2)

No reliable population prevalence/incidence estimates were found in the retrieved evidence.

9.2 Inheritance

See Section 2.2 (digenic/triallelic model in early report; recessive H6PD LOF patterns in later cohort; heterozygous HSD11B1 families reported). (draper2003mutationsinthe pages 1-2, lawson2011cortisonereductasedeficiencyassociated pages 1-2, g2008steroidbiomarkersand pages 1-2)

10. Diagnostics

10.1 Core clinical tests and biomarkers

  • Urinary steroid metabolomics by GC/MS: hallmark low THF+5α-THF/THE (or THF+allo-THF/THE) ratio. Thresholds reported include <0.1 (typical CRD) with reference ranges approximately 0.7–1.2, and individual patient ratios ~0.03–0.05. (g2008steroidbiomarkersand pages 1-2, zajkowska2017afollowuphistory pages 1-2)
  • The Nature Genetics table demonstrates ratios 0.03–0.04 vs reference 0.7–1.1. (draper2003mutationsinthe media 390e56cf)
  • Additional urinary metrics: cortols/cortolones ratio used as a measure of 11β-HSD1 activity. (lawson2011cortisonereductasedeficiencyassociated pages 1-1)
  • Blood tests in reported cases: plasma androgens (DHEAS, androstenedione, testosterone), and sometimes 17-hydroxyprogesterone elevations. (zajkowska2017afollowuphistory pages 1-2)

10.2 Genetic testing

  • Targeted sequencing of H6PD and HSD11B1 is supported by cohort studies. (g2008steroidbiomarkersand pages 1-2)
  • Whole-exome sequencing (WES) enabled diagnosis in the 2024 pediatric CRD2 report with identification of an HSD11B1 frameshift. (almache2024migueldelos pages 2-5)

10.3 Differential diagnosis

Because CRD/ACRD can mimic common hyperandrogenism disorders, differential diagnosis includes: - Polycystic ovary syndrome (PCOS) phenocopy (explicitly noted as a clinical resemblance). (draper2003mutationsinthe pages 1-2) - Congenital adrenal hyperplasia (e.g., 21-hydroxylase deficiency) as a diagnostic alternative in hyperandrogenic/precocious puberty presentations.

11. Outcome / prognosis

Formal survival/mortality statistics were not identified (rare, non-lethal endocrine disorder). Reported long-term outcomes include attainment of near-target adult height in one male pediatric ACRD follow-up when treatment was titrated carefully, with mild therapy-related adverse effects noted. (zajkowska2017afollowuphistory pages 5-6)

Key prognosis determinants appear to include: - Degree and duration of androgen excess (bone age advancement) - Side effects of chronic glucocorticoid suppression strategies (e.g., risk of iatrogenic Cushingoid effects). (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23, zajkowska2017afollowuphistory pages 5-6)

12. Treatment

12.1 Mechanism-based endocrine management (real-world implementations)

Goal: suppress ACTH-driven adrenal androgen excess and manage consequences (puberty progression, fertility, androgenic symptoms).

  • Dexamethasone: suppresses ACTH and androgens; serum androgens fall with dexamethasone in reviewed cases. (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23)
  • Hydrocortisone: may be ineffective in ACRD due to rapid metabolism to cortisone; a pediatric ACRD follow-up described ineffective hydrocortisone and improved biochemical control after switching to dexamethasone. (zajkowska2017afollowuphistory pages 2-4)
  • Antiandrogen strategies: prednisone plus antiandrogens (e.g., cyproterone acetate, spironolactone) improved symptoms in an adult female case. (biasonlauber2000apparentcortisonereductase pages 1-3)
  • Precocious puberty regimens (2024 case): GnRH analogue (triptorelin), antiandrogen (bicalutamide), aromatase inhibitor (letrozole) and glucocorticoid adjustments in a child with CRD2. (almache2024migueldelos pages 1-2, almache2024migueldelos pages 5-5)

12.2 Suggested MAXO terms (examples)

  • Glucocorticoid therapy / ACTH suppression (MAXO concept: corticosteroid therapy)
  • Gonadotropin-releasing hormone agonist therapy (for central precocious puberty)
  • Aromatase inhibitor therapy
  • Antiandrogen therapy

(These are standard intervention categories; the specific clinical implementations are supported by cited case literature.) (zajkowska2017afollowuphistory pages 2-4, almache2024migueldelos pages 5-5)

12.3 Clinical trials

No CRD/ACRD-specific interventional trials were identified in the clinical trial search results available in this run. (clinical trials tool output: none relevant)

Related translational landscape: Seckl (2024) summarizes broad development of 11β-HSD1 inhibitors in other diseases, noting that metabolic benefits in humans have often been modest and “the magnitude of benefits has been insufficient to support progression” for metabolic indications, while other indications (including brain-related) remain under evaluation. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 3-4)

13. Prevention

No primary prevention is described (genetic disorder). Practical prevention pertains to: - Genetic counseling and cascade testing in families once a pathogenic variant is identified.

No newborn screening or population screening strategies were found in retrieved sources.

14. Other species / natural disease

No naturally occurring veterinary analogs were identified in the retrieved evidence.

15. Model organisms

The retrieved evidence base for this run did not include detailed CRD-specific model organism phenotyping text, though it references broader mouse mechanistic work in reviews and pathway studies (e.g., H6PD knockout physiology is discussed in related literature outside the disease report focus). (white2018alterationsofcortisol pages 3-4)

Recent developments (2023–2024 priority) and expert analysis

2024 expert synthesis: mechanistic refinement and translational outlook

Seckl (2024, Journal of Internal Medicine, publication month Nov 2024, URL https://doi.org/10.1111/joim.13741) emphasizes that 11β-HSD1 is a tissue amplifier of glucocorticoid action and that its reductase directionality depends on ER NADPH supply by H6PDH. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2)

Seckl (2024) provides a frank translational assessment: although 11β-HSD1 inhibitors show metabolic improvements in some human trials, clinical impact has often been insufficient for progression in metabolic disease development programs. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 3-4)

2024 case-based expansion of clinical spectrum

A 2024 pediatric case report (publication year 2024; details as retrieved) describes “cortisone reductase type 2 deficiency” diagnosed by WES with HSD11B1 frameshift c.513delG:p.(Ala172Leufs*47) and complex management of precocious puberty (GnRHa, aromatase inhibitor, antiandrogen, and corticosteroid changes due to Cushingoid signs). (almache2024migueldelos pages 2-5, almache2024migueldelos pages 5-5)

Key quantitative statistics and data (from recent/primary studies)

  • Urinary steroid ratio (diagnostic): tetrahydrocortisols/tetrahydrocortisone reference ~0.7–1.1; CRD examples 0.03–0.04. (draper2003mutationsinthe media 390e56cf)
  • Diagnostic threshold (cohort statement): THF + 5α-THF / THE typically <0.1 in CRD vs reference 0.7–1.2. (g2008steroidbiomarkersand pages 1-2)
  • Rarity counts: ~11 cases described as of a 2004 synthesis; ~16 cases noted in a 2017 review/case report context. (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23, zajkowska2017afollowuphistory pages 1-2)

Comparative summary table (CRD vs ACRD and variants)

Entity Causal gene(s) Inheritance model reported Core biochemical signature (urinary steroid ratios) Key clinical features Key references (year, journal, DOI)
CRD HSD11B1 with interacting H6PD variants reported in early cases; later reports also identified H6PD inactivating mutations without enzyme-affecting HSD11B1 mutations in the studied cohort (draper2003mutationsinthe pages 1-2, g2008steroidbiomarkersand pages 1-2) Digenic/triallelic model proposed in 2003 involving intronic HSD11B1 variants plus H6PD mutations; 2008 cohort showed 3 homozygous and 1 compound heterozygous H6PD genotypes, consistent with recessive inheritance in those families (draper2003mutationsinthe pages 1-2, g2008steroidbiomarkersand pages 1-2) Markedly reduced urinary tetrahydrocortisols/tetrahydrocortisone ratio; reported values 0.03, 0.032, 0.04 vs reference 0.7–1.1; 2008 review/cohort states THF + 5α-THF / THE <0.1 vs reference 0.7–1.2 (draper2003mutationsinthe pages 1-2, g2008steroidbiomarkersand pages 1-2, draper2003mutationsinthe media 390e56cf) ACTH-driven adrenal androgen excess; hyperandrogenism with hirsutism, oligo-/amenorrhea, infertility in females and premature pseudopuberty in males; cortisol regenerated poorly from cortisone (g2008steroidbiomarkersand pages 1-2, g2008steroidbiomarkersand pages 2-3, draper2003mutationsinthe pages 1-2) Draper et al. 2003, Nature Genetics, doi: 10.1038/ng1214; Lavery et al. 2008, J Clin Endocrinol Metab, doi: 10.1210/jc.2008-0743 (draper2003mutationsinthe pages 1-2, g2008steroidbiomarkersand pages 1-2)
ACRD H6PD (hexose-6-phosphate dehydrogenase), impairing NADPH supply to 11β-HSD1; Horm Res Paediatr 2018 also notes apparent cortisone reductase deficiency can result from HSD11B1 loss-of-function or H6PD defects affecting 11β-HSD1 activity (zajkowska2017afollowuphistory pages 1-2, white2018alterationsofcortisol pages 3-4) 2017 case report identifies ACRD as resulting from inactivating H6PD mutations; no explicit Mendelian label quoted in the snippet, but mutation-based disease mechanism is stated (zajkowska2017afollowuphistory pages 1-2) Very low THF+allo-THF/THE (or THF+5α-THF/THE) ratio; 2017 example 0.021 with normal approximately 0.7–1.2; hydrocortisone did not normalize the ratio, whereas dexamethasone improved biochemical control (zajkowska2017afollowuphistory pages 1-2, zajkowska2017afollowuphistory pages 2-4) Adrenal androgen excess with precocious pubarche, elevated plasma androgens, increased 17-hydroxyprogesterone; rare hyperandrogenic syndrome in women or children (zajkowska2017afollowuphistory pages 1-2, white2018alterationsofcortisol pages 3-4) Zajkowska et al. 2017, Pediatr Endocrinol Diabetes Metab, doi: 10.18544/pedm-23.01.0073; White 2018, Horm Res Paediatr, doi: 10.1159/000485508 (zajkowska2017afollowuphistory pages 1-2, white2018alterationsofcortisol pages 3-4)
CRD associated with heterozygous HSD11B1 variants HSD11B1 missense variants c.409C>T (R137C) and c.561G>T (K187N) reported in two cases; H6PD normal in those cases (lawson2011cortisonereductasedeficiencyassociated pages 1-2) Heterozygous, maternally inherited biochemical phenotype reported; mothers showed urine biochemistry similar to affected offspring, fathers were normal (lawson2011cortisonereductasedeficiencyassociated pages 1-2) The provided snippet links these cases to abnormal urinary biochemistry characteristic of cortisone-reductase deficiency, but does not restate exact ratio values in the excerpt (lawson2011cortisonereductasedeficiencyassociated pages 1-2) CRD phenotype as in prior reports; article title and context associate these cases with cortisone-reductase deficiency (lawson2011cortisonereductasedeficiencyassociated pages 1-2) Lawson et al. 2011, PNAS, doi: 10.1073/pnas.1014934108 (lawson2011cortisonereductasedeficiencyassociated pages 1-2)

Table: This table compares cortisone reductase deficiency and apparent cortisone reductase deficiency using only the provided evidence snippets. It highlights genes, reported inheritance patterns, diagnostic urinary steroid signatures, clinical manifestations, and the most relevant supporting references.

Visual evidence (urinary steroid ratios)

A key diagnostic table from the landmark Nature Genetics report shows dramatically reduced urinary tetrahydrocortisols/tetrahydrocortisone ratios in CRD vs reference range. (draper2003mutationsinthe media 390e56cf)

Reference URLs (selected)

  • Draper et al., Nature Genetics (Aug 2003): https://doi.org/10.1038/ng1214 (draper2003mutationsinthe pages 1-2)
  • Lavery et al., J Clin Endocrinol Metab (Oct 2008): https://doi.org/10.1210/jc.2008-0743 (g2008steroidbiomarkersand pages 1-2)
  • Lawson et al., PNAS (Feb 2011): https://doi.org/10.1073/pnas.1014934108 (lawson2011cortisonereductasedeficiencyassociated pages 1-2)
  • Zajkowska et al., Pediatr Endocrinol Diabetes Metab (Jan 2017): https://doi.org/10.18544/pedm-23.01.0073 (zajkowska2017afollowuphistory pages 1-2)
  • White, Horm Res Paediatr (May 2018): https://doi.org/10.1159/000485508 (white2018alterationsofcortisol pages 3-4)
  • Seckl, J Intern Med (Nov 2024): https://doi.org/10.1111/joim.13741 (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2)

References

  1. (g2008steroidbiomarkersand pages 1-2): G G Lavery, E A Walker, A Tiganescu, J P Ride, C H L Shackleton, J W Tomlinson, J M C Connell, D W Ray, A Biason-Lauber, E M Malunowicz, W Arlt, and P M Stewart. Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. The Journal of clinical endocrinology and metabolism, 93 10:3827-32, Oct 2008. URL: https://doi.org/10.1210/jc.2008-0743, doi:10.1210/jc.2008-0743. This article has 109 citations.

  2. (draper2003mutationsinthe pages 1-2): Nicole Draper, Elizabeth A Walker, Iwona J Bujalska, Jeremy W Tomlinson, Susan M Chalder, Wiebke Arlt, Gareth G Lavery, Oliver Bedendo, David W Ray, Ian Laing, Ewa Malunowicz, Perrin C White, Martin Hewison, Philip J Mason, John M Connell, Cedric H L Shackleton, and Paul M Stewart. Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nature Genetics, 34:434-439, Aug 2003. URL: https://doi.org/10.1038/ng1214, doi:10.1038/ng1214. This article has 376 citations and is from a highest quality peer-reviewed journal.

  3. (zajkowska2017afollowuphistory pages 1-2): Adrianna Zajkowska, Marta Rydzewska, Katarzyna Wojtkielewicz, Janusz Pomaski, Tomasz Romer, and Artur Bossowski. A follow-up history of young man with apparent cortisone reductase deficiency (acrd) – several years after diagnosis. Pediatric Endocrinology Diabetes and Metabolism, 23:42-48, Jan 2017. URL: https://doi.org/10.18544/pedm-23.01.0073, doi:10.18544/pedm-23.01.0073. This article has 2 citations.

  4. (white2018alterationsofcortisol pages 3-4): Perrin C. White. Alterations of cortisol metabolism in human disorders. Hormone Research in Paediatrics, 89:320-330, May 2018. URL: https://doi.org/10.1159/000485508, doi:10.1159/000485508. This article has 31 citations and is from a peer-reviewed journal.

  5. (almache2024migueldelos pages 2-5): ON Almache, RL de Lama, and EC Tejada. Miguel de los santos la torre, pamela azabache tafur. case report:“precocious puberty in a child with cortisone reductase type 2 deficiency”. Unknown journal, 2024.

  6. (biasonlauber2000apparentcortisonereductase pages 1-3): Anna Biason-Lauber, Stephan L. Suter, Cedric H.L. Shackleton, and Milo Zachmann. Apparent cortisone reductase deficiency: a rare cause of hyperandrogenemia and hypercortisolism. Hormone Research in Paediatrics, 53:260-266, Nov 2000. URL: https://doi.org/10.1159/000023577, doi:10.1159/000023577. This article has 49 citations and is from a peer-reviewed journal.

  7. (lawson2011cortisonereductasedeficiencyassociated pages 1-2): Alexander J. Lawson, Elizabeth A. Walker, Gareth G. Lavery, Iwona J. Bujalska, Beverly Hughes, Wiebke Arlt, Paul M. Stewart, and Jonathan P. Ride. Cortisone-reductase deficiency associated with heterozygous mutations in 11β-hydroxysteroid dehydrogenase type 1. Proceedings of the National Academy of Sciences, 108:4111-4116, Feb 2011. URL: https://doi.org/10.1073/pnas.1014934108, doi:10.1073/pnas.1014934108. This article has 74 citations and is from a highest quality peer-reviewed journal.

  8. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 2-2): Jonathan Seckl. 11β‐hydroxysteroid dehydrogenase and the brain: not (yet) lost in translation. Journal of Internal Medicine, 295:20-37, Nov 2024. URL: https://doi.org/10.1111/joim.13741, doi:10.1111/joim.13741. This article has 41 citations and is from a domain leading peer-reviewed journal.

  9. (lawson2011cortisonereductasedeficiencyassociated pages 1-1): Alexander J. Lawson, Elizabeth A. Walker, Gareth G. Lavery, Iwona J. Bujalska, Beverly Hughes, Wiebke Arlt, Paul M. Stewart, and Jonathan P. Ride. Cortisone-reductase deficiency associated with heterozygous mutations in 11β-hydroxysteroid dehydrogenase type 1. Proceedings of the National Academy of Sciences, 108:4111-4116, Feb 2011. URL: https://doi.org/10.1073/pnas.1014934108, doi:10.1073/pnas.1014934108. This article has 74 citations and is from a highest quality peer-reviewed journal.

  10. (tomlinson200411βhydroxysteroiddehydrogenasetype pages 22-23): Jeremy W. Tomlinson, Elizabeth A. Walker, Iwona J. Bujalska, Nicole Draper, Gareth G. Lavery, Mark S. Cooper, Martin Hewison, and Paul M. Stewart. 11β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocrine Reviews, 25:831-866, Oct 2004. URL: https://doi.org/10.1210/er.2003-0031, doi:10.1210/er.2003-0031. This article has 1273 citations and is from a domain leading peer-reviewed journal.

  11. (almache2024migueldelos pages 1-2): ON Almache, RL de Lama, and EC Tejada. Miguel de los santos la torre, pamela azabache tafur. case report:“precocious puberty in a child with cortisone reductase type 2 deficiency”. Unknown journal, 2024.

  12. (almache2024migueldelos pages 5-5): ON Almache, RL de Lama, and EC Tejada. Miguel de los santos la torre, pamela azabache tafur. case report:“precocious puberty in a child with cortisone reductase type 2 deficiency”. Unknown journal, 2024.

  13. (draper2003mutationsinthe media 390e56cf): Nicole Draper, Elizabeth A Walker, Iwona J Bujalska, Jeremy W Tomlinson, Susan M Chalder, Wiebke Arlt, Gareth G Lavery, Oliver Bedendo, David W Ray, Ian Laing, Ewa Malunowicz, Perrin C White, Martin Hewison, Philip J Mason, John M Connell, Cedric H L Shackleton, and Paul M Stewart. Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency. Nature Genetics, 34:434-439, Aug 2003. URL: https://doi.org/10.1038/ng1214, doi:10.1038/ng1214. This article has 376 citations and is from a highest quality peer-reviewed journal.

  14. (zajkowska2017afollowuphistory pages 5-6): Adrianna Zajkowska, Marta Rydzewska, Katarzyna Wojtkielewicz, Janusz Pomaski, Tomasz Romer, and Artur Bossowski. A follow-up history of young man with apparent cortisone reductase deficiency (acrd) – several years after diagnosis. Pediatric Endocrinology Diabetes and Metabolism, 23:42-48, Jan 2017. URL: https://doi.org/10.18544/pedm-23.01.0073, doi:10.18544/pedm-23.01.0073. This article has 2 citations.

  15. (zajkowska2017afollowuphistory pages 2-4): Adrianna Zajkowska, Marta Rydzewska, Katarzyna Wojtkielewicz, Janusz Pomaski, Tomasz Romer, and Artur Bossowski. A follow-up history of young man with apparent cortisone reductase deficiency (acrd) – several years after diagnosis. Pediatric Endocrinology Diabetes and Metabolism, 23:42-48, Jan 2017. URL: https://doi.org/10.18544/pedm-23.01.0073, doi:10.18544/pedm-23.01.0073. This article has 2 citations.

  16. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 3-4): Jonathan Seckl. 11β‐hydroxysteroid dehydrogenase and the brain: not (yet) lost in translation. Journal of Internal Medicine, 295:20-37, Nov 2024. URL: https://doi.org/10.1111/joim.13741, doi:10.1111/joim.13741. This article has 41 citations and is from a domain leading peer-reviewed journal.

  17. (g2008steroidbiomarkersand pages 2-3): G G Lavery, E A Walker, A Tiganescu, J P Ride, C H L Shackleton, J W Tomlinson, J M C Connell, D W Ray, A Biason-Lauber, E M Malunowicz, W Arlt, and P M Stewart. Steroid biomarkers and genetic studies reveal inactivating mutations in hexose-6-phosphate dehydrogenase in patients with cortisone reductase deficiency. The Journal of clinical endocrinology and metabolism, 93 10:3827-32, Oct 2008. URL: https://doi.org/10.1210/jc.2008-0743, doi:10.1210/jc.2008-0743. This article has 109 citations.

  18. (seckl202411β‐hydroxysteroiddehydrogenaseand pages 1-2): Jonathan Seckl. 11β‐hydroxysteroid dehydrogenase and the brain: not (yet) lost in translation. Journal of Internal Medicine, 295:20-37, Nov 2024. URL: https://doi.org/10.1111/joim.13741, doi:10.1111/joim.13741. This article has 41 citations and is from a domain leading peer-reviewed journal.