Complete androgen insensitivity syndrome

Mendelian MONDO:0021023 Pathograph 8 Androgen insensitivity syndrome 46,XY disorder of sex development Androgen receptor signaling disorder

Complete androgen insensitivity syndrome is an X-linked disorder of sex development caused by pathogenic variants in AR, the androgen receptor gene. Individuals have a 46,XY karyotype and testes that produce age-appropriate androgens, but target tissues are unable to respond to androgen signaling. The result is female external genitalia, absent or sparse pubic and axillary hair, primary amenorrhea, absent Mullerian-derived internal reproductive structures, and undescended testes.

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1
Mappings
1
Inheritance
8
Pathophys.
25
Phenotypes
8
Pathograph
1
Genes
3
Treatments
8
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0021023 complete androgen insensitivity syndrome
skos:exactMatch MONDO
Primary MONDO identifier for the disease.
👪

Inheritance

1
X-linked recessive HP:0001419
Complete androgen insensitivity syndrome is inherited in an X-linked recessive pattern through hemizygous pathogenic variants in AR.
X-linked recessive inheritance
Show evidence (2 references)
ORPHA:99429 SUPPORT Other
"X-linked recessive"
Orphanet lists X-linked recessive inheritance for complete androgen insensitivity syndrome.
PMID:29785970 SUPPORT Human Clinical
"A pathogenic mutation of the androgen receptor gene (AR; OMIM# 313700) is the only established molecular cause of the X-linked recessive inherited disease."
This AIS cohort/review statement directly supports AR-based X-linked recessive inheritance.
⚙

Pathophysiology

8
AR Germline Pathogenic Variant
Hemizygous pathogenic variants in AR disrupt the androgen receptor, the X-linked nuclear receptor that mediates testosterone and dihydrotestosterone responses.
AR link
androgen receptor signaling pathway link ↓ DECREASED
Downstream
Androgen Receptor Dysfunction AR variants impair receptor expression, ligand binding, DNA binding, or receptor-dependent transcriptional signaling.
Show evidence (2 references)
ORPHA:99429 SUPPORT Other
"AR | androgen receptor | hgnc:644 | Disease-causing germline mutation(s) in"
Orphanet records germline AR variants as disease-causing in CAIS.
PMID:22698698 SUPPORT Human Clinical
"Pathogenesis is the result of mutations in the X-linked androgen"
The Lancet seminar identifies X-linked AR mutations as the pathogenic basis.
Androgen Receptor Dysfunction
Dysfunctional androgen receptor protein reduces androgen-dependent nuclear receptor signaling and transcriptional activation in androgen-responsive tissues.
androgen receptor signaling pathway link ↓ DECREASED
Downstream
Androgen Target-Tissue Resistance Reduced receptor signaling makes androgen-responsive tissues resistant to otherwise age-appropriate androgen exposure.
Show evidence (2 references)
PMID:29785970 SUPPORT Human Clinical
"This protein functions as a steroid hormone-activated transcription factor"
The cohort paper describes the androgen receptor's normal transcription-factor function.
PMID:32338288 SUPPORT Human Clinical
"Impairment in androgen or DNA binding is the most common mechanism"
The paper supports impaired ligand or DNA binding as common mechanisms of AR dysfunction.
Androgen Target-Tissue Resistance
Complete androgen resistance prevents androgen-dependent masculinization of external genitalia and terminal sexual hair despite a 46,XY karyotype and testes.
Downstream
Female 46XY External Phenotype Complete androgen resistance produces female external genitalia in a 46,XY individual.
Sparse or Absent Terminal Sexual Hair Pubic and axillary hair development is reduced because terminal sexual hair growth depends on androgen receptor signaling.
Undescended Testes Complete androgen resistance is associated with normal testis development but failure of descent into the scrotum.
Show evidence (2 references)
PMID:22698698 SUPPORT Human Clinical
"female phenotype in an individual with an XY"
The Lancet seminar defines complete AIS as female phenotype with XY karyotype and testes producing normal androgens.
PMID:32338288 SUPPORT Human Clinical
"a normal amount of testosterone secretion but with symptoms and signs of androgen deficiency or reduction"
This statement captures androgen resistance despite preserved testosterone secretion.
Female 46XY External Phenotype
Affected individuals have female external genitalia in the setting of a 46,XY karyotype and testes, often presenting with inguinal swelling in infancy or primary amenorrhea at puberty.
Show evidence (2 references)
ORPHA:99429 SUPPORT Other
"HP:0008730 | Female external genitalia in individual with 46,XY karyotype | Very frequent (99-80%)"
Orphanet records the defining 46,XY female-external-genital phenotype as very frequent.
PMID:29785970 SUPPORT Human Clinical
"Affected individuals typically exhibit inguinal swelling during infancy or primary amenorrhea during puberty."
The AIS cohort paper describes common CAIS presentations by life stage.
Sparse or Absent Terminal Sexual Hair
Pubic and axillary hair are sparse or absent in many postpubertal affected individuals because androgen receptor signaling is required for normal androgen-dependent terminal hair development.
Show evidence (2 references)
ORPHA:99429 SUPPORT Other
"HP:0002221 | Absent axillary hair | Frequent (79-30%)"
Orphanet records absent axillary hair as frequent in CAIS.
ORPHA:99429 SUPPORT Other
"HP:0002555 | Absent pubic hair | Frequent (79-30%)"
Orphanet records absent pubic hair as frequent in CAIS.
Mullerian-Derived Structure Aplasia
Testicular development and anti-Mullerian hormone production generally produce regression of Mullerian-derived internal reproductive structures, so the uterus, fallopian tubes, and cervix are absent or hypoplastic.
Show evidence (2 references)
PMID:32338288 SUPPORT Human Clinical
"Müllerian derivatives are generally not found in individuals with AIS."
The AIS heterogeneity paper states that Mullerian derivatives are generally absent in AIS.
ORPHA:99429 SUPPORT Other
"HP:0000151 | Aplasia of the uterus | Very frequent (99-80%)"
Orphanet records uterine aplasia as very frequent in CAIS.
Undescended Testes
Testes are commonly intra-abdominal, inguinal, or labial rather than scrotal in complete androgen insensitivity syndrome.
Downstream
Gonadal Germ Cell Tumor Risk Retained undescended gonadal tissue creates a tumor-risk management issue that informs gonadectomy decisions.
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0008689 | Bilateral cryptorchidism | Very frequent (99-80%)"
Orphanet records bilateral cryptorchidism as very frequent.
Gonadal Germ Cell Tumor Risk
Retained gonadal tissue in CAIS carries recognized tumor risk, including germ cell neoplasia and reported Leydig cell tumors.
Show evidence (2 references)
ORPHA:99429 SUPPORT Other
"HP:0100728 | Germ cell neoplasia | Very rare (<4-1%)"
Orphanet records germ cell neoplasia as a rare CAIS phenotype.
PMID:36851849 SUPPORT Human Clinical
"A Leydig cell tumour of"
This case report documents testicular tumor detection after gonadectomy in an adult with CAIS.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Complete androgen insensitivity syndrome 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

25
Endocrine 1
Delayed puberty FREQUENT Delayed puberty (HP:0000823)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0000823 | Delayed puberty | Frequent (79-30%)"
Orphanet records delayed puberty as frequent in CAIS.
Genitourinary 4
Primary amenorrhea VERY_FREQUENT Primary amenorrhea (HP:0000786)
Show evidence (2 references)
ORPHA:99429 SUPPORT Other
"HP:0000786 | Primary amenorrhea | Very frequent (99-80%)"
Orphanet records primary amenorrhea as very frequent in CAIS.
PMID:29785970 SUPPORT Human Clinical
"six (aged 16–31 years) visited their physician owing to primary amenorrhea"
This AIS cohort supports primary amenorrhea as a postpubertal presentation.
Male infertility VERY_FREQUENT Male infertility (HP:0003251)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0003251 | Male infertility | Very frequent (99-80%)"
Orphanet records male infertility as very frequent in CAIS.
Female external genitalia in individual with 46,XY karyotype VERY_FREQUENT Female external genitalia in individual with 46,XY karyotype (HP:0008730)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0008730 | Female external genitalia in individual with 46,XY karyotype | Very frequent (99-80%)"
Orphanet records this defining phenotype as very frequent in CAIS.
Testicular neoplasm OCCASIONAL Testicular neoplasm (HP:0010788)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0010788 | Testicular neoplasm | Occasional (29-5%)"
Orphanet records testicular neoplasm as occasional in CAIS.
Immune 1
Acne VERY_RARE Acne (HP:0001061)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0001061 | Acne | Very rare (<4-1%)"
Orphanet records acne as very rare in CAIS.
Integument 1
Absent axillary hair FREQUENT Absent axillary hair (HP:0002221)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0002221 | Absent axillary hair | Frequent (79-30%)"
Orphanet records absent axillary hair as frequent in CAIS.
Nervous System 2
Depression OCCASIONAL Depression (HP:0000716)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0000716 | Depression | Occasional (29-5%)"
Orphanet records depression as occasional in CAIS.
Anxiety FREQUENT Anxiety (HP:0000739)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0000739 | Anxiety | Frequent (79-30%)"
Orphanet records anxiety as frequent in CAIS.
Growth 1
Tall stature VERY_FREQUENT Tall stature (HP:0000098)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0000098 | Tall stature | Very frequent (99-80%)"
Orphanet records tall stature as very frequent in CAIS.
Other 15
Abnormal morphology of female internal genitalia VERY_FREQUENT Abnormal morphology of female internal genitalia (HP:0000008)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0000008 | Abnormal morphology of female internal genitalia | Very frequent (99-80%)"
Orphanet records this phenotype as very frequent in CAIS.
Aplasia of the uterus VERY_FREQUENT Aplasia of the uterus (HP:0000151)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0000151 | Aplasia of the uterus | Very frequent (99-80%)"
Orphanet records uterine aplasia as very frequent in CAIS.
Sparse axillary hair FREQUENT Sparse axillary hair (HP:0002215)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0002215 | Sparse axillary hair | Frequent (79-30%)"
Orphanet records sparse axillary hair as frequent in CAIS.
Sparse pubic hair FREQUENT Sparse pubic hair (HP:0002225)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0002225 | Sparse pubic hair | Frequent (79-30%)"
Orphanet records sparse pubic hair as frequent in CAIS.
Absent pubic hair FREQUENT Absent pubic hair (HP:0002555)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0002555 | Absent pubic hair | Frequent (79-30%)"
Orphanet records absent pubic hair as frequent in CAIS.
Aplasia or hypoplasia of the fallopian tube VERY_FREQUENT Aplasia/Hypoplasia of the fallopian tube (HP:0008655)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0008655 | Aplasia/Hypoplasia of the fallopian tube | Very frequent (99-80%)"
Orphanet records fallopian tube aplasia or hypoplasia as very frequent in CAIS.
Bilateral cryptorchidism VERY_FREQUENT Bilateral cryptorchidism (HP:0008689)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0008689 | Bilateral cryptorchidism | Very frequent (99-80%)"
Orphanet records bilateral cryptorchidism as very frequent in CAIS.
Elevated circulating luteinizing hormone level VERY_FREQUENT Elevated circulating luteinizing hormone level (HP:0011969)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0011969 | Elevated circulating luteinizing hormone level | Very frequent (99-80%)"
Orphanet records elevated LH as very frequent in CAIS.
Abnormal uterine cervix morphology VERY_FREQUENT Abnormal uterine cervix morphology (HP:0012888)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0012888 | Abnormality of the uterine cervix | Very frequent (99-80%)"
Orphanet records abnormal uterine cervix morphology as very frequent in CAIS.
Increased serum estradiol VERY_FREQUENT Increased serum estradiol (HP:0025134)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0025134 | Increased serum estradiol | Very frequent (99-80%)"
Orphanet records increased serum estradiol as very frequent in CAIS.
Increased serum testosterone level VERY_FREQUENT Increased serum testosterone level (HP:0030088)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0030088 | Increased serum testosterone level | Very frequent (99-80%)"
Orphanet records increased serum testosterone as very frequent in CAIS.
Abnormal circulating follicle-stimulating hormone concentration VERY_RARE Abnormal circulating follicle-stimulating hormone concentration (HP:0030346)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0030346 | Abnormal circulating follicle-stimulating hormone level | Very rare (<4-1%)"
Orphanet records abnormal circulating FSH as very rare in CAIS.
Increased circulating antimullerian hormone concentration FREQUENT Increased circulating antimullerian hormone concentration (HP:0031102)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0031102 | Increased antimullerian hormone level | Frequent (79-30%)"
Orphanet records increased AMH as frequent in CAIS.
Blind vagina VERY_FREQUENT Blind vagina (HP:0040314)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0040314 | Blind vagina | Very frequent (99-80%)"
Orphanet records blind vagina as very frequent in CAIS.
Germ cell neoplasia VERY_RARE Germ cell neoplasia (HP:0100728)
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0100728 | Germ cell neoplasia | Very rare (<4-1%)"
Orphanet records germ cell neoplasia as very rare in CAIS.
🧬

Genetic Associations

1
AR (Causal hemizygous pathogenic variant)
Show evidence (3 references)
ORPHA:99429 SUPPORT Other
"AR | androgen receptor | hgnc:644 | Disease-causing germline mutation(s) in"
Orphanet records AR as the CAIS disease gene.
PMID:30251955 SUPPORT Human Clinical
"All of the complete AIS (CAIS) cases were genetically confirmed"
This tertiary-center cohort supports AR molecular confirmation in CAIS.
PMID:29785970 SUPPORT Human Clinical
"Sequence analysis revealed that all ten patients harbored AR mutations."
This AIS cohort confirms pathogenic AR variants across clinically characterized patients.
💊

Treatments

3
Individualized gonadectomy
Action: gonadectomy MAXO:0001055
Gonadectomy is used to remove retained testes when tumor-risk management, timing of spontaneous puberty, patient goals, and sex-hormone replacement planning support removal.
Show evidence (2 references)
PMID:22698698 SUPPORT Human Clinical
"include gonadectomy to avoid gonad tumours in later"
The Lancet seminar supports gonadectomy as part of AIS management to reduce later gonadal tumor risk.
PMID:39600030 SUPPORT Human Clinical
"postponed gonadectomy until post-puberty"
This case report supports individualized timing of gonadectomy, including postpubertal deferral.
Estrogen sex hormone replacement
Action: sex hormone modifying agent therapy MAXO:0000282
Agent: estradiol ↗
Estrogen replacement is used after gonadectomy or when endogenous sex steroid production is insufficient, aiming to maintain feminization and reduce consequences of estrogen deficiency.
Show evidence (2 references)
PMID:22698698 SUPPORT Human Clinical
"appropriate sex-hormone replacement at puberty and beyond"
The Lancet seminar supports sex-hormone replacement in AIS management.
PMID:39600030 SUPPORT Human Clinical
"tailored estrogen replacement therapy"
This CAIS case report specifically supports estrogen replacement therapy.
Vaginal dilation
Action: therapeutic procedure of reproductive system MAXO:0001420
Vaginal dilation can be used when vaginal length is short to improve functional vaginal length and reduce dyspareunia risk.
Show evidence (1 reference)
PMID:26012135 SUPPORT Human Clinical
"Vaginal length may be short requiring"
This CAIS case report supports vaginal dilation when clinically needed.
🔬

Biochemical Markers

3
Testosterone (NORMAL_OR_ELEVATED_MALE_RANGE)
Context: Testes produce age-appropriate male-range androgens, so the biochemical pattern differs from testosterone biosynthesis defects.
Show evidence (2 references)
PMID:22698698 SUPPORT Human Clinical
"testes producing age-appropriate normal concentrations of"
The Lancet seminar supports preserved age-appropriate androgen production in complete AIS.
PMID:32338288 SUPPORT Human Clinical
"normal amount of testosterone secretion"
The AIS heterogeneity paper supports normal testosterone secretion despite androgen resistance.
Estradiol (INCREASED)
Context: Serum estradiol is frequently increased.
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0025134 | Increased serum estradiol | Very frequent (99-80%)"
Orphanet records increased serum estradiol as very frequent in CAIS.
Luteinizing hormone (INCREASED)
Context: Luteinizing hormone is very frequently elevated.
Show evidence (1 reference)
ORPHA:99429 SUPPORT Other
"HP:0011969 | Elevated circulating luteinizing hormone level | Very frequent (99-80%)"
Orphanet records elevated circulating luteinizing hormone level as very frequent in CAIS.
{ }

Source YAML

click to show 
name: Complete androgen insensitivity syndrome
creation_date: "2026-05-11T04:48:29Z"
updated_date: "2026-05-11T04:48:29Z"
category: Mendelian
description: >-
  Complete androgen insensitivity syndrome is an X-linked disorder of sex
  development caused by pathogenic variants in AR, the androgen receptor gene.
  Individuals have a 46,XY karyotype and testes that produce age-appropriate
  androgens, but target tissues are unable to respond to androgen signaling.
  The result is female external genitalia, absent or sparse pubic and axillary
  hair, primary amenorrhea, absent Mullerian-derived internal reproductive
  structures, and undescended testes.
disease_term:
  preferred_term: complete androgen insensitivity syndrome
  term:
    id: MONDO:0021023
    label: complete androgen insensitivity syndrome
synonyms:
- CAIS
- Complete androgen resistance syndrome
- Complete testicular feminization syndrome
parents:
- Androgen insensitivity syndrome
- 46,XY disorder of sex development
- Androgen receptor signaling disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0021023
      label: complete androgen insensitivity syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO identifier for the disease.
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    Complete androgen insensitivity syndrome is inherited in an X-linked
    recessive pattern through hemizygous pathogenic variants in AR.
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "X-linked recessive"
    explanation: Orphanet lists X-linked recessive inheritance for complete androgen insensitivity syndrome.
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A pathogenic mutation of the androgen receptor gene (AR; OMIM# 313700) is the only established molecular cause of the X-linked recessive inherited disease."
    explanation: This AIS cohort/review statement directly supports AR-based X-linked recessive inheritance.
prevalence:
- population: Worldwide
  percentage: "1-9 / 1,000,000"
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Worldwide | Point prevalence"
    explanation: Orphanet records a worldwide point-prevalence estimate for CAIS.
- population: Europe
  percentage: "1-9 / 100,000"
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Europe | Annual incidence"
    explanation: Orphanet records a European annual-incidence estimate for CAIS.
pathophysiology:
- name: AR Germline Pathogenic Variant
  description: >-
    Hemizygous pathogenic variants in AR disrupt the androgen receptor, the
    X-linked nuclear receptor that mediates testosterone and dihydrotestosterone
    responses.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  biological_processes:
  - preferred_term: androgen receptor signaling pathway
    term:
      id: GO:0030521
      label: androgen receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AR | androgen receptor | hgnc:644 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records germline AR variants as disease-causing in CAIS.
  - reference: PMID:22698698
    reference_title: Androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenesis is the result of mutations in the X-linked androgen"
    explanation: The Lancet seminar identifies X-linked AR mutations as the pathogenic basis.
  downstream:
  - target: Androgen Receptor Dysfunction
    causal_link_type: DIRECT
    description: >-
      AR variants impair receptor expression, ligand binding, DNA binding, or
      receptor-dependent transcriptional signaling.
    evidence:
    - reference: PMID:32338288
      reference_title: Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There are at least five potential mechanisms by which AR variants reduce or abolish AR function"
      explanation: This review/case study summarizes the principal mechanisms by which AR variants impair receptor function.
- name: Androgen Receptor Dysfunction
  description: >-
    Dysfunctional androgen receptor protein reduces androgen-dependent nuclear
    receptor signaling and transcriptional activation in androgen-responsive
    tissues.
  biological_processes:
  - preferred_term: androgen receptor signaling pathway
    term:
      id: GO:0030521
      label: androgen receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This protein functions as a steroid hormone-activated transcription factor"
    explanation: The cohort paper describes the androgen receptor's normal transcription-factor function.
  - reference: PMID:32338288
    reference_title: Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impairment in androgen or DNA binding is the most common mechanism"
    explanation: The paper supports impaired ligand or DNA binding as common mechanisms of AR dysfunction.
  downstream:
  - target: Androgen Target-Tissue Resistance
    causal_link_type: DIRECT
    description: >-
      Reduced receptor signaling makes androgen-responsive tissues resistant to
      otherwise age-appropriate androgen exposure.
    evidence:
    - reference: PMID:29785970
      reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "partial or complete inability of specific tissues to respond"
      explanation: The AIS cohort paper directly links AR mutations to androgen target-tissue resistance.
- name: Androgen Target-Tissue Resistance
  description: >-
    Complete androgen resistance prevents androgen-dependent masculinization of
    external genitalia and terminal sexual hair despite a 46,XY karyotype and
    testes.
  evidence:
  - reference: PMID:22698698
    reference_title: Androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "female phenotype in an individual with an XY"
    explanation: The Lancet seminar defines complete AIS as female phenotype with XY karyotype and testes producing normal androgens.
  - reference: PMID:32338288
    reference_title: Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a normal amount of testosterone secretion but with symptoms and signs of androgen deficiency or reduction"
    explanation: This statement captures androgen resistance despite preserved testosterone secretion.
  downstream:
  - target: Female 46XY External Phenotype
    causal_link_type: DIRECT
    description: Complete androgen resistance produces female external genitalia in a 46,XY individual.
    evidence:
    - reference: ORPHA:99429
      reference_title: Complete androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "female external genitalia in a 46,XY individual"
      explanation: Orphanet directly states the CAIS external-genital phenotype.
  - target: Sparse or Absent Terminal Sexual Hair
    causal_link_type: DIRECT
    description: >-
      Pubic and axillary hair development is reduced because terminal sexual
      hair growth depends on androgen receptor signaling.
    evidence:
    - reference: PMID:29785970
      reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "scant or absent pubic and/or axillary hair"
      explanation: The AIS cohort reports scant or absent pubic and axillary hair in postpubertal patients.
  - target: Undescended Testes
    causal_link_type: DIRECT
    description: >-
      Complete androgen resistance is associated with normal testis development
      but failure of descent into the scrotum.
    evidence:
    - reference: ORPHA:99429
      reference_title: Complete androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "normal testis development but undescended testes and unresponsiveness to age-appropriate levels of androgens."
      explanation: Orphanet directly links CAIS androgen unresponsiveness with undescended testes.
- name: Female 46XY External Phenotype
  description: >-
    Affected individuals have female external genitalia in the setting of a
    46,XY karyotype and testes, often presenting with inguinal swelling in
    infancy or primary amenorrhea at puberty.
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008730 | Female external genitalia in individual with 46,XY karyotype | Very frequent (99-80%)"
    explanation: Orphanet records the defining 46,XY female-external-genital phenotype as very frequent.
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals typically exhibit inguinal swelling during infancy or primary amenorrhea during puberty."
    explanation: The AIS cohort paper describes common CAIS presentations by life stage.
- name: Sparse or Absent Terminal Sexual Hair
  description: >-
    Pubic and axillary hair are sparse or absent in many postpubertal affected
    individuals because androgen receptor signaling is required for normal
    androgen-dependent terminal hair development.
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002221 | Absent axillary hair | Frequent (79-30%)"
    explanation: Orphanet records absent axillary hair as frequent in CAIS.
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002555 | Absent pubic hair | Frequent (79-30%)"
    explanation: Orphanet records absent pubic hair as frequent in CAIS.
- name: Mullerian-Derived Structure Aplasia
  description: >-
    Testicular development and anti-Mullerian hormone production generally
    produce regression of Mullerian-derived internal reproductive structures,
    so the uterus, fallopian tubes, and cervix are absent or hypoplastic.
  evidence:
  - reference: PMID:32338288
    reference_title: Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Müllerian derivatives are generally not found in individuals with AIS."
    explanation: The AIS heterogeneity paper states that Mullerian derivatives are generally absent in AIS.
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000151 | Aplasia of the uterus | Very frequent (99-80%)"
    explanation: Orphanet records uterine aplasia as very frequent in CAIS.
- name: Undescended Testes
  description: >-
    Testes are commonly intra-abdominal, inguinal, or labial rather than
    scrotal in complete androgen insensitivity syndrome.
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008689 | Bilateral cryptorchidism | Very frequent (99-80%)"
    explanation: Orphanet records bilateral cryptorchidism as very frequent.
  downstream:
  - target: Gonadal Germ Cell Tumor Risk
    causal_link_type: DIRECT
    description: >-
      Retained undescended gonadal tissue creates a tumor-risk management issue
      that informs gonadectomy decisions.
    evidence:
    - reference: PMID:22698698
      reference_title: Androgen insensitivity syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "include gonadectomy to avoid gonad tumours in later"
      explanation: The Lancet seminar links gonadectomy decisions to avoiding later gonadal tumors.
- name: Gonadal Germ Cell Tumor Risk
  description: >-
    Retained gonadal tissue in CAIS carries recognized tumor risk, including
    germ cell neoplasia and reported Leydig cell tumors.
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100728 | Germ cell neoplasia | Very rare (<4-1%)"
    explanation: Orphanet records germ cell neoplasia as a rare CAIS phenotype.
  - reference: PMID:36851849
    reference_title: "Complete androgen insensitivity syndrome: a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A Leydig cell tumour of"
    explanation: This case report documents testicular tumor detection after gonadectomy in an adult with CAIS.
phenotypes:
- name: Abnormal morphology of female internal genitalia
  category: Genitourinary
  frequency: VERY_FREQUENT
  description: Internal genital tract anatomy is abnormal, usually with absent Mullerian-derived structures.
  phenotype_term:
    preferred_term: Abnormal morphology of female internal genitalia
    term:
      id: HP:0000008
      label: Abnormal morphology of female internal genitalia
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000008 | Abnormal morphology of female internal genitalia | Very frequent (99-80%)"
    explanation: Orphanet records this phenotype as very frequent in CAIS.
- name: Tall stature
  category: Growth
  frequency: VERY_FREQUENT
  description: Tall stature is very frequently reported.
  phenotype_term:
    preferred_term: Tall stature
    term:
      id: HP:0000098
      label: Tall stature
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000098 | Tall stature | Very frequent (99-80%)"
    explanation: Orphanet records tall stature as very frequent in CAIS.
- name: Aplasia of the uterus
  category: Genitourinary
  frequency: VERY_FREQUENT
  description: The uterus is usually absent.
  phenotype_term:
    preferred_term: Aplasia of the uterus
    term:
      id: HP:0000151
      label: Aplasia of the uterus
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000151 | Aplasia of the uterus | Very frequent (99-80%)"
    explanation: Orphanet records uterine aplasia as very frequent in CAIS.
- name: Depression
  category: Neuropsychiatric
  frequency: OCCASIONAL
  description: Depression is reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000716 | Depression | Occasional (29-5%)"
    explanation: Orphanet records depression as occasional in CAIS.
- name: Anxiety
  category: Neuropsychiatric
  frequency: FREQUENT
  description: Anxiety is frequently reported.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000739 | Anxiety | Frequent (79-30%)"
    explanation: Orphanet records anxiety as frequent in CAIS.
- name: Primary amenorrhea
  category: Genitourinary
  frequency: VERY_FREQUENT
  description: Primary amenorrhea is a common presentation at puberty.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000786 | Primary amenorrhea | Very frequent (99-80%)"
    explanation: Orphanet records primary amenorrhea as very frequent in CAIS.
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "six (aged 16–31 years) visited their physician owing to primary amenorrhea"
    explanation: This AIS cohort supports primary amenorrhea as a postpubertal presentation.
- name: Delayed puberty
  category: Endocrine
  frequency: FREQUENT
  description: Pubertal development may be delayed or atypical.
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000823 | Delayed puberty | Frequent (79-30%)"
    explanation: Orphanet records delayed puberty as frequent in CAIS.
- name: Acne
  category: Dermatologic
  frequency: VERY_RARE
  description: Acne is rarely reported.
  phenotype_term:
    preferred_term: Acne
    term:
      id: HP:0001061
      label: Acne
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001061 | Acne | Very rare (<4-1%)"
    explanation: Orphanet records acne as very rare in CAIS.
- name: Sparse axillary hair
  category: Dermatologic
  frequency: FREQUENT
  description: Axillary hair is often sparse.
  phenotype_term:
    preferred_term: Sparse axillary hair
    term:
      id: HP:0002215
      label: Sparse axillary hair
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002215 | Sparse axillary hair | Frequent (79-30%)"
    explanation: Orphanet records sparse axillary hair as frequent in CAIS.
- name: Absent axillary hair
  category: Dermatologic
  frequency: FREQUENT
  description: Axillary hair may be absent.
  phenotype_term:
    preferred_term: Absent axillary hair
    term:
      id: HP:0002221
      label: Absent axillary hair
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002221 | Absent axillary hair | Frequent (79-30%)"
    explanation: Orphanet records absent axillary hair as frequent in CAIS.
- name: Sparse pubic hair
  category: Dermatologic
  frequency: FREQUENT
  description: Pubic hair is often sparse.
  phenotype_term:
    preferred_term: Sparse pubic hair
    term:
      id: HP:0002225
      label: Sparse pubic hair
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002225 | Sparse pubic hair | Frequent (79-30%)"
    explanation: Orphanet records sparse pubic hair as frequent in CAIS.
- name: Absent pubic hair
  category: Dermatologic
  frequency: FREQUENT
  description: Pubic hair may be absent.
  phenotype_term:
    preferred_term: Absent pubic hair
    term:
      id: HP:0002555
      label: Absent pubic hair
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002555 | Absent pubic hair | Frequent (79-30%)"
    explanation: Orphanet records absent pubic hair as frequent in CAIS.
- name: Male infertility
  category: Reproductive
  frequency: VERY_FREQUENT
  description: Individuals with CAIS and testes are infertile.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003251 | Male infertility | Very frequent (99-80%)"
    explanation: Orphanet records male infertility as very frequent in CAIS.
- name: Aplasia or hypoplasia of the fallopian tube
  category: Genitourinary
  frequency: VERY_FREQUENT
  description: Fallopian tubes are absent or hypoplastic.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the fallopian tube
    term:
      id: HP:0008655
      label: Aplasia/Hypoplasia of the fallopian tube
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008655 | Aplasia/Hypoplasia of the fallopian tube | Very frequent (99-80%)"
    explanation: Orphanet records fallopian tube aplasia or hypoplasia as very frequent in CAIS.
- name: Bilateral cryptorchidism
  category: Genitourinary
  frequency: VERY_FREQUENT
  description: Both testes are undescended.
  phenotype_term:
    preferred_term: Bilateral cryptorchidism
    term:
      id: HP:0008689
      label: Bilateral cryptorchidism
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008689 | Bilateral cryptorchidism | Very frequent (99-80%)"
    explanation: Orphanet records bilateral cryptorchidism as very frequent in CAIS.
- name: Female external genitalia in individual with 46,XY karyotype
  category: Genitourinary
  frequency: VERY_FREQUENT
  description: Affected individuals have female external genitalia despite a 46,XY karyotype.
  phenotype_term:
    preferred_term: Female external genitalia in individual with 46,XY karyotype
    term:
      id: HP:0008730
      label: Female external genitalia in individual with 46,XY karyotype
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008730 | Female external genitalia in individual with 46,XY karyotype | Very frequent (99-80%)"
    explanation: Orphanet records this defining phenotype as very frequent in CAIS.
- name: Testicular neoplasm
  category: Neoplastic
  frequency: OCCASIONAL
  description: Testicular neoplasia can occur in retained gonads.
  phenotype_term:
    preferred_term: Testicular neoplasm
    term:
      id: HP:0010788
      label: Testicular neoplasm
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010788 | Testicular neoplasm | Occasional (29-5%)"
    explanation: Orphanet records testicular neoplasm as occasional in CAIS.
- name: Elevated circulating luteinizing hormone level
  category: Endocrine
  frequency: VERY_FREQUENT
  description: Luteinizing hormone levels are often elevated.
  phenotype_term:
    preferred_term: Elevated circulating luteinizing hormone level
    term:
      id: HP:0011969
      label: Elevated circulating luteinizing hormone level
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011969 | Elevated circulating luteinizing hormone level | Very frequent (99-80%)"
    explanation: Orphanet records elevated LH as very frequent in CAIS.
- name: Abnormal uterine cervix morphology
  category: Genitourinary
  frequency: VERY_FREQUENT
  description: The uterine cervix is absent or otherwise abnormal.
  phenotype_term:
    preferred_term: Abnormal uterine cervix morphology
    term:
      id: HP:0012888
      label: Abnormal uterine cervix morphology
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012888 | Abnormality of the uterine cervix | Very frequent (99-80%)"
    explanation: Orphanet records abnormal uterine cervix morphology as very frequent in CAIS.
- name: Increased serum estradiol
  category: Endocrine
  frequency: VERY_FREQUENT
  description: Serum estradiol is frequently elevated relative to the clinical context.
  phenotype_term:
    preferred_term: Increased serum estradiol
    term:
      id: HP:0025134
      label: Increased serum estradiol
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025134 | Increased serum estradiol | Very frequent (99-80%)"
    explanation: Orphanet records increased serum estradiol as very frequent in CAIS.
- name: Increased serum testosterone level
  category: Endocrine
  frequency: VERY_FREQUENT
  description: Serum testosterone is frequently in the male or elevated range.
  phenotype_term:
    preferred_term: Increased serum testosterone level
    term:
      id: HP:0030088
      label: Increased serum testosterone level
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030088 | Increased serum testosterone level | Very frequent (99-80%)"
    explanation: Orphanet records increased serum testosterone as very frequent in CAIS.
- name: Abnormal circulating follicle-stimulating hormone concentration
  category: Endocrine
  frequency: VERY_RARE
  description: Follicle-stimulating hormone concentration may be abnormal in rare cases.
  phenotype_term:
    preferred_term: Abnormal circulating follicle-stimulating hormone concentration
    term:
      id: HP:0030346
      label: Abnormal circulating follicle-stimulating hormone concentration
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030346 | Abnormal circulating follicle-stimulating hormone level | Very rare (<4-1%)"
    explanation: Orphanet records abnormal circulating FSH as very rare in CAIS.
- name: Increased circulating antimullerian hormone concentration
  category: Endocrine
  frequency: FREQUENT
  description: Antimullerian hormone concentration is frequently increased.
  phenotype_term:
    preferred_term: Increased circulating antimullerian hormone concentration
    term:
      id: HP:0031102
      label: Increased circulating antimullerian hormone concentration
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031102 | Increased antimullerian hormone level | Frequent (79-30%)"
    explanation: Orphanet records increased AMH as frequent in CAIS.
- name: Blind vagina
  category: Genitourinary
  frequency: VERY_FREQUENT
  description: The vagina commonly ends blindly and may be short.
  phenotype_term:
    preferred_term: Blind vagina
    term:
      id: HP:0040314
      label: Blind vagina
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0040314 | Blind vagina | Very frequent (99-80%)"
    explanation: Orphanet records blind vagina as very frequent in CAIS.
- name: Germ cell neoplasia
  category: Neoplastic
  frequency: VERY_RARE
  description: Germ cell neoplasia is reported rarely.
  phenotype_term:
    preferred_term: Germ cell neoplasia
    term:
      id: HP:0100728
      label: Germ cell neoplasia
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100728 | Germ cell neoplasia | Very rare (<4-1%)"
    explanation: Orphanet records germ cell neoplasia as very rare in CAIS.
biochemical:
- name: Testosterone
  presence: NORMAL_OR_ELEVATED_MALE_RANGE
  context: >-
    Testes produce age-appropriate male-range androgens, so the biochemical
    pattern differs from testosterone biosynthesis defects.
  biomarker_term:
    preferred_term: testosterone
    term:
      id: CHEBI:17347
      label: testosterone
  evidence:
  - reference: PMID:22698698
    reference_title: Androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "testes producing age-appropriate normal concentrations of"
    explanation: The Lancet seminar supports preserved age-appropriate androgen production in complete AIS.
  - reference: PMID:32338288
    reference_title: Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal amount of testosterone secretion"
    explanation: The AIS heterogeneity paper supports normal testosterone secretion despite androgen resistance.
- name: Estradiol
  presence: INCREASED
  context: Serum estradiol is frequently increased.
  biomarker_term:
    preferred_term: estradiol
    term:
      id: CHEBI:23965
      label: estradiol
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025134 | Increased serum estradiol | Very frequent (99-80%)"
    explanation: Orphanet records increased serum estradiol as very frequent in CAIS.
- name: Luteinizing hormone
  presence: INCREASED
  context: Luteinizing hormone is very frequently elevated.
  biomarker_term:
    preferred_term: Luteinizing hormone
    term:
      id: CHEBI:81568
      label: Luteinizing hormone
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011969 | Elevated circulating luteinizing hormone level | Very frequent (99-80%)"
    explanation: Orphanet records elevated circulating luteinizing hormone level as very frequent in CAIS.
genetic:
- name: AR
  association: Causal hemizygous pathogenic variant
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  notes: >-
    Pathogenic AR variants include missense, nonsense, splice-site, deletion,
    duplication, frameshift, and occasional mosaic variants. CAIS is most often
    genetically confirmed when the phenotype is complete.
  evidence:
  - reference: ORPHA:99429
    reference_title: Complete androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AR | androgen receptor | hgnc:644 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records AR as the CAIS disease gene.
  - reference: PMID:30251955
    reference_title: "Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the complete AIS (CAIS) cases were genetically confirmed"
    explanation: This tertiary-center cohort supports AR molecular confirmation in CAIS.
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis revealed that all ten patients harbored AR mutations."
    explanation: This AIS cohort confirms pathogenic AR variants across clinically characterized patients.
diagnosis:
- name: Clinical DSD presentation
  description: >-
    CAIS is suspected in a phenotypically female infant or adolescent with
    inguinal/labial testes, inguinal hernia, primary amenorrhea, absent uterus,
    and sparse or absent pubic and axillary hair.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  results: Female phenotype with signs of a 46,XY DSD.
  evidence:
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical diagnosis of CAIS is typically based on primary amenorrhea at puberty or inguinal hernia and labial swelling in a female infant with a 46, XY karyotype."
    explanation: This directly describes typical clinical diagnostic triggers.
- name: Karyotyping
  description: Karyotyping identifies the 46,XY chromosomal sex in a phenotypically female patient.
  diagnosis_term:
    preferred_term: karyotyping
    term:
      id: MAXO:0001611
      label: karyotyping
  results: 46,XY karyotype.
  evidence:
  - reference: PMID:26012135
    reference_title: "[Complete androgen insensitivity syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cytogenetic analysis showed a 46 XY karyotype."
    explanation: This CAIS case report supports karyotyping as part of diagnostic evaluation.
- name: Hormone measurement
  description: >-
    Hormone testing shows male-range androgen production with androgen
    resistance rather than a testosterone biosynthesis defect.
  diagnosis_term:
    preferred_term: hormone measurement
    term:
      id: MAXO:0035058
      label: hormone measurement
  results: Age-appropriate male-range androgens with androgen-resistance phenotype.
  evidence:
  - reference: PMID:26012135
    reference_title: "[Complete androgen insensitivity syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The values of sex hormones were"
    explanation: This CAIS case report supports hormone measurement showing male-range sex hormones.
  - reference: PMID:32338288
    reference_title: Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After hCG stimulation, testosterone showed a normal rise, and testosterone synthesis defects were thus excluded"
    explanation: This supports hormone testing to distinguish AIS from testosterone synthesis defects.
- name: Pelvic and gonadal imaging
  description: >-
    Pelvic imaging helps document absent Mullerian structures and locate
    intra-abdominal, inguinal, or labial testes.
  diagnosis_term:
    preferred_term: pelvis ultrasonography
    term:
      id: MAXO:0010219
      label: pelvis ultrasonography
  results: Absent uterus with inguinal, abdominal, or pelvic testicular tissue.
  evidence:
  - reference: PMID:26012135
    reference_title: "[Complete androgen insensitivity syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as in adult males. The multi-sliced computed tomography (MSCT) showed structures"
    explanation: This CAIS case report supports imaging to locate retained testes.
- name: AR molecular genetic testing
  description: >-
    Molecular testing for a pathogenic AR variant confirms the diagnosis and
    supports family counseling.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  results: Hemizygous pathogenic AR variant.
  evidence:
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "usefulness of AR gene sequencing to support a diagnosis of AIS and to enable"
    explanation: The cohort paper supports AR sequencing as diagnostic evidence for AIS.
  - reference: PMID:30251955
    reference_title: "Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The aim of this study was the molecular characterization of the AR"
    explanation: This cohort supports AR molecular characterization as a diagnostic approach.
treatments:
- name: Individualized gonadectomy
  description: >-
    Gonadectomy is used to remove retained testes when tumor-risk management,
    timing of spontaneous puberty, patient goals, and sex-hormone replacement
    planning support removal.
  treatment_term:
    preferred_term: gonadectomy
    term:
      id: MAXO:0001055
      label: gonadectomy
  evidence:
  - reference: PMID:22698698
    reference_title: Androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "include gonadectomy to avoid gonad tumours in later"
    explanation: The Lancet seminar supports gonadectomy as part of AIS management to reduce later gonadal tumor risk.
  - reference: PMID:39600030
    reference_title: "Complexities of complete androgen insensitivity syndrome: insights from a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "postponed gonadectomy until post-puberty"
    explanation: This case report supports individualized timing of gonadectomy, including postpubertal deferral.
- name: Estrogen sex hormone replacement
  description: >-
    Estrogen replacement is used after gonadectomy or when endogenous sex
    steroid production is insufficient, aiming to maintain feminization and
    reduce consequences of estrogen deficiency.
  treatment_term:
    preferred_term: sex hormone modifying agent therapy
    term:
      id: MAXO:0000282
      label: sex hormone modifying agent therapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:23965
        label: estradiol
  evidence:
  - reference: PMID:22698698
    reference_title: Androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "appropriate sex-hormone replacement at puberty and beyond"
    explanation: The Lancet seminar supports sex-hormone replacement in AIS management.
  - reference: PMID:39600030
    reference_title: "Complexities of complete androgen insensitivity syndrome: insights from a case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tailored estrogen replacement therapy"
    explanation: This CAIS case report specifically supports estrogen replacement therapy.
- name: Vaginal dilation
  description: >-
    Vaginal dilation can be used when vaginal length is short to improve
    functional vaginal length and reduce dyspareunia risk.
  treatment_term:
    preferred_term: therapeutic procedure of reproductive system
    term:
      id: MAXO:0001420
      label: therapeutic procedure of reproductive system
  evidence:
  - reference: PMID:26012135
    reference_title: "[Complete androgen insensitivity syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vaginal length may be short requiring"
    explanation: This CAIS case report supports vaginal dilation when clinically needed.
clinical_trials: []
datasets: []
notes: >-
  CAIS management should be individualized in an experienced multidisciplinary
  DSD setting with transparent counseling, psychological support, attention to
  fertility and sexual function, gonadal tumor-risk management, and shared
  decisions about timing of gonadectomy and hormone replacement. ORPHA:754 for
  the broader androgen insensitivity syndrome parent was not present in the
  local Orphadata index, so this entry uses the directly available ORPHA:99429
  structured disease record for complete androgen insensitivity syndrome.
references:
- reference: ORPHA:99429
  title: Complete androgen insensitivity syndrome
  tags: []
  findings:
  - statement: >-
      Orphanet structured record supporting CAIS definition, X-linked
      inheritance, AR disease-gene association, prevalence estimates, exact
      MONDO/OMIM cross-references, and CAIS phenotype frequencies.
- reference: PMID:29785970
  title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
  tags: []
  findings:
  - statement: >-
      AIS cohort supporting AR mutations, receptor-domain mechanisms, clinical
      presentation, AR sequencing, and complete/partial AIS phenotypic
      distinctions.
- reference: PMID:32338288
  title: Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome.
  tags: []
  findings:
  - statement: >-
      AIS case and review supporting androgen-resistance physiology, AR
      functional mechanisms, normal testosterone secretion, and heterogeneity
      modifiers.
- reference: PMID:30251955
  title: "Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort."
  tags: []
  findings:
  - statement: >-
      Tertiary-center cohort supporting genetic confirmation of CAIS and AR
      mutation distribution across the receptor coding sequence.
- reference: PMID:39600030
  title: "Complexities of complete androgen insensitivity syndrome: insights from a case report and literature review."
  tags: []
  findings:
  - statement: >-
      CAIS case report and literature review supporting diagnostic complexity,
      multidisciplinary management, postpubertal gonadectomy timing, and
      estrogen replacement therapy.
- reference: PMID:36851849
  title: "Complete androgen insensitivity syndrome: a case report and literature review."
  tags: []
  findings:
  - statement: >-
      CAIS case report supporting recurrent inguinal-hernia misdiagnosis,
      46,XY karyotype, bilateral gonadectomy, hormone replacement therapy, and
      postoperative Leydig cell tumor detection.
- reference: PMID:26012135
  title: "[Complete androgen insensitivity syndrome]."
  tags: []
  findings:
  - statement: >-
      CAIS case report supporting karyotyping, hormone analysis, imaging,
      gonadectomy, hormone replacement after gonadectomy, and vaginal dilation
      when needed.
- reference: PMID:22698698
  title: Androgen insensitivity syndrome.
  tags: []
  findings:
  - statement: >-
      Lancet seminar supporting CAIS definition, X-linked AR pathogenesis,
      mechanism of androgen action, multidisciplinary care, gonadectomy,
      sex-hormone replacement, and disclosure-centered management.
📚

References & Deep Research

References

8
ORPHA:99429
Complete androgen insensitivity syndrome
1 finding
Orphanet structured record supporting CAIS definition, X-linked inheritance, AR disease-gene association, prevalence estimates, exact MONDO/OMIM cross-references, and CAIS phenotype frequencies.
PMID:29785970
Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
1 finding
AIS cohort supporting AR mutations, receptor-domain mechanisms, clinical presentation, AR sequencing, and complete/partial AIS phenotypic distinctions.
PMID:32338288
Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome.
1 finding
AIS case and review supporting androgen-resistance physiology, AR functional mechanisms, normal testosterone secretion, and heterogeneity modifiers.
PMID:30251955
Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort.
1 finding
Tertiary-center cohort supporting genetic confirmation of CAIS and AR mutation distribution across the receptor coding sequence.
PMID:39600030
Complexities of complete androgen insensitivity syndrome: insights from a case report and literature review.
1 finding
CAIS case report and literature review supporting diagnostic complexity, multidisciplinary management, postpubertal gonadectomy timing, and estrogen replacement therapy.
PMID:36851849
Complete androgen insensitivity syndrome: a case report and literature review.
1 finding
CAIS case report supporting recurrent inguinal-hernia misdiagnosis, 46,XY karyotype, bilateral gonadectomy, hormone replacement therapy, and postoperative Leydig cell tumor detection.
PMID:26012135
[Complete androgen insensitivity syndrome].
1 finding
CAIS case report supporting karyotyping, hormone analysis, imaging, gonadectomy, hormone replacement after gonadectomy, and vaginal dilation when needed.
PMID:22698698
Androgen insensitivity syndrome.
1 finding
Lancet seminar supporting CAIS definition, X-linked AR pathogenesis, mechanism of androgen action, multidisciplinary care, gonadectomy, sex-hormone replacement, and disclosure-centered management.

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Complete androgen insensitivity syndrome. Core disease mechanisms, molecul...
Asta Scientific Corpus Retrieval 20 citations 2026-05-10T21:49:41.918086

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Complete androgen insensitivity syndrome. Core disease mechanisms, molecul...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Phenotypic and molecular characteristics of androgen insensitivity syndrome patients

  • Authors: Shimin Yuan, Ya-Nan Zhang, J. Du, Wen Li, C. Tu et al.
  • Year: 2018
  • Venue: Asian Journal of Andrology
  • URL: https://www.semanticscholar.org/paper/44a0ebbf510a1f0d97912e5814e737f441017d73
  • DOI: 10.4103/aja.aja_17_18
  • PMID: 29785970
  • PMCID: 6116692
  • Citations: 21
  • Summary: The spectrum of AR gene mutations is expanded and the usefulness ofAR gene sequencing to support a diagnosis of AIS and to enable prenatal or antenatal screening is confirmed.
  • Evidence snippets:
  • Snippet 1 (score: 0.480) > Androgen insensitivity syndrome (AIS; OMIM# 300068) is a common 46,XY disorder of sex development (DSD) resulting from complete or partial resistance to the biological actions of androgens. Affected individuals typically exhibit inguinal swelling during infancy or primary amenorrhea during puberty. 1 According to the degree of androgen responsiveness, AIS presents with a broad spectrum of defects in the external genitalia and can be subdivided into three phenotypes: complete androgen insensitivity syndrome (CAIS) with typical female external genitalia, partial androgen insensitivity syndrome (PAIS) with predominantly male or ambiguous external genitalia, and mild androgen insensitivity syndrome (MAIS) with typical male external genitalia or an isolated micropenis, but with gynecomastia at puberty and infertility in adulthood. 2 Of these categories, CAIS is the classic manifestation of AIS. The clinical diagnosis of CAIS is typically based on primary amenorrhea at puberty or inguinal hernia and labial swelling in a female infant with a 46,XY karyotype. 1 A pathogenic mutation of the androgen receptor gene (AR; OMIM# 313700) is the only established molecular cause of the X-linked recessive inherited disease. > The AR gene is located on chromosome Xq11-12 and contains eight exons that encode a protein of 920 amino acid residues. This protein functions as a steroid hormone-activated transcription factor and contains four major functional domains: the N-terminal

[2] Novel compound variants of the AR and MAP3K1 genes are related to the clinical heterogeneity of androgen insensitivity syndrome

  • Authors: Yiping Cheng, Yan Sun, Y. Ji, Dongqing Jiang, Guoxin Teng et al.
  • Year: 2020
  • Venue: Bioscience Reports
  • URL: https://www.semanticscholar.org/paper/2b9b4c76dc7fafdafac1bbde29d6a89cb4e457e1
  • DOI: 10.1042/BSR20200616
  • PMID: 32338288
  • PMCID: 7953519
  • Citations: 7
  • Summary: The phenotype of the patient with AIS may be caused by defects in both the AR and MAP3K1 signaling pathways, and whole-exome sequencing might reveal genetic variants that explain the heterogeneity of AIS.
  • Evidence snippets:
  • Snippet 1 (score: 0.473) > gene might act as a genetic modifier of the phenotype, as the patient has rudimentary Müllerian structures, which is uncommon in AIS. Therefore, we consider that the two pathogenic variants are the cause of AIS and that they are the exclusive causative agents of the phenotype of the described patient. Moreover, the confirmation of an AIS diagnosis by WES can reveal additional genetic variants to explain the heterogeneity of the disease. > AIS is highly heterogeneous and divided into three categories according to the degree of genital masculinization: mild androgen insensitivity syndrome (MAIS), partial androgen insensitivity syndrome (PAIS) and complete androgen insensitivity syndrome (CAIS). The clinical phenotypes range from a typical male habitus with mild spermatogenic defects and reduced secondary terminal hair to a full female habitus despite the presence of a Y chromosome. The correlation of genotype and phenotype has not yet been established. > AIS is a congenital disorder in which a defect in the AR gene leads to cellular resistance to androgens. More than 1000 AIS-causing mutations in the AR gene have been identified [24]. The types of AR gene variants include gene deletions, splice site mutations, premature stop codons and missense mutations, among others. The most common genetic abnormalities are missense mutations, which often occur in two important segments of the receptor protein: the DBD and LDB regions. Missense mutations that result in a single amino acid substitution are known to produce the most phenotypic diversity. > There are at least five potential mechanisms by which AR variants reduce or abolish AR function (Figure 6): androgen and AR binding disorders, androgen-AR complex and DNA-binding disorders, truncated AR proteins, altered ligand specificity and defective signal transduction downstream of AR. Impairment in androgen or DNA binding is the most common mechanism [25,26]. First, exons 5-8 and part of exon 4 encode the LBD, which includes residues 664-920 [27], and variants that cause androgen-AR-binding disorders are commonly reported in exons 4-8 [28,[29][30][31].

[3] [Somatic mutations in the androgen receptor gene as the cause of androgen insensitivity syndrome].

  • Authors: N. Kalinchenko, A. A. Kolodkina, V. Petrov, E. V. Vasiliev, A. Tiulpakov
  • Year: 2019
  • Venue: Problemy endokrinologii
  • URL: https://www.semanticscholar.org/paper/85dfb56e658632c648c25d9ba3e79714f2653af1
  • DOI: 10.14341/PROBL10166
  • PMID: 32202729
  • Citations: 1
  • Summary: The phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene are described.
  • Evidence snippets:
  • Snippet 1 (score: 0.466) > Androgen insensitivity syndrome is an X-linked disorder characterized by either complete or partial insensitivity of target tissues to androgens. This disease is caused by mutations in the AR gene located on the Х chromosome. Currently, there are no distinct clinical, biochemical, or hormonal markers that would allow one to differentiate androgen insensitivity syndrome from a number of other forms of 46,XY disorders of sex development. Therefore, final verification of this condition is based on the results of molecular genetic tests. Although more than 1,000 point mutations in the AR gene have been reported, somatic mutations in this gene have been described rather rarely. However, this very type of mutations makes the course of this disease difficult to predict, since various cells in the human body contain both normal and mutant receptors. Somatic mosaicism can cause spontaneous masculization during puberty in individuals born with a completely normal female phenotype. In this case report, we describe the phenotypic and molecular genetic characteristics of eight patients with various forms of androgen insensitivity syndrome caused by somatic mutations in the AR gene.

[4] The role of androgens and global and tissue-specific androgen receptor expression on body composition, exercise adaptation, and performance

  • Authors: Sabrina Tzivia Barsky, D. A. Monks
  • Year: 2025
  • Venue: Biology of Sex Differences
  • URL: https://www.semanticscholar.org/paper/7426826fc1f798d8afecfd9acef3bb3272f5eb79
  • DOI: 10.1186/s13293-025-00707-6
  • PMID: 40269952
  • PMCID: 12016402
  • Citations: 10
  • Summary: The understood mechanisms of action of AR and its interactions with exercise, specifically on outcomes of body composition and muscle function, and the global- and tissue-specific role of AR in regulating skeletal muscle, adipose, and bone morphology are summarized.
  • Evidence snippets:
  • Snippet 1 (score: 0.452) > Clinical observations of androgen insensitivity syndrome were first presented by Morris in 1953 [162] (then described as testicular feminization) in humans, and later in rats [163] and mice [33]. Cases of androgen insensitivity can be classified as complete, partial, or mild, and diagnoses are made by observation of female external genitalia in a XY karyotype male fetus (ie., complete androgen insensitivity), gynecomastia and atypical genitalia at puberty (ie., partial androgen insensitivity), or unaffected genitalia yet presence of male infertility (ie., mild androgen insensitivity). Complete androgen insensitivity was discovered and propagated in a substrain of rats, lending an in vivo model to study the molecular underpinnings of androgen insensitivity and the influence of lost AR function on sex development, aptly named the testicular feminized (Tfm) rat. Tfm males develop testes, which remain undescended in the inguinal canal, appearing to have immature Sertoli cells limiting the progression of spermatogenesis [164] and hyperplasia of Leydig cells allowing for normal to excess androgen production [165]. Additionally, Tfm males do not develop male accessory sex organs (ie., prostate, epididymis, ductus deferens, seminal vesicles). Studies attempting to identify mechanisms of androgen insensitivity in the Tfm rat revealed that cytoplasmic AR was decreased in target organs [166,167] and had reduced binding capacity for androgens [168], which resulted from a single base mutation in the AR gene [169]. The limitations in the Tfm model included male sterility and no opportunity to study females with complete aberrant AR function, as female carriers of Tfm are genetic mosaics for androgen insensitivity [170]. This brought forth the production of the androgen receptor knockout mouse (ARKO) [68].

[5] Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis

  • Authors: Yajie Peng, Hui Zhu, B. Han, Yue Xu, Xuemeng Liu et al.
  • Year: 2021
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/10bfaf772debd7b833a9c0a820696d4329d5881e
  • DOI: 10.3389/fendo.2021.731107
  • PMID: 34867780
  • PMCID: 8637961
  • Citations: 4
  • Summary: Light is shed on the molecular mechanisms underlying the pathogenesis and progression of AIS, providing potential targets for diagnosis and future investigation and manual screening of tissue-specific gene expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.434) > Background Androgen insensitivity syndrome (AIS) is a rare X-linked genetic disease and one of the causes of 46,XY disorder of sexual development. The unstraightforward diagnosis of AIS and the gender assignment dilemma still make a plague for this disorder due to the overlapping clinical phenotypes. Methods Peripheral blood mononuclear cells (PBMCs) of partial AIS (PAIS) patients and healthy controls were separated, and RNA-seq was performed to investigate transcriptome variance. Then, tissue-specific gene expression, functional enrichment, and protein–protein interaction (PPI) network analyses were performed; and the key modules were identified. Finally, the RNA expression of differentially expressed genes (DEGs) of interest was validated by quantitative real-time PCR (qRT-PCR). Results In our dataset, a total of 725 DEGs were captured, with functionally enriched reproduction and immune-related pathways and Gene Ontology (GO) functions. The most highly specific systems centered on hematologic/immune and reproductive/endocrine systems. We finally filtered out CCR1, PPBP, PF4, CLU, KMT2D, GP6, and SPARC by the key gene clusters of the PPI network and manual screening of tissue-specific gene expression. These genes provide novel insight into the pathogenesis of AIS in the immune system or metabolism and bring forward possible molecular markers for clinical screening. The qRT-PCR results showed a consistent trend in the expression levels of related genes between PAIS patients and healthy controls. Conclusion The present study sheds light on the molecular mechanisms underlying the pathogenesis and progression of AIS, providing potential targets for diagnosis and future investigation.

[6] Genotype and phenotype of Vietnamese patients with androgen insensitivity syndrome

  • Authors: V. Dũng, M. Fukami, C. T. B. Ngọc, Bùi Phương Thảo, N. Khánh et al.
  • Year: 2013
  • Venue: International Journal of Pediatric Endocrinology
  • URL: https://www.semanticscholar.org/paper/b0aa73b6d8e6147c51f4c4346817d70c4db38af6
  • DOI: 10.1186/1687-9856-2013-S1-P194
  • PMCID: 3850449
  • Summary: Five different mutations of AR were identified from 7 cases of 3 unrelated families including three novel ones and two reported mutation in the AR gene that may provide new insights into the molecular mechanisms of AIS.
  • Evidence snippets:
  • Snippet 1 (score: 0.427) > Androgen insensitivity syndrome (AIS) is the most common specific cause of 46,XY disorder in sex development. The androgen signaling pathway is complex but so far, the only gene linked with AIS is the androgen receptor (AR). Mutations in the AR are found in most subjects with complete AIS but in partial AIS, the rate has varied 28–73%, depending on the case selection. More than over 800 entries of mutations causing AIS, representing over 500 different AR mutations from more than 850 patients with AIS have been reported. We aim to describe clinical manifestations and to identify mutation of AR in Vietnamese patients with AIS. > This case series study included 12 patients from 9 unrelated families with AIS. The gonadal position and external genitalia were evaluated clinicaly and using ultrasound. The mutation analysis of AR was performed using PCR and direct sequencing. > The age of diagnosis was 1 to 83 years old. 8/12 cases were complete androgen insensitivity syndrome (CAIS) (female external genitalia) and 4 cases were predominantly female partial AIS phenotype. Four cases had two labial testes, six cases had inguinal testes and 2 cases had abdominal testes. Five different mutations of AR were identified from 7 cases of 3 unrelated families including three novel ones. The novel missense mutation p.L701F (c.2103G>T) was identified in a patient of 83 year of age. The novel missense mutation p.L705F (c.2113C>T) was identified in two sibs. The novel mutation p. W752S (c. 2256 G>T) was identified in a child with CAIS phenotype and had family history. The reported missense mutation p.V747M was identified in two sibs. The reported mutation p.V867M (c.2599 G>A) was identified in a child with female phenotype. > Our study identified three novel and two reported mutation in the AR gene that may provide us new insights into the molecular mechanisms of AIS. The expanded database of these mutations should benefit patients in the diagnosis and treatment of this syndrome.

[7] An exposition on complete androgen insensitivity syndrome and a case report

  • Authors: S. Morkos, M. Al Qasem, M. Aldam, H. K. Bhotla, A. Meyyazhagan et al.
  • Year: 2025
  • Venue: Obstetrics, Gynecology and Reproduction
  • URL: https://www.semanticscholar.org/paper/3f16155635424f053f16454fef1b4264f53d6b85
  • DOI: 10.17749/2313-7347/ob.gyn.rep.2025.539
  • Citations: 2
  • Summary: The paper reports a case of CAIS in a 16-year-old woman with no menarche and 46,XY karyotyping and results showed hyperplasia of Leydig cells.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > An exposition on complete androgen insensitivity syndrome and a case report

[8] Complexities of complete androgen insensitivity syndrome: insights from a case report and literature review

  • Authors: E. Asanidze, Jenaro Kristesashvili, Aleksandre Asanidze, A. Jibladze, Giorgi Gaphrindashvili et al.
  • Year: 2024
  • Venue: The Journal of International Medical Research
  • URL: https://www.semanticscholar.org/paper/93c78b9dcfb14ce1a50ed9471967c8f0322cff20
  • DOI: 10.1177/03000605241300058
  • PMID: 39600030
  • PMCID: 11603565
  • Citations: 7
  • Influential citations: 1
  • Summary: This retrospective case report analyzes the clinical data, genetic testing, hormonal profiling, and imaging studies of a patient who was initially misdiagnosed during hernioplasty and later misidentified as having Mayer-Rokitansky-Küster-Hauser syndrome to highlight the necessity of a multidisciplinary approach to managing CAIS.
  • Evidence snippets:
  • Snippet 1 (score: 0.415) > Complexities of complete androgen insensitivity syndrome: insights from a case report and literature review

[9] Network analysis of an in vitro model of androgen-resistance in prostate cancer

  • Authors: S. Detchokul, Aparna Elangovan, E. Crampin, Melissa J. Davis, A. Frauman
  • Year: 2015
  • Venue: BMC Cancer
  • URL: https://www.semanticscholar.org/paper/b1ceea1ad550c95910c1b68491f4fb638c8aedd3
  • DOI: 10.1186/s12885-015-1884-7
  • PMID: 26553226
  • PMCID: 4640359
  • Citations: 6
  • Summary: An in vitro model of androgen-resistance is developed to characterise molecular changes occurring as androgen resistance evolves over time and reveals several potential mechanisms and network interactions, including cooperative behaviours of other nuclear receptors, in particular the subfamily of steroid hormone receptors such as PGR and alteration to gene expression in both the MAPK and PI3K-Akt signalling pathways.
  • Evidence snippets:
  • Snippet 1 (score: 0.413) > We used a published clinical dataset [10] to determine whether our cell line model of androgen insensitivity displays molecular features in common with human disease. We found 213 genes were differentially expressed in both experiments. This highlights that while there are definite differences in the molecular phenotypes of our data, our model nonethe-less recapitulates molecular features found in advanced human disease. We also examined the pathways that are enriched for differentially expressed genes in each experiment, and found that differential expression in both datasets converged at the pathway level (full results Additional file 1: Table S1 and S2); in particular, two related pathways, MAPK and PI3K signalling are both strongly implicated by the differentially expressed genes of both datasets. Previous reports adopting disease-associated gene network and pathway analyses in PCa have revealed novel regulatory mechanisms and were more powerful than the analysis of gene expression level alone [20][21][22][23][24].

[10] Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

  • Authors: Aasems Jacob, Rishi Raj, Derek B. Allison, Zin W. Myint
  • Year: 2021
  • Venue: Cancers
  • URL: https://www.semanticscholar.org/paper/93d425f8fbbccd8b90f442fbef73e8e7508c3ee3
  • DOI: 10.3390/cancers13215417
  • PMID: 34771580
  • PMCID: 8582395
  • Citations: 105
  • Influential citations: 3
  • Summary: This review article details the current evidence on clinically relevant driver mechanisms, relevant biomarkers, and treatment modalities to overcome resistance of androgen receptor (AR) in prostate cancer.
  • Evidence snippets:
  • Snippet 1 (score: 0.409) > Simple Summary Early-stage and castration-sensitive prostate cancer (PCa) growth is solely mediated by androgen signaling pathways. AR signaling inhibitors (ARSIs) have significantly improved clinical outcomes among men with PCa. In the metastatic castration-resistant PCa, there is presence of both androgen-dependent and androgen-independent cells driving the tumor growth. Despite the use of ARSIs, disease progression ultimately occurs in all patients with PCa and is due to genetic alterations in ARs, resulting in the outgrowth of androgen-independent cells. The possible mechanisms include development of AR splice variants of which AR-V7 is more common, AR point mutations, and AR overexpression. In addition, restoration of downstream signaling through alternate pathways can also lead to androgen-independent growth of PCa. Therapeutic strategies to overcome these resistance mechanisms and establish predictive biomarkers are still in clinical trials. This review article details the current evidence on clinically relevant driver mechanisms, relevant biomarkers, and treatment modalities to overcome resistance. Abstract Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

[11] Do Androgens Modulate the Pathophysiological Pathways of Inflammation? Appraising the Contemporary Evidence

  • Authors: A. Traish, J. Bolanos, S. Nair, F. Saad, A. Morgentaler
  • Year: 2018
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/bd2b08e1b03260eb1c0af1f2b650f0390775b18e
  • DOI: 10.3390/jcm7120549
  • PMID: 30558178
  • PMCID: 6306858
  • Citations: 134
  • Influential citations: 3
  • Summary: It is suggested that testosterone therapy attenuates the inflammatory process and reduces the burden of disease by mechanisms inhibiting inflammatory cytokine expression and function.
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > The role of testosterone in the pathophysiology of inflammation is of critical clinical importance; however, no universal mechanism(s) has been advanced to explain the complex and interwoven pathways of androgens in the attenuation of the inflammatory processes. PubMed and EMBASE searches were performed, including the following key words: “testosterone”, “androgens”, “inflammatory cytokines”, “inflammatory biomarkers” with focus on clinical studies as well as basic scientific studies in human and animal models. Significant benefits of testosterone therapy in ameliorating or attenuating the symptoms of several chronic inflammatory diseases were reported. Because anti–tumor necrosis factor therapy is the mainstay for the treatment of moderate-to-severe inflammatory bowel disease; including Crohn’s disease and ulcerative colitis, and because testosterone therapy in hypogonadal men with chronic inflammatory conditions reduce tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6, we suggest that testosterone therapy attenuates the inflammatory process and reduces the burden of disease by mechanisms inhibiting inflammatory cytokine expression and function. Mechanistically, androgens regulate the expression and function of inflammatory cytokines, including TNF-α, IL-1β, IL-6, and CRP (C-reactive protein). Here, we suggest that testosterone regulates multiple and overlapping cellular and molecular pathways involving a host of immune cells and biochemical factors that converge to contribute to attenuation of the inflammatory process.

[12] [Complete androgen insensitivity syndrome].

  • Authors: T. Gajić, S. Vujović, M. Ivović, L. Marina, Zorana Arizanović et al.
  • Year: 2015
  • Venue: Srpski arhiv za celokupno lekarstvo
  • URL: https://www.semanticscholar.org/paper/2f4e08b20a5510e39ec8f9cd3d331d4ea75a1064
  • DOI: 10.2298/SARH1504214T
  • PMID: 26012135
  • Summary: The diagnosis of complete androgen insensitivity syndrome is based on clinical findigs, hormonal analysis karyotype, visualization methods and genetic analysis.
  • Evidence snippets:
  • Snippet 1 (score: 0.402) > [Complete androgen insensitivity syndrome].

[13] The Glucocorticoid Resistance Syndrome. Two Cases of a Novel Pathogenic Variant in the Glucocorticoid Receptor Gene

  • Authors: S. Mauri, Javier Nieto‐Moragas, María Obón, Josep Oriola
  • Year: 2023
  • Venue: JCEM Case Reports
  • URL: https://www.semanticscholar.org/paper/c235337d68758a5c0be34cf84b2574c0f34cc1e5
  • DOI: 10.1210/jcemcr/luad153
  • PMID: 38170043
  • PMCID: 10759794
  • Citations: 5
  • Summary: A mother and her son with a mild hyperandrogenic phenotype and a novel genetic variant of the NR3C1 gene predicting a truncated protein and causing glucocorticoid resistance syndrome are described.
  • Evidence snippets:
  • Snippet 1 (score: 0.400) > Abstract Glucocorticoid resistance syndrome is a rare genetic condition characterized by generalized or partial target-tissue insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic-pituitary-adrenal axis. Clinical manifestations may include mineralocorticoid and/or androgen excess without manifestations of Cushing syndrome. At a cellular level, glucocorticoid actions are mediated by the nuclear glucocorticoid receptor encoded by the NR3C1 gene. To date, only 33 glucocorticoid receptor loss-of-function pathogenic variants have been associated with glucocorticoid resistance syndrome. The NR3C1 gene has 2 known disease-causing mechanisms: haploinsufficiency and negative dominance. We describe a mother and her son with a mild hyperandrogenic phenotype and a novel genetic variant of the NR3C1 gene predicting a truncated protein and causing glucocorticoid resistance syndrome. To date, no accurate genotype-phenotype correlation has been found.

[14] Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort

  • Authors: M. Touzon, N. Garrido, R. Marino, P. Ramírez, M. Costanzo et al.
  • Year: 2018
  • Venue: Journal of Clinical Research in Pediatric Endocrinology
  • URL: https://www.semanticscholar.org/paper/d7e11b725a46255f4237c9c85a20ff85305dac04
  • DOI: 10.4274/jcrpe.galenos.2018.2018.0185
  • PMID: 30251955
  • PMCID: 6398199
  • Citations: 20
  • Influential citations: 1
  • Summary: Improved knowledge of the components of the AR complex and signaling network might contribute to long term outcome and genetic counseling in AIS patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.399) > Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort

[15] Complete androgen insensitivity syndrome: a case report and literature review

  • Authors: Min Guo, Jincheng Huang, Cuiyun Li, Yan-yan Liu
  • Year: 2023
  • Venue: The Journal of International Medical Research
  • URL: https://www.semanticscholar.org/paper/cb2580d74b5059c07d657b5a92eeefeeced3f6ab
  • DOI: 10.1177/03000605231154413
  • PMID: 36851849
  • PMCID: 9983103
  • Citations: 11
  • Influential citations: 1
  • Summary: A 31-year-old phenotypically female patient with CAIS who was misdiagnosed twice previously with an inguinal hernia is described who underwent a bilateral gonadectomy and long-term hormone replacement therapy.
  • Evidence snippets:
  • Snippet 1 (score: 0.395) > Complete androgen insensitivity syndrome: a case report and literature review

[16] Complete Androgen Insensitivity Syndrome: A Case Report and Literature Review

  • Authors: Liang-min Fu, penju li, Jiefei Xiao, Junhang Luo, Wei Chen
  • Year: 2022
  • Venue: International Journal of Diabetes & Metabolic Disorders
  • URL: https://www.semanticscholar.org/paper/48a1aea99a58a9053171f3c811d41ab9724a1e4e
  • DOI: 10.33140/ijdmd.07.01.10
  • Summary: Individuals with CAIS need appropriate care from doctors and support from their families, and the diagnosis, treatment, and management of CAIS also require a multidisciplinary approach.
  • Evidence snippets:
  • Snippet 1 (score: 0.395) > Complete Androgen Insensitivity Syndrome: A Case Report and Literature Review

[17] A novel androgen resistance gene mutation (p.G590W) in complete androgen insensitivity syndrome: Emphasizing the need for early gonadectomy and integrated patient care

  • Authors: Hai-yan Sun, Xu Wang, Li-Xian Wang, Hui Zhang
  • Year: 2025
  • Venue: The Journal of International Medical Research
  • URL: https://www.semanticscholar.org/paper/3561243c5f38d987d3d1b3624d342298e4d25a47
  • DOI: 10.1177/03000605251350626
  • PMID: 40552659
  • PMCID: 12188037
  • Citations: 1
  • Summary: The case of a 30-year-old woman who was diagnosed with complete androgen insensitivity syndrome at 18 years of age during evaluation for primary amenorrhea and later presented with a palpable abdominal mass underscores the importance of genetic analysis, early prophylactic gonadectomy, and multidisciplinary care in managing complete androgen insensitivity syndrome to mitigate tumor risk and optimize outcomes.
  • Evidence snippets:
  • Snippet 1 (score: 0.393) > ][3] The AR gene encodes a nuclear receptor that is critical for mediating androgen signaling. 4 ][7] CAIS results from mutations causing complete receptor dysfunction, characterized by female external genitalia despite a 46,XY karyotype. In contrast, PAIS and MAIS involve partial receptor impairment, leading to a range of phenotypes from ambiguous genitalia (PAIS) to mild undervirilization and infertility (MAIS). Individuals with CAIS typically present with primary amenorrhea, absent or rudimentary Mu¨llerian structures, female external genitalia, and a short blind-ending vagina, with gonads frequently located intra-abdominally or in the inguinal region. 8,9 utations in the AR gene associated with CAIS are highly heterogeneous, encompassing missense, nonsense, and frameshift mutations as well as and splicesite alterations. 10 Clinical phenotypes vary considerably depending on the mutation type, with frameshift and nonsense mutations typically associated with more severe androgen insensitivity phenotypes due to complete loss of receptor function, while missense mutations may produce a spectrum of phenotypic outcomes dependent on the specific location and functional domain affected. To date, hundreds of such mutations have been documented in the Androgen Receptor Mutation Database (http://androgendb.mcgill.ca/), many of which are linked to severe androgen insensitivity phenotypes. However, novel pathogenic variants continue to be identified, underscoring the complexity of the genotype-phenotype relationships in CAIS. Characterizing these novel variants is essential for advancing our understanding of the molecular mechanisms underlying AR dysfunction and for developing improved diagnostic, prognostic, and therapeutic strategies. > A significant clinical challenge in managing CAIS is the heightened risk of gonadal germ cell tumors, 11 particularly seminomas, arising due to undescended or dysgenetic gonads. Recent systematic reviews suggest malignancy risks ranging from 15% to as high as 30% in patients with CAIS, underscoring the importance of timely prophylactic gonadectomy to prevent tumor development and progression. 12

[18] COMPLETE ANDROGEN INSENSITIVITY SYNDROME : A CASE REPPORT AND REVIEW OF LITERATURE

  • Authors: Dorkami K., B. S., Asmouki H., F. B., B. A. et al.
  • Year: 2022
  • Venue: International Journal of Advanced Research
  • URL: https://www.semanticscholar.org/paper/ed44196c8db3e521ef71754157930ea84ab588ee
  • DOI: 10.21474/ijar01/14630
  • Summary: The case of two young patients aged 23 and 21 with a TF syndrome discovered during the exploration of primary amenorrhea, with a bilateral orchiectomy was performed with institution of estrogen-progestogen hormone treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > COMPLETE ANDROGEN INSENSITIVITY SYNDROME : A CASE REPPORT AND REVIEW OF LITERATURE

[19] Molecular pathogenesis, diagnosis, and management challenges in complete androgen insensitivity syndrome

  • Authors: Chunqing Wang, Q. Tian
  • Year: 2025
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/0dfa1b0b315d4c8d02b7c91c57e6c48c50cd3624
  • DOI: 10.3389/fendo.2025.1600343
  • PMID: 41163677
  • PMCID: 12558735
  • Summary: The diagnosis of CAIS after puberty is similar to the diagnostic workflow of PA with additional tests and should be differentiated with PA-related etiologies and other kinds of DSD, such as Swyer syndrome, Mayer–Rokitanskey–Küster–Haüser syndrome, Leydig cell hypoplasia, and several steroidogenic enzymatic deficiencies.
  • Evidence snippets:
  • Snippet 1 (score: 0.387) > Molecular pathogenesis, diagnosis, and management challenges in complete androgen insensitivity syndrome

[20] Complete androgen insensitivity syndrome: A rare case report

  • Authors: T. Kambale, P. Patel, Yaminy Ingale, C. Gore
  • Year: 2022
  • Venue: National Journal of Clinical Anatomy
  • URL: https://www.semanticscholar.org/paper/29d40247619e9781f629d528d4342fae9bd0384e
  • DOI: 10.4103/NJCA.NJCA_144_22
  • Citations: 2
  • Summary: This was a rare case of a 22-year-old female patient who presented with primary amenorrhea and increased in level of serum testosterone, follicle-stimulating hormone along with the luteinizing hormone was seen.
  • Evidence snippets:
  • Snippet 1 (score: 0.387) > Complete androgen insensitivity syndrome: A rare case report

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.