Androgen Insensitivity Syndrome

Mendelian MONDO:0019154 Pathograph 64 Show in embeddings browser 46,XY disorder of sex development Androgen receptor signaling disorder

Androgen insensitivity syndrome (AIS) is an AR-related difference of sex development in which 46,XY individuals have testes and impaired tissue responses to androgen. Complete AIS usually has female external genitalia; partial AIS has variable genital virilization; mild AIS can present with infertility or pubertal undervirilization despite typical male external genitalia. Germline and postzygotic AR variants can impair ligand binding, DNA binding or transcriptional regulation, but residual activity does not reliably predict an individual phenotype, especially in partial AIS. Fetal testicular AMH activity is generally preserved, so Müllerian structures are absent or rudimentary. Age, gonadal status, tissue sensitivity and clinical goals shape endocrine findings and care.

Ask OpenScientist

Ask a research question about Androgen Insensitivity Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🔗

Mappings

MONDO

MONDO:0019154 androgen insensitivity syndrome

Primary MONDO identifier for the disease. The two MONDO descendants, complete (MONDO:0021023) and partial (MONDO:0010720) androgen insensitivity syndrome, are curated as has_subtypes entries carrying their own subtype_term.

👪

Inheritance

X-linked recessive HP:0001419

AIS usually follows X-linked inheritance through a hemizygous pathogenic AR variant. De novo variants and postzygotic mosaicism also occur. A heterozygous carrier has a 50% probability of transmitting the variant in each pregnancy; phenotype depends on chromosomal and biological context. A negative maternal blood test does not exclude germline mosaicism, and blood mosaic fractions do not specify fetal genital-tissue fractions.

X-linked recessive inheritance

Show evidence (3 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Androgen insensitivity syndrome (AIS) is a rare inherited condition caused by X-linked pathogenic mutations in the androgen receptor (AR) gene"

Guideline synthesis of established AR-related inheritance.

PMID:30251955 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In four individuals (P5, P6, P8 and P16), 17% of AR-mutated gene patients, somatic mosaicism of mutant and wild type alleles was detected in DNA derived from blood leukocytes."

Four of 24 AR-positive cases in a selected tertiary-center series, not a population mosaicism frequency.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"the chance of transmitting it in each pregnancy is 50%."

Maternal heterozygote transmission probability in GeneReviews counseling.

◆

Subtypes

Complete Androgen Insensitivity Syndrome (CAIS) MONDO:0021023

AR hgnc:644

Markedly reduced androgen responsiveness with female external genitalia, usually absent or rudimentary Müllerian structures, a short blind-ending vagina, sparse sexual hair and inguinal, labial or abdominal testes. Presentations include childhood inguinal hernia or adolescent primary amenorrhea. Occasional Wolffian remnants and atypical findings prevent an absolute internal-anatomy rule.

Partial Androgen Insensitivity Syndrome (PAIS) MONDO:0010720

AR hgnc:644

Variable incomplete androgen responsiveness with predominantly male, predominantly female or ambiguous external genitalia. Pubertal virilization, gynecomastia and fertility vary. Genotype and in-vitro receptor assays do not determine an individual pubertal outcome.

Mild Androgen Insensitivity Syndrome (MAIS)

AR hgnc:644

Typical male external genitalia with possible infertility, impaired pubertal virilization or gynecomastia. A distinct ontology descendant is not required to retain this recognized clinical subtype.

Discussions and Knowledge Gaps

How should the previously attributed Ser176Arg case be interpreted after variant reclassification?

INTERPRETATION OPEN ais-ser176arg-reclassification

Attached to

genetic#AR diagnosis#AR molecular testing and variant interpretation

The 2020 case report nominated AR c.528C>A p.Ser176Arg by exome prioritization without a functional assay and reported substantial East Asian population frequency. ClinVar VCV000804018.30, checked 2026-09-21, aggregates benign/likely benign classifications without conflict. This weakens the molecular AIS attribution; the child may still have a difference of sex development requiring an alternative explanation. Its short androgen exposure is not used as AIS-specific efficacy evidence.

Show evidence (2 references)

PMID:33363845 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a relatively high prevalence of this AR variant in East Asia (1%‐1.5%)"

The original source itself notes a relatively common population allele.

url:https://www.ncbi.nlm.nih.gov/clinvar/variation/804018/ SUPPORT DIRECT PRIMARY RESULT Other

"Benign (2); Likely benign (3)"

Current primary variant record.

Does the reported MAP3K1 variant modify AR-related AIS?

KNOWLEDGE GAP OPEN ais-map3k1-modifier-hypothesis

Attached to

experimental_models#AR and MAP3K1 coexpression in HEK293T/17 cells

One proband and the mother shared AR and MAP3K1 variants. The source calls AR likely pathogenic but MAP3K1 Arg260Cys a VUS; no replicated segregation or developmental assay establishes modification. HEK293T/17 immunoblots measure abundance, not transactivation, and single versus dual plasmid doses differ. A rudimentary uterine structure is an atypical observation, not proof of a MAP3K1-mediated AMH defect. The paper repeatedly writes His690Glu for AR c.2070C>A, while Results says glutamine and Figure 2 labels H690Q; the inconsistent protein expansion is not propagated as verified nomenclature.

Show evidence (3 references)

PMID:32338288 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The MAP3K1 variant is a variant of “unknown significance” according to ACMG criteria."

The source qualification takes precedence over stronger abstract language.

PMID:32338288 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"there is a lack of basic experiments to validate regulatory mechanism between the AR and MAP3K1 gene."

Authors explicitly identify the unresolved mechanism.

PMID:32338288 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The hemizygous variant occurs at position 690 (H690Q)."

Figure caption differs from the erroneous Glu expansion.

How can gonadal cancer risk and surveillance be estimated for a particular AIS patient?

KNOWLEDGE GAP OPEN ais-gonadal-risk-and-surveillance

Attached to

treatments#Shared decisions about gonadal retention or gonadectomy treatments#Retained-gonad follow-up

Published cohorts mix age, subtype, genotype confirmation, gonadal location and surgical ascertainment. Benign stromal lesions, precursor lesions and invasive germ-cell cancer should not be pooled as one outcome. The low prepubertal risk and benefit of spontaneous CAIS puberty inform shared decisions, but neither normal imaging nor isolated benign case reports establish a universally safe retention schedule.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"There is an ongoing debate about the need to perform gonadectomy after puberty since the risk of invasive GGCC development is still uncertain."

Guideline acknowledges uncertainty.

PMID:36851849 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Leydig cell tumour of the right testis. It was a benign testicular tumour."

Specific benign stromal histology.

Which tissue and developmental factors explain the variable phenotype of the same AR variant?

KNOWLEDGE GAP OPEN ais-genotype-and-tissue-heterogeneity

Attached to

pathophysiology#Pathogenic AR Variation experimental_models#Exploratory PAIS peripheral-blood transcriptome study

Residual receptor activity matters, but PAIS genotype-phenotype correlation and puberty prediction remain imperfect. Blood mosaicism is observed; fetal genital-tissue proportions and functional effects are often unmeasured. The exploratory three-case PBMC expression study supplies candidate associations, not a diagnostic assay or causal explanation for genital variation.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In contrast to the clinical findings, the functional analysis of AR variants did not appear to predict pubertal outcome"

Clinical prediction limit.

PMID:30251955 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In four individuals (P5, P6, P8 and P16), 17% of AR-mutated gene patients, somatic mosaicism of mutant and wild type alleles was detected in DNA derived from blood leukocytes."

Observed blood mosaicism, not measured fetal tissue mosaicism.

⚙

Pathophysiology

Pathogenic AR Variation

Hemizygous pathogenic germline variants and postzygotic mosaic AR variants can impair androgen receptor signaling. Defects differ by allele and domain; not every variant affects ligand binding, DNA binding and receptor abundance together. Genotype-phenotype correlation is especially limited in PAIS.

AR hgnc:644

Downstream

Reduced Androgen Binding Some ligand-binding-domain variants reduce affinity, increase dissociation or otherwise impair ligand responsiveness.

Impaired AR DNA Binding Some DNA-binding-domain variants impair recognition of androgen response elements.

Reduced AR-Dependent Transcription Other defects can reduce transactivation without a demonstrated ligand-binding defect.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Androgen insensitivity syndrome (AIS) is a rare inherited condition caused by X-linked pathogenic mutations in the androgen receptor (AR) gene"

Established gene-disease relationship.

Reduced Androgen Binding

Selected pathogenic AR variants impair ligand binding through altered affinity, dissociation kinetics or temperature sensitivity. Normal binding in a tested variant does not exclude defective downstream transactivation.

Downstream

Reduced AR-Dependent Transcription Impaired activation by androgen can reduce target-gene transcription.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"impair androgen binding and impair transactivation by the AR. Some decrease only the apparent equilibrium affinity constant; some increase only the non-equilibrium dissociation rate; others do both, either with all androgens or selectively with certain androgens."

Review synthesis of variant-specific receptor assays.

Impaired AR DNA Binding

Selected variants in the receptor DNA-binding domain impair interaction with androgen response elements. This mechanism is distinct from reduced ligand binding.

Downstream

Reduced AR-Dependent Transcription Reduced response-element binding impairs transcriptional regulation of androgen-responsive targets.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Single-nucleotide variants in the zinc fingers or α-helical portions of the DNA-binding domain impair binding to a sequence of regulatory nucleotides known as an androgen response element. Such binding is essential for the androgen receptor to exert transcriptional regulatory control..."

Domain-specific functional synthesis.

Reduced AR-Dependent Transcription

Reduced androgen-dependent transcription alters tissue responses during fetal development, puberty and adult life. The relevant target genes and co-regulatory effects vary by tissue; receptor activity measured in a reporter system is not a deterministic clinical severity scale.

androgen receptor signaling pathway GO:0030521 ↓ DECREASED

Downstream

Impaired External Genital Virilization Developmental effect of reduced AR activity.

Impaired Wolffian Duct Development Typical androgen-dependent internal tract development.

Reduced Androgen Negative Feedback Central AR action and feedback.

Reduced Androgen-Dependent Hair Development Tissue response summarized in the guideline.

Impaired Testicular Descent Clinical location supports the developmental consequence.

Reduced Pubertal AMH Suppression Androgen-dependent regulation at puberty.

Reduced Bone Mineral Accrual Multifactorial skeletal association; no single intermediary is established.

Reduced Sertoli Androgen Signaling Reduced receptor function impairs androgen-responsive Sertoli support.

Tall stature Associated androgen-responsive clinical finding; age, tissue effects and other mediators remain incompletely resolved.

Delayed puberty Associated androgen-responsive clinical finding; age, tissue effects and other mediators remain incompletely resolved.

Abnormally high-pitched voice Associated androgen-responsive clinical finding; age, tissue effects and other mediators remain incompletely resolved.

Male sexual dysfunction Associated androgen-responsive clinical finding; age, tissue effects and other mediators remain incompletely resolved.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Variant-associated impaired transactivation, separate from normal-function context.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The androgen receptor is a well-defined transcriptional regulatory factor. Once activated by binding to androgen, it collaborates with other co-regulatory proteins (some involve DNA binding, others do not) to achieve control over the rate of transcription of an androgen target"

Normal molecular function underlying the signaling defect.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In contrast to the clinical findings, the functional analysis of AR variants did not appear to predict pubertal outcome"

Limits prediction from functional assays.

Impaired External Genital Virilization

Reduced androgen response during fetal life impairs external genital masculinization, ranging from female external genitalia in CAIS to hypospadias, micropenis and variable labioscrotal fusion in PAIS. This node concerns anatomy and does not determine gender identity.

Animal models

Ubiquitous androgen receptor knockout mouse Mouse recapitulates Global receptor loss produces a female external phenotype.

Downstream

Female external genitalia in individual with 46,XY karyotype Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.

Hypospadias Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.

Perineal hypospadias Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.

Micropenis Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.

Ambiguous genitalia Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.

Bifid scrotum Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.

Clitoral hypertrophy Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.

Fused labia majora Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.

Urogenital sinus anomaly Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Reduced AR residual activity results in PAIS with variable virilisation of the external genitalia during fetal life."

Clinical-developmental synthesis.

Impaired Wolffian Duct Development

Androgen resistance can impair differentiation of epididymis, vas deferens and other Wolffian structures. Their absence is typical of CAIS but occasional development is reported; Müllerian regression is a separate AMH-dependent process.

Animal models

Ubiquitous androgen receptor knockout mouse Mouse recapitulates Wolffian derivatives were absent in the global knockout.

Sertoli-cell androgen receptor knockout mouse Mouse fails to recapitulate Androgen-dependent internal ducts developed normally in SCARKO.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Furthermore, Wolffian structures do not develop due to the insensitivity to testosterone."

Typical developmental mechanism; GeneReviews qualifies occasional exceptions.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"On occasion, wolffian duct development is observed"

Clinical exception to an absolute absence rule.

Reduced Androgen Negative Feedback

Reduced central androgen action weakens testosterone feedback on the hypothalamic-pituitary axis. Estrogen feedback and Sertoli-derived signals remain relevant, so LH, FSH and testosterone need not all be elevated together or at every age.

Downstream

Increased Luteinizing Hormone Secretion Reduced androgen feedback permits greater LH drive when the axis is active.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The resulting testosterone secretion from the Leydig cells in the testes fails to exert negative feedback to the hypothalamic-pituitary axis due to insufficient central AR action."

Guideline endocrine mechanism.

Increased Luteinizing Hormone Secretion

LH is often increased during puberty and adulthood with retained testes, while values can be normal in younger children. FSH can remain within its reference range because its regulation also involves estrogen and inhibin.

Downstream

Increased Testicular Testosterone Production Greater LH drive can stimulate Leydig-cell androgen production, although circulating values may remain within the male range.

Elevated circulating luteinizing hormone level Greater secretion can produce an elevated measured level when interpreted by age and gonadal status.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Thus, the LH/FSH ratio is typically relatively high in CAIS and PAIS"

Endocrine pattern is typical, not obligatory.

Increased Testicular Testosterone Production

Retained testes can produce normal male-range or elevated testosterone despite tissue androgen resistance. An apparently high concentration against a female comparator does not by itself establish excess relative to the appropriate testicular reference range.

Downstream

Increased serum testosterone level Some individuals have concentrations above the male range; normal male-range values are also compatible with AIS.

Peripheral Testosterone Aromatization Available testosterone supplies peripheral estrogen synthesis.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range"

Explicit comparator and gonadal context.

Peripheral Testosterone Aromatization

Conversion of testosterone to estrogen persists despite AR dysfunction. In CAIS with retained testes, estrogen concentrations generally exceed male values but remain below usual female values; this can support spontaneous breast development. In PAIS, estrogen action relative to impaired androgen action contributes to gynecomastia.

Downstream

Gynecomastia Relative estrogenic effects can produce gynecomastia in PAIS; breast development in CAIS is expected puberty rather than a gynecomastia phenotype.

Increased serum estradiol Measured estradiol may be high relative to a male reference range.

Gynecomastia in mild AIS Relative estrogen and androgen effects can contribute to pubertal gynecomastia in MAIS.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Preserved steroid conversion and reference-range context.

Reduced Androgen-Dependent Hair Development

Reduced receptor action limits pubic, axillary and other androgen-dependent terminal hair. Sparse or absent hair is typical in CAIS and variable in PAIS or MAIS.

Downstream

Sparse axillary hair Reduced androgen-dependent terminal hair development can produce this finding.

Absent axillary hair Reduced androgen-dependent terminal hair development can produce this finding.

Sparse pubic hair Reduced androgen-dependent terminal hair development can produce this finding.

Absent pubic hair Reduced androgen-dependent terminal hair development can produce this finding.

Abnormality of secondary sexual hair Reduced androgen-dependent terminal hair development can produce this finding.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The patients develop no or scarce pubic and axillary hair."

Clinical androgen-responsive tissue finding.

Impaired Testicular Descent

Reduced androgen action can impair descent, leaving testes abdominal, inguinal or labial. A Sertoli-specific mouse knockout retained normal descent, showing that this developmental consequence cannot be assigned to Sertoli AR loss alone.

Animal models

Sertoli-cell androgen receptor knockout mouse Mouse fails to recapitulate The tested conditional knockout retained normal testis descent.

Downstream

Bilateral cryptorchidism Incomplete descent can leave both testes outside the scrotum.

Inguinal hernia Inguinal testicular location can accompany a hernia presentation; the source does not isolate a single anatomic causal sequence.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The testes are typically located within the abdomen, inguinal canal or in the labia majora"

Typical human location.

PMID:14745012 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract."

Primary mouse experiment distinguishes cell-specific from global AR loss.

Reduced Sertoli Androgen Signaling

Sertoli-cell AR signaling supports germ-cell development. Conditional mouse loss establishes a somatic supporting-cell requirement; it does not imply that germ cells require their own AR or that all human infertility is caused by this one cell type.

Sertoli cell CL:0000216

Animal models

Sertoli-cell androgen receptor knockout mouse Mouse perturbs Conditional Ar deletion selectively removes the receptor from Sertoli cells.

Downstream

Impaired Spermatogenesis Loss of Sertoli AR signaling impairs meiotic progression and later germ-cell survival through incompletely resolved Sertoli-germ-cell interactions.

Show evidence (1 reference)

PMID:14745012 SUPPORT DIRECT PRIMARY RESULT Model Organism

"It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/survival critically depends on androgens."

Primary mouse perturbation; human extrapolation remains bounded.

Impaired Spermatogenesis

Impaired androgen action can limit sperm production, with additional effects of gonadal location and testicular development. CAIS is associated with infertility; PAIS and MAIS show variable impairment. Azoospermia is not obligatory across the entire spectrum.

spermatogenesis GO:0007283 ↓ DECREASED

Animal models

Sertoli-cell androgen receptor knockout mouse Mouse recapitulates Selective Sertoli AR loss impairs germ-cell progression and survival despite descended testes.

Downstream

Azoospermia Severe impairment can eliminate sperm from the ejaculate.

Male infertility Impaired sperm production contributes to infertility, with variable severity in milder AIS.

Show evidence (2 references)

PMID:14745012 SUPPORT DIRECT PRIMARY RESULT Model Organism

Experimental supporting-cell requirement.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Spermatogenesis may or may not be impaired."

GeneReviews specifically describes variability in MAIS.

Reduced Pubertal AMH Suppression

Pubertal androgen action normally suppresses Sertoli-cell AMH. With impaired AR action, AMH may remain at prepubertal levels despite increasing testosterone. This is distinct from preserved fetal AMH secretion and does not imply elevated AMH in every neonate.

Downstream

Increased circulating antimullerian hormone concentration Failure of the expected pubertal decline can yield a high concentration relative to age-matched reference values.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"With rising intratesticular testosterone levels, AMH secretion is inhibited in a subject with normal AR function, whereas a boy with PAIS continues to have prepubertal levels of AMH due to lack of inhibition."

Age-specific endocrine mechanism.

Preserved Fetal AMH Secretion

Fetal Sertoli cells generally retain AMH production in AIS. This is parallel developmental context, not a consequence of AR-induced negative-feedback failure. Testicular rather than ovarian differentiation also explains absent ovaries; ovaries are not Müllerian derivatives.

Downstream

Müllerian Duct Regression AMH signaling promotes regression of Müllerian ducts despite impaired androgen responsiveness.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Sertoli cells that produce AMH resulting in the regression of Mullerian structures prenatally. Thus, the uterus, fallopian tubes and upper part of the vagina are absent."

Preserved testicular AMH pathway.

Müllerian Duct Regression

Preserved AMH action usually leads to absent or rudimentary uterus, fallopian tubes and cervix, with a short blind-ending vagina. Rare retained structures warrant careful reassessment; they do not establish a MAP3K1 modifier pathway.

Downstream

Abnormal morphology of female internal genitalia Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.

Aplasia of the uterus Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.

Aplasia or hypoplasia of the fallopian tube Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.

Abnormal uterine cervix morphology Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.

Blind vagina Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.

Primary amenorrhea Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Sertoli cells that produce AMH resulting in the regression of Mullerian structures prenatally. Thus, the uterus, fallopian tubes and upper part of the vagina are absent."

Typical developmental consequence.

Reduced Bone Mineral Accrual

CAIS can be associated with low bone mineral density through limited androgen action and relative estrogen deficiency. Gonadectomy without adequate replacement adds risk. This is multifactorial and does not make osteoporosis obligatory or demonstrate a particular fracture rate.

Downstream

Decreased bone mineral density Reduced accrual and later loss can produce low measured bone mineral density.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Women with CAIS and intact gonads have an increased risk of developing low BMD due to bone insensitivity to testosterone and relative oestrogen deficiency. After gonadectomy, the risk of developing low BMD further increases."

Guideline synthesis of bone-health observations.

✶

Histopathology

Impaired germ-cell development and gonadal fibrosis

Selected gonadectomy specimens show immature seminiferous tubules, fibrosis and absent germ cells. This is not a universal biopsy requirement and does not establish that all infertility is due to cryptorchidism.

Show evidence (1 reference)

PMID:29785970 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Large areas of prepubertal tubules (arrow) surrounded by some fibrosis (arrowhead) are visualized, with no germ cells in the gonads."

Case 8 histological caption; selected tissue, not prevalence.

Benign testicular stromal lesions

Benign Leydig-cell tumor and Sertoli-rich hamartomas have been documented in individual CAIS reports. These must be distinguished from germ-cell neoplasia and malignant cancer when discussing gonadal risk.

Show evidence (1 reference)

PMID:36851849 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Leydig cell tumour of the right testis. It was a benign testicular tumour."

Single clinically diagnosed CAIS case without AR molecular confirmation.

⬡

Pathograph

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

●

Phenotypes

Breast 2

Gynecomastia FREQUENT HP:0000771

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000771 | Gynecomastia | Frequent (79-30%)"

Orphanet records gynecomastia as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Gynecomastia in mild AIS HP:0000771

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"They usually present with gynecomastia at puberty."

GeneReviews MAIS clinical subsection.

Digestive 1

Inguinal hernia HP:0000023

Show evidence (1 reference)

PMID:29785970 SUPPORT DIRECT BACKGROUND Human Clinical

"Affected individuals typically exhibit inguinal swelling during infancy or primary amenorrhea during puberty."

Background clinical presentation described by the cohort authors.

Endocrine 11

Delayed puberty FREQUENT HP:0000823

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000823 | Delayed puberty | Frequent (79-30%)"

Orphanet records delayed puberty as frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Elevated circulating luteinizing hormone level VERY_FREQUENT HP:0011969

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0011969 | Elevated circulating luteinizing hormone level | Very frequent (99-80%)"

Orphanet records elevated LH as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Elevated circulating luteinizing hormone level VERY_FREQUENT HP:0011969

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0011969 | Elevated circulating luteinizing hormone level | Very frequent (99-80%)"

Orphanet records elevated LH as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Increased serum estradiol VERY_FREQUENT HP:0025134

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0025134 | Increased serum estradiol | Very frequent (99-80%)"

Orphanet records increased serum estradiol as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Increased serum testosterone level VERY_FREQUENT HP:0030088

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0030088 | Increased serum testosterone level | Very frequent (99-80%)"

Orphanet records increased serum testosterone as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Increased serum testosterone level VERY_FREQUENT HP:0030088

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0030088 | Increased serum testosterone level | Very frequent (99-80%)"

Orphanet records increased serum testosterone level as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Abnormal circulating follicle-stimulating hormone concentration VERY_RARE HP:0030346

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0030346 | Abnormal circulating follicle-stimulating hormone level | Very rare (<4-1%)"

Orphanet records abnormal circulating FSH as very rare in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Increased circulating antimullerian hormone concentration FREQUENT HP:0031102

Show evidence (2 references)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0031102 | Increased antimullerian hormone level | Frequent (79-30%)"

Orphanet records increased AMH as frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

PMID:30251955 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"AMH serum concentrations during the neonatal period were within the normal male reference range in the only two PAIS cases in whom it was assessed"

Two measured neonatal cases limit a universal elevation claim.

Abnormal circulating estrogen level FREQUENT HP:0025132

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0025132 | Abnormal circulating estrogen level | Frequent (79-30%)"

Orphanet records abnormal circulating estrogen level as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Increased serum estradiol OCCASIONAL HP:0025134

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0025134 | Increased serum estradiol | Occasional (29-5%)"

Orphanet records increased serum estradiol as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Increased circulating antimullerian hormone concentration VERY_FREQUENT HP:0031102

Show evidence (2 references)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0031102 | Increased antimullerian hormone level | Very frequent (99-80%)"

Orphanet records increased antimullerian hormone level as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

PMID:30251955 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"AMH serum concentrations during the neonatal period were within the normal male reference range in the only two PAIS cases in whom it was assessed"

Two measured neonatal cases limit a universal elevation claim.

Genitourinary 28

Abnormal morphology of female internal genitalia VERY_FREQUENT HP:0000008

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000008 | Abnormal morphology of female internal genitalia | Very frequent (99-80%)"

Orphanet records this phenotype as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Aplasia of the uterus VERY_FREQUENT HP:0000151

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000151 | Aplasia of the uterus | Very frequent (99-80%)"

Orphanet records uterine aplasia as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Aplasia of the uterus VERY_FREQUENT HP:0000151

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000151 | Aplasia of the uterus | Very frequent (99-80%)"

Orphanet records uterine aplasia as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Primary amenorrhea VERY_FREQUENT HP:0000786

Show evidence (2 references)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000786 | Primary amenorrhea | Very frequent (99-80%)"

Orphanet records primary amenorrhea as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

PMID:29785970 SUPPORT DIRECT PRIMARY RESULT 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 HP:0003251

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0003251 | Male infertility | Very frequent (99-80%)"

Orphanet records male infertility as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Male infertility VERY_FREQUENT HP:0003251

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0003251 | Male infertility | Very frequent (99-80%)"

Orphanet records male infertility as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Aplasia or hypoplasia of the fallopian tube VERY_FREQUENT Aplasia/Hypoplasia of the fallopian tube HP:0008655

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Bilateral cryptorchidism VERY_FREQUENT HP:0008689

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0008689 | Bilateral cryptorchidism | Very frequent (99-80%)"

Orphanet records bilateral cryptorchidism as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Female external genitalia in individual with 46,XY karyotype VERY_FREQUENT HP:0008730

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Testicular neoplasm OCCASIONAL HP:0010788

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0010788 | Testicular neoplasm | Occasional (29-5%)"

Orphanet records testicular neoplasm as occasional in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Abnormal uterine cervix morphology VERY_FREQUENT HP:0012888

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0012888 | Abnormality of the uterine cervix | Very frequent (99-80%)"

Orphanet records abnormal uterine cervix morphology as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Germ cell neoplasia VERY_RARE HP:0100728

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0100728 | Germ cell neoplasia | Very rare (<4-1%)"

Orphanet records germ cell neoplasia as very rare in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Azoospermia OCCASIONAL HP:0000027

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000027 | Azoospermia | Occasional (29-5%)"

Orphanet records azoospermia as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Hypospadias FREQUENT HP:0000047

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000047 | Hypospadias | Frequent (79-30%)"

Orphanet records hypospadias as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Bifid scrotum OCCASIONAL HP:0000048

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000048 | Bifid scrotum | Occasional (29-5%)"

Orphanet records bifid scrotum as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Perineal hypospadias OCCASIONAL HP:0000051

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000051 | Perineal hypospadias | Occasional (29-5%)"

Orphanet records perineal hypospadias as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Micropenis OCCASIONAL HP:0000054

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000054 | Micropenis | Occasional (29-5%)"

Orphanet records micropenis as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Ambiguous genitalia FREQUENT HP:0000062

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000062 | Ambiguous genitalia | Frequent (79-30%)"

Orphanet records ambiguous genitalia as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Primary amenorrhea OCCASIONAL HP:0000786

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000786 | Primary amenorrhea | Occasional (29-5%)"

Orphanet records primary amenorrhea as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Clitoral hypertrophy OCCASIONAL HP:0008665

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0008665 | Clitoral hypertrophy | Occasional (29-5%)"

Orphanet records clitoral hypertrophy as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Bilateral cryptorchidism FREQUENT HP:0008689

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0008689 | Bilateral cryptorchidism | Frequent (79-30%)"

Orphanet records bilateral cryptorchidism as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Aplasia of the ovary VERY_FREQUENT HP:0010463

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0010463 | Aplasia of the ovary | Very frequent (99-80%)"

Orphanet records ovarian aplasia as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Fused labia majora OCCASIONAL HP:0025486

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0025486 | Fused labia majora | Occasional (29-5%)"

Orphanet records fused labia majora as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Male sexual dysfunction VERY_FREQUENT HP:0040307

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0040307 | Male sexual dysfunction | Very frequent (99-80%)"

Orphanet records male sexual dysfunction as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Germ cell neoplasia OCCASIONAL HP:0100728

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0100728 | Germ cell neoplasia | Occasional (29-5%)"

Orphanet records germ cell neoplasia as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Urogenital sinus anomaly OCCASIONAL HP:0100779

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0100779 | Urogenital sinus anomaly | Occasional (29-5%)"

Orphanet records urogenital sinus anomaly as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Immune 1

Acne VERY_RARE HP:0001061

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0001061 | Acne | Very rare (<4-1%)"

Orphanet records acne as very rare in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Integument 5

Sparse axillary hair FREQUENT HP:0002215

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0002215 | Sparse axillary hair | Frequent (79-30%)"

Orphanet records sparse axillary hair as frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Absent axillary hair FREQUENT HP:0002221

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0002221 | Absent axillary hair | Frequent (79-30%)"

Orphanet records absent axillary hair as frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Sparse pubic hair FREQUENT HP:0002225

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0002225 | Sparse pubic hair | Frequent (79-30%)"

Orphanet records sparse pubic hair as frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Absent pubic hair FREQUENT HP:0002555

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0002555 | Absent pubic hair | Frequent (79-30%)"

Orphanet records absent pubic hair as frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Abnormality of secondary sexual hair OCCASIONAL HP:0009888

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0009888 | Abnormality of secondary sexual hair | Occasional (29-5%)"

Orphanet records abnormality of secondary sexual hair as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Metabolism 1

Insulin insensitivity OCCASIONAL HP:0008189

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0008189 | Insulin insensitivity | Occasional (29-5%)"

Orphanet records insulin insensitivity as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Musculoskeletal 1

Decreased bone mineral density Reduced bone mineral density HP:0004349

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Guideline synthesis of AIS bone-health evidence.

Nervous System 3

Depression OCCASIONAL HP:0000716

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000716 | Depression | Occasional (29-5%)"

Orphanet records depression as occasional in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Anxiety FREQUENT HP:0000739

Show evidence (1 reference)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000739 | Anxiety | Frequent (79-30%)"

Orphanet records anxiety as frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Abnormally high-pitched voice OCCASIONAL HP:0001620

Show evidence (1 reference)

ORPHA:90797 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0001620 | Abnormally high-pitched voice | Occasional (29-5%)"

Orphanet records abnormally high-pitched voice as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

Growth 1

Tall stature VERY_FREQUENT HP:0000098

Show evidence (2 references)

ORPHA:99429 SUPPORT DIRECT PRIMARY RESULT Other

"HP:0000098 | Tall stature | Very frequent (99-80%)"

Orphanet records tall stature as very frequent in CAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"final height is generally above the mean female final height but below the average height of the male population"

Defines the height comparator.

🧬

Genetic Associations

AR (Causal pathogenic variants, including germline and postzygotic mosaic variants)

Gene: AR hgnc:644 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Androgen insensitivity syndrome (AIS) is a rare inherited condition caused by X-linked pathogenic mutations in the androgen receptor (AR) gene"

Established gene relationship.

PMID:30251955 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All of the CAIS cases (n=11) were genetically confirmed, while in PAIS (n=30) a mutation in AR was detected in only 13 patients (43.3%)."

Explicit Results numerators; the Discussion uses a discrepant percentage.

PMID:30251955 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In four individuals (P5, P6, P8 and P16), 17% of AR-mutated gene patients, somatic mosaicism of mutant and wild type alleles was detected in DNA derived from blood leukocytes."

Blood-detected mosaicism in this cohort.

+ 1 more reference

💊

Medical Actions

Multidisciplinary DSD care and psychological support

Action: Multidisciplinary DSD care and psychological support Ontology label: Supportive Care NCIT:C15747

Coordinate endocrinology, genetics, urology/gynecology and psychological or sexual-health support. Explain the diagnosis transparently and sensitively, and revisit fertility, body image, sexual function and patient goals over time. Gender identity should be assessed before PAIS puberty induction; genital anatomy does not determine identity or mandate irreversible procedures.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Careful counselling by a multidisciplinary team is therefore required before any decision about hormonal treatment is taken."

AIS-specific guideline counseling recommendation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"It is best if the diagnosis of AIS is explained to the affected individual and family in an empathic environment, with both professional and family support."

GeneReviews care framework.

Shared decisions about gonadal retention or gonadectomy

Action: Shared decisions about gonadal retention or gonadectomy Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Discuss gonadal location, subtype, uncertain age-specific tumor risk, spontaneous puberty, surveillance limits and lifelong hormone needs. The 2022 guideline recommends spontaneous puberty in CAIS with retained testes. Gonadectomy after puberty or continued retention are individualized decisions; prepubertal removal is not a universal requirement. A suspicious mass needs specialist evaluation, but benign Leydig or Sertoli lesions must not be relabeled germ-cell cancer.

Mechanism Target:

INHIBITS Germ cell neoplasia — Removal of at-risk gonadal tissue is intended to prevent future gonadal neoplasia when selected after counseling; the optimal timing and absolute risk reduction are not established by the cited guidance.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients with CAIS and intraabdominal testes might be at increased risk of developing gonadal germ cell cancers (GGCC), mainly seminomas, but this risk seems to be low before/during puberty"

Guideline identifies the indication and its age-specific uncertainty.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Delaying gonadectomy allows for spontaneous pubertal development which is thought to be more satisfactory to the individual and also allows the patient to be fully involved in the shared decision-making to remove their gonads or not."

Guideline rationale for avoiding an automatic early-removal rule.

Show evidence (3 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Patients with CAIS and intraabdominal testes might be at increased risk of developing gonadal germ cell cancers (GGCC), mainly seminomas, but this risk seems to be low before/during puberty"

Guideline identifies the indication and its age-specific uncertainty.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Guideline rationale for avoiding an automatic early-removal rule.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"There is an ongoing debate about the need to perform gonadectomy after puberty since the risk of invasive GGCC development is still uncertain."

Explicit uncertainty in the evidence base.

Retained-gonad follow-up

Action: Retained-gonad follow-up Ontology label: Supportive Care NCIT:C15747

Arrange specialist follow-up when gonads are retained, including examination and selected ultrasound or MRI. Self-examination is feasible only for accessible inguinal gonads. Imaging and tumor markers have limited ability to exclude precursor lesions, so normal results should not be presented as a guarantee of safety.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Yearly follow-up if the gonads are retained was advised including self-examination and imaging (ultrasound/MRI)"

Guideline summarizes an expert algorithm; this is not a validated surveillance sensitivity estimate.

PMID:36851849 SUPPORT DIRECT BACKGROUND Human Clinical

"but these are not specific detection methods for gonadal malignant transformation in CAIS patients."

The preceding source list includes imaging and serum markers; this is background synthesis, not a tested screening sensitivity.

Estrogen replacement and pubertal induction after gonadectomy

Action: Estrogen replacement and pubertal induction after gonadectomy Ontology label: Pharmacotherapy NCIT:C15986

Agent: 17beta-estradiol CHEBI:16469

Platform: Small molecule

After gonadectomy, provide individualized estrogen replacement and gradual puberty induction when needed. Endo-ERN recommends starting induction around age 11 in gonadectomized CAIS, with very low-certainty evidence. Monitor pubertal progression, satisfaction, hormone exposure and bone health; routine progestin is generally unnecessary without a uterus. Retained testes usually support spontaneous CAIS puberty. The same induction principles apply to PAIS patients seeking female puberty when endogenous hormone production is absent or inadequate. During induction, the guideline recommends review every three to six months.

Mechanism Target:

MODULATES Delayed puberty — Individualized management of the indicated manifestation; no correction of the AR variant is implied.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In girls with CAIS who have been gonadectomised, pubertal induction should start at the age of 11 years in accordance with the current treatment recommendations to mimic normal pubertal development."

Guideline recommendation R6.2, graded +OOO.

MODULATES Reduced Bone Mineral Accrual — Replacement addresses estrogen deficiency as one contributor to bone-health risk; it does not reverse androgen resistance or guarantee normal bone density.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Treatment with sex steroids aims to prevent osteoporosis and other metabolic complications"

Guideline states the treatment aim rather than proven prevention of every clinical outcome.

Show evidence (5 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Guideline recommendation R6.2, graded +OOO.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Because of the absence of a uterus, the addition of treatment with progestins is generally not required."

Avoids routine progesterone without an indication.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Regular follow-up with clinical parameters (breast development, height), patient’s satisfaction and bone density."

Monitoring during induction.

+ 2 more references

Bone health surveillance and supportive treatment

Action: Bone health surveillance and supportive treatment Ontology label: Supportive Care NCIT:C15747

Monitor bone mineral density as clinically appropriate, including adult DXA, and review hormone replacement, nutrition and physical activity. Weight-bearing exercise, adequate calcium and vitamin D are advised. Bisphosphonates may be considered for selected patients with low density or fractures; they are not routine therapy for everyone with AIS.

Mechanism Target:

MODULATES Decreased bone mineral density — Individualized management of the indicated manifestation; no correction of the AR variant is implied.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Regular weight-bearing exercises and supplemental calcium and vitamin D are recommended to optimize bone health; bisphosphonate therapy may be indicated for those with evidence of decreased bone mineral density and/or multiple fractures."

GeneReviews individualized bone care.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

GeneReviews individualized bone care.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Bone risk persists with intact gonads and can increase after removal.

Selected testosterone trial for PAIS pubertal undervirilization

Action: Selected testosterone trial for PAIS pubertal undervirilization Ontology label: Pharmacotherapy NCIT:C15986

Agent: testosterone CHEBI:17347

Platform: Small molecule

For PAIS patients seeking male pubertal development, the guideline suggests a selected midpubertal testosterone trial with reassessment after six months. This is a very low-certainty suggestion without randomized trials. Judge response by clinical development and wellbeing rather than serum testosterone alone, and monitor hematocrit and other treatment effects. This recommendation does not rely on the reclassified Ser176Arg case.

Mechanism Target:

MODULATES Micropenis — Individualized management of the indicated manifestation; no correction of the AR variant is implied.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"If clinical signs of hypoandrogenism such as micropenis and gynaecomastia are present, we suggest treating with the addition of testosterone for 6 months and then evaluating the effect."

Recommendation R7.4, graded +OOO.

Show evidence (3 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"If clinical signs of hypoandrogenism such as micropenis and gynaecomastia are present, we suggest treating with the addition of testosterone for 6 months and then evaluating the effect."

Recommendation R7.4, graded +OOO.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Anecdotally, patients report a beneficial effect on genital growth and wellbeing, but no randomised trials exist."

Explicit evidence limit.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Clearly, serum testosterone concentrations cannot be used to monitor efficacy, which relies exclusively on clinical improvement and general wellbeing."

Clinical response is the efficacy assessment.

Individualized pubertal suppression while clarifying treatment goals

Action: Individualized pubertal suppression while clarifying treatment goals Ontology label: Pharmacotherapy NCIT:C15986

When PAIS adolescents have uncertainty about the desired direction of puberty, a specialist team may consider temporary GnRH-agonist suppression with psychological follow-up and shared decisions. This is individualized support, not a routine AIS requirement or a claim that estrogen alone suppresses endogenous virilization.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In case there are uncertainties about gender identity, puberty can be delayed by the use of GnRH agonists."

Guideline option with psychological follow-up and eventual hormone planning.

Vaginal dilation when desired and indicated

Action: Vaginal dilation when desired and indicated Ontology label: Supportive Care NCIT:C15747

For a person with a short vagina who desires improved vaginal function, gradual dilation is generally the initial option. Surgery is considered selectively if needed and may still require maintenance dilation. This is patient-directed functional care, not a mandatory procedure based on anatomy.

Mechanism Target:

MODULATES Blind vagina — Dilation can lengthen the vaginal canal and improve desired function; it does not restore a cervix or uterus or reverse the blind-ending anatomy.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Vaginal dilation to augment vaginal length and to avoid dyspareunia is typically the treatment of choice for those with short vaginal length."

GeneReviews supports dilation as the usual first approach.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Vaginal dilation to augment vaginal length and to avoid dyspareunia is typically the treatment of choice for those with short vaginal length."

GeneReviews supports dilation as the usual first approach.

Individualized urologic procedures

Action: Individualized urologic procedures Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Orchiopexy or hypospadias repair can be considered in PAIS according to anatomy, function and informed goals. Timing requires multidisciplinary and patient/family discussion. These procedures address anatomy and do not restore receptor function or guarantee fertility.

Mechanism Target:

MODULATES Hypospadias — Individualized management of the indicated manifestation; no correction of the AR variant is implied.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Those individuals with PAIS who are raised as males may undergo urologic surgery such as orchiopexy and hypospadias repair."

GeneReviews describes possible procedures; historical wording is interpreted through individualized care.

MODULATES Bilateral cryptorchidism — Orchiopexy can address gonadal position when appropriate; it does not remove all tumor or fertility uncertainty.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Those individuals with PAIS who are raised as males may undergo urologic surgery such as orchiopexy and hypospadias repair."

GeneReviews describes possible procedures; historical wording is interpreted through individualized care.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Those individuals with PAIS who are raised as males may undergo urologic surgery such as orchiopexy and hypospadias repair."

GeneReviews describes possible procedures; historical wording is interpreted through individualized care.

Gynecomastia management

Action: Gynecomastia management Ontology label: Supportive Care NCIT:C15747

Discuss observation, distress and functional impact, with reduction surgery when appropriate in PAIS or MAIS. Tamoxifen has only limited AIS-specific case evidence, including two PAIS patients; long-term efficacy and prophylactic benefit are not established. Testosterone can have variable effects on gynecomastia.

Mechanism Target:

MODULATES Gynecomastia — Individualized management of the indicated manifestation; no correction of the AR variant is implied.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The effect of medical treatment on gynaecomastia is variable and most males decide to undergo mastectomy."

Guideline synthesis; individual preference remains central.

Show evidence (3 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The effect of medical treatment on gynaecomastia is variable and most males decide to undergo mastectomy."

Guideline synthesis; individual preference remains central.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Successful use of tamoxifen, a selective oestrogen receptor blocker, to reduce gynaecomastia was described in two patients with PAIS"

Small case evidence, not a controlled efficacy estimate.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"However, long-term studies are lacking, and whether or not there is a role for oestrogen blockers to prevent gynecomastia remains to be studied."

Limits both treatment and prevention claims.

Genetic counseling and family evaluation

Action: Genetic counseling and family evaluation Ontology label: Genetic Counseling NCIT:C15240

Explain X-linked transmission, de novo and postzygotic variants, possible maternal germline mosaicism, variable expression and testing limitations. Offer appropriate testing of at-risk relatives and reproductive counseling when a familial pathogenic variant is known. A blood mosaic fraction does not specify genital-tissue or germline burden. Support fertility counseling without promising assisted-reproduction success for an uncharacterized patient.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"the chance of transmitting it in each pregnancy is 50%."

GeneReviews maternal heterozygote transmission counseling.

PMID:30251955 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In four individuals (P5, P6, P8 and P16), 17% of AR-mutated gene patients, somatic mosaicism of mutant and wild type alleles was detected in DNA derived from blood leukocytes."

Primary blood mosaicism evidence; no tissue fraction or universal recurrence risk.

Testosterone as an alternative replacement in selected gonadectomized adults with CAIS

Action: Testosterone as an alternative replacement in selected gonadectomized adults with CAIS Ontology label: Pharmacotherapy NCIT:C15986

Agent: testosterone CHEBI:17347

Platform: Small molecule

A randomized crossover trial enrolled 26 gonadectomized adult women with genetically confirmed CAIS; 18 contributed to the primary analysis after withdrawals. Testosterone and estradiol did not differ significantly for the primary mental-health quality-of-life outcome. Testosterone improved only the sexual-desire component of the sexual-function questionnaire. This small secondary-endpoint finding can inform individualized specialist discussion but does not prove overall superiority, equivalence or long-term safety.

Show evidence (3 references)

PMID:30075954 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Mental health-related quality of life did not differ between treatment groups (linear mixed model, p=0·794)"

Primary outcome in the randomized crossover trial; full original manuscript was not recovered.

PMID:30075954 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"For the FSFI, testosterone was superior to oestradiol only in improving sexual desire (linear mixed model, p=0·018)."

Secondary subscale result, not improvement in all sexual-function domains.

PMID:30075954 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"No virilisation was observed, and gonadotrophin concentrations remained stable in both treatment groups."

Observation during the trial, not evidence of lifelong safety.

🔬

Biochemical Markers

Testosterone

Context: Normal male-range or elevated concentrations with retained testes, interpreted by age and treatment. A normal postnatal value does not prove normal fetal steroid synthesis, and hCG response does not exclude every biosynthetic disorder.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Guideline specifies the reference range and retained-gonad context.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Normal serum concentrations of T, DHT, and LH after birth do not prove that the concentration was normal during the critical period of fetal genital masculinization."

Limits retrospective inference from postnatal hormones.

Estradiol

Context: Aromatization produces estradiol despite AR resistance. Concentrations in CAIS with retained testes are generally above male but below female reference values; postgonadectomy levels depend on replacement.

Show evidence (1 reference)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Comparator-specific synthesis.

Luteinizing hormone and follicle-stimulating hormone

Context: LH is often elevated when the axis is active; FSH can remain normal under estrogen/inhibin feedback. Normal gonadotropins were the most common pattern in one selected pediatric cohort, so elevation is not required at every age.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Thus, the LH/FSH ratio is typically relatively high in CAIS and PAIS"

Typical pubertal physiology.

PMID:30251955 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In agreement with previous reports, normal gonadotropin levels were the most frequent finding"

Observed cohort hormone pattern.

Antimullerian hormone

Context: Normal prepubertal values can be followed by failure of the expected pubertal fall. This age-specific pattern reflects impaired androgen suppression of Sertoli AMH and is distinct from fetal Müllerian regression.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Pubertal regulation.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The testicular Sertoli cell markers inhibin B and AMH are within the normal prepubertal male range"

Prepubertal comparator.

🔬

Diagnosis

Clinical phenotype, anatomy and chromosome assessment

Evaluate genital anatomy, gonadal location, pubertal development, menstrual history and fertility with chromosome testing. CAIS may present as childhood inguinal hernia or adolescent primary amenorrhea; PAIS and MAIS have different patterns. Clinical appearance alone does not establish an AR-related diagnosis or determine gender identity.

Integrated DSD evaluation NCIT:C124351

Show evidence (2 references)

PMID:29785970 SUPPORT DIRECT BACKGROUND Human Clinical

"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."

Clinical background within a cohort report.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Mild androgen insensitivity syndrome (MAIS) with typical male external genitalia"

Milder clinical spectrum.

Age-appropriate endocrine assessment

Measure testosterone, DHT, LH, FSH and relevant steroid precursors with age, gonadal status and replacement therapy in mind. Selected hCG stimulation testing assesses Leydig response. Normal testosterone or a response to hCG does not by itself exclude all biosynthetic defects or establish normal fetal androgen exposure.

Endocrine laboratory assessment NCIT:C25294

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Expected endocrine pattern with important normal-range overlap.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Normal serum concentrations of T, DHT, and LH after birth do not prove that the concentration was normal during the critical period of fetal genital masculinization."

Explicit diagnostic limitation.

AR molecular testing and variant interpretation

Sequence AR and assess deletions or duplications when indicated; broader DSD testing can identify phenocopies. A compatible pathogenic or likely pathogenic variant supports molecular diagnosis. An uncertain variant does not establish or exclude AIS, and somatic mosaicism may require sensitive testing. Family studies support interpretation and counseling.

AR and DSD genetic testing NCIT:C15709

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"does not establish or rule out the diagnosis."

GeneReviews statement specifically concerns an AR variant of uncertain significance.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"to detect multiexon or whole-gene deletions or duplications may be considered if a"

GeneReviews advises copy-number testing when sequencing is unrevealing.

PMID:30251955 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All of the CAIS cases (n=11) were genetically confirmed, while in PAIS (n=30) a mutation in AR was detected in only 13 patients (43.3%)."

Diagnostic yield in one selected cohort, not universal sensitivity.

Pelvic and gonadal imaging

Ultrasound and selected MRI identify gonadal location and internal anatomy and can assess a new mass. Imaging and serum tumor markers cannot reliably exclude microscopic germ-cell precursor lesions. Apparent Müllerian remnants require careful interpretation; benign stromal nodules are not synonymous with cancer.

Show evidence (3 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Yearly follow-up if the gonads are retained was advised including self-examination and imaging (ultrasound/MRI)"

Retained-gonad surveillance recommendation; self-examination is feasible only for accessible gonads.

PMID:36851849 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Leydig cell tumour of the right testis. It was a benign testicular tumour."

A postoperative benign stromal diagnosis limits equating every mass with malignancy.

PMID:36851849 SUPPORT DIRECT BACKGROUND Human Clinical

"but these are not specific detection methods for gonadal malignant transformation in CAIS patients."

The preceding source list includes imaging and serum markers; this is background synthesis, not a tested screening sensitivity.

📈

Progression

Presentation across the AIS spectrum

CAIS may be recognized with an inguinal mass or hernia in childhood or primary amenorrhea after spontaneous breast development. PAIS is often recognized from atypical genital anatomy at birth; MAIS may first be investigated for pubertal gynecomastia or infertility. These are alternative presentations, not a fixed sequence.

Show evidence (2 references)

PMID:29785970 SUPPORT DIRECT BACKGROUND Human Clinical

"Affected individuals typically exhibit inguinal swelling during infancy or primary amenorrhea during puberty."

Background CAIS presentation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In some instances, the only observed abnormality appears to be male infertility"

MAIS clinical presentation.

Puberty and adult follow-up

With retained testes, CAIS usually undergoes spontaneous breast development; gonadectomized individuals require planned replacement. PAIS virilization is variable and cannot be predicted from an AR assay alone. Gonadal, bone, sexual and psychological follow-up continues into adulthood.

Show evidence (2 references)

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Puberty treatment is not indicated in girls with retained testes."

CAIS recommendation context.

PMID:35353710 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In contrast to the clinical findings, the functional analysis of AR variants did not appear to predict pubertal outcome"

PAIS prediction limit.

📊

Prevalence

Worldwide

Point Prevalence 0.1–0.9 per 100,000 1–9 per 1,000,000 CAIS

Show evidence (1 reference)

ORPHA:99429 SUPPORT Other

"1-9 / 1 000 000 | Worldwide | Point prevalence"

Orphanet records a worldwide point-prevalence estimate for CAIS.

Europe

Annual Incidence 1.0–9.0 per 100,000 1–9 per 100,000 per year CAIS

Show evidence (1 reference)

ORPHA:99429 SUPPORT Other

"1-9 / 100 000 | Europe | Annual incidence"

Orphanet records a European annual-incidence estimate for CAIS.

Worldwide

Point Prevalence Unknown PAIS

Show evidence (1 reference)

ORPHA:90797 SUPPORT Other

"Unknown | Worldwide | Point prevalence"

Orphanet records the worldwide point prevalence as unknown.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Androgen Insensitivity Syndrome:

Mayer-Rokitansky-Küster-Hauser syndrome

Overlapping Features Amenorrhea and absent Müllerian structures can resemble CAIS, but MRKH usually has a 46,XX karyotype and ovarian rather than testicular gonads.

Distinguishing Features

Chromosome result and gonadal identity; pubic hair is generally androgen responsive.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Individuals with MRKH can be distinguished from those with CAIS by confirmation of a 46,XX"

GeneReviews differential diagnosis; raw HTML interrupts the following karyotype term.

Steroid 5-alpha-reductase 2 deficiency

Overlapping Features SRD5A2-related impaired conversion of testosterone to DHT can cause undervirilization with testes and preserved Müllerian regression. Steroid profiles, pubertal course and molecular testing distinguish it from AIS.

Distinguishing Features

Reduced DHT formation with compatible biallelic SRD5A2 variants; a single testosterone value is insufficient.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The enzyme converts testosterone to dihydrotestosterone (DHT), which is primarily responsible for the development of the external genitalia before birth."

GeneReviews SRD5A2 differential mechanism.

17-beta-hydroxysteroid dehydrogenase 3 deficiency and other steroidogenic defects

Overlapping Features HSD17B3 and other biosynthetic disorders can overlap with clinical PAIS. Compensatory LH stimulation can yield a normal testosterone concentration despite a partial biosynthetic defect.

Distinguishing Features

Steroid precursor pattern, stimulation testing and molecular findings.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Elevated levels of testosterone precursors caused by a partial testosterone biosynthetic defect in which compensatory serum LH concentrations stimulate a normal plasma testosterone concentration"

Explicit diagnostic pitfall.

46,XY gonadal dysgenesis

Overlapping Features Impaired testicular development can reduce both androgen and AMH production, unlike the usually preserved AMH pathway in AIS. Retained Müllerian structures or a broader syndromic phenotype should prompt reconsideration.

Distinguishing Features

Gonadal differentiation, AMH function, internal anatomy and the causal molecular diagnosis.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The presence of müllerian duct derivatives as a result of a testicular organogenesis defect with impaired Sertoli cell production of anti-müllerian hormone"

GeneReviews differential mechanism.

🔬

Clinical Trials

DRKS00003136 PHASE_III COMPLETED

Prospectively registered randomized, blinded crossover comparison of transdermal testosterone and estradiol in adults with genetically confirmed CAIS after gonadectomy. The registry lists 30 planned and 26 final participants, completion in January 2016 and EudraCT 2010-021790-37. The primary mental-health quality-of-life comparison was not significant; a sexual-desire subscale favored testosterone. The metabolic publication is an exploratory secondary analysis of this same trial.

Show evidence (4 references)

url:https://drks.de/search/en/trial/DRKS00003136 SUPPORT DIRECT BACKGROUND Human Clinical

"Postpubertal adult patient with complete androgen insensitivity syndrome classified as either Sinnecker Type 5A or 5B"

Registry eligibility; mutation confirmation and prior gonadectomy are adjacent criteria.

PMID:30075954 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Mental health-related quality of life did not differ between treatment groups (linear mixed model, p=0·794)"

Original trial primary outcome.

PMID:35258786 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here we report the results of a secondary metabolic outcome analysis of the first multicentre, randomised, double-dummy, double-blind crossover trial investigating the effects of estradiol in comparison to testosterone replacement therapy in CAIS probands"

Full secondary manuscript establishes cohort overlap.

+ 1 more reference

🧫

Experimental Models

AR and MAP3K1 coexpression in HEK293T/17 cells CELL_LINE

Transient expression of wild-type or variant AR and MAP3K1 plasmids measured AR protein band abundance after 48 hours. The one-family study reported lower AR abundance with the AR variant alone and higher signal in selected MAP3K1-mutant/coexpression conditions. It did not measure androgen binding, DNA binding, reporter transactivation, kinase signaling, receptor half-life or clinical rescue. Single-plasmid and dual-plasmid conditions used different per-plasmid doses. Thus these results do not establish MAP3K1 modifier causality and are not connected to a proven clinical signaling route.

Cell source

HEK293T/17 kidney-derived cell line

Show evidence (2 references)

PMID:32338288 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The cells lysates were used to analyze the AR protein expression by Western blot."

Measured endpoint is protein abundance, not receptor activity.

PMID:32338288 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The transfection concentration of a single plasmid was 2.5 μg/ml. When the cotransfection of the two plasmids was conducted, the concentration of each plasmid is 1.5 μg/ml."

Dose difference limits a clean interaction interpretation.

Exploratory PAIS peripheral-blood transcriptome study OTHER

RNA sequencing compared isolated PBMCs from three AR-variant PAIS patients with three age-matched male volunteers. The reported 725 differentially expressed genes and computational network/enrichment analyses are exploratory associations, not a validated diagnostic signature or evidence that candidate immune/metabolic pathways cause genital development. Only CCR1 was significantly different in the reported qPCR follow-up; the other selected genes were not significant. The Methods cites a mouse GRCm38 annotation despite human samples, an unresolved source reporting issue. No independent diagnostic validation cohort or controlled AR perturbation was provided.

Cell source

Uncultured peripheral blood mononuclear cells from three PAIS patients and three controls

Show evidence (3 references)

PMID:34867780 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The peripheral blood of three PAIS patients and three healthy male volunteers (age-matched) was obtained from Shanghai Ninth People’s Hospital"

Human observational sampling, not a six-patient series.

PMID:34867780 SUPPORT DIRECT PRIMARY RESULT Computational

"a total of 725 DEGs, including 495 upregulated and 230 downregulated genes, were identified in PAIS patients"

Exploratory differential-expression output with the study threshold.

PMID:34867780 SUPPORT DIRECT PRIMARY RESULT Other

"GENCODE (Release M22, GRCm38. p6)"

Source-internal reference-annotation mismatch; not corrected or silently assumed away.

🐁

Animal Models

Ubiquitous androgen receptor knockout mouse GENETIC

Global deletion of exon 2 eliminates functional AR and produces a CAIS-like female external phenotype with small abdominal or inguinal testes and absent androgen-dependent internal ducts. Müllerian derivatives were absent, consistent with preserved non-AR fetal testicular function. This does not recreate every patient allele or isolate the cell type responsible for infertility.

Species

Mouse

Genotype

Ar exon 2 deletion induced by ubiquitous PGK-Cre

Genes

AR hgnc:644

Publication

PMID:14745012

Pathograph links

Impaired External Genital Virilization recapitulates fidelity: moderate Global receptor loss produces a female external phenotype.

Limitations: Complete engineered receptor loss is not a variant-specific human PAIS model. Analyses used selected mouse ages and mixed genetic backgrounds. In the global knockout, abdominal gonadal location confounds attribution of spermatogenic loss to receptor signaling alone.

Readouts

Male external genital development

Direction: DECREASED

Interpretation: Global receptor loss produces a female external phenotype.

Show evidence (1 reference)

PMID:14745012 SUPPORT DIRECT PRIMARY RESULT Model Organism

"AR knockout males displayed a complete androgen insensitivity phenotype."

Primary phenotype summary.

Show evidence (1 reference)

PMID:14745012 SUPPORT DIRECT PRIMARY RESULT Model Organism

"AR knockout males displayed a complete androgen insensitivity phenotype."

Primary phenotype summary.

Impaired Wolffian Duct Development recapitulates fidelity: moderate Wolffian derivatives were absent in the global knockout.

Readouts

Wolffian derivatives

Direction: DECREASED

Interpretation: Wolffian derivatives were absent in the global knockout.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Structures derived from the Wolffian ducts (ductus deferens, epididymis, and seminal vesicles) or urogenital sinus (prostate) were absent. No uterus or fallopian tubes were observed."

Primary dissection result.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Structures derived from the Wolffian ducts (ductus deferens, epididymis, and seminal vesicles) or urogenital sinus (prostate) were absent. No uterus or fallopian tubes were observed."

Primary dissection result.

Show evidence (2 references)

PMID:14745012 SUPPORT DIRECT PRIMARY RESULT Model Organism

"AR knockout males displayed a complete androgen insensitivity phenotype. Testes were located abdominally, and germ cell development was severely disrupted."

Primary global mouse phenotype.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Structures derived from the Wolffian ducts (ductus deferens, epididymis, and seminal vesicles) or urogenital sinus (prostate) were absent. No uterus or fallopian tubes were observed."

Full manuscript documents internal tract findings.

Sertoli-cell androgen receptor knockout mouse GENETIC

Amh-Cre activity begins around embryonic day 15, before normal neonatal Sertoli AR expression. Selective receptor loss markedly reduces androgen-responsive Pem expression and impairs meiotic progression, with increased germ-cell apoptosis and no elongated spermatids at day 50. Stereological nuclear-volume estimates, rather than direct absolute cell counts, gave spermatocyte and round-spermatid values of 64% and 3% of controls. Sertoli nuclear volume was not significantly changed. Testicular descent, external development and androgen-dependent ducts were preserved; LH and testosterone were not significantly different, while FSH was higher.

Species

Mouse

Genotype

Ar exon 2 deletion induced by Amh-Cre (SCARKO)

Genes

AR hgnc:644

Publication

PMID:14745012

Pathograph links

Reduced Sertoli Androgen Signaling perturbs fidelity: moderate Conditional Ar deletion selectively removes the receptor from Sertoli cells.

Limitations: Complete developmental loss precedes normal expression; it is not an adult pharmacological inhibition or a specific patient missense allele.

Readouts

Sertoli-cell AR staining

Direction: DECREASED

Interpretation: Conditional Ar deletion selectively removes the receptor from Sertoli cells.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"no immunopositive staining was detected in SC"

Immunohistochemical loss in SCARKO while Leydig and peritubular nuclei remained positive.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"no immunopositive staining was detected in SC"

Immunohistochemical loss in SCARKO while Leydig and peritubular nuclei remained positive.

Impaired Spermatogenesis recapitulates fidelity: moderate Selective Sertoli AR loss impairs germ-cell progression and survival despite descended testes.

Limitations: Mechanisms of Sertoli-germ-cell interaction remain unresolved. Stereology used five WT and three SCARKO mice; nuclear volumes approximate cell numbers. This does not exclude contributions from other somatic cell types in human AIS.

Readouts

Meiotic progression and spermatid development

Direction: DECREASED

Interpretation: Selective Sertoli AR loss impairs germ-cell progression and survival despite descended testes.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Morphological analysis of SCARKO testes established that germ cell entry into meiosis appeared normal, but there was progressive loss of pachytene primary spermatocytes between stages VI and XII."

Primary conditional genetic perturbation.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Morphological analysis of SCARKO testes established that germ cell entry into meiosis appeared normal, but there was progressive loss of pachytene primary spermatocytes between stages VI and XII."

Primary conditional genetic perturbation.

Impaired Testicular Descent fails to recapitulate fidelity: low The tested conditional knockout retained normal testis descent.

Limitations: A tested negative specific to Sertoli AR loss; it does not refute the role of AR in other tissues or global AIS.

Readouts

Testicular descent

Direction: UNCHANGED

Interpretation: The tested conditional knockout retained normal testis descent.

Show evidence (1 reference)

PMID:14745012 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract."

Direct conditional/global contrast.

Show evidence (1 reference)

PMID:14745012 SUPPORT DIRECT PRIMARY RESULT Model Organism

"In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract."

Direct conditional/global contrast.

Impaired Wolffian Duct Development fails to recapitulate fidelity: low Androgen-dependent internal ducts developed normally in SCARKO.

Limitations: Cell-lineage-specific negative result, not universal preservation in human AIS.

Readouts

Wolffian duct development

Direction: UNCHANGED

Interpretation: Androgen-dependent internal ducts developed normally in SCARKO.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"SCARKO males displayed normal development of epididymis, ductus deferens, coagulating gland, seminal vesicles, and prostate."

Primary dissection finding.

Show evidence (1 reference)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"SCARKO males displayed normal development of epididymis, ductus deferens, coagulating gland, seminal vesicles, and prostate."

Primary dissection finding.

Show evidence (3 references)

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Morphological analysis of SCARKO testes established that germ cell entry into meiosis appeared normal, but there was progressive loss of pachytene primary spermatocytes between stages VI and XII."

Detailed histological result in the full manuscript.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"No elongated spermatids were detected."

Primary spermatogenic endpoint.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Serum levels of testosterone and LH revealed no significant difference between WT and SCARKO animals"

Separates this conditional model from a universal LH/testosterone elevation claim.

{ }

Source YAML

click to show

name: Androgen Insensitivity Syndrome
creation_date: '2026-05-11T04:48:29Z'
category: Mendelian
description: Androgen insensitivity syndrome (AIS) is an AR-related difference of sex development in which 46,XY individuals have testes and impaired tissue responses to androgen. Complete AIS usually has female external genitalia; partial AIS has variable genital virilization; mild AIS can present with infertility or pubertal undervirilization despite typical male external genitalia. Germline and postzygotic AR variants can impair ligand binding, DNA binding or transcriptional regulation, but residual activity does not reliably predict an individual phenotype, especially in partial AIS. Fetal testicular AMH activity is generally preserved, so Müllerian structures are absent or rudimentary. Age, gonadal status, tissue sensitivity and clinical goals shape endocrine findings and care.
disease_term:
  preferred_term: androgen insensitivity syndrome
  term:
    id: MONDO:0019154
    label: androgen insensitivity syndrome
synonyms:
- AIS
- Androgen resistance syndrome
- Testicular feminization
- CAIS
- PAIS
- Complete androgen insensitivity syndrome
- Partial androgen insensitivity syndrome
- Complete androgen resistance syndrome
- Partial androgen resistance syndrome
- Complete testicular feminization syndrome
- MAIS
- Mild androgen insensitivity syndrome
parents:
- 46,XY disorder of sex development
- Androgen receptor signaling disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019154
      label: androgen insensitivity syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO identifier for the disease. The two MONDO descendants, complete (MONDO:0021023) and partial (MONDO:0010720) androgen insensitivity syndrome, are curated as has_subtypes entries carrying their own subtype_term.
has_subtypes:
- name: CAIS
  display_name: Complete Androgen Insensitivity Syndrome (CAIS)
  subtype_term:
    preferred_term: complete androgen insensitivity syndrome
    term:
      id: MONDO:0021023
      label: complete androgen insensitivity syndrome
  description: Markedly reduced androgen responsiveness with female external genitalia, usually absent or rudimentary Müllerian structures, a short blind-ending vagina, sparse sexual hair and inguinal, labial or abdominal testes. Presentations include childhood inguinal hernia or adolescent primary amenorrhea. Occasional Wolffian remnants and atypical findings prevent an absolute internal-anatomy rule.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
- name: PAIS
  display_name: Partial Androgen Insensitivity Syndrome (PAIS)
  subtype_term:
    preferred_term: partial androgen insensitivity syndrome
    term:
      id: MONDO:0010720
      label: partial androgen insensitivity syndrome
  description: Variable incomplete androgen responsiveness with predominantly male, predominantly female or ambiguous external genitalia. Pubertal virilization, gynecomastia and fertility vary. Genotype and in-vitro receptor assays do not determine an individual pubertal outcome.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
- name: MAIS
  display_name: Mild Androgen Insensitivity Syndrome (MAIS)
  description: Typical male external genitalia with possible infertility, impaired pubertal virilization or gynecomastia. A distinct ontology descendant is not required to retain this recognized clinical subtype.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: AIS usually follows X-linked inheritance through a hemizygous pathogenic AR variant. De novo variants and postzygotic mosaicism also occur. A heterozygous carrier has a 50% probability of transmitting the variant in each pregnancy; phenotype depends on chromosomal and biological context. A negative maternal blood test does not exclude germline mosaicism, and blood mosaic fractions do not specify fetal genital-tissue fractions.
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Androgen insensitivity syndrome (AIS) is a rare inherited condition caused by X-linked pathogenic mutations in the androgen receptor (AR) gene
    explanation: Guideline synthesis of established AR-related inheritance.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In four individuals (P5, P6, P8 and P16), 17% of AR-mutated gene patients, somatic mosaicism of mutant and wild type alleles was detected in DNA derived from blood leukocytes.
    explanation: Four of 24 AR-positive cases in a selected tertiary-center series, not a population mosaicism frequency.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: the chance of transmitting it in each pregnancy is 50%.
    explanation: Maternal heterozygote transmission probability in GeneReviews counseling.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_low: 0.1
  rate_high: 0.9
  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.
  subtype: CAIS
- population: Europe
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 1.0
  rate_high: 9.0
  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.
  subtype: CAIS
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: UNKNOWN
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Unknown | Worldwide | Point prevalence
    explanation: Orphanet records the worldwide point prevalence as unknown.
  subtype: PAIS
pathophysiology:
- name: Pathogenic AR Variation
  description: Hemizygous pathogenic germline variants and postzygotic mosaic AR variants can impair androgen receptor signaling. Defects differ by allele and domain; not every variant affects ligand binding, DNA binding and receptor abundance together. Genotype-phenotype correlation is especially limited in PAIS.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Androgen insensitivity syndrome (AIS) is a rare inherited condition caused by X-linked pathogenic mutations in the androgen receptor (AR) gene
    explanation: Established gene-disease relationship.
  downstream:
  - target: Reduced Androgen Binding
    description: Some ligand-binding-domain variants reduce affinity, increase dissociation or otherwise impair ligand responsiveness.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: impair androgen binding and impair transactivation by the AR. Some decrease only the apparent equilibrium affinity constant; some increase only the non-equilibrium dissociation rate; others do both, either with all androgens or selectively with certain androgens.
      explanation: GeneReviews describes allele-dependent biochemical defects.
  - target: Impaired AR DNA Binding
    description: Some DNA-binding-domain variants impair recognition of androgen response elements.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Single-nucleotide variants in the zinc fingers or &#x003b1;-helical portions of the DNA-binding domain impair binding to a sequence of regulatory nucleotides known as an androgen response element. Such binding is essential for the androgen receptor to exert transcriptional regulatory control over most of its target genes.
      explanation: Domain-specific molecular mechanism.
  - target: Reduced AR-Dependent Transcription
    description: Other defects can reduce transactivation without a demonstrated ligand-binding defect.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: impair androgen binding and impair transactivation by the AR. Some decrease only the apparent equilibrium affinity constant; some increase only the non-equilibrium dissociation rate; others do both, either with all androgens or selectively with certain androgens.
      explanation: GeneReviews explicitly links pathogenic binding-domain variants to impaired transactivation.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
- name: Reduced Androgen Binding
  description: Selected pathogenic AR variants impair ligand binding through altered affinity, dissociation kinetics or temperature sensitivity. Normal binding in a tested variant does not exclude defective downstream transactivation.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: impair androgen binding and impair transactivation by the AR. Some decrease only the apparent equilibrium affinity constant; some increase only the non-equilibrium dissociation rate; others do both, either with all androgens or selectively with certain androgens.
    explanation: Review synthesis of variant-specific receptor assays.
  downstream:
  - target: Reduced AR-Dependent Transcription
    description: Impaired activation by androgen can reduce target-gene transcription.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: impair androgen binding and impair transactivation by the AR. Some decrease only the apparent equilibrium affinity constant; some increase only the non-equilibrium dissociation rate; others do both, either with all androgens or selectively with certain androgens.
      explanation: The source explicitly connects binding defects with impaired transactivation.
- name: Impaired AR DNA Binding
  description: Selected variants in the receptor DNA-binding domain impair interaction with androgen response elements. This mechanism is distinct from reduced ligand binding.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Single-nucleotide variants in the zinc fingers or &#x003b1;-helical portions of the DNA-binding domain impair binding to a sequence of regulatory nucleotides known as an androgen response element. Such binding is essential for the androgen receptor to exert transcriptional regulatory control over most of its target genes.
    explanation: Domain-specific functional synthesis.
  downstream:
  - target: Reduced AR-Dependent Transcription
    description: Reduced response-element binding impairs transcriptional regulation of androgen-responsive targets.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Single-nucleotide variants in the zinc fingers or &#x003b1;-helical portions of the DNA-binding domain impair binding to a sequence of regulatory nucleotides known as an androgen response element. Such binding is essential for the androgen receptor to exert transcriptional regulatory control over most of its target genes.
      explanation: The source states why DNA binding is needed for target-gene control.
- name: Reduced AR-Dependent Transcription
  description: Reduced androgen-dependent transcription alters tissue responses during fetal development, puberty and adult life. The relevant target genes and co-regulatory effects vary by tissue; receptor activity measured in a reporter system is not a deterministic clinical severity scale.
  biological_scale: MOLECULAR
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: impair androgen binding and impair transactivation by the AR. Some decrease only the apparent equilibrium affinity constant; some increase only the non-equilibrium dissociation rate; others do both, either with all androgens or selectively with certain androgens.
    explanation: Variant-associated impaired transactivation, separate from normal-function context.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The androgen receptor is a well-defined transcriptional regulatory factor. Once activated by binding to androgen, it collaborates with other co-regulatory proteins (some involve DNA binding, others do not) to achieve control over the rate of transcription of an androgen target
    explanation: Normal molecular function underlying the signaling defect.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In contrast to the clinical findings, the functional analysis of AR variants did not appear to predict pubertal outcome
    explanation: Limits prediction from functional assays.
  biological_processes:
  - preferred_term: androgen receptor signaling pathway
    term:
      id: GO:0030521
      label: androgen receptor signaling pathway
    modifier: DECREASED
  downstream:
  - target: Impaired External Genital Virilization
    description: Developmental effect of reduced AR activity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Reduced AR residual activity results in PAIS with variable virilisation of the external genitalia during fetal life.
      explanation: Developmental effect of reduced AR activity.
  - target: Impaired Wolffian Duct Development
    description: Typical androgen-dependent internal tract development.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Furthermore, Wolffian structures do not develop due to the insensitivity to testosterone.
      explanation: Typical androgen-dependent internal tract development.
  - target: Reduced Androgen Negative Feedback
    description: Central AR action and feedback.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: The resulting testosterone secretion from the Leydig cells in the testes fails to exert negative feedback to the hypothalamic-pituitary axis due to insufficient central AR action.
      explanation: Central AR action and feedback.
  - target: Reduced Androgen-Dependent Hair Development
    description: Tissue response summarized in the guideline.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: The patients develop no or scarce pubic and axillary hair.
      explanation: Tissue response summarized in the guideline.
  - target: Impaired Testicular Descent
    description: Clinical location supports the developmental consequence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: The testes are typically located within the abdomen, inguinal canal or in the labia majora
      explanation: Clinical location supports the developmental consequence.
  - target: Reduced Pubertal AMH Suppression
    description: Androgen-dependent regulation at puberty.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: With rising intratesticular testosterone levels, AMH secretion is inhibited in a subject with normal AR function, whereas a boy with PAIS continues to have prepubertal levels of AMH due to lack of inhibition.
      explanation: Androgen-dependent regulation at puberty.
  - target: Reduced Bone Mineral Accrual
    description: Multifactorial skeletal association; no single intermediary is established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Women with CAIS and intact gonads have an increased risk of developing low BMD due to bone insensitivity to testosterone and relative oestrogen deficiency. After gonadectomy, the risk of developing low BMD further increases.
      explanation: Multifactorial skeletal association; no single intermediary is established.
  - target: Reduced Sertoli Androgen Signaling
    description: Reduced receptor function impairs androgen-responsive Sertoli support.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:14745012
      reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/survival critically depends on androgens.
      explanation: Mouse intervention establishes a cell-specific role; human alleles need not reproduce a complete knockout.
  - target: Tall stature
    description: Associated androgen-responsive clinical finding; age, tissue effects and other mediators remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Delayed puberty
    description: Associated androgen-responsive clinical finding; age, tissue effects and other mediators remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Abnormally high-pitched voice
    description: Associated androgen-responsive clinical finding; age, tissue effects and other mediators remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0001620 | Abnormally high-pitched voice | Occasional (29-5%)
      explanation: Orphanet records abnormally high-pitched voice as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Male sexual dysfunction
    description: Associated androgen-responsive clinical finding; age, tissue effects and other mediators remain incompletely resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0040307 | Male sexual dysfunction | Very frequent (99-80%)
      explanation: Orphanet records male sexual dysfunction as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
- name: Impaired External Genital Virilization
  description: Reduced androgen response during fetal life impairs external genital masculinization, ranging from female external genitalia in CAIS to hypospadias, micropenis and variable labioscrotal fusion in PAIS. This node concerns anatomy and does not determine gender identity.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Reduced AR residual activity results in PAIS with variable virilisation of the external genitalia during fetal life.
    explanation: Clinical-developmental synthesis.
  downstream:
  - target: Female external genitalia in individual with 46,XY karyotype
    description: Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Hypospadias
    description: Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000047 | Hypospadias | Frequent (79-30%)
      explanation: Orphanet records hypospadias as frequent in PAIS.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Perineal hypospadias
    description: Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000051 | Perineal hypospadias | Occasional (29-5%)
      explanation: Orphanet records perineal hypospadias as occasional in PAIS.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Micropenis
    description: Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000054 | Micropenis | Occasional (29-5%)
      explanation: Orphanet records micropenis as occasional in PAIS.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Ambiguous genitalia
    description: Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000062 | Ambiguous genitalia | Frequent (79-30%)
      explanation: Orphanet records ambiguous genitalia as frequent in PAIS.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Bifid scrotum
    description: Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000048 | Bifid scrotum | Occasional (29-5%)
      explanation: Orphanet records bifid scrotum as occasional in PAIS.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Clitoral hypertrophy
    description: Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0008665 | Clitoral hypertrophy | Occasional (29-5%)
      explanation: Orphanet records clitoral hypertrophy as occasional in PAIS.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Fused labia majora
    description: Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0025486 | Fused labia majora | Occasional (29-5%)
      explanation: Orphanet records fused labia majora as occasional in PAIS.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Urogenital sinus anomaly
    description: Variable manifestation of impaired fetal genital virilization; subtype-specific curated evidence is retained.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0100779 | Urogenital sinus anomaly | Occasional (29-5%)
      explanation: Orphanet records urogenital sinus anomaly as occasional in PAIS.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
- name: Impaired Wolffian Duct Development
  description: Androgen resistance can impair differentiation of epididymis, vas deferens and other Wolffian structures. Their absence is typical of CAIS but occasional development is reported; Müllerian regression is a separate AMH-dependent process.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Furthermore, Wolffian structures do not develop due to the insensitivity to testosterone.
    explanation: Typical developmental mechanism; GeneReviews qualifies occasional exceptions.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: On occasion, wolffian duct development is observed
    explanation: Clinical exception to an absolute absence rule.
- name: Reduced Androgen Negative Feedback
  description: Reduced central androgen action weakens testosterone feedback on the hypothalamic-pituitary axis. Estrogen feedback and Sertoli-derived signals remain relevant, so LH, FSH and testosterone need not all be elevated together or at every age.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The resulting testosterone secretion from the Leydig cells in the testes fails to exert negative feedback to the hypothalamic-pituitary axis due to insufficient central AR action.
    explanation: Guideline endocrine mechanism.
  downstream:
  - target: Increased Luteinizing Hormone Secretion
    description: Reduced androgen feedback permits greater LH drive when the axis is active.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: resulting in persistently elevated LH concentrations.
      explanation: CAIS with retained testes; not a neonatal universal.
- name: Increased Luteinizing Hormone Secretion
  description: LH is often increased during puberty and adulthood with retained testes, while values can be normal in younger children. FSH can remain within its reference range because its regulation also involves estrogen and inhibin.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Thus, the LH/FSH ratio is typically relatively high in CAIS and PAIS
    explanation: Endocrine pattern is typical, not obligatory.
  downstream:
  - target: Increased Testicular Testosterone Production
    description: Greater LH drive can stimulate Leydig-cell androgen production, although circulating values may remain within the male range.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: The resulting testosterone secretion from the Leydig cells in the testes fails to exert negative feedback to the hypothalamic-pituitary axis due to insufficient central AR action.
      explanation: Physiological sequence summarized by the guideline.
  - target: Elevated circulating luteinizing hormone level
    description: Greater secretion can produce an elevated measured level when interpreted by age and gonadal status.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: resulting in persistently elevated LH concentrations.
      explanation: Clinical endocrine consequence.
- name: Increased Testicular Testosterone Production
  description: Retained testes can produce normal male-range or elevated testosterone despite tissue androgen resistance. An apparently high concentration against a female comparator does not by itself establish excess relative to the appropriate testicular reference range.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range
    explanation: Explicit comparator and gonadal context.
  downstream:
  - target: Increased serum testosterone level
    description: Some individuals have concentrations above the male range; normal male-range values are also compatible with AIS.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range
      explanation: The source allows normal and increased values.
  - target: Peripheral Testosterone Aromatization
    description: Available testosterone supplies peripheral estrogen synthesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range
      explanation: Aromatization is described explicitly.
- name: Peripheral Testosterone Aromatization
  description: Conversion of testosterone to estrogen persists despite AR dysfunction. In CAIS with retained testes, estrogen concentrations generally exceed male values but remain below usual female values; this can support spontaneous breast development. In PAIS, estrogen action relative to impaired androgen action contributes to gynecomastia.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range
    explanation: Preserved steroid conversion and reference-range context.
  downstream:
  - target: Gynecomastia
    description: Relative estrogenic effects can produce gynecomastia in PAIS; breast development in CAIS is expected puberty rather than a gynecomastia phenotype.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Oestradiol circulates in high-normal concentrations (compared to the male reference range) resulting in gynaecomastia in many boys with PAIS
      explanation: Specific PAIS clinical consequence.
  - target: Increased serum estradiol
    description: Measured estradiol may be high relative to a male reference range.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range
      explanation: Comparator-specific observation.
  - target: Gynecomastia in mild AIS
    description: Relative estrogen and androgen effects can contribute to pubertal gynecomastia in MAIS.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: They usually present with gynecomastia at puberty.
      explanation: GeneReviews MAIS clinical subsection.
- name: Reduced Androgen-Dependent Hair Development
  description: Reduced receptor action limits pubic, axillary and other androgen-dependent terminal hair. Sparse or absent hair is typical in CAIS and variable in PAIS or MAIS.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The patients develop no or scarce pubic and axillary hair.
    explanation: Clinical androgen-responsive tissue finding.
  downstream:
  - target: Sparse axillary hair
    description: Reduced androgen-dependent terminal hair development can produce this finding.
    causal_link_type: DIRECT
    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.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Absent axillary hair
    description: Reduced androgen-dependent terminal hair development can produce this finding.
    causal_link_type: DIRECT
    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.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Sparse pubic hair
    description: Reduced androgen-dependent terminal hair development can produce this finding.
    causal_link_type: DIRECT
    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.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Absent pubic hair
    description: Reduced androgen-dependent terminal hair development can produce this finding.
    causal_link_type: DIRECT
    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.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Abnormality of secondary sexual hair
    description: Reduced androgen-dependent terminal hair development can produce this finding.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0009888 | Abnormality of secondary sexual hair | Occasional (29-5%)
      explanation: Orphanet records abnormality of secondary sexual hair as occasional in PAIS.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: Impaired Testicular Descent
  description: Reduced androgen action can impair descent, leaving testes abdominal, inguinal or labial. A Sertoli-specific mouse knockout retained normal descent, showing that this developmental consequence cannot be assigned to Sertoli AR loss alone.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The testes are typically located within the abdomen, inguinal canal or in the labia majora
    explanation: Typical human location.
  - reference: PMID:14745012
    reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract.
    explanation: Primary mouse experiment distinguishes cell-specific from global AR loss.
  downstream:
  - target: Bilateral cryptorchidism
    description: Incomplete descent can leave both testes outside the scrotum.
    causal_link_type: DIRECT
    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.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Inguinal hernia
    description: Inguinal testicular location can accompany a hernia presentation; the source does not isolate a single anatomic causal sequence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29785970
      reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: Affected individuals typically exhibit inguinal swelling during infancy or primary amenorrhea during puberty.
      explanation: Background clinical presentation described by the cohort authors.
- name: Reduced Sertoli Androgen Signaling
  description: Sertoli-cell AR signaling supports germ-cell development. Conditional mouse loss establishes a somatic supporting-cell requirement; it does not imply that germ cells require their own AR or that all human infertility is caused by this one cell type.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:14745012
    reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/survival critically depends on androgens.
    explanation: Primary mouse perturbation; human extrapolation remains bounded.
  downstream:
  - target: Impaired Spermatogenesis
    description: Loss of Sertoli AR signaling impairs meiotic progression and later germ-cell survival through incompletely resolved Sertoli-germ-cell interactions.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
      reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: The mechanism by which inactivation of the AR in SC disturbs progression of germ cells through meiosis remains to be investigated.
      explanation: The full primary manuscript identifies the unresolved intermediary.
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
- name: Impaired Spermatogenesis
  description: Impaired androgen action can limit sperm production, with additional effects of gonadal location and testicular development. CAIS is associated with infertility; PAIS and MAIS show variable impairment. Azoospermia is not obligatory across the entire spectrum.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:14745012
    reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: It is concluded that cell-autonomous action of the AR in SC is an absolute requirement for androgen maintenance of complete spermatogenesis, and that spermatocyte/spermatid development/survival critically depends on androgens.
    explanation: Experimental supporting-cell requirement.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Spermatogenesis may or may not be impaired.
    explanation: GeneReviews specifically describes variability in MAIS.
  downstream:
  - target: Azoospermia
    description: Severe impairment can eliminate sperm from the ejaculate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:90797
      reference_title: Partial androgen insensitivity syndrome
      supports: SUPPORT
      evidence_source: OTHER
      snippet: HP:0000027 | Azoospermia | Occasional (29-5%)
      explanation: Orphanet records azoospermia as occasional in PAIS.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Male infertility
    description: Impaired sperm production contributes to infertility, with variable severity in milder AIS.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  biological_processes:
  - preferred_term: spermatogenesis
    term:
      id: GO:0007283
      label: spermatogenesis
    modifier: DECREASED
- name: Reduced Pubertal AMH Suppression
  description: Pubertal androgen action normally suppresses Sertoli-cell AMH. With impaired AR action, AMH may remain at prepubertal levels despite increasing testosterone. This is distinct from preserved fetal AMH secretion and does not imply elevated AMH in every neonate.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: With rising intratesticular testosterone levels, AMH secretion is inhibited in a subject with normal AR function, whereas a boy with PAIS continues to have prepubertal levels of AMH due to lack of inhibition.
    explanation: Age-specific endocrine mechanism.
  downstream:
  - target: Increased circulating antimullerian hormone concentration
    description: Failure of the expected pubertal decline can yield a high concentration relative to age-matched reference values.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: With rising intratesticular testosterone levels, AMH secretion is inhibited in a subject with normal AR function, whereas a boy with PAIS continues to have prepubertal levels of AMH due to lack of inhibition.
      explanation: Relative persistence, rather than universal fetal overproduction.
- name: Preserved Fetal AMH Secretion
  description: Fetal Sertoli cells generally retain AMH production in AIS. This is parallel developmental context, not a consequence of AR-induced negative-feedback failure. Testicular rather than ovarian differentiation also explains absent ovaries; ovaries are not Müllerian derivatives.
  biological_scale: CELLULAR
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Sertoli cells that produce AMH resulting in the regression of Mullerian structures prenatally. Thus, the uterus, fallopian tubes and upper part of the vagina are absent.
    explanation: Preserved testicular AMH pathway.
  downstream:
  - target: Müllerian Duct Regression
    description: AMH signaling promotes regression of Müllerian ducts despite impaired androgen responsiveness.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Sertoli cells that produce AMH resulting in the regression of Mullerian structures prenatally. Thus, the uterus, fallopian tubes and upper part of the vagina are absent.
      explanation: Parallel fetal pathway.
- name: Müllerian Duct Regression
  description: Preserved AMH action usually leads to absent or rudimentary uterus, fallopian tubes and cervix, with a short blind-ending vagina. Rare retained structures warrant careful reassessment; they do not establish a MAP3K1 modifier pathway.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Sertoli cells that produce AMH resulting in the regression of Mullerian structures prenatally. Thus, the uterus, fallopian tubes and upper part of the vagina are absent.
    explanation: Typical developmental consequence.
  downstream:
  - target: Abnormal morphology of female internal genitalia
    description: Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Aplasia of the uterus
    description: Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Aplasia or hypoplasia of the fallopian tube
    description: Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Abnormal uterine cervix morphology
    description: Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Blind vagina
    description: Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  - target: Primary amenorrhea
    description: Typical internal tract anatomy or its menstrual consequence; rudimentary structures can occur.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
- name: Reduced Bone Mineral Accrual
  description: CAIS can be associated with low bone mineral density through limited androgen action and relative estrogen deficiency. Gonadectomy without adequate replacement adds risk. This is multifactorial and does not make osteoporosis obligatory or demonstrate a particular fracture rate.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Women with CAIS and intact gonads have an increased risk of developing low BMD due to bone insensitivity to testosterone and relative oestrogen deficiency. After gonadectomy, the risk of developing low BMD further increases.
    explanation: Guideline synthesis of bone-health observations.
  downstream:
  - target: Decreased bone mineral density
    description: Reduced accrual and later loss can produce low measured bone mineral density.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: Women with CAIS and intact gonads have an increased risk of developing low BMD due to bone insensitivity to testosterone and relative oestrogen deficiency. After gonadectomy, the risk of developing low BMD further increases.
      explanation: Clinical skeletal consequence.
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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Tall stature
  category: Growth
  frequency: VERY_FREQUENT
  description: Final height in CAIS is generally above the female population mean but below the male mean. The retained Orphanet band refers to CAIS and does not imply tall stature against every comparator.
  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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: final height is generally above the mean female final height but below the average height of the male population
    explanation: Defines the height comparator.
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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:90797
    reference_title: Partial 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 PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - 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.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Delayed puberty
  category: Endocrine
  frequency: FREQUENT
  description: Delayed pubertal development is reported, but spontaneous breast development is usual in CAIS with retained testes. Gonadectomy and hormone replacement history affect pubertal timing.
  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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Male infertility
  category: Reproductive
  frequency: VERY_FREQUENT
  description: Infertility is typical of CAIS and frequent in PAIS. Impaired spermatogenesis can be the only presentation of MAIS, but it is not inevitable in every mild case. The Orphanet frequency combines CAIS and PAIS only, not unmeasured MAIS.
  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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Male infertility
  category: Reproductive
  frequency: VERY_FREQUENT
  description: Infertility is typical of CAIS and frequent in PAIS. Impaired spermatogenesis can be the only presentation of MAIS, but it is not inevitable in every mild case. The Orphanet frequency combines CAIS and PAIS only, not unmeasured MAIS.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial 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 PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Testicular neoplasm
  category: Neoplastic
  frequency: OCCASIONAL
  description: Retained gonads can develop benign stromal lesions or germ-cell neoplasia; these are distinct histologies. A reported Leydig-cell tumor was benign, and a later childhood case had benign Sertoli-rich hamartomas. The curated band is not an age-specific malignant cancer incidence.
  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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Elevated circulating luteinizing hormone level
  category: Endocrine
  frequency: VERY_FREQUENT
  description: LH is often elevated with an active pubertal/adult axis and retained testes, but normal values occur. Age, gonadal status and hormone therapy must be considered; the Orphanet band is not a universal diagnostic requirement.
  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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Elevated circulating luteinizing hormone level
  category: Endocrine
  frequency: VERY_FREQUENT
  description: LH is often elevated with an active pubertal/adult axis and retained testes, but normal values occur. Age, gonadal status and hormone therapy must be considered; the Orphanet band is not a universal diagnostic requirement.
  phenotype_term:
    preferred_term: Elevated circulating luteinizing hormone level
    term:
      id: HP:0011969
      label: Elevated circulating luteinizing hormone level
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial 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 PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Increased serum estradiol
  category: Endocrine
  frequency: VERY_FREQUENT
  description: Estradiol can be increased relative to male reference values through aromatization of testosterone. In CAIS with retained testes it generally remains below the usual female range; it is not universally elevated against both comparators.
  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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Increased serum testosterone level
  category: Endocrine
  frequency: VERY_FREQUENT
  description: Testosterone can exceed the male reference range, but normal age-appropriate male-range values are also compatible with AIS. Comparison with a female range alone should not be interpreted as excessive testicular production.
  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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Increased serum testosterone level
  category: Endocrine
  frequency: VERY_FREQUENT
  description: Testosterone can exceed the male reference range, but normal age-appropriate male-range values are also compatible with AIS. Comparison with a female range alone should not be interpreted as excessive testicular production.
  phenotype_term:
    preferred_term: Increased serum testosterone level
    term:
      id: HP:0030088
      label: Increased serum testosterone level
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial 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 level as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Abnormal circulating follicle-stimulating hormone concentration
  category: Endocrine
  frequency: VERY_RARE
  description: FSH may be abnormal, particularly with altered gonadal function or after gonadectomy, but it commonly remains within the male reference range because estrogen and inhibin regulation persist.
  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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Increased circulating antimullerian hormone concentration
  category: Endocrine
  frequency: FREQUENT
  description: AMH can remain high relative to pubertal age because androgen-dependent suppression is impaired. Normal prepubertal concentrations are reported; fetal AMH secretion is not inferred to be universally 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: AMH serum concentrations during the neonatal period were within the normal male reference range in the only two PAIS cases in whom it was assessed
    explanation: Two measured neonatal cases limit a universal elevation claim.
  subtype: 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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Germ cell neoplasia
  category: Neoplastic
  frequency: VERY_RARE
  description: Germ-cell neoplasia is a potential gonadal complication. Age, subtype, gonadal location, molecular confirmation and surgical selection affect published estimates. The Orphanet band is not a cumulative or age-specific malignancy risk and excludes benign stromal tumors.
  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. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: CAIS
- name: Azoospermia
  category: Reproductive
  frequency: OCCASIONAL
  description: Azoospermia is reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000027 | Azoospermia | Occasional (29-5%)
    explanation: Orphanet records azoospermia as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Hypospadias
  category: Genitourinary
  frequency: FREQUENT
  description: Hypospadias is frequently reported.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000047 | Hypospadias | Frequent (79-30%)
    explanation: Orphanet records hypospadias as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Bifid scrotum
  category: Genitourinary
  frequency: OCCASIONAL
  description: Bifid scrotum is reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Bifid scrotum
    term:
      id: HP:0000048
      label: Bifid scrotum
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000048 | Bifid scrotum | Occasional (29-5%)
    explanation: Orphanet records bifid scrotum as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Perineal hypospadias
  category: Genitourinary
  frequency: OCCASIONAL
  description: Perineal hypospadias is reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Perineal hypospadias
    term:
      id: HP:0000051
      label: Perineal hypospadias
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000051 | Perineal hypospadias | Occasional (29-5%)
    explanation: Orphanet records perineal hypospadias as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Micropenis
  category: Genitourinary
  frequency: OCCASIONAL
  description: Micropenis is reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Micropenis
    term:
      id: HP:0000054
      label: Micropenis
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000054 | Micropenis | Occasional (29-5%)
    explanation: Orphanet records micropenis as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Ambiguous genitalia
  category: Genitourinary
  frequency: FREQUENT
  description: Ambiguous genitalia are frequently reported.
  phenotype_term:
    preferred_term: Ambiguous genitalia
    term:
      id: HP:0000062
      label: Ambiguous genitalia
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000062 | Ambiguous genitalia | Frequent (79-30%)
    explanation: Orphanet records ambiguous genitalia as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Gynecomastia
  category: Endocrine
  frequency: FREQUENT
  description: Gynecomastia is frequently reported.
  phenotype_term:
    preferred_term: Gynecomastia
    term:
      id: HP:0000771
      label: Gynecomastia
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000771 | Gynecomastia | Frequent (79-30%)
    explanation: Orphanet records gynecomastia as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Primary amenorrhea
  category: Genitourinary
  frequency: OCCASIONAL
  description: Primary amenorrhea may occur in phenotypically female or predominantly female presentations.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0000786 | Primary amenorrhea | Occasional (29-5%)
    explanation: Orphanet records primary amenorrhea as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Abnormally high-pitched voice
  category: Endocrine
  frequency: OCCASIONAL
  description: Voice masculinization may be reduced.
  phenotype_term:
    preferred_term: Abnormally high-pitched voice
    term:
      id: HP:0001620
      label: Abnormally high-pitched voice
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0001620 | Abnormally high-pitched voice | Occasional (29-5%)
    explanation: Orphanet records abnormally high-pitched voice as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Insulin insensitivity
  category: Endocrine
  frequency: OCCASIONAL
  description: Insulin insensitivity is reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Insulin insensitivity
    term:
      id: HP:0008189
      label: Insulin insensitivity
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0008189 | Insulin insensitivity | Occasional (29-5%)
    explanation: Orphanet records insulin insensitivity as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Clitoral hypertrophy
  category: Genitourinary
  frequency: OCCASIONAL
  description: Clitoral hypertrophy is reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Clitoral hypertrophy
    term:
      id: HP:0008665
      label: Clitoral hypertrophy
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0008665 | Clitoral hypertrophy | Occasional (29-5%)
    explanation: Orphanet records clitoral hypertrophy as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Bilateral cryptorchidism
  category: Genitourinary
  frequency: FREQUENT
  description: Both testes may remain undescended.
  phenotype_term:
    preferred_term: Bilateral cryptorchidism
    term:
      id: HP:0008689
      label: Bilateral cryptorchidism
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0008689 | Bilateral cryptorchidism | Frequent (79-30%)
    explanation: Orphanet records bilateral cryptorchidism as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Abnormality of secondary sexual hair
  category: Dermatologic
  frequency: OCCASIONAL
  description: Secondary sexual hair may be reduced or otherwise abnormal.
  phenotype_term:
    preferred_term: Abnormality of secondary sexual hair
    term:
      id: HP:0009888
      label: Abnormality of secondary sexual hair
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0009888 | Abnormality of secondary sexual hair | Occasional (29-5%)
    explanation: Orphanet records abnormality of secondary sexual hair as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Aplasia of the ovary
  category: Genitourinary
  frequency: VERY_FREQUENT
  description: This Orphanet PAIS annotation reflects testicular rather than ovarian differentiation in the 46,XY context. Ovaries are not Müllerian derivatives, and their absence is not caused by AMH-mediated Müllerian regression.
  phenotype_term:
    preferred_term: Aplasia of the ovary
    term:
      id: HP:0010463
      label: Aplasia of the ovary
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0010463 | Aplasia of the ovary | Very frequent (99-80%)
    explanation: Orphanet records ovarian aplasia as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Abnormal circulating estrogen level
  category: Endocrine
  frequency: FREQUENT
  description: Circulating estrogen levels are frequently abnormal.
  phenotype_term:
    preferred_term: Abnormal circulating estrogen level
    term:
      id: HP:0025132
      label: Abnormal circulating estrogen level
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0025132 | Abnormal circulating estrogen level | Frequent (79-30%)
    explanation: Orphanet records abnormal circulating estrogen level as frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Increased serum estradiol
  category: Endocrine
  frequency: OCCASIONAL
  description: Estradiol can be increased relative to male reference values through aromatization of testosterone. In CAIS with retained testes it generally remains below the usual female range; it is not universally elevated against both comparators.
  phenotype_term:
    preferred_term: Increased serum estradiol
    term:
      id: HP:0025134
      label: Increased serum estradiol
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0025134 | Increased serum estradiol | Occasional (29-5%)
    explanation: Orphanet records increased serum estradiol as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Fused labia majora
  category: Genitourinary
  frequency: OCCASIONAL
  description: Fused labia majora are reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Fused labia majora
    term:
      id: HP:0025486
      label: Fused labia majora
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0025486 | Fused labia majora | Occasional (29-5%)
    explanation: Orphanet records fused labia majora as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Increased circulating antimullerian hormone concentration
  category: Endocrine
  frequency: VERY_FREQUENT
  description: AMH can remain high relative to pubertal age because androgen-dependent suppression is impaired. Normal prepubertal concentrations are reported; fetal AMH secretion is not inferred to be universally increased.
  phenotype_term:
    preferred_term: Increased circulating antimullerian hormone concentration
    term:
      id: HP:0031102
      label: Increased circulating antimullerian hormone concentration
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0031102 | Increased antimullerian hormone level | Very frequent (99-80%)
    explanation: Orphanet records increased antimullerian hormone level as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: AMH serum concentrations during the neonatal period were within the normal male reference range in the only two PAIS cases in whom it was assessed
    explanation: Two measured neonatal cases limit a universal elevation claim.
  subtype: PAIS
- name: Male sexual dysfunction
  category: Reproductive
  frequency: VERY_FREQUENT
  description: Male sexual dysfunction is very frequently reported.
  phenotype_term:
    preferred_term: Male sexual dysfunction
    term:
      id: HP:0040307
      label: Male sexual dysfunction
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0040307 | Male sexual dysfunction | Very frequent (99-80%)
    explanation: Orphanet records male sexual dysfunction as very frequent in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Blind vagina
  category: Genitourinary
  frequency: OCCASIONAL
  description: A blind-ending vagina is reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Blind vagina
    term:
      id: HP:0040314
      label: Blind vagina
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0040314 | Blind vagina | Occasional (29-5%)
    explanation: Orphanet records blind vagina as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Germ cell neoplasia
  category: Neoplastic
  frequency: OCCASIONAL
  description: Germ-cell neoplasia is a potential gonadal complication. Age, subtype, gonadal location, molecular confirmation and surgical selection affect published estimates. The Orphanet band is not a cumulative or age-specific malignancy risk and excludes benign stromal tumors.
  phenotype_term:
    preferred_term: Germ cell neoplasia
    term:
      id: HP:0100728
      label: Germ cell neoplasia
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0100728 | Germ cell neoplasia | Occasional (29-5%)
    explanation: Orphanet records germ cell neoplasia as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Urogenital sinus anomaly
  category: Genitourinary
  frequency: OCCASIONAL
  description: Urogenital sinus anomaly is reported in a minority of affected individuals.
  phenotype_term:
    preferred_term: Urogenital sinus anomaly
    term:
      id: HP:0100779
      label: Urogenital sinus anomaly
  evidence:
  - reference: ORPHA:90797
    reference_title: Partial androgen insensitivity syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: HP:0100779 | Urogenital sinus anomaly | Occasional (29-5%)
    explanation: Orphanet records urogenital sinus anomaly as occasional in PAIS. This is an Orphanet subtype-specific curated frequency band, not a newly measured population proportion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  subtype: PAIS
- name: Decreased bone mineral density
  category: Musculoskeletal
  description: Low bone mineral density can occur with retained testes and can worsen after gonadectomy without adequate hormone replacement. No population frequency or inevitable fracture outcome is established.
  phenotype_term:
    preferred_term: Decreased bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Women with CAIS and intact gonads have an increased risk of developing low BMD due to bone insensitivity to testosterone and relative oestrogen deficiency. After gonadectomy, the risk of developing low BMD further increases.
    explanation: Guideline synthesis of AIS bone-health evidence.
  subtype: CAIS
- name: Inguinal hernia
  category: Genitourinary
  description: An inguinal hernia or inguinal/labial mass can be the initial childhood presentation of CAIS and should prompt assessment for testicular tissue in the appropriate context.
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Affected individuals typically exhibit inguinal swelling during infancy or primary amenorrhea during puberty.
    explanation: Background clinical presentation described by the cohort authors.
  subtype: CAIS
- name: Gynecomastia in mild AIS
  category: Genitourinary
  description: Pubertal gynecomastia can occur despite typical male external genitalia in MAIS.
  phenotype_term:
    preferred_term: Gynecomastia in mild AIS
    term:
      id: HP:0000771
      label: Gynecomastia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: They usually present with gynecomastia at puberty.
    explanation: GeneReviews MAIS clinical subsection.
  subtype: MAIS
biochemical:
- name: Testosterone
  context: Normal male-range or elevated concentrations with retained testes, interpreted by age and treatment. A normal postnatal value does not prove normal fetal steroid synthesis, and hCG response does not exclude every biosynthetic disorder.
  biomarker_term:
    preferred_term: testosterone
    term:
      id: CHEBI:17347
      label: testosterone
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range
    explanation: Guideline specifies the reference range and retained-gonad context.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Normal serum concentrations of T, DHT, and LH after birth do not prove that the concentration was normal during the critical period of fetal genital masculinization.
    explanation: Limits retrospective inference from postnatal hormones.
- name: Estradiol
  context: Aromatization produces estradiol despite AR resistance. Concentrations in CAIS with retained testes are generally above male but below female reference values; postgonadectomy levels depend on replacement.
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range
    explanation: Comparator-specific synthesis.
- name: Luteinizing hormone and follicle-stimulating hormone
  context: LH is often elevated when the axis is active; FSH can remain normal under estrogen/inhibin feedback. Normal gonadotropins were the most common pattern in one selected pediatric cohort, so elevation is not required at every age.
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Thus, the LH/FSH ratio is typically relatively high in CAIS and PAIS
    explanation: Typical pubertal physiology.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In agreement with previous reports, normal gonadotropin levels were the most frequent finding
    explanation: Observed cohort hormone pattern.
- name: Antimullerian hormone
  context: Normal prepubertal values can be followed by failure of the expected pubertal fall. This age-specific pattern reflects impaired androgen suppression of Sertoli AMH and is distinct from fetal Müllerian regression.
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: With rising intratesticular testosterone levels, AMH secretion is inhibited in a subject with normal AR function, whereas a boy with PAIS continues to have prepubertal levels of AMH due to lack of inhibition.
    explanation: Pubertal regulation.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The testicular Sertoli cell markers inhibin B and AMH are within the normal prepubertal male range
    explanation: Prepubertal comparator.
genetic:
- name: AR
  association: Causal pathogenic variants, including germline and postzygotic mosaic variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  notes: AR is the established AIS gene. Pathogenic missense, truncating, splice and copy-number variants can cause disease; variant-specific binding and transactivation effects differ. One selected cohort identified AR variants in 11/11 suspected CAIS and 13/30 suspected PAIS cases, with blood mosaicism in 4/24 AR-positive individuals. These are diagnostic-cohort proportions, not population prevalence. Some AR-negative clinical PAIS presentations have other diagnoses. The previously cited p.Ser176Arg candidate is currently benign/likely benign in ClinVar and should not be treated as a confirmed causal AIS allele.
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Androgen insensitivity syndrome (AIS) is a rare inherited condition caused by X-linked pathogenic mutations in the androgen receptor (AR) gene
    explanation: Established gene relationship.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All of the CAIS cases (n=11) were genetically confirmed, while in PAIS (n=30) a mutation in AR was detected in only 13 patients (43.3%).
    explanation: Explicit Results numerators; the Discussion uses a discrepant percentage.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In four individuals (P5, P6, P8 and P16), 17% of AR-mutated gene patients, somatic mosaicism of mutant and wild type alleles was detected in DNA derived from blood leukocytes.
    explanation: Blood-detected mosaicism in this cohort.
  - reference: url:https://www.ncbi.nlm.nih.gov/clinvar/variation/804018/
    reference_title: VCV000804018.30 - ClinVar - NCBI
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Benign (2); Likely benign (3)
    explanation: Current primary ClinVar aggregate for c.528C>A p.Ser176Arg, checked 2026-09-21.
diagnosis:
- name: Clinical phenotype, anatomy and chromosome assessment
  description: Evaluate genital anatomy, gonadal location, pubertal development, menstrual history and fertility with chromosome testing. CAIS may present as childhood inguinal hernia or adolescent primary amenorrhea; PAIS and MAIS have different patterns. Clinical appearance alone does not establish an AR-related diagnosis or determine gender identity.
  diagnosis_term:
    preferred_term: Integrated DSD evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    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: Clinical background within a cohort report.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Mild androgen insensitivity syndrome (MAIS) with typical male external genitalia
    explanation: Milder clinical spectrum.
- name: Age-appropriate endocrine assessment
  description: Measure testosterone, DHT, LH, FSH and relevant steroid precursors with age, gonadal status and replacement therapy in mind. Selected hCG stimulation testing assesses Leydig response. Normal testosterone or a response to hCG does not by itself exclude all biosynthetic defects or establish normal fetal androgen exposure.
  diagnosis_term:
    preferred_term: Endocrine laboratory assessment
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Testosterone levels are within or above the normal male range in patients with retained testes. Testosterone is peripherally aromatised to oestrogen resulting in endogenous oestrogen levels which are above the male range but generally lower than the normal female range
    explanation: Expected endocrine pattern with important normal-range overlap.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Normal serum concentrations of T, DHT, and LH after birth do not prove that the concentration was normal during the critical period of fetal genital masculinization.
    explanation: Explicit diagnostic limitation.
- name: AR molecular testing and variant interpretation
  description: Sequence AR and assess deletions or duplications when indicated; broader DSD testing can identify phenocopies. A compatible pathogenic or likely pathogenic variant supports molecular diagnosis. An uncertain variant does not establish or exclude AIS, and somatic mosaicism may require sensitive testing. Family studies support interpretation and counseling.
  diagnosis_term:
    preferred_term: AR and DSD genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: does not establish or rule out the diagnosis.
    explanation: GeneReviews statement specifically concerns an AR variant of uncertain significance.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: to detect multiexon or whole-gene deletions or duplications may be considered if a
    explanation: GeneReviews advises copy-number testing when sequencing is unrevealing.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: All of the CAIS cases (n=11) were genetically confirmed, while in PAIS (n=30) a mutation in AR was detected in only 13 patients (43.3%).
    explanation: Diagnostic yield in one selected cohort, not universal sensitivity.
- name: Pelvic and gonadal imaging
  description: Ultrasound and selected MRI identify gonadal location and internal anatomy and can assess a new mass. Imaging and serum tumor markers cannot reliably exclude microscopic germ-cell precursor lesions. Apparent Müllerian remnants require careful interpretation; benign stromal nodules are not synonymous with cancer.
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Yearly follow-up if the gonads are retained was advised including self-examination and imaging (ultrasound/MRI)
    explanation: Retained-gonad surveillance recommendation; self-examination is feasible only for accessible gonads.
  - reference: PMID:36851849
    reference_title: 'Complete androgen insensitivity syndrome: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Leydig cell tumour of the right testis. It was a benign testicular tumour.
    explanation: A postoperative benign stromal diagnosis limits equating every mass with malignancy.
  - reference: PMID:36851849
    reference_title: 'Complete androgen insensitivity syndrome: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: but these are not specific detection methods for gonadal malignant transformation in CAIS patients.
    explanation: The preceding source list includes imaging and serum markers; this is background synthesis, not a tested screening sensitivity.
treatments:
- name: Multidisciplinary DSD care and psychological support
  description: Coordinate endocrinology, genetics, urology/gynecology and psychological or sexual-health support. Explain the diagnosis transparently and sensitively, and revisit fertility, body image, sexual function and patient goals over time. Gender identity should be assessed before PAIS puberty induction; genital anatomy does not determine identity or mandate irreversible procedures.
  treatment_term:
    preferred_term: Multidisciplinary DSD care and psychological support
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Careful counselling by a multidisciplinary team is therefore required before any decision about hormonal treatment is taken.
    explanation: AIS-specific guideline counseling recommendation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: It is best if the diagnosis of AIS is explained to the affected individual and family in an empathic environment, with both professional and family support.
    explanation: GeneReviews care framework.
- name: Shared decisions about gonadal retention or gonadectomy
  description: Discuss gonadal location, subtype, uncertain age-specific tumor risk, spontaneous puberty, surveillance limits and lifelong hormone needs. The 2022 guideline recommends spontaneous puberty in CAIS with retained testes. Gonadectomy after puberty or continued retention are individualized decisions; prepubertal removal is not a universal requirement. A suspicious mass needs specialist evaluation, but benign Leydig or Sertoli lesions must not be relabeled germ-cell cancer.
  treatment_term:
    preferred_term: Shared decisions about gonadal retention or gonadectomy
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Patients with CAIS and intraabdominal testes might be at increased risk of developing gonadal germ cell cancers (GGCC), mainly seminomas, but this risk seems to be low before/during puberty
    explanation: Guideline identifies the indication and its age-specific uncertainty.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Delaying gonadectomy allows for spontaneous pubertal development which is thought to be more satisfactory to the individual and also allows the patient to be fully involved in the shared decision-making to remove their gonads or not.
    explanation: Guideline rationale for avoiding an automatic early-removal rule.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: There is an ongoing debate about the need to perform gonadectomy after puberty since the risk of invasive GGCC development is still uncertain.
    explanation: Explicit uncertainty in the evidence base.
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Germ cell neoplasia
    treatment_effect: INHIBITS
    description: Removal of at-risk gonadal tissue is intended to prevent future gonadal neoplasia when selected after counseling; the optimal timing and absolute risk reduction are not established by the cited guidance.
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Patients with CAIS and intraabdominal testes might be at increased risk of developing gonadal germ cell cancers (GGCC), mainly seminomas, but this risk seems to be low before/during puberty
      explanation: Guideline identifies the indication and its age-specific uncertainty.
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Delaying gonadectomy allows for spontaneous pubertal development which is thought to be more satisfactory to the individual and also allows the patient to be fully involved in the shared decision-making to remove their gonads or not.
      explanation: Guideline rationale for avoiding an automatic early-removal rule.
- name: Retained-gonad follow-up
  description: Arrange specialist follow-up when gonads are retained, including examination and selected ultrasound or MRI. Self-examination is feasible only for accessible inguinal gonads. Imaging and tumor markers have limited ability to exclude precursor lesions, so normal results should not be presented as a guarantee of safety.
  treatment_term:
    preferred_term: Retained-gonad follow-up
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Yearly follow-up if the gonads are retained was advised including self-examination and imaging (ultrasound/MRI)
    explanation: Guideline summarizes an expert algorithm; this is not a validated surveillance sensitivity estimate.
  - reference: PMID:36851849
    reference_title: 'Complete androgen insensitivity syndrome: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: but these are not specific detection methods for gonadal malignant transformation in CAIS patients.
    explanation: The preceding source list includes imaging and serum markers; this is background synthesis, not a tested screening sensitivity.
- name: Estrogen replacement and pubertal induction after gonadectomy
  description: After gonadectomy, provide individualized estrogen replacement and gradual puberty induction when needed. Endo-ERN recommends starting induction around age 11 in gonadectomized CAIS, with very low-certainty evidence. Monitor pubertal progression, satisfaction, hormone exposure and bone health; routine progestin is generally unnecessary without a uterus. Retained testes usually support spontaneous CAIS puberty. The same induction principles apply to PAIS patients seeking female puberty when endogenous hormone production is absent or inadequate. During induction, the guideline recommends review every three to six months.
  treatment_term:
    preferred_term: Estrogen replacement and pubertal induction after gonadectomy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: 17beta-estradiol
      term:
        id: CHEBI:16469
        label: 17beta-estradiol
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In girls with CAIS who have been gonadectomised, pubertal induction should start at the age of 11 years in accordance with the current treatment recommendations to mimic normal pubertal development.
    explanation: Guideline recommendation R6.2, graded +OOO.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Because of the absence of a uterus, the addition of treatment with progestins is generally not required.
    explanation: Avoids routine progesterone without an indication.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Regular follow-up with clinical parameters (breast development, height), patient’s satisfaction and bone density.
    explanation: Monitoring during induction.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In children with PAIS identifying as as girls, the general recommendations for pubertal induction in CAIS as formulated under R 6.2–6.3 apply.
    explanation: Recommendation R7.3 extends the induction framework to this PAIS context.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: We recommend treatment monitoring every 3–6 months during puberty induction.
    explanation: Recommendation R6.3.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Delayed puberty
    treatment_effect: MODULATES
    description: Individualized management of the indicated manifestation; no correction of the AR variant is implied.
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: In girls with CAIS who have been gonadectomised, pubertal induction should start at the age of 11 years in accordance with the current treatment recommendations to mimic normal pubertal development.
      explanation: Guideline recommendation R6.2, graded +OOO.
  - target: Reduced Bone Mineral Accrual
    treatment_effect: MODULATES
    description: Replacement addresses estrogen deficiency as one contributor to bone-health risk; it does not reverse androgen resistance or guarantee normal bone density.
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Treatment with sex steroids aims to prevent osteoporosis and other metabolic complications
      explanation: Guideline states the treatment aim rather than proven prevention of every clinical outcome.
- name: Bone health surveillance and supportive treatment
  description: Monitor bone mineral density as clinically appropriate, including adult DXA, and review hormone replacement, nutrition and physical activity. Weight-bearing exercise, adequate calcium and vitamin D are advised. Bisphosphonates may be considered for selected patients with low density or fractures; they are not routine therapy for everyone with AIS.
  treatment_term:
    preferred_term: Bone health surveillance and supportive treatment
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Regular weight-bearing exercises and supplemental calcium and vitamin D are recommended to optimize bone health; bisphosphonate therapy may be indicated for those with evidence of decreased bone mineral density and/or multiple fractures.
    explanation: GeneReviews individualized bone care.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Women with CAIS and intact gonads have an increased risk of developing low BMD due to bone insensitivity to testosterone and relative oestrogen deficiency. After gonadectomy, the risk of developing low BMD further increases.
    explanation: Bone risk persists with intact gonads and can increase after removal.
  target_mechanisms:
  - target: Decreased bone mineral density
    treatment_effect: MODULATES
    description: Individualized management of the indicated manifestation; no correction of the AR variant is implied.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Regular weight-bearing exercises and supplemental calcium and vitamin D are recommended to optimize bone health; bisphosphonate therapy may be indicated for those with evidence of decreased bone mineral density and/or multiple fractures.
      explanation: GeneReviews individualized bone care.
- name: Selected testosterone trial for PAIS pubertal undervirilization
  description: For PAIS patients seeking male pubertal development, the guideline suggests a selected midpubertal testosterone trial with reassessment after six months. This is a very low-certainty suggestion without randomized trials. Judge response by clinical development and wellbeing rather than serum testosterone alone, and monitor hematocrit and other treatment effects. This recommendation does not rely on the reclassified Ser176Arg case.
  treatment_term:
    preferred_term: Selected testosterone trial for PAIS pubertal undervirilization
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: If clinical signs of hypoandrogenism such as micropenis and gynaecomastia are present, we suggest treating with the addition of testosterone for 6 months and then evaluating the effect.
    explanation: Recommendation R7.4, graded +OOO.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Anecdotally, patients report a beneficial effect on genital growth and wellbeing, but no randomised trials exist.
    explanation: Explicit evidence limit.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Clearly, serum testosterone concentrations cannot be used to monitor efficacy, which relies exclusively on clinical improvement and general wellbeing.
    explanation: Clinical response is the efficacy assessment.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Micropenis
    treatment_effect: MODULATES
    description: Individualized management of the indicated manifestation; no correction of the AR variant is implied.
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: If clinical signs of hypoandrogenism such as micropenis and gynaecomastia are present, we suggest treating with the addition of testosterone for 6 months and then evaluating the effect.
      explanation: Recommendation R7.4, graded +OOO.
- name: Individualized pubertal suppression while clarifying treatment goals
  description: When PAIS adolescents have uncertainty about the desired direction of puberty, a specialist team may consider temporary GnRH-agonist suppression with psychological follow-up and shared decisions. This is individualized support, not a routine AIS requirement or a claim that estrogen alone suppresses endogenous virilization.
  treatment_term:
    preferred_term: Individualized pubertal suppression while clarifying treatment goals
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In case there are uncertainties about gender identity, puberty can be delayed by the use of GnRH agonists.
    explanation: Guideline option with psychological follow-up and eventual hormone planning.
- name: Vaginal dilation when desired and indicated
  description: For a person with a short vagina who desires improved vaginal function, gradual dilation is generally the initial option. Surgery is considered selectively if needed and may still require maintenance dilation. This is patient-directed functional care, not a mandatory procedure based on anatomy.
  treatment_term:
    preferred_term: Vaginal dilation when desired and indicated
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Vaginal dilation to augment vaginal length and to avoid dyspareunia is typically the treatment of choice for those with short vaginal length.
    explanation: GeneReviews supports dilation as the usual first approach.
  target_mechanisms:
  - target: Blind vagina
    treatment_effect: MODULATES
    description: Dilation can lengthen the vaginal canal and improve desired function; it does not restore a cervix or uterus or reverse the blind-ending anatomy.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Vaginal dilation to augment vaginal length and to avoid dyspareunia is typically the treatment of choice for those with short vaginal length.
      explanation: GeneReviews supports dilation as the usual first approach.
- name: Individualized urologic procedures
  description: Orchiopexy or hypospadias repair can be considered in PAIS according to anatomy, function and informed goals. Timing requires multidisciplinary and patient/family discussion. These procedures address anatomy and do not restore receptor function or guarantee fertility.
  treatment_term:
    preferred_term: Individualized urologic procedures
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Those individuals with PAIS who are raised as males may undergo urologic surgery such as orchiopexy and hypospadias repair.
    explanation: GeneReviews describes possible procedures; historical wording is interpreted through individualized care.
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Hypospadias
    treatment_effect: MODULATES
    description: Individualized management of the indicated manifestation; no correction of the AR variant is implied.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Those individuals with PAIS who are raised as males may undergo urologic surgery such as orchiopexy and hypospadias repair.
      explanation: GeneReviews describes possible procedures; historical wording is interpreted through individualized care.
  - target: Bilateral cryptorchidism
    treatment_effect: MODULATES
    description: Orchiopexy can address gonadal position when appropriate; it does not remove all tumor or fertility uncertainty.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
      reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Those individuals with PAIS who are raised as males may undergo urologic surgery such as orchiopexy and hypospadias repair.
      explanation: GeneReviews describes possible procedures; historical wording is interpreted through individualized care.
- name: Gynecomastia management
  description: Discuss observation, distress and functional impact, with reduction surgery when appropriate in PAIS or MAIS. Tamoxifen has only limited AIS-specific case evidence, including two PAIS patients; long-term efficacy and prophylactic benefit are not established. Testosterone can have variable effects on gynecomastia.
  treatment_term:
    preferred_term: Gynecomastia management
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The effect of medical treatment on gynaecomastia is variable and most males decide to undergo mastectomy.
    explanation: Guideline synthesis; individual preference remains central.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Successful use of tamoxifen, a selective oestrogen receptor blocker, to reduce gynaecomastia was described in two patients with PAIS
    explanation: Small case evidence, not a controlled efficacy estimate.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: However, long-term studies are lacking, and whether or not there is a role for oestrogen blockers to prevent gynecomastia remains to be studied.
    explanation: Limits both treatment and prevention claims.
  target_mechanisms:
  - target: Gynecomastia
    treatment_effect: MODULATES
    description: Individualized management of the indicated manifestation; no correction of the AR variant is implied.
    evidence:
    - reference: PMID:35353710
      reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The effect of medical treatment on gynaecomastia is variable and most males decide to undergo mastectomy.
      explanation: Guideline synthesis; individual preference remains central.
- name: Genetic counseling and family evaluation
  description: Explain X-linked transmission, de novo and postzygotic variants, possible maternal germline mosaicism, variable expression and testing limitations. Offer appropriate testing of at-risk relatives and reproductive counseling when a familial pathogenic variant is known. A blood mosaic fraction does not specify genital-tissue or germline burden. Support fertility counseling without promising assisted-reproduction success for an uncharacterized patient.
  treatment_term:
    preferred_term: Genetic counseling and family evaluation
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: the chance of transmitting it in each pregnancy is 50%.
    explanation: GeneReviews maternal heterozygote transmission counseling.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In four individuals (P5, P6, P8 and P16), 17% of AR-mutated gene patients, somatic mosaicism of mutant and wild type alleles was detected in DNA derived from blood leukocytes.
    explanation: Primary blood mosaicism evidence; no tissue fraction or universal recurrence risk.
- name: Testosterone as an alternative replacement in selected gonadectomized adults with CAIS
  description: A randomized crossover trial enrolled 26 gonadectomized adult women with genetically confirmed CAIS; 18 contributed to the primary analysis after withdrawals. Testosterone and estradiol did not differ significantly for the primary mental-health quality-of-life outcome. Testosterone improved only the sexual-desire component of the sexual-function questionnaire. This small secondary-endpoint finding can inform individualized specialist discussion but does not prove overall superiority, equivalence or long-term safety.
  treatment_term:
    preferred_term: Testosterone as an alternative replacement in selected gonadectomized adults with CAIS
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: testosterone
      term:
        id: CHEBI:17347
        label: testosterone
  evidence:
  - reference: PMID:30075954
    reference_title: 'Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a multicentre, randomised, double-dummy, double-blind crossover trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Mental health-related quality of life did not differ between treatment groups (linear mixed model, p=0·794)
    explanation: Primary outcome in the randomized crossover trial; full original manuscript was not recovered.
  - reference: PMID:30075954
    reference_title: 'Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a multicentre, randomised, double-dummy, double-blind crossover trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: For the FSFI, testosterone was superior to oestradiol only in improving sexual desire (linear mixed model, p=0·018).
    explanation: Secondary subscale result, not improvement in all sexual-function domains.
  - reference: PMID:30075954
    reference_title: 'Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a multicentre, randomised, double-dummy, double-blind crossover trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: No virilisation was observed, and gonadotrophin concentrations remained stable in both treatment groups.
    explanation: Observation during the trial, not evidence of lifelong safety.
  therapeutic_modality: SMALL_MOLECULE
notes: This entry retains complete, partial and mild AIS as clinical subtypes of the AR-related spectrum. Orphanet phenotype-frequency bands are retained with their original CAIS/PAIS scope and are not extrapolated to MAIS. Historical synonyms are preserved for retrieval. Gonadal anatomy, hormone reference ranges and gender identity are distinct dimensions. Management requires individualized multidisciplinary counseling; older case-report recommendations for routine early gonadectomy or sex assignment are not treated as current universal care.
references:
- reference: url:https://drks.de/search/en/trial/DRKS00003136
  title: German Clinical Trials Register
  tags: []
  findings:
  - statement: Primary completed phase III crossover registry, final enrollment 26; includes protocol eligibility and links the 2018 publication. Registry status is separate from the outcome evidence.
- reference: PMID:20301602
  title: Androgen Insensitivity Syndrome.
  tags:
  - GeneReviews
  findings:
  - statement: GeneReviews bibliographic baseline; the complete chapter is cited through its generated Bookshelf URL.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
  title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
  tags: []
  findings:
  - statement: Complete GeneReviews chapter covers the three AIS subtypes, diagnosis and variant interpretation, care, counseling and molecular receptor function; last updated 2017 and interpreted alongside newer guidance.
- reference: PMID:35353710
  title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
  tags: []
  findings:
  - statement: 'Endo-ERN 2022 guideline: age- and gonad-specific endocrine physiology, spontaneous CAIS puberty, low-certainty replacement and selected PAIS androgen recommendations, and individualized counseling.'
- reference: PMID:14745012
  title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
  tags: []
  findings:
  - statement: Primary global versus Sertoli-specific mouse AR knockout; the complete manuscript is separately available through the generated PMC URL.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
  title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
  tags: []
  findings:
  - statement: Complete primary knockout manuscript with Methods, Tables 1–3 and Discussion. Sertoli-specific deletion impairs spermatogenesis but preserves descent and male tract development; nuclear volumes approximate cell numbers.
- reference: url:https://www.ncbi.nlm.nih.gov/clinvar/variation/804018/
  title: VCV000804018.30 - ClinVar - NCBI
  tags: []
  findings:
  - statement: Primary ClinVar aggregate for AR c.528C>A p.Ser176Arg is benign/likely benign as checked 2026-09-21; this revises the interpretation of the 2020 case report.
- 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: One-family AR/MAP3K1 co-occurrence and HEK293T/17 AR-abundance assays. MAP3K1 is a VUS and its modifier role remains unproven; no receptor transactivation or developmental rescue was tested.
- reference: PMID:33363845
  title: 'Male pseudohermaphroditism: A case study of 46,XY disorder of sexual development using whole-exome sequencing.'
  tags: []
  findings:
  - statement: Clinically labeled PAIS toddler with candidate Ser176Arg, no variant functional assay and current benign/likely benign classification; retained as an interpretation caution, not confirmed AIS treatment efficacy.
- reference: PMID:30251955
  title: 'Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort.'
  tags: []
  findings:
  - statement: 'Selected 41-case cohort: 11/11 CAIS and 13/30 PAIS AR-positive; blood mosaicism in 4/24 molecular diagnoses, not a population frequency. Normal neonatal AMH and gonadotropins qualify universal endocrine claims.'
- reference: PMID:29785970
  title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
  tags: []
  findings:
  - statement: Ten selected Chinese patients, nine CAIS and one PAIS, with AR variants; no new functional receptor assay. Case 8 histology shows fibrosis and absent germ cells. The manuscript incorrectly lists ovaries among Müllerian derivatives.
- reference: PMID:32202729
  title: '[Somatic mutations in the androgen receptor gene as the cause of androgen insensitivity syndrome].'
  tags: []
  findings:
  - statement: Eight selected postzygotic-mosaic case reports in full Russian text; blood findings do not quantify fetal genital or germline fractions. Historical surgical advice and source inconsistencies are not used as universal care.
- reference: PMID:34867780
  title: Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis.
  tags: []
  findings:
  - statement: Three PAIS versus three control PBMC transcriptomes; exploratory differential expression and computational networks, with limited qPCR and an unresolved human/mouse annotation statement. No validated diagnostic accuracy or gonadal causal pathway.
- reference: PMID:36851849
  title: 'Complete androgen insensitivity syndrome: a case report and literature review.'
  tags: []
  findings:
  - statement: Clinically diagnosed, genetically untested adult CAIS case with a benign Leydig-cell tumor, not a malignant germ-cell tumor.
- reference: PMID:39600030
  title: 'Complexities of complete androgen insensitivity syndrome: insights from a case report and literature review.'
  tags: []
  findings:
  - statement: Genetically untested adolescent CAIS case with deferred gonadectomy and replacement; not controlled evidence of optimal surgery timing or long-term prevention.
- reference: PMID:40496184
  title: 'Serial evaluation of gonads of complete androgen insensitivity syndrome from birth to puberty: Is gonadectomy necessary?'
  tags: []
  findings:
  - statement: Serial genetically confirmed CAIS case with benign Sertoli-rich hamartomas after gonadectomy at 12.5 years. Imaging abnormalities did not prove malignancy, and the case does not establish safety of a counterfactual retention plan.
- reference: PMID:30075954
  title: 'Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a multicentre, randomised, double-dummy, double-blind crossover trial.'
  tags: []
  findings:
  - statement: Randomized crossover trial of estradiol versus testosterone in 26 gonadectomized CAIS adults; 18 in the primary analysis. No significant primary quality-of-life difference; secondary sexual-desire benefit only. Original full manuscript not recovered.
- reference: PMID:35258786
  title: Metabolic effects of estradiol versus testosterone in complete androgen insensitivity syndrome.
  tags: []
  findings:
  - statement: Exploratory metabolic analysis from the same hormone trial, not independent replication. No broad between-treatment metabolic superiority or cardiovascular outcome benefit; within-person lipid/BMI changes and limited sample size require caution.
- reference: PMID:31491747
  title: Bone mineral density, body composition and metabolic profiles in adult women with complete androgen insensitivity syndrome and removed gonads using oral or transdermal estrogens.
  tags: []
  findings:
  - statement: Abstract-supported observational bone cohort in 32 gonadectomized CAIS women, with 28 longitudinally followed. Route-related bone associations are not randomized evidence of superiority.
- reference: PMID:41163677
  title: Molecular pathogenesis, diagnosis, and management challenges in complete androgen insensitivity syndrome.
  tags: []
  findings:
  - statement: Recent general AIS review used as contextual cross-check; inherited mechanistic overstatements and uncertain tumor-risk estimates were not adopted.
- reference: PMID:22698698
  title: Androgen insensitivity syndrome.
  tags: []
  findings:
  - statement: Abstract-supported Lancet review of AIS pathogenesis and multidisciplinary care.
- reference: PMID:26303086
  title: Androgen receptor roles in spermatogenesis and infertility.
  tags: []
  findings:
  - statement: Abstract-supported review distinguishing somatic testicular AR roles from germ-cell-autonomous androgen action.
- reference: PMID:26012135
  title: '[Complete androgen insensitivity syndrome].'
  tags: []
  findings:
  - statement: Abstract-supported individual CAIS report using chromosome/hormone evaluation, MSCT, gonadectomy, replacement and dilation; no comparative efficacy estimate.
- reference: ORPHA:99429
  title: Complete androgen insensitivity syndrome
  tags: []
  findings:
  - statement: Complete structured CAIS record, including curated phenotype bands and prevalence metadata; not primary cohort numerators.
- reference: ORPHA:90797
  title: Partial androgen insensitivity syndrome
  tags: []
  findings:
  - statement: Complete structured PAIS record, including curated phenotype bands and unknown prevalence; not evidence that all bands apply to MAIS.
differential_diagnoses:
- name: Mayer-Rokitansky-Küster-Hauser syndrome
  description: Amenorrhea and absent Müllerian structures can resemble CAIS, but MRKH usually has a 46,XX karyotype and ovarian rather than testicular gonads.
  distinguishing_features:
  - Chromosome result and gonadal identity; pubic hair is generally androgen responsive.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Individuals with MRKH can be distinguished from those with CAIS by confirmation of a 46,XX
    explanation: GeneReviews differential diagnosis; raw HTML interrupts the following karyotype term.
- name: Steroid 5-alpha-reductase 2 deficiency
  description: SRD5A2-related impaired conversion of testosterone to DHT can cause undervirilization with testes and preserved Müllerian regression. Steroid profiles, pubertal course and molecular testing distinguish it from AIS.
  distinguishing_features:
  - Reduced DHT formation with compatible biallelic SRD5A2 variants; a single testosterone value is insufficient.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The enzyme converts testosterone to dihydrotestosterone (DHT), which is primarily responsible for the development of the external genitalia before birth.
    explanation: GeneReviews SRD5A2 differential mechanism.
- name: 17-beta-hydroxysteroid dehydrogenase 3 deficiency and other steroidogenic defects
  description: HSD17B3 and other biosynthetic disorders can overlap with clinical PAIS. Compensatory LH stimulation can yield a normal testosterone concentration despite a partial biosynthetic defect.
  distinguishing_features:
  - Steroid precursor pattern, stimulation testing and molecular findings.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Elevated levels of testosterone precursors caused by a partial testosterone biosynthetic defect in which compensatory serum LH concentrations stimulate a normal plasma testosterone concentration
    explanation: Explicit diagnostic pitfall.
- name: 46,XY gonadal dysgenesis
  description: Impaired testicular development can reduce both androgen and AMH production, unlike the usually preserved AMH pathway in AIS. Retained Müllerian structures or a broader syndromic phenotype should prompt reconsideration.
  distinguishing_features:
  - Gonadal differentiation, AMH function, internal anatomy and the causal molecular diagnosis.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The presence of m&#x000fc;llerian duct derivatives as a result of a testicular organogenesis defect with impaired Sertoli cell production of anti-m&#x000fc;llerian hormone
    explanation: GeneReviews differential mechanism.
histopathology:
- name: Impaired germ-cell development and gonadal fibrosis
  description: Selected gonadectomy specimens show immature seminiferous tubules, fibrosis and absent germ cells. This is not a universal biopsy requirement and does not establish that all infertility is due to cryptorchidism.
  evidence:
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Large areas of prepubertal tubules (arrow) surrounded by some fibrosis (arrowhead) are visualized, with no germ cells in the gonads.
    explanation: Case 8 histological caption; selected tissue, not prevalence.
- name: Benign testicular stromal lesions
  description: Benign Leydig-cell tumor and Sertoli-rich hamartomas have been documented in individual CAIS reports. These must be distinguished from germ-cell neoplasia and malignant cancer when discussing gonadal risk.
  evidence:
  - reference: PMID:36851849
    reference_title: 'Complete androgen insensitivity syndrome: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Leydig cell tumour of the right testis. It was a benign testicular tumour.
    explanation: Single clinically diagnosed CAIS case without AR molecular confirmation.
progression:
- phase: Presentation across the AIS spectrum
  notes: CAIS may be recognized with an inguinal mass or hernia in childhood or primary amenorrhea after spontaneous breast development. PAIS is often recognized from atypical genital anatomy at birth; MAIS may first be investigated for pubertal gynecomastia or infertility. These are alternative presentations, not a fixed sequence.
  evidence:
  - reference: PMID:29785970
    reference_title: Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Affected individuals typically exhibit inguinal swelling during infancy or primary amenorrhea during puberty.
    explanation: Background CAIS presentation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/
    reference_title: Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In some instances, the only observed abnormality appears to be male infertility
    explanation: MAIS clinical presentation.
- phase: Puberty and adult follow-up
  notes: With retained testes, CAIS usually undergoes spontaneous breast development; gonadectomized individuals require planned replacement. PAIS virilization is variable and cannot be predicted from an AR assay alone. Gonadal, bone, sexual and psychological follow-up continues into adulthood.
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Puberty treatment is not indicated in girls with retained testes.
    explanation: CAIS recommendation context.
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In contrast to the clinical findings, the functional analysis of AR variants did not appear to predict pubertal outcome
    explanation: PAIS prediction limit.
clinical_trials:
- name: DRKS00003136
  phase: PHASE_III
  status: COMPLETED
  description: Prospectively registered randomized, blinded crossover comparison of transdermal testosterone and estradiol in adults with genetically confirmed CAIS after gonadectomy. The registry lists 30 planned and 26 final participants, completion in January 2016 and EudraCT 2010-021790-37. The primary mental-health quality-of-life comparison was not significant; a sexual-desire subscale favored testosterone. The metabolic publication is an exploratory secondary analysis of this same trial.
  notes: Registry checked 2026-09-21; last update 2025-02-13. Registry age ceiling is 55, while the publication reports participants aged 18–54. Withdrawal and missing visits reduced analysis populations. The 2022 abstract says 17 completed; its Methods describes 18 analyzed with permitted missing visits. No independent replication, long-term cardiovascular benefit or overall treatment equivalence is established.
  evidence:
  - reference: url:https://drks.de/search/en/trial/DRKS00003136
    reference_title: German Clinical Trials Register
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Postpubertal adult patient with complete androgen insensitivity syndrome classified as either Sinnecker Type 5A or 5B
    explanation: Registry eligibility; mutation confirmation and prior gonadectomy are adjacent criteria.
  - reference: PMID:30075954
    reference_title: 'Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a multicentre, randomised, double-dummy, double-blind crossover trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Mental health-related quality of life did not differ between treatment groups (linear mixed model, p=0·794)
    explanation: Original trial primary outcome.
  - reference: PMID:35258786
    reference_title: Metabolic effects of estradiol versus testosterone in complete androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Here we report the results of a secondary metabolic outcome analysis of the first multicentre, randomised, double-dummy, double-blind crossover trial investigating the effects of estradiol in comparison to testosterone replacement therapy in CAIS probands
    explanation: Full secondary manuscript establishes cohort overlap.
  - reference: PMID:35258786
    reference_title: Metabolic effects of estradiol versus testosterone in complete androgen insensitivity syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the study may be underpowered for the detection of more subtle group effects in other parameters.
    explanation: Explicit limitation of nonsignificant metabolic comparisons.
animal_models:
- name: Ubiquitous androgen receptor knockout mouse
  species: Mouse
  genotype: Ar exon 2 deletion induced by ubiquitous PGK-Cre
  category: GENETIC
  publication: PMID:14745012
  description: Global deletion of exon 2 eliminates functional AR and produces a CAIS-like female external phenotype with small abdominal or inguinal testes and absent androgen-dependent internal ducts. Müllerian derivatives were absent, consistent with preserved non-AR fetal testicular function. This does not recreate every patient allele or isolate the cell type responsible for infertility.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  evidence:
  - reference: PMID:14745012
    reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: AR knockout males displayed a complete androgen insensitivity phenotype. Testes were located abdominally, and germ cell development was severely disrupted.
    explanation: Primary global mouse phenotype.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
    reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Structures derived from the Wolffian ducts (ductus deferens, epididymis, and seminal vesicles) or urogenital sinus (prostate) were absent. No uterus or fallopian tubes were observed.
    explanation: Full manuscript documents internal tract findings.
  modeled_mechanisms:
  - target: Impaired External Genital Virilization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Global receptor loss produces a female external phenotype.
    limitations: Complete engineered receptor loss is not a variant-specific human PAIS model. Analyses used selected mouse ages and mixed genetic backgrounds. In the global knockout, abdominal gonadal location confounds attribution of spermatogenic loss to receptor signaling alone.
    evidence:
    - reference: PMID:14745012
      reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: AR knockout males displayed a complete androgen insensitivity phenotype.
      explanation: Primary phenotype summary.
    readouts:
    - name: Male external genital development
      target: Impaired External Genital Virilization
      direction: DECREASED
      interpretation: Global receptor loss produces a female external phenotype.
      evidence:
      - reference: PMID:14745012
        reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: AR knockout males displayed a complete androgen insensitivity phenotype.
        explanation: Primary phenotype summary.
  - target: Impaired Wolffian Duct Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Wolffian derivatives were absent in the global knockout.
    limitations: Complete engineered receptor loss is not a variant-specific human PAIS model. Analyses used selected mouse ages and mixed genetic backgrounds. In the global knockout, abdominal gonadal location confounds attribution of spermatogenic loss to receptor signaling alone.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
      reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Structures derived from the Wolffian ducts (ductus deferens, epididymis, and seminal vesicles) or urogenital sinus (prostate) were absent. No uterus or fallopian tubes were observed.
      explanation: Primary dissection result.
    readouts:
    - name: Wolffian derivatives
      target: Impaired Wolffian Duct Development
      direction: DECREASED
      interpretation: Wolffian derivatives were absent in the global knockout.
      evidence:
      - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
        reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Structures derived from the Wolffian ducts (ductus deferens, epididymis, and seminal vesicles) or urogenital sinus (prostate) were absent. No uterus or fallopian tubes were observed.
        explanation: Primary dissection result.
- name: Sertoli-cell androgen receptor knockout mouse
  species: Mouse
  genotype: Ar exon 2 deletion induced by Amh-Cre (SCARKO)
  category: GENETIC
  publication: PMID:14745012
  description: Amh-Cre activity begins around embryonic day 15, before normal neonatal Sertoli AR expression. Selective receptor loss markedly reduces androgen-responsive Pem expression and impairs meiotic progression, with increased germ-cell apoptosis and no elongated spermatids at day 50. Stereological nuclear-volume estimates, rather than direct absolute cell counts, gave spermatocyte and round-spermatid values of 64% and 3% of controls. Sertoli nuclear volume was not significantly changed. Testicular descent, external development and androgen-dependent ducts were preserved; LH and testosterone were not significantly different, while FSH was higher.
  genes:
  - preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
    reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Morphological analysis of SCARKO testes established that germ cell entry into meiosis appeared normal, but there was progressive loss of pachytene primary spermatocytes between stages VI and XII.
    explanation: Detailed histological result in the full manuscript.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
    reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: No elongated spermatids were detected.
    explanation: Primary spermatogenic endpoint.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
    reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Serum levels of testosterone and LH revealed no significant difference between WT and SCARKO animals
    explanation: Separates this conditional model from a universal LH/testosterone elevation claim.
  modeled_mechanisms:
  - target: Reduced Sertoli Androgen Signaling
    relationship: PERTURBS
    fidelity: MODERATE
    description: Conditional Ar deletion selectively removes the receptor from Sertoli cells.
    limitations: Complete developmental loss precedes normal expression; it is not an adult pharmacological inhibition or a specific patient missense allele.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
      reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: no immunopositive staining was detected in SC
      explanation: Immunohistochemical loss in SCARKO while Leydig and peritubular nuclei remained positive.
    readouts:
    - name: Sertoli-cell AR staining
      target: Reduced Sertoli Androgen Signaling
      direction: DECREASED
      interpretation: Conditional Ar deletion selectively removes the receptor from Sertoli cells.
      evidence:
      - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
        reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: no immunopositive staining was detected in SC
        explanation: Immunohistochemical loss in SCARKO while Leydig and peritubular nuclei remained positive.
  - target: Impaired Spermatogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Selective Sertoli AR loss impairs germ-cell progression and survival despite descended testes.
    limitations: Mechanisms of Sertoli-germ-cell interaction remain unresolved. Stereology used five WT and three SCARKO mice; nuclear volumes approximate cell numbers. This does not exclude contributions from other somatic cell types in human AIS.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
      reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Morphological analysis of SCARKO testes established that germ cell entry into meiosis appeared normal, but there was progressive loss of pachytene primary spermatocytes between stages VI and XII.
      explanation: Primary conditional genetic perturbation.
    readouts:
    - name: Meiotic progression and spermatid development
      target: Impaired Spermatogenesis
      direction: DECREASED
      interpretation: Selective Sertoli AR loss impairs germ-cell progression and survival despite descended testes.
      evidence:
      - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
        reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: Morphological analysis of SCARKO testes established that germ cell entry into meiosis appeared normal, but there was progressive loss of pachytene primary spermatocytes between stages VI and XII.
        explanation: Primary conditional genetic perturbation.
  - target: Impaired Testicular Descent
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: The tested conditional knockout retained normal testis descent.
    limitations: A tested negative specific to Sertoli AR loss; it does not refute the role of AR in other tissues or global AIS.
    evidence:
    - reference: PMID:14745012
      reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract.
      explanation: Direct conditional/global contrast.
    readouts:
    - name: Testicular descent
      target: Impaired Testicular Descent
      direction: UNCHANGED
      interpretation: The tested conditional knockout retained normal testis descent.
      evidence:
      - reference: PMID:14745012
        reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: In contrast, SC AR knockout males showed normal testis descent and development of the male urogenital tract.
        explanation: Direct conditional/global contrast.
  - target: Impaired Wolffian Duct Development
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: Androgen-dependent internal ducts developed normally in SCARKO.
    limitations: Cell-lineage-specific negative result, not universal preservation in human AIS.
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
      reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: SCARKO males displayed normal development of epididymis, ductus deferens, coagulating gland, seminal vesicles, and prostate.
      explanation: Primary dissection finding.
    readouts:
    - name: Wolffian duct development
      target: Impaired Wolffian Duct Development
      direction: UNCHANGED
      interpretation: Androgen-dependent internal ducts developed normally in SCARKO.
      evidence:
      - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1
        reference_title: A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        directness: DIRECT
        snippet: SCARKO males displayed normal development of epididymis, ductus deferens, coagulating gland, seminal vesicles, and prostate.
        explanation: Primary dissection finding.
experimental_models:
- name: AR and MAP3K1 coexpression in HEK293T/17 cells
  experimental_model_type: CELL_LINE
  description: Transient expression of wild-type or variant AR and MAP3K1 plasmids measured AR protein band abundance after 48 hours. The one-family study reported lower AR abundance with the AR variant alone and higher signal in selected MAP3K1-mutant/coexpression conditions. It did not measure androgen binding, DNA binding, reporter transactivation, kinase signaling, receptor half-life or clinical rescue. Single-plasmid and dual-plasmid conditions used different per-plasmid doses. Thus these results do not establish MAP3K1 modifier causality and are not connected to a proven clinical signaling route.
  cell_source: HEK293T/17 kidney-derived cell line
  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: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The cells lysates were used to analyze the AR protein expression by Western blot.
    explanation: Measured endpoint is protein abundance, not receptor activity.
  - 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: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The transfection concentration of a single plasmid was 2.5 μg/ml. When the cotransfection of the two plasmids was conducted, the concentration of each plasmid is 1.5 μg/ml.
    explanation: Dose difference limits a clean interaction interpretation.
- name: Exploratory PAIS peripheral-blood transcriptome study
  experimental_model_type: OTHER
  description: RNA sequencing compared isolated PBMCs from three AR-variant PAIS patients with three age-matched male volunteers. The reported 725 differentially expressed genes and computational network/enrichment analyses are exploratory associations, not a validated diagnostic signature or evidence that candidate immune/metabolic pathways cause genital development. Only CCR1 was significantly different in the reported qPCR follow-up; the other selected genes were not significant. The Methods cites a mouse GRCm38 annotation despite human samples, an unresolved source reporting issue. No independent diagnostic validation cohort or controlled AR perturbation was provided.
  cell_source: Uncultured peripheral blood mononuclear cells from three PAIS patients and three controls
  evidence:
  - reference: PMID:34867780
    reference_title: Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The peripheral blood of three PAIS patients and three healthy male volunteers (age-matched) was obtained from Shanghai Ninth People’s Hospital
    explanation: Human observational sampling, not a six-patient series.
  - reference: PMID:34867780
    reference_title: Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a total of 725 DEGs, including 495 upregulated and 230 downregulated genes, were identified in PAIS patients
    explanation: Exploratory differential-expression output with the study threshold.
  - reference: PMID:34867780
    reference_title: Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: GENCODE (Release M22, GRCm38. p6)
    explanation: Source-internal reference-annotation mismatch; not corrected or silently assumed away.
discussions:
- discussion_id: ais-ser176arg-reclassification
  kind: INTERPRETATION
  status: OPEN
  prompt: How should the previously attributed Ser176Arg case be interpreted after variant reclassification?
  rationale: The 2020 case report nominated AR c.528C>A p.Ser176Arg by exome prioritization without a functional assay and reported substantial East Asian population frequency. ClinVar VCV000804018.30, checked 2026-09-21, aggregates benign/likely benign classifications without conflict. This weakens the molecular AIS attribution; the child may still have a difference of sex development requiring an alternative explanation. Its short androgen exposure is not used as AIS-specific efficacy evidence.
  attaches_to:
  - genetic#AR
  - diagnosis#AR molecular testing and variant interpretation
  evidence:
  - reference: PMID:33363845
    reference_title: 'Male pseudohermaphroditism: A case study of 46,XY disorder of sexual development using whole-exome sequencing.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a relatively high prevalence of this AR variant in East Asia (1%‐1.5%)
    explanation: The original source itself notes a relatively common population allele.
  - reference: url:https://www.ncbi.nlm.nih.gov/clinvar/variation/804018/
    reference_title: VCV000804018.30 - ClinVar - NCBI
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Benign (2); Likely benign (3)
    explanation: Current primary variant record.
- discussion_id: ais-map3k1-modifier-hypothesis
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does the reported MAP3K1 variant modify AR-related AIS?
  rationale: One proband and the mother shared AR and MAP3K1 variants. The source calls AR likely pathogenic but MAP3K1 Arg260Cys a VUS; no replicated segregation or developmental assay establishes modification. HEK293T/17 immunoblots measure abundance, not transactivation, and single versus dual plasmid doses differ. A rudimentary uterine structure is an atypical observation, not proof of a MAP3K1-mediated AMH defect. The paper repeatedly writes His690Glu for AR c.2070C>A, while Results says glutamine and Figure 2 labels H690Q; the inconsistent protein expansion is not propagated as verified nomenclature.
  attaches_to:
  - experimental_models#AR and MAP3K1 coexpression in HEK293T/17 cells
  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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The MAP3K1 variant is a variant of “unknown significance” according to ACMG criteria.
    explanation: The source qualification takes precedence over stronger abstract language.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: there is a lack of basic experiments to validate regulatory mechanism between the AR and MAP3K1 gene.
    explanation: Authors explicitly identify the unresolved mechanism.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The hemizygous variant occurs at position 690 (H690Q).
    explanation: Figure caption differs from the erroneous Glu expansion.
- discussion_id: ais-gonadal-risk-and-surveillance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How can gonadal cancer risk and surveillance be estimated for a particular AIS patient?
  rationale: Published cohorts mix age, subtype, genotype confirmation, gonadal location and surgical ascertainment. Benign stromal lesions, precursor lesions and invasive germ-cell cancer should not be pooled as one outcome. The low prepubertal risk and benefit of spontaneous CAIS puberty inform shared decisions, but neither normal imaging nor isolated benign case reports establish a universally safe retention schedule.
  attaches_to:
  - treatments#Shared decisions about gonadal retention or gonadectomy
  - treatments#Retained-gonad follow-up
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: There is an ongoing debate about the need to perform gonadectomy after puberty since the risk of invasive GGCC development is still uncertain.
    explanation: Guideline acknowledges uncertainty.
  - reference: PMID:36851849
    reference_title: 'Complete androgen insensitivity syndrome: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Leydig cell tumour of the right testis. It was a benign testicular tumour.
    explanation: Specific benign stromal histology.
- discussion_id: ais-genotype-and-tissue-heterogeneity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which tissue and developmental factors explain the variable phenotype of the same AR variant?
  rationale: Residual receptor activity matters, but PAIS genotype-phenotype correlation and puberty prediction remain imperfect. Blood mosaicism is observed; fetal genital-tissue proportions and functional effects are often unmeasured. The exploratory three-case PBMC expression study supplies candidate associations, not a diagnostic assay or causal explanation for genital variation.
  attaches_to:
  - pathophysiology#Pathogenic AR Variation
  - experimental_models#Exploratory PAIS peripheral-blood transcriptome study
  evidence:
  - reference: PMID:35353710
    reference_title: 'Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In contrast to the clinical findings, the functional analysis of AR variants did not appear to predict pubertal outcome
    explanation: Clinical prediction limit.
  - 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
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In four individuals (P5, P6, P8 and P16), 17% of AR-mutated gene patients, somatic mosaicism of mutant and wild type alleles was detected in DNA derived from blood leukocytes.
    explanation: Observed blood mosaicism, not measured fetal tissue mosaicism.
review_notes: Comprehensive review consumed the full original entry, both matching CAIS/PAIS deep-research reports, all original cached sources and the complete GeneReviews NBK1429 clinical, diagnostic, management, counseling and molecular sections. The 2022 Endo-ERN guideline was read in full in the related DSD reviews, with all AIS-specific recommendations, rationale and evidence limitations rechecked here. Full scientific bodies, Methods, Results, Discussion and available tables/captions were read for PMID29785970, 30251955, 32202729 (Russian PDF), 33363845, 34867780, 36851849, 39600030, 41163677, 35258786 and 40496184. A peer independently read the complete 32338288 body and its experimental limits; claim-local passages were checked here. The complete 14745012 manuscript was recovered through a generated public PMC URL cache after canonical retrieval failures, including its stereological methods, tables and conditional/global knockout contrast. The original 2018 hormone trial PMID30075954, the 2019 bone cohort31491747, and older22698698/26303086/26012135 remain abstract-supported; none is presented as a fully inspected manuscript. Both complete Orphanet structured subtype records
  were read. All cache changes were generated with just fetch-reference. Material corrections include removal of established MAP3K1 modifier attribution and reclassified Ser176Arg case efficacy, addition of MAIS, separation of allele-dependent binding/transcription defects, preserved fetal AMH versus pubertal suppression, and explicit hormone age/comparator/gonadal context. Ovaries are not Müllerian derivatives despite erroneous wording in a cited cohort. The selected 30251955 Results gives 13/30 PAIS molecular diagnoses, whereas its Discussion percentage is inconsistent. The 32202729 source has case-level age/HGVS inconsistencies and an overstrong recurrence assertion; these are not exported. The 34867780 Methods names a mouse reference annotation for human PBMC samples, which remains unresolved. The MAP3K1 report has AR protein-name and plasmid-dose inconsistencies. The metabolic hormone paper is a secondary analysis of the same crossover trial, not independent replication. Historical early surgery guidance, case-derived cancer risks and unvalidated transcriptomic mechanisms are not promoted to universal recommendations. Deep-research false positives involving cancer therapy resistance,
  glucocorticoid resistance and unrelated endocrine conditions were excluded.

📚

References & Deep Research

References

url:https://drks.de/search/en/trial/DRKS00003136

German Clinical Trials Register

1 finding

Primary completed phase III crossover registry, final enrollment 26; includes protocol eligibility and links the 2018 publication. Registry status is separate from the outcome evidence.

PMID:20301602

Androgen Insensitivity Syndrome.

1 finding

GeneReviews bibliographic baseline; the complete chapter is cited through its generated Bookshelf URL.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1429/

Androgen Insensitivity Syndrome - GeneReviews® - NCBI Bookshelf

1 finding

Complete GeneReviews chapter covers the three AIS subtypes, diagnosis and variant interpretation, care, counseling and molecular receptor function; last updated 2017 and interpreted alongside newer guidance.

PMID:35353710

Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline.

1 finding

Endo-ERN 2022 guideline: age- and gonad-specific endocrine physiology, spontaneous CAIS puberty, low-certainty replacement and selected PAIS androgen recommendations, and individualized counseling.

PMID:14745012

A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis.

1 finding

Primary global versus Sertoli-specific mouse AR knockout; the complete manuscript is separately available through the generated PMC URL.

url:https://pmc.ncbi.nlm.nih.gov/articles/PMC337052/?pdf=1

A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis - PMC

1 finding

Complete primary knockout manuscript with Methods, Tables 1–3 and Discussion. Sertoli-specific deletion impairs spermatogenesis but preserves descent and male tract development; nuclear volumes approximate cell numbers.

url:https://www.ncbi.nlm.nih.gov/clinvar/variation/804018/

VCV000804018.30 - ClinVar - NCBI

1 finding

Primary ClinVar aggregate for AR c.528C>A p.Ser176Arg is benign/likely benign as checked 2026-09-21; this revises the interpretation of the 2020 case report.

PMID:32338288

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

1 finding

One-family AR/MAP3K1 co-occurrence and HEK293T/17 AR-abundance assays. MAP3K1 is a VUS and its modifier role remains unproven; no receptor transactivation or developmental rescue was tested.

PMID:33363845

Male pseudohermaphroditism: A case study of 46,XY disorder of sexual development using whole-exome sequencing.

1 finding

Clinically labeled PAIS toddler with candidate Ser176Arg, no variant functional assay and current benign/likely benign classification; retained as an interpretation caution, not confirmed AIS treatment efficacy.

PMID:30251955

Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort.

1 finding

Selected 41-case cohort: 11/11 CAIS and 13/30 PAIS AR-positive; blood mosaicism in 4/24 molecular diagnoses, not a population frequency. Normal neonatal AMH and gonadotropins qualify universal endocrine claims.

PMID:29785970

Phenotypic and molecular characteristics of androgen insensitivity syndrome patients.

1 finding

Ten selected Chinese patients, nine CAIS and one PAIS, with AR variants; no new functional receptor assay. Case 8 histology shows fibrosis and absent germ cells. The manuscript incorrectly lists ovaries among Müllerian derivatives.

PMID:32202729

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

1 finding

Eight selected postzygotic-mosaic case reports in full Russian text; blood findings do not quantify fetal genital or germline fractions. Historical surgical advice and source inconsistencies are not used as universal care.

PMID:34867780

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

1 finding

Three PAIS versus three control PBMC transcriptomes; exploratory differential expression and computational networks, with limited qPCR and an unresolved human/mouse annotation statement. No validated diagnostic accuracy or gonadal causal pathway.

PMID:36851849

Complete androgen insensitivity syndrome: a case report and literature review.

1 finding

Clinically diagnosed, genetically untested adult CAIS case with a benign Leydig-cell tumor, not a malignant germ-cell tumor.

PMID:39600030

Complexities of complete androgen insensitivity syndrome: insights from a case report and literature review.

1 finding

Genetically untested adolescent CAIS case with deferred gonadectomy and replacement; not controlled evidence of optimal surgery timing or long-term prevention.

PMID:40496184

Serial evaluation of gonads of complete androgen insensitivity syndrome from birth to puberty: Is gonadectomy necessary?

1 finding

Serial genetically confirmed CAIS case with benign Sertoli-rich hamartomas after gonadectomy at 12.5 years. Imaging abnormalities did not prove malignancy, and the case does not establish safety of a counterfactual retention plan.

PMID:30075954

Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a multicentre, randomised, double-dummy, double-blind crossover trial.

1 finding

Randomized crossover trial of estradiol versus testosterone in 26 gonadectomized CAIS adults; 18 in the primary analysis. No significant primary quality-of-life difference; secondary sexual-desire benefit only. Original full manuscript not recovered.

PMID:35258786

Metabolic effects of estradiol versus testosterone in complete androgen insensitivity syndrome.

1 finding

Exploratory metabolic analysis from the same hormone trial, not independent replication. No broad between-treatment metabolic superiority or cardiovascular outcome benefit; within-person lipid/BMI changes and limited sample size require caution.

PMID:31491747

Bone mineral density, body composition and metabolic profiles in adult women with complete androgen insensitivity syndrome and removed gonads using oral or transdermal estrogens.

1 finding

Abstract-supported observational bone cohort in 32 gonadectomized CAIS women, with 28 longitudinally followed. Route-related bone associations are not randomized evidence of superiority.

PMID:41163677

Molecular pathogenesis, diagnosis, and management challenges in complete androgen insensitivity syndrome.

1 finding

Recent general AIS review used as contextual cross-check; inherited mechanistic overstatements and uncertain tumor-risk estimates were not adopted.

PMID:22698698

Androgen insensitivity syndrome.

1 finding

Abstract-supported Lancet review of AIS pathogenesis and multidisciplinary care.

PMID:26303086

Androgen receptor roles in spermatogenesis and infertility.

1 finding

Abstract-supported review distinguishing somatic testicular AR roles from germ-cell-autonomous androgen action.

PMID:26012135

[Complete androgen insensitivity syndrome].

1 finding

Abstract-supported individual CAIS report using chromosome/hormone evaluation, MSCT, gonadectomy, replacement and dilation; no comparative efficacy estimate.

ORPHA:99429

Complete androgen insensitivity syndrome

1 finding

Complete structured CAIS record, including curated phenotype bands and prevalence metadata; not primary cohort numerators.

ORPHA:90797

Partial androgen insensitivity syndrome

1 finding

Complete structured PAIS record, including curated phenotype bands and unknown prevalence; not evidence that all bands apply to MAIS.

Ask OpenScientist

OpenScientist Report

Mappings

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References