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Androgen Insensitivity Syndrome

Androgen Insensitivity Syndrome. X-Linked : Xq11-12 1:20,000-64,000 (rare) One of most common forms of male pseudohermaphroditism Normal androgen production and metabolism End-organ resistance to androgen action mainly due to defective androgen receptors.

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Androgen Insensitivity Syndrome

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  1. Androgen Insensitivity Syndrome

  2. X-Linked : Xq11-12 • 1:20,000-64,000 (rare) • One of most common forms of male pseudohermaphroditism • Normal androgen production and metabolism • End-organ resistance to androgen action mainly due to defective androgen receptors. • Mutations can be sporadic or familial (maternal carriers) • 2 Forms: • Complete androgen insensitivity syndrome (CAIS) • Partial androgen insensitivity syndrome (PAIS)

  3. CLINICAL FEATURES • CAIS: • Female habitus with normal female breast development • Absence of pubic and axillary hair • Female external genitalia: underdeveloped labia, normal/small clitoris • Blind-ending vaginas (often short) • No male pattern of temporal balding • Taller than average female height • Internal genitalia: Undescended aspermatogenic testes with normal testicular function (Leydig cell testosterone synthesis, Sertoli cell AMH synthesis) • Absence of uterus and Fallopian tubes (Normal Müllerian structure regression) • Majority raised as females

  4. CLINICAL FEATURES • PAIS: • Wide range of phenotypes: • Genital ambiguity - perineal hypospadias • clitoromegaly/micropenis • perineal orifice with labioscrotal folds • bifid scrotum • Normal male phenotype with infertility (oligo/azoospermia) • Predominantly male external genitalia • Female phenotype with sparse, scant pubic and axillary hair • 59% raised as male

  5. CLINICAL FEATURES A. CAIS B. PAIS grade 3; micro penis, hypospadal urethral orifice and bilateral cryptorchidism A. B.

  6. MOLECULAR ACTION OF ANDROGENS • Testosterone diffuses into cell. • Binds to intracellular androgen receptor • Dissociation of heat shock protein on ligand binding • Transport of ligand-receptor complex to nucleus through nuclear pores • Binding of receptor complex to specific hormone response elements via DNA binding domain • Binding of p160 family of co-factors and enzymes • Transcriptional activation • Expression of proteins in response to androgen Neurological development Male phenotype Immunity Maintenance of male phenotype

  7. PATHOPHYSIOLOGY • Mutation within androgen receptor: • Failure to bind to ligand • Failure to bind to DNA • Failure to form functioning androgen receptor – • Truncated proteins, mRNA splicing errors, Failure to fold into functioning 3D protein structure. • Even with normal androgen production and metabolism: no target organ response due to androgen receptor resistance. • Unopposed oestrogen activity (testes and peripheral aromatisation) in utero and in vivo

  8. INVESTIGATIONS Presentation: Child: indirect inguinal hernia ambiguous genitalia PAIS – mostly present in 1st month of life CAIS - median age: 1 yr Testes palpable in 77% CAIS, 41% PAIS

  9. INVESTIGATIONS Presentation: Adolescent - Primary amenorrhoea Adult - May be in denial of abnormality of the years. Few sexual relationships?

  10. INVESTIGATIONS History: 50% of CAIS have a positive family history Important for genetic counselling Indicates for family screening Heterozygous 46,XX Females with sparse, delayed asymmetric pubic or axillary hair or delayed menarche (Carriers) Infertile 46,XY Maternal aunts or uncles

  11. EXAMINATION B. A. • Classification system: 1= least severe, 7= most severe • External masculinisation score 12 = normal male external genitalia

  12. INVESTIGATING PRESENCE OF Y CHROMOSOME • Differentially diagnose genital ambiguity • Peripheral leukocyte karyotyping • Gold standard • Array of metaphasic chromosomes • 46,XY males vs 46, XX females (CAH)

  13. INVESTIGATING PRESENCE OF Y CHROMOSOME • Fluorescence in situ hybridisation (FISH) with cDNA probes specific to X and Y chromatin. • X = Green signal • Y = Orange/red signal • Quicker than karyotyping

  14. DIFFERENTIAL DIAGNOSES FOR MALE PSEUDOHERMAPHRODITISM • AIS • XY gonadal dysgenesis (streak gonads) • Testicular regression syndrome • Leydig cell hypoplasia • Enzymatic defects: 5α-reductase deficiency 17α-hydroxylase deficiency

  15. IMAGING • Ultrasound scanning for presence of uterus, ovaries (Müllerian) • Ultrasound scanning for presence of testes if non-palpable (Transvaginal) • MRI/LAPAROSCOPY – If USS not useful Disadvantages: Invasive, anaesthesia, children

  16. PRENATAL PELVIC ULTRASOUND • When there is discrepancy between genotype and phenotype • Useful for mother’s with positive family history • 22-24 wks will show abnormality

  17. HORMONAL ANALYSES

  18. GONADAL BIOPSY • Functioning testes: Sertoli cell function normal (AMH production) Leydig cell function normal (T and E2) • Absence of germ cells, aspermatogenic semniferous tubules

  19. GENITAL SKIN BIOPSY • Highly sensitive to androgens • Cultured fibroblasts • Study androgen binding activity, to evaluate severity of AIS • No binding = CAIS

  20. DNA ANALYSIS • Screen Families (Buccal smears, CAG repeats in exon 1) • Prenatal screening 9-12 weeks by chorionic villus sampling of foetal side • 16th week by ultrasound and amniocentesis • Bloods taken from patient

  21. DNA ANALYSIS • Northern Blots to assess AR mRNA expression • PCR regions of DNA containing AR exons • Failure to amplify regions suggests large deletions • Denaturing gradient gel electrophoresis • Single strand polymorphism analysis • Automated DNA sequencing

  22. AR MUTATIONS • Large deletions • 1-4 base pair insertions / deletions • Nonsense mutations (Premature termination stop codons) • Missense: Single amino acid substitutions (>90%) • A given AR mutation can be causally related to AIS by recreating mutant in AR cDNA and demonstrating abnormality after transfection into AR-free host cells

  23. REFERENCES • Ahmed SF, Cheng L, Dovey L, Hawkins JR, Martin H, Rowland J, Shimura N, Tait AD, Hughes IA. Phenotypic features, androgen receptor binding and mutational analysis in 278 clinical cases reported as AIS J Clin Endocrinol Metab 2000;85(2):658-665 • www.androgendb.mcgill.ca • www.medhelp.org/www/ais • Turner HE, Wass JAH. Oxford handbook of Endocrinology and Diabetes. Oxford University Press 2003 • Quigley CA, De Bellis A, Marschke KB, El-Awady MK, Wilson EM, French FS. Androgen receptor defects: Historical, clinical, and molecular perspectives Endocrin Rev 1995;16(3):271-321 • Gobinet J, Poujol N, Sultan C. Molecular action of androgens Mol Cell Endocrinol 2002;198:15-24 • Ahmed SF, Hughes IA. The clinical asessment of intersex Curr Paed 2000;10:269-274 • Pinhas-Hamiel O, Zalel Y, Smith E, Mazkareth R, Aviram A, Lipitz S, Achiron R. Prenatal diagnosis of sex differentiation disorders: the role of fetal ultrasound J Clin Endocrinol Metab 2002;87(10):4547-4553

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