What are the differences between Androgen Insensitivity Syndrome (AIS), Müllerian Agenesis, and Turner Syndrome in terms of karyotype, key features, and Müllerian duct abnormalities, including bicornuate and didelphic uterus?

Comparison of Androgen Insensitivity Syndrome, Müllerian Agenesis, and Turner Syndrome

Karyotype and Genetic Basis

The three conditions have distinct karyotypes that are diagnostic: Complete Androgen Insensitivity Syndrome (CAIS) presents with 46,XY karyotype, Müllerian agenesis with 46,XX karyotype, and Turner syndrome with 45,X or mosaic variants. 1, 2

• CAIS: 46,XY karyotype with X-linked mutations in the androgen receptor gene causing complete peripheral androgen resistance 3, 4
• Müllerian Agenesis (MRKH): 46,XX karyotype with normal ovarian function but congenital absence of Müllerian structures 1
• Turner Syndrome: 45,X (monosomy) or mosaic karyotypes (e.g., 45,X/46,XX) resulting from complete or partial loss of the second X chromosome 5

Key Clinical Features

Complete Androgen Insensitivity Syndrome

CAIS patients present with female external genitalia, absent uterus and fallopian tubes, intra-abdominal or inguinal testes, and characteristically sparse or absent pubic/axillary hair. 6, 1

• Female phenotype with normal breast development at puberty due to peripheral conversion of testosterone to estrogen 6
• Primary amenorrhea with blind-ending vagina 4, 7
• Male-range testosterone levels with elevated LH 3, 7
• Testes may be intra-abdominal, inguinal (83% present with inguinal hernia in childhood), or labial 8
• Absent Müllerian structures (no uterus, cervix, fallopian tubes, or upper vagina) 4, 9
• Vas deferens and epididymis (Wolffian remnants) are typically present 9
• Feminine gender identity and sexual orientation 6

Müllerian Agenesis (MRKH Syndrome)

Müllerian agenesis presents with normal female external genitalia, normal breast development, normal pubic/axillary hair, but congenital absence of the uterus and upper vagina. 1

• Primary amenorrhea in otherwise normally developed females 1
• Normal female testosterone levels (not male-range) 1
• Functional ovaries with normal ovulation and hormone production 1
• Normal secondary sexual characteristics including pubic and axillary hair 1
• Blind-ending or shortened vagina 1

Turner Syndrome

Turner syndrome presents with short stature, ovarian dysgenesis with hypergonadotropic hypogonadism, cardiovascular malformations, and characteristic dysmorphic features. 2, 5

• Short stature is nearly universal 5
• Ovarian failure with elevated FSH/LH and low estrogen (hypergonadotropic hypogonadism) 2
• Cardiovascular abnormalities: bicuspid aortic valve (15-30%), aortic coarctation (7-18%), ascending aortic dilation (33%) 2, 5
• Webbed neck (pterygium colli) 2
• Lymphedema of hands and feet, particularly in infancy 2
• Increased risk of hypothyroidism and autoimmune disorders 2
• Absent or streak gonads (not functional ovaries) 2
• Prenatal presentation may include cystic hygroma (50-80% of cases) and nonimmune hydrops fetalis 2

Diagnostic Algorithm

Karyotype analysis is the definitive test to differentiate these three conditions in patients presenting with primary amenorrhea. 1

Initial Assessment for Primary Amenorrhea:

1. Hormonal assessment: Measure FSH, LH, testosterone, and estradiol 1

   • CAIS: Male-range testosterone, elevated LH, normal/high estradiol 3
   • Müllerian agenesis: Normal female testosterone, normal FSH/LH 1
   • Turner syndrome: Low estradiol, markedly elevated FSH/LH 2

2. Karyotype analysis: This definitively distinguishes the three conditions 1

3. Imaging evaluation: Pelvic ultrasound or MRI 1, 4

   • CAIS: Absent uterus, testes visible (intra-abdominal or inguinal) 4
   • Müllerian agenesis: Absent uterus, normal ovaries present 1
   • Turner syndrome: Streak gonads, may have uterus (hypoplastic) 2

4. Physical examination findings:

   • Pubic/axillary hair: Sparse/absent in CAIS, normal in Müllerian agenesis and Turner syndrome 1
   • Breast development: Normal in CAIS and Müllerian agenesis, absent/poor in untreated Turner syndrome 6, 2
   • Height: Short stature in Turner syndrome, normal in CAIS and Müllerian agenesis 5

Müllerian Duct Abnormalities: Bicornuate vs Didelphic Uterus

These represent different classes of Müllerian duct fusion defects that are distinct from complete Müllerian agenesis. 6

Bicornuate Uterus:

• Results from incomplete fusion of the Müllerian ducts 6
• Single cervix with varying degrees of uterine body separation 6
• Two uterine horns that join at the lower uterine segment 6
• Single vagina 6

Didelphic Uterus (Uterus Didelphys):

• Results from complete failure of Müllerian duct fusion 6
• Two separate uterine bodies, two cervices 6
• May have longitudinal vaginal septum creating two vaginal canals 6
• Represents the most complete form of duplication 6

Critical distinction: Both bicornuate and didelphic uteri represent partial Müllerian development with fusion abnormalities, whereas Müllerian agenesis (MRKH) represents complete absence of Müllerian structures 6. Patients with bicornuate or didelphic uteri have normal 46,XX karyotype, functional ovaries, and typically normal menstruation (though may have obstetric complications), unlike the three primary conditions discussed above 6.

Critical Diagnostic Pitfalls

• Do not confuse CAIS with Müllerian agenesis: Both present with primary amenorrhea and absent uterus, but karyotype (46,XY vs 46,XX), testosterone levels (male-range vs female-range), and presence/absence of pubic hair definitively distinguish them 1, 7
• Inguinal hernia in a phenotypic female child should raise suspicion for CAIS: 83% of CAIS patients present with inguinal hernia in childhood, yet diagnosis is often delayed until primary amenorrhea occurs 8
• In Turner syndrome, always use indexed aortic measurements (ASI) rather than absolute dimensions: Small body size can mask significant aortic dilation, leading to underestimation of dissection risk 2, 5
• Baseline cardiac MRI is mandatory at Turner syndrome diagnosis: Echocardiography alone misses important structural abnormalities 2, 5