How to differentiate Mullerian (Mullerian) agenesis from Androgen Insensitivity Syndrome (AIS)?

Differentiating Müllerian Agenesis from Androgen Insensitivity Syndrome

The key differentiating factor is karyotype: Müllerian agenesis patients have 46,XX karyotype with normal female testosterone levels, while Complete Androgen Insensitivity Syndrome (CAIS) patients have 46,XY karyotype with male-range testosterone levels. 1

Clinical Presentation Similarities

Both conditions present with:

• Primary amenorrhea in otherwise normally developed females 2, 3
• Normal female external genitalia 2, 4
• Absence of uterus and upper vagina 3, 4
• Normal breast development at puberty 2, 3

Critical Distinguishing Features

Karyotype Analysis

• Müllerian agenesis: 46,XX (genetic female) 3, 5
• CAIS: 46,XY (genetic male with female phenotype) 1, 4

Testosterone Levels

• Müllerian agenesis: Normal female range testosterone 5
• CAIS: Male-range or higher testosterone levels due to functioning testes 1, 4

Gonadal Tissue

• Müllerian agenesis: Normal ovaries present (may be identified on imaging) 3, 5
• CAIS: Testes present (may be intra-abdominal, inguinal, or labial) 2, 4

Physical Examination Clues

• Müllerian agenesis: Normal pubic and axillary hair distribution 3
• CAIS: Sparse or absent pubic and axillary hair due to androgen receptor defects 2, 1

Inguinal Masses/Hernias

• Müllerian agenesis: Not characteristic 3
• CAIS: Bilateral inguinal masses or hernias are highly suggestive, especially with family history of similar presentations 1

Diagnostic Algorithm

Step 1: Initial Hormonal Assessment

• Measure serum testosterone, LH, FSH 1
• Male-range testosterone strongly suggests CAIS 1
• Normal female testosterone suggests Müllerian agenesis 5

Step 2: Karyotype Analysis

• This is the definitive test 1, 4
• 46,XX confirms Müllerian agenesis 3
• 46,XY confirms CAIS 1, 4

Step 3: Imaging Evaluation

• MRI is superior to ultrasound for identifying Müllerian structures and gonadal location 1, 4
• Look for presence/absence of ovaries versus testes 4
• Identify location of gonads if testes present (intra-abdominal, inguinal, labial) 4

Step 4: Physical Examination Details

• Assess pubic/axillary hair distribution 1
• Palpate for inguinal masses 1
• Evaluate for associated anomalies (renal, skeletal in Müllerian agenesis) 3, 5

Common Pitfalls to Avoid

Do not rely on imaging alone: Two-dimensional ultrasound is unreliable for diagnosing Müllerian agenesis and cannot differentiate it from CAIS 5. MRI showing absent Müllerian structures can occur in both conditions 1.

Do not skip karyotyping: The case report by 1 demonstrates how MRI findings of absent Müllerian structures led to initial misdiagnosis as Müllerian agenesis when the patient actually had CAIS—only karyotyping revealed the correct diagnosis.

Family history matters: A family history of female relatives with infertility and bilateral inguinal hernias should raise suspicion for CAIS 1.

Management Implications

For CAIS

• Gonadectomy is required due to malignancy risk in undescended testes 1, 4
• Timing of gonadectomy (prepubertal vs. postpubertal) should consider age-related malignancy risk 1
• Lifelong hormone replacement therapy after gonadectomy 1

For Müllerian Agenesis

• Nonsurgical vaginal dilation is first-line treatment (90-96% success rate) 3
• Evaluation for associated renal and skeletal anomalies 3, 5
• No gonadectomy needed; ovaries function normally 3

Both conditions require comprehensive psychological counseling and discussion of fertility options including adoption and gestational surrogacy 3, 6.