What is the likely diagnosis and management plan for a 13-year-old girl with primary amenorrhea, a knob-like uterus, normal lower vagina, breast development at Tanner stage 2, and absence of axillary or pubic hair?

Primary Amenorrhea with Delayed Puberty and Absent Pubic/Axillary Hair

This clinical presentation—primary amenorrhea at age 13 with Tanner 2 breast development, absent pubic/axillary hair, and a rudimentary ("knob-like") uterus—most likely represents hypergonadotropic hypogonadism (gonadal dysgenesis/streak gonads), and requires immediate hormonal evaluation with FSH, LH, estradiol, and karyotype analysis to guide definitive management. 1, 2

Immediate Diagnostic Workup

The absence of pubic and axillary hair despite some breast development is a critical red flag that distinguishes this from simple constitutional delay. 3

Essential first-line laboratory tests:

• FSH and LH levels to differentiate hypergonadotropic (elevated FSH) from hypogonadotropic (low/normal FSH) hypogonadism 1, 2
• Estradiol level to assess ovarian function; low estradiol (<30 pg/mL) confirms hypoestrogenism 2
• Karyotype analysis is mandatory given the rudimentary uterus and absent adrenarche, as this presentation raises concern for 46,XY disorders of sex development (DSD) including Swyer syndrome or streak gonad syndrome 4, 5, 6

Imaging studies:

• Pelvic ultrasound to assess uterine size, endometrial thickness, and identify or rule out gonadal structures 1, 2
• The "knob-like" uterus suggests underdevelopment consistent with inadequate estrogen exposure 7

Differential Diagnosis Based on Clinical Features

Most Likely: Streak Gonad Syndrome (Gonadal Dysgenesis)

The combination of primary amenorrhea, minimal breast development (Tanner 2), complete absence of pubic and axillary hair, and rudimentary uterus strongly suggests streak gonad syndrome. 5

Cardinal features of streak gonad syndrome include:

• Female phenotype with primary amenorrhea 5
• Infantile breast status (though minimal development can occur from peripheral estrogen conversion) 5
• Sparse or absent pubic and axillary hair 5
• Infantile external genitalia and vagina 5
• Immature/rudimentary uterus 5
• Elevated FSH with low estrogen 5

Critical consideration: If karyotype reveals 46,XY (Swyer syndrome), bilateral gonadectomy is mandatory due to high risk (25-35%) of gonadoblastoma and malignant germ cell tumor development. 4, 6

Alternative Diagnoses to Exclude

Complete Androgen Insensitivity Syndrome (CAIS):

• Would present with well-developed breasts (Tanner 4-5), absent pubic/axillary hair, and blind-ending vagina 8
• However, this patient has only Tanner 2 breast development, making CAIS less likely 6, 8
• Testosterone levels would be in male range with CAIS 6

17α-hydroxylase/17,20-lyase deficiency:

• Can present with 46,XY karyotype, primary amenorrhea, and spontaneous breast development 6
• Distinguished by low testosterone and specific hormonal pattern 6
• Also requires gonadectomy if 46,XY 6

Interpretation of Hormonal Results

If FSH is elevated (>20-30 mIU/mL) with low estradiol:

• Confirms hypergonadotropic hypogonadism (primary ovarian/gonadal failure) 1, 2
• Proceed immediately to karyotype analysis 1, 7
• If 46,XX: Turner syndrome variant or XX gonadal dysgenesis 5
• If 46,XY: Swyer syndrome—urgent referral for gonadectomy 4, 6

If FSH is low/normal with low estradiol:

• Suggests hypogonadotropic hypogonadism (hypothalamic or pituitary dysfunction) 2
• Less likely given the rudimentary uterus and absent adrenarche 1
• Would still require karyotype given anatomical abnormalities 7

Management Algorithm

Step 1: Urgent Referral (Within 2 Weeks)

Refer immediately to pediatric endocrinology or adolescent gynecology for any 13-year-old with no signs of puberty or failure of pubertal progression. 1, 2

Step 2: Surgical Intervention (If 46,XY Karyotype)

• Laparoscopic bilateral gonadectomy must be performed due to 25-35% risk of gonadoblastoma in dysgenetic gonads with Y chromosome material 4, 6
• Delayed diagnosis increases risk of malignant transformation with poor prognosis 4

Step 3: Hormone Replacement Therapy

Initiate estrogen replacement therapy after gonadectomy (if applicable) or once diagnosis confirmed:

• Start with low-dose estrogen (transdermal estradiol 100 μg patch twice weekly preferred over oral) 2
• Gradually increase over 2-3 years to mimic physiological puberty 1
• Add cyclic micronized progesterone (200 mg for 12 days/month) after adequate breast development and uterine maturation to induce withdrawal bleeding 1, 2

Critical rationale for hormone replacement:

• Prevent osteoporosis and cardiovascular complications from prolonged hypoestrogenism 3, 1, 2
• Promote normal pubertal progression and secondary sexual characteristic development 1
• Improve quality of life and psychological well-being 7

Step 4: Long-Term Monitoring

• Annual assessment of height, weight, and Tanner staging 1
• DXA scan for bone mineral density if hypoestrogenic state persists >6 months 2
• Psychological support and counseling regarding fertility implications 7

Critical Pitfalls to Avoid

Do not assume benign constitutional delay when pubic/axillary hair is completely absent despite some breast development—this pattern demands karyotype analysis. 4, 5, 6

Do not delay karyotype testing in primary amenorrhea with anatomical abnormalities (rudimentary uterus), as 46,XY DSD requires urgent gonadectomy. 4, 6

Do not prescribe oral contraceptives as first-line therapy—physiologic estrogen replacement with transdermal estradiol better protects bone health and mimics normal puberty. 2

Do not overlook malignancy risk in dysgenetic gonads with Y chromosome material—gonadoblastoma can grow and metastasize rapidly if gonadectomy is delayed. 4