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Disorders of Gonadal Differentiation

Klinefelter syndrome (XXY)

• Most common abnormality of sexual development
• Seminiferous tubules degenerate, replaced with hyaline - testes small/firm, < 3.5cm
• Hormonal findings: low/normal T, elevated LH/FSH, elevated E
• Azoospermia common, microTESE with 40-50% sperm retrieval, 43% live birth rate per ICSI cycle
• Cancer risk: breast cancer 8x higher, increased risk for germ cell and Leydig/Sertoli tumors
• Management: androgen replacement, reduction mammoplasty, testis self-exams

46 XX male

• Normal testis development but all are infertile and 10% have hypospadias
• No benefit in microTESE
• Management: androgen replacement, reduction mammoplasty

Turner syndrome (X0)

• Female phenotype, short stature, lack secondary sexual characteristics, somatic abnormalities
• Prenatal US findings: increased nuchal translucency, lymphedema, cystic hygroma, aortic coarctation, renal anomalies
• Streak gonads: inadequate follicular cell protection leads to rapid oocyte apoptosis, leading to fibrous ovaries (streaks)
• Hormonal findings: increased FSH/LH, low E/T
• Physical exam findings caused by lymphedema during critical developmental stages - short stature, broad chest, widespread nipples, neck webbing, short 4th metacarpal, hypoplastic nails
• Presence of Y chromosome adds risk for gonadoblastoma (12-20%) - prophylactic gonadal removal recommended
• Screen for renal and cardiac anomalies
• Pregnancy is possible but spontaneous fertilization rare (more likely if mosaic)
• Management: growth hormone, hormonal therapy at puberty

Mixed gonadal dysgenesis (MGD)

• Definition: streak gonad on one side and dysgenetic/absent testis on the other side, asymmetric atypical genitalia on exam
• Internal anatomy: Mullerian structures usually seen on streak gonad side and Wolffian on the other side (but not a rule)
• Karyotype: most patients are mosaic 45 X0 / 46 XY, but this finding does not make the MGD diagnosis
• Prevalence: second most common cause of ambiguous genitalia after CAH
• Management: gender assignment (gender incongruence reported as 12%), gonadectomy (if appropriate), screening for Wilms tumor
• Gonadoblastoma or dysgerminoma seen in 15-35%
• Denys Drash syndrome: nephropathy (FSGS), Wilms tumor, and male gonadal dysgenesis (hypospadias, cryptorchidism, MGD)
• Frasier syndrome: later onset of nephropathy (FSGS), 60% gonadoblastoma risk if XY
• Partial gonadal dysgenesis: bilateral dysgenetic testes, risk for Denys Drash and gonadal tumors, manage similarly

Pure gonadal dysgenesis

• Normal internal/external female structures, bilateral streak gonads, elevated LH/FSH
• 46 XX: no somatic signs of Turner syndrome, manage with hormone replacement without gonadectomy
• 46 XY (Swyer syndrome): 35% risk for gonadal tumor by 30yo, manage with hormone replacement and bilateral gonadectomy

Embryonic testicular regression + Bilateral vanishing testes syndromes

• Diagnosis: 46 XY karyotype, castrate T levels, elevated FSH/LH
• Phenotypic spectrum from external female genitalia to male with microphallus and empty scrotum
• Surgery demonstrates cord structures, no remnant testis tissue
• Management: gender assigment, hormone replacement, consider testicular prosthesis

Other DSD diagnoses

Ovotesticular DSD (true hermaphroditism)

• Presence of both testicular tissue (seminiferous tubules present) and ovarian tissue (primordial follicles present)
• May have one ovary + one testis, or one/two ovotestes
• 80% males with hypospadias/chordee
• 67% females with clitoromegaly
• Almost all patients have urogenital sinus and uterus
• Ovary always associated with fallopian tube, and testis always associated with testis, ovotestis may have either one
• Ovary more likely on left side, testis more likely on right side
• Management: gender assignment, potential fertility considerations, removal of opposite-gendered organs, potential gonadectomy (for XY tissue)

Cloaca + Urogenital sinus

• Cloaca: common opening for urinary, genital, and GI tracts, variety of external appearances
• Urogenital sinus: common opening for urinary and genital tracts, may drain into urethral or vaginal opening
• Prenatal US findings: dilated pelvic cystic structures, may show hydronephrosis and oligohydramnios
• US demonstrates pelvic anatomy and renal appearance
• Genitogram: place foley with balloon occluding perineal opening and inject contrast, cervical impression at vaginal dome indicates mullerian structures
• Endoscopy of common opening can be performed at time of reconstructive surgery, may be required to decompress vagina/rectum
• Consider echocardiography, MR lumbosacral region
• Surgical planning: location of vagina in relation to bladder neck is most important compared to length of common channel
• Surgical plan for urogenital sinus: clitoroplasty (maintain innervation for sexual function!), labioplasty, and vaginoplasty
• Surgical plan for cloacas: decompress GI tract (colostomy), decompress GU tract (catheterization), correct potential obstructive uropathies, definitive repair (6-12mo)