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Evaluation/Management of Ambiguous Genitalia

History/Physical

• Family history: virilization, amenorrhea, infertility, infant death (think untreated CAH)
• Maternal medication use during pregnancy: steroids, hormonal meds
• Exam: assess general appearance, abdominopelvic masses, phallus size, palpable gonads
• Palpable gonads: ovaries do not descend, therefore any palpable gonads equal testis tissue, Ovotestis may decend but can be differentiated based on exam and US findings, bilateral nonpalpable testes or unilateral nonpalpable testis + hypospadias warrant further workup

Adjuncts

• Pelvic US: assess for evidence Mullerian structures, nonpalpable gonads, gonadal cyst (concern for ovotestis)
• Karyotype: assess presence of X + Y chromosomes
• FISH: rapidly identifies X + Y, takes hours (karyotype takes 2 days), identifies SRY gene
• Labs: consider T/DHT (may drop quickly after birth), electrolytes (salt-wasting CAH), 17OH-progesterone (wait 3-4 days due to false elevation after birth), AMH (present with testes), and LH/FSH
• Retrograde studies: can delineate connections in urogenital sinus
• Gonadal biopsy: consider only if needed for diagnosis, do not perform gonadectomy at this time

Tenets of assigning gender

• Maximize reproductive potential
• Maximize sexual function
• Minimize medical procedures
• Optimize gender-appropriate appearance
• Optimize stable gender identity
• Optimize psychosocial well-being
• Goal: avoid irreversible treatments and allow for maximal long-term function and QoL

Germ cell tumor risk

• Higher risk when Y chromosome present in non-scrotal environment or gonadal dysgenesis
• High risk (40-60%, gonadectomy recommended): Denys Drash, Fraiser, PAIS nonscrotal testes, gonadal dysgenesis with intraabdominal testes, StAR deficiency
• Intermediate risk (12-28%, surveillance/biopsy): Turner syndrome with Y chromosome, 17B-hydroxysteroid deficiency, PAIS or gonadal dysgenesis with scrotal testes
• Low risk (1-3%, surveillance): CAIS, ovotesticular DSD, Turner syndrome without Y chromosome

Genital Appearance	Karyotype	Gonads	Diagnosis
Female	46 XY	Testis	Complete androgen insensitivity syndrome
			5a-reductase deficiency
			StAR deficiency
		Absent	Absent testis
		Streak	Swyer syndrome
	45 X0		Turner Syndrome
Male	46 XX	Testis	46 XX with SRY+
	46 XY		Persistent mullerian duct syndrome
	47 XXY		Klinefelter syndrome
Ambiguous	46 XX	Testis	46 XX testicular DSD, SRY-
		Ovary	11B-Hydroxylase deficiency
			Excess maternal androgens
			21a-Hydroxylase deficiency
			3B-HSD deficiency
	46 XY	Testis	3B-HSD deficiency
			17B-HSD deficiency
			17-20 Desmolase deficiency
			17a-Hydroxylase deficiency
			Partial androgen insensitivity syndrome
			Leydig cell hypoplasia
	46 XY / 46 X	Testis and streak	Mixed gonadal dysgenesis
	46 XX, 46 XY, 46 XX / 46 XY	Testis and ovotestis	Ovotesticular DSD

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)

• Unilateral testis + contralateral streak gonad + persistent mullerian structures
• Most patients 45 X0 / 46 XY
• Second most common cause of ambiguous genitalia after CAH
• 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
• Management: gender assignment, gonadectomy (if appropriate), screening for Wilms tumor
• 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

46 XX DSD (masculinized female)

Congenital adrenal hyperplasia (CAH)

• Patients may have salt-wasting, virilization, or neither
• Salt-wasting may cause severe vomiting and can be mistaken for pyloric stenosis
• Female infants present with virilization, male infants present with precocious puberty
• 21a-hydroxylase: elevated progesterone and 12-hydroxyprogesterone
• 11B-hydroxylase: elevated 11-deoxycortisol, 11-DOC
• Adrenal glands have cerebriform appearance
• Adrenal rest tumors may occur in male patients and can cause infertility, require annual testicular US for screening
• Management: glucocorticoid replacement, can pretreat with dexamethasone if diagnosed prenatally, surgical reconstruction depends on individual situation
• (Typical) surgical management: urethroplasty/vaginoplasty (create separate openings), clitoroplasty (reduce masculinized clitoris), vulvoplasty/labioplasty (define external genitalia)

External hormone production

• Be careful of materal administration of progesterone, danazol
• Virilizing tumors are rare

46 XY DSD (undermasculinized male)

Subcatigories of XY DSD

• Abnormal testis development: dysgenetic testis, testicular agenesis
• Abnormal androgen production: leydig cell aplasia, T-synthesis disorders
• Abnormal androgen receptors: Androgen insensitivity syndromes
• Other: persistent Mullerian duct, vanishing testis, hypogonadotropic hypogonadism

Leydig cell aplasia

• 46 XY + normal female phenotype, but no mullerian structures
• Testes palpable in inguinal canals or labia majora
• Diagnosis: no rise in testosterone after HCG administration, absence of leydig cells on gonadal biopsy

Testosterone biosynthesis disorders

• Congenital lipoid adrenal hyperplasia (StAR deficiency): 46 XY, female/ambiguous genitalia and absent mullerian structures, manage with steroid replacement and gonadectomy
• Cytochrome p450 oxidoreductase (POR) deficiency: ambiguous genitalia, +/- skeletal dysplasia (Antley-Bixler syndrome)
• 3B-HSD deficiency: incomplete masculinization and salt wasting, incomplete virilization, normal wolffian ducts, elevated 3B-HSD, manage with steroid replacement
• 17a-hydroxylase deficiency: undervirilized spectrum with HTN + hypokalemia + salt/water retention, manage with steroid replacement
• 17,20-Lyase deficiency: undervirilization without mullerian structures or salt-wasting
• 17B-HSD oxiodoreductase deficiency: undervirilization with female phenotype at birth, intraabdominal testes and wolffian ducts, puberty causes development of male secondary sexual characteristics, HCG stimulation results in an increased testosterone/androstenedione ratio

Androgen insensitivity syndrome

• All will have 46 XY + normal hormone profile, but spectrum of external genital appearance
• Complete (cAIS): 46 XY, bilateral testes, female external genitalia, absent mullarian structures, decreased axillary/pubic hair, amenorrhea, manage with gonadectomy (postpubertal), hormone replacement
• Gonadal tumors occur in 0.8-2% with cAIS
• Inguinal hernia: 50% with cAIS have inguinal hernias, 1-2% female infants with inguinal hernias have cAIS
• Partial (pAIS): spectrum of ambiguous external genitalia
• Mild (mAIS): male phenotype with potential mild hypospadias, gynecomastia, azoospermia/oligospermia
• Gonad management: previously recommended gonadectomy, now recommend maintaining gonads (can reposition out of inguinal canal) to provide natural T->E production (instead of E supplementation), discuss low but potential cancer risk and can screen annually with US

5a-reductase deficiency

• Neonatal presentation with female to ambiguous genitalia
• Elevated T:DHT ratio, > 20:1 after HCG stimulation
• Gender assignment is individual decision

Persistent Mullerian duct syndrome

• 46 XY and normal male external genitalia...but persistent mullerian structures
• Usually present with one/both undescended testes, bilateral fallopian tubes, uterus, and upper vagina draining into prostatic utricle
• Perform orchiopexy as indicated, removal of structures not necessary

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)