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Disorders of Sexual Development (DSD) - A Postgraduate Reference

1. DEFINITION AND CLASSIFICATION

"DSDs are congenital diseases in which the chromosomal, gonadal, or anatomic sex is abnormal and embraces a wide-ranging spectrum of phenotypes classified in five different groups." - Campbell-Walsh-Wein Urology

2006 Chicago Consensus Classification:

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2. NORMAL SEXUAL DIFFERENTIATION (Embryological Basis)

Step 1: Chromosomal Sex (Fertilization)

• XX = genetic female; XY = genetic male
• The SRY gene (Sex-determining Region on Y chromosome, located on the short arm of Y) is the master switch for testicular development
• SRY activates a cascade involving SOX-9, SF-1, WT-1, FTZ-F1, and LIM-1 which direct testis formation
• In XX females, two copies of DAX-1 (on Xp) suppress StAR protein and inhibit testicular development, defaulting to ovarian development

Step 2: Gonadal Sex (Weeks 6-7)

• Gonads arise from urogenital ridges (week 4) - bipotential until week 6-7
• Primordial germ cells migrate from yolk sac endoderm
• In XY: SRY directs Sertoli cell differentiation → Sertoli cells produce AMH (Anti-Mullerian Hormone) → Müllerian regression; Leydig cells produce testosterone → Wolffian duct development
• In XX: Ovarian development is the "default" pathway; granulosa cells form, Müllerian ducts persist (form uterus, fallopian tubes, upper vagina)

Step 3: Phenotypic Sex (Weeks 8-12)

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3. WHEN DSD IS SUSPECTED

1. Newborn period: atypical/ambiguous genitalia, or discordant phenotype from prenatal karyotype
2. Inappropriate pubertal development: virilization in a genetic female, or feminization in a genetic male
3. Delayed puberty: primary amenorrhea or absent pubertal changes
4. Later in life: infertility, inguinal hernia containing testis in a phenotypic female

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4. INITIAL CLINICAL EVALUATION

History

• Family history of unexplained infant deaths, infertility, amenorrhea, hirsutism
• Drug ingestion during pregnancy (progestogens, androgens, finasteride, danazol, stilbestrol - see table below)
• Maternal virilization during pregnancy (suggests virilizing tumor)
• Consanguinity (autosomal recessive disorders)

• C21-steroid medroxyprogesterone acetate (progesterone)
• Finasteride, Leuprolide acetate
• Stilbestrol, Danazol, Norethynodrel, Ethisterone, Norethindrone

Physical Examination

• Palpate gonads: a gonad in the inguinal canal or labioscrotal fold is almost always a testis (ovaries do not descend) - this virtually excludes 46,XX DSD
• Assess phallus size: stretched penile length < 2.5 cm = micropenis; clitoromegaly = > 1 cm
• Labioscrotal fusion: degree (partial vs. complete) and pigmentation
• Urogenital sinus: presence suggests androgen excess in 46,XX
• Midline structures: palpate for uterus abdominally and rectally
• Stigmata: web neck, shield chest, cardiac murmurs (Turner), gynecomastia (Klinefelter)
• Prader staging for degree of virilization in 46,XX DSD (I-V)

Investigations

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5. 46,XX DSD (Masculinized Female / Former Female Pseudohermaphroditism)

"46,XX DSD is a disorder of phenotypic sexual development in which 46,XX individuals with ovaries have partially masculinized phenotype and ambiguous genitalia." - Campbell-Walsh-Wein Urology

Causes of 46,XX DSD:

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5.1 Congenital Adrenal Hyperplasia (CAH) - Most Common Cause

Enzyme Defects in the Cortisol Pathway:

Cholesterol
   ↓ StAR → P450scc
Δ5-Pregnenolone → 17α-OH Pregnenolone → DHEA
   ↓ 3β-HSD                                    ↓ 3β-HSD
Progesterone → 17α-OH Progesterone → Androstenedione → Testosterone
   ↓ 21-OH        ↓ 21-OH
11-DOC          DOC → Corticosterone → Aldosterone
   ↓ 11β-OH
Cortisol

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5.1a: 21-Hydroxylase Deficiency (95% of all CAH)

• Block in cortisol synthesis → ↑ ACTH → adrenal hyperplasia → ↑ 17-OHP → shunted to androgens (androstenedione → testosterone)
• Aldosterone synthesis also impaired in severe form → salt wasting

• At birth: ambiguous genitalia - clitoromegaly, labioscrotal fusion, urogenital sinus
• Prader grading I-V (I = mild clitoromegaly; V = complete penile urethra, fused scrotum)
• Normal Müllerian structures (uterus, ovaries intact)
• Salt-wasting crisis at 1-3 weeks of life (feeding difficulties, vomiting, dehydration, hyperpigmentation from ACTH excess)
• Without treatment: progressive virilization, advanced bone age, short final height

• Genital phenotype normal at birth
• Salt-wasting crisis if severe
• Precocious pseudo-puberty (pubic hair, penile growth, accelerated growth, advanced bone age but testes remain prepubertal)
• Testicular adrenal rest tumors (TART) in adulthood - can cause infertility

• Serum 17-OHP: markedly elevated (>100 ng/mL in classic; 10-100 in non-classic); the definitive diagnostic marker
• Serum electrolytes: Na↓, K↑ (salt-wasting)
• Plasma renin activity: elevated in salt-wasting
• Androstenedione, DHEAS: elevated
• Karyotype: 46,XX
• Pelvic ultrasound: normal Müllerian structures, adrenal enlargement
• Neonatal screening: 17-OHP heel-prick test (day 2-4 of life) - now standard in many countries
• ACTH stimulation test for non-classic: 17-OHP >10 ng/mL at 60 min is diagnostic
• HLA typing (6p21.3 haplotype)
• CYP21A2 gene mutation analysis

• Glucocorticoid replacement: Hydrocortisone 10-15 mg/m²/day in 3 divided doses (preferred in children to minimize growth suppression); prednisolone or dexamethasone in adults
• Mineralocorticoid replacement (salt-wasting): Fludrocortisone 0.05-0.2 mg/day + sodium chloride supplementation (1-2 g/day) in infants
• Monitoring: 17-OHP, androstenedione, plasma renin activity, growth velocity, bone age
• Stress dosing: 2-3x maintenance dose during illness, surgery, trauma ("stress rule")
• Prenatal treatment (experimental/controversial): Dexamethasone 20 µg/kg/day started before 8 weeks gestation to prevent virilization of affected female fetus (must diagnose early via CVS)

• Indicated for Prader III-V degree of virilization
• Timing: traditionally at 2-6 months of age (clitoroplasty, vaginoplasty); modern consensus favors deferring vaginoplasty to adolescence
• Clitoroplasty: nerve-sparing reduction; never total clitorectomy (preserves sensation and sexual function)
• Vaginoplasty: flap vaginoplasty or pull-through procedure
• Ongoing psychosocial support and gender identity counseling

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5.1b: 11β-Hydroxylase Deficiency (5-8% of CAH)

• Block at 11β-hydroxylase (CYP11B1) → ↑ 11-deoxycortisol (compound S) and 11-deoxycorticosterone (DOC) → DOC has mineralocorticoid activity → hypertension
• Androgenic pathway is intact → virilization

• Virilization of 46,XX female (ambiguous genitalia at birth)
• Hypertension (characteristic feature, not seen in 21-OH deficiency)
• Hypokalemia (from DOC excess)
• Low aldosterone and renin (suppressed by DOC)
• No salt wasting (DOC provides mineralocorticoid effect)

• Elevated 11-deoxycortisol and 11-DOC
• Elevated 17-OHP (modest, less than 21-OH deficiency)
• Elevated DHEAS, androstenedione
• Low renin activity

• Glucocorticoid replacement (suppresses DOC → corrects hypertension)
• Surgical reconstruction as needed
• No mineralocorticoid supplementation needed

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5.1c: 3β-Hydroxysteroid Dehydrogenase (3β-HSD) Deficiency

• Block in conversion of Δ5 to Δ4 steroids → accumulation of DHEA, pregnenolone
• DHEA is a weak androgen → mild virilization in 46,XX females
• Severe salt wasting because both cortisol and aldosterone synthesis are impaired

• Mild virilization (clitoromegaly) - less severe than 21-OH deficiency
• Severe salt-wasting crisis
• Elevated DHEA/DHEAS, low cortisol, low aldosterone

• Paradoxically - undervirilization (ambiguous genitalia) because testosterone synthesis requires 3β-HSD
• Salt wasting

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5.1d: 17α-Hydroxylase Deficiency

• CYP17A1 enzyme deficiency
• In 46,XX: no sex steroid production → primary amenorrhea, sexual infantilism, no virilization
• Excess mineralocorticoids (DOC, corticosterone) → hypertension, hypokalemia

• Normal or female-appearing external genitalia at birth
• Primary amenorrhea, sexual infantilism at puberty
• Hypertension, hypokalemia

• Female or ambiguous external genitalia (no testosterone synthesis)
• See Section 6 (46,XY DSD) for details

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5.2 Maternal Androgen Excess (Exogenous/Endogenous)

• 46,XX infant, normal Müllerian structures, normal ovaries
• Virilized external genitalia only (not progressive)
• Spontaneous improvement after delivery as maternal hormones clear
• No adrenal insufficiency

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5.3 Ovotesticular DSD (Former True Hermaphroditism)

• In 46,XX cases: cryptic Y-DNA (SRY translocation to X chromosome or autosome), or SRY-independent gonadal sex reversal
• Gonads may be an ovotestis, or separate ovary on one side and testis on the other

• Variable - ambiguous genitalia at birth most common
• Uterus usually present (can vary)
• 70% raised as males
• Breast development and menstruation possible at puberty
• Inguinal hernia in 50%

• Gender assignment based on gonadal anatomy, potential for function, and family/cultural factors
• Remove discordant gonadal tissue
• Gonadal cancer risk: ~4% (lower than gonadal dysgenesis)

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6. 46,XY DSD (Undervirilized Male / Former Male Pseudohermaphroditism)

In 46,XY DSD, the karyotype is male (46,XY), testes are usually present, but external genitalia are incompletely virilized ranging from female-appearing to ambiguous.

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6.1 Disorders of Androgen Synthesis

6.1a: StAR Protein Deficiency (Congenital Lipoid Adrenal Hyperplasia)

• StAR (Steroidogenic Acute Regulatory protein) transports cholesterol across the mitochondrial membrane - the first and rate-limiting step in steroidogenesis
• Complete block → no sex steroids, no glucocorticoids, no mineralocorticoids
• Most severe form of adrenal hyperplasia

• 46,XY: female or ambiguous external genitalia (no testosterone or DHT)
• 46,XX: normal female genitalia
• Both: severe salt-wasting crisis in neonatal period (life-threatening)
• Massive adrenal enlargement (lipid-laden adrenal cortex on imaging)
• Primary adrenal insufficiency

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6.1b: 3β-HSD Deficiency in 46,XY

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6.1c: 17α-Hydroxylase / 17,20-Lyase Deficiency in 46,XY

• CYP17A1 encodes both 17α-hydroxylase and 17,20-lyase activities
• Deficiency → no sex steroid synthesis (no DHEA, no androstenedione, no testosterone)
• Excess DOC and corticosterone → hypertension, hypokalemia

• Female or ambiguous external genitalia
• No Müllerian structures (AMH from testes is normal)
• Absent pubertal development
• Hypertension and hypokalemia
• Elevated progesterone and pregnenolone; low cortisol

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6.1d: 17β-Hydroxysteroid Dehydrogenase (17β-HSD) Deficiency

• 17β-HSD converts androstenedione to testosterone (and estrone to estradiol)
• Deficiency → cannot synthesize testosterone from androstenedione
• Autosomal recessive; gene HSD17B3 on chromosome 9q22

• Female-appearing external genitalia at birth (no scrotum, no penis; testes often undescended)
• No Müllerian structures (AMH normal - Müllerian regression occurs)
• At puberty: virilization occurs (androstenedione peripherally converted to testosterone by other isoenzymes of 17β-HSD)
• Clitoral/penile enlargement, virilization, often with gender role change to male
• Elevated androstenedione/testosterone ratio (>3:1) is diagnostic

• If raised female: gonadectomy before puberty, estrogen replacement at puberty
• If male identity: testosterone therapy, surgical correction of genitalia

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6.2 5α-Reductase Type 2 Deficiency

"5α-Reductase type 2 deficiency is an autosomal recessive transmitted disorder affecting the formation of the male genitalia." - Smith & Tanagho's General Urology

• SRD5A2 gene mutation → failure to convert testosterone (T) to dihydrotestosterone (DHT)
• DHT is 5-10x more potent than T and is essential for external genitalia formation
• Type 2 5α-reductase predominates in external genitalia and prostate; type 1 in skin and nongenital tissues
• DHT is localized to the midline urethral seam during fetal development; failure of seam fusion → hypospadias

• At birth: small phallus, severe hypospadias, bifid scrotum, blind vaginal pouch / residual prostatic utricle
• Testes often undescended (inguinal)
• Müllerian structures absent (AMH normal)
• Wolffian structures present (epididymis, vas deferens)
• At puberty: significant virilization - phallic enlargement, scrotal development, voice change (testosterone levels surge and overwhelm the deficiency via type 1 enzyme or receptor saturation)
• Gender identity: predominantly male despite female-rearing in many cultures. In Dominican Republic (high prevalence), the condition was called "guevedoces" (testicles at twelve) - most children change gender identity from female to male at puberty

• T:DHT ratio > 30:1 (normally < 10:1) after hCG stimulation
• Elevated testosterone, low DHT
• SRD5A2 gene mutation analysis
• Normal karyotype (46,XY)
• Normal AMH

• Male sex assignment: testosterone or DHT therapy; hypospadias repair, orchiopexy
• Female sex assignment: gonadectomy before puberty, estrogen replacement; vaginal reconstruction
• Pregnancies reported via ICSI (preserved spermatogenesis in some cases)

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6.3 Androgen Insensitivity Syndrome (AIS)

"Androgen resistance ranges from partial to complete owing to a defect in the AR. Patients with complete androgen resistance have a 46,XY karyotype but have unambiguous female external genitalia, hypoplastic labia majora, a blind vaginal pouch, and an absent uterus." - Smith & Tanagho's General Urology

• Testes develop normally (SRY intact), AMH produced normally → Müllerian regression (no uterus, no tubes)
• Testosterone is produced normally or in excess (due to LH elevation)
• However, testosterone/DHT cannot act on target tissues (AR mutation) → no male differentiation of external genitalia
• Peripheral aromatization of excess testosterone to estradiol → breast development (via ER, which is functional)
• Brain "masculinization" also fails (functional AR required)

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6.3a: Complete AIS (CAIS) - "Testicular Feminization"

• Unambiguous female external genitalia
• Blind vaginal pouch (shortened vagina, no cervix, no uterus)
• Absent or sparse axillary and pubic hair (androgens drive hair growth)
• Normal breast development at puberty
• Primary amenorrhea - most common presentation in adolescence
• Testes may be in abdomen, inguinal canal (presents as inguinal hernia in ~1% of prepubertal females undergoing hernia repair - a classic exam question), or labia majora
• Gender identity: female (brain "masculinization" absent)

• Karyotype: 46,XY in a phenotypic female
• Serum testosterone: elevated (male range or above)
• LH: elevated (loss of androgen feedback on hypothalamus-pituitary)
• FSH: normal or mildly elevated
• AMH: detectable (confirms testes present)
• Serum estradiol: elevated (aromatization from excess T)
• Pelvic ultrasound/MRI: absent uterus, blind vaginal pouch; testes located intra-abdominally or inguinally
• Androgen receptor binding assay (fibroblast culture): absent or decreased binding
• AR gene sequencing: confirms mutation

• Gonadectomy: the gonads carry a 10% risk of malignancy post-puberty (most commonly dysgerminoma/seminoma). Options:
  • Delay gonadectomy until after puberty (allows natural breast development, bone density accrual), then gonadectomy + estrogen replacement
  • Early gonadectomy (at diagnosis) + exogenous estrogen at puberty
  • Current preference: most centers defer until after puberty
• Hormone replacement: estrogen replacement lifelong after gonadectomy (maintains bone density, cardiovascular health)
• Vaginal augmentation: if vaginal length is inadequate; self-dilation (Frank technique) preferred first-line; surgical vaginoplasty (McIndoe procedure) if dilation fails
• Psychological support: disclosure is critical - full open communication with the patient about their diagnosis is now the standard approach
• Fertility: no fertility possible (no uterus); sperm retrieval not possible (testes are dysgenetic)

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6.3b: Partial AIS (PAIS) - Reifenstein Syndrome and Others

• Wide spectrum: from mild hypospadias with gynecomastia to micropenis with cryptorchidism to severe ambiguous genitalia with clitoromegaly
• Classic Reifenstein syndrome: hypospadias, cryptorchidism, gynecomastia, infertility
• No Müllerian structures (AMH present)
• Virilizes partially at puberty

• Sex assignment is complex and individualized
• Male assignment: orchiopexy, hypospadias repair, testosterone therapy; gynecomastia surgery
• Female assignment: gonadectomy, estrogen replacement, vaginal reconstruction
• The decision depends on degree of virilization, AR function, potential for erectile function, and psychosocial factors

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6.4 XY Complete Gonadal Dysgenesis (Swyer Syndrome)

• Mutations in SRY (15-20%), SOX9, SF1, DHH, or unknown factors → failure of testicular differentiation → no testosterone, no AMH production
• No androgens → female external genitalia
• No AMH → Müllerian structures present (uterus, tubes)
• Streak gonads cannot sustain ovarian function

• Normal female external genitalia
• Uterus and fallopian tubes present (Müllerian structures intact)
• Primary amenorrhea at puberty, sexual infantilism
• Short stature possible
• Streak gonads (bilateral, risk of malignancy)

• Karyotype: 46,XY
• Serum testosterone: very low
• LH, FSH: markedly elevated (hypergonadotropic hypogonadism)
• AMH: undetectable
• Pelvic ultrasound/MRI: streak gonads, uterus present
• SRY and other gene mutation analysis

• Prophylactic bilateral gonadectomy as soon as diagnosed (high malignancy risk)
• Estrogen replacement at puberty (for feminization, bone density, cardiovascular health)
• Cyclic progesterone after estrogen to induce withdrawal bleeding if desired
• Fertility: possible via donor egg + own uterus (IVF/embryo transfer)

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6.5 XY Partial (Mixed) Gonadal Dysgenesis

• Highly variable phenotype (female, male, or ambiguous)
• Typically: one streak gonad + one dysgenetic testis
• Asymmetric genital development
• Short stature, possible Turner-like stigmata
• Risk of gonadoblastoma (intermediate, ~15%)

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6.6 Persistent Müllerian Duct Syndrome (PMDS)

• Mutations in AMH gene (chromosome 19p13) or AMH receptor (AMHR2) gene
• Testosterone synthesis and action are normal → male external genitalia
• AMH absent or non-functional → Müllerian structures fail to regress

• Normal male external genitalia
• Cryptorchidism (testes drawn into hernia sac or pelvis by Müllerian remnants)
• Discovered incidentally during hernia repair or orchiopexy when uterus/tubes are found
• Fertility may be impaired due to cryptorchidism and associated traction on vas deferens

• AMH level: very low or undetectable (AMH gene mutation)
• AMH receptor gene mutation analysis
• Imaging: uterus/tubes on MRI

• Orchiopexy (preserving vas deferens, which may be adherent to Müllerian structures)
• Müllerian remnant removal where technically feasible without vas injury

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7. SEX CHROMOSOME DSD

7.1 Turner Syndrome (45,X)

• Absence of second sex chromosome → bilateral streak gonads (no follicles; cortical stroma only)
• Streak gonads produce no estrogen or AMH → Müllerian structures present (uterus present but infantile), no feminization at puberty
• Haploinsufficiency of genes on X (particularly SHOX) → short stature, skeletal anomalies

• Short stature (most consistent feature; average adult height ~147 cm)
• Webbed neck (pterygium colli)
• Low posterior hairline
• Shield chest, wide-spaced nipples
• Lymphedema (hands and feet) at birth
• Cubitus valgus (wide carrying angle)
• Short 4th metacarpals
• Coarctation of the aorta (15-20%), bicuspid aortic valve (30%)
• Gonadal dysgenesis → primary amenorrhea, sexual infantilism, infertility
• Renal anomalies (horseshoe kidney, duplicated collecting system)
• Hypothyroidism (30%), autoimmune
• Cognitive: generally normal IQ but impaired spatial reasoning

• Karyotype (peripheral blood, 25-30 cells)
• Pelvic ultrasound: streak gonads, infantile uterus
• LH, FSH: markedly elevated
• Estradiol: very low
• Echocardiogram (cardiac anomalies)
• Renal ultrasound
• Thyroid function tests
• Audiometry (sensorineural hearing loss)
• Bone age X-ray

• Growth hormone therapy: Started as early as possible (FDA approved); significantly improves final height (gains of 5-10 cm)
• Estrogen replacement: low-dose estrogen started at ~11-12 years (before expected puberty) to induce feminization; progesterone added after 1-2 years for cyclic withdrawal bleeding
• Cardiac surveillance: MRI aorta every 5-10 years (risk of aortic dissection)
• Fertility: very rarely spontaneous pregnancy in mosaic forms; egg donation/IVF for most; careful cardiac evaluation before pregnancy (aortic dissection risk)
• Hormone replacement maintained through menopause age

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7.2 Klinefelter Syndrome (47,XXY)

• Additional X chromosome → progressive hyalinization and fibrosis of seminiferous tubules post-puberty → azoospermia
• Leydig cell dysfunction → testosterone deficiency (variable; many have low-normal T)
• Elevated LH, FSH (primary hypogonadism)

• Tall stature (long legs), eunuchoid habitus
• Small, firm testes (< 4 mL in adults; fibrosis)
• Azoospermia - infertility in virtually all
• Gynecomastia (due to ↑ E2:T ratio)
• Reduced facial and body hair
• Sparse pubic hair
• Often normal or near-normal male phenotype (many undiagnosed)
• Learning disabilities (reading/language difficulties)
• Increased risk of breast cancer, autoimmune disease, osteoporosis

• Karyotype: 47,XXY
• Testosterone: low to low-normal
• LH, FSH: markedly elevated
• Estradiol: elevated
• Semen analysis: azoospermia
• Testicular biopsy: hyalinized tubules, absence of spermatogenesis in most areas

• Testosterone replacement therapy: IM testosterone enanthate/cypionate 200 mg every 2-3 weeks, or transdermal formulations; normalize libido, energy, bone density, reduce gynecomastia
• Fertility: Microdissection testicular sperm extraction (microTESE) can retrieve sperm in 30-70% of cases for use with ICSI; best outcomes before age 35
• Gynecomastia: subcutaneous mastectomy if significant
• Psychological support; occupational therapy for learning disabilities

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8. MANAGEMENT PRINCIPLES FOR DSD - MULTIDISCIPLINARY APPROACH

• Pediatric endocrinologist
• Pediatric urologist / pediatric surgeon
• Clinical psychologist / psychiatrist
• Geneticist
• Radiologist
• Neonatologist
• Social worker
• Ethicist (where needed)
• Adult endocrinologist (for transition)

Key Ethical and Management Principles (Post-2006 Consensus):

1. Avoid irreversible surgical procedures in infancy/childhood unless medically necessary - allow the individual to participate in gender decision
2. Openness and full disclosure to the family (and eventually to the patient) about the diagnosis - the older practice of withholding the karyotype is no longer acceptable
3. Gender assignment should be based on: karyotype, gonadal histology, degree of virilization, potential for adult sexual function, fertility potential, risk of malignancy, and family preference
4. Gonadectomy timing: when indicated, balance malignancy risk vs. endocrine function preservation
5. Psychosocial support: ongoing, from diagnosis through adulthood; address gender identity, sexual function, and disclosure
6. Fertility counseling: early discussion even if fertility is not immediately possible
7. Long-term follow-up: transition from pediatric to adult care is critical

Malignancy Risk Summary by Condition:

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9. SUMMARY TABLE: KEY DISTINGUISHING FEATURES

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• Smith & Tanagho's General Urology, 19th Edition - Chapter 43: Disorders of Sex Development
• Campbell-Walsh-Wein Urology - Chapter on Intersex/DSD and Chapter on CAH
• Harrison's Principles of Internal Medicine 22E (2025) - Chapters on Gonadal Disorders and Androgen Insensitivity
• Creasy & Resnik's Maternal-Fetal Medicine - Revised Classification for DSD