Differences (disorders) of sex development

Differences (disorders) of sex development (DSDs; formerly known as “intersex conditions”) are a group of congenital conditions characterized by the atypical development of chromosomal, gonadal, and/or phenotypic sex. The underlying genetic mutations can affect the number and function of sex chromosomes (e.g., in Turner syndrome), cause structural changes that influence the sensitivity of hormone receptors (e.g., androgen insensitivity syndrome), and alter the function of enzymes responsible for sex hormone synthesis (e.g., congenital adrenal hyperplasia). Features vary depending on the specific disorder but may include the mismatch between sexual genotype and phenotype, reduced fertility or infertility, and organ malformations (e.g., cardiac abnormalities). The discrepancy between sexual phenotype and genotype can cause difficulties in gender identification with considerable subsequent psychological distress. The diagnosis of DSDs is based on clinical features, evaluation of hormone levels, and genetic testing. Differential diagnosis should take into account other anomalies of the male and female genital tracts (see the articles on “Anomalies of the female genital tract” and “Infertility”). Treatment should be provided based on patient preference and sexual identification as well as clinical necessity backed by strong ethical principles. If treatment is necessary and/or desired, it generally follows a multidisciplinary approach involving hormone substitution and psychological counseling. Gender affirmation surgery should only be performed if the patient expressly requests the procedure and can provide informed consent.

Differences (disorders) of sex development ^[1]

Definitions

• Differences (disorders) of sex development (DSDs): a group of congenital conditions characterized by the atypical development of chromosomal, gonadal, and/or phenotypic sex
• Historical terms
  • Intersex
    • A historical term replaced now by the widely accepted terms “disorders of sex development” proposed in the 2006 Chicago consensus statement or the more recently introduced variation “differences of sex development” ^[2]
    • This notwithstanding, the term “intersex” may be an accurate sex assignment designator for certain individuals with a DSD who do not identify as binary male or female.
  • True hermaphroditism: presence of both male and female reproductive tissue and/or organs
  • Pseudohermaphroditism: mismatch between gonads and secondary sexual characteristics
    • Male pseudohermaphroditism: male gonads, female secondary sexual characteristics
    • Female pseudohermaphroditism: female gonads, male secondary sexual characteristics

Classification ^[2][3]

• 46,XY DSD
  • Androgen insensitivity syndrome (most common cause)
  • 5-alpha reductase deficiency
  • 17β-hydroxysteroid dehydrogenase 3 deficiency
  • Kallmann syndrome
  • Persistent Mullerian duct syndrome
  • 46,XY complete gonadal dysgenesis (Swyer syndrome)
• 46,XX DSD
  • Congenital adrenal hyperplasia (most common cause)
  • Exposure to exogenous androgens during pregnancy
  • Ovotesticular disorder of sex development
  • Aromatase deficiency
  • 46,XX gonadal dysgenesis
  • 46,XX testicular DSD
• Sex chromosome DSD
  • Turner syndrome (45,XO)
  • Klinefelter syndrome (47,XXY)
  • Double Y syndrome (47,XYY)

Treatment

• The clinical management of DSDs involves a multidisciplinary approach guided by clinical necessity, patient choice, and strong ethical principles.
• Physicians should consider the following when determining the best treatment options for patients with DSDs:
  • Ethical and human rights aspects of sex assignment and reassignment surgery
  • Patient gender identity independent of chromosomal or phenotypical sex
  • Psychological distress resulting from stigmatization, discrimination, and difficulties developing gender identity (e.g., gender dysphoria)
  • Patient choice
  • Clinical necessity
• Types of treatment
  • Hormone substitution
  • Psychological support
  • Surgery
    • Gonadectomy
    • Gender affirmation surgery

Chromosomal abnormalities

Genetic disorders

Congenital malformations of the reproductive system

• Prevalence: 2–5:100,000 genetically male population in the US ^[4]
• Etiology: : X-linked recessive mutation of the gene encoding the androgen receptor (AR gene)
• Karyotype: : 46,XY
• Pathophysiology: Defects in the androgen receptor result in varying degrees of end-organ insensitivity to androgens.
• Clinical features
  • Complete androgen insensitivity
    • Female external genitalia and physique
      • Due to increased aromatization of androgens to estrogens
      • Includes testicular feminization and female breast development
    • Blind-ended vaginal pouch, uterine and fallopian tube agenesis (due to testicular anti-Mullerian hormone secretion)
    • Absent male internal genitalia (with the exception of the testes)
    • Cryptorchid testes: intralabial, inguinal, or abdominal localization of undescended testicles
    • Scant or no pubic hair
    • Primary amenorrhea, infertility (no menarche)
  • Partial androgen insensitivity: various phenotypical configurations possible, depending on the degree of androgen insensitivity
• Diagnostics
  • Clinical presentation
  • Before puberty: ↑ testosterone
  • After puberty: ↑ LH, ↑ estrogen, and normal/↑ testosterone levels (no virilization)
  • Genetic testing
• Treatment: depends on receptor status as well as on the phenotype and gender identity
  • Hormone treatment
    • Complete androgen insensitivity: estrogen replacement
    • Partial androgen insensitivity: high-dose androgen therapy in patients with male gender identity
  • Gonadectomy: for intraabdominal/intralabial testicles
    • Typically performed after puberty
    • Prevents malignant transformation of the abnormally localized gonads
  • Psychological support

• Prevalence: rare ^[5]
• Etiology: autosomal recessive mutations in the CYP19A1 gene that encodes the enzyme aromatase ^[6]
• Karyotype: 46,XX or 46,XY (normal sexual development in males)
• Pathophysiology: defective/absent aromatase → ↓ conversion of testosterone to estrogen → ↓ serum estrogen and ↑ serum testosterone
• Clinical features
  • 46,XX individuals
    • At birth
      • Ambiguous external genitalia
      • Normal internal genital organs
    • Puberty
      • Impaired maturation of secondary sexual characteristics (e.g., breast growth)
      • Primary amenorrhea
      • Virilization (features include hirsutism, severe acne)
  • 46,XY individuals
    • Abnormal sperm production
    • Small or undescended testes
    • Decreased sex drive
  • Both 46,XX and 46,XY individuals
    • Tall stature (due to excessive bone growth with slowed mineralization)
    • Osteoporosis (may result in fractures following minimal trauma)
    • Hyperglycemia (due to impaired tissue response to insulin)
    • Weight gain and fatty liver
• Diagnostics
  • Before birth: maternal virilization during pregnancy (due to fetal androgens crossing the placenta and entering maternal circulation)
  • After birth
    • Clinical presentation of the newborn
    • Hormone levels: ↑ testosterone, ↑ androstenedione, ↓ estrogen
    • Karyotyping: normal 46,XX or 46,XY karyotype
• Treatment
  • Estrogen and progesterone replacement therapy
  • Calcium and vitamin D supplementation
  • Surgical correction of ambiguous genitalia (depending on the patient's gender identity and preference)

• Prevalence: rare disease (exact incidence unknown) ^[7]
• Etiology: rare autosomal recessive loss-of-function mutation of the SRD5A2 gene on chromosome 2
• Karyotype: : 46,XY
• Pathophysiology: defective 5-alpha-reductase → ↓ conversion of testosterone to dihydrotestosterone (DHT) → ↓ DHT-dependent masculinization of external genitalia and the prostate (despite normal testosterone production)
• Clinical features ^[8]
  • Female external genitalia at birth
  • Possibly pseudovaginal perineoscrotal hypospadias (PPSH): a symptom constellation of hypospadias, a micropenis that resembles a clitoris, and an incompletely closed urogenital opening that resembles a vagina
  • Male internal genital organs
  • Development of the secondary sexual male characteristics (phallic growth, testicular descent) in puberty due to high testosterone levels
• Diagnosis
  • Clinical presentation
  • Hormone levels
    • Normal/↑ testosterone, ↓ DHT (testosterone:DHT ratio > 20)
    • Normal estrogen
    • Normal or ↑ LH
  • Genetic testing: confirms the diagnosis
• Treatment
  • Female gender identity: gonadectomy and estrogen substitution therapy upon completion of longitudinal growth
  • Male gender identity: testosterone substitution
  • Surgical correction of hypospadias and cryptorchidism

• Prevalence
  • Approx. 1:650 population in the US ^[9]
  • One of the most common causes of male hypogonadism
• Etiology
  • Usually due to nondisjunction of sex chromosomes during meiosis
  • Associated with advanced maternal age
• Karyotype
  • 47,XXY (rarely 48,XXXY or 48,XXYY)
  • Presence of a Barr body (inactivated X chromosome)
• Pathophysiology
  • Testicular dysgenesis leads to:
    • Seminiferous tubules dysgenesis → loss of Sertoli cells → ↓ inhibin B → ↑ FSH
    • Leydig cell dysfunction → ↓ testosterone → ↑ LH
  • Both ↑ LH and ↑ FSH lead to increased conversion of testosterone to estrogen.
• Clinical features: Testicular dysgenesis and subsequent testosterone deficiency manifest at the onset of puberty (symptoms are rare during childhood).
  • Signs and symptoms of hypoandrogenism
    • Eunuchoid growth pattern: tall, slim stature with long extremities (Growth plate closure is delayed; )
    • Gynecomastia
    • Reduced facial and body hair
    • Testicular atrophy ^[10]
    • Reduced fertility and libido
    • Frequent azoospermia
    • Micropenis
    • Osteoporosis (common feature in adulthood)
  • Possible developmental delay
    • Neurocognitive dysfunction (impaired executive function and memory, decreased intelligence)
    • Language impairment (affects expression more than comprehension)
    • Poor social skills
  • Associated disorders
    • Mitral valve prolapse
    • Increased risk of breast and testicular cancer
    • Metabolic syndrome
• Diagnostics
  • Clinical presentation
  • Hormone levels
    • ↑ FSH and LH
    • ↓ Testosterone with ↑ aromatase and ↑ estrogen levels
  • Testicular biopsy (performed after puberty)
    • Seminiferous tubules fibrosis
    • Leydig cells hyperplasia
  • Karyotyping: confirmatory test
• Treatment: life-long testosterone substitution

• Prevalence: approx. 1:1,000 male newborns in the US ^[11]
• Etiology: paternal meiotic nondisjunction
• Karyotype: 47,XYY or 46,XY/47,XYY mosaicism
• Clinical features ^[12]
  • Male phenotype (patients often remain undiagnosed)
  • Tall stature
  • May manifest with severe acne
  • Normal fertility and pubertal development
  • Mild delays in motor and language development ^[11]
  • Higher rates of ADHD, autism spectrum disorder, and learning disabilities
• Diagnostics
  • Clinical presentation
  • Karyotyping (confirmatory tests)
• Treatment
  • Not recommended in asymptomatic patients
  • Neurodevelopmental evaluation and treatment for ADHD or autism may be indicated.

Contrary to what is frequently still stated in the literature, there is no evidence that individuals with double Y syndrome have higher levels of aggression compared to karyotypically normal male individuals with comparable levels of intelligence.

• Prevalence: less than 1:20,000 population in the US ^[13]
• Etiology: SRY gene translocation from the Y to the X chromosome (rarely to other chromosomes)
• Karyotype: : typically normal (46,XX is more common than 46,XY)
• Pathophysiology: SRY gene translocation results in simultaneous development of male and female gonads (ovotestis).
• Clinical features ^[13]
  • 46,XX individuals
    • At birth
      • Labial fusion
      • Urogenital sinus
      • Polycystic ovaries
    • Puberty/adulthood: primary amenorrhea, if the uterus does not form
  • 46,XY individuals
    • At birth
      • Hypospadias
      • Cryptorchidism
    • Puberty/adulthood
      • Gynecomastia
      • Recurrent groin or scrotal pain
      • Testicular enlargement
  • Both female and male individuals
    • Ambiguous genitalia (ovotestis)
      • Can be bilateral (more common) or unilateral
      • Descent depends on amount of testicular tissue present in ovotestis.
      • Can be intraabdominal (most commonly), inguinal, or labioscrotal
      • In some cases, a single testis and contralateral ovary may be present.
    • Infertility
• Diagnostics
  • Clinical presentation
  • Chromosomal and genetic testing
  • Biopsy of the gonads shows both testicular and ovarian tissue
• Treatment: surgical removal of male or female genital structures for normal sexual development according to gender identity and preference ^[14]

• Description
  • A group of DSDs characterized by gonadal underdevelopment during embryogenesis (see “Classification” below).
  • Results in different degrees of hypogonadism and sex development
  • Typically results in the development of malfunctioning gonads (streak gonads) with fibrous tissue instead of normal germ cells, increasing the risk of malignancy (e.g., dysgerminoma, seminoma)
• Classification
  • Turner syndrome (45,XO)
  • Pure gonadal dysgenesis (or complete gonadal dysgenesis)
    • 46,XY gonadal dysgenesis (Swyer syndrome)
    • 46,XX gonadal dysgenesis
• General clinical features
  • Delayed puberty
  • Infertility
  • Streak gonads
  • High risk for malignancies (e.g., dysgerminoma, seminoma)
• Diagnosis
  • Clinical presentation
  • Genetic analysis
  • Karyotyping
  • Laboratory findings of hypergonadotropic hypogonadism
  • Imaging tests (to assess for streak gonads)
• Treatment
  • Lifelong estrogen and progesterone substitution
  • Surgical removal of streak gonads

• Prevalence
  • Approx. 1:2,500 genetically female population in the US ^[15]
  • Most common cause of ovarian dysgenesis and primary ovarian insufficiency
• Etiology: chromosomal nondisjunction during meiosis or mitosis
• Karyotype
  • Meiotic nondisjunction (most often in paternal gametes) → complete sex chromosomal monosomy (45,XO; no Barr body)
  • Mitotic nondisjunction of an embryonic cell → sex chromosomal mosaicism (45,XO/46,XX) → mild phenotypic expression
• Pathophysiology: chromosomal nondisjunction → X chromosome monosomy/mosaicism → impaired ovarian development → malfunctioning streak gonads with connective tissue instead of normal germ cells → estrogen and progesterone deficiencies
• Clinical features
  • Sex development
    • Female phenotype
    • Primary ovarian insufficiency with:
      • Delayed puberty
      • Primary amenorrhea
      • Infertility: Pregnancy is still possible via IVF using donor oocytes and exogenous estradiol 17β and progesterone (similar rates of success to those in the general population). ^[16]
  • Lymphatic system abnormalities
    • Cystic hygroma
    • Lymphedema of the hands and feet in the neonatal period
  • Musculoskeletal findings
    • Short stature: due to the presence of only one copy of the SHOX (short stature homeobox) gene, normally located on the X chromosome
    • Shield chest: broad chest with widely spaced nipples
    • Webbed neck: skin folds along the side of the neck between the mastoid process and the acromion
    • Cubitus valgus
    • Short fourth metacarpals/metatarsals, nail dysplasia
    • High arched palate
    • Low-set posterior hairline
    • Osteoporosis and pathologic fractures
  • Cardiovascular abnormalities
    • Bicuspid aortic valve: increased risk of premature aortic stenosis and/or insufficiency
    • Coarctation of the aorta with brachial-femoral delay
    • Aortic dissection and rupture
    • Hypertension (even in children) ^[17]
  • Other disorders ^[18]
    • Gonadoblastoma (especially in patients with 45,XO/46,XY mosaicism)
    • Malformations of the kidney and ureters (especially horseshoe kidney)
    • Hashimoto thyroiditis
    • Type 2 diabetes mellitus
• Diagnostics
  • Clinical presentation
  • Hypergonadotropic hypogonadism: ↓ estrogen, ↓ androgens, ↑ FSH, ↑ LH
  • Karyotyping: confirmatory test
• Treatment
  • Estrogen and progestogen substitution
  • Growth hormone (GH) therapy
  • Surgical removal of streak gonads

Unlike Klinefelter syndrome, Turner syndrome is not associated with advanced maternal age.

Most patients with Turner syndrome have normal intelligence. ^[19]

Evaluate for X-linked recessive conditions in patients with Turner syndrome, as this group lacks a second X chromosome.

• Prevalence: approx. 1:20,000 population in the US ^[20]
• Etiology: mutations of genes involved in male sex development after the 8^th embryonic week
  • Mutation of SRY gene on chromosome Y in approx. 20% of affected individuals
  • Other potentially involved genes: MAP3K1, NR5A1, and DHH genes
• Karyotype: 46,XY
• Pathophysiology ^[21]
  • Impaired testicular development and the subsequent underproduction of testosterone and anti-Mullerian hormone, which results in:
    • Persistence of Mullerian ducts → development of female genitalia (except ovaries) despite the presence of Y chromosome
    • Underdevelopment of Wolffian ducts → absence of male genitalia
  • Development of streak gonads → ↓ estrogen and progesterone → ↓ negative feedback → ↑ FSH and LH → delayed puberty and infertility
• Clinical features ^[22]
  • Typically female phenotype
  • Childhood: normal female development without evidence of a chromosomal aberration
  • Puberty: estrogen deficiency due to the absence of functional ovaries ^[23]
    • Primary amenorrhea
    • Infertility
    • Small uterus
    • Enlarged clitoris
    • Absence of breast enlargement
• Diagnostics: See “Diagnosis” in “Gonadal dysgenesis” section above.
• Treatment: See “Treatment” in “Gonadal dysgenesis” section above. ^[24]

• Prevalence: less than 1:10,000 population worldwide ^[25]
• Etiology: Underlying etiology is unknown, but several gene mutations (esp. of the BMP15 and NR5A1 genes), have been implicated.
• Karyotype: 46,XX
• Pathophysiology
  • Gene mutations → impaired ovarian development during embryogenesis → premature depletion of ovarian follicles with the development of streak ovaries
  • Impaired estrogen secretion results in the underdevelopment of secondary sexual characteristics
• Clinical features ^[26]
  • Female phenotype
  • Childhood: normal development of female genitals (uterus and vagina)
  • Puberty
    • Impaired maturation of secondary sexual characteristics
    • Primary (rarely secondary) amenorrhea
    • Infertility
    • Streak gonads
• Diagnostics: See “Diagnosis” in “Gonadal dysgenesis” section above.
• Treatment: See “Treatment” in “Gonadal dysgenesis” section above.

• Prevalence: approx. 1:20,000 male individuals in the US ^[27]
• Etiology: translocation of the SRY gene onto an X chromosome
• Karyotype: 46,XX
• Clinical features ^[27]
  • Male phenotype
  • Small or undescended testes
  • Absent Mullerian duct structures
  • Gynecomastia
  • Infertility (due to azoospermia)
  • Erectile dysfunction
  • Short stature
• Diagnostics ^[28]
  • Clinical findings
  • Hormone levels: hypergonadotropic hypogonadism
  • FISH or PCR: SRY gene translocation
• Treatment: testosterone replacement therapy to induce the development of male secondary sex characteristics and prevent the development of gynecomastia

• Prevalence: 3:100,000 male and 0.8:100,000 female population in the US ^[29]
• Karyotype: 46,XY or 46,XX
• Etiology: : associated with more than 20 different gene mutations that result in the development of hypogonadotropic hypogonadism with hyposmia/anosmia
• Pathophysiology ^[30]
  • Defective migration of GnRH-releasing neurons from the olfactory bulbs to the hypothalamic preoptic nuclei → ↓ GnRH secretion and underdevelopment of the olfactory bulbs
  • ↓ GnRH → ↓ pituitary secretion of FSH and LH → ↓ testosterone in male individuals and ↓ estrogen in female individuals
• Clinical features: Phenotype according to karyotype ^[30]
  • Anosmia or hyposmia
  • Infertility
    • Male individuals: cryptorchidism and low sperm count
    • Female individuals: primary amenorrhea
  • Absent or attenuated pubertal changes
    • Decreased growth spurt
    • Male individuals: reduced or no facial and body hair, lack of voice changes, no muscle bulk
    • Female individuals: reduced or no axillary hair, absent thelarche
  • Osteoporosis
  • In rare cases: neurological manifestations (e.g., ataxia, focal dystonia, bimanual synkinesia) ^[31]
  • Associated disorders
    • Renal agenesis
    • Cleft lip/cleft palate
    • Dental agenesis
    • Cleft hand or foot
    • Syndactyly
    • Hearing loss
• Diagnostics
  • Clinical presentation
  • Hormone levels: ↓ levels of GnRH, FSH, LH, estrogen/testosterone (otherwise normal pituitary function)
• Treatment ^[32]
  • Hormone replacement therapy is given in puberty to stimulate the development of secondary sexual characteristics.
    • In male individuals: testosterone
    • In female individuals: estrogen and progesterone combination therapy
  • Gonadotropins or pulsatile GnRH therapy can be used to increase fertility.
    • In male individuals: stimulates testicular growth and sperm production
    • In female individuals: stimulates ovulation

• Prevalence: rare disease; exact prevalence unknown
• Etiology: insufficient anti-Mullerian hormone (AMH) or insensitivity to AMH due to AMH gene or AMHR2 gene mutation
• Karyotype: 46,XY
• Pathophysiology: AMH deficiency/insensitivity → persistence of the Mullerian duct → development of uterus, cervix, fallopian tubes, and upper two thirds of the vagina in 46,XY individuals ^[33]
• Clinical features ^[34]
  • Normal male external genitalia and secondary sexual characteristics
  • Female internal genitalia
  • Increased risk of cryptorchidism and inguinal herniation in infancy
  • Hematospermia and hematuria
  • Infertility
• Diagnostics
  • Often discovered incidentally during orchidopexy
  • ELISA: decreased levels of AMH
• Treatment ^[35]
  • Orchidopexy/herniotomy
  • Surgical removal of remnants of the Mullerian duct

• Prevalence: approx. 1:147,000 individuals ^[37]
• Etiology: autosomal recessive mutation of the HSD17B3 gene, which encodes for the enzyme 17β-hydroxysteroid dehydrogenase 3
• Karyotype: 46,XY
• Pathophysiology: ↓ 17β-hydroxysteroid dehydrogenase 3 → ↓ conversion of androstenedione to testosterone → ↓ testosterone levels → signs and symptoms of hypoandrogenism
• Clinical features
  • Before puberty
    • Male internal genitalia (testes)
    • Ambiguous or undervirilized external genitalia
      • Female type: blind-ending vaginal pouch with clitoromegaly and/or labial fusion
      • Male type: micropenis with hypospadias
  • After puberty
    • Development of male secondary sex characteristics (e.g., male hair distribution, voice deepening)
    • Gynecomastia
    • Infertility
• Diagnostics ^[36]
  • Clinical presentation
  • Positive hCG stimulation test: ↑ androstenedione levels and ↓ testosterone:androstenedione ratio after hCG administration
• Treatment: surgical correction of ambiguous genitalia and/or gonadectomy (based on the patient's gender identity and preference)