Disorders of sex development

Disorders of sex development are a group of congenital conditions that affect the development of the chromosomal, gonadal, or phenotypic sex. The underlying genetic mutations affect the number and function of sex chromosomes (e.g., in Turner syndrome), lead to structural changes with altered sensitivity of hormone receptors (e.g., androgen insensitivity syndrome), or alter the function of enzymes responsible for sex hormone synthesis (e.g., congenital adrenal hyperplasia). The most characteristic clinical feature is the development of a sexual phenotype which does not correspond to the sexual genotype. Other common features include reduced fertility or infertility and concomitant organ malformations (e.g., cardiac abnormalities). Disorders of sex development can also present with difficulties in gender identification and cause considerable psychological distress. The diagnosis of these conditions is based on characteristic clinical features, evaluation of hormone levels, and genetic testing. Management includes hormone substitution, possibly sex reassignment surgery, and psychological counseling.

• See congenital adrenal hyperplasia

• Incidence:approx. 1:20,000 genetically male individuals in the US ^[1]
• Etiology: X-linked recessive mutation of the gene encoding the androgen receptor
• 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
      • Attributed to increased aromatization of androgens to estrogens
      • Includes testicular feminization and female breast development
    • Blind-ended vaginal pouch, uterine agenesis (due to anti-Mullerian hormone secretion)
    • Absent male internal genitalia (with the exception of the testes)
    • Cryptorchid testes: intra-labial, inguinal or abdominal localization of undescended testicles
    • Scant or no pubic hair
    • Primary amenorrhea, infertility (no menarche)
  • Partial androgen insensitivity: various phenotypes, depending on the degree of androgen insensitivity
• Diagnosis
  • 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 patient's phenotype and gender identity
  • Hormone treatment
    • Complete androgen insensitivity: estrogen replacement
    • Partial androgen insensitivity: high-dose androgen therapy can be used in patients with male gender identity
  • Gonadectomy for intra-abdominal/intra-labial testicles
    • Typically performed after puberty
    • Prevents malignant transformation of the abnormally localized gonads
  • Psychological support

References:^[2]

• Karyotype: 46 XX or 46 XY (normal sex development)
• Pathophysiology: : Mutations in the CYP19A1 gene which encodes for the enzyme aromatase → ↓ serum estrogen and ↑ serum testosterone
• Clinical features
  • Females (46 XX)
    • Birth: Ambiguous genitalia despite normal internal genital organs
    • Puberty
      • Impaired maturation of secondary sexual characteristics
      • Primary amenorrhea
      • Virilization (e.g., hirsutism, severe acne)
  • Both males and females
    • Childhood
      • Tall stature
      • Osteoporosis (e.g., fractures following minimal trauma)
  • Mothers of affected children may experience virilization during pregnancy (may start at 12 weeks' gestation and typically disappear after delivery)
• Treatment
  • Estrogen and progesterone replacement therapy
  • Calcium and vitamin D supplementation
  • Surgical correction of ambiguous genitalia

References:^[3][4]

• Synonym: pseudovaginal perineoscrotal hypospadias (PPSH)
• Etiology: : rare autosomal recessive loss-of-function mutation of chromosome 2
• Karyotype: 46,XY
• Pathophysiology
  • Normal testosterone production
  • Defective 5-alpha-reductase: testosterone not converted into dihydrotestosterone (DHT) → DHT-dependent virilization of genitalia does not occur
• Clinical features
  • Female external genitalia at birth, sometimes with pseudovaginal perineoscrotal hypospadias
  • Internal urogenital organs are male
  • In puberty, increasing synthesis of testosterone leads to virilization (phallic growth, testicular descent, development of male gender identity).
• Diagnostics
  • Hormone levels: n/↑ testosterone, ↓ DHT (elevated testosterone-to-DHT ratio)
  • Genetic testing for definitive diagnosis
• Therapy
  • Female gender identity: gonadectomy; estrogen substitution therapy upon completion of longitudinal growth
  • Male gender identity: testosterone substitution

References:^[5][6]

• Karyotype: 47 XXY, rarely 48 XXXY and 48 XXYY
• Incidence: approximately 1:600 children ^[7][8]
• Etiology: most commonly due to nondisjunction of sex chromosomes during meiosis of parental germ cells
• Clinical features
  • Male phenotype; symptoms rarely observed during childhood
  • Testicular dysgenesis and subsequent testosterone deficiency become apparent at the onset of puberty.
    • Eunuchoid growth pattern; : tall, slim stature with long extremities ^[7]
    • Gynecomastia, reduced body hair
    • Testicular hypoplasia with a normal sized penis
    • Reduced fertility, frequent azoospermia
    • Osteoporosis frequently observed in adulthood
  • Associations:
    • Mitral valve prolapse
• Diagnostics: : primarily a clinical diagnosis; karyotyping confirms the diagnosis
• Complications: Increased risk of breast cancer development due to decreased levels of testosterone and increased levels of estrogen.
  • Testicular hypoplasia → ↓ testosterone → loss of negative feedback on gonadotropins → ↑ FSH → ↑ aromatase activity → ↑ testosterone to estradiol conversion
• Therapy: life-long testosterone substitution ^[7]

References:^[7][8][9]

• Karyotype
  • Typically normal (46 XX > 46 XY)
• Incidence: rare
• Pathophysiology
  • Both ovarian and testicular tissue are present (true hermaphroditism)
    • Bilateral (50%) or unilateral (20%) ovotestes
      • The descent and position of the ovotestes depends on the amount of testicular tissue present in the ovotestes
        • 50% are found intra-abdominally
        • 25% in the inguinal region
        • 25% in the labio-scrotal region
    • Unilateral testes and contralateral ovary (30%)
  • The type of internal genitalia depends on the nature of the adjacent gonad
    • Fallopian tube develops beside the ovary and vas deferens with an epididymis develops beside the testicle
    • In the case of ovotestes, fallopian tubes develop in 60–70% of cases
    • A uterus can develop in the case of a unilateral ovotestis with a contralateral ovary
• Clinical features
  • At birth: most patients have ambiguous genitalia
    • Male karyotype
      • Hypospadias
      • Cryptorchidism
    • Female karyotype
      • Labial fusion
      • Urogenital sinus
  • Puberty and adulthood
    • Male karyotype
      • Gynecomastia
      • Recurrent groin or scrotal pain
      • Testicular enlargement
      • Infertility
    • Female karyotype
      • Primary amenorrhea if the uterus does not form
      • Infertility

• Karyotype
  • Nondisjunction during meiosis → complete sex chromosomal monosomy → 45 XO, no Barr body
  • Nondisjunction during mitosis of an embryonic cell → sex chromosomal mosaicism (45,XO/46,XX); Barr body may be present in cells with 46,XX karyotype → mild phenotype
• Incidence: 1:2000 children
• Clinical features
  • Female phenotype
  • Lymphedema in the neonatal period affecting the hands and feet (due to abnormal development of the lymphatic system)
  • Short stature, shield chest, widely spaced nipples, cubitus valgus; , nail dysplasia, short fourth metacarpals/metatarsals
  • High arched palate, low-set posterior hairline
  • Webbed neck: skin folds along the side of the neck between the mastoid process and the acromion
  • Hypertension (even in children)
  • Gonadal dysgenesis with streak gonads : insufficient hormone production → estrogen and progestogen deficiency
    • Delayed puberty
    • Primary amenorrhea
    • Infertility: Pregnancy is still possible through IVF using donor oocytes, with similar rates of success to that of the general population
  • Associations:
    • Cardiovascular abnormalities
      • Bicuspid aortic valve
        • Increased risk of premature aortic stenosis and/or insufficiency
      • Coarctation of the aorta
      • Aortic dissection and rupture
    • Kidney and ureter malformations; (especially horseshoe kidney; possibly agenesis, rotational anomalies, obstructions)
    • Osteoporosis and pathologic fractures
• Diagnostics:
  • Hypergonadotropic hypogonadism → ↓ estrogen, ↓ androgens, ↑ follicle stimulating hormone, ↑ luteinizing hormone
  • Karyotyping confirms the diagnosis
• Therapy: estrogen and progestogen substitution
• Prognosis: life expectancy is significantly reduced (> 10 years)

References:^{[7][10][11][12][13][14][15]}

• Karyotype: 46 XY
• Pathophysiology: normal development until the 8^th embryonic week → SRY gene mutation → gonads do not develop into testes → no production of testosterone and anti-Müllerian hormone (AMH) → male genital organs do not develop → uterus and vagina develop despite the presence of XY chromosomes
• Clinical features
  • Female phenotype
  • Childhood: normal female development without evidence of a chromosomal aberration
  • Puberty: estrogen deficiency due to the absence of functional ovaries (streak gonads)
    • Primary amenorrhea
    • Infertility
• Therapy
  • Lifelong estrogen and progestogen substitution
  • Removal of streak gonads

References:^[16][17][18]

• Karyotype: 46 XX
• Pathophysiology: Various mutations lead to impaired ovarian development or premature depletion of ovarian follicles → impaired estrogen secretion → secondary sexual characteristics do not develop
• Clinical features
  • Female phenotype
  • Childhood: normal development of female genital organs (uterus and vagina)
  • Puberty:
    • Impaired maturation of secondary sexual characteristics
    • Primary (rarely secondary) amenorrhea
    • Infertility
• Treatment: lifelong estrogen and progestogen substitution

References:^[19]

• Definition: a form of hypogonadotropic hypogonadism, associated with hyposmia/anosmia
• Incidence: most common in male individuals (♂:♀ = 4:1) ^[20]
• Karyotype: 46,XY or 46,XX
• Etiology: associated with more than 20 different gene mutations
• Pathophysiology ^[21]
  • 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 ^[21]
  • Anosmia or hyposmia
  • Infertility
    • In male individuals: cryptorchidism and low sperm count
    • In female individuals: primary amenorrhea
  • Absent or attenuated pubertal changes (e.g., absent thelarche in female individuals, decreased growth spurt)
  • Associated disorders
    • Renal agenesis
    • Cleft lip/palate
• Diagnosis
  • Clinical presentation
  • Hormone levels: low levels of GnRH, FSH, LH, estrogen/testosterone (otherwise normal pituitary function)
• Treatment ^[22]
  • Hormone replacement therapy is given in puberty to stimulate the development of secondary sexual characteristics.
    • For men: testosterone
    • For women: estrogen and progesterone combination therapy
  • Gonadotropins or pulsatile GnRH therapy is used to increase fertility.
    • In men: stimulates testicular growth and sperm production
    • In women: stimulates ovulation