Androgen insensitivity syndrome

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Feature	Müllerian agenesis	Androgen insensitivity syndrome	5-alpha reductase deficiency
Karyotype	46,XX	46,XY	46,XY
Pathogenesis	Absent or hypoplastic müllerian ducts	Androgen resistance due to X-linked androgen receptor mutation	Deficient conversion of testosterone to dihydrotestosterone (DHT)
Hormone levels	Normal estrogen & testosterone	↑ Testosterone & estrogen (aromatization)	↑ Testosterone, ↓ DHT
Reproductive organs	Absent or rudimentary uterus/upper vagina, normal ovaries	No uterus/upper vagina; cryptorchid testes	No uterus/upper vagina; may have cryptorchid or descended testes
Breasts	Normal	Normal	Minimal to absent (Testosterone is enough to suppress breast)
Axillary & pubic hair	Normal	Minimal to absent	Sparse to normal (varies)
External genitalia	Normal female	Female appearance	Often ambiguous at birth, may virilize at puberty
Wolffian structures	Absent	Absent	Partial development
Gender identity	Female	Usually female	May change to male at puberty
Timing of diagnosis	Usually at adolescence (primary amenorrhea)	May be diagnosed at birth, puberty, or adulthood	Often at birth (ambiguous genitalia) or puberty
Risk of malignancy	No increased risk	↑ Risk of gonadal tumors after puberty	↑ Risk of gonadal tumors

Klinefelter syndrome

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Epidemiology

• One of the most common causes of male hypogonadism

Etiology

• Associated with advanced maternal age

Pathophysiology

• 47,XXY (rarely 48,XXXY or 48,XXYY)
  • Presence of a Barr body (inactivated X chromosome)
• 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

• Eunuchoid growth pattern: tall, slim stature with long extremities (Growth plate closure is delayed )
• Gynecomastia
• Testicular atrophy
• Possible developmental delay
  • Neurocognitive dysfunction (impaired executive function and memory, decreased intelligence)
• Associated disorders
  • Mitral valve prolapse
  • Increased risk of breast and testicular cancer
    • Due to increased estrogen

Turner syndrome

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Pathophysiology

Chromosomal nondisjunction → chromosome X monosomy/mosaicism → impaired ovarian development → malfunctioning streak gonads with connective tissue instead of normal germ cells → estrogen and progesterone deficiencies

• Karyotype
  • Meiotic nondisjunction (most often in paternal gametes) → complete sex chromosomal monosomy (45,XO; no Barr body)
    • Barr body: The inactive X chromosome present in all female somatic cells. Appears as a small, dark-staining spot at the periphery of the nucleus. Consists of tightly-packed, transcriptionally-inactive, heterochromatin.
  • Mitotic nondisjunction of an embryonic cell → sex chromosomal mosaicism (45,XO/46,XX) → mild phenotypic expression

Clinical features

• Lymphatic system abnormalities
  • Cystic hygroma
    • a congenital lymphatic cyst (macrocystic lymphangioma) in the posterior triangle of the neck caused by malformation and obstruction of the fetal lymphatic system
    • Present at birth as a soft, compressible, painless, posterior triangle neck mass
    • Can cause dysphagia or airway compromise
  • 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
  • Scoliosis are common
  • 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
    • As a result of valve calcification.
  • Coarctation of the aorta with brachial-femoral delay
  • Aortic dissection and rupture
  • Hypertension (even in children)
• Other disorders
  • 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

Tip

Most patients with Turner syndrome have normal intelligence.

Kallmann syndrome

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Etiology

Hypogonadotropic hypogonadism with hyposmia/anosmia

Pathophysiology

• 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

• Anosmia or hyposmia
• Infertility