Buzzwords

• Klinefelter (47,XXY): Tall male, gynecomastia, small/firm testes, infertility, ↑FSH/LH.

• Turner (45,XO): Short stature, webbed neck, shield chest, streak ovaries, bicuspid aortic valve, coarctation.

• Androgen Insensitivity (46,XY): Phenotypic female, blind-ending vagina, absent uterus, scant pubic hair, cryptorchid testes.

• 5α-Reductase Deficiency (46,XY): Ambiguous genitalia at birth, virilization at puberty ("penis at 12"), ↑Testosterone:DHT ratio.

• Müllerian Agenesis (46,XX): Primary amenorrhea w/ normal secondary sex characteristics, absent uterus, normal ovaries.

• 21-Hydroxylase Deficiency (CAH):

  • 46,XX: Ambiguous genitalia (virilization).
  • Both: Salt-wasting (hypotension, ↓Na+, ↑K+), precocious puberty.
  • Buzzword Lab: ↑ 17-hydroxyprogesterone.

• Swyer Syndrome (46,XY Gonadal Dysgenesis): Phenotypic female, has a uterus, "streak gonads" (must be removed), no puberty (no breasts/menses).

• Kallmann Syndrome: Anosmia (can't smell) + hypogonadism (delayed puberty); ↓GnRH, ↓FSH, ↓LH.

Androgen insensitivity syndrome

Klinefelter syndrome

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

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
  • The absence of a second X chromosome disrupts X-linked survival signals, causing primordial germ cells to undergo accelerated apoptosis, leading to near-total germ cell loss by birth. Without germ cells, ovarian structures (e.g., follicles) fail to develop, and regressing gonadal ridges are replaced by fibrous connective tissue, forming non-functional streak gonads.
• 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

Kallmann syndrome

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

Androgen insensitivity syndrome

• Pathophysiology
  • Dysfunction of the AR in the hypothalamus and pituitary leads to loss of feedback inhibition of gonadotropin-releasing hormone (GnRH), FSH, and LH. This results in the following hormonal findings:
    • GnRH induces increased LH secretion, which leads to increased testosterone production in the testes.
    • FSH secretion is increased by GnRH but suppressed by inhibin from the seminiferous tubules and is often normal.
    • Estrogen, which is derived by aromatization of testosterone, may be normal or elevated.
• Diagnostics
  • Clinical presentation
  • Before puberty: ↑ testosterone
  • After puberty: ↑ LH, ↑ estrogen, and normal/↑ testosterone levels (no virilization)
  • Genetic testing

SRY Gene Translocation

• SRY Gene Function: The Sex-determining Region Y (SRY) gene, located on the Y chromosome, is the primary trigger for male sex determination. It codes for a protein (testis-determining factor) that initiates the development of testes from the bipotential embryonic gonads.

• Patho/Etiology: Abnormal crossing-over during paternal meiosis moves the SRY gene from the Y to the X chromosome.

  • 46,XX Testicular DSD: Individual is XX but has the SRY gene, leading to a male phenotype.
  • 46,XY Gonadal Dysgenesis (Swyer Syndrome): Individual is XY but has a deleted/mutated SRY gene, leading to a female phenotype due to lack of testes development.

• Presentation:

  • 46,XX Male: Presents with small testes, gynecomastia, and infertility. Phenotypically male.
  • 46,XY Female (Swyer): Presents with primary amenorrhea and lack of secondary sex characteristics. Has a uterus but streak gonads. Phenotypically female.

• Dx:

  • Karyotype shows discordance between genotype (e.g., 46,XX) and phenotype (male).
  • FISH or PCR confirms SRY gene presence on X-chromosome (in 46,XX male) or its absence/mutation (in 46,XY female).
  • Hormones: Elevated LH/FSH. Low testosterone (XX male) or low estrogen (XY female).

• Mgmt:

  • 46,XX Male: Testosterone replacement for virilization.
  • 46,XY Female (Swyer): Estrogen/progestin HRT for female development. Prophylactic gonadectomy is crucial due to high risk of gonadoblastoma.

• Key Complications:

  • Infertility (universal).
  • Gonadoblastoma risk in the streak gonads of 46,XY Swyer Syndrome.
  • Psychosocial distress.

Treatment

• Hormone Therapy: Often essential.
  • For 46,XY DSDs (like Androgen Insensitivity Syndrome, 5-alpha reductase deficiency, Swyer Syndrome): Estrogen or testosterone may be used depending on the specific condition and gender identity. Gonadectomy (removal of testes) is common in AIS and Swyer Syndrome due to cancer risk.
  • For 46,XX DSDs (like Congenital Adrenal Hyperplasia, Aromatase Deficiency, 46,XX Testicular DSD): Corticosteroids are vital for CAH. Estrogen is used for conditions like Aromatase Deficiency and XX Gonadal Dysgenesis. Testosterone may be used for 46,XX Testicular DSD.
  • For Sex Chromosome DSDs: Growth hormone and estrogen for Turner Syndrome (45,XO); testosterone for Klinefelter Syndrome (47,XXY).
• Specific Interventions:
  • Kallmann Syndrome: Hormone replacement to induce puberty.
  • Congenital Adrenal Hyperplasia (CAH): Lifelong corticosteroids to manage hormone imbalances.
  • Ovotesticular DSD: Individualized hormone therapy and surgery based on gonadal tissue and gender identity.
  • Double Y Syndrome (47,XYY): No direct cure; treatment is supportive (e.g., speech therapy).