Typical genotype-phenotype relationships:

46 XX, female-typical phenotype

• Primordial germ cells in the gonadal ridge induce ovarian differentiation, in approximately week 8.
• Genes from the Wnt family and others transform the paramesonephric ducts to produce the uterine tubes, uterus, and the vagina.
• Estrogen from the fetal ovaries and placenta guide formation of the vulva, aka, the female external genitalia.

46 XY, male-typical phenotype

• The SRY gene in the somatic cells of the gonadal ridge induces testes differentiation.
• Subsequently, the testes produce androgens and anti-Mullerian hormone (AMH), which facilitate transformation of the mesonephric ducts to produce the tubules of the testes, the epididymis, and the ductus deferens.
• Androgens also guide formation of the male external genitalia, the penis and scrotum.

DSDs caused by atypical sex chromosome number:

DSD 45 X_, aka, Turner Syndrome

• The genotype tells us that there are 45 total chromosomes, with one X chromosome; thus, one of the sex chromosomes is missing.
• Gonads do not fully differentiate, and typically present as fibrous, non-functional streak ovaries.
  • As a result, most 45 X_ individuals do not pass through puberty, and typically have impaired fertility.
  • Other notable characteristics include short stature, which becomes noticeable during childhood; broad chest; and a “webbed” neck, with extra skin folds. Be aware that these features are not present in every individual, but, when present, may be indicative of an atypical genotype.
  • Clinical concerns include cardiac and renal defect, and lymphedema.

DSD 47 XXY, aka, Klinefelter’s syndrome.

• Extra X chromosome in each cell.
• The extra X chromosome impairs testes development, resulting in small testicles that produce less testosterone.
• Thus, puberty is often delayed or incomplete, and fertility is impaired.
• Individuals tend to experience gynecomastia (enlargement of the breast tissue); reduced body and facial hair; and, perhaps most obviously, tall stature with long extremities.
• Clinical concerns are increased breast cancer risk (relative to typical male rates) and, in some cases, learning disabilities.

DSD 45 X, 46 XY, aka, mixed gonadal dysgenesis

• A type of mosaicism; in these individuals, some cells have the 45 X genotype, others have the 46 XY genotype.
• Streak ovaries and testis, which is likely to be undescended; puberty is likely to be incomplete, and fertility is impaired.
• Clinical implications are short stature and cardiac and renal defects (similar to Turner Syndrome).

DSD 46 XX, 46 XY, aka, chromosomal ovotesticular DSD

• Mosaic
• Both testicular and ovarian tissues are present, either symmetrically or asymmetrically.
• The resulting phenotype depends on the functionality of the gonadal tissues and the hormones they produce.
• Clinical concerns include hypospadias (displaced urethral opening) and cryptorchidism (undescended testes), both of which are likely the result of deficient androgen influence.