Sex development, congenital anomalies and maternal factors

Read every disorder of sex development (DSD) layer by layer. Chromosomes: SRY on the Y switches the bipotential gonad toward a testis (via SOX9); without it an ovary forms. Gonads → internal ducts: testicular Sertoli cells secrete anti-Müllerian hormone (AMH, MIF), which makes the Müllerian ducts (future uterus, tubes, upper vagina) regress; Leydig cells secrete testosterone, which, acting through the androgen receptor, stabilizes the Wolffian ducts (epididymis, vas deferens, seminal vesicles). External genitalia: 5α-reductase type 2 converts testosterone to dihydrotestosterone (DHT), which builds the penis, scrotum and prostate. With no testis, Müllerian ducts persist, Wolffian ducts regress and the external genitalia are female.

Here the gonadal layer itself is mixed: both ovarian tissue (with follicles) and testicular tissue (with seminiferous tubules) are present, as an ovary on one side and a testis on the other, or as one or two ovotestes. Most patients are 46,XX (some carry SRY translocated to an X); others are 46,XX/46,XY chimeras or mosaics, and a few are 46,XY. Each gonad acts locally: the side with testicular tissue may lose its Müllerian duct and keep its Wolffian duct. External genitalia are usually ambiguous, and histology of the gonads, not the karyotype, makes the diagnosis.

Androgen insensitivity syndrome (testicular feminization) is a mutation in the androgen receptor gene on the X chromosome. The person is 46,XY with testes, often found in the inguinal canal or abdomen (sometimes as “hernias” in a girl). Sertoli cells make AMH, so there is no uterus, tubes or upper vagina; the receptor cannot respond to testosterone or DHT, so Wolffian structures regress and the external genitalia are female, with a short vagina ending in a blind pouch. At puberty, high testosterone is aromatized to estradiol: breasts develop (the lecture's “gynecomastia”) while pubic and axillary hair stay scant. The usual presentation is primary amenorrhea in a teenager with normal breasts. Testes left in place carry a risk of germ-cell tumors (gonadoblastoma, seminoma), so they are removed, usually after puberty in the complete form.

5α-reductase type 2 deficiency (autosomal recessive) leaves testosterone normal but DHT low. Testosterone alone is enough for the Wolffian ducts, so the epididymis, vas deferens and seminal vesicles are present; DHT-dependent structures (penis, scrotum, prostate) are underdeveloped, so the genitalia look ambiguous or female at birth. At puberty the testosterone surge (and the type 1 isoenzyme) virilizes: the voice deepens, muscles and phallus grow, and there are no breasts. Many children raised as girls change gender identity at puberty.

The most common cause of ambiguous genitalia in a 46,XX newborn is 21-hydroxylase deficiency (CYP21A2, autosomal recessive). The adrenal cannot make enough cortisol (and often aldosterone). Low cortisol removes feedback, ACTH rises, and the adrenal cortex becomes hyperplastic. Precursors pile up behind the block (17-hydroxyprogesterone is the diagnostic marker) and are shunted into androgens. The internal layers are unaffected: the girl has ovaries, a uterus and tubes, but adrenal androgens virilize the external genitalia (clitoromegaly, labial fusion).

About three quarters of classic cases also lack aldosterone: in the first two weeks they waste salt, with vomiting, hyponatremia, hyperkalemia and shock. Boys look normal at birth, so they present with a salt-wasting crisis or, later, early pubic hair and growth (precocious pseudopuberty). Treatment replaces cortisol (which also lowers ACTH and androgens) and, if needed, mineralocorticoid. The lecture also names 11β-hydroxylase deficiency: virilization as well, but 11-deoxycorticosterone accumulates and acts as a mineralocorticoid, so these patients become hypertensive rather than salt-wasting.

The name of an anomaly says how it arose, and that predicts both prognosis and recurrence. A malformation is an intrinsic error of development, mostly during organogenesis (weeks 3–8), and may recur if the cause is genetic. A deformation is a normally formed part pushed out of shape by external force after organogenesis; it often corrects after birth and rarely recurs. A disruption is destruction of a part that had formed normally (vascular accident, amniotic bands, a teratogen); it does not recur.

Some maternal conditions harm the fetus through a substance that crosses the placenta: glucose, an IgG autoantibody, too little thyroid hormone, a drug. Timing matters, because exposure during organogenesis causes malformations, while later exposure affects growth and function.