Differences of sex development: CAH, AIS and 5α-reductase !

Malformation

Conditions in which chromosomes, gonads and genitalia do not follow the typical pattern. They have specific causes that can be investigated.

Updated 2026-11-01

See it in 3D: Clitoris · Labia majora · Scrotum · Body of uterus · Vagina · Left adrenal gland · Right adrenal gland

What it is

Differences of sex development (DSD) are congenital conditions in which chromosomal, gonadal or anatomical sex does not match the typical pattern. They are classified by karyotype as 46,XX DSD, 46,XY DSD and sex chromosome DSD. Three causes cover most exam questions: congenital adrenal hyperplasia from 21-hydroxylase deficiency, androgen insensitivity and 5α-reductase type 2 deficiency.

Key facts

First test for atypical genitalia: the karyotype.
Presence or absence of a uterus tells whether AMH (and so a working testis) was present.
In CAH, 17-hydroxyprogesterone is high; many programmes include it in newborn screening.
In 5α-reductase deficiency the testosterone/DHT ratio is raised.
In androgen insensitivity, testosterone and LH are normal or high.

Embryological cause

21-hydroxylase CAH: the fetal adrenal makes too little cortisol, ACTH rises and precursors are shunted to androgens that virilize the external genitalia of a 46,XX fetus (clitoromegaly, labioscrotal fusion). There is no AMH, so uterus and tubes are normal.
Androgen insensitivity: the androgen receptor does not work. The testis makes AMH (no uterus) and testosterone, but the Wolffian ducts are not kept and the external genitalia develop as female. The lower vagina, from the urogenital sinus, does form.
5α-reductase type 2 deficiency: testosterone acts (normal Wolffian ducts), but there is not enough DHT to masculinize the external genitalia and prostate. At puberty rising testosterone causes partial virilization.
Sex chromosome DSD: 45,X (Turner, streak gonads), 47,XXY (Klinefelter) and mosaicism such as 45,X/46,XY.

Three classic causes of DSD compared

Condition	Karyotype	Gonads	Uterus	External genitalia
21-hydroxylase CAH	46,XX	Ovaries	Yes	Virilized
Complete androgen insensitivity	46,XY	Testes	No	Female
5α-reductase deficiency	46,XY	Testes	No	Atypical; virilize at puberty

Markers

CYP21A2
AR
SRD5A2
SRY
17-OHP

How it presents

46,XX newborn with CAH: clitoromegaly and fused labia, no palpable gonads; vomiting, dehydration and shock in the salt-wasting form.
Complete insensitivity: a girl with an inguinal hernia containing a testis, or a teenager with primary amenorrhoea, developed breasts and sparse pubic hair.
Partial insensitivity: a spectrum of atypical genitalia, from hypospadias to clitoromegaly.
5α-reductase deficiency: atypical or female genitalia at birth; at puberty the phallus and muscle mass grow, with little facial hair and a small prostate.
Signs pointing to a DSD: proximal hypospadias with cryptorchidism, bilateral impalpable testes, an inguinal mass in a girl, clitoromegaly.

Diagnosis

Karyotype (and SRY testing): separates 46,XX, 46,XY and sex chromosome DSD.
17-hydroxyprogesterone and serum electrolytes when CAH is suspected.
Pelvic ultrasound or MRI: presence of a uterus and location of the gonads.
Testosterone, DHT, LH, FSH and anti-Müllerian hormone to separate disorders of androgen synthesis from disorders of action.

Test yourself

Think of the answer, then tap the question to see it.

What is the commonest cause of atypical genitalia in a 46,XX newborn?

Congenital adrenal hyperplasia from 21-hydroxylase deficiency (CYP21A2 gene), which produces excess adrenal androgens.

Why does a person with complete androgen insensitivity have a short vagina but no uterus?

AMH from the testes removes the Müllerian ducts (uterus and upper vagina), while the lower vagina forms from the urogenital sinus without needing androgens.

What separates 5α-reductase deficiency from complete androgen insensitivity?

In 5α-reductase deficiency testosterone acts: Wolffian ducts are present and virilization occurs at puberty; in complete insensitivity androgens act in no tissue.

Which electrolyte pattern suggests salt-wasting CAH?

Hyponatraemia with hyperkalaemia in the first weeks of life, from lack of aldosterone.

What is the first test for a newborn with atypical genitalia?

The karyotype, together with electrolytes and 17-hydroxyprogesterone because of the risk of salt-wasting CAH.

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See it in 3D

The structures of Durgical's 3D anatomy where it is found.

← All of embryology

Educational content on embryonic development; not a guide to prenatal diagnosis or to medicines in pregnancy and no substitute for a health professional's advice. No doses are given.

Sources: Ambiguous Genitalia and Disorders of Sexual Differentiation - StatPearls - NCBI Bookshelf (StatPearls Publishing (NCBI Bookshelf), 2023); 21-hydroxylase deficiency: MedlinePlus Genetics (MedlinePlus, U.S. National Library of Medicine, 2024); Androgen insensitivity syndrome: MedlinePlus Genetics (MedlinePlus, U.S. National Library of Medicine, 2024); 5-alpha reductase deficiency: MedlinePlus Genetics (MedlinePlus, U.S. National Library of Medicine, 2024).

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Representative model, for educational purposes only.