Disorders of Sex Development
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Direct answer
Disorders of sex development are congenital conditions in which the chromosomal, gonadal or anatomical sex is atypical, so the external genitalia may look ambiguous or fail to match the karyotype. The commonest cause of ambiguous genitalia in a 46,XX infant is congenital adrenal hyperplasia from 21-hydroxylase deficiency, which can cause a life-threatening salt-losing crisis. Every ambiguous newborn needs urgent electrolytes, glucose and karyotype before any sex is announced.
What you must remember
- Main groups: 46,XX disorders usually involve androgen excess, 46,XY disorders involve incomplete androgen action or synthesis, and sex chromosome disorders include Turner and Klinefelter syndromes.
- Commonest 46,XX cause: 21-hydroxylase deficiency, the classic form of congenital adrenal hyperplasia, often with salt wasting.
- Salt-losing crisis: hyponatraemia, hyperkalaemia, hypoglycaemia and hypotension in the first weeks of life, which is an emergency.
- Complete androgen insensitivity: a 46,XY karyotype with a female phenotype, a blind vaginal pouch, no uterus and testes that are often intra-abdominal or inguinal.
- Gonadectomy timing: in complete androgen insensitivity the gonads are retained until after puberty and then removed because of malignancy risk, with oestrogen replacement.
- First tests: serum sodium, potassium and glucose, karyotype, 17-hydroxyprogesterone and a pelvic ultrasound.
- Hydrocortisone first: start it whenever adrenal crisis is possible, without waiting for the karyotype.
- Counselling: a multidisciplinary team counsels the family before any sex is announced.
Approach to ambiguous genitalia in the newborn
A 5-day-old girl has clitoromegaly, fused labia and no palpable gonads, and the family is waiting for an answer. The first task is to exclude the life-threatening causes, because a salt-losing adrenal crisis can progress quickly while the diagnosis is still being worked out.
- Stabilise first: check for shock, dehydration and hypoglycaemia, and give hydrocortisone if adrenal crisis is possible. Treatment does not wait for the laboratory results.
- Send baseline tests: measure serum sodium, potassium and glucose, and send a karyotype with rapid FISH where it is available.
- Measure the hormones: request 17-hydroxyprogesterone and androgen levels, since a raised 17-hydroxyprogesterone points strongly to congenital adrenal hyperplasia.
- Examine the anatomy: note the phallus size, the position of the urethral opening, labial fusion, palpable gonads and any hypospadias.
- Image the pelvis: an ultrasound shows whether a uterus is present and where the gonads lie, which helps separate the 46,XX and 46,XY groups.
- Form a working diagnosis: combine karyotype, hormones and anatomy to place the infant in a category, then counsel the family in stages.
Where the exam tries to catch you
The distractors usually exploit the gap between phenotype and karyotype.
- Trap: choosing the sex from the external genitalia alone. Correct: the karyotype and hormone profile decide the category, because the phenotype can mislead, as in complete androgen insensitivity.
- Trap: treating ambiguous genitalia as a cosmetic problem that can wait. Correct: salt-losing CAH can kill within days, so electrolytes and hydrocortisone come first.
- Trap: ordering only a karyotype for a 46,XX infant with virilisation. Correct: 17-hydroxyprogesterone and electrolytes are needed, because CAH is the commonest cause and it is treatable.
Frequently asked questions
Which test quickly separates 46,XX from 46,XY in an ambiguous newborn?
Rapid FISH on a cell sample can show whether X and Y chromosome signals are present within a day or two. A full karyotype takes longer but gives the complete picture. Both are needed before the category is finalised.
Why is 21-hydroxylase deficiency so important in ambiguous genitalia?
21-hydroxylase deficiency is the commonest cause of ambiguous genitalia in a 46,XX infant, because excess androgens virilise the female fetus. The salt-wasting form also loses sodium and water, and can cause a crisis in the first weeks of life. Prompt hydrocortisone treatment prevents that crisis.
What is the usual management of complete androgen insensitivity?
Most children with complete androgen insensitivity are raised as girls, since the phenotype is female. The testes are retained until after puberty and then removed because of malignancy risk. Oestrogen replacement follows gonadectomy.
Why is hydrocortisone started before the karyotype result?
Hydrocortisone is started before the karyotype result because an adrenal crisis from congenital adrenal hyperplasia can cause collapse within days. Karyotype results take time, so waiting risks a preventable death. Treatment can be adjusted once the diagnosis is clear.