Differences in sex development

Sex is built up in layers: the set of chromosomes, the way the gonads are arranged, the internal organs, the outward shape of the body, and how the tissues answer hormones. The layers usually agree with each other, but not always. In roughly one newborn in a few thousand the anatomy is distinctive enough that doctors cannot say straight away whether this is a boy or a girl; milder variations are far commoner and are sometimes found only in adolescence or in adult life. This is not an illness in the everyday sense and it is nobody's fault. Most people need clear information, follow-up and time to decide rather than surgery, and only some have a condition that requires treatment, including one that is a genuine emergency.

What the words mean

There is still no single term that satisfies everyone. Medical records now tend to say differences in sex development; the older wording was disorders, and it is being dropped because it describes a variation in anatomy as a breakdown. Variations in sex characteristics is also used. Many people with these characteristics describe themselves as intersex, a word that came from the community rather than from the clinic and is used in speaking about oneself, not as a diagnosis.

Three things are constantly confused and are worth separating. How the body is built is one. Gender identity, the inner sense of who one is, is another, and it forms in exactly the same way as it does in everyone else. Attraction and orientation are a third. Anatomy does not dictate identity or orientation, and the reverse holds just as firmly.

Why development takes a different route

In the first weeks after conception the beginnings of the gonads look the same in every embryo and can develop either way. What happens next is decided by genes and hormones: some switch on the development of testes, others of ovaries, and the hormones produced then shape the internal ducts and the external anatomy. For a hormone to have any effect it also needs a receptor, the part in the tissue that recognises it.

A hitch at any of these steps gives its own variation. Tissues may not register male hormones even when there is plenty of hormone about. A hormone may be produced in the wrong quantity because a single enzyme is missing. There may be one chromosome more or one fewer than usual, and a piece of genetic material occasionally sits somewhere other than its normal place. Some causes are inherited, but very often no cause is found at all, and that is a normal outcome of the assessment rather than a sign that it was done badly.

What the differences look like

Many variations have been described; those below are the ones met most often.

• XX chromosomes with external anatomy formed differently. The gonads are ovaries and the uterus is present, but the external organs have been shaped before birth by an excess of male hormones: a larger clitoris, a narrowed or closed vaginal opening. The commonest cause is congenital adrenal hyperplasia, which has a section to itself below, because it is the one variant that can threaten life.
• XY chromosomes with external anatomy closer to female, or in between. This includes insensitivity to male hormones, where the receptors fail to recognise them. In the complete form the body develops along female lines: the external anatomy is that of any girl, there is no uterus, and the testes lie inside the abdomen and are often discovered only in adolescence when the first period does not arrive. The partial form gives an intermediate picture that varies enormously. Other causes are shortages of the enzymes needed to make or convert male hormones, and gonads that have not developed fully.
• Marked hypospadias in a boy. The opening of the urethra lies not at the tip but lower down, sometimes at the base, and the scrotum can look divided in two. Hypospadias of this degree together with testes that cannot be felt always calls for assessment; treating it as simple undescended testes is not acceptable.
• Changes in the number of sex chromosomes. A single X instead of two is Turner syndrome: short stature, puberty that does not start on its own, and often features of the heart, the aorta and the kidneys that call for regular follow-up. An extra X in a boy is Klinefelter syndrome: tall stature, small testes, a shortage of testosterone from adolescence onwards, difficulties with speech and learning in some children, and infertility in most.
• Absent uterus with otherwise typical anatomy. The uterus and the upper third of the vagina have not formed, but the ovaries work, the breasts develop, body hair is as expected and the chromosomes are XX. It comes to light almost always because periods never begin. About a third of these young women also have differences in the kidneys, so the kidneys are always checked.
• Both kinds of gonadal tissue. A very rare variation in which the body contains both ovarian and testicular tissue. The external anatomy can be anything at all.

The first days of life: what must not be missed

Of everything listed above, one condition genuinely threatens life, and every parent of such a child should know about it. In congenital adrenal hyperplasia an enzyme is missing, so the adrenal glands produce no cortisol and often none of the hormone that holds on to salt either. One to three weeks after birth a salt-losing crisis can develop: the body loses sodium and water, potassium builds up instead, and blood pressure falls. This is not a kidney problem, as it is sometimes described, but an acute failure of adrenal hormones, and untreated it ends in death within hours.

Call an ambulance, which in most European countries means 112, if a newborn has:

• persistent vomiting, or refuses to feed;
• floppiness, unusual sleepiness, a weak cry, difficulty being woken;
• weight going down instead of up, dry lips, a dry nappy, a sunken soft spot;
• grey or blotchy skin, cold hands and feet, fast breathing.

This matters especially if the baby's external anatomy is unusual, or if someone in the family has had the same thing. Boys are the more vulnerable here: the anatomy looks ordinary, nothing at birth raises any question, and the crisis comes as a complete surprise. In many countries a test for this condition is part of the newborn heel-prick screen, but the list of conditions screened for differs everywhere, so the symptoms are worth knowing whatever the screening result was. Once the diagnosis is confirmed, the child receives hormone replacement for life, and the parents are given written instructions and a supply of medication for illness, fever or injury, when the dose has to be increased at once.

When it comes to light later

Not every difference is visible at birth. Some are found in adolescence, and the usual prompts are these: puberty does not start when it should; it has started but no periods follow; there are no periods although the breasts have developed normally; features typical of the other sex appear; growth lags noticeably behind other children of the same age or is unusually rapid. In adults the prompt is most often infertility or pain when attempting intercourse.

These are the things to take to a doctor, who will refer on to the right specialist, usually a paediatric endocrinologist, a gynaecologist or a urologist. It is not worth putting off: some conditions need hormonal support precisely at the age of puberty so that the bones form properly, and years lost then cannot be made up afterwards.

How the assessment is done

The assessment is rarely quick, and that is as it should be: the aim is not to produce some diagnosis by tomorrow but to understand how this particular body is put together. It usually takes examination by a specialist, an ultrasound scan of the internal organs, blood tests for hormones including stimulation tests, urine tests, and genetic testing to establish the chromosomes and to look for changes in individual genes. Magnetic resonance imaging, examination under anaesthetic or a biopsy of a gonad are added in some cases.

Care is provided not by one doctor but by a team: an endocrinologist, a surgeon or urologist, a gynaecologist, a geneticist, a psychologist, a specialist nurse who keeps it all joined up. The gonads deserve a separate mention. In some variations, particularly where a gonad has not developed fully and the cells carry Y chromosome material, the risk of a tumour is raised, so the gonad is monitored and removal is sometimes offered. That decision is always discussed case by case and is not a rule for everyone.

Decisions that should not be rushed

The most important thing to say to the parents of a newborn is that only the medical questions are urgent. A life-threatening salt-losing crisis, an inability to pass urine, a severe infection: those are emergencies. Deciding the sex for official documents, and still more any surgery on the external organs, are not.

The deadline for registering a birth varies from country to country, and almost everywhere it can be extended while the assessment is unfinished; check this with the local office that registers births and ask your medical team to write a letter confirming the situation. Later in life an adult can change their legal sex if they wish, and here too the procedure depends on the country.

On surgery, the approach has shifted appreciably in recent years. An operation is done without delay when there is a medical reason for it: urine cannot drain, health is at risk. Operations whose purpose is to bring the appearance closer to the typical are increasingly deferred until the person is old enough to take part in the decision, since they are irreversible, can reduce sensation and often need repeating. Parents are entitled to ask direct questions: what happens if nothing is done now, can this wait, what do the results look like years later. For many women with an underdeveloped vagina the answer is not surgery but gradual stretching with dilators, which is the first choice and gives good results.

Future fertility is worth talking about early. The possibilities vary widely: some people have children in the ordinary way, some need hormonal support, others are helped by assisted reproduction, donor cells or adoption, and where there is no uterus, surrogacy is available in some countries. It is sometimes sensible to store one's own cells or gonadal tissue before treatment begins, so ask about it before anything is removed. Last in order but not in importance: psychological support and contact with people who have been through the same thing give more than any single test. Patient organisations exist for almost every condition named here, and a doctor can point you to the right one.

Online consultation

Remotely it is easy to take the first step, the one so often put off out of awkwardness: to describe the situation calmly and work out which specialist to see and which investigations make sense. A doctor can go through the tests and reports you already have, explain what the chromosome and hormone results mean, help you put your questions to the specialist team into words, and point out what does not have to be hurried. For a teenager or an adult it is a chance to talk about their body, puberty, relationships and plans for children without an examination and without a waiting room. One thing is not suited to being handled at a distance: a newborn who is vomiting, floppy and losing weight needs an ambulance, immediately.

This material is for information only and does not replace medical advice.