DiGeorge syndrome (22q11.2 deletion)

This is a condition present from birth in which a small piece of DNA is missing from chromosome 22. The piece is tiny, but it holds several dozen genes that govern how the heart, the palate, the thymus and the parathyroid glands are built in the embryo. Hence the extraordinary spread of presentations: one baby is born with a serious heart defect and seizures in the first days, another has only a nasal-sounding voice and trouble at school, and a third learns of the diagnosis at forty, when their own child is being investigated. The same genetic change, wildly different severity, and no way to predict it in advance.

What lies behind the diagnosis

The condition has collected many names over the years: DiGeorge syndrome, velocardiofacial syndrome, Shprintzen syndrome. All of them describe one and the same genetic finding, and it is now usually named for what it actually is, a 22q11.2 deletion. It occurs in roughly one in two to four thousand newborns, which makes it one of the most common microdeletions in humans.

It almost always arises by chance, while the egg or the sperm is forming, and it is not the result of an illness, a medicine, stress, or anything the parents did during the pregnancy. In nine cases out of ten neither parent carries the deletion. In the tenth the child inherited it from a parent who may not even know their own diagnosis, because in them it amounted to no more than unclear speech or a short stature.

One detail matters a great deal: the size of the missing piece is much the same in everyone, while the severity is completely different, and that holds true even between relatives in a single family. Someone else's case history therefore tells you nothing about your child.

What the picture is made of

Almost nobody has the full set. The features that recur most often are these:

• heart defects, in roughly half of cases, and usually of a particular type affecting how the great vessels leave the heart;
• differences in the palate, such as a cleft hidden under the lining or a weak soft palate, which produce a nasal voice, milk or food coming back through the nose, and choking during feeds;
• low calcium from underdeveloped parathyroid glands, ranging from trembling and tingling to seizures;
• weakened defences from a small thymus, with frequent and drawn-out infections of the ears, throat and chest;
• delayed speech and learning difficulties, attention deficit and, less often, autism spectrum disorder;
• hearing loss, usually temporary, on the back of repeated ear infections;
• kidney differences such as a single kidney or one of reduced size, generally found on a scan;
• short stature, curvature of the spine, and unusual shaping of the neck vertebrae.

Facial features are also slightly distinctive, but the diagnosis does not rest on them: they are subtle and mostly visible to a trained eye.

What to watch for in the first months

A child with this diagnosis needs clear landmarks rather than anxiety. Seek advice without delay if any of the following appear:

• twitching, trembling, cramping of the hands, tingling around the mouth and, all the more so, a seizure, which is how falling calcium shows itself;
• blue lips, heavy sweating and rapid tiring during feeds, fast breathing, poor weight gain, which point to the heart;
• fever with listlessness and refusal to feed, especially in a baby in the first months of life;
• stubborn oral thrush, diarrhoea that will not settle, and infections that do not clear with the usual treatment.

A seizure, a blue colour, breathing that stops or is visibly laboured, and unusual drowsiness all mean calling an ambulance rather than waiting for an appointment. Across most of Europe the single emergency number 112 will reach one.

There is also a rare and by far the most severe variant, the one in which the thymus is missing altogether. These children are born with essentially no cellular immunity, and an ordinary infection can kill them. It affects fewer than one per cent, and that is exactly why the immune system of every child with a confirmed deletion is assessed as early as possible: this form is now treated with a transplant of thymus tissue or bone marrow, and the outcome depends directly on whether it was done before the first severe infection.

Immunity: vaccines, infections and transfusions

In most people the immune defect is partial, and it softens on its own over the years. Even so, two decisions should never be made without an immunologist.

The first concerns live vaccines. Those against measles, mumps and rubella, against chickenpox, the rotavirus vaccine and BCG all contain a weakened but living organism. With a marked shortage of T lymphocytes they are dangerous; with a mild one they are given in the ordinary way. That call is made on a blood result, not on how well the child looks. Inactivated vaccines, by contrast, are not merely permitted but necessary, since they are the main line of protection, and the yearly flu vaccine belongs on that list.

The second concerns blood transfusion. Until immunity has been assessed, blood components must be irradiated; otherwise donor lymphocytes can take hold and attack the child's own body. This is worth remembering before any operation and worth telling the surgeon and the anaesthetist, along with the fact that the child's calcium can run low.

How it is confirmed and what is checked afterwards

The diagnosis comes from a genetic blood test, either a chromosomal microarray or a test aimed specifically at this deletion. A conventional chromosome study will miss it, because the missing piece is too small. The reason to send the sample arises when a newborn turns out to have a heart defect of that particular kind, an unexplained low calcium or a cleft palate, and later on when delayed speech sits alongside repeated infections. In pregnancy the suspicion may be raised by a screening test on the mother's blood or by a scan, but confirmation requires sampling the amniotic fluid or the chorionic villi.

Once it is confirmed, the child is assessed on every front at once: an echocardiogram, calcium and parathyroid hormone, immune blood tests, a kidney scan, a hearing check, examination of the palate and a look at the spine. Parents are offered a test of their own as well, because the risk to any future children hangs on it.

After that the follow-up becomes routine, and there is a point to it: calcium is quite capable of dropping again years later, alongside an illness, an operation, puberty or a pregnancy, so it is not measured once in a lifetime but at intervals and without fail at those moments. The thyroid, the blood count and how the child is coping with schoolwork are reviewed on the same regular basis.

Growing up, and mental health

With time a great deal gets easier: the heart has been repaired, speech therapy has done its work, calcium is under control. What moves to the foreground instead is learning, behaviour and the mind.

This is not a delicate subject to be skirted around; it is the single most useful piece of knowledge about the syndrome. Roughly one adult in four with a 22q11.2 deletion develops a psychotic illness, most often schizophrenia, and anxiety disorders and depression are markedly more common than among peers. It usually begins in the teens or in young adulthood and almost never appears out of nowhere: first the person withdraws, stops sleeping, drops out of study, becomes suspicious, hears or sees things that are not there. Seeking help at the first such changes is not overcaution, because the earlier treatment starts the better it works, and the whole family is better off knowing those signs.

Less often, autoimmune conditions join in: of the thyroid, of the joints, or a fall in the platelet count. Most people with this syndrome reach adulthood, study, work and live independently; average life expectancy is somewhat shorter than usual, and the heart accounts for most of that difference rather than anything else.

If another child is being considered

One test settles the question here. If neither parent carries the deletion, the chance that it will arise in the next child is under one per cent. If one parent does carry it, the risk of passing it on is fifty per cent in every pregnancy, and it does not go down because the previous child was born healthy.

Families who already have a child with this diagnosis, or who know of it in a relative, are therefore best served by seeing a geneticist before a pregnancy rather than during one. Prenatal diagnosis can be discussed, and where it is available so can testing of embryos before transfer. One thing is said honestly in advance: the test will show whether the deletion is present, but it will not say how severely the child will be affected.

Online consultation

A remote appointment is well suited to exactly what tends to go unanswered between one specialist visit and the next. The doctor can pull the scattered reports from the cardiologist, the ear specialist and the geneticist into one coherent follow-up plan, explain which tests are due now and by when, and work through the question of live vaccines and what the anaesthetist needs to be told before surgery. It is also the place to bring worrying changes in a teenager's behaviour and the question of risk in a future pregnancy. A seizure, a blue colour, laboured breathing or a high fever in a baby cannot be handled through a screen: that means an ambulance straight away.

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