Noonan syndrome

Noonan syndrome is a condition present from birth in which a change in a single gene alters a great many things at once: the features of the face, the pace of growth, the shape of a heart valve, the way blood clots. It is not something a person acquires — it is there from the start. It comes to light in very different ways. In some babies the combination of features is obvious on the maternity ward; in others everything stays within the ordinary range until school age, when the child begins to fall visibly behind classmates in height. It is not especially rare: roughly one baby in every one to two and a half thousand, equally often in boys and girls and in every country. The picture varies so widely that within one family one person may know the diagnosis from infancy while another finds out at forty, when their own child is investigated.

Where it comes from and who inherits it

The cause is a change in one of the genes that control a single chain of signals inside the cell. That chain decides when a cell should divide and what it should become, and it operates everywhere in the body at once — which is why the consequences spread so far, from the shape of the eyelids to the thickness of the heart muscle. The gene most often altered is PTPN11, in about half of cases; behind the rest stand SOS1, RAF1, RIT1, KRAS, LZTR1 and several others. Related conditions caused by faults in the same chain are grouped together as one family, because their features overlap in places.

Knowing which gene is involved tells you something about what to expect. A change in PTPN11 is more often found alongside narrowing of the pulmonary valve, and RAF1 alongside thickening of the heart muscle. This is neither a sentence nor a guarantee, but it helps the doctor decide in advance what to watch most closely.

The condition is passed on in a dominant way: one altered copy of the gene, received from either parent, is enough, and the chance of passing it to each child is one in two. A parent who carries it usually has the syndrome too, simply in a form so mild that they have never known. In a substantial share of children, though, the change arises afresh as the reproductive cells mature, and neither parent carries it — in that case the chance of it happening again in the family is very small.

A geneticist is the person who sorts out which situation applies: both parents are offered a blood test. If neither carries the altered gene, the risk for a further child is put at under one per cent; if the gene is found, at one in two. From there the counsellor goes through the options with the family, from testing during pregnancy to selecting embryos in IVF, supplying exact figures instead of guesswork.

What shows in a person's appearance

Any single feature is also seen in perfectly healthy people — it is the combination that counts. The list usually given is:

• a high, broad forehead and drooping upper eyelids;
• wider than usual spacing between the eyes, with the outer corner of the eye sitting lower than the inner;
• a short nose with a broad base and a flattened bridge;
• low-set ears turned towards the back of the head, with a thick rim;
• a small lower jaw and a deep groove above the upper lip;
• a short neck, sometimes with folds of skin at the sides, and a low hairline at the back;
• an unusually shaped chest — pushed out above and sunken below, with widely spaced nipples;
• curly, coarse hair and sparse eyebrows.

Newborn babies may have puffy hands and feet, which settle over the first few months. With age the features generally soften: in an adult they are far less striking than in childhood photographs, and appearance alone is often no longer enough to raise the suspicion.

The heart, the thing watched most closely

Most people with the syndrome have a heart defect of some kind, and it is the heart that decides how serious the picture turns out to be. Almost always it is one of three.

• Narrowing of the pulmonary valve. The valve through which blood leaves the heart for the lungs does not open fully, and the right ventricle has to work against a load. In this syndrome the valve leaflets are often thickened and stiff rather than simply fused, so stretching the valve with a balloon on a catheter works less well than in ordinary narrowing, and some people need surgery.
• Thickening of the heart muscle. The ventricle wall becomes excessively thick and gets in the way both of filling and of pumping. It may appear in infancy or show itself later, which is why monitoring carries on into adult life.
• A hole between the upper chambers. A small one sometimes closes by itself; a large one overloads the right side of the heart and the lung vessels and has to be closed.

As soon as the diagnosis is made, an echocardiogram and an electrocardiogram are done — in this syndrome the tracing shows fairly characteristic changes that by themselves point towards it. After that the tests are repeated on a schedule the doctor sets according to the particular defect, and they are not dropped once the child grows up. One further practical point: with a heart defect it is worth keeping teeth and gums in good order and telling the dentist about the diagnosis, because infection from diseased teeth can reach the heart valves.

Growth and puberty

Babies are born a normal length. The gap opens up towards the age of two: the child grows, but more slowly, and gradually drifts below the growth curve. Feeding difficulties in the first year play a part, and so do the properties of that same cellular chain, which leave the body responding less well to its own growth hormone.

Puberty is usually a couple of years late, and the growth spurt that goes with it is weaker than usual or does not happen at all. Without treatment the average adult height in this syndrome is around 162 cm for men and around 153 cm for women, but the spread is wide and many people end up within the ordinary range.

If growth is genuinely poor, treatment with injected growth hormone is discussed. It is usually started in the preschool years and continued until growth finishes; the final result is noticeable, though the centimetres it adds are not unlimited. One condition is not negotiable — the heart is monitored throughout treatment, particularly where the heart muscle is thickened. The decision is taken by the endocrinologist together with the cardiologist, and prescribing rules differ from country to country.

The blood: clotting and the marrow

Blood clotting. Between a third and a half of people with the syndrome clot less well than usual: one of the clotting factors is in short supply, or the platelets do not work properly. Day to day this shows as easy bruising, long nosebleeds and heavy periods, but the point that really matters is a different one — say so before any operation, before a tooth is taken out, before giving birth and before any medicine is prescribed. Non-steroidal anti-inflammatory painkillers, ibuprofen among them, and aspirin still more, interfere further with the platelets; so with a bleeding tendency they are not taken from the cupboard "just in case" but agreed with a doctor. Aspirin is not given to children and adolescents.

Blood counts. Some babies have a temporary excess of immature white cells during the first year, which settles by itself but needs a haematologist keeping watch. The risk of leukaemia in this syndrome is a little above average, so a blood count is part of the routine reviews.

What else may be involved

The lymphatic system. Swelling of the feet and lower legs is possible, as is a collection of lymph around the lungs, which shows up as breathlessness. In an unborn baby this is sometimes already visible on the scan.

Feeding in infancy. Weak sucking, bringing up milk and slow weight gain are often the first problem. It usually resolves by one or two years of age; in severe cases a feeding tube is used for a few months.

Muscle tone and movement. Tone is often reduced, so sitting and walking come later; work with a physiotherapist brings this along.

Eyes and hearing. A squint, long sight and astigmatism, a lazy eye; on the ear side, repeated middle ear infections and sometimes lasting hearing loss. Both are checked early, because speech and learning depend on them.

Testicles and fertility. In many boys one or both testicles fail to descend into the scrotum. In adult men fertility may be reduced; in women it is usually unaffected.

Kidneys. Occasionally there are structural differences — a single kidney, say, or a widened renal pelvis — picked up on ultrasound.

Learning. Intelligence is within the normal range for most, though on average slightly below that of their peers. A minority have learning difficulties, generally mild; more often the obstacles are problems with attention, with language and with reading emotions.

A variant with many dark brown spots on the skin, hearing loss and thickening of the heart muscle used to be called LEOPARD syndrome; it is now regarded as the same condition and called Noonan syndrome with multiple lentigines.

How the diagnosis is reached

The doctor first assembles the picture: facial features, height plotted on the chart, a heart murmur, undescended testicles, swelling, family history. External features alone are not enough to diagnose — similar faces occur in other conditions and simply by inheritance from a parent.

What confirms the diagnosis is a genetic blood test, a panel that checks all the known genes of this group in one go. Its limitation matters: in roughly one case in five no change is found in any known gene, and that does not overturn the diagnosis. If the clinical picture is convincing, the doctor manages the person as having Noonan syndrome even with a negative test.

Once it is confirmed, further tests map out the extent: echocardiogram and electrocardiogram, clotting tests, kidney ultrasound, an eye examination, a hearing test, and an assessment of development and school progress. Some of these are then repeated at intervals.

In pregnancy, testing is offered if the altered gene is already known in the family, or if the scan shows findings that give cause for concern — increased nuchal translucency, fluid around the lungs or under the skin, excess amniotic fluid. The sample is obtained by chorionic villus sampling or amniocentesis; the risk of losing the pregnancy with these procedures is low, current estimates being fractions of one per cent, and your doctor will give the exact figure for your situation. The result is discussed with the geneticist, who explains what has been found and what follows from it.

When help is needed straight away

Call an ambulance (in Spain, Italy, Portugal, Poland and Ukraine that is 112) if a child or adult with the syndrome develops:

• blue or grey skin, lips or tongue — on brown and black skin this is easier to see on the palms and soles;
• laboured, rapid breathing, the spaces between the ribs pulling in, or grunting in a baby;
• a faint or loss of consciousness, especially during exertion;
• chest pain or violent palpitations on physical effort;
• bleeding that cannot be stopped within twenty minutes, or heavy bleeding after an injury, a dental extraction or an operation.

See a doctor the same day, though without an ambulance, if a baby sweats and struggles for breath while feeding, tires and lets go of the breast, has stopped gaining weight or has become listless; if a child has become breathless on everyday exertion that used to be no trouble; if bruises appear without knocks, or bleeding lasts longer than it used to.

How it is managed and what helps

There is no single treatment for the syndrome: what is treated is not the gene but the individual problems, and different doctors deal with them, so someone needs to hold the overall picture — usually the paediatrician or the family doctor. The cardiologist, endocrinologist, haematologist, ophthalmologist, ear nose and throat doctor, speech and language therapist and, where needed, the surgeon all report back to them.

What is actually done depends on the finding. Undescended testicles are generally operated on early, since that offers the better chance of preserving fertility. Feeding and speech are the speech and language therapist's territory, movement the physiotherapist's. With learning difficulties most children attend mainstream school, but they need a written support plan: extra time, help with language, attention to hearing and vision in the classroom.

With the years, less help is usually needed: the features soften, feeding settles, some problems are dealt with once and for good. Almost all children reach adult life and live independently. One thing stays constant — keeping an eye on the heart, and it should not be dropped when the person stops being a paediatric patient.

Online consultation

An online appointment is convenient once the diagnosis is made but plenty of questions remain around it. The doctor will go through your reports and the genetic result with you in plain language, help you put together a monitoring schedule — what to check and how often — explain what the dentist and the surgeon need to be told, and point you to the right specialist for the complaint you have now, so you do not go round in circles. It is useful too for parents who have only just begun to suspect something in their child: the doctor will say whether a referral to a geneticist is warranted and which results to bring to that first visit.

What an online appointment does not replace: a physical examination, an echocardiogram, blood tests and the genetic test itself. And with the signs listed in the section on urgent help, the person to contact is not a doctor in a chat window but the ambulance service.

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