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Jacqueline Noonan, M.D., Professor of Pediatrics: "Noonan syndrome: A Clinical Description Emphasising the Cardiac Findings"

The first description of a patient with 'Noonan Syndrome' was made by Koblinsky in 1883, although it was not until 1962 that the condition began to be named after Dr Jacqueline Noonan.

Dr Noonan is a pediatric cardiologist and pediatrician, who qualified in Boston in 1956. When she subsequently began work at the University of Iowa as their first pediatric cardiologist, she became interested in why some children had congenital heart disease and other abnormalities that may occur with it. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1962 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". This described 9 children who in addition to congenital heart disease had characteristic faces, chest deformities and short stature. Both males and females were found to be similarly affected, and the chromosomes were apparently 'normal'.

It was Dr John Opetz, a former student of Dr Noonan, who first began to call the condition "Noonan Syndrome" when he saw children who looked like those whom Dr Noonan had described. Dr Noonan later produced a paper entitled "Hypertelorism with Turner Phenotype", and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.

General Findings

At birth babies with NS may look quite normal, being of average length and weight, but tend to become shorter than average as they grow and to have a delayed bone age. The average adult height is 5'4" for males and 5' for females. Females with NS are normally taller than females with Turners Syndrome, with which NS is occasionally confused.

A study of 151 patients was done, and in around a third of cases the mother had suffered from polyhydramnios (excess amniotic fluid) whilst pregnant. Looking at the babies feeding history around a quarter had no problems, but over a half had feeding problems. It is not really understood why these occur.

Feeding problems may partly account for slow growth during the first years of life, but these generally improve - as indeed do most things in Noonan Syndrome. Children may be a little slower reaching developmental milestones such as walking and talking, but most end up going to regular school. Mental retardation per se is not common, but does occur; average IQ's may be slightly below the normal mean but are still within the normal range, and high IQ's do occur.

Learning problems are common, and there is a high incidence of hearing loss. Only 3 children out of a study of 58 had perfectly normal eyes, and refractive errors are very common. Most ptosis however does not require surgery. Undescended testes occur in a high percentage of males, and delayed puberty is common - those with NS may still be growing at the age of 20 or 21 as opposed to around 18 years in normal individuals. The average age at which girls begin their periods is around 14 - around 2 years later than average.

Renal anomalies may be present but do not require treatment. Chest deformities are common (pectus excavatum / carinatum), and scoliosis sometimes occurs; this may continue to worsen until the mid-twenties.

Children with NS often have lax joints and are hypotonic (have poor muscle tone), although this generally improves with age. This may account for the delays in sitting and standing.

Unexplained enlargement of the liver and spleen may be seen especially in babies, but this doesn't cause any problems and tends to disappear on it's own.

Thick curly hair is very common, as are multiple lentigenes - this may be confused with Leopard Syndrome.

Lymphatic problems are uncommon, but when they do occur can cause serious problems in the lungs and gut.

Cardiovascular Problems

Pulmonary Stenosis (PS) is the most common heart defect in Noonan Syndrome, and Hypertrophic Cardiomyopathy (HCM) also occurs quite frequently. Atrial and ventricular septal defects are also seen, as is mitral valve prolapse. Other defects occur less commonly. Most children with NS will have some form of heart disease.

Pulmonary stenosis also occurs in Beagles, and in one study 10 matings produced 35 pups, of which approximately a quarter had PS. The genetics of PS is complex, but it is thought that both typical and dysplastic PS share a common developmental mechanism.

In the usual kind of pulmonary stenosis where the valve is thin and fused, it is possible to dilate the valve using a balloon catheter. But this is not easy in most patients with NS as the whole valve is often malformed and is itself causing the blockage. In this case a valvectomy may be done to relieve the obstruction.

There must be something about the pulmonary valve that could give us a clue as to the cause of Noonan Syndrome. Some years ago a study of the valve was done yet nothing was found, but now a lot more markers are available to use in microscopic techniques that weren't available before. Finding out what causes the dysplastic valve and what in what way it is different from a normal valve may be helpful in looking for a specific gene marker.

This point was made because in Williams Syndrome there are problems not only in the heart but also in the blood vessels: supravalvular aortic stenosis. 6 patients who were diagnosed within a short space of time were studied, and tissue samples taken from all of them; 4 when they underwent surgery, and 2 who died prior to surgery. By comparing tissue from the Williams patients with that taken from patients with familial aortic valvular stenosis, it was found that the same heart lesion can occur in an autosomal dominant form in families with normal appearance as can occur in those with Williams syndrome - but also with dysmorphic features. In both cases the lesion was identical, whether familial or Williams syndrome; there was some defect in the elastin tissue. And 2 years ago the gene which causes Williams Syndrome was found to be an elastin gene.

However the defect in the elastin gene doesn't explain the characteristic facial appearance of those with Williams syndrome, and it is very difficult to understand or to find a gene that does all these things. Williams syndrome patients have been found to have only 1 elastin gene instead of two, so in the case of NS perhaps more studies on the heart should be done, and collaboration may help.

The ECG in Noonan's is typical, i.e. a left axis deviation; this is not common in pulmonary stenosis in children who do not have NS.

Management of pulmonary stenosis. Often the PS is mild and so no treatment is necessary; but if it is causing an obstruction and making the right-hand side of the heart work too hard and become hypertrophied, it is often necessary to perform surgery as opposed to balloon valvoplasty. Sometimes however a balloon may reduce the pressure gradient sufficiently so that surgery is unnecessary, but very often surgery is required.

Often in addition to the valve problems there is a lot of extra muscle in the heart and it may be necessary to resect the muscle bundles. Sometimes it is even necessary to patch across the right ventricular outflow to enable it to be opened up enough so that there won't be any high pressure in the right ventricle.

Sometimes an atrial septal defect occurs too, and that can also be closed. However both PS and ASD can be managed, so surgery is usually successful.

Hypertrophic cardiomyopathy. HCM is an autosomally dominant form of heart disease seen in otherwise normal appearing people. This is the sort of condition which may worry athletes and is hard to detect from ECG alone - so many competitive sports may require screening using echocardiograms, since HCM may be completely asymptomatic.

The cause of HCM is complicated because it is not caused by just one gene; a whole host of different genes may be found in different families. Likewise, we must be prepared for the fact that Noonan Syndrome is not just caused by a single gene but may be due to several as in HCM.

Some patients with HCM may have a worse prognosis than others; some patients who have a certain gene may be more likely to die from Sudden Unexplained Death, whilst other individuals with HCM may have a normal life with little chance of dying prematurely from it.

Cardiomyopathy may cause obstruction as the heart contracts so that blood cannot get into the aorta. In obstructive cardiomyopathy a pressure gradient can be seen, but in non-obstructive cardiomyopathy the heart wall is thick but there is no obstruction. But in a few cases non-obstructive cardiomyopathy can worsen with age and end up causing obstruction and also sudden death.

HCM can develop and progress over time. The heart muscle in Noonan Syndrome and Familial Cardiomyopathy look similar with muscle disarray occurring in both, although it is possible to have massive hypertrophy without obstruction.

The familial kind of HCM may not show up until the teenage years, appearing normal in infancy. But looking at 20 patients with HCM that presented in infancy, 9 died between 1 and 11 months (7 of whom had been asymptomatic), and 13 had been symptomatic and were doing well. Only 4 had a family history of HCM, and several had obstruction of the right ventricle as well (which is not normally seen in familial HCM), so it is possible that some were actually NS patients.

Hypertrophic cardiomyopathy in Noonan Syndrome generally falls into three categories: that which is present at birth, that which develops in infancy, and that developing in early/late childhood. It can affect the right as well as the left ventricle, making it different from the more usual HCM. Muscle disarray is common in NS, and if the HCM is obstructive it may require surgery. Both types of HCM may be helped by medication.

Noonan syndrome should be suspected in infants who present with HCM, particularly if they also have valve dysplasia. There are a number of metabolic problems and mitochondrial diseases that can have HCM, but most of these don't have pulmonary valve dysplasia. It is important to look carefully for any familial features to distinguish Noonan Syndrome because symptomatic HCM presenting in infancy is a serious disease.

Some cases of HCM in Noonan Syndrome will regress, some respond to propranalol, and others seem to progress. But deaths form HCM in NS only seem to occur in symptomatic cases, and are not cases of sudden unexplained death.

Sudden unexplained death does occur in the familial form of cardiomyopathy, presumably due to arryhthmias (probably ventricular fibrillation). In a study of 37 familial cases,18 children died, of which 11 died suddenly. The mean age at death was 14 years. Of the 37 cases, 19 were asymptomatic and 18 had some kind of symptoms (eg shortness of breath or syncope). Sudden death occurred in 4 (21%) of the asymptomatic and 7 (40%) of the symptomatic patients, so although it appears that there is a higher incidence of death in those with symptoms, even those who are asymptomatic may die suddenly.

Sudden death in Noonan's patients who have HCM is not common, but can occur. The incidence however is not known, which is why large groups such as TNSSG are very important sources of information. (Dr. Noonan is intending to conduct a study into the natural history of heart disease in NS. For details of how you can help, please contact Wanda Robinson)

To summarise, hypertrophic cardiomyopathy in Noonan Syndrome is variable and may progress through infancy or be stable for many years. Prognosis is poor for symptomatic infants, and although the risk of sudden death is not known, it is thought to be slightly increased.

The management of HCM may involve the use of -blockers (propranolol), or for older children, calcium channel blockers. Surgery may be helpful in symptomatic obstructive cases, although occasionally (in very severe cases) cardiac transplant may be required.

A new method of treatment (as yet only tried in older patients) involves inducing a mild heart attack in the thickened area of septum to scar it and thus reduce it down; this has not as yet been done in children.

Lymphangiectasia is not common, but when it occurs can cause serious difficulties.

Summary

Noonan Syndrome is second only to Downs Syndrome as one of the most common syndromes associated with congenital heart disease. Of a study of 835 children with congenital heart disease, 1% were found to have Noonan Syndrome.

All patients with Noonan Syndrome need routine cardiology, hearing and eye evaluation.

Although growth hormone is sometimes used in NS, there is no data as yet to show whether or not the children treated will have an increased adult height as a result, although they do gain height more quickly at a younger age.

Noonan Syndrome occurs world-wide, affects boys and girls in more or less equal numbers, and has a very variable clinical picture. It may be dominantly inherited, or occur sporadically. It is known that there is a link to a gene on chromosome 12, but there may also be other causes - which is where studies on large groups such as those at the meeting will help.

It was suggested that more studies should be done on the dysplastic pulmonary valve to see if any clues can be found as to its cause, and then we could look for a gene that might relate to that.


The Noonan Syndrome Support Group, Inc. and any associated parties will not be held responsible for any actions readers take based on their interpretation of published or disseminated material. Please review medical treatment and decisions with your physician.