Bryan Hall M.D., Chief Professor of Pediatrics
"Noonan syndrome: An overview plus discussion of other similar entities"
Dr Hall began by commenting that from all the parent group meetings he had attended he felt that had gained far more information than he had given out. This is because a lot of day-to-day worries and problems that we may have with our children may not otherwise be recognised by the medical profession, as parents may feel that they are not necessarily medical or not important enough to share with the doctor on a one-to-one basis. But in actual fact these are things that doctors would like to find out about, even though they can't necessarily provide any answers, and in group meetings it is possible to get very useful factual information within a very short period of time.
He went on to add that sometimes he could raise a question which he thought would give a negative answer, only to find that many parents will say "my child does that" or "my child doesn't do that", and this can be extremely useful.
Dr Hall then went on to show a sequence of slides showing children with Noonan Syndrome, and the following is a summary of his comments.
Noonan Syndrome is actually a very common disorder, and from a listing of the most common disorders that were seen at the University of Kentucky between 1981 and 1995, NS was about the 5th most common among multiple congenital anomaly syndromes. But it's actually more common than this as not all NS patients get seen or included in the figures. Also, physicians in general don't seem to be particularly good at diagnosing NS (although almost all of them have heard of it), many cases may be misdiagnosed.
The web neck and the ptosis (droopiness of the eyes) can often lead to misdiagnosis as there are many conditions that can have these features, and that along with the pectus excavatum, again leads many physicians astray as there are many syndromes that can mimic this.
Looking at a typical child (of around 8-10) with NS, you will notice the light coloured irises of the eyes, curly hair, and flat-appearing nose, and relatively flat cheekbones make the mandible or lower jaw look a lot larger. There are also low-set and somewhat thick ears, but the often the most striking feature are the beautiful eyes, which are very typical.
Diagnosis of NS is largely by facial features and so these are extremely important. And because they're variable in the degree in which they are expressed, Noonan's individuals can look quite different one from the other, and also age is a major factor.
The new-born can be quite difficult to diagnose facially because of the fat cheeks, and the oedema, and in some cases a diagnosis is only suspected and has to be followed up. But it is possible to make a diagnosis based on the heart findings.
The short stature is proportionate, meaning that there is no undue shortness of any area of the body, and is also not specifically reflected in the child's health. Many individuals with NS will be short regardless of their health and regardless of their cardiac status. But because they have a number of problems relative to poor tone in early infancy, feeding, they often fail to thrive and that will often accentuate their smallness. So there's two factors going on many times in the shortness, particularly early along and if they have many illnesses.
The ptosis (down-slanting eyes) is very typical, because the cheekbones are normally flat and so don't support the lower eyelids, so that the eyes slant downwards. There's actually a fairly high nasal bridge; the reason that many children with NS look like they have a flat bridge is because the bridge is wide, and the width of the bridge gives an impression of space and flatness. But even in the new-born the nasal bridge is already well-developed and relatively high, even though it may give an appearance of being flat.
There is often malar flattening (flat cheekbones), and a high palate (roof of the mouth). But note that most patients with NS don't have hypertelorism (wide-spaced eyes); they usually have inter-pupilary distances (the major measure of hypertelorism) in the 70th-80th percentile, so they're wider than average but they're not out of the range of normal. A few will have truly wide-spaced eyes, but if you look at some of the medical reports, they don't actually measure the inter-pupilary distance, but just make the general comment the patient has wide-spaced eyes.
The web neck occurs often, and because the skin doesn't follow the contours of the shoulders, it takes on a more diagonal appearance. The extra skin on the nape of the neck is as a result of extra fluid in the foetal development. Patients with NS do not actually have short necks and the vertebrae are normal; the neck simply looks short because the webbing reduces the impression of distance. This may also makes the hairline appear low-set, where in actual fact it is not. So a lot of terms are used in NS as if they were real whereas in fact they're imaginary; they're simply the appearance thereof. So in some instances that helps to rule out other conditions, because there are actually very few short-neck syndromes in genetics.
Dr Hall then showed a picture of an older girl with more marked ptosis than many patients with Noonan's have, and said that in many cases patients with N don't have ptosis at all. Ptosis is the droopiness of the upper eyelid that incringes on the pupil, and can effect vision in that those with ptosis may have to tip their head back a little so that they can see. This appearance may accentuate the misconception that these children are dull or retarded, but they're not. Another thing that you may see is the sclera (white areas) below the iris at 6 o'clock. You shouldn't see those, and that's why there's a down-slanting appearance to the eye, because the cheekbones below the lower lid are so underdeveloped that they don't support the lower lid and it drops or droops. The girl also had flat cheekbones, which made the mandible (jaw) look larger. It is often said that children with NS have a small lower jaw or mandible, and on occasions they do. But more often as they get older they are said to have a prognathic (larger than average) mandible, but which in fact is actually a normal mandible that looks large because the upper part of the face, specifically the cheekbones, are too flat.
Another common facial feature is epicanthal folds (in the inner corner of the eye), and these can be very dramatic. But as the bridge of the nose grows these folds generally dissipate; if the child genuinely has wide-spaced eyes, these folds may persist for a number of years and may never go away, but in most children they do.
The hair in NS is often very curly, and although in some cases it may be straight, most will have some degree of curling and some will be quite dramatic.
There seems to be a subset of children with NS that not only have down-slanted eyes and ptosis, but the orbits in which the eyes sit are smaller so that the eyes protrude more, and it tends to relate more to those that so actually have wide-spaced eyes.
Pectus excavatum (or caved-in chest) is often seen in NS. This is the most common type of chest deformity, and frequently with pectus excavatum you will get also a pectus carinatum, (a prominent chest), and often the upper part of the chest is prominent and the lower part depressed, so usually you will get both pectus carinatum and pectus excavatum in the same individual. This also distorts where the nipples are placed, making them appear widely spaced.
Cryptorchidism (failure of one or both testes to descend) happens in over 50% of the males.
A typical ear for an individual with NS, looking small but usually measuring in the 10-25th percentile, and their major characteristic is that they are thick all over; the superior helix, posterior helix, inferior helix, lobule, even the tragus and antitragus are all thick. They also tend to be low-set and retroverted, i.e. slope backwards.
Some children with Noonan's tend to have a reduced muscle mass, and it makes their shoulders muscles and in some cases the muscles in their limbs look thinner, and in fact they are thinner, although it's not know why.
Less common clinical features include lymphoedema, naevi, macrocephaly, iris coloboma, and sometimes contractures of the fingers, which are also uncommon.
The lymphoedema is of interest as there are many syndromes including Turners which can have oedema of the hands, feet and neck at the time of birth. But lymphoedema of the limbs in Noonan Syndrome is relatively rare; the oedema that causes most problems in Noonan's children is the oedema that can get into the lungs, and this occurs more often and can lead to trouble breathing. Oedema of the intestines has also been seen, with some associated absorption problems.
The naevi that may occur are usually dark brown or black spots on the skin that can sometimes be confused with neurofibromatosis.
About 45% of patients have a large head (macrocephaly), although very small percentage will actually have a small head. Macrocephaly does not normally lead to any problems, although a few of these children can actually have hydrocephalus and need medical intervention because of it.
The facial appearance tends to change with age: the younger child is broader and fuller faced, but as they get older the majority tend to become very thin-faced, particularly in adulthood. There are however exceptions.
But this changing phenotype is one of the reasons that doctors may have trouble diagnosing the adult with NS, because their idea of NS is that of the typical child.
Other non-physical problems include coagulation defects; bruising is common in children with NS, and about a third will actually have detectable problems with bleeding such as low platelets or Factor XI deficiency, or mild von Willebrand's disease. Some of these children may need to be treated before surgery, but most are asymptomatic.
Delayed or inadequate puberty can occur in both males and females, but marked reduction in fertility can occur in males, mainly due to the failure of the testes to descend. A percentage will also have thyroid problems; usually asymptomatic and only picked up when they are studied.
There is a questionable progressive hydrocephalus; there have been more cases reported in which the hydrocephalus has progressed requiring shunting later in childhood than those who have had required shunting at birth.
Seizures are of low frequency, hearing problems occur in between 2 an 12% of the children, no major behavioural problems, although there may of course be individual idiosyncrasies.
There is an ongoing behaviour study run by Dr Witt, and you would expect specific syndromes, since they involve the same gene, to have recurring behaviour profiles that may or may not be good. But you need to know what they are to explain why your child does or doesn't do certain things.
The incidence of Noonan Syndrome is about 1:1000 to 1:2000. It's a dominantly inherited condition, meaning that a single gene in a person will give you the Noonan's phenotype and medical problems. Estimates of the number of inherited cases (i.e. where one of the parents have NS) vary between 10% and 35%.
The affected gene has been isolated to a particular area of chromosome 12, but there may also be other genes involved. If you have the affected gene then you will show it, but it has a variable expression in the individual so that each individual will have more or less of the problems and physical characteristics.
In familial cases the expression from parent to child is not predictable; a parent with a milder expression of Noonan's can have a child who appears more severely affected, or vice versa. Where parents are only mildly affected, they are often only diagnosed when they have a child with NS.
Polydactyly may be a low frequency of NS, and low frequency can be important because they confuse doctors and make them think of other syndromes and consequently misdiagnosis can occur.
Dr Hall then went on to discuss other syndromes that can mimic and be confused with Noonan Syndrome (some more than others).
Watson Syndrome is a syndrome associated with café au lait spots (brown spots on the skin), pulmonary stenosis, and sometimes short stature and ptosis. Some individuals actually have neurofibromas under the skin, and it's thought that patients with Watsons have some form of Neurofibromatosis, the gene for which is on the long arm of the 17th chromosome. And so they are often called allelic, meaning that they are very similar.
A typical female with Turner's syndrome has the chest deformity, the wide-spaced nipples, the web neck, cubus valgus (an inability to hold the arms down by the sides). A few patients with NS also have cubus valgus. But patients with Turner's are always female as they only have one X chromosome, which is why initially boys showing similar symptoms were said to have 'Male Turners'; in fact these patients all had Noonan Syndrome.
A picture of a boy showing typical symptoms of Nerurofibromatosis was shown, displaying multiple café au lait spots, and lumps all over his body - neurofibromas, ptosis of the eyelid, pectus excavatum, and also pulmonary stenosis. But despite the similarities with NS, individuals with NF do not have the abnormality of the gene on the 12th chromosome known to occur with NS, so this is something different .
Cardiofasciocutaneous Syndrome (CFC) is often misdiagnosed as NS as the children often have down-slanting eyes, flat malar bones, low-set ears, marked problems with the hair (irregular and/or coarse), and often very dry skin and sometimes icthyosis (scaliness of the skin). The are often more severely mentally retarded than individuals with NS, and we do not know specifically the ideology for this disorder.
The Costello Syndrome, Meisner Rabson-Mendenhall Syndrome, Multiple Lentigenes Syndrome, Villonodular Synovitis, and King Syndrome are also ones that can be confused with NS.
Costello Syndrome may have many of the same features (e.g. the dry skin and the curly hair), but they have large lips, very hyperextensible fingers, and very deep creases on the hands. This is also a recessively inherited disorder, so parents of this syndrome can be carriers, unlike in NS.
Patients with Meisner, Rabson-Mendenhall Syndrome may have hypertrophic cardiomyopathy or something similar to what is seen in NS, very curly hair, some ptosis, and very dry skin, but this is an insulin disorder. Another feature is Acanthosis nigricans, or darkening of the skin wherever it is compressed, and this is also a recessive disorder.
Multiple Lentigenes Syndrome may also be confused with NS as these patients may be short, they can have PS, hearing loss, and pectus excavatum. But the face is different and the multiple pigmented spots are far in excess of what you would see in NS. This a dominantly inherited disorder.
Villonodular Synovitis can be confused with NS (particularly early on) because of the short stature, PS, flattened malar bones, and ptosis, but can be differentiated by the severe problems in the joints, that don't occur with NS. All the cases so far have been sporadic, so the genetics is not known.
King Syndrome is a syndrome which is a myopathy - the muscles are not normal and are usually very thin and weak. This can make the face look myopathic (not much expression) and causing drooping of the eyelids. These individuals have problems anaesthesia - malignant hypothermia.
Other syndromes that can be confused with NS include Klippel Feil Syndrome, Pterigium and web-neck Syndromes, Ptosis or Blepharophimosis Syndrome, Coffin-Lowry Syndrome, Williams Syndrome and Aarskog Syndrome.
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