Dr. Alicia Romano

In 1998 here is what Dr. Romano reported at out meeting:

Alicia Romano M.D., Director of Paediatrics: Noonan Syndrome, Endocrinology and Growth Hormone

To date there have been no double-blind, placebo controlled studies that clearly show that Growth Hormone is both safe and effective in Noonan Syndrome. These studies would involve dividing similar patients with NS into two groups, one of which is treated with GH and the other not, and looking at their final adult heights. It is not therefore possible to say with any certainty that use of GH is safe or beneficial. There is data available but it is incomplete, which puts anyone with a child with NS in the difficult position of having to make a decision about their child's growth and use of GH without knowing all the facts. It is therefore important to learn about Growth Hormone, although it should be appreciated that its use in Noonan Syndrome is not medically indicated, but simply cosmetic.

The data that is available does not relate to final height as the children involved have not yet finished growing; and by the time that this information is available, most of the children attending this conference will be beyond the age at which they can still receive GH. So as was mentioned before, we unfortunately have to make a decision on whether or not to give GH at a time when there is still incomplete information.

Noonan Syndrome is relatively common, and has a compilation of features including short stature; more than 80% of those with NS will be shorter than average. Although the birth weight and length is typically normal, there is often progressive growth failure with time, with most children falling on or below the 3rd centile on the growth charts. (There are in fact special growth charts available for children with NS.) The final mean adult height is 152cm (5') for females, and 162cm (5'4") for males. However there will always be some who are taller and some who are shorter.

The hypothalamus and pituitary glands lie inside the head, the hypothalamus controlling the pituitary gland and stimulating it to produce growth hormone. Growth hormone then circulates throughout the blood stream and has direct effects on tissues responsive to growth; it also probably mediates growth through the production of other growth factors, one of which is IGF1 (Insulin-like Growth Factor 1). All of these hormones increase cell proliferation and protein synthesis, and cause growth. Much of this growth is epiphysial, i.e. occurs at the ends of the long bones (the 'growth plates').

Many children with delayed growth will have their bone age determined; this is assessed by x-raying the hand and wrist and looking at the epiphysial area to see how open it is and thus how much growth potential is available for the child.

At different stages in development children develop at different rates, and infancy and puberty are two periods when the growth rate is highest. (Growth tends to slow a little during childhood.) In children who do not have Noonan Syndrome the average growth rate is 2 to 2" per year, which will maintain the child on the normal growth chart. It is very important in terms of monitoring growth that the growth parameters are measured at regular intervals and plotted on an appropriate growth chart; if measurements are sporadic they are not as useful.

Often in paediatric offices once children learn to stand they are measured standing up instead of lying down, thus measuring height as opposed to length. These measurements can be quite different, and only length should be plotted the specific growth chart for children 0 - 36 months of age; if height is plotted on a length chart, the child can appear a lot shorter than they actually are.

When a child is evaluated due to growth problems, the child's history will be record and physical examinations, laboratory tests, x-rays and further studies may be done. The physical will include evaluation of height and weight over time, and screening tests that may be done are:

Bone age x-rays look at the epiphysial centres of growth to see how much growth potential the child has left. Most children with NS have delayed bone age, which is actually good because it means that they have an increased potential for growth. If a child of 10 has a bone age of 8, then it means that they have the growth potential of an 8 year-old, and should thus have an extra 2 years of growing potential left. Sometimes 'scatter' may be mentioned, which means that some parts on the x-ray may appear older than others, but this is quite common and no cause for concern.

A lot of the evaluation done for growth is to make sure that the child is basically well and there is no other illness that could be affecting growth; the most important of these is malnutrition. Many children with Noonan's have a lot of feeding problems in the first few years of life, but beyond that as children get older, very often their food preferences don't give them and adequate calorie intake for growth. This may be particularly common in families who follow low-fat diets where there is not a lot of fatty food in the house. Very often when children are seen who are very thin and are not getting adequate calories, the first thing that will be done is just to try to increase the calorie intake. Beyond the toddler stage, when feeding problems are not such an issue, we need to make sure that children eat enough calorificaly dense food, for example whole milk as opposed to skimmed, giving extra snacks etc.

Other endocrine causes for poor growth include and under-active thyroid gland; all children with growth problems should be tested for this, and it can be easily treated.

Assuming a child is not growing and that preliminary tests have ruled out other reasons for slow growth, eventually we may consider whether or not the child produces adequate growth hormone.

Growth Hormone mediates growth in children and is secreted by the pituitary gland in pulses around 8 times per day. The level is therefore not constant but peaks at times during the day, which is why random GH tests are useless in children as they may give misleading results due to the growth hormones episodic release. So growth hormone levels are usually tested using stimulation or provocative testing. These tests give standardised results by looking at the body's ability to secrete GH in response to agents given to stimulate its production (e.g. clonidine, l-dopa, and others) This is similar to glucose tolerance testing. To test for GH, a baseline level is obtained and then a suitable substance given to the child to stimulate GH production. Blood is then tested every half hour for 1 to 2 hours to see whether GH is secreted; a level of 10 or greater is considered to be adequate. (Before approving a child for GH therapy, most insurance companies will insist that at least 2 provocative tests have been done, and that the GH level was found to be less than 10.)

Some centres may use other tests such as overnight sampling every 10 minutes as so, but these are not thought to be as accurate.

To qualify for growth hormone therapy, the following criteria are normally required to be met:

However, many children being treated with GH today are actually found to make GH by the provocative tests, and they are given GH because they still do not grow sufficiently. This may be because although they produce growth hormone in response to the agents given for testing, they do not produce enough spontaneous GH, or because the GH they are making may not be a bioactive form. Paediatric endocrinologists still don't really have all the answers as yet, and views on treating children who are not growth hormone deficient with GH vary.

Growth Hormone first became available in 1965 when it was obtained from the pituitary gland of cadavers. But some of this cadaveric growth hormone was found to be contaminated with infectious agents and in some cases caused fatal disease, and so it was taken off the market in 1985 when biosynthetic GH became available. This meant that it was no longer necessary to use cadavers as large quantities of synthetic GH could be produced in the laboratory that was totally free of contamination. Synthetic GH has been approved and used since 1985.

But should growth hormone be thought of as some sort of 'wonder drug'? Despite the fact that it's effects are purely cosmetic, kids who are short can be very aware of the fact and may suffer from teasing and bullying at school, and so often an increase in height can be quite beneficial.

Dr Romano described the case of a boy who at the age of 10 had started to 'fall off' the growth chart. His mother was only 4'11" and his father 5'1", so for years physicians had told him that his short stature was familial and that nothing could be done about it. He was evaluated when he was 14 and had two stimulation tests, and was found to have GH levels of around 18. But his predicted adult height was only 5'1", and in the United States males with a predicted adult height of less than 5'5" are usually considered to be candidates for GH therapy. He was therefore given GH on a trial basis to which he showed an excellent response, despite the fact that he was shown to produce GH himself in the stimulation tests. When he started college he was 5'7" tall, and made the decision himself to discontinue GH treatment.

His brother fell off the charts at a slightly earlier age and was actually found to be GH deficient when tested at 9 years of age. He was given GH, and at 13 he is now on the growth chart.

However not everybody that doesn't grow needs growth hormone. A little boy was mentioned whose growth was actually on the growth chart around the 5th centile, but would have been expected to have been nearer to the 25th to 75th centiles based on parental height. But it turned out that the boy was a very poor eater and was terrified of using the bathroom at school, so wouldn't eat anything all day. When his diet was changed he started to grow and gain weight, emphasising the fact that nutrition is also very important.

Growth hormone therapy can also produce good results if given later on: a patient with NS was seen at 16 years of age and was on the 5th centile on the charts. He was started on GH therapy and is now on the 10th centile, and his bone age indicates that he still has around a years growth potential left.

A few studies have been published on GH therapy in Noonan Syndrome, although generally they have been short-term and with small numbers of patients. In 1995 a paper was published by Dr Romano et al summarising the NCGS data from Genentech, which followed 150 children with NS on GH therapy. The response of these children was compared to the response to GH of 2000 Turners patients, and 8091 patients with GH deficiency.

Looking at the age that therapy was begun, the patients with NS were on average a little older (10 yrs) than those with GH deficiency, but looking at their bone age the patients with NS had a much greater bone age delay. However the baseline growth rate of the groups was similar, with NS patients growing an average of 4.3 cm/year and the GH deficient children an average of 4.5 cm/year. After a year of GH therapy, the children with NS were found to have grown 8 cm/year, and those with idiopathic GH deficiency 9.8 cm/year. Growth continued through years 2, 3 and 4, but at a continuously decreasing rate; however this was still greater than the rate of growth pre-treatment.

Compared to patients with Turners Syndrome, children with NS grow substantially more. Growth Hormone was approved by the FDA around a year ago for use in Turners Syndrome, but the response in patients with NS is actually better.

From this study it was concluded that no significant adverse events were seen in NS patients when treated with growth hormone, although this was only a small trial of 150 patients. One patient had transient joint swelling and another joint aches and pains, but nothing that was believed to be related to the GH.

The Noonan's patients in this group were considered small even by NS standards, and it was interesting to note when looking at their GH testing results, around a half were GH deficient, and the other half not. All obviously had poor growth and were not growing well, and some still made GH on provocative testing, so it seems that even if a child is making GH, it does not necessarily mean that they will grow well. The other important finding was that there was absolutely no correlation between how well a child grew on GH, and whether or not they made GH on stimulation testing. So provocative testing cannot therefore be used to predict whether or not a child will grow well.

In otherwise healthy children there did not seem to be any significant side effects, and no worsening of cardiac abnormalities was seen. This was however, only a small scale, short-term study (150 children and 1 year), and so any child on GH should have cardiac screening before commencing treatment and at 3-6 monthly intervals thereafter.


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