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Keywords:

  • Noonan;
  • short stature;
  • growth hormone

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Short stature is a very common manifestation of Noonan syndrome (NS) and is accompanied by a variable delay in bone age. Although reports of adult height in NS are uncommon, some feel growth hormone therapy will increase adult height. We report our findings in 73 adults over 21 years of age with NS. Thirty percent of this group had an adult height in the normal range between 10th percentile and 90th percentile. Over half of the females and nearly 40% of males had an adult height below the 3rd percentile. The presence or severity of heart disease was not a factor, and none of the adults with a normal height had been treated with growth hormone. Serial measurements of height for many years through childhood to adulthood were available in only a few patients, but their pattern of growth suggests catch up may occur in late adolescence. To evaluate the benefit of growth hormone therapy, long term serial height measurements over a period of years comparing treated and untreated patients are needed. It will be important to determine what role, if any, the mutated PTPN 11 gene plays in the short stature common in NS. © 2003 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Short stature is a very common manifestation of Noonan syndrome (NS) [Noonan, 1968; Sharland et al., 1992] and is accompanied by a variable delay in bone age. Although growth hormone deficiency is not commonly found, growth hormone therapy is frequently recommended and is felt, by some, to increase ultimate adult height. Unfortunately, few measurements of adult height have been reported [Romano et al., 1996]. Witt et al. [1986] reported growth curves for height in NS. Eighteen males over 18 years of age had a mean height of 161.0 cm (63 ½ in) and 19 females had a mean height of 150.5 cm (59 ½ in). Ranke et al. [1988] reported 20 males over 19 years of age with a mean height of 162.5 cm (63 ¾ in) and 18 females with a height of 152.7 cm (60 in).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We report the results of a study of 73 adults over 21 years of age. Twenty-two adults were seen in a NS support group meeting, 23 were patients seen by Dr. Jacqueline A. Noonan, 28 patients were previously reported in the Witt et al. [1986] publication. There were 29 male and 44 female adults (Table I). Instead of reporting a mean value, all heights were plotted on a standard growth chart. Two separate groups emerged (Figs. 1 and 2). Nine of 29 males (31%) had heights in the normal range that ranged between 10th percentile and 90th percentile. The remainder were all 167 cm (66 in) or less, and fell below the 10th percentile. Of the 44 females, 13 (32%) had a height in the normal range between 155 cm and 173 cm (61–68 in). The remainder were all 60 in or less and ranged from 132 cm to 152 cm (52–60 in) and were below the 10th percentile. There was no apparent height difference among the NS support group, Dr. Noonan's patients, or the Witt et al. patients (Table I). The presence or severity of heart defects was not a factor in ultimate height. Females, overall, were more severely affected than males with 54.5% falling below the 3rd percentile while 38% of males had a final height below the 3rd percentile (Table II). These results suggest that there are two separate groups of patients with NS, one without growth failure and a more common second group whose final heights were all below the 10th percentile and with many falling below the 3rd percentile. None of the adults with normal height had been treated with growth hormone.

Table I. Adult NS Patients
Study groupsMalesFemales
NS support group1012
Dr. Noonan's patients1013
Witt et al. [1986] publication919
Total2944
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Figure 1. Adult height of males.

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Figure 2. Adult height of females.

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Table II. Adult Stature in NS
Adult heightMalesFemales
10th percentile or >9/29 (31%)13/44 (32%)
Below 3rd percentile38%54.5%

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The cause of short stature in NS is unknown. Newborns with NS are in the lower range of normal for height, but begin to fall off of the curve by 3 months of age. Growth hormone studies in NS have shown variable results and abnormalities in growth hormone secretion are frequently reported [Ahmed et al., 1991; Thomas and Stanhope, 1993]. Growth hormone secretion data, however, has not shown any relation to the response to growth hormone treatment [Noordam et al., 2001]. Although growth hormone treatment may modulate growth, there is little evidence to implicate growth hormone deficiency as the cause of short stature [Cotterill et al., 1996]. Unfortunately, there are very few reports of serial measurements in children with NS to compare the results of untreated patients with those who have received growth hormone treatment. Figures 3 and 4 are growth charts from two patients followed for many years by Dr. Jacqueline A. Noonan. Figure 3 shows a patient with a height between 5th percentile and 10th percentile at the age of 3 9/12 year. By age 7 ½, he had fallen below the 3rd percentile and remained below the 3rd percentile until he was about 17 years of age when he reached the 5th percentile. By the time he had achieved his full growth, his height, again, was between 5th percentile and 10th percentile. Figure 4 is another patient who ended up with a height in the normal range. His height, at the age of 6, was between 10th percentile and 25th percentile. By the age of 13, it had dropped to 3rd percentile and fell below the 3rd percentile by the age of 15. His height then slowly increased and at 21 years of age, he was, again, between 10th percentile and 25th percentile. Since patients with NS do have a delay in bone age, growth hormone therapy would be expected to cause acceleration in height. Unfortunately, this is accompanied by a similar acceleration of bone age. It is likely that growth hormone therapy will accelerate the time to which patients reach adult height. There is still little evidence to show the ultimate adult height will be significantly increased in NS. Should bone age acceleration exceed the acceleration in height, it is even possible that growth hormone therapy could actually decrease the adult height. Long term, serial, height measurements over years comparing treated and untreated patients is needed to clearly show the benefit of growth hormone therapy [Municchi et al., 1995].

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Figure 3. Growth chart of patient with short stature.

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Figure 4. Growth chart of patient achieving normal height.

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Short stature certainly can be extreme in some patients with NS and it would be helpful if the cause of this short stature was known. It is likely that there is a genetic cause for this growth failure. Recently, a missence mutation in the PTPN11 gene [Tartaglia et al., 2001] has been found to be present in about half of the patients with NS. It will be of interest and importance to do genetic studies on patients with NS who have normal height as well as those with short stature to see if there is a relationship between the mutated PTPN11 gene and short stature.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We thank Dr. Judith Allanson for providing the heights of patients from the Witt et al. paper. We also thank Wanda Robinson and the NS support group for their help.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES