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Growth Hormone Therapy and Growth in Children with Noonan’s Syndrome: Results of 3 Years’ Follow-Up*

Department of Child Life and Health (C.E.M., D.C.B., C.J.H.K.), University of Edinburgh, Edinburgh EH9 1UW; Departments of Genetics and Cardiology (M.A.P., W.J.M.), St. George’s Hospital, London SW17 OQT; Department of Endocrinology (L.B.J., M.O.S.), St. Bartholomew’s Hospital, London EC1A 7BE; and Department of Paediatrics, John Radcliffe Hospital (D.B.D.), Oxford OX3 9DU, United Kingdom

Address correspondence and requests for reprints to: Dr. C. J. H. Kelnar, Department of Child Life and Health, University of Edinburgh, 20 Sylvan Place, Edinburgh EH9 1UW, United Kingdom. * Supported by Serono Laboratories, Inc., United Kingdom.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Growth data from the first 3 yr of a multicenter study examining the efficacy and safety of recombinant human GH [rhGH; 4 IU (1.3 mg)/m²·day, sc] in children with Noonan’s syndrome (NS) are reported for 23 subjects. Sixteen male and seven female patients (age, 9.3 ± 2.6 yr at onset of GH therapy, mean ± SD; range, 4.8–13.7) were each assessed at 1, 2, and 3 yr after starting treatment. Comparisons were made with a group of eight subjects (six males and two females, age, 9.0 ± 4.1 yr; range, 4.1–14.8) with NS, not treated with rhGH, measured over the same period. All treated subjects underwent annual cardiac assessment.

Height SD score increased from -2.7 ± 0.4 at the start of GH therapy to -1.9 ± 0.9 3 yr later (P < 0.001, two-tailed t test). This corresponded to an increase in height from 116.1 ± 13.2 to 137.3 ± 14.0 cm. Height velocity increased from 4.4 ± 1.7 cm/yr in the year before treatment to 8.4 ± 1.7 (P < 0.001), 6.2 ± 1.7 (P < 0.001), and 5.8 ± 1.8 (P = 0.01, two-tailed t test compared with baseline) during the first, second, and third years of GH treatment, respectively. Height acceleration was not significant during the second or third years when pubertal subjects were excluded. The comparison group showed an increase in height from 116.0 ± 19.8 to 131.9 ± 21.1 cm over the 3 yr (height SD score, -2.7 ± 0.6 to -2.4 ± 0.7, P = 0.3). None of the 23 children developed hypertrophic cardiomyopathy during GH treatment.

The increase in growth rate in NS resulting from 1 yr of GH therapy seems to be maintained during the second year, although height velocity shows a less significant increase over pretherapy values. Possible abnormal anabolic effects of rhGH on myocardial thickness were not confirmed, and no treated patient developed features of hypertrophic cardiomyopathy.

	Introduction

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IN 1963 NOONAN and Ehmke (1) described six male and three female patients with supravalvar pulmonary stenosis and a distinct clinical appearance. Short stature, hypertelorism, and mild mental retardation characterized these children. Ptosis, down-slanting palpebral fissures, low-set posteriorly rotated ears, undescended testes, and skeletal malformations are noted in some cases (2, 3, 4, 5, 6, 7). Noonan’s syndrome (NS) is an autosomal dominant condition with an incidence of between 1 in 1000 and 1 in 2500 live births, with equal male to female ratio, 50% of cases being sporadic. It is diagnosed clinically, but the gene for NS has recently been mapped to chromosome 12 (8, 9). The characteristic cardiac anomalies are pulmonary valve stenosis (62%) and left ventricular (LV) hypertrophy (20%; Refs. 4, 5 , and 7).

Growth retardation is a consistent feature, with the majority of affected patients having height below the third percentile (4, 10, 11, 12). Children with NS are not usually GH deficient, although there may be abnormalities in the GH/insulin-like growth factor axis (13, 14, 15, 16). Recombinant human GH (rhGH) has been shown to improve growth rate in patients with NS in a similar fashion to that seen in patients with Turner’s syndrome (15, 17, 18). A major concern regarding the use of rhGH had been that there may be a risk of alteration of cardiac function, particularly the development or deterioration of LV hypertrophic cardiomyopathy (HCM). This was shown not to take place during 1 yr of therapy in our previous study of rhGH in 30 children with NS (19). Three years of growth data following commencement of GH are now available for 23 of these subjects.

	Subjects and Methods

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This multicenter study was designed to evaluate the efficacy and cardiac safety of 3 yr of rhGH therapy in children with NS. The study was approved at each center by the local Ethics Committee. Parents and children over 12 yr gave written informed consent.

Subjects and diagnosis of NS

The diagnosis was made by a single clinical geneticist (M.A.P.) based on the typical facies, normal karyotype, and, in addition, at least one of the following features: cardiac defect, short stature, coagulation defect, and undescended testes in the male (4, 5). Criteria for entry into the study are shown in Table 1. Of the 30 subjects in the original study, growth data for 3 yr following commencement of GH was available for 23 subjects (16 males and 7 females; age, 9.3 ± 2.6 yr; range, 4.8–13.7). Of the seven subjects for whom 3 yr of growth data were not available (three males and four females; age, 7.4 ± 1.6 yr; range, 5.2–9.9), three had withdrawn from the study voluntarily, one emigrated, and three failed to attend for appropriate review.

The growth of a group of eight children with NS, not treated with GH (six males and two females; age, 9.0 ± 4.1 yr; range, 4.1–14.8), was monitored over a 3-yr period for comparison (Table 2, subjects 41–48).

After recruitment, rhGH (Serono Laboratories, Inc. Ltd., Middlesex UK) was administered in a dose of 4 IU/m²·day (0.33 mg/kg·week). The standing height (by stadiometry), weight, and pubertal stage of each child were assessed every 3 months, and the dose of rhGH was adjusted according to changes in body surface area. Empty vials were collected at each visit, and an assessment of compliance based on these returns was made. Blood sampling for hematology screen and biochemistry (renal function, liver function, triglycerides, cholesterol, T₄, thyroid-stimulating hormone, and HbA1/HbA1c) was carried out every 6 months. Echocardiograms were recorded, or videos reviewed, by a single author (W.J.M.) at the start, after 12 months, and after 3 yr of treatment. Each patient was studied with a combination of M-mode and two-dimensional echocardiography at 8-, 12-, 16-, or 24-cm depths using a 2.5 or 3.5 MHz transducer with a Hewlett-Packard Co. (Palo Alto, CA) 1000 ultrasound scanner. Wall thickness measurements were made at the quadrants from short axis views at mitral valve and papillary muscle level and, where possible, more distally in the left ventricle guided by the apical image from the four-chamber view.

	Results

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Anthropometry

Height data were converted to SD scores for chronological age using United Kingdom standards (11, 12). Of the 23 subjects analyzed on an "intention to treat" basis, over 3 yr height rose from 116.1 ± 13.2 to 137.3 ± 14.0 cm, corresponding to increases in height SD score from -2.7 ± 0.4 to -1.9 ± 0.9 (P < 0.001, two-tailed t test). Height velocity (HV) increased during therapy from pretherapy HV 4.4 ± 1.7 cm/yr to 8.4 ± 1.7 (P < 0.001 vs. pretherapy), 6.2 ± 1.7 (P < 0.001), and 5.8 ± 1.8 (P = 0.01) during the first, second, and third years of therapy, respectively (Table 4). During the first year of therapy, 18 (78.3%) of the 23 subjects had an increase in HV of 2 cm or greater per year. During the second and third years this figure fell to 12 (52.2%) and 7 (30.4%), respectively.

A comparison of the 19 fully adherent subjects with the comparison group revealed similar trends in HV (yr 1, 8.4 ± 1.5 cm/yr, P < 0.001 vs. comparison group; yr 2, 6.4 ± 1.5, P = 0.19; yr 3, 6.2 ± 1.6, P = 0.14), suggesting that nonadherence is not responsible for the drop in height acceleration during yr 2 and 3.

Echocardiographic evaluation

Echocardiographic evaluation was performed before GH treatment in all 23 children. Cardiac abnormalities were common (Table 2). No significant changes were observed after 12 months. After 3 yr of GH treatment, 14 of the 23 patients were reevaluated at St. George’s Hospital (London, UK). One, who at initial evaluation had mild LV hypertrophy, had no change in wall thickness measurements, which, after growth, were within normal limits for size. Two others developed mild increase in LV wall thickness to the upper limit of normal for age and body surface area, without other features of HCM. One underwent a successful surgical right ventricular outflow tract procedure without complication. The remaining 11 subjects showed no significant change. The nine subjects who did not undergo reevaluation at St. George’s Hospital had electrocardiography and/or echocardiography performed at their local centers, with no evidence of HCM.

Prepubertal and early pubertal subjects

Before completion of 3 yr of GH therapy, four boys attained mean testes volume (TV) of 8 mL or greater, and one other boy reached a TV of 4 mL. The age of these five boys at reaching genitalia stage 2 was 12.9 ± 0.9 yr. Four girls reached breast stage 2 (B2) at age 12.1 ± 1.4 yr. To ensure that significant growth acceleration was not only due to pubertal progress, those children who had advanced into puberty [girls, B2, n = 4; boys, TV 8 mL, n = 4) were excluded from a separate analysis of clinically prepubertal (girls) and pre/early pubertal (boys) subjects.

The HV of the remaining 15 children increased from pretherapy values of 4.7 ± 1.8 cm/yr to 8.2 ± 1.8 (P < 0.001 vs. pretherapy), 5.8 ± 1.6 (P = 0.09), and 5.9 ± 1.9 (P = 0.09) during the first, second, and third years of therapy, respectively. Thus, height acceleration was only significant during the first year of GH therapy for children who did not advance to a stage of puberty that might be expected to enhance growth.

Hematology and biochemical analysis

There were no abnormalities noted in hematology screening or biochemistry (renal function, liver function, triglycerides, cholesterol, T₄, thyroid-stimulating hormone, and HbA1/HbA1c) during the 3 yr of therapy.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study investigated the effect of 3 yr of rhGH therapy on growth in children with NS. The results of the first year of GH therapy in these children have already been published (19).

A single clinical geneticist (M.A.P.) confirmed the diagnosis of NS in all the children studied. This was important because the phenotype varies widely even within families (9). The syndrome has been difficult to differentiate from other similar syndromes, for example, cardio-facio-cutaneous syndrome. However, a gene mapped to chromosome 12 is now thought to be responsible for some 80% of familial cases of NS (8). Further understanding of the pathogenesis of short stature in this condition may lead to more specific targeting of therapy.

In the first study of 30 subjects, GH therapy increased HV by 2 cm/yr or more in 80% of the children (19). This study demonstrates a significant increase in HV in children with NS during the first year of GH treatment. This trend is maintained during the second year of treatment, albeit with a less significant increase over the baseline value.

In normal children, GH and the sex steroids estradiol and testosterone act synergistically to stimulate overall growth at puberty. Boys reach a maximum HV in late puberty at around 12 mL TV; girls reach peak HV at B2 to B3, and velocity is decelerating by menarche. The onset of puberty in some NS children is delayed in this and other studies (20). The eight children likely to have had pubertal growth acceleration were excluded from the analysis of data in the second part of the results. Regarding only girls at stage B1 or boys with TV 8 mL or less, HV increases (compared with pretherapy and comparison values) remained significant only for the first year of therapy.

The effect of prolonged administration of high-dose rhGH must be monitored for metabolic complications such as increase in lipids or glycemia. There were no changes in HbA1/HbA1c, triglyceride, and cholesterol over the 3 yr of GH therapy in this study. Addressing concerns regarding the risk of rhGH in the development and deterioration of HCM, in this study no patient showed any indication of incipient ventricular hypertrophy or any feature diagnostic of HCM on echocardiography. The entry criteria for this study, however, excluded subjects with any clinical features of HCM. It remains our practice to exclude cardiomyopathy before rhGH administration.

Because the number of children in our study is relatively small, following them through to final height will provide yet more valuable data. Additional studies, for example, looking at intermittent GH therapy, may identify the optimum treatment regimens to enhance growth in these children (21). It may be significant that studies demonstrating more sustained growth improvement in NS have used doses of rhGH similar to those used for Turner’s syndrome, rather than the dose used here, which compares with that used for children with GH deficiency (22). Concerns regarding the possibility that rhGH may lead to the development of HCM associated with NS were not confirmed.

	Acknowledgments

Received January 22, 2000.

Revised May 24, 2000.

Revised January 19, 2001.

Accepted January 22, 2001.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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