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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 8 2740-2743
Copyright © 2000 by The Endocrine Society

Original Studies

Does Growth Hormone (GH) Enhance Growth in GH-Deficient Children with Myelomeningocele?

R. Trollmann, E. Strehl, D. Wenzel and H. G. Dörr

Hospital for Children and Adolescents, University Erlangen, 91054 Erlangen, Germany

Address all correspondence and requests for reprints to: Regina Trollmann, M.D., University Hospital for Children and Adolescents, Loschgestrasse 15, 91054 Erlangen, Germany.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GH deficiency (GHD) in patients with myelomeningocele leads to the question of whether these disabled patients should be treated with human GH. To date, only a few short-term reports of GH therapy are available in the literature, and long-term data for final height are lacking. We report auxological and laboratory data for seven prepubertal myelomeningocele patients with proven GHD (idiopathic GHD or neurosecretory dysfunction) during GH treatment.

All patients (five males and two females; median chronological age, 6.6 yr) had shunted hydrocephalus and were treated with GH (0.5 IU/kg·week; 0.15 mg/kg·week; daily sc injections) over a median period of 38 months (range, 35–49 months). GH secretion was analyzed by measurement of spontaneous overnight GH secretion and two standard stimulation tests. Auxological parameters, bone age, serum levels of insulin-like growth factor I and insulin-like growth factorbinding protein-3, and neurological and orthopedic status were documented regularly.

Median growth velocity of supine length improved during treatment (at start, 3.7 cm/yr; after 36 months, 5.7 cm/yr; P < 0.05), with highest levels 6 months after the start of therapy (8.1 cm/yr). The growth velocity of arm span was greater than these values. Supine length SD score for chronological age increased from -4.71 (at start) to -3.35 (after 36 months; P = NS), length SD score for bone age increased from -2.70 to -2.23 (P = NS), and arm span SD score increased from -2.98 to -1.75 (P < 0.05). The growth velocities of length and arm span remained significantly above the pretreatment values (P < 0.05). Symptomatic tethered cord associated with progression of scoliosis developed in two of seven children.

GH treatment significantly improved the growth velocities of body length and arm span. However, the increase in length SD score was not significant, whereas arm span SD scores significantly improved over the study period.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DUE TO INTERDISCIPLINARY long-term follow-up programs, children with myelomeningocele (MMC) have improved life expectancy and quality of life. Therefore, more attention has been placed on disturbances of growth and pubertal development of MMC patients (1, 2, 3, 4, 5, 6, 7). Several reasons for disturbed growth and development have been found. Firstly, spinal cord lesion, vertebral anomalies, and various skeletal deformities reduce the growth of the lower limbs and the spine. Secondly, due to complex central nervous system anomalies, including hydrocephalus, Arnold-Chiari malformation, midline defects, neural migration abnormalities, and morphological anomalies of the pituitary gland, patients are at risk of hypothalamo-pituitary dysfunctions, such as central precocious puberty (4, 8) and GH deficiency (GHD) (9, 10, 11, 12, 13).

During the last years, human GH has been used as a therapeutic option for short-statured (physically disabled) MMC patients with GHD, but worldwide, only a limited number of reports on short-term treatment effects are available (10, 11, 12). The longest experience has been reported by Rotenstein et al. (11), who found a significant improvement of growth velocity and height after a treatment interval of 6 months (n = 22) to 6 yr (n = 2) as well as of muscle strength and mobility (14). In this report we present longitudinal auxological and laboratory data of seven MMC patients who were treated with GH for a median period of 38 months.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

Our study includes seven prepubertal MMC patients (four males and three females) with short stature (length and arm span SD score, less than -2) and proven GHD [idiopathic GHD (IGHD), n = 4; or neurosecretory dysfunction (NSD), n = 3] (Table 1Go). The median chronological age (CA) at the start of treatment was 6.6 yr. Bone age was retarded in all patients and ranged from 2.5–7.5 yr (Table 1Go).


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  		Table 1. Endocrine data in seven prepubertal MMC patients with GHD (n = 4) and NSD (n = 3) before GH treatment

 
All patients had hydrocephalus and Arnold-Chiari malformation. Ventriculo-peritoneal shunt implantation was performed in the neonatal period. Shunt dysfunction was excluded at the time of biochemical investigation [clinical signs and magnetic resonance imaging (MRI)].

The level of spinal lesion was Th12–L2 in two, L3–L4 in two, and L5–S2 in three patients. Three patients were community walkers; others were household walkers. Scoliosis was present in two patients (Cobb grades, 36° and 57°) without signs of symptomatic tethered cord syndrome at initiation of GH therapy. One of them had required surgical release of tethered spinal cord at the age of 4.7 yr (3 yr before initiation of GH treatment). Two patients had lumbar kyphosis caused by associated vertebral anomalies.

Linear growth was assessed every 3 months during the first year and thereafter at 6-months intervals, including supine length, upper and lower segment lengths, arm span, and weight. Length was measured from vertex to sole with subject supine as straight as possible. If there were length differences between left and right sides, data for the longer side were used (with the same side at each visit). Arm span was defined as the distance between the two middle fingers (D3) with arms maximally outstretched in a horizontal position. Upper segment length was measured from vertex to symphysis (with subject supine). Lower segment length was defined as the difference between supine length and upper segment length. Measurements were made using a horizontal stadiometer and a metal measuring tape.

SD scores were calculated for each measurement (length and arm span) using age- and gender-matched length data from the First Zurich Longitudinal Growth Study (15) and arm span reference data from the report by Flügel et al. (16). The pretreatment growth rate was based on 6 months of observation. Bone age (BA) was determined every 6–12 months by the atlas method of Greulich and Pyle (17). Weight was measured without braces, and the body mass index (BMI; kilograms per m2) was calculated. BMI values were compared to the data reported by Rolland-Cachera et al. (18).

No other hormonal abnormalities other than IGHD or NSD were evident. All patients had normal thyroid function (assessed by normal basal TSH and free T4 levels) as well as normal basal cortisol serum levels.

Neuropediatric and orthopedic examinations were performed every 6 months, including x-ray of the spine every 12 months. Magnetic resonance tomography of the spine was performed before treatment and thereafter if clinical signs of tethered spinal cord were obvious.

Laboratory methods

Insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) serum levels were measured by commercial RIAs (BioMerieux, Nürtingen, Germany). During treatment, measurements were performed every 6 months.

GH secretion was assessed by spontaneous nocturnal GH secretion for 10 h (blood samples every 20 min) and two standard iv stimulation tests (clonidine, 150 µg/m2; arginine, 0.5 g/kg). The diagnosis of GHD was based on a low mean nocturnal GH secretion (<3.0 µg/L; area under the baseline, <75 µg/L·24 h) and maximum GH peaks below 10 µg/L in both stimulation tests. If the spontaneous secretion was low, but the responses to stimulation tests were normal (>10 µg/L), NSD was diagnosed. GH was measured by enzyme-linked immunosorbent assay (Pharmacia Biotech, Uppsala, Sweden).

Treatment regimen

All patients received a normal starting dose of recombinant human GH (0.5 IU/kg per week; 0.15 mg/kg per week) by daily sc injections. The median duration of treatment was 38 months (range, 35–49 months). The median GH dose for each 6-month period is summarized in Table 3Go. During our study period, the patients remained prepubertal.


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  		Table 3. SD score of IGF-I and IGFBP-3 in MMC patients (n = 7) during GH treatment (median, range)

 
Statistics

The SD score was calculated as: (x - xCA) : SDca, where x is the observed value, xCA is the value expected for age and gender, and SDca is the SD. One-way ANOVA together with Tukey-Kramer multiple comparisons test were used to calculate the statistical differences (P < 0.05) of auxological parameters during GH therapy. Reported data are shown as the median and range.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Auxological data

During GH therapy, the growth velocities of supine length and arm span improved in all patients, with highest growth rates during the first 6 months of therapy, and were significantly above pretreatment rates through yr 3 of treatment (P < 0.05; Table 2Go). During the study period, the growth rate of arm span was better than that of supine length in all patients.


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  		Table 2. Auxological data (median, range) of MMC patients at start and during GH treatment (n = 7)

 
Table 2Go summarizes the course of length SD score (for CA and BA) and arm span at the start and during treatment. Overall, the median length SD score for CA increased from -4.71 to -3.35 (P = NS), median length SD score for BA increased from -2.70 to -2.23 (P = NS). In relation to the level of lesion the median increase in length SD score for CA was from -4.89 to -3.84 (Th12–L2; n = 2), from -5.07 to -4.37 (L3–L4; n = 2), and from -4.71 to -2.15 (L5–S1; n = 3). Only the increase in arm span SD score was significant (P < 0.05) from -2.98 (start) to -1.75 (3 yr) during GH treatment. Body proportions, calculated as upper to lower segment ratios, remained unchanged. BA was delayed in all patients at the start of treatment and did not accelerate during the observation period. The median body mass index SD score was in the normal range at start of treatment (+0.30) and decreased to -0.38 SD score after 3 yr (Table 2Go).

Laboratory data

Serum IGF-I and IGFBP-3 SD scores in relation to BA improved from -1.51 and -2.38, respectively, to +1.68 and +1.06 (P < 0.05; Table 3Go).

Clinical problems during the treatment period

Two patients developed shunt dysfunction and required surgical revision. In three children, symptomatic tethered cord was diagnosed by clinical and MRI findings. Two of them showed a significant progression of their scoliosis present before the start of therapy (see Patients above). MRI showed in one of them an underlying syringomyelia (C6–L4). Detethering and spondylodesis were performed without complications. GH therapy was stopped in one patient.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Various spinal, orthopedic, as well as infectious and nutritional factors contribute to short stature in MMC patients (1, 2, 3, 4, 5, 6). Adults reach final heights between 142 cm (women) and 152 cm (men) (1, 4, 6). Additionally, hypothalamo-pituitary dysfunction resulting in central precocious puberty and GHD limit growth development and final height in MMC patients (7, 9, 10, 12, 13). As 50–60% of MMC patients are of short stature, we recently proposed to use IGF-I and IGFBP-3 serum levels and arm span as screening methods for GHD in these patients (13) in addition to growth parameters such as supine length, growth velocity, and BA. We assessed linear growth routinely by measurement of supine length and arm span, as arm span is not influenced by skeletal deformities (12, 19, 20). In our MMC patients, GH secretion was analyzed only in short-statured patients with reduced arm span (less than -2 SD score) and low serum levels of IGF-I and/or IGFBP-3 (9, 20, 21, 22). Patients with proven GHD were treated with GH if severe skeletal deformities were absent, and mental development was normal. Decision to initiate GH therapy was made by an interdisciplinary team, consisting of neuropediatrician, orthopedist, pediatric endocrinologist, and the family (patient). There is an ongoing discussion in our group about whether to treat physically disabled MMC patients with GH. The efficacy of GH treatment in MMC patients might be influenced by spinal lesions (paresis, syringomyelia, and tethered spinal cord), skeletal deformities (scoliosis, vertebral anomalies, or contractures), and advanced pubertal development.

In 1989, Rotenstein et al. (10) reported for the first time the improvement of growth velocity from 1.7 ± 0.2 cm/yr at the start of treatment to 7.9 ± 3.4 cm/yr after 6 months of treatment (n = 7). In a further study (11), the group showed a significant improvement of height SD score in 64% of the patients after a median treatment interval of 37.6 months. GHD was documented in 9 of 22 patients. The researchers did not differentiate between GH-deficient patients and short-statured MMC patients without GHD regarding the growth response. Moreover, the study included 7 pubertal patients. Therefore, it might be difficult to distinguish between the effects of puberty and those of GH therapy.

In accordance with former studies of prepubertal MMC patients (10, 12, 24), we found an improvement of growth velocities of length and arm span in our patients during GH treatment. The overall increase in length SD score for CA was comparable to those reported by Rotenstein et al. (10, 24) and Satin-Smith et al. (12), but was not significant in our group. This could be due to the fact that our GH dose was lower than the dose used in the above-mentioned studies (0.3 mg/kg per week). On the other hand, it must be kept in mind that two of our patients developed a symptomatic tethered spinal cord with progressive scoliosis. A former study of 22 patients reported a development of tethered cord syndrome in 5 patients and progression of scoliosis in 1 patient during GH therapy (11). Based on growth data from 7 patients with tethered cord syndrome, Rotenstein et al. (24) recommended an early detethering to optimize growth velocity and prevent progression of scoliosis. According to Rotenstein’s data and our own experience, we perform detethering when first clinical signs of tethering occur. In general, it is well known that 11–20% of MMC patients develop symptomatic tethered cord in childhood. Our sample size is too small to draw any definite conclusions about the increase in tethering during GH treatment. However, awareness of neurological deteriorations due to tethered cord syndrome has to be kept in mind in GH-treated MMC patients.

Our data show a different growth of arm span and supine length during GH treatment. Arm span might be a useful and practicable parameter to monitor GH efficacy in MMC children (12). This is not surprising when considering the neurological lesion with sensorimotor and trophic failures of the lower limbs as well as spine deformities. Considering methodological measurement problems (25) as well as neurological differences between upper and lower limbs, regular measurements of both parameters, supine length and arm span, are needed to estimate the response to GH. As shown by our data, the discrepancy between arm span SD score and supine length SD score during GH therapy has to be taken into account with regard to body proportions. The individual patient might profit from an increase in arm span. However, the overall expectations of the parents and patients concerning the long-term improvement in length SD score, especially in patients with thoracic and upper lumbar level lesions, must be relativated with regard to our experience.

Considering the complexity of effects of GH on different tissues (e.g. lipid or bone metabolism) and the multifactorial problems of MMC patients, we recommend performing multicenter long-term GH studies until achievement of final adult height. Among the various outcomes to be assessed are, for example, effects on self-esteem, quality of life issues, development of obesity, muscle strength, bone density, and rehabilitation potential.


   Acknowledgments
 
We thank the team of the spina bifida out-patient clinic for their support and cooperation.

Received November 19, 1999.

Revised March 9, 2000.

Revised April 21, 2000.

Accepted April 24, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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