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Biochemical Tests in the Diagnosis of Childhood Growth Hormone Deficiency¹

Royal Manchester Children’s Hospital, Christie Hospital (S.M.S.), Manchester; Sheffield Children’s Hospital (J.K.W.), Sheffield; General Infirmary (J.M.B.), Leeds; and South Cleveland Hospital (M.S.K.), Middlesbrough, United Kingdom

Address all correspondence and requests for reprints to: Dr. Peter E. Clayton, Department of Endocrinology, Royal Manchester Children’s Hospital, Manchester, M27 4HA, UK.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
GH stimulation tests are widely used in the diagnosis of GH deficiency (GHD), although they are associated with a high false positive rate. We have examined, therefore, the performance of other tests of the GH axis [urinary GH excretion, serum insulin-like growth factor I (IGF-I), and IGF-binding protein-3 (IGFBP-3) levels] compared with GH stimulation tests in identifying children defined clinically as GH deficient.

Group I comprised 60 children (mean age, 10.3 ± 4.8 yr) whose diagnosis of GHD was based on a medical history indicative of pituitary dysfunction (n = 43) or on the typical phenotypic features and appropriate auxological characteristics of isolated GHD (n = 17). Group II comprised 110 short children (mean age, 9.8 ± 4 yr) in whom GHD was not suspected, but needed exclusion.

The best sensitivity for a single GH test was 85% at a peak GH cut-off level of 10 ng/mL, whereas the best specificity was 92% at 5 ng/mL. The sensitivities of IGF-I, IGFBP-3, and urinary GH, using a cut-off of -2 SD score were poor at 34%, 22%, and 25%, respectively, with specificities of 72%, 92%, and 76% respectively. Only 2 of 21 pubertal children in group I and none of the 27 subjects with radiation-induced GHD had an IGFBP-3 SD score less than -1.5. We devised a scoring system based on the positive predictive value of each test, incorporating data from the GH test and the IGF-I and IGFBP-3 levels. A specificity of 94% could be achieved with a score of 10 or more (maximum 17) (sensitivity 34%). The latter could not be improved above 81% with a score of 5 points or more (specificity, 69%).

A high score was, therefore, highly indicative of GHD, but was achieved by few patients. A normal IGFBP-3 level, however, did not exclude GHD, particularly in patients with radiation-induced GHD and those in puberty. A GH test with a peak level more than 10 ng/mL was the most useful single investigation to exclude a diagnosis of GHD.

	Introduction

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IT IS WIDELY recognized that the diagnosis of GH deficiency (GHD) in childhood can be difficult. Even in specialist growth centers, 25% of children treated for GHD are found to have a normal peak GH concentration during a stimulation test, when evaluated at the end of growth (1, 2). This can occur despite the application of the classical criteria for GHD at the time of diagnosis and the exclusion of other causes of growth failure. It is no surprise that the issue of the diagnosis of childhood GHD has been revisited (3). Investigators have sought therefore to find other tests of the GH-IGF axis that could be used in diagnosis. Serum insulin-like growth factor I (IGF-I) levels are low in GHD (4), but can overlap levels found in short normal and normal children (5, 6, 7). Hence, the specificity of this test in the confirmation of GHD is relatively low (54%) (8). IGFBP-3, the major serum carrier protein for circulating IGFs, is regulated by GH and has been reported to have an excellent sensitivity and specificity in the diagnosis of GHD (8). However, in other studies the performance of IGFBP-3 in this context has been poor (9, 10).

It has been recognized that clinical evaluation is the most valuable aspect of assessment in growth disorders (3). Nevertheless, most clinicians will undertake tests of the GH axis. This study was designed, therefore, to compare the performance of GH stimulation tests with that of a single serum IGF-I, IGF-binding protein-3 (IGFBP-3), and urinary GH (uGH) level, using the clinical diagnosis of the growth disorder as the base standard.

	Subjects and Methods

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Patients

Two hundred and one patients (mean age, 9.9 ± 4.2 yr; 117 boys and 84 girls) were recruited to the study on the basis that a GH test was to be carried out for the evaluation of growth failure (n = 187) or reassessment of pituitary function at the end of growth or GH treatment (n = 14). A clinical diagnosis of the presence or absence of GHD was made in each case by the physicians responsible for the patient’s medical care. All had long-standing experience in the diagnosis and treatment of GHD. Sixty patients were diagnosed clinically as GH deficient (group I; Table 1). In 43 patients this was based in part on medical history [central nervous system (CNS) irradiation, tumors of the hypothalamic-pituitary region, and organic hypopituitarism]. In the remaining 17 children, a diagnosis of isolated idiopathic GHD was made on the basis of 1) the presence of more than one typical phenotypic feature (frontal bossing, immature face, midfacial hypoplasia, truncal adiposity, fat dimpling, hypogenitalism in a male, and high-pitched voice), 2) appropriate auxological characteristics (height SD score <-2, height velocity below the 10th percentile over >6 months, and a bone age delayed by >2 yr), and 3) the exclusion of other endocrinopathies and chronic disease. A subset of group I (n = 19), in which the diagnosis of GHD was supported by specific hypothalamic-pituitary pathology, was also identified. This included the children with septooptic dysplasia, congenital hypopituitarism, tumors of the hypothalamic-pituitary area, and 6 with isolated GHD who had abnormal findings (empty sella or stalk lesion) on computed tomography or magnetic resonance imaging scan.

All children had a GH stimulation test (arginine = 90; glucagon = 65; clonidine = 38; insulin = 6; exercise = 2) carried out in a standard manner. If a child had two GH tests, the results of the first test were used in analysis. Sex steroid priming before GH tests was carried out in three of the five centers in children over 9 yr of age who were prepubertal or in early puberty (n = 24). Fifty-four other children in this category were not primed. Serum IGF-I and IGFBP-3 concentrations were measured in a single sample taken before the GH stimulation test, whereas uGH was measured in an overnight urine sample collected on that morning. Height SD score was calculated from the new British standards (12), and height velocity was compared to Tanner standards (13). Body mass index (BMI) was calculated as weight (kilograms)/height (meters²). Bone age was estimated by the method of Greulich and Pyle (14).

Assays

GH was measured at four different laboratories using two-site immunoradiometric assays with standard commercial kits [Netria (London, UK) and IDS (Tyne and Wear, UK)]. All laboratories participated in the UK National External Quality Assurance Scheme, and each assay conformed to acceptable standards, being calibrated against the International Standard 80/505: the mean bias for the four assays was +2.1% (range, -9.9% to +9.3%).

Serum IGF-I, after acid ethanol extraction, and IGFBP-3 were measured by RIA using standard commercial kits (Nichols Institute Diagnostics, Somerville, NJ). The intraassay coefficient of variation ranged from 2.4–3.0%, and the interassay coefficient of variation ranged from 4–5.2% for IGF-I; these values were 3.4–8.0% and 5.3–6.3%, respectively, for IGFBP-3. Results were expressed as the SD score, using the normal ranges, standardized by age and sex, provided by Nichols Institute Diagnostics.

uGH excretion in overnight urine was measured by two-site immunoradiometric assay, described previously (15), and the results were expressed as the SD score, using our own standardized normal ranges (15).

Statistical analysis

We have used clinical assessment of GH status to define groups I (GHD) and II (non-GHD). Test performance is based, therefore, on this classification. Sensitivity was defined as the number of true positive results (below the cut-off point) divided by the total number of results in group I. Specificity was defined as the number of true negative results (above the cut-off point) divided by the total number of results in group II. Efficiency was defined as the number of correct results divided by the total number of tests in both groups. The positive predictive value was defined as the number of positive results in the GHD group divided by the total number of positive results. All values were expressed as a percentage. Student’s t test and the Kruskal-Wallis test were used to compare data between groups.

	Results

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Patient characteristics

The subjects fell into a broad range of diagnostic categories, illustrating the numerous etiologies associated with growth failure, where evaluation of the GH axis may be required (Table 1). Patients with isolated idiopathic GHD could not be distinguished from those in group II by age (mean ± SD, 7.9 ± 3.4 vs. 9.6 ± 3.8 yr), height SD score (-2.7 ± 1.0 vs. -2.6 ± 1.1), height velocity (4.2 ± 1.6 vs. 4.3 ± 1.8 cm/yr), body mass index (16.5 ± 3.1 vs. 16.9 ± 4.0), or bone age delay (-1.5 ± 1.3 vs. -1.8 ± 1.4).

Test performance

The efficiency, sensitivity, and specificity of all tests at defined cut-off points are shown in Table 2.

uGH estimations. There was no significant difference between uGH excreted in groups I and II (Table 3). It proved to be a poor test, with an efficiency of 56%, even at a cut-off value of -2 SD score.

Serum IGF-I concentration. Values were significantly reduced compared with those for a normal population in both groups, but were not different between the groups. Twenty subjects (34%) in group I and 31 in group II (28%) had an IGF-I SD score below -2, whereas the efficiency in corroborating the clinical diagnosis was very poor and similar to that of uGH (Table 2a). The sensitivity of IGF-I at a cut-off of -2 SD score was particularly poor for children receiving CNS radiation (Table 2b).

Serum IGFBP-3 concentration. The IGFBP-3 SD score was significantly lower in group I than that in group II (Table 3). Group II, in fact, had a distribution of IGFBP-3 values very similar to that in a normal population. However, only 2 of 21 pubertal subjects in group I had an IGFBP-3 SD score less than -1.5.

Thirteen subjects in group I (22%) and 9 in group II (8%) had an IGFBP-3 SD score below -2, indicative of the poor sensitivity of this test. The latter did improve, but only to 53%, when the test was applied to the group I subset with definitive GHD. The sensitivity of this test was very poor in those undergoing retesting or receiving CNS radiation (Table 2b); none of the 27 subjects with radiation-induced GHD had an IGFBP-3 SD score less than -1.5, although 16 had a GH peak value below 7.5 ng/mL. This test did, however, have a very good specificity (92%; Table 2a).

Scoring system

To incorporate data from all tests, we devised a scoring system based on the positive predictive value of each test in the group I subset with definitive GHD (Table 4). No score was allocated to an IGF-I SD score above -2 or to any value of uGH because the predictive value fell below 20%. The performance of this system is shown in Table 5. All patients with definitive GHD and 81% of group I achieved at least 5 points with a maximum up to 17 points. Ten of the 11 subjects who scored less than 5 points were in the radiation-induced GHD group. Sixty-nine percent of group II scored less than 5 points, with a maximum of 12 points.

View this table: [in this window] [in a new window]   Table 5. Sensitivity, specificity, and efficiency (expressed as number of patients and as percentage of patients) using the scoring system (see Table 4) at the given cut-off score

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The best approach to the investigation of the child with growth failure has been the subject of many studies (reviewed in Refs. 3, 8, and 16–18). In recent years, the debate has widened as alternative tests of the GH axis have become increasingly available (3, 18). A single measurement of serum IGF-I and IGFBP-3, both partly under GH control, provides data on the integrity of the GH transduction pathway, contributing not only to the evaluation of GHD, but also to the determination of GH insensitivity (19). This study was designed to assess the performance of these tests in corroborating the clinical diagnosis of GHD.

To evaluate a test, it is necessary to use a gold standard. In the case of GHD, this has proved difficult to define. For instance, if an unsatisfactory growth rate is used as the standard, then relatively poor sensitivity (69%) and specificity (63%) were achieved with a cut-off peak GH value of 7.5 ng/mL during an insulin tolerance test (20). If the peak GH responses during stimulation tests are used to define the disease, then at least 25% will have normal GH secretion as young adults (1, 2).

We have chosen, therefore, a specific approach in this study in which initial clinical evaluation (based on history, examination, and growth parameters) has been used as the gold standard. Our subjects represent a heterogeneous group with disordered growth recruited from a number of growth centers, but including a subset with a very high likelihood of GHD. We believe that this is a realistic clinical setting in which test performance can be properly evaluated. To compare test sensitivity within the subgroups, analysis has also been undertaken separately on the group with definitive GHD, those young people who received a retest at the end of GH treatment, and those treated with CNS radiation to a lesion outside the hypothalamic-pituitary axis.

A single peak GH concentration (using a cut-off level of 7.5 ng/mL) during standard stimulation tests proved to be the most efficient (81%) of the tests. Nevertheless, this still resulted in a false positive rate of 15% and a false negative rate of 27%, broadly in agreement with the many previous assessments of GH tests (1, 2, 21, 22). However, the alternative tests, uGH, serum IGF-I, and IGFBP-3 levels, when used alone performed less well. The sensitivity of the GH test was lowest in those receiving CNS radiation (63% at a cut-off of 7.5 ng/mL), but similar in those with a definitive diagnosis of GHD (84%) and those retested at the end of growth (82%).

Skinner et al. (23) have shown previously that a sensitivity of 70% and a specificity of 98% could be achieved using a single uGH estimation at a cut-off level of -2 SD. The patients with GHD in that study all had peak GH levels below 4 ng/mL, whereas the short normal group were relatively homogeneous, with 90% having familial short stature and/or delayed growth. If this GH criteria is applied in the present study, then the sensitivity of uGH increases to 75%. A uGH test is, therefore, only helpful in subjects with severe GHD.

Serum IGF-I levels were unhelpful in discriminating among our patient groups. This held true across the age range studied despite previous studies suggesting that IGF-I is more informative in older children with GHD (24). We found a similar specificity, but lower sensitivity, for this test than those in other studies (5, 8), with the sensitivity not substantially altered by a change in the cut-off value. This test would certainly not be useful for screening purposes.

An IGFBP-3 level has been proposed as an excellent test of GH status (8, 25, 26). We certainly confirmed that this test has a high specificity (92%), and therefore, the finding of a low IGFBP-3 level is highly suggestive of GHD (given that GH insensitivity has been excluded). However, a significant number of children with GHD had normal IGFBP-3 levels; therefore, the sensitivity of the test is poor even in those with a definitive diagnosis of GHD, in agreement with recent studies (10, 27). We also found that children with radiation-induced GHD had consistently normal IGFBP-3 concentrations, as previously noted by Sklar et al. (28). In addition IGFBP-3 levels tended to fall within the normal range in subjects from groups I and II who were in puberty compared to standards for either chronological or bone age. Therefore, IGFBP-3 alone could not be used to exclude the diagnosis of GHD.

We went on to explore the use of combined data from the most useful tests, as defined by their positive predictive value in subjects with definitive GHD. Although the efficiency of this system did not exceed that of a single GH test, it was possible to improve specificity and, therefore, confirmation of the diagnosis. In those children not allocated to group I or II, this system has helped to define the GH status of 61%. Half of the remaining 39% had radiation-induced GHD, in which IGFBP-3 levels do not appear to reflect GH status.

Although a single GH test remains the most powerful biochemical tool in the evaluation of a child with growth failure, the test remains far from ideal. The combination of this result with a single serum IGF-I and IGFBP-3 measurement can be used very effectively in the confirmation of GHD. If careful clinical assessment and growth rate documented over at least 6 months indicate that biochemical evaluation of the GH-IGF axis should be undertaken, then we recommend the use of a single GH test, followed by serum measurements of IGF-I and IGFBP-3 in those whose peak GH levels fall below 10 ng/mL.

	Footnotes

 
¹ The work, M.S.G., and A.J.W. were supported by grants from Serono UK. V.T. is a training fellow supported by the ESPE.

Received April 3, 1996.

Revised September 18, 1996.

Accepted September 24, 1996.

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