David A. Price

Serum leptin through childhood and adolescence

Leptin is the protein product of the recently cloned ob gene, that has been implicated in the control of body weight and thermogenesis, but also independently stimulates the reproductive axis. As major changes in body composition and gonadal function occur during human adolescence, we have assessed serum leptin concentration through childhood.

Normal growth despite abnormalities of growthhormone secretion in children treated for acute leukemia

We have studied the relationship between abnormalities of the growth hormone-somatomedin axis and growth in 26 children previously treated for acute lymphatic leukemia. Each child had previously received cranial irradiation, was in complete clinical and hematologic remission, and off all drugs. The mean standing height SDS of the 26 children was significantly less than normal. There was no significant difference between the mean standing height SDS, height velocity SDS, somatomedin activities, and degree of bone age retardation between the 17 children who received the higher dose of cranial irradiation (Group 1) and the nine who had the lower dose of cranial irradiation (Group II). Furthermore, there was no significant reduction in mean height velocity SDS, somatomedin activity, or bone age in either group when compared to normal age-matched controls. The peak GH responses to both insulin hypoglycemia and an arginine test were significantly lowered in Groups I and II when compared to a control group of children. We conclude that only a minority of children, who previously received cranial irradiation for ALL were clinically GH deficient and, therefore, likely to benefit from GH therapy despite the finding that the majority of these children had reduced GH responses to pharmacologic stimuli.

Biochemical tests in the diagnosis of childhood growth hormone deficiency

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.

Final height in boys with untreated constitutional delay in growth and puberty.

To determine the natural history and psychological impact of the growth pattern in boys with constitutional delay in growth and puberty (CDGP), 43 boys presenting with short stature due to CDGP were followed up to final height. At presentation mean (SD) chronological age was 14.0 (1.9) years, bone age delay 2.7 (1.0) years, standing height standard deviation score (SDS) -3.4 (0.6), and predicted adult height SDS -1.3 (0.7). Final adult height SDS was -1.6 (0.9), measured at 21.2 (2.6) years. There was no significant difference between final height and predicted adult height, but there was a significant difference between final height and measured mid-parental height. Psychological questionnaires showed no significant difference in self esteem, marital, or employment state between the CDGP group and a control group. There was no correlation between self esteem and final height, but 25 felt their growth delay had affected their success either at school, work, or socially and 20 would rather have had treatment to advance their growth spurt. This study supports the more frequent use of active medical treatment to advance growth in boys with CDGP, and shows that although boys with CDGP reach their predicted heights, this is short for their families.

Gonadal dysfunction due to cis‐platinum

Gonadal function was studied in 15 patients, 12 pubertal or postpubertal, and three prepubertal, who had been treated during childhood for nonmetastatic osteosarcoma of the long bones by chemotherapy regimens that included cis-platinum and adriamycin. Of seven postpubertal female patients assessed (mean age at diagnosis 16.5 years), three were amenorrhoeic and showed evidence of ovarian damage with raised gonadotrophin levels and a low serum oestradiol concentration. One patient who had regular periods had a raised lutealphase follicle-stimulating hormone (FSH) concentration suggestive of gonadal dysfunction. Severe oligospermia or reduced testicular volumes in the presence of raised gonadotrophin levels were observed in three of the five pubertal males (mean age at diagnosis 13.25 years). A reliable assessment of gonadal function was not possible in three male patients who remained prepubertal at the time of study. The median total dose of cis-platinum received by those patients with gonadal damage (median dose, 490 mg) was significantly higher than in those patients with normal gonadal function (median dose, 300 mg) (P = 0.01). In the boys the damage to the testes was primarily directed at the germinal epithelium. Leydig cell function was intact and the males progressed spontaneously through puberty. In the girls, unlike the boys, there was evidence of reversibility of gonadal damage with time. This is the first study to show gonadal dysfunction due to cis-platinum and adriamycin therapy in childhood.

Final height after long-term growth hormone treatment in Turner syndrome

OBJECTIVES To study final height after long-term growth hormone (GH) treatment in girls with Turner syndrome (TS). PATIENTS One hundred fifty three patients with TS, participating in five European trials, were included. They started GH treatment in 1987-1989 at an age of 10 years or older. Mean age at start of treatment ranged between 11.7 and 14.6 years among countries and mean bone age between 9.4 and 11.8 years. Fourteen girls were lost to follow-up, leaving 139 for analysis. Most girls have now attained final height (FH), defined as a linear growth velocity (GV) of 4 mm/yr or less, measured over at least 6 months (group 1, n = 56), or near-FH, defined as a GV of 5 to 9 mm/yr (group 2, n = 22). Sixty-one girls were still growing 10 mm/yr or more. METHODS AND MAIN RESULTS At the last measurement, mean (SD) height was 150.7 (4.9) cm in group 1 and 148.5 (5.1) cm in group 2. The differences between FH and projected final height based on extrapolation of the initial height-standard deviation score on Turner syndrome reference values, were 2.9 (3.8) and 3.0 (3.3) cm, respectively. The mean gain over the Bayley-Pinneau prediction of FH was 3.3 (3.9) cm in both groups. No significant differences between countries were found. The range of gains over projected height (-4.7 to 12.1 cm) was large, and 25% of gains were 5 cm or more. Gain over initial projection was strongly related to initial growth delay and to growth response during the first 2 years of treatment. A logistic regression model is presented that predicts gain of more than 5 cm with a positive predictive value of 62% and a negative predictive value of 84%. CONCLUSIONS Long-term GH treatment in girls with TS, starting treatment at a relatively advanced age ( > 10 years) resulted in a modest mean gain in FH of 3 cm, with wide interindividual variation.

Factors Determining Pubertal Growth and Final Height in Growth Hormone Treatment of Idiopathic Growth Hormone Deficiency

A total of 195 children (117 males and 78 females) with idiopathic growth hormone deficiency (IGHD) treated with growth hormone (GH) for at least 1 year before puberty onset and who had completed treatment to adult height, were selected from the KIGS database for study of growth during puberty. Spontaneous and induced puberty started at 13.8 and 14.9 years in boys and at 12.9 and 13.7 years in girls, respectively. Duration of GH treatment and height gained prepubertally were greater when puberty was induced; prepubertal catch up growth (expressed as a percentage of the difference between target height and height at start of GH) was greater when puberty was induced in boys (59% induced vs. 45% spontaneous, p < 0.001), and in girls (72% induced vs. 53.9% spontaneous, p < 0.01). Final height was attained at 17.8 and 19.2 years in boys and at 16.0 and 17.0 years in girls following spontaneous and induced puberty, respectively. Final heights were greater after induced puberty compared with spontaneous puberty in boys (171.3 vs. 166.0 cm, p < 0.001) and in girls (157.0 vs. 155.0 cm, n.s.). Target height was also significantly greater in boys with spontaneous puberty (172.2 cm vs. induced = 174.2 cm) as compared to girls (spontaneous = 158 cm vs. induced = 160 cm). Duration of pubertal growth was longer in boys compared to girls (3.6 vs. 3.0 years, p < 0.001) and was negatively correlated with age, height, and distance from target height at onset of puberty, but was not correlated with the dose of GH. Catch-up growth during puberty (expressed as a percentage of the difference between target height and height at puberty onset) after induced and spontaneous puberty was 87.9% and 80.5% (not significant) in boys and 66.4% and 75.5% (not significant in girls. Total pubertal growth (TPG) (cm) was inversely correlated with prepubertal growth by simple linear regression. Multiple linear regression analysis indicated 5 independent predictors of TPG accounting for 78% of the variability, namely sex (boys grew more), distance of target height from height at onset of puberty (+), dose of GH at onset of puberty (+), age at onset of puberty (-), and age at end of growth (+).

Does growth hormone cause relapse of brain tumours

Tumour relapse rates in 14 patients with medulloblastoma, 8 with glioma, 2 with ependymoma, 6 with leukaemia, and 1 with T-cell lymphoma who received growth hormone (GH) treatment for growth failure secondary to cranial irradiation were compared with rates among patients treated with radical radiotherapy for the same types of tumour. Five relapses (in 5 patients) occurred (1 optic nerve glioma, 2 medulloblastomas, and 2 ependymomas), three during and two after completion of GH treatment. Patients with medulloblastoma and ependymoma who relapsed were older at tumour diagnosis, underweight at the start of GH therapy, and entered puberty later than similar relapse-free patients. The late relapse rate of medulloblastoma and glioma was unaltered by GH therapy. Ependymoma carries a poor prognosis, and of the 4 late survivors, the 2 who received GH relapsed. No leukaemic relapse has been associated with GH treatment. The findings indicate that GH therapy does not increase the relapse rate of medulloblastoma, glioma, and leukaemia.

Efficacy and Safety of Growth Hormone Treatment in Children with Prior Craniopharyngioma: An Analysis of the Pharmacia and Upjohn International Growth Database (KIGS) from 1988 to 1996

We studied short- and long-term responses to growth hormone (GH) treatment and adverse medical events (AE) in 488 patients with craniopharyngioma who were entered into the Kabi International Growth Study (KIGS). First-year growth response and responsiveness (n = 394) were similar to those seen in children with idiopathic GH deficiency. The growth response over 5 years (n = 152) was unaffected by the recurrence of tumour and prior tumour management, but was greater in those receiving thyroxine. Mean height standard deviation scores (SDS) at the end of GH treatment (n = 129) was –0.7 ± 1.2, and 79% achieved a height over –2 SD of target height, with evidence of further growth potential. Final height SDS correlated positively with height SDS at the start of treatment and with target height SDS, whereas gain in height SDS was inversely correlated with height SDS and bone age at the start of GH treatment. The rate of recurrence of tumour, 0.045/treatment year, was greater in those who had been treated with surgery alone compared to surgery and cranial irradiation. Other AE included headaches, fluid retention and convulsions occurring at rates of 0.025, 0.005 and 0.004/treatment year, respectively. We concluded that GH treatment is safe and effective in children with craniopharyngioma and provide data for counselling of parents about outcome during GH treatment.

Adrenal function following topical steroid treatment in children with atopic dermatitis

Summary Adrenal suppression is a potential complication of topical corticosteroid treatment in atopic dermatitis. We used a low‐dose adrenocorticotrophic hormone (ACTH) test (500 ng/1.73 m2) to detect subtle changes in adrenal glucocorticoid function in 14 prepubertal children with moderate or severe atopic dermatitis affecting 16–90% (median 58%) of the body surface area. All had received regular treatment with mild potency BNF (British National Formulary) classification topical corticosteroid ointments (hydrocortisone 48.7–223.2 mg/m2 body surface area/day; median 134.2) for 3–10 years (median 6.5 years). Nine children had also intermittently used moderate potency preparations. However, none had been treated with corticosteroids by any other route in the preceding 6 months. Fourteen prepubertal children with constitutional short stature, without atopic disease, served as controls.