Noonan's Syndrome: Abnormalities of the Growth Hormone/IGF-I Axis and the Response to Treatment with Human Biosynthetic Growth Hormone

ABSTRACT. Auxological and endocrine data from 6 children (3 male, 3 female) aged 8.5–12.8 years with Noonan's syndrome and the results of treatment with human biosynthetic growth hormone (hGH) are presented. All the children were short (Ht SDS -3.5 to -2.3) and height velocity SDS ranged between -1.76 and +0.03. The maximum plasma growth hormone (GH) response to standard provocation tests ranged from 17 to 52 mU/l, yet, plasma insulin-like growth factor I (IGF-I) concentrations were low or low normal. Overnight GH secretory profiles were normal in all but 2 children who had disordered pulsatility with high trough concentrations. In 5 children who have completed one year of hGH therapy mean height velocity increased from 4.8 to 7.4 cm/year and the height velocity SDS ranged from +0.2 to +3.75. This improvement was associated with an increase in plasma IGF-I in three subjects. These results suggest that a defect of the GH/IGF-I axis may be present in some children with Noonan's syndrome and hGH therapy may have a role in the management of the short stature in these children.     

Growth Response to Human Growth Hormone Treatment in Children with Partial and Total Growth Hormone Deficiency

ABSTRACT. The growth response during the first and second years of human growth hormone (hGH) treatment was studied in 14 prepubertal children with so-called "partial" GH deficiency (peak GH between 8 and 15 mU/1) and compared to 28 prepubertal children with "total" GH deficiency (peak GH less than 8 mU/1). There was no difference in growth acceleration between children with partial and total GH deficiency, when initial covariables were taken into account. In a stepwise multiple regression analysis initial stature, pre-treatment growth velocity and skinfold thickness were shown to be most related to growth response, but after exclusion of 3 children with a genetic form of total GH deficiency and partial TSH deficiency this relationship was lost. GH levels during provocation tests and auxological criteria have a poor predictive value for growth response to hGH therapy.     

Growth hormone therapy for 3 years: The OZGROW experience

Objective : To examine the growth response over 3 years of growth hormone deficient (GHD) and non-GHD children who have received growth hormone (GH) in Australia.
Methodology : A retrospective study of a group of patients (1362 children) who commenced GH prior to 1 September 1990. Data were collected at 12 growth centres located in major cities throughout Australia. The data were transferred after informed consent to the national OZGROW database located at the Royal Alexandra Hospital for Children, Sydney, NSW. Of the 1362 children, 898 had received 3 years or more GH therapy and were eligible for this analysis. This cohort was then categorized by diagnosis. Growth response was assessed using height standard deviation score, estimated mature height, growth velocity (GV), GH dose and bone age (years).
Results : For children who completed 3 years therapy, the baseline characteristics among diagnostic groups were similar with mean height standard deviation score (SDS) less than – 3 SDS (except for the malignancy group) and mean GV ranging from 3.5 to 4.4 cm/year. The GV during the first year improved in all groups (7.7-9.4 cm/year) followed by an attenuated response during the second and third years of therapy. After 3 years GH therapy the GHD group with peak levels <10 mU/L demonstrated the greatest change in estimated mature height and height SDS. The GHD group with peak levels between £10 but <20 mU/L had a growth response similar to the non-GHD children for all outcome parameters. Change in bone age ranged from 3.1 to 3.8 years with no differences being noted between the diagnostic groups, nor consistently with pubertal status.
Conclusions : Australian GH guidelines have targeted very short children when compared to other series. This large cohort of non-GHD children has demonstrated short-term benefits of GH therapy; however, the long-term benefit remains unclear until these children reach final adult height.     

Occurrence of acute megakaryoblastic leukemia in a patient with idiopathic growth hormone deficiency

We describe a case of a 15 year old boy who developed acute megakaryoblastic leukemia (AMKL) while receiving treatment with human growth hormone (hGH) for idiopathic growth hormone deficiency (GHD). He was diagnosed as having idiopathic GHD and given hGH from December 1991. The examination of his peripheral blood showed mild pancytopenia 2 months before the start of the hGH therapy. Since January 1992, paleness of the skin, general fatigue and fervescence progressed gradually. In February 1992, because of the occurrence of acute leukemia, administration of hGH was discontinued. Judging from the results of surface marker analysis of the blast cells, the patient was diagnosed as having AMKL. He was treated with chemotherapy for acute non-lymphoblastic leukemia from March 1992. A complete remission was obtained after 4 weeks of treatment. The chemotherapy was completed in July 1993. He remains in complete remission 26 months after diagnosis. This case suggests the importance of hematological examination and, when there is any abnormality which is not caused by GHD, such as pancytopenia, more detailed medical examinations (for example bone marrow examination) are necessary.     

Noonan's syndrome: abnormalities of the growth hormone/IGF-I axis and the response to treatment with human biosynthetic growth hormone

Auxological and endocrine data from 6 children (3 male, 3 female) aged 8.5-12.8 years with Noonan's syndrome and the results of treatment with human biosynthetic growth hormone (hGH) are presented. All the children were short (Ht SDS -3.5 to -2.3) and height velocity SDS ranged between -1.76 and +0.03. The maximum plasma growth hormone (GH) response to standard provocation tests ranged from 17 to 52 mU/l, yet, plasma insulin-like growth factor I (IGF-I) concentrations were low or low normal. Overnight GH secretory profiles were normal in all but 2 children who had disordered pulsatility with high trough concentrations. In 5 children who have completed one year of hGH therapy mean height velocity increased from 4.8 to 7.4 cm/year and the height velocity SDS ranged from +0.2 to +3.75. This improvement was associated with an increase in plasma IGF-I in three subjects. These results suggest that a defect of the GH/IGF-I axis may be present in some children with Noonan's syndrome and hGH therapy may have a role in the management of the short stature in these children.     

Growth hormone state after completion of treatment with growth hormone.

After completion of treatment with growth hormone (GH) 19 patients with isolated ''idiopathic'' GH deficiency and 15 with post-irradiation GH deficiency underwent retesting of GH secretion with an insulin tolerance test or an arginine stimulation test, or both. Patients with post-irradiation GH deficiency comprised 13 patients with central nervous system tumours distant from the hypothalamo-pituitary axis and two with acute lymphoblastic leukaemia, who had received cranial or craniospinal irradiation. All 15 patients with post-irradiation GH deficiency remained GH deficient (peak GH response less than 7 mU/l (n = 10) and 7-15 mU/l (n = 5)). Of the 19 retested patients with idiopathic GH deficiency, however, five (26%) had peak GH responses of greater than 15 mU/l (regarded now as transient or false idiopathic GH deficiency) and were indistinguishable from the remainder (permanent or true idiopathic GH deficiency, peak GH responses less than 7 mU/l (n = 12) and 7-15 mU/l (n = 2)), by pretreatment anthropometry and post-treatment height standard deviation score, but had a lower first year height velocity (mean (SD) velocity 5.6 (0.5) cm/year for false idiopathic deficiency v 8.7 (1.75) cm/year for true idiopathic deficiency, p less than 0.01) and height increment on treatment (mean (SD) increment 2.2 (1.5) cm/year for false idiopathic deficiency v 5.2 (2.3) cm/year for true idiopathic deficiency, p less than 0.05). By current practices two patients with false idiopathic deficiency may have been distinguished by sex steroid priming. Thus post-irradiation GH deficiency seems to be permanent, but errors in diagnosis in idiopathic GH deficiency are common.     

The diagnosis of childhood growth hormone insufficiency and growth hormone resistance

Growth hormone insufficiency (GHI) is an uncommon though treatable cause of retarded growth velocity and short stature in childhood, the diagnosis generally requiring the demonstration of a subnormal growth hormone (GH) response to a physiological or pharmacological stimulus. Physiological and pharmacological GH release is a continuous variable and the relationship between spontaneous GH secretion and height velocity is asymptotic. Cut-off points for defining GH insufficiency are largely derived from adult observations, but have been extrapolated to children, for whom normative data are relatively scanty. There is no absolute cut-off that discriminates between normal and abnormal GH response. Moreover, poor reproducibility, sensitivity and specificity of the many dynamic tests available, particularly when performed in the very young child or in early adolescence, together with the confounding effects of assay performance, further weaken the diagnostic efficiency of biochemical investigations. Between 20-40% of children retested at the completion of GH therapy demonstrate a normal GH response to a provocative stimulus. Such limitations mitigate against over-reliance on GH provocation tests in diagnosis, and further emphasize the importance of careful auxology in evaluating the short child.     

Physiological Growth Hormone Secretion and Response to Growth Hormone Treatment in Children with Short Stature and Intrauterine Growth Retardation

Stanhope, R., Ackland, F., Hamill, G., Clayton, J., Jones, J. and Preece, M.A. (Department of Growth and Development, Institute of Child Health, London and Serono Laboratories, UK). Physiological growth hormone secretion and response to growth hormone treatment in children with short stature and intrauterine growth retardation. Acta Paediatr Scand [Suppl] 349: 47, 1989.
Physiological growth hormone (GH) secretion was examined in 31 children (8 girls, 23 boys) with short stature secondary to intrauterine growth retardation (IUGR). Seventeen (4 girls, 13 boys) had dysmorphic features of Russell-Silver syndrome. Four of the 31 children had GH insufficiency with peak GH levels of < 20 mU/I during the night. Nine of the patients (8 of whom had Russell-Silver syndrome) had a single nocturnal GH pulse. Twenty-three children (6 girls, 17 boys) were randomized into two groups treated with either 15 or 30 U/m²/week of GH by daily subcutaneous injections. Age, sex distribution, pretreatment height velocity SD score (SDS), and distribution of dysmorphic and non-dysmorphic children were similar in both groups. The group treated with 15 U/m2/week for a mean of 0.82 years showed an increase in mean height velocity SDS from - 0.61 to +1.09, and the group treated with 30 U/m²/week for a mean of 0.92 years showed an increase in mean height velocity SDS from -0.69 to +3.48. The results suggest that physiological GH insufficiency is probably common in children with Russell-Silver syndrome and that both dysmorphic and non-dysmorphic children with short stature secondary to IUGR will respond to GH treatment. Initial evidence suggests that the increase in short-term growth velocity does not result in an improved final height prognosis.     

Improved growth response to GH treatment in irradiated children

The growth response to two years of GH treatment was studied in fifteen children after radiotherapy for a cranial tumor. The growth response was compared to that of short children (-2 SD) and that of children with idiopathic growth hormone deficiency (GHD) of similar ages. All children were treated with hGH 0.1 IU/kg/day s.c.; which is a higher dose and frequency than previously reported for irradiated children. On this protocol the growth rate increased 5.0 +/- 0.5 cm/y (mean +/- SEM) the first year and 3.8 +/- 0.7 cm/y the second year compared to the growth rate the year before GH-treatment. Although the net gain in growth was higher than previously reported, the first year growth response was significantly reduced (p less than 0.05) compared to that of GHD-children (7.6 +/- 0.5 cm/y) but exceeded (p less than 0.05) that of short children (3.4 +/- 0.3 cm/y). The median spontaneous 24 h-GH secretion was 209 mU/l in the short children, 52 mU/l in the irradiated children and 16 mU/l in the idiopathic GHD children. Thus the growth increment varied inversely to the spontaneous GH secretion observed in the three groups.     

Growth Hormone Treatment in Non-Growth Hormone-Deficient Children: Effects of Stopping Treatment

ABSTRACT. Overnight physiological growth hormone (GH) secretion was evaluated in 95 short, prepubertal children (73 boys, 22 girls). All the children were below the 3rd centile for height and achieved CH levels greater than 15 mU/1 following pharmacological stimulation. The mean average GH level was 7.1 mU/l and the mean sum of pulse amplitudes 80.4 mU/l. No relationship was found between age, height or height velocity and any of the parameters of GH secretion. The group was randomized to receive placebo, GH or remain under observation for the first 6 months and then all patients received GH treatment for a further 6 months. Those treated with GH, 0.27 IU/kg (0.1 mg/kg) three times weekly, in the first phase. demonstrated a mean increase in height velocity SDS of 3.24. There was no difference in growth response between the placebo or observation groups. In the second 6-month period. all children received GH according to the same dose regimen: they were then observed for a further 6 months following its discontinuation. In the 6 months following withdrawal of GH, all groups showed a significant fall in height velocity SDS, which returned to pretreatment levels, without demonstrating'catch-down'growth. Repeat sampling of overnight GH secretion within 3 days of discontinuing GH showed normal secretory patterns with a small reduction in mean peak amplitude. These results suggest that short children without classic GH insufficiency respond well to exogenous GH in the short term and return to pretreatment height velocities afterwards. Consequently, it may be possible to increase final adult height in such children by GH treatment.     

Screening test for growth hormone deficiency: Usefulness of L-dopa-propranolol provocative test

This is a retrospective review of 185 short children who were tested for growth hormone (GH) secretion using the L-dopa-propranolol provocative test. One hundred and thirty-three children were deemed to have passed the screening test when a GH concentration of greater than 15 miu/L was elicited after stimulation. Fifty-two failed the screening test, of which 33 were diagnosed as having growth hormone deficiency (GHD) when they had inadequate growth hormone response to insulin-induced hypoglycaemia. The other 19 were low-responders since they showed adequate GH response to insulin tolerance test (ITT). The low-responder rate to L-dopa-propranolol provocative test among short children who are not GH deficient was 12.5%. The low cost of L-dopa and propranolol, the simplicity and safety of the test, and the acceptable rate of low-responders make the test an effective screening test for GHD.     

Comparison of growth hormone releasing hormone therapy and growth hormone therapy in growth hormone deficiency

Seven children with growth hormone deficiency of hypothalamic origin responded to an i.v. bolus of growth hormone releasing hormone (GHRH) (1–29)-NH2 with a mean serum increase of 10.7 ng/ml growth hormone (GH) (range 2.5–29.3 ng/ml). Continuous s.c. administration of GHRH of 4–6 g/kg twice daily for at least 6 months did not improve the growth rate in five of the patients. One patient increased his growth rate from 1.9 to 3.8 cm/year and another from 3.5 to 8.2 cm/year; however, the growth rate of the latter patient then decreased to 5.4 cm/year. When treatment was changed to recombinant human growth hormone (rhGH) in a dose of 2 U/m² daily, given s.c. at bedtime, the growth rate improved in all patients to a mean of 8.5 cm/year (range: 6.2 to 14.6). Presently GHRH cannot be recommended for the routine therapy of children with growth hormone deficiency since a single daily dose of rhGH produced catch-up growth which GHRH therapy did not.Abbreviations GH growth hormone - GHD growth hormone deficiency - GHRH growth hormone releasing hormone - hGH human growth hormone - rhGH recombinant human growth hormone - SM C/IGF I somatomedin C/insulin-like growth factor I On the occasion of the 85th birthday of Prof. Dr.Dr.h.c. mult. Adolf Butenandt     

COMBINED TEST OF HYPOTHALAMIC-PITUITARY FUNCTION IN GROWTH RETARDED CHILDREN TREATED WITH GROWTH HORMONE I. Secretion of Growth Hormone and Somatomedin before and after Treatment

Abstract. Kastrup, K. W., Andersen, H., Eskildsen, P. C., Jacobsen, B. B., Krabbe, S. and Petersen, K. E. (Children's Hospital, Fuglebakken and Herlev Hospital, Copenhagen, Denmark). Combined test of hypothalamic—pituitary function in growth retarded children treated with growth hormone. Acta Paediatr Scand, Suppl 277: 9, 1979.—In 23 growth retarded children two consecutive insulin tolerance tests (ITT) were performed to establish a diagnosis of growth hormone (GH) deficiency. Nine children did not respond (GH peak value less than 8 mU/l), whereas 14 were classified as having partial GH deficiency (GH peak value less than 20 mU/l). All were treated for an average period of 40 months with human growth hormone (HGH). In a combined stimulation test at the end of the treatment period 9 children demonstrated a persistent GH deficiency, whereas a normal response was found in 14 of the previous partial GH deficient children. During treatment the monthly growth rate rose from 0.21 cm to 0.58 cm in the GH deficient children and from 0.31 cm to 0.70 cm in the partial deficient children, in most of whom spontaneous pubertal development occurred during treatment. Somatomedin (SM) values were decreased in the GH deficient children before and after treatment but increased to normal levels during treatment. Growth velocity in these children during treatment was correlated to SM values before treatment. In the partial GH deficient children SM values were subnormal before but normal after treatment. This supports the assumption that in some children with constitutional delay in puberty a reversible functional hypopituitarism exists, which is normalized after the onset of puberty, due to androgens sensitizing growth hormone releasing mechanisms. Treatment with HGH may induce increased growth velocity in some of these patients.     

Growth hormone treatment of short children born small for gestational age: metanalysis of four independent, randomized, controlled, multicentre studies

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch-up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. The effect of GH administration was evaluated over 2 years in short prepubertal children born SGA. The children ( n = 244), who were taking part in four independent multicentre studies, had been randomly allocated to groups receiving either no treatment or GH treatment at a daily dose of 0.1, 0.2 or 0.3 IU/kg (0.033, 0.067 or 0.1 mg/kg) s.c. At birth, their mean length SD score (SDS) was -3.6 and their mean weight SDS -2.6; at the start of the study, mean age was 5.2 years, bone age 3.8 years, height SDS -3.3, height SDS adjusted for parental height -2.4, weight SDS -4.7 and body mass index (BMI) SDS -1.4. The untreated children had a low-normal growth velocity and poor weight gain. Although bone maturation progressed more slowly than chronological age, final height prognosis tended to decrease, according to height SDS for bone age. GH treatment induced a dose-dependent effect on growth, up to a near doubling of height velocity and weight gain; BMI SDS was not altered. Bone maturation was also accelerated differentially; however, final height prognosis increased in all GH treatment groups. The more pronounced growth responses were observed in younger children with a lower height and weight SDS. In conclusion, GH administration is a promising therapy for normalizing short stature and low weight after insufficient catch-up growth in children born SGA. Long-term strategies incorporating GH therapy now remain to be established.     

Investigation of Growth Hormone Secretion in Patients with Intrauterine Growth Retardation

Rochiccioli, P., Tauher, M., Moisan, V. and Pienkowski C. (Department of Paediatrics, CHU Rangneil, Toulonse Cedex, France). Investigations of growth hormone secretion in patients with intrauterine growth retardation. Acta Paediatr Scand [Suppl] 349: 42, 1989.
Growth hormone (GH) deficiencies have rarely been reported in intrauterine growth retardation (IUGR). This study has investigated GH secretion using GH provocation tests, 24-hour GH secretory profiles, and insulin-like growth factor I (IGF-I) measurements in 24 children with intrauterine growth retardation. The criteria for diagnosis were a birth length and weight below the 10th percentile for gestational age. The average age at investigation was 5.5 years, and the average growth retardation was -3.3 SD. Twenty children had shown catch-up growth between the ages of 6 months and 3 years, followed by varying decreases in growth velocity. Studies of GH secretion demonstrated GH deficiency in 16 patients, with neurosecretory dysfunction in six. Treatment with pituitary GH in nine children increased mean growth velocity from 3.5 cm/year to 7 cm/year. GH therapy should thus be effective in improving the height prognosis of children with intrauterine growth retardation.     

The Effects of Cranial Irradiation on Growth Hormone Secretion

ABSTRACT. Growth hormone (GH) secretion has been studied under physiological conditions and in response to standard pharmacological stimuli in 14 children, who had previously received cranial irradiation between two and fourteen years earlier. All fourteen showed a blunted GH response to insulin hypoglycaemia and, in twelve, the GH response to arginine stimulation was also subnormal. Physiological GH secretion was studied by measuring integrated GH concentrations in 30 min blood samples collected over a 24 hour period by a continuous withdrawal pump. Compared to normal controls ( n =5), the irradiated patients showed a significant reduction in the mean integrated GH concentration (2.2: 8.8 mU/l; p < 0.002), the total 24 hour GH output (mean 105.7 mU vs. 391.7 mU; p < 0.002) and the mean GH output during the first six hours of sleep (mean 48.2 mU vs. 226 mU; p < 0.002). There was no significant correlation between the maximum peak GH response to either pharmacological test and the total 24 hour GH output. Conventionally most short children undergo two provocative tests of GH release and if the GH response to one of the two tests is normal, it is usually assumed that GH production is adequate. Adopting these criteria in this study it would have been assumed incorrectly that GH production was normal in two children. Nonetheless all 14 children showed a blunted GH response to an ITT as well as a reduced total 24 hour GH output. Therefore we would suggest that in children suspected of radiation-induced GH deficiency pharmacological tests of GH secretion remain useful, the ITT being the test of choice because of the marked radiation sensitivity of the GH response to hypoglycaemia.     

Confirming the diagnosis of growth hormone deficiency (GHD) and transitioning the care of patients with childhood-onset GHD

Growth hormone deficiency (GHD) diagnosed in childhood may persist into adult life. After attainment of final height, retesting of the patient's growth hormone-insulin-like growth factor (GH-IGF) axis using the adult GHD diagnostic criteria should be performed after an appropriate interval of 1-3 months off GH therapy. At the time of retesting, other pituitary hormones and serum IGF-I levels should also be measured. The opportunity should be taken to assess body composition, bone mineral density, and fasting lipid and insulin levels. Patients with severe, long-standing, multiple pituitary hormone deficiency, genetic defects, or severe organic GHD can be excluded from GH retesting. When the diagnosis of adult GHD is established, continuation of GH therapy can be recommended unless there is a known risk of diabetes mellitus or malignancy. The patient's transition to GH replacement in adulthood should be arranged as a close collaboration between the pediatric and adult endocrinologists, who should discuss the reinitiation of treatment with the patient.     

Improved Growth Response to GH Treatment in Irradiated Children

ABSTRACT. The growth response to two years of GH treatment was studied in fifteen children after radiotherapy for a cranial tumor. The growth response was compared to that of short children (– 2 SD) and that of children with idiopathic growth hormone deficiency (GHD) of similar ages. All children were treated with hGH 0.1 IU/kg/day s.c; which is a higher dose and frequency than previously reported for irradiated children. On this protocol the growth rate increased 5.0 ± 0.5 cm/y (mean ± SEM) the first year and 3.8 ± 0.7 cm/y the second year compared to the growth rate the year before GH-treatment. Although the net gain in growth was higher than previously reported, the first year growth response was significantly reduced ( p < 0.05) compared to that of GHD-children (7.6 ± 0.5 cm/y) but exceeded ( p < 0.05) that of short children (3.4 ± 0.3 cm/y). The median spontaneous 24 h-GH secretion was 209 mU/I in the short children, 52 mU/I in the irradiated children and 16 mU/1 in the idiopathic GHD children. Thus the growth increment varied inversely to the spontaneous GH secretion observed in the three groups.     

The effect of human growth hormone therapy on skinfold thickness in growth hormone-deficient children

Skinfold thickness (ST) was measured in 43 children with various forms of growth hormone (GH) deficiency during the first year of GH therapy. The average (and SEM) initial ST, expressed as standard deviation score (SDS) was 1.17 (0.25) for subscapular, 0.63 (0.18) for triceps, and 0.40 (0.21) for biceps ST. During therapy the average decrease is 1 SD. Children in the pubertal age group and those with partial GH deficiency showed smaller decreases. A larger decrease of triceps ST was associated with lower GH and insulin peaks, and lower age, bone age and initial weight-for-height. Some correlations between ST decrease and growth response in the first year were significant, but still too low to allow of reliable predictions. The same was true for other clinical parameters. These data indicate that a chronic lack of GH leads to unequal fat distribution, possibly due to different sensitivities to GH in the trunk and extremities. The variability of ST responses to GH therapy limits clinical applications.Abbreviations GH growth hormone - hGH human growth hormone - SDS standard deviation score - SDS_BA standard deviation score for bone age - SDS_CA standard deviation score for chronological age - SEM standard error of the mean - ST skin fold thickness - ST-SDS skinfold thickness, expressed as a standard deviation score - ST-log skinfold thickness, expressed as 100.log₁₀ (reading in 0.1 mm-18) - TSH thyroid stimulating hormone     

Hypothalamo-pituitary-adrenal axis integrity after cranial irradiation for childhood posterior fossa tumours

BACKGROUND: The evolution of anterior pituitary deficits after treatment for pituitary tumours has been largely attributed to local irradiation, but may be influenced as much by tumour mass or surgery. Other than growth hormone (GH) insufficiency, the late endocrinopathies after survival from non-central brain tumours have been little documented. The aim of this study was to investigate the hypothalamic-pituitary-adrenal (HPA) axis in long-term survivors of cranial irradiation for childhood posterior fossa tumours. PROCEDURE: We studied long-term data in patients treated prepubertally for posterior fossa brain tumours and systematically referred by radiation oncologists for growth and pubertal monitoring to the London Centre for Paediatric Endocrinology over the last 25 years. They must have undergone HPA axis assessment twice, first prepubertally at documentation of growth failure, and second at completion of growth and puberty. Data on sixteen patients (12 males, 4 females; median age: 5.7 years, range: 2.5-8.8 years), who had undergone excision surgery with high dose cranial irradiation and/or chemotherapy for childhood posterior fossa tumours, were examined. Patients were followed for a median of 11.0 (range: 6.8-21.4) years after radiotherapy. HPA axis assessment was undertaken with the insulin-induced hypoglycaemia test (ITT). Basal thyroid, cortisol and gonadal function tests were undertaken annually throughout the follow-up period and any deficits replaced. RESULTS: At each ITT, all patients mounted an inadequate GH response. By the end of the follow-up period all patients remained severely GH deficient, two (12.5%) had partial ACTH insufficiency, one (6.3%) had secondary hypothyroidism but none were gonadotropin deficient or hyperprolactinaemic. CONCLUSIONS: Unlike the severe, evolving multiple pituitary deficits after treatment of pituitary or central tumours in adults, these findings in children with posterior fossa tumours suggest that, with the exception of GH, neurotoxicity due to irradiation per se is associated with a low prevalence of anterior pituitary hormone deficiencies, even at a long follow-up. Since the children in this study were selected for assessment on the basis of growth failure, the high prevalence of GH insufficiency at first testing is to be expected; however, the early onset (within 1-3 years of irradiation) and permanence we have identified supports the view that GH is the most sensitive hormone to radiation injury.