Subnormal Growth During Puberty in Children Treated for Acute Lymphoblastic Leukemia

Growth was studied longitudinally in 19 children who were long-term survivors after acute lymphoblastic leukemia (ALL). Of the children, 13 were girls; 6 were boys. They had all undergone a 3-year cytostatic treatment period which included vincristine, adriamycin, asparaginase, methotrexate, purinethol, and prednisone. Prophylactic cerebral irradiation (20-24 Gy) had been given to all children; 4 of them had also been given irradiation to the spine (10 Gy). The pattern of growth was nearly identical in girls and boys. Growth in relation to the therapy was almost normal, whereas growth during puberty was subnormal and final height was 1.3 SD less than expected at onset of disease. The growth pattern was the same for children with cerebrospinal irradiation as for those with cerebral irradiation. In view of the present results and previous studies on growth hormone (GH) secretion after cerebral irradiation, we suggest that treatment with luteinizing hormone releasing hormone (LHRH) or GH could be considered at puberty for children who have been treated for ALL, including cerebral irradiation, and who have a poor prognosis for final height.     

Disturbed Pubertal Growth in Girls after Acute Leukaemia: a Relative Growth Hormone Insufficiency with Late Presentation

Long-term follow-up of growth and development after acute lymphoblastic leukaemia (ALL) in childhood has previously been limited to the prepubertal period. This study describes pubertal growth, final height and the spontaneous secretion of GH in girls treated for ALL, including CNS irradiation with 24 Gy. Ten girls, treated earlier for ALL, experienced the menarche at a mean age of 12.2 years. This is significantly earlier than the mean for Swedish girls. Prepubertal growth was near normal after the end of therapy for leukaemia. Mean final height was -1.7 SD, which is 1.5 SD less than at onset and 1.0 SD less than 1 year after the end of treatment. Thirteen other girls had a blunted spontaneous secretion of GH, several years after treatment for ALL: there was no increase in GH secretion during puberty. These results suggest that girls who have been treated for ALL, including CNS irradiation, have a relative GH insufficiency. This insufficiency becomes obvious only when the girls cannot respond to the increased need for GH during the pubertal spurt.     

A longitudinal study of growth and growth hormone secretion in children during treatment for acute lymphoblastic leukemia

Diminished growth rate during treatment for acute lymphoblastic leukemia (ALL) is of the multifactorial etiology. Effects on GH secretion have been shown after discontinuation of treatment including prophylactic CNS irradiation. Seventeen children treated for ALL with three different CNS preventive schedules were followed longitudinally with repeated estimations of the spontaneous GH secretion during a 24-month period. No difference was found in GH secretion during this time between patients who had received no radiotherapy and those who had received 18 or 24 Gy as CNS prophylaxis. During dexamethasone treatment the GH secretion was completely suppressed, which can be a mediator for the diminished growth rate during the first 2 years of ALL treatment. We conclude that there is no clinical reason to perform GH analysis within the first 24 months of treatment for ALL.     

Suppressed spontaneous secretion of growth hormone in girls after treatment for acute lymphoblastic leukaemia.

The spontaneous secretion of growth hormone during a 24 hour period and the response of growth hormone to growth hormone releasing hormone was studied in 13 girls who had received treatment for acute lymphoblastic leukemia that included cranial irradiation with 20-24 Gy in 12-14 fractions. At the time of investigation the girls were at varying stages of puberty and had normal concentrations of thyroid hormones. The mean interval between the end of treatment and investigation was 4.6 years. The mean age at onset of the disease was 3.2 years and at investigation 10.7 years. The average attained height equalled -0.3 SD at onset, and -1.0 SD at the time of investigation. Secretion of growth hormone was substantially reduced compared with controls and did not increase during puberty. A prompt rise in growth hormone secretion was seen after injection of growth hormone releasing hormone, but the mean maximum growth hormone concentration was, however, only 25 mU/l. There was no correlation between the 24 hour secretion and growth hormone response to growth hormone releasing hormone, or the time since irradiation. These results confirm earlier work that suggested that girls who had received treatment for acute lymphoblastic leukaemia, that included cranial irradiation, have a comparative growth hormone insufficiency characterised by normal prepubertal growth and slow growth during puberty because of an inability to respond to the increased demands for growth hormone at that time.     

Response to Growth Hormone Treatment and Final Height after Cranial or Craniospinal Irradiation

ABSTRACT. Growth hormone (GH) deficiency (GHD) induced by cranial irradiation has become a frequent indication of hGH substitutive therapy. This study analyses the growth response to hGH therapy and the factors involved in the decrease in growth velocity observed after cranial irradiation. One hundred children (61 boys and 39 girls) given cranial radiation for pathology distant from the hypothalamo-pituitary area were studied. Fifty-six of them received hGH therapy for GHD resulting in decreased growth velocity. The initial annual height gain in the cranial-irradiated group was comparable to that of patients treated for idiopathic GHD; additional spinal irradiation significantly reduced the growth response. Twenty-eight hGH-treated patients reached final heights which were compared to those of 2 untreated irradiated groups, one with GHD (n=27) and the other with normal GH secretion (n= 17). The height SD score changes observed in hGH therapy were +0.3 in the cranial (n=10) and - 1.2 SD in the craniospinal (n = 18) groups. GH deficiency had contributed to a mean height loss of 1 SD and spinal irradiation to a loss of 1.4 SD. The small effect of hGH therapy on final height is probably linked to the small bone age retardation at onset of hGH therapy and to the fact that irradiated children entered puberty at a younger age in terms of chronological age (10.6±0.3 yr in girls and 11.0± 0.3 yr in boys) and bone age (9.6 ± 0.4 yr in girls and 12.6 ± 0.3 in boys) than the idiopathic GHD patients. These data suggest that the results of hGH therapy in irradiated children might be improved with higher and more fractionated hGH doses and, in some patients, by delaying puberty using luteinizing hormone releasing hormone analogs.     

Response to growth hormone treatment and final height after cranial or craniospinal irradiation

Growth hormone (GH) deficiency (GHD) induced by cranial irradiation has become a frequent indication of hGH substitutive therapy. This study analyses the growth response to hGH therapy and the factors involved in the decrease in growth velocity observed after cranial irradiation. One hundred children (61 boys and 39 girls) given cranial radiation for pathology distant from the hypothalamo-pituitary area were studied. Fifty-six of them received hGH therapy for GHD resulting in decreased growth velocity. The initial annual height gain in the cranial-irradiated group was comparable to that of patients treated for idiopathic GHD; additional spinal irradiation significantly reduced the growth response. Twenty-eight hGH-treated patients reached final heights which were compared to those of 2 untreated irradiated groups, one with GHD (n = 27) and the other with normal GH secretion (n = 17). The height SD score changes observed in hGH therapy were +0.3 in the cranial (n = 10) and -1.2 SD in the craniospinal (n = 18) groups. GH deficiency had contributed to a mean height loss of 1 SD and spinal irradiation to a loss of 1.4 SD. The small effect of hGH therapy on final height is probably linked to the small bone age retardation at onset of hGH therapy and to the fact that irradiated children entered puberty at a younger age in terms of chronological age (10.6 +/- 0.3 yr in girls and 11.0 +/- 0.3 yr in boys) and bone age (9.6 +/- 0.4 yr in girls and 12.6 +/- 0.3 in boys) than the idiopathic GHD patients. These data suggest that the results of hGH therapy in irradiated children might be improved with higher and more fractionated hGH doses and, in some patients, by delaying puberty using luteinizing hormone releasing hormone analogs.     

Growth hormone response to growth hormone-releasing hormone (hp GHRH1-44) as an index of growth hormone secretory dysfunction after prophylactic cranial irradiation for acute lymphoblastic leukemia (24 grays)

The growth hormone response to growth hormone releasing hormone hp GHRH1-44 (2 micrograms/kg i.v.) was studied in 19 prepubertal children who had been irradiated with 24 Gy for acute lymphoblastic leukemia (ALL) or lymphosarcoma (LS) at a mean chronological age of 4 10/12 years (limits 10/12 to 9 years). They were evaluated after a mean time interval of 4 8/12 +/- 3/12 years and compared to 14 prepubertal children with constitutional short stature (CSS). The individual responses to GHRH were decreased in all but three of the irradiated children. The mean GH response was 16.7 +/- 2.5 ng/ml as compared to 52.6 +/- 8.5 ng/ml in the control group (p less than 0.001). The GH response to GHRH was not correlated with the GH response to arginine-insulin tolerance test (AITT). A decreased response to GHRH with values between 12.5 and 19.4 ng/ml was observed in four cases with normal growth rates and normal GH responses to AITT. These results suggest that an impaired GH response to GHRH is a frequent finding after cranial irradiation for ALL or LS and may be the only sign of GH secretory dysfunction. It is probably indicative of early hypothalamic impairment of GH secretion.     

Adult height after cranial irradiation with 24 Gy: factors and markers of height loss

The decrease in adult height of children who have been given cranial irradiation (24 Gy) for acute lymphoblastic leukaemia is attributed to chemotherapy, growth hormone (GH) deficiency and early puberty. This study evaluates the factors involved in the height loss between irradiation and adult height and its markers in 43 patients irradiated at 5.8 ± 0.4 (SEM) years. The mean height loss was 0.9 ± 0.2 SD in the children with a normal GH peak ( n = 11), 1.7 ± 0.2 SD in those with a low GH peak and untreated ( n = 15) and 0.6 ± 0.2 SD in those treated with GH ( n = 17). The adult height was significantly lower than target height in all three groups. The height loss correlated negatively with the GH peak ( p < 0.02) and with the age at onset of puberty ( p < 0.05) in the first two groups with spontaneous growth, but not with the chemotherapy regimen or its duration, or the plasma insulin-like growth factor I (IGFI) and its GH-dependent binding protein (BP-3). Early puberty (onset at 8-10 years) occurred in 6 girls from the first two groups. At the first evaluation, 5.6 ± 0.4 years after irradiation, the GH peak values after arginine-insulin stimulation correlated with the age at irradiation ( p < 0.03), taking into account the time since irradiation. The plasma 1GF1 and BP-3 values were correlated with each other, but not with the GH peak. In conclusion, this study demonstrates the impact of GH deficiency and GH replacement therapy on adult height in children given cranial irradiation for leukaemia. They therefore should be evaluated for their GH secretion 1 2 years after the end of chemotherapy. GH therapy is indicated for those with low GH peak and decreased growth rate or no increase in growth rate despite puberty.     

Management of Growth Hormone Deficiency Through Puberty

ABSTRACT. As a model of the growth hormone (GH) dependence of growth in prepuberty and puberty, the growth of 182 children (93 boys, 89 girls) who survived in first remission for treatment of acute lymphoblastic leukaemia was examined. Chemotherapy regimens, including intrathecal methotrexate, were similar in all patients, but CNS treatment differed, in that one group received 2400 cGy cranial irradiation, while the other received 1800 cGy. There was a significant decrease in height SDS during prepuberty, which was equivalent in both sexes, whereas there was a much greater decrease in pubertal growth in girls than in boys. Girls treated with the lower dose regimen of cranial irradiation had their onset of pubertal maturation significantly advanced, to a mean of 9.9 years ( p < 0.001). Previous studies have indicated that the duration of puberty is shortened by GH treatment in patients with idiopathic multiple pituitary hormone deficiency or isolated GH deficiency (GHD). To determine whether an increase in the dose of GH administered during the adolescent growth spurt would improve final height, a prospective randomized trial was performed in 32 children (25 boys, 7 girls) with isolated GHD treated with a GH dose regimen of 15 IU/m²/week as daily s.c. injections. At the onset of the pubertal growth spurt, the patients were randomized either to an unchanged dose or to 30 IU/m²/week. There was no significant change in height velocity with the doubled dose of GH, but there was a trend in the advancement of pubertal maturation which was considered to be dose related. It is suggested that these findings are of relevance to the treatment of GHD in puberty, especially in girls with early or precocious puberty occurring as a consequence of low-dose cranial irradiation. It is concluded that optimum final heights may not be achieved in these patients without the therapeutic manipulation of the onset and/or duration of puberty.     

Growth Hormone Response to Growth Hormone-Releasing Hormone (hp GHRH-1-44) as an Index of Growth Hormone Secretory Dysfunction after Prophylactic Cranial Irradiation for Acute Lymphoblastic Leukemia (24 Grays)

ABSTRACT. The growth hormone response to growth hormone releasing hormone hp GHRH_1-14 (2 μg/kg i.v.) was studied in 19 prepubertal children who had been irradiated with 24 Gy for acute lymphoblastic leukemia (ALL) or lymphosarcoma (LS) at a mean chronological age of 410/12 years (limits 10/12 to 9 years). They were evaluated after a mean time interval of 4 8/12±3/12 years and compared to 14 prepubertal children with constitutional short stature (CSS). The individual responses to GHRH were decreased in all but three of the irradiated children. The mean GH response was 16.7±2.5 ng/ml as compared to 52.6±8.5 ng/ml in the control group ( p <0.001). The GH response to GHRH was not correlated with the GH response to arginine-insulin tolerance test (AITT). A decreased response to GHRH with values between 12.5 and 19.4 ng/ml was observed in four cases with normal growth rates and normal GH responses to AITT. These results suggest that an impaired GH response to GHRH is a frequent finding after cranial irradiation for ALL or LS and may be the only sign of GH secretory dysfunction. It is probably indicative of early hypothalamic impairment of GH secretion.     

Pulsatile growth hormone secretion in peripubertal patients with chronic renal failure. Cooperative Study Group on Pubertal Development in Chronic Renal Failure

The pubertal growth spurt has been associated with changes of physiologic pulsatile growth hormone (GH) secretion, and abnormalities of the central regulation of GH release have been found by pharmacologic testing in patients with chronic renal failure. To assess the characteristics of GH pulsatility in chronic renal failure and their relationship to pubertal growth, we studied spontaneous nighttime GH plasma profiles in 80 patients (61 boys) aged 10 to 20 years receiving conservative treatment (n = 29) or dialysis (n = 18) or after renal transplantation (n = 33). Tanner genital stages 1 to 4 in boys and breast stages 1 to 3 in girls were represented. Growth hormone pulse analysis was performed by the PULSAR algorithm. Growth hormone concentration profiles were pulsatile in each patient. Growth hormone mean and baseline levels and pulse amplitudes were higher in patients receiving conservative or dialysis treatment than in patients who had undergone renal transplantation. Peak frequency was similar in all treatment groups in boys but higher in girls who had undergone transplantation than in girls receiving conservative or dialysis treatment. Growth hormone peak amplitude and mean levels were lowest in patients in late puberty. The physiologic elevation of GH amplitudes around midpuberty was observed in boys receiving conservative and dialysis treatment but not after transplantation. Growth hormone mean and baseline levels were positively correlated with plasma androgen levels in boys. Growth hormone peak amplitude was correlated with 6-month height velocity after transplantation but not in patients receiving conservative treatment or dialysis. A strong inverse relationship was observed between GH peak amplitude and corticosteroid dosage in patients undergoing transplantation. The lack of relationship between circulating GH levels and growth in patients receiving conservative or dialysis treatment is compatible with end-organ hyporesponsiveness to GH. Pubertal growth failure despite successful transplantation appears to be related to steroid-induced GH hyposecretion.     

Growth response to growth hormone therapy following cranial irradiation

The growth response to growth hormone (GH) therapy has been studied in 12 children who received irradiation to the cranium alone either for brain gliomas, distant from the hypothalamic-pituitary axis, or as prophylaxis against CNS leukaemia. Seven children have completed GH treatment (mean duration 4 years) and five are presently on GH (mean duration 1.2 years). This response has been compared to that seen in 14 children with isolated idiopathic GH deficiency (IGHD), following GH therapy. Before treatment, the cranially irradiated patients (C-PRGHD) had higher standard deviation scores (SDS) for standing height, sitting height and leg length, and less bone age (BA) retardation, but started treatment at a similar age, and with a similar pre-treatment growth velocity and GH peak to standard provocative tests, compared to IGHD patients. GH produced a significant and similar increase in growth velocity (cm/year and SDS for BA) over the first 2 years' treatment in both groups. However C-PRGHD patients entered puberty and thus completed growth earlier than the IGHD group. As a result, cranially-irradiated children showed no change in height SDS with GH therapy, compared to catch-up growth in IGHD. Nevertheless, GH has enabled C-PRGHD patients to maintain their centile position and to achieve a more acceptable final height.Abbreviations GH growth hormone - IGHD idiopathic growth hormone deficiency - C-PRGHD post cranial-irradiation growth hormone deficiency - SDS standard deviation score - BA bone age - ALL acute lymphatic leukaemia - TSH thyroid stimulating hormone - CA chronological age - HA height age     

Cranial irradiation of female rats causes dose-dependent and age-dependent activation or inhibition of pubertal development

Cranial irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to late puberty. To unravel the underlying mechanisms, we developed a rat model with selective cranial Co60-irradiation technique. Infantile (12-16 d old) or juvenile (21-23 d old) female Sprague-Dawley rats received a single dose of 4, 5, 6, 9 or 2 x 9 Gy (at days 21 and 23). Each group consisted of 7-20 animals. High radiation doses (9 Gy and more) caused retardation of sexual development, whereas low radiation doses (5 or 6 Gy) led to accelerated onset of puberty in 20% of infantile irradiated rats animals as determined by vaginal opening. Interestingly, at peripubertal age (postnatal day 32-34), 5 or 6 Gy infantile irradiated rats had significantly higher serum LH levels stimulated by GnRH and estradiol levels (p < 0.05). 2 x 9 Gy irradiated rats had at the age of 3 mo a marked growth retardation and significantly lower GH levels than the controls (p < 0.05) whereas prolactin, FSH, TSH, T4, and corticosterone levels were comparable with controls. These studies demonstrate that the GnRH-pulse generator is very radiosensitive as precocious activation occurred after low dose irradiation (5 or 6 Gy) of infantile rats without any other endocrine disorder. High radiation doses (9 or 2 x 9 Gy) induced retardation of sexual maturation and later on growth hormone deficiency. Moreover this model of cranial irradiation seems to be suitable to study the molecular mechanisms of radiation induced pubertal changes.     

Growth hormone secretion, puberty and adult height after cranial irradiation with 18 Gy for leukaemia

The dose of prophylactic cranial irradiation given to patients for acute lymphoblastic leukaemia has been decreased from 24 to 18 Gy, but the beneficial effect of this decrease on growth is controversial. This study compares the growth hormone (GH) secretion and growth of 35 patients (20 boys) given 18 Gy at 3.7 ± 0.3 (SE) years, and routinely evaluated 5.4 ± 0.4 years after irradiation to define the indications for GH treatment in these patients. Of these, 63% had a low GH peak (<10 μg/l) after one (22 cases) or two (17 cases) stimulation tests. The plasma concentrations of insulin-like growth factor I and its GH-dependent binding protein were normal for age in all but two cases. The height changes between irradiation and evaluation were correlated with the GH peaks (P < 0.03) and were concordant, except in patients with early puberty. This occurred in 16 patients including all 12 girls irradiated before 4 years of age. A significant (P < 0.03) reduction in height (SD) between irradiation and adult height occurred in untreated GH-deficient patients (−1 ± 0.3, n = 6), but not in GH-deficient patients given GH (−0.6 ± 0.3, n = 8) or in those with normal GH peak (−0.4 ± 0.3, n = 7). Conclusion In children irradiated for acute lymphoblastic leukaemia, GH deficiency is frequent after 18 Gy but its impact on adult height is smaller than after higher doses. We suggest that the indications for gonadotropin releasing hormone analogue therapy should be broad in patients with early or rapidly progressing puberty and those for GH therapy in those patients with a below average constitutional height before irradiation. Received: 17 November 1997 / Accepted: 9 February 1998     

CNS late effects after ALL therapy in childhood. Part I: Neuroradiological findings in long-term survivors of childhood ALL—an evaluation of the interferences between morphology and neuropsychological performance

The effect of cranial irradiation on possible therapy-induced morphological central nervous system (CNS) side effects of children cured from acute lymphoblastic leukemia (ALL) is controversially discussed. In a retrospective multicenter study, 118 former ALL patients in first continous remission were investigated using cranial computerised tomography (CCT) or magnetic resonance imaging (MRI) scans to evaluate CNS related impairments. Corresponding to the different kinds of CNS prophylaxis, the patient sample was divided: group A (n = 39) receiving intrathecal methotrexate (ITMTX) and systemical medium-high-dose methotrexate (SMHDMTX), group B (n = 41) cranial irradiated (in mean 16.8 Gy) and administering ITMTX and SMHDMTX, group C (n = 38) irradiated (in mean 17.1 Gy) and getting ITMTX. Pathologic scans showed atrophy, leukoencephalopathy, calcifications or grey matter changes. These findings were compared with the neuropsychological test results. Abnormal MRI or CCT scans were found in 61/118 patients (51.7%). Fifteen belonged to group A (38.5%), 23 to B (56.1%) and 23 to C (60.5%). Patients with definite CNS changes show reduced neuropsychological test results. The prevalence of brain alterations seems to appear twice increased after lengthening the post-therapeutic interval in irradiated patients as in nonirradiated patients. Irradiated patients with an age younger than 2 years at diagnosis may show a lower prevalence for developing CNS alterations. CNS alterations are not sex-related. Children treated with cranial irradiation in combination with SMHDMTX and/or ITMTX were at greater risk of developing morphological brain alterations than patients with chemotherapy alone. These alterations are partly correlated with reduced neuropsychological performances and seem to stay with a longer post-therapeutic interval. Med. Pediatr. Oncol. 28: 387–400, 1997. © 1997 Wiley-Liss, Inc.     

Growth, puberty and obesity after treatment for leukaemia

Final height, body proportions, pubertal growth and body mass index were studied retrospectively in 142 survivors of acute lymphoblastic leukaemia (ALL). Treatment consisted of combination chemotherapy and cranial irradiation (18 or 24 Gy). Significant standing height loss and disproportion, with a relatively short back, was seen in both radiation dose groups. Girls were more severely affected than boys. Pubertal growth was adversely affected, with a reduction in peak height velocity in both sexes. Puberty occurred early in girls but at the normal time in boys. Nearly half the group were obese at final height, with no significant difference in incidence between the sexes. The relative roles of cranial irradiation and chemotherapy in the disturbance of growth, puberty and body composition observed in survivors of childhood ALL remain unclear. The aetiology is almost certainly multifactorial, with radiation-induced growth hormone insufficiency, early puberty, steroids and chemotherapy all having a role.     

Adult height after growth hormone (GH) treatment for GH deficiency due to cranial irradiation

BACKGROUND: The indications and factors affecting the growth in response to treatment with growth hormone (GH) of patients with cranial irradiation-induced GH deficiency remain unclear. PROCEDURE: The adult heights of 56 patients treated with GH (0.4-0.6 U/kg/week) as daily sc injections were analysed. They had been given 18 or 24 Grays (Gy) cranial irradiation for leukemia (group 1, 26 cases), 50 +/- 1 Gy for various tumors (group 2, 13 cases), 46 +/- 1 Gy for retinoblastoma (group 3, 8 cases), or 34 +/- 2 Gy with spinal irradiation for medulloblastoma (group 4, 9 cases). Twenty- five of these 56 patients had early puberty and were also treated with gonadotropin-releasing hormone (GnRH) analog. RESULTS: The standing (-1.0 +/- 0.2 in group 1, -0.7 +/- 0.3 in group 2, -1.1 +/- 0.3 in group 3, and -2.0 +/- 0.4 SD in group 4) and sitting (-1.8 +/- 0.2 in group 1, -0.4 +/- 0.4 in group 2, -1.2 +/- 0.4 in group 3, and -3. 4 +/-0.4 SD in group 4) adult heights were shor ter (P < 0.05 for standing and P < 0.001 for sitting heights) for group 4 than for each of the other groups. Of the 47 patients given cranial (and not craniospinal) irradiation, sitting adult height was shorter (P = 0. 02) and the difference between standing adult and target heights greater (P = 0.03) in those patients in whom puberty occurred at a normal age than in those treated with GnRH analog. Conclusion. The incomplete catch-up of growth seems to be mainly due to the reduction in sitting height of patients given spinal irradiation and in whom puberty occurred at a normal age. This suggests that GnRH analog treatment should be more widely used to treat children with early and/or rapidly progressing puberty after cranial irradiation.     

Growth and endocrine disorders in optic glioma

Hypothalamo-pituitary function in children with optic glioma may be impaired by the tumour itself and by the high cranial radiation doses used in treatment. This study evaluates the effect of optic glioma and its treatment on patient growth and pubertal development. Twenty-one patients (13 boys, 8 girls), treated for optic glioma by cranial irradiation (45–55 Grays) at a mean age of 5.4 years, were evaluated before (n=10) and/or after (n=21) irradiation. Growth hormone (GH) deficiency was present in only 1 patient tested before irradiation and in all patients after irradiation. Precocious puberty occurred in 7/21 cases, before irradiation in 5 patients and after irradiation in 2 patients. The cumulative height loss during the 2 years after irradiation was 0.2±0.2 SD (m±SEM) in 7 patients with precocious puberty and 1.1±0.2 SD in 14 prepubertal patients (P<0.01). The corresponding bone age advance over chronological age, evaluated 1–3 years after irradiation, was 1.1±0.5 and –0.7±0.3 year in the two groups (P<0.01). The mean height loss between time of irradiation and the final height was 2.3±0.6 SD (n=6). Primary amenorrhoea, associated with low oestradiol levels, occurred in two of the three girls of pubertal age. These data indicate that the high dose of cranial radiation used to treat optic glioma invariably results in GH deficiency within 2 years and that hGH therapy is required when GH deficiency is documented. Precocious puberty, resulting in apparently normal growth velocity in spite of GH deficiency, should be treated with luteinizing hormone-releasing hormone analogues because of the risk of accelerated bone maturation and reduced final height.     

Differential effects of 18- and 24-Gy cranial irradiation on growth rate and growth hormone release in children with prolonged survival after acute lymphocytic leukemia

To evaluate the effects of two different doses of cranial irradiation on growth and growth hormone (GH) release, we studied 61 children with acute lymphocytic leukemia who had survived at least five years in continuous complete remission. Forty-three children received 24 Gy (group 1) and 18 children received 18 Gy (group 2). Height was evaluated at diagnosis, at the end of treatment, and 6, 12, and 24 months later. Growth hormone release was evaluated by arginine and levodopa tests after the end of treatment. After diagnosis, the height SD score decreased significantly in both groups; two years after the end of treatment, only group 1 showed an SD score for height that was still significantly lower than at diagnosis. Group 1 showed impaired GH responses to the tests and, compared with controls, group 1 in fact included a percentage of subjects with a normal response to levodopa (ie, greater than 8 micrograms/L) that was significantly lower (56.4% vs 83.3%) and a percentage of nonresponders to both tests that was significantly higher (21.6% vs 0%). These data indicate that only patients treated with lower cranial irradiation dosage (18 Gy) had complete growth recovery and normal GH responses to pharmacologic tests.     

Disproportionate short stature after cranial irradiation and combination chemotherapy for leukaemia

The effect of combination chemotherapy and cranial irradiation on final height and body proportions was retrospectively examined in a cohort of 142 children treated for acute lymphoblastic leukaemia (ALL). Eighty four children (48 girls, 36 boys) received 24 Gy cranial irradiation and 58 (35 girls, 23 boys) 18 Gy. None had received testicular or spinal irradiation. A significant reduction in standing height SD score from diagnosis to final height was seen in all groups. Of the 109 children in whom sitting height measurements were available, 88 (81%) had relatively shorter backs than legs and in 25 (23%) this disproportion was of a marked degree. After mathematical correction for sitting height loss there was no longer a significant reduction in standing height SD score at final height in all except the 24 Gy group of girls. These data suggest that disproportion is a common finding after treatment for ALL and that, at least in some children, much if not all of the height loss seen is due to a reduction in sitting height. Possible explanations for this disproportion include a disturbance of puberty or an effect of chemotherapy on spinal growth, or both.