| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CLINICAL CASE SEMINAR |
Université Paris-Descartes (R.B.), Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Unité d’Endocrinologie Pédiatrique, 94270 Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (C.T., J.-C.S.), Hôpital Necker-Enfants Malades, Service d’Explorations Fonctionnelles, 75743 Paris, France; Université Paris-Descartes (M.Z., C.S.-R.), Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Neurochirurgie Pédiatrique, 75743 Paris, France; Université Paris-Descartes (F.D.), Institut Curie, Département d’Oncologie Pédiatrique, 75248 Paris, France; and Département d’Oncologie Pédiatrique (C.K.), Institut Gustave Roussy, 94805 Villejuif, France
Address all correspondence and requests for reprints to: R. Brauner, 211 Avenue Daumesnil, 75012 Paris, France. E-mail: raja.brauner{at}wanadoo.fr.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Objective: The objective of the study was to assess the relationship between the tumor and its treatment and the weight, growth rate, and onset of puberty, using the diencephalic syndrome of emaciation as model.
Patients: Eleven patients seen before 1 yr of age, except one aged 9 yr, for diencephalic syndrome of emaciation due to hypothalamic pilocytic astrocytoma, were treated by surgical resection (n = 9), cranial irradiation (n = 7), and/or chemotherapy (n = 10).
Results: At diagnosis, growth rate was normal, despite the emaciation, and there was no hypothalamic-pituitary deficiency, except in the oldest patient. After tumor treatment, all had GH and thyroid-stimulating hormone deficiencies, but only three, who underwent major surgical resection, also had ACTH deficiency and diabetes insipidus. Eight became obese, and all but the oldest had transient precocious puberty. Plasma leptin concentrations were very low at diagnosis, increased after tumor treatment, and decreased transiently in one boy when the testosterone increased. The plasma soluble leptin receptor concentrations changed in the opposite direction, leading to an increase in the free leptin index, including in the three patients whose tumor was reduced without surgery. The body mass index was correlated positively with plasma leptin (rho = 0.73, P = 0.0004) and free leptin index (rho = 0.63, P < 0.004) and negatively with ghrelin (rho = –0.49, P < 0.03) concentrations.
Conclusions: The obesity that occurs after treatment of hypothalamic tumors is not due to dysregulation of leptin secretion because it and plasma soluble leptin receptor remain regulated by factors like testosterone. This study also shows the influence of weight, possibly via leptin secretion, on the transient hypothalamic-pituitary-gonadal activation that occurs during the first year of life.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
These features pose to the physicians difficult problems of diagnosis of the tumor, with the risk of blindness and endocrine management, particularly GH treatment in those cases with a tumor residue, but they also pose questions about the pathogenesis. Of special interest is the relationship among weight, growth rate, and the induction of puberty. The signal to induce puberty sent by the increase in body fat is unclear. Whereas the role of increased leptin secretion is important, other factors, like IGF-I, glucose, insulin, and ghrelin, may also be involved.
We studied 11 patients with DS due to hypothalamic pilocytic astrocytomas. The treatment of the tumor was followed by obesity in eight and PP in all but one. We therefore assessed the relationship between the tumor and its treatment and the weight, growth rate, and onset of puberty, using the DS as model.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Eleven (five boys) of the 12 patients seen for DS by the same physician (R.B.) between 1989 and 2002 were included. One girl was excluded because she was lost to follow-up after the initial evaluation. Written informed consent for the evaluation and treatment was obtained from the parents. The patients were aged less than 1 yr at diagnosis, except for case 1 (Table 1
). The tumors were hypothalamic (n = 6) or hypothalamochiasmatic (n = 5), associated with hydrocephalus in seven patients. All were biopsied and were pilocytic astrocytoma. The treatment depended on the patient’s age, risk to vision, and evolution of the tumor. It included subtotal (n = 2) or partial (n = 7) surgical resection (except cases 6 and 7), fractionated cranial irradiation (45–55 Gy, except cases 5–7 and 10), and/or chemotherapy (except case 7). The chemotherapy was baby brain French society of pediatric oncology (BBSFOP, n = 10) (5) and Packer as a second chemotherapy (n = 5) (6). One (case 7), treated by subtotal resection alone, died due to tumor enlargement. Five became blind or visually handicapped. The patient with a neurofibromatosis 1 became epileptic and developed a carotid stenosis after irradiation (case 8). One had leukemia after BBSFOP chemotherapy (case 9). At the last evaluation, eight patients had a stable tumor residue and two were still on chemotherapy because of tumor growth.
|
GH secretion was evaluated before (n = 6) and after (n = 10) treatment of the tumor. It was stimulated by GHRH (n = 2), arginine-insulin (n = 1), arginine (n = 1), or ornithine (n = 2) before treatment and by ornithine (n = 8), arginine-insulin (n = 3), and/or glucagon (n = 1) after treatment. GH deficiency was defined by a GH peak less than 10 µg/liter after two different stimulation tests. GH treatment (0.23 mg/kg·wk, administered as six sc injections per week) was given to four patients with low growth rate for age and a stable tumor residue more than 2 yr after treatment.
PP was defined by breast development before 8 yr in girls and testicular enlargement before 9 yr in boys. Pubertal delay was defined by the absence of these developments after 13 yr in girls and 14 yr in boys. The hypothalamic-pituitary-gonadal axis was assessed in cases of PP and pubertal delay by measuring basal and GnRH (100 µg/m2; maximum dose 150 µg)-stimulated FSH and LH and the plasma concentrations of testosterone in boys and estradiol in girls. Among the 10 patients with PP, seven were treated with GnRH analog and three were not treated because the PP was transient. The patients who had no sex steroid secretion and were of pubertal age were given testosterone heptylate (25 mg per 14 d im in case 1) or ethinyl estradiol (oral 2 µg/d in cases 6 and 8). The doses were increased when growth was completed and were associated with progestin replacement in girls.
The hypothalamic-pituitary-thyroid axis was assessed by measuring plasma free T4 and any deficiency (<10 pmol/liter) was treated with T4 (75–100 µg/m2·d). The hypothalamic-pituitary-adrenal axis was assessed by measuring plasma cortisol at 0800 h, and any deficiency (<80 µg/liter) was treated with hydrocortisone (10–15 mg/m2·d). Central diabetes insipidus was treated with oral desmopressin, given twice daily at a dose that kept the urine volume normal.
Leptin and its soluble leptin receptor (sOB-R) (both assessed with kits from Diagnostic Systems Laboratories, Inc., Webster, TX) and total ghrelin (RIA from Linco Research, St. Charles, MO) were measured on the most recent plasma samples obtained from fasting patients and stored at –20 C. All samples assayed for a given biological parameter were included in the same run. The detection limits of the assays were 0.10 µg/liter for leptin, 0.14 µg/liter for sOB-R, and 93 pg/liter for ghrelin. Within-run coefficients of variation were less than 5% for leptin, 13% for sOB-R, and 10% for ghrelin. The leptin receptor assay was not affected by adding up to 300 µg/liter recombinant leptin to serum samples. The free leptin index (FLI) was determined by calculating the ratio between the concentrations of leptin and sOB-R, multiplied by 100.
Height and body mass index (BMI) are expressed as SD scores for chronological age (7, 8). Data are means ± SD. Correlations were analyzed using the Spearman test.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Height, weight, and cranial circumference at birth of the seven patients for whom data were available were normal. At diagnosis, all the patients had stopped gaining weight, which was not explained by vomiting, diarrhea, or decreased caloric intake, but their statural growth rate was normal (Fig. 1). All but three with a hypothalamic tumor (cases 1, 5, and 6) had associated nystagmus and/or strabismus. There was no hypothalamic-pituitary deficiency, except in the patient aged 9 yr (case 1), who presented with headache, major asthenia, and diffuse pain and had a complete GH deficiency (Table 1
), although his other pituitary functions were normal. Three patients had a high basal GH concentration (31, 22, and 30 µg/liter in cases 5, 8, and 10, respectively) and peaks.
|
Weight, growth rate, and puberty
BMI increased from –3.5 ± 0.2 SD before tumor treatment to 2.8 ± 1.4 SD at the last evaluation (Fig. 2 and Table 1). After tumor treatment, all except case 1 had PP; it occurred at age 5.2 ± 1.1 yr in boys and 5.3 ± 1.9 yr in girls. The mean increases in BMI between the diagnosis and onset of PP were 5.9 ± 1.7 SD in boys and 5.2 ± 2.2 SD in girls. PP was followed by no further development of puberty in all patients, including the three who were not treated with GnRH analog. This treatment was therefore stopped for all patients. At the last evaluation, the plasma concentrations were less than 0.05 µg/liter for testosterone in boys and less than 10 pg/ml for estradiol in girls with a gonadotropin response to the GnRH test less than 0.4 IU/liter when evaluated (Table 1).
|
). These changes paralleled those of the BMI. They also occurred in three patients whose tumors were reduced by chemotherapy alone (cases 6 and 11) or chemotherapy plus cranial irradiation (case 8), without surgery. Conversely, the BMI did not increase in the three cases whose tumor was not reduced by chemotherapy alone as first treatment (cases 2, 4, and 9) until surgery or radiotherapy. In the boy evaluated longitudinally (Fig. 3), PP was associated with decrease in the plasma concentrations of leptin and FLI. This change was transient and paralleled that of the plasma testosterone concentration. In the girls evaluated, PP was associated with high FLI concentrations.
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Diagnosis and management of DS
All except one of the patients in this study were less than 1 yr old at diagnosis, as previously reported (9). DS has been reported in 5% of the intracranial tumors occurring during the first year of life (10), 15% of the optic pathway tumors (5), and 21% of hypothalamic glioma (11). The DS is difficult to diagnose, as is the tumor and management of the endocrine deficiencies. Because arrested weight increase in a given baby is usually due to a gastrointestinal disorder and rarely to a hypothalamic tumor, the diagnosis may be delayed, increasing the risk of blindness. The characteristics suggesting DS in a baby whose weight does not increase are the absence of gastrointestinal symptoms and the conservation of a normal growth rate. These children require careful ophthalmic examination to detect nystagmus, strabismus, and optic atrophy, followed if necessary by neuroradiological examination. Cerebral ultrasound examination may reveal the tumor and associated hydrocephalus in babies with an open anterior fontanelle. If these signs are absent, neuroradiological examination should be performed. Endocrine evaluation is not useful for diagnosing the tumor, and the low plasma IGF-I concentrations may be due to cachexia. Complete surgical removal of the hypothalamic tumor is difficult. Cranial irradiation is to be avoided in young patients and those with associated neurofibromatosis 1. A biopsy is usually performed at the initial evaluation if diagnosis of the type of the tumor is difficult, and an emergency derivation may be necessary. Otherwise, chemotherapy is usually the first treatment, initially by BBSFOP (5), followed by Packer (6). Endocrine management after tumor removal is difficult for several reasons, including the persistence of a tumor residue, making it difficult to decide on GH treatment; the persistence of a normal statural growth rate, probably due to overweight, despite GH deficiency; and the transient PP followed by the gonadotropin deficiency.
Mechanism of cachexia in DS
How the tumor causes cachexia is not known. Our patients gained weight rapidly after treatment of the tumor, leading to obesity in eight of 11, as previously reported (6). Lesion of the hypothalamic region due to surgery or radiotherapy may not be the only explanation for this rapid weight increase. Indeed, the decrease in tumor size after chemotherapy was also followed by rapid weight gain. Perhaps the tumor itself is responsible for emaciation, by secreting a so-called fat-mobilizing substance (12, 13). Some of our patients (cases 2, 4, 5, and 11) rapidly lost weight after an initial period of treatment, indicating a recurrence of the tumor, as found by others (14).
Weight and growth rate
All our patients had a normal growth rate at diagnosis, despite their lack of weight gain. Among the six patients for whom GH-stimulated peak was available at diagnosis, three had a normal peak with elevated basal GH concentrations and normal or low IGF-I. The GH results for these three patients are consistent with recent data indicating increased basal GH concentrations, incomplete GH suppression after a glucose load, and normal IGF-I in DS patients before treatment of the tumor, suggesting a partial resistance to GH (15). This partial resistance to GH may be related to the cachexia, as in other situations associated with low body weight (16). In addition, the concentrations of ghrelin before treatment were more than twice those of normal weight controls in some of our patients, and this may enhance an already increased GH secretion.
Weight, puberty, and appetite-modulating substances
Others have reported PP in DS (11, 12, 17). The transient activation of the hypothalamic-pituitary-gonadal axis after treatment of the tumor is concomitant with rapid weight gain. This may suggest that a biological factor produced by the fat tissue is responsible for the PP. Leptin may be this factor because it may facilitate human pubertal development (18). The administration of leptin to a 9-yr-old girl with a congenital leptin deficiency induced a pulsatile pattern of gonadotropin secretion consistent with early puberty (19). Leptin also increases the mean LH concentration and pulse frequency in women with hypothalamic amenorrhea (20). In girls with anorexia nervosa, resumption of menstrual function, but not weight recovery alone, was associated with a significant increase in FLI (21). Finally, changes in bioavailable leptin (as assessed with the FLI) are more likely to influence pubertal maturation than are changes in leptin alone (22, 23, 24, 25).
We found that plasma leptin concentrations were positively correlated with the BMI, whereas those of sOB-R were negatively correlated. The leptin and sOB-R concentrations were similar to those of BMI-matched controls. The weight of one boy (case 5) increased after treatment of the tumor, as did his circulating leptin, whereas his sOB-R decreased. When PP occurred, the increase in his testosterone was associated with a decrease in the plasma concentration of leptin and an increase in that of sOB-R, leading to a dramatic decrease in FLI, whatever the weight. These data suggest that the regulation of the leptin axis is not altered by the tumor and its treatment and are at variance with previous data (26, 27). Similarly, ghrelin regulation does not seem to be altered in these patients. We found high plasma concentrations of ghrelin, which decreased after treatment of the tumor when the BMI and leptin increased, with a significant negative correlation between ghrelin and BMI or leptin.
Conclusion
The treatment of the tumor causing DS, even when the hypothalamic-pituitary region is preserved, is followed by a dramatic weight increase and PP in all cases diagnosed during the first year of life. Although we have few data, they do not indicate any dysregulation of the leptin or ghrelin axes in DS. The rapid changes in leptin and ghrelin concentrations accompanying the posttreatment weight increase may be involved in PP.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
First Published Online April 18, 2006
Abbreviations: BBSFOP, Baby brain French society of pediatric oncology; BMI, body mass index; DS, diencephalic syndrome; FLI, free leptin index; PP, precocious puberty; sOB-R, soluble leptin receptor.
Received February 13, 2006.
Accepted April 12, 2006.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
