Energy expenditure in obesity associated with craniopharyngioma.

BACKGROUND AND PURPOSE: Obesity is a common yet incompletely understood complication of childhood craniopharyngioma. We hypothesized that craniopharyngioma is associated with specific defects in energy balance compared to obese control children. METHODS: Eleven craniopharyngioma patients were recruited for a study on body composition and energy balance. Eight subjects were obese. The obese craniopharyngioma patients had a mean age (+/-SD) of 11.2 +/- 1.7 years. The average body mass index z score was 2.33 (+/-0.32). A previously studied group of obese children (BMI z score 2.46 +/- 0.46) served as controls. Resting energy expenditure (REE) was determined by indirect calorimetry and body composition by dual energy X-ray absorptiometry in all children. RESULTS: Obese craniopharyngioma patient subjects had increased mean (+/-standard error) fat-free mass compared to obese controls (57% +/- 0.88 % vs 50.0% +/- 0.87%, p = 0.02). The obese craniopharyngioma patients had a 17% lower REE compared to values expected from the World Health Organization equation (1,541 +/- 112.6 vs 1,809 +/- 151.8 kcal; p = 0.01). In contrast, the obese control children had measured REE within 1% of predicted (1,647 +/- 33.2 vs. 1,652 +/- 40.2; p = 0.8). In a linear regression model, REE remained significantly lower than predicted after controlling for FFM. CONCLUSIONS: Lower REE may be a factor contributing to obesity in children with craniopharyngioma. Further study is needed into the mechanisms for reduced energy expenditure in patients with craniopharyngioma.

Late effects in survivors of tandem peripheral blood stem cell transplant for high-risk neuroblastoma.

BACKGROUND: Increasing numbers of children with advanced neuroblastoma are achieving cure. We describe the clinical late effects specific to survivors of stage IV neuroblastoma all similarly treated using tandem autologous peripheral blood stem cell rescue with TBI. METHOD: The medical records of 35 neuroblastoma patients treated at CHOP between 1997 and 2001 were examined. Eighteen of the 35 patients died of progressive disease, and 4 were lost to follow-up. Thirteen patients continue to follow-up in our Multidisciplinary Cancer Survivorship Clinic where they are evaluated and monitored by a consistent group of subspecialists that evaluate long-term sequelae. Data on treatment exposures including TBI and treatment related sequelae identified by clinician assessment and/or diagnostic testing were collected. RESULTS: Results indicate late effects were present in all 13 subjects, 12 of whom suffered from multiple negative sequelae, including issues with growth hormone deficiency, dental problems, osteochondromas and hearing deficiencies, among others, most at higher rates than reported previously. CONCLUSIONS: The findings in this small cohort indicate the need for future prospective studies of this intensive pediatric cancer treatment, and underscore the importance of medical intervention and long-term monitoring of these at-risk subjects to increase overall quality-of-life.

Use of the recombinant human TSH stimulated thyroglobulin level and diagnostic whole body scan in children with differentiated thyroid carcinoma.

The recombinant human thyrotropin (TSH) (rhTSH) stimulated thyroglobulin (Tg) level is a useful tumor marker for disease surveillance in adults with differentiated thyroid carcinoma (DTC). We report our institution's experience using rhTSH in children. Seven children with DTC on thyroid hormone suppressive therapy after total thyroidectomy and radioablation received rhTSH (0.9 mg i.m.) on day 1 and 2. TSH rose to 224 +/- 93 mIU/l on day 2 and 13 +/- 5 mIU/l on day 5. Serum Tg level and diagnostic whole body radioiodine scan (DxWBS) were assessed on day 5. Five children were disease free: all had negative DxWBS; two had Tg < or = 2.1 ng/ml; two had anti-Tg antibodies; and one had no Tg measured. Two children had recurrent disease: one had a negative DxWBS and Tg of 15 ng/ml; and one had a positive DxWBS and no Tg measured. There were no adverse effects from rhTSH. These results suggest that rhTSH can be safely used for disease surveillance in children with DTC.

Salutary effects of combining early very low-dose systemic estradiol with growth hormone therapy in girls with Turner syndrome.

CONTEXT: Optimizing pubertal estrogen replacement in girls with Turner syndrome is important. OBJECTIVE: The study objective was to test the hypotheses that physiological estradiol replacement administered early with GH will preserve height potential as much as if administered late and that it will bring about a greater height gain than standard oral estrogen therapy combined with GH. DESIGN: The study was randomized to early or late estrogen treatment; follow-up was at 3.5 yr or later. SETTING: This was a multicenter outpatient study. PATIENTS: Turner syndrome girls 12.0-12.9 yr (n = 7) or 14.0-14.9 yr (n = 7) of age who began GH before age 12.0 yr were the patients. The girls were matched to National Cooperative Growth Study registry patients who began GH and oral conjugated estrogen at similar ages and were similarly followed to adult or near-adult height. INTERVENTIONS: Depot estradiol, 0.2 mg/month i.m., was given initially and gradually increased; GH was 0.05 mg/kg daily. MAIN OUTCOME VARIABLE: Adult or near-adult height was the main outcome variable. RESULTS: Depot estradiol treatment resulted in height significantly taller than predicted at 12 yr of age (P < 0.02). All height potential was gained in the first 2 yr of the study, during which the early group grew 3.5 cm more than the late group, which was receiving GH alone (P < 0.01). The early depot estradiol group also gained 5.9 cm more height after starting estrogen than did the early National Cooperative Growth Study group (P < 0.05). Although feminization proceeded slowly on the lowest dose of estradiol, it advanced normally thereafter. CONCLUSIONS: These results suggest that very low-dose parenteral estradiol permits relatively age-appropriate feminization without interfering with the effect of GH on the enhancement of height potential.

Adult height and adult sitting height in childhood medulloblastoma survivors.

Outcome in adult height and sitting height is poor in children surviving medulloblastoma due to craniospinal irradiation (CSRT) and chemotherapy. We evaluated adult height and sitting height in 51 medulloblastoma patients stratified into four groups: G1, GH-deficient (GHD) patients treated with 23-39 Gy CSRT but not treated with GH [recombinant human (rh)GH]; G2, patients treated with rhGH; G3, patients who were not GHD; and G4, patients treated with 18 Gy CSRT and rhGH. Standing/sitting height of each group was compared with parental height and previously reported outcome studies. The rhGH dose was 0.3 mg/kg.wk, a higher dose compared with other reports of adult heights. The adult heights were significantly taller in group G2 [mean height SD score (SDS) = -1.86] than that achieved in previous studies (P < 0.0001), but not different from group G3, non-GHD (mean SDS = -1.55). The tallest stature achieved was in group G4 (18 Gy CSRT), a height SDS of -1.01. Sitting heights were significantly less than the normal population, with mean SDS of -2.96 but -1.62 in group G4. We conclude that adult heights but not sitting heights in medulloblastoma survivors are significantly improved with the higher dose of rhGH. The lower dose of CSRT further improves not only adult height but also sitting height.

Adult heights attained by children with hypothalamic/chiasmatic glioma treated with growth hormone.

Hypothalamic/chiasmatic gliomas (H/CG) in children are commonly accompanied by endocrine dysfunction due to mass effects of the tumor itself or as a consequence of tumor therapy, with GH deficiency (GHD) being the most common disorder. We report the height outcomes of GH-treated H/CG patients with GHD. We reviewed the records of 14 GHD patients with H/CG who were treated with human GH. A comparison group of non-GH-treated H/CG patients was also identified. Heights were expressed as sd scores (SDS). For GH-treated patients, the mean initial height was -0.7 +/- 0.3 (+/-se). Their mean final height was -0.3 +/- 0.3. The mean change in height SDS for the GH-treated group was +0.4. The mean initial and final height SDS for the non-GHD patients were 0.6 (se = 0.4) and 0.0 (se = 0.4), respectively. The mean change in height SDS was -0.6. The GHD patients had significantly lower initial height SDS compared with the non-GHD patients (P = 0.01) and had a significantly greater change in their height SDS (P = 0.04). GH treatment for H/CG patients restores much of their growth potential and improves adult height to within normal limits.

Long-term (15 years) outcome in an infant with metastatic adrenocortical carcinoma.

Adrenocortical carcinoma is a rare malignancy in children, with a high mortality. Little is known about long-term outcome, especially in infants treated with mitotane. We report the successful long-term outcome of a case of metastatic adrenocortical carcinoma presenting in infancy treated with surgical resection and mitotane. The patient presented at 2 months of age with Cushing's syndrome, a large adrenal mass, and elevated adrenal steroid levels. The tumor was removed surgically. Intraoperative findings included an adrenal tumor (confirmed malignant pathologically) invading the adrenal vein and vena cava. After surgery he was treated with mitotane at a dose of 2 g/d. Six months after surgery 11-deoxycortisol levels increased, and a computed tomography scan showed a pulmonary metastasis. Mitotane was increased to 2.5 g/d, and the metastasis was removed surgically. Plasma mitotane levels ranged 10-15 micro g/ml. Tumor markers remained normal, and mitotane was discontinued at 18 months. During therapy the patient's somatic growth was poor. His motor and speech development was delayed. After mitotane was discontinued he demonstrated catch-up growth. This case shows successful long-term outcome and recovery from the toxic effects of mitotane.

Effect of growth hormone (GH) treatment on bone in postpubertal GH-deficient patients: a 2-year randomized, controlled, dose-ranging study.

GH treatment in children with GH deficiency is frequently terminated at final height. However, in healthy individuals bone mass continues to accrue until peak bone mass is achieved. Because no prospective data specifically prove the role of GH in attainment of peak bone mass, we performed a multinational, controlled, 2-yr study in patients who had terminated pediatric GH at final height. Patients were randomized to: GH at 25.0 microg/kg x day (pediatric dose, n = 58) or 12.5 microg/kg x day (adult dose, n = 59), or no GH treatment (control, n = 32). Bone mineral content (BMC) and density were measured by dual-energy x-ray absorptiometry and evaluated centrally. Laboratory measurements were also performed centrally. After 2 yr, significant increases were seen with both GH treatments, compared with control in bone-specific alkaline phosphatase (P = 0.004) and type I collagen C-terminal telopeptide:creatinine ratio (P < 0.001), but there were no significant dose effects. Total BMC increased by 9.5 +/- 8.4% in the adult dose group, 8.1 +/- 7.6% in the pediatric dose group, and 5.6 +/- 8.4% in controls (analysis of covariance, P = 0.008), with no significant GH dose effect. BMC increased predominantly at the lumbar spine (11.0 +/- 10.6%, P = 0.015) rather than at the femoral neck or hip. In contrast, a significant dose-dependent increase was seen in IGF-I concentrations (adult dose: 114.5 +/- 119.4 microg/liter; pediatric dose: 178.5 +/- 143.7 microg/liter; P = 0.023). There were no gender-related differences in BMC changes with either dose, whereas the IGF-I increase was significantly higher with the pediatric than with the adult dose in females (P < 0.001) but not males (P = 0.606). In summary, reinstitution of GH replacement after final height in severely GH-deficient patients induced significant progression toward peak bone mass. Although there was a by-gender dose effect on IGF-I concentration, the treatment effect on bone was obtained in both males and females with the adult GH dose regimen.

Endocrine outcome in children with medulloblastoma treated with 18 Gy of craniospinal radiation therapy.

Craniospinal radiation therapy (CSRT) combined with chemotherapy results in significant endocrine morbidity. Between 1987 and 1990, a trial using 18 Gy was conducted to treat 10 young children with medulloblastoma. There were 7 survivors. We compared the endocrine outcome in these children (group 18 Gy) to that of a comparable group treated with conventional doses of CSRT that ranged from 23 to 39 Gy (group CD). Both groups had an identical history of chemotherapy and tumor stage and were treated with recombinant growth hormone therapy (rhGH). The mean age of group 18 Gy at diagnosis was 4.0 years, and rhGH treatment was initiated in 6 children at age 9.2 years. Group CD (12 children) was diagnosed at a mean age of 5.8 years and rhGH started in 11 children at a mean age of 9.6 years. The dose of rhGH used in both groups was identical (0.3 mg/kg/wk). For group 18 Gy, adult heights and sitting heights (a mean standard deviation score of -1.01 +/- 1.11 and -1.62 +/- 1.16, respectively) were statistically greater (P < 0.05) than those for group CD (mean standard deviation score of -2.04 +/- 0.83 and -3.16 +/- 1.43, respectively). Moreover, adult heights of group 18 Gy were not different from midparental heights, unlike group CD, whose adult heights were less than midparental heights (P < 0.0001). Of other endocrine sequelae, 10 patients of the CD group were hypothyroid, 3 had adrenal insufficiency, 3 had hypogonadism, and 2 had early puberty. In contrast, within group 18 Gy, only 1 was hypothyroid (P = 0.006) and 1 had early puberty. We conclude that endocrine morbidity was significantly reduced with 18 Gy CSRT in young children with medulloblastoma.

Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults.

PURPOSE: The optimal management of craniopharyngiomas remains controversial, especially in children and young adults. This study reports a single institution's experience with such patients. METHODS AND MATERIALS: Between 1974 and 2001, 76 patients were treated for craniopharyngioma at the Children's Hospital of Philadelphia and the Hospital of University of Pennsylvania (HUP). Of these, 75 patients (97%) were evaluable with long-term follow-up. Although all patients underwent attempted gross total resection, 27 had documentation of less than total resection with 18 of these patients receiving immediate postoperative radiotherapy (RT). An additional 22 patients received RT at HUP after failing surgery alone. RESULTS: Median follow-up for all patients was 7.6 years. The 10-year actuarial overall survival, relapse-free survival, and local control (LC) rates for all patients were 85%, 48%, and 53%, respectively. When comparing the 57 patients treated with surgery alone to the 18 treated with subtotal resection (STR) followed by RT, a significant difference in LC rates at 10 years (42% vs. 84%, respectively; p = 0.004) was noted. However, no statistically significant difference in overall survival was found between the two groups, because RT was highly effective as salvage therapy. Twenty-two patients at HUP treated with RT after relapse had a 10-year ultimate LC rate comparable to that of patients who received RT immediately after STR. CONCLUSION: RT given either immediately after STR or at relapse is effective in controlling craniopharyngiomas.

Prolactin levels during long-term risperidone treatment in children and adolescents.

BACKGROUND: This analysis was designed to investigate prolactin levels in children and adolescents on long-term risperidone treatment and explore any relationship with side effects hypothetically attributable to prolactin (SHAP). METHOD: Data from 5 clinical trials (total N = 700) were pooled for this post hoc analysis. Children and adolescents aged 5 to 15 years with subaverage intelligence quotients and conduct or other disruptive behavior disorders received risperidone treatment (0.02-0.06 mg/kg/day) for up to 55 weeks. Outcome measures analyzed included serum prolactin levels, reported adverse events, and the conduct problem subscore of the Nisonger Child Behavior Rating Form. RESULTS: Mean prolactin levels rose from 7.8 ng/mL at baseline to a peak of 29.4 ng/mL at weeks 4 to 7 of active treatment, then progressively decreased to 16.1 ng/mL at weeks 40 to 48 (N = 358) and 13.0 ng/mL at weeks 52 to 55 (N = 42). There was no relationship between pro-lactin levels and age. Females returned to a mean value within the normal range (

Vasopressin and desmopressin in central diabetes insipidus: adverse effects and clinical considerations.

The management of central diabetes insipidus has been greatly simplified by the introduction of desmopressin (DDAVP). Its ease of administration, safety and tolerability make DDAVP the first line agent for outpatient treatment of central diabetes insipidus. The major complication of DDAVP therapy is water intoxication and hyponatremia. The risk of hyponatremia can be reduced by careful dose titration when initiating therapy and by close monitoring of serum osmolality when DDAVP is used with other medications affecting water balance. Herein we review the adverse effects of DDAVP and its predecessor, vasopressin, as well as discuss important clinical considerations when using these agents to treat central diabetes insipidus.

Pediatric thyroid-associated orbitopathy: the Children's Hospital of Philadelphia experience and literature review.

BACKGROUND: As Graves' disease is uncommon in children, Graves' eye disease should be even more unusual. Here we report our experience with Graves' eye disease at the Children's Hospital of Philadelphia and review the literature on ophthalmic findings in children with Graves' disease. SUMMARY: A retrospective review identified 152 children with Graves' disease seen in the endocrinology clinic of the Children's Hospital of Philadelphia over a 3-year period. Of this cohort, only 26 (17%) were referred to ophthalmology because of prominent ophthalmic manifestations. The ages of the patients ranged from 4 months to 17 years. Sixteen of 26 patients were female. Most patients had mild findings consistent with Graves' disease. Proptosis was noted in 10 of 26 (38%). Lid retraction was present in 6 of 26 (23%). Mild corneal punctuate staining was identified in only 3 of the 26 patients (12%). No patients had strabismus or optic neuropathy. Three newly diagnosed Graves' patients who were seen as the retrospective review was being completed were all girls. All three had normal vision, motility, and fundus exams. Two had mild proptosis, lid retraction, and lid lag on down gaze. None had corneal, motility, or optic nerve pathology. These findings are consistent with previous studies in the literature. CONCLUSIONS: Eye findings in pediatric Graves' disease are usually mild and typically respond to local measures and control of disturbed thyroid function. Surgery is indicated in a small number of patients for cornea exposure or appearance issues. Graves' disease-associated optic neuropathy has never been reported in the pediatric population.

Increased prevalence of ADHD in Turner syndrome with no evidence of imprinting effects.

BACKGROUND: Turner syndrome (TS) results from the loss of part or all of one X chromosome in females. It can result in short stature, various dysmorphic findings, and difficulties with psychosocial adjustment. Girls with TS have previously been found to exhibit increased levels of hyperactivity and inattention. However, no studies have assessed whether individuals with TS meet strict (DSM-IV) criteria for attention-deficit/hyperactivity disorder (ADHD). OBJECTIVE: We looked at the prevalence of ADHD in girls with TS and evaluated the contribution of imprinting on cognitive performance (IQ) and ADHD. METHODS: We tested 50 girls with TS for ADHD, IQ, academic performance, and parental origin of the X chromosome. RESULTS: We report an 18-fold increase in the prevalence of ADHD in girls with TS (24%) compared with girls in the general population (1.3%) (p < .01) and a 4.8 fold increase when compared with boys and girls in the general population (5%) (p < .05). In contrast to previous reports, our molecular studies in females with 45,X also showed no association between IQ scores and the parental origin of the intact X chromosome. CONCLUSIONS: We find an increased prevalence of ADHD in girls with TS but no evidence for imprinting effects for cognitive performance.

Multiple endocrine neoplasia type 2A in a kindred with C634Y mutation.

Multiple endocrine neoplasia type 2A (MEN 2A) is most frequently caused by codon 634 activating mutations. Medullary thyroid carcinoma has occurred before the age of 2, with pheochromocytomas and primary hyperparathyroidism occurring later in childhood. We report cases of 4 siblings with C634Y-positive MEN 2A (all <11 years old): 3 with medullary thyroid carcinoma (1 had nodal metastasis, and another had a parathyroid adenoma) and 1 with C-cell hyperplasia.

Growth hormone releasing hormone plus arginine stimulation testing in young adults treated in childhood with cranio-spinal radiation therapy.

OBJECTIVE: Growth hormone deficiency (GHD) secondary to cranio-spinal radiation therapy (CSRT) is a complication seen in medulloblastoma survivors. The standard for diagnosis of adult GHD is a peak GH < 3 microg/l by the insulin tolerance test (ITT). However, insulin tolerance testing exposes patients to the risks of hypoglycaemia. Recent studies suggest that the GH releasing hormone + arginine (GHRH + ARG) test can identify GHD in cranially irradiated patients at longer time intervals after radiation. We evaluated the GHRH + ARG stimulation test compared to the ITT in young adults diagnosed with medulloblastoma during childhood. PATIENTS: We evaluated 10 young adult patients (age range 17-26 years) who were treated with CSRT during childhood for medulloblastoma, and who had resultant childhood-onset GHD. MEASUREMENTS: Subjects underwent GH provocative testing with the ITT and the GHRH + ARG test. IGF-I and IGFBP3 levels were also measured at baseline. RESULTS: Insulin tolerance testing and GHRH + arginine stimulation were performed at a mean +/- SD 14 +/- 4.4 years after cranial radiation. All patients failed the ITT with median peak GH 0.40 microg/l (range < 0.05-2.2). GHRH + arginine gave higher peak GH levels with a mean of 7.9 +/- 5.7 microg/l (P = 0.003). Four patients had peak GH > 9 microg/l and were between 7.8 and 19.6 years from cranial radiation. There was no correlation of peak GH levels with time interval since CSRT. Thirty-three per cent of subjects had normal IGF-I; neither IGF-I nor IGFBP3 standard deviation scores (SDS) correlated with ITT results. CONCLUSIONS: Using a GHRH + arginine cut-off for GHD of 9 microg/l, four patients would have been misclassified as GH sufficient, despite being > 7 years (with two patients being nearly 20 years) out from CSRT. These findings suggest that the pituitary GH-producing cells of young adults continue to maintain responsiveness to GHRH + arginine more than 5-10 years after cranial irradiation.

Expanded spectrum of recombinant human growth hormone therapy.

The efficacy of recombinant human growth hormone in the treatment of growth hormone deficiency is well established. In recent years, the use of recombinant human growth hormone as a therapeutic modality has greatly increased and has expanded beyond the realm of replacement for growth hormone deficiency. Recombinant human growth hormone has been employed to ameliorate growth failure in multiple other disorders. For some, like Turner syndrome, recombinant human growth hormone has become the standard of care. For others, the ultimate benefit of recombinant human growth hormone remains to be determined. Although recent investigations provide encouraging short-term data, it is important to recognize that the impact of recombinant human growth hormone therapy on adult height has not been established in a number of conditions.

Is treatment with growth hormone effective in children with cerebral palsy?

Children with cerebral palsy (CP) often have poor linear growth during childhood, resulting in a diminished final adult height. Here we report a female with CP and short stature but without growth hormone (GH) deficiency who exhibited increased growth during treatment with GH. We also report two other children with CP who were treated with GH: one female with a history of leukemia, and a male with Klinefelter syndrome. These two children were both found to be GH-deficient by insulin provocative GH testing and responded to treatment with increased growth rate. Growth improved to a greater extent in the two children with apparent GH deficiency. In summary, it is felt that GH therapy might be beneficial for children with CP and warrants further investigation.