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To identify the 3-year follow-up management and education patterns of primary care clinicians and pediatric endocrinologists for children diagnosed with congenital hypothyroidism (CH) through newborn screening programs, the Region 4 Midwest Genetics Collaborative, made up of seven regional states (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, Wisconsin), performed a survey study of parents and physicians caring for children identified with CH. The clinicians and parents of 409 children with CH regionally identified in 2007 were invited to participate in a voluntary survey. Responses relating to treatment, monitoring practices, educational resources, genetic counseling, and services provided/received were collected from 214 clinicians and 77 parents. In total, 99% had undergone a confirmatory test following positive newborn screening and 55% had imaging at diagnosis, but only 50% were identified as having the etiology identified. Thyroid withdrawal challenge testing was the choice method for re-evaluating thyroid function, but the approach varied. Clinician and parent responses to education and genetic counseling also differed. Clinicians report face-to-face education as the most common method, with less than 50% providing handouts to patients. Only 14% of patients were referred to a genetics counselor. Of parents reporting on their educational experience, 86% received face-to-face education from a pediatric endocrinologist and 4% received education from a genetic counselor. Only 65%, however, were satisfied with their education. These survey data suggest a lack of a standardized approach to diagnosis, follow-up, education, and genetic counseling. This collaborative effort provides insight into developing three-year follow-up, education and genetic counseling guidelines for children diagnosed with CH., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest., (© 2018 by the authors.)

Newborn screening (NBS) identifies infants with rare conditions to prevent death or the onset of irreversible morbidities. Conditions on the Health and Human Services Secretary's Recommended Uniform Screening Panel have been adopted by most state NBS programs, providing a consistent approach for identification of affected newborns across the United States. Screen-positive newborns are identified and referred for confirmatory diagnosis and follow-up. The designation of a clinically significant phenotype precursor to a clinical diagnosis may vary between clinical specialists, resulting in diagnostic variation. Determination of disease burden and birth prevalence of the screened conditions by public health tracking is made challenging by these variations. This report describes the development of a core group of new case definitions, along with implications, plans for their use, and links to the definitions that were developed by panels of clinical experts. These definitions have been developed through an iterative process and are piloted in NBS programs. Consensus public health surveillance case definitions for newborn screened disorders will allow for consistent categorization and tracking of short- and long-term follow-up of identified newborns at the local, regional, and national levels., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

The cure rate for paediatric malignancies is increasing, and most patients who have cancer during childhood survive and enter adulthood. Surveillance for late endocrine effects after childhood cancer is required to ensure early diagnosis and treatment and to optimize physical, cognitive and psychosocial health. The degree of risk of endocrine deficiency is related to the child's sex and their age at the time the tumour is diagnosed, as well as to tumour location and characteristics and the therapies used (surgery, chemotherapy or radiation therapy). Potential endocrine problems can include growth hormone deficiency, hypothyroidism (primary or central), adrenocorticotropin deficiency, hyperprolactinaemia, precocious puberty, hypogonadism (primary or central), altered fertility and/or sexual function, low BMD, the metabolic syndrome and hypothalamic obesity. Optimal endocrine care for survivors of childhood cancer should be delivered in a multidisciplinary setting, providing continuity from acute cancer treatment to long-term follow-up of late endocrine effects throughout the lifespan. Endocrine therapies are important to improve long-term quality of life for survivors of childhood cancer.

Objective: To examine whether attention-deficit/hyperactivity disorder (ADHD) stimulant medication modified the linear growth response to growth hormone (GH) treatment in children enrolled in the American Norditropin Studies: Web-Enabled Research Program., Study Design: Short, GH treatment-naive children with or without GH deficiency (GHD) received GH therapy. A subset also received ADHD stimulant medication (n = 1190), and others did not (n = 7230). Linear mixed models (adjusted means) examined height SDS (HSDS) and body mass index (BMI) SDS from baseline through year 4. Analyses were repeated with ADHD groups matched for baseline age, height, weight, BMI, and sex. Groups with and without GHD were compared between ADHD groups., Results: Adjusted change in HSDS for the group receiving ADHD stimulant medication was slightly lower than that for patients not receiving stimulant medication at years 1 to 4 (P < .05). However, adjusted change in HSDS was similar between children receiving and not receiving ADHD stimulant medication when matched for baseline measurements. At year 4, 86.7% of patients receiving ADHD stimulant medication, 86.8% of total patients not receiving ADHD stimulant medication, and 84.6% of matched group patients not receiving ADHD stimulant medication achieved HSDS >-2. Year 4 adjusted change in BMI SDS was greater in the patients receiving ADHD stimulant medication compared with both groups not receiving ADHD stimulant medication (P < .05). Patients with GHD showed comparable differences in adjusted change in BMI SDS among the ADHD groups at year 4, whereas patients without GHD showed no significant differences., Conclusions: ADHD medication did not affect the linear growth response of children treated with GH when those receiving or not receiving ADHD stimulant medication were matched for baseline measurements. Underlying reasons for the observed greater increase in BMI in patients with GHD concomitantly treated with ADHD medication remain to be elucidated., Trial Registration: ClinicalTrials.gov: NCT01009905., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Traumatic brain injuries (TBI) are common occurrences in childhood, often resulting in long term, life altering consequences. Research into endocrine sequelae following injury has gained attention; however, there are few studies in children. This paper reviews the pathophysiology and current literature documenting risk for endocrine dysfunction in children suffering from TBI. Primary injury following TBI often results in disruption of the hypothalamic-pituitary-adrenal axis and antidiuretic hormone production and release, with implications for both acute management and survival. Secondary injuries, occurring hours to weeks after TBI, result in both temporary and permanent alterations in pituitary function. At five years after moderate to severe TBI, nearly 30% of children suffer from hypopituitarism. Growth hormone deficiency and disturbances in puberty are the most common; however, any part of the hypothalamic-pituitary axis can be affected. In addition, endocrine abnormalities can improve or worsen with time, having a significant impact on children's quality of life both acutely and chronically. Since primary and secondary injuries from TBI commonly result in transient or permanent hypopituitarism, we conclude that survivors should undergo serial screening for possible endocrine disturbances. High indices of suspicion for life threatening endocrine deficiencies should be maintained during acute care. Additionally, survivors of TBI should undergo endocrine surveillance by 6-12 months after injury, and then yearly, to ensure early detection of deficiencies in hormonal production that can substantially influence growth, puberty and quality of life.

Pediatric tectal plate gliomas are indolent slow-growing gliomas that often present with increased intracranial pressure or incidentally on routine brain imaging. We investigated clinical outcomes, endocrinopathies, and neuropsychological sequelae associated with tectal plate gliomas. Twenty-six patients with tectal plate glioma were identified in a 20-year retrospective review. Clinical outcomes, treatments, endocrine function, neuropsychological testing outcomes and radiographic imaging were reviewed for possible signs correlating with tumor progression. Among 26 patients, 19 presented with signs or symptoms of increased intracranial pressure (73 %) versus an incidental finding in 7 (27 %). Median follow-up was 46 months (range 8-143 months). Six of 26 (23 %) experienced progressive disease after diagnosis. Five of 26 (19 %) required more than one surgical procedure due to failure of initial endoscopic third ventriculostomy. Seven of 26 had history of endocrine dysfunction, of which, five presented with endocrine dysfunction (precocious puberty or short stature), 1 developed menstrual irregularities after surgical intervention and 1 had preexisting pan hypopituitarism. Of 12 patients with available neuropsychological testing, eleven had at least one indicator of executive functioning in the low-average to impaired range. While tectal plate gliomas have been considered indolent tumors that are rarely progressive, 23 % of patients in our cohort experienced disease progression and required further therapy. Neurocognitive deficits may occur, while endocrine deficiency is uncommon. Regular multidisciplinary oncology follow-up, routine monitoring with MRI and formal neurocognitive evaluation are imperative to provide early recognition of disease progression or recurrent hydrocephalus and to improve school functioning in this population.

Background: Diamond-Blackfan anemia (DBA), an inherited marrow failure syndrome, has severe hypoplastic anemia in infancy and association with aplastic anemia, MDS/leukemia, and other malignancies. Short stature is present in most patients. Isolated cases have demonstrated improved growth on growth hormone (GH) therapy., Procedures: GH treatment data were obtained from 19 children with DBA (6 at our site and 13 from Genentech). Control data from 44 non-GH treated children were provided by Diamond Blackfan Anemia Registry. Annual growth velocity (GV) and height-for-age Z-scores (HAZ) were compared between groups and for up to 4y of GH treatment., Results: Constructed DBA-specific male and female height-for-age charts for non-GH treated patients revealed short stature compared to CDC norms. GH-treated patients had significantly lower HAZ prior to treatment initiation compared to non-GH-treated controls. Among GH-treated patients, GV significantly improved in the first two years relative to pre-treatment. HAZ significantly improved in each of 4y of GH therapy compared to baseline. After 2y of therapy, HAZ for GH-treated patients were not significantly different from controls, demonstrating successful catch-up growth., Conclusions: GH treatment in children with DBA improves both GV and HAZ during treatment sustained for up to 4y. Very short children with DBA can be treated successfully with GH to restore stature to levels comparable to less affected patients. DBA height charts are useful tools for assessing age-specific growth in this typically short population. Careful consideration of individualized benefit of GH therapy versus risk is important in view of long-term underlying ∼5% malignancy risk in DBA., (© 2014 Wiley Periodicals, Inc.)

Context: Endocrine problems are common in patients with Fanconi anemia (FA). About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. The goal of this report is to provide an overview of endocrine abnormalities and guidelines for routine screening and treatment to allow early diagnosis and timely intervention., Evidence Acquisition: This work is based on a comprehensive literature review, including relevant articles published between 1971 and 2014, and proceedings of a Consensus Conference held by the Fanconi Anemia Research Fund in 2013., Evidence Synthesis: The panel of experts collected published evidence and discussed its relevance to reflect current information about the endocrine care of children and adults with FA before the Consensus Conference and through subsequent deliberations that led to the consensus., Conclusions: Individuals with FA should be routinely screened for endocrine abnormalities, including evaluation of growth; glucose, insulin, and lipid metabolism; thyroid function; puberty; gonadal function; and bone mineral metabolism. Inclusion of an endocrinologist as part of the multidisciplinary patient care team is key to providing comprehensive care for patients with FA.

Background: A majority of Fanconi anemia (FA) patients will experience bone marrow failure (BMF) and androgen therapy (most often oxymetholone) may be utilized as a treatment to improve BMF-related cytopenias. However, oxymetholone is associated with toxicities making identification of other agents of interest. In this study we aimed to evaluate the toxicity profile and hematologic response in patients with FA who are treated with low-dose oxandrolone, a synthetic non-fluorinated anabolic steroid, similar to oxymetholone, with known dosing thresholds for virilization., Procedure: A single arm, Phase I/II study was designed to treat patients on low-dose oxandrolone. If no toxicity or hematologic response was noted at 16 weeks, a single dose escalation was offered. Subjects were regularly assessed for toxicity, including determinations of virilization, behavioral changes, and liver and kidney function. At 32 weeks, those who demonstrated hematologic response were allowed to continue study treatment, and those without improvement were deemed non-responsive., Results: Nine subjects completed the study and were followed for a median of 99 weeks (46-136 weeks). Three (33.3%) subjects developed mild sub-clinical virilization and continued treatment with a dose reduction. None (0%) had adverse behavioral changes. Two (22.2%) developed elevated liver function tests at 42 and 105 weeks. Seven (77.8%) subjects had a hematologic response., Conclusion: Oxandrolone appears to be well-tolerated, has limited toxicities at the administered doses in FA with patients, and may be an alternative androgen for the treatment of BMF in FA., (© 2013 Wiley Periodicals, Inc.)

Objective: To characterize the endocrine phenotype of patients with Shwachman-Diamond syndrome (SDS)., Study Design: Clinically indicated endocrine screening data from 43 patients with SDS or SDS-like presentation were analyzed according to sex, age, and genetic testing. In addition to 25 patients with biallelic Shwachman-Bodian-Diamond syndrome (SBDS) gene mutations, we evaluated 18 patients with cytopenias who were receiving pancreatic enzyme replacement but were without SBDS mutation. We performed a retrospective review of growth records and clinically indicated endocrine evaluations., Results: Of patients with SBDS mutations, 2 had low stimulated growth hormone levels, 2 had mildly elevated thyrotropin levels, 5 had abnormal glucose levels, and 1 had an elevated follicle-stimulating hormone level (post transplantation). In contrast, 1 patient without SBDS mutations had postprandial hyperglycemia and 3 had mildly low free thyroxine levels without short stature. Endocrine abnormalities were identified in 19% of short patients and 26% of the whole group. Of patients with SBDS mutations, 56% had a height expressed in SD units from the mean for age and sex of <-1.8, in contrast to only 12% of patients without SBDS mutations (38% of the whole group). Body mass index z score was significantly greater in the group with SBDS mutations (P<.001)., Conclusion: Although short stature was more common in patients with SBDS mutations, no consistent endocrine phenotype was observed in patients with SDS regardless of genetic testing., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Features of Fanconi anemia (FA) are well known, including bone marrow failure, congenital anomalies such as radial anomalies, renal and ear anomalies, tracheo-esophageal fistula, imperforate anus, and elevated risk for cancer. We sought to further characterize the endocrine phenotype in children and adults with FA., Procedure: Clinically indicated endocrine evaluation data from 120 persons with FA, including 78 children (43 female) and 42 young adults (who had achieved adult height, 19 female), were entered in an institutional review board-approved database. Data were analyzed according to gender, birth weight, FA complementation group, and whether or not the patient had completed linear growth or had undergone hematopoietic cell transplant, using Wilcoxon Rank Sum or Chi-square, as appropriate., Results: Overall, 60% of children and 58% of adults with FA had short stature, 68% of children and 30% of adults had glucose intolerance, 61% of children and 37% of adults had mild hypothyroidism, and 40% of adults had evidence of hypogonadism (not possible to fully assess in children). In general, bone mineral density (BMD) was normal in adults, while BMD in children was normal when results were adjusted for bone size/thickness using height age., Conclusions: We have evaluated in detail children and adults with FA for their growth and endocrine function. Overall, 79% of children and adults with FA had one or more endocrine abnormality., (Copyright © 2012 Wiley Periodicals, Inc.)

Growth hormone (GH) is approved by the US Food and Drug Administration (FDA) for use in pediatric patients with disorders of growth failure or short stature and in adults with growth hormone deficiency (GHD) and HIV/AIDS wasting and cachexia. For pediatric patients, guidelines for the use of GH have been developed by several organizations that have identified specific criteria for initiating GH therapy for each FDA-approved indication. Guidelines for adults have also been developed and include recommendations for transition (adolescent) patients with GHD. These patients are often treated with GH as children but may require continued treatment as young adults to attain full skeletal mineralization and improve cardiovascular risk factors. Adult and pediatric guidelines are supported by efficacy and safety studies, which show that, when started at an early age, GH treatment can increase growth velocity and that GH is safe and well-tolerated. We summarize the guidelines that are available for all FDA-approved indications among pediatric and transition patients. Adherence to these guidelines will help to ensure that patients with disorders of growth failure or short stature receive the necessary therapy to increase linear growth and transition smoothly to healthy adulthood.

Traumatic brain injury (TBI) is a very common occurrence in childhood, and can lead to devastating long term consequences. Recent research has focused on the potential endocrine consequences of TBI in adults. The research in children is less robust. This paper reviews current literature regarding TBI and possible hypothalamic and pituitary deficiencies in childhood. Acute endocrine changes are commonly found after TBI in pediatric patients, which can include changes in hypothalamic-pituitary-adrenal axis and antidiuretic hormone production and release. In the long term, both temporary and permanent alterations in pituitary function have been found. About 30% of children have hypopituitarism up to 5 years after injury. Growth hormone deficiency and disturbances in puberty are the most common, but children can also experience ACTH deficiency, diabetes insipidus, central hypothyroidism, and elevated prolactin. Every hormonal axis can be affected after TBI in children, although growth hormone deficiency and alterations in puberty are the most common. Because transient and permanent hypopituitarism is common after TBI, survivors should be screened serially for possible endocrine disturbances. These children should undergo routine surveillance at least 1 year after injury to ensure early detection of deficiencies in hormonal production in order to permit normal growth and development.

Context: This is a case report of a proband and his family presenting with apparent autosomal dominant 25-hydroxylase enzyme deficiency and bone disease., Objective: The aim of the study was to present an alternative pattern of transmission of 25-hydroxylase enzyme deficiency other than autosomal recessive., Design: We diagnosed our patient with 25-hydroxylase enzyme deficiency, treated him, and examined his DNA for mutations. Evaluations at other institutions, clinical history of all family members, and laboratory testing for the mother, aunt, and maternal grandmother were reviewed. Family consent was obtained for all testing and record review., Setting: The patient was evaluated serially in an outpatient clinic. Routine laboratory studies for proband, mother, and maternal grandmother were obtained. Genetic testing was performed in another institution after obtaining family consent., Interventions: No research intervention was performed., Main Outcome Measures: Routine clinical care included an evaluation of growth pattern. Laboratory evaluation included 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], alkaline phosphatase, intact PTH, phosphate, calcium, ionized calcium, and magnesium levels., Results: Results showed consistently low 25-hydroxylase enzyme function. They also showed elevated alkaline phosphatase and PTH, as well as decreased phosphate and calcium. These abnormalities were corrected with 1,25(OH)(2)D therapy., Conclusion: We conclude that 25-hydroxylase enzyme deficiency can be inherited in an autosomal dominant pattern. This case raises a question about different tributary pathways affecting the function of the 25-hydroxylase enzyme. Physiological dosing of 1,25(OH)(2)D was sufficient for treatment. There were no detectable mutations in any of the coding regions of the gene or its intronic junctions.

We hypothesized that because 45,X/46,XY (X/XY) children share a cell line with Turner syndrome (TS), they also share co-morbidities described in TS. In addition, the presence of the Y chromosome in brain and in other body tissues would influence their function. On the basis of our findings, we aimed to establish optimal procedures for clinical evaluation, management, and follow-up of these children. Sixteen X/XY children were evaluated and managed at a single institution as part of standard clinical care as established at the time between 1969 and 2009. In January of 2005, we started retrospective record review of all X/XY children in combination with cohort follow-up (of those who had not reached adult height) until August of 2009. The study included review of clinical presentation, clinical characteristics, diagnostic measures, radiologic studies, karyotype studies, psycho-endocrinology evaluation, and growth-promoting treatments. There was no specific intervention. Phenotype reflected cell line distribution. The presence of 45,X cell line explains how X/XY children have abnormalities similar to girls with TS, while presence of Y chromosome explains why they have tomboyish behavior. In conclusion, these children require clinical evaluation similar to that performed in female children with TS, including cardiovascular, renal, endocrine, growth and development, autoimmune, psychological, and educational evaluation. Specific management needs to be tailored to the presence of Y chromosomal material.

Background: Conflicting data exist regarding whether low bone mineral density (BMD) is associated with Fanconi anemia (FA). The current study identified the frequency of low BMD in FA, expecting low BMD even in childhood and before HCT., Procedure: Thirty-seven FA patients (18 prior HCT, 19 no prior HCT), participating in an IRB-approved database, had clinical assessment of DXA of lumbar spine BMD. Four had used androgens, one later underwent HCT. Most had used glucocorticoids after HCT (prolonged in five), and one more with no HCT. BMD [in standard deviation units from mean for age (SD), gender, and ethnicity (BMD Z-score)] was then adjusted for height age, and separately for bone maturation (BA). Data were collected for height SD, pubertal stage, and duration since HCT., Results: BMD Z-score (without adjustment) was <-1 SD in half of FA children. BA-adjusted BMD Z-score was similar. (BA was not usually delayed, although most patients were short.) In contrast, height age-adjusted BMD Z-score was normal in most with FA (only below -2.0 in one child after prolonged glucocorticoids). Mean duration after HCT until DXA test was 6.2 years (median 4.2 years, range 1-18 years)., Conclusions: Children and adolescents with FA have normal BMD prior to and after HCT, when DXA results are adjusted for bone size/height age. In contrast, BA-adjustment of BMD was not useful in this population. Individual BMD results may be influenced by gonadal function, transplantation status, and prolonged glucocorticoid therapy., (Copyright © 2011 Wiley-Liss, Inc.)

Objective: To identify the incidence of endocrine dysfunction in children following traumatic brain injury (TBI)., Study Design: This was a prospective evaluation of 31 children after TBI. Inclusion criteria included Glasgow Coma Scale score ≤ 12 and age 1.5-18 years. We evaluated thyroid function, insulin-like growth factor I, insulin-like growth factor-binding protein 3, and cortisol at 1, 3, 6, and 12 months after injury, and assessed prolactin at 3 and 6 months. At 6 months, we also assessed overnight spontaneous growth hormone secretion, nocturnal thyrotropin surge, adrenal reserve, and serum and urine osmolarity., Results: The average patient age was 11.6 years, and mean Glascow Coma Scale score was 6. The incidence of endocrine dysfunction was 15% at 1 month, 75% at 6 months, and 29% at 12 months. At 12 months after injury, 14% had precocious puberty, 9% had hypothyroidism, and 5% had growth hormone deficiency. Endocrine dysfunction at 1 year did not correlate with the severity of injury., Conclusions: Endocrine dysfunction after TBI is common in children, but most cases resolve by 1 year. We recommend endocrine surveillance at both 6 and 12 months following moderate or severe TBI to ensure early intervention for persistent or late-occurring endocrine sequelae., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Objective: Newborn-screening false-positive rates (FPRs) are disproportionately increased in preterm infants. The objective of this study was to determine variation in newborn screening FPRs according to birth weight and gestational age. Our secondary objective was to examine the effect of postnatal age on FPRs in preterm infants., Methods: The Ohio State Newborn Screening Program Database was analyzed to determine the overall and birth weight-specific FPRs for 18 analytes. Data were stratified into birth weight categories (<1000 g, 1000-1499 g, 1500-2499 g, 2500-3999 g, and >4000 g). In addition, to examine the effect of postnatal age on FPRs, we examined the 2 analytes with the highest FPRs, thyrotropin with back-up thyroxine and 17-hydroxyprogesterone, in infants whose gestational age was <32 weeks, determined on the basis of postnatal age at screening., Results: Data from 448 766 neonates were reviewed. Infants with very low birth weight (VLBW) comprised 1.9% of the study cohort, but accounted for 18% of false-positive results. For 14 of 18 analytes studied, FPRs increased with decreasing birth weight/gestational age and were significantly increased in infants with VLBW compared with infants who weighed 2500 to 3999 g (P < .001). Thyrotropin/back-up thyroxine and 17-hydroxyprogesterone accounted for 62% of total false-positive results in VLBW infants. When blood specimens were collected at a postnatal age of ≥ 48 hours in infants born at <32 weeks, a 44% relative reduction in 17-hydroxyprogesterone false-positive results was detected., Conclusions: False-positive newborn-screening rates are disproportionately increased in VLBW infants. FPRs may be reduced by delaying screening of <32 weeks' gestation, preterm infants until 24 to 48 hours' postnatal age.

Context: Several studies showed a decrease in height velocity during GnRH analogue (GnRHa) treatment. No information is available on GH levels during GnRHa treatment in short SGA girls., Objective: To study overnight GH profiles and IGF-I and IGFBP-3 levels in girls with Tanner stage 2 and stage 3, before and after 3 months of GnRHa treatment, and to compare levels with those found in prepubertal short SGA girls., Patients: Twenty-four pubertal and 16 prepubertal short SGA girls., Intervention: After baseline overnight GH profiles, pubertal girls received leuprorelide acetate depots of 3.75 mg subcutaneously every 4 weeks., Outcome Measures: GH, IGF-I and IGFBP-3 levels., Results: At baseline, GH levels were comparable to levels found in prepubertal short SGA girls and IGF-I and IGFBP-3 SDS were significantly below the population mean. After 3 months of GnRHa treatment, AUC(0) (P = 0.02), mean (P = 0.02) and maximum GH levels (P = 0.008) had significantly decreased. Mean GH levels were significantly lower than in prepubertal short SGA girls (P = 0.03). Eight girls with more than 40% decrease in mean GH levels also had a significantly greater decrease in IGF-I and IGFBP-3 levels. Mean and maximum GH levels at baseline correlated significantly with those after 3 months of GnRHa treatment., Conclusion: Short SGA girls lack the normal increase in GH levels seen in puberty and have reduced IGF-I and IGFBP-3 levels, which might explain their reduced pubertal growth spurt. GnRHa treatment led to a significant reduction in GH levels. Therefore, combining GnRHa treatment with GH treatment might improve adult height of short SGA girls.

Background: Delivery of GH via inhalation is a potential alternative to injection. Previous studies of inhaled GH in adults have demonstrated safety and tolerability., Objective: We sought to assess safety and tolerability of inhaled GH in children and to estimate relative bioavailability and biopotency between inhaled GH and sc GH., Design/methods: This pediatric multicenter, randomized, double-blind, placebo-controlled, crossover trial had two 7-d treatment phases. Patients received inhaled GH and sc GH in the alternate phase. Placebo was administered by the route opposite from active drug. GH and IGF-I levels were measured at multiple time points. Pharmacokinetics were assessed using noncompartmental methods., Results: Twenty-two GH-deficient children aged 6-16 yr were treated. Absorption of GH appeared to be faster after inhalation with maximum serum concentrations measured at 1-4 h compared with 2-8 h for sc GH. Mean relative bioavailability for inhaled GH was 3.5% (90% confidence interval 2.7-4.4%). Mean relative biopotency, based on IGF-I response, was 5.5% (confidence interval 5.2-5.8%). Similar dose-dependent increases in mean serum GH area under the curve and IGF-I changes from baseline were seen after inhaled and sc GH doses. Inhaled GH was well tolerated and preferred to injection. No significant changes in pulmonary function tests were seen., Conclusions: In this first pediatric trial of GH delivered by inhalation, it was well tolerated and resulted in dose-dependent increases in serum GH and IGF-I levels. This study establishes that delivery of GH via the deep lung is feasible in children.

Context: The diagnostic value of tests for detecting hypothalamic-pituitary adrenal insufficiency (HPAI) is controversial., Objective: Our objective was to compare standard-dose and low-dose corticotropin tests for diagnosing HPAI., Data Sources: We searched the PubMed database from 1966-2006 for studies reporting diagnostic value of standard-dose or low-dose corticotropin tests, with patient-level data obtained from original investigators., Study Selection: Eligible studies had more than 10 patients. All subjects were evaluated because of suspicion for chronic HPAI, and patient-level data were available. We excluded studies with no accepted reference standard for HPAI (insulin hypoglycemia or metyrapone test) if test subjects were in the intensive care unit or if only normal healthy subjects were used as controls., Data Extraction: We constructed receiver operator characteristic (ROC) curves using patient-level data from each study and then merged results to create summary ROC curves, adjusting for study size and cortisol assay method. Diagnostic value of tests was measured by calculating area under the ROC curve (AUC) and likelihood ratios., Data Synthesis: Patient-level data from 13 of 23 studies (57%; 679 subjects) were included in the metaanalysis. The AUC were as follows: low-dose corticotropin test, 0.92 (95% confidence interval 0.89-0.94), and standard-dose corticotropin test, 0.79 (95% confidence interval 0.74-0.84). Among patients with paired data (seven studies, 254 subjects), diagnostic value of low-dose corticotropin test was superior to standard-dose test (AUC 0.94 and 0.85, respectively; P<0.001)., Conclusions: Low-dose corticotropin test was superior to standard-dose test for diagnosing chronic HPAI, although it has technical limitations.

Background: Children with Fanconi anemia (FA) tend to have short stature, mild thyrotropin (TSH) elevation, and borderline low free thyroxine (FT4). Objective was to examine whether thyroid hormone therapy improves linear growth in children with FA and borderline thyroid function tests, Procedure: Thyroid function tests were performed in 63 children with FA. Eight subjects participated in a random order, double-blind, cross-over treatment for 7 months with levothyroxine and for 7 months with placebo. Monitoring included growth measurements and laboratory assays at 1, 4 and 7 months of each phase. A 1 month lead in/wash out period was excluded from analysis of each treatment phase., Results: The majority (63%) of FA children had borderline thyroid function tests. All eight FA subjects enrolled in the treatment study had FT4 in the lowest third of the normal range of 0.8-1.8 ng/dL (10.3-23.2 pmol/L) [FT4 0.9 +/- 0.1 ng/dL (mean +/- SD), range 0.8-1.2 ng/dL (10.3-15.4 pmol/L)]. TSH (optimal range 0.5-3 mU/L) was borderline elevated in six of eight subjects (4.0 +/- 1.5 mU/L, 1.9-7.3 mU/L). Growth velocity was slow at baseline and improved significantly during the thyroid phase compared to the placebo phase (2.1 +/- 1.2 cm/year vs. 5.4 +/- 1.7 cm/year, P < 0.05)., Conclusions: Thyroid hormone therapy is safe and may improve linear growth velocity in children with FA who have borderline thyroid function. Subtle hypothyroidism has importance for growth in children. Whether thyroid hormone treatment improves adult height in these children remains to be elucidated., ((c) 2008 Wiley-Liss, Inc.)

Background: To determine prevalence of abnormal glucose metabolism in Fanconi Anemia (FA)., Procedure: Thirty-nine children with FA underwent 2-hr oral glucose tolerance test (OGTT). Reference lean adolescents (REF) were older than FA patients (mean +/- SD: FA 8.6 +/- 3.9 years, REF 19.8 +/- 0.3 years, P < 0.001), but comparable in BMI Z-scores (FA 1.25 +/- 0.58, REF -0.02 +/- 0.24; P = 0.24). Patients had normal glucose tolerance (NGT) or abnormal glucose metabolism (AGM) by American Diabetes Association Criteria. Insulinogenic index estimated beta-cell function. Insulin resistance estimation used homeostatic model assessment (HOMA-IR). Insulin secretion estimation relative to insulin sensitivity used disposition index (DI)., Results: Among FA patients, 46% had AGM. Compared to REF, there were significant differences in glycemic responses (area under curve: FA-NGT 344 +/- 42, FA-AGM 596 +/- 35, REF 208 +/- 25 mM, P < 0.0001) and insulinogenic index (FA-NGT 105 +/- 29, FA-AGM 44 +/- 8, and REF 173 +/- 41 pM/mM, P < 0.05). Insulin sensitivity did not differ among NGT, AGM, and REF (HOMA-IR: FA-NGT 1.9 +/- 0.4, FA-AGM 2.2 +/- 0.5, REF 1.3 +/- 0.2, P = NS). However, DI was significantly lower in both FA groups than REF [NGT 63.6 +/- 16.5 vs. AGM 26.4 +/- 3.5 (P < 0.048); REF 132.6 +/- 24.5 (NGT and AGM vs. REF, both P < 0.0002)]., Conclusion: Abnormalities in glucose metabolism are frequent in young FA patients without prior diagnosis of diabetes, and are associated with marked defects in insulin secretion.

The arginine-clonidine growth hormone (GH) stimulation test causes hypotension, requiring intravenous fluids to stabilize blood pressure (BP) and delaying departure from clinic. We hypothesized that oral hydration during the stimulation test would decrease need for intravenous fluids and shorten clinic stay. Children drank a diet electrolyte drink (10 ml/kg) on arrival to the test, which was repeated after clonidine. Fifteen children (7 girls) were tested without oral hydration, and 23 (6 girls) were tested with oral hydration (age range, 2-15 years). Compared with no oral hydration, intake of >13 ml/kg rarely required intravenous fluids, improved diastolic BP, and permitted discharge at the end of the GH test, with a higher BP.

Background: Fanconi anemia (FA) is a genetic disorder associated with multiple congenital anomalies, bone marrow failure, and pituitary hypofunction including hypogonadism, thyroid dysfunction, and growth hormone (GH) deficiency., Procedure: Among 44 patients with FA referred to Cincinnati Children's Hospital Medical Center (CCHMC) between 1975 and 2005, 33 had neuroimaging studies, including 11 cranial magnetic resonance imaging (MRIs). Two separate measurements per patient from these MRIs were used to evaluate pituitary height compared to on-site control data of similar measurements of cranial MRIs on 22 age and gender-matched children without any pathology involving the hypothalamic-pituitary system. Growth pattern and endocrine studies were reviewed to assess potential correlation with pituitary size., Results: When compared to the age-gender matched on-site control sample, the mean pituitary height of FA patients was significantly smaller (P < 0.0001; mean +/- SE from mixed effects model with age and gender as covariates: 3.96 +/- 0.32 vs. 5.76 +/- 0.24). Upon further adjusting for the effect of the small head size by including bi-parietal diameter (BPD) as a covariate, the difference remained statistically significant (P = 0.0013). Findings on the growth pattern and endocrinological measurements are as follows: 50% of patients with small pituitary gland were short. GH and adrenal function tests were normal in all tested patients. Thyroid, pubertal status, and glucose regulation were abnormal in 30, 50, and 75% of patients tested., Conclusions: Children with FA tend to have unsuspected small pituitary glands beyond what is expected from the effects of their stunted growth. Further studies are required to reveal the clinical implications of this finding.

Background: A 14-year-old boy presented with daytime somnolence, intermittent emesis and hypothyroidism. Neuroimaging revealed a calcified suprasellar intracranial mass, suspected to be a craniopharyngioma. Subtotal resection of the tumor confirmed the diagnosis. Extreme obesity (BMI >60 kg/m(2)) and hyperinsulinemia followed tumor resection and cranial irradiation. Dietary interventions were unsuccessful, and pharmacologic intervention (i.e. octreotide) only slowed the rate of weight gain., Investigations: Radiography documented the suprasellar mass. Following surgical resection and radiotherapy, hypothalamic-pituitary deficiencies were found. Preprandial and postprandial excursions of insulin, active ghrelin and leptin were measured before and after gastric bypass surgery., Diagnosis: Panhypopituitarism, hypothalamic obesity and hyperinsulinemia following craniopharyngioma therapy., Management: Severe caloric restriction, octreotide, and pituitary hormone replacement did not produce weight loss. Gastric bypass surgery led to reduced food cravings, significant weight loss, and amelioration of obesity-related comorbidities. Correction of fasting hyperinsulinemia, normalization of postprandial insulin responses, and reductions in active ghrelin and leptin concentrations were also observed.

As survivors of pediatric allogeneic hematopoietic stem cell transplantations (HSCTs) increase in number, it is increasingly important to evaluate their well-being. We conducted this prospective cohort study to evaluate the cumulative incidence and risk factors for late sequelae of HSCT. Comprehensive surveillance tests were performed annually on every participant, regardless of signs and symptoms, to obtain accurate information on the time-of-onset of each late event to allow hazard function analyses. All participants included in this report had been followed for at least 3 years after HSCT. With a median follow-up of 9 years and a current age of 18.5 years, only 20 of the 155 participants (13%) had no late sequelae; 18 survivors (12%) had 1 chronic health condition, 71 (46%) had 2-4 conditions, and 46 (30%) had 5-9 conditions. Risk factors for increasing number of chronic conditions included young age at the time of HSCT, female sex, high radiation dose, and history of chronic graft-versus-host disease. The cumulative incidence at 10 years for common late events was as follows (ordered by the median time-of-onset): osteonecrosis 13.8%, chronic renal insufficiency 26.8%, hypothyroidism 45.1%, growth hormone deficiency 31.2%, female hypogonadism 57.4%, osteopenia 47.7%, cataracts 43.4%, pulmonary dysfunction 63.2%, and male hypogonadism 20.3%. Coexistence of multiple late sequelae was common in HSCT survivors. Our findings provide a basis for more effective patient counseling, optimal surveillance, and early intervention.

Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis. Efforts are ongoing to establish the optimal therapy that leads to maximum potential for normal development for infants with congenital hypothyroidism. Remaining controversy centers on infants whose abnormality in neonatal thyroid function is transient or mild and on optimal care of very low birth weight or preterm infants. Of note, thyroid-stimulating hormone is not elevated in central hypothyroidism. An algorithm is proposed for diagnosis and management. Physicians must not relinquish their clinical judgment and experience in the face of normal newborn thyroid test results. Hypothyroidism can be acquired after the newborn screening. When clinical symptoms and signs suggest hypothyroidism, regardless of newborn screening results, serum free thyroxine and thyroid-stimulating hormone determinations should be performed.

Background: There is little information about factors modulating bone mineral density (BMD) in survivors of childhood acute lymphoblastic leukemia (ALL)., Procedure: We analyzed data from 57 survivors (26 male, 52 Caucasian) who underwent two serial quantitative computed tomography (QCT) studies of BMD. Using multiple linear regression, we evaluated the association of BMD change with demographic variables, treatment history, hormone therapy, exercise, and tobacco and alcohol use., Results: The median age was 3.4 years (range, 0.9-17.4 years) at diagnosis of ALL; the median age at the first QCT (Study I) was 15.0 years (range, 10.6-31.0 years) and at the second QCT (Study II) was 18.2 years (range, 14.2-35.3 years). Mean height increased 4.7 cm and mean weight increased 8.8 kg between Studies I and II. While the mean BMD increased 9.33 mg/cc (P = 0.003), the BMD Z-score increased only slightly (0.21 SD, P = 0.035). Cortical bone density increased significantly (approximately 25.3 mg/cc; P = 0.001), but the ratio of trabecular to cortical BMD decreased significantly (P = 0.045). Factors independently associated with unfavorable BMD changes included older age at diagnosis (P = 0.001), female sex (P = 0.018), and nutritional supplementation (0.032). Alcohol (P = 0.009) was an unfavorable factor in a univariable analysis., Conclusions: Bone mineral accretion during adolescence is attenuated in childhood ALL survivors by a comparative deficit in trabecular versus cortical bone deposition. BMD is influenced favorably by exercise in early adolescence and unfavorably by the use of nutritional supplements and alcohol. These results provide new information about behavioral factors that affect bone accrual in survivors of childhood ALL and warrant definitive evaluation in a larger cohort.

Background: Adrenocorticotropin deficiency (ACTHD) can be clinically subtle, but life-threatening if not recognized. We assessed the prevalence of ACTHD in survivors of childhood cancer according to tumor diagnosis/therapy., Procedure: Chart review of endocrine/oncology history was performed in 310 childhood cancer survivors. Patients were referred to endocrine clinic because of slow growth, fatigue, or abnormal pubertal timing. Evaluation of growth hormone (GH), thyrotropin (TSH), ACTH, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) was performed. Low response to metyrapone and/or low dose ACTH test defined ACTHD., Results: ACTHD was identified in 56 (18%), [44 of 182 (24%) central nervous system (CNS) tumors, 3 of 18 (17%) non-CNS cranial tumors, 9 of 97 (9%) hematologic malignancies]. Of the 56 with ACTHD, 53 (95%) had received cranial irradiation (mean 45.5 Gy, range 14-70 Gy); three had not: one each with craniopharyngioma, hypothalamic astrocytoma, and brain stem glioma. All but one also had GH deficiency and/or central hypothyroidism., Conclusions: Childhood cancer survivors with greatest risk for ACTHD had craniopharyngioma, other suprasellar tumor, or medulloblastoma or > or =24 Gy cranial irradiation. We recommend annual testing for ACTHD for 10-15 years and continued lifelong surveillance after CNS tumor or cranial irradiation, in patients with other hypothalamic-pituitary deficiencies or symptoms of ACTHD., ((c) 2005 Wiley-Liss, Inc.)

Deletion of a segment of the long arm of chromosome 18 causes characteristic physical features and mental retardation. Autoimmune disorders have been described with this syndrome in a limited number of reports. We describe 2 cases of autoimmune hypothyroidism in children with 18q deletion syndrome.

Context: Recombinant human GH was approved by the United States Food and Drug Administration in 2003 for the treatment of idiopathic short stature (ISS). However, to date, the safety of GH in this patient population has not been rigorously studied., Objective: The objective of this study was to address the safety of GH treatment in children with ISS compared with GH safety in patient populations for which GH has been approved previously: Turner syndrome (TS) and GH deficiency (GHD)., Design/setting: The rates of serious adverse events (SAEs) and adverse events (AEs) of particular relevance to GH-treated populations were compared across the three patient populations among five multicenter GH registration studies., Patients: Children with ISS, TS, or GHD were studied., Intervention: Treatment consisted of GH doses ranging from 0.18-0.37 mg/kg.wk., Main Outcome Measures: The main outcome measures were rates of SAEs and AEs of special relevance to patients receiving GH. Laboratory measures of carbohydrate metabolism were used as outcome measures for the ISS studies., Results: Within the ISS studies, comprising one double-blind, placebo-controlled study and one open-label, dose-response study, SAEs (mainly hospitalizations for accidental injury or acute illness unrelated to GH exposure) were reported for 13-14% of GH-treated patients. Overall AE rates (serious and nonserious) as well as rates of potentially GH-related AEs were similar in the GHD, TS, and ISS studies (for ISS studies combined: otitis media, 8%; scoliosis, 3%; hypothyroidism, 0.7%; changes in carbohydrate metabolism, 0.7%; hypertension, 0.4%). Measures of carbohydrate metabolism were not affected by GH treatment in patients with ISS. There was no significant GH effect on fasting blood glucose in either study (GH dose range, 0.22-0.37 mg/kg.wk) or on insulin sensitivity (placebo-controlled study only)., Conclusion: GH appears safe in ISS; however, the studies were not powered to assess the frequency of rare GH-related events, and longer-term follow-up studies of GH-treated patients with ISS are warranted.

Chromosome 18q deletions (18q-) are survivable autosomal deletions, having an estimated incidence of one in 40,000 live births. Our long-term goals were to 1) comprehensively define the endocrine phenotype, 2) determine the natural history, and 3) identify key genes leading to particular phenotypes. This report specifically emphasizes the thyroid phenotype. Medical record review and comprehensive clinical assessment(s) were performed on 120 individuals with 18q- at the Chromosome 18 Clinical Research Center, the largest group of individuals with 18q- ever assembled. Affected subjects ranged in age from 6 wk to 32 yr at initial assessment. Due to case reports of thyroid dysfunction in 18q deletions and the well-established association between hypothyroidism and aneusomies, we undertook thyroid testing in all individuals and completed TRH studies on 50 of them. Our studies demonstrated that 12% had hypothyroidism, and the results were consistent with primary thyroidal dysfunction. Furthermore, two individuals progressed from normal to abnormal over the course of 2 yr. Based on these studies, it appears that, as is the case in other aneusomies, annual thyroid testing, using TSH as a primary screening tool, is indicated. The mechanism of the hypothyroidism is not yet known, and the genetic basis has not been delineated.

The influence of short stature on psychological adaptation in childhood and adolescence is controversial. GH is currently used to treat children with idiopathic short stature (ISS, also known as non-GH-deficient short stature). This study represents the first double-blind, placebo-controlled trial of the effects of GH on the psychological adaptation of children and adolescents with ISS, treated with GH until adult height was attained.Sixty-eight children (53 males, 15 females), 9-16 yr old, with marked ISS (measured height or predicted adult height -2.5 sd or less) received either GH 0.074 mg/kg or placebo sc three times per week until height velocity decreased to less than 1.5 cm/yr. Parents completed the Child Behavior Checklist (CBCL) and children the Self-Perception Profile (SPP) and Silhouette Apperception Technique at baseline and annually thereafter. Baseline behavioral/emotional adjustment (CBCL) and self-concept (SPP) scores for children with ISS were within the normative range. The two study groups exhibited similar behavioral and self-concept profiles (CBCL) during the first 2 yr of the study. However, CBCL behavior problems (internalizing, externalizing, and total problems) appeared to decline, in yr 3 and 4, in the GH-treated group relative to the placebo-treated group. Group differences in CBCL competency domains and the SPP were not observed at any point during the study. Short stature among children with ISS enrolled in this long-term, placebo-controlled study was not associated with problems in psychological adaptation or self-concept with the psychological instruments employed. GH treatment was associated with a trend toward improvement in problem behaviors, as measured by questionnaires (CBCL) completed by study participants' parents. It remains to be determined whether GH treatment significantly impacts adaptation, psychosocial function, or quality of life in children with ISS.

GH is often used to treat children with idiopathic short stature despite the lack of definitive, long-term studies of efficacy. We performed a randomized, double-blind, placebo-controlled trial to determine the effect of GH on adult height in peripubertal children. Subjects (n = 68; 53 males and 15 females), 9-16 yr old, with marked, idiopathic short stature [height or predicted height < or = -2.5 sd score (SDS)] received either GH (0.074 mg/kg) or placebo sc three times per week until they were near adult height. At study termination, adult height measurements were available for 33 patients after mean treatment duration of 4.4 yr. Adult height was greater in the GH-treated group (-1.81 +/- 0.11 SDS, least squares mean +/- sem) than in the placebo-treated group (-2.32 +/- 0.17 SDS) by 0.51 SDS (3.7 cm; P < 0.02; 95% confidence interval, 0.10-0.92 SDS). A similar GH effect was demonstrated in terms of adult height SDS minus baseline height SDS and adult height SDS minus baseline predicted height SDS. Modified intent-to-treat analysis in 62 patients treated for at least 6 months indicated a similar GH effect on last observed height SDS (0.52 SDS; 3.8 cm; P < 0.001; 95% confidence interval, 0.22-0.82 SDS) and no important dropout bias. In conclusion, GH treatment increases adult height in peripubertal children with marked idiopathic short stature.

Autoimmune thyroiditis developed in a 9-year-old girl with precocious puberty approximately 8 months after initiation of Leuprolide acetate therapy. In addition, gonadotropin concentrations as measured by radioimmunoassay appeared high. Treatment with levothyroxine, in addition to continued Leuprolide acetate treatment, resolved gonadotropin elevation and hypothyroidism.

Background: The management of children with hypothalamic (H) and/or chiasmatic (C) tumors remains controversial. We evaluated the impact of clinical and neuroimaging parameters and primary therapy on overall (OS) and progression-free (PFS) survival and on neuroendocrine and neurocognitive outcome in children with H and/or C tumors., Methods: Records were reviewed for 73 children with H and/or C tumors treated at St. Jude Children's Research Hospital between October 1981 and December 1999., Results: Thirty-six patients received irradiation or chemotherapy immediately postdiagnosis and 37 were observed. The 6-year OS and PFS rates were 86 +/- 5%; and 36 +/- 7%, respectively. The 6-year PFS rates for the irradiation, chemotherapy, and observation groups were 69 +/- 16%, 12 +/- 11%, and 37 +/- 9%, respectively. In multivariate analysis, intracranial NF1 lesions (P = 0.015) and initial irradiation (P = 0.056) led to better PFS rates. There was no difference in OS between those initially treated or observed. Mean serial intelligence quotient (IQ) scores were 86 and 86 at diagnosis and at 6 years later, respectively. Patients younger than 5 years old had a lower mean IQ score at diagnosis (79.1) than older patients (96.3; P = 0.003). Patients who were irradiated at diagnosis had a significantly higher cumulative incidence of endocrinopathy at 3 years (P = 0.008)., Conclusions: Overall survival for children with H and/or C tumors is excellent. Initial treatment with radiation and the presence of intracranial NF1 lesions were positive predictors of PFS. Mean IQ is significantly compromised at diagnosis, but does not change over time or with irradiation. Overall survival is not affected by initial observation. We recommend observation in asymptomatic patients, platinum-based chemotherapy in younger patients, and irradiation in older symptomatic patients., (Copyright 2003 American Cancer Society)

Hypothalamic obesity, a syndrome of intractable weight gain due to hypothalamic damage, is an uncommon but devastating complication for children surviving brain tumors. We undertook a retrospective evaluation of the body mass index (BMI) curves for the St. Jude Children's Research Hospital brain tumor population diagnosed between 1965 and 1995 after completion of therapy to determine risk factors for the development of obesity. Inclusion criteria were: diagnosis less than 14 yr of age, no spinal cord involvement, ambulatory, no supraphysiologic hydrocortisone therapy (>12 mg/m(2) x d), treatment and follow-up at St. Jude Children's Research Hospital, and disease-free survival greater than 5 yr (n = 148). Risk factors examined were age at diagnosis, tumor location, histology, extent of surgery, hydrocephalus requiring ventriculoperitoneal shunting, initial high-dose glucocorticoids, cranial radiation therapy, radiation dosimetry to the hypothalamus, intrathecal chemotherapy, and presence of endocrinopathy. Analyses were performed both between groups within a risk factor and against BMI changes for age in normal children older than 5.5 yr (the age of adiposity rebound). Risk factors were: age at diagnosis (P = 0.04), radiation dosimetry to the hypothalamus (51-72 Gy, P = 0.002 even after hypothalamic and thalamic tumor exclusion), and presence of any endocrinopathy (P = 0.03). In addition, risk factors when compared with BMI slope for the general American pediatric population included: tumor location (hypothalamic, P = 0.001), tumor histology (craniopharyngioma, P = 0.009; pilocytic astrocytoma, P = 0.043; medulloblastoma, P = 0.039); and extent of surgery (biopsy, P = 0.03; subtotal resection, P = 0.018). These results verify hypothalamic damage, either due to tumor, surgery, or radiation, as the primary cause of obesity in survivors of childhood brain tumors. In particular, hypothalamic radiation doses of more than 51 Gy are permissive. These results reiterate the importance of the hypothalamus in energy balance, provide risk assessment criteria for preventative measures before the development of obesity in at-risk patients, and suggest therapeutic strategies to reduce the future development of obesity.

Purpose: Little is known about the long-term efficacy or adverse effects of growth hormone (GH) replacement therapy in survivors of childhood acute lymphoblastic leukemia (ALL) who have GH deficiency. We investigated the adult height of patients who had received GH and estimated their risk of leukemia relapse or development of a second malignancy., Patients and Methods: Of 910 patients treated for ALL at a single institution, 47 had received GH replacement therapy. The linear growth of these 47 patients was retrospectively evaluated. Their risk of leukemia relapse or second malignancy was compared with that of survivors who did not undergo GH therapy., Results: The median height SD score at the start of GH therapy had decreased by 1.0 since the time of diagnosis of ALL. After a median duration of 4.5 years of GH therapy, adult height SD scores improved and approached height SD scores at the time of diagnosis of ALL. The median adult height for male patients was 173.2 cm (range, 157 to 191.9 cm), and for female patients, it was 158.1 cm (range, 141 to 168 cm). None of the patients developed adverse effects requiring discontinuation of GH treatment. At the 7-year and 11-year landmarks in continuous hematologic remission, there was no statistical evidence that GH therapy was associated with leukemia relapse or development of a second malignancy., Conclusion: This study suggests that GH replacement therapy is safe and efficacious for the correction of GH deficiency in survivors of childhood ALL.