George A. Burghen

Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist.

OBJECTIVE Hypothalamic obesity is a rare sequela of cranial insult, for which pathogenesis and treatment remain obscure. In rodents ventromedial hypothalamic damage causes hyperphagia, obesity, hyperinsulinism, and insulin resistance. Reduction of insulin secretion in humans may attenuate weight gain. METHODS Eight children with intractable obesity after therapy for leukemia or brain tumors underwent oral glucose tolerance testing (OGTT) with simultaneous insulin levels before and after treatment with octreotide for 6 months. RESULTS In comparison with a 6-month pre-study observation period, patients exhibited weight loss (+6.0 +/- 0.7 kg vs -4.8 +/- 1.8 kg; P =.04) and decrease in body mass index (+2.1 +/- 0.3 kg/m(2) vs -2.0 +/- 0.7 kg/m(2); P =.0001). Recall calorie count decreased during the 6 months of treatment (P =. 015). OGTT demonstrated biochemical glucose intolerance in 5 of 8 patients initially and in 2 of 7 at study end, whereas insulin response was decreased (281 +/- 47 microU/mL vs 114 +/- 35 microU/mL; P =.04). Percent weight change correlated with changes in insulin response (r = 0.72, P =.012) and changes in plasma leptin r = 0.76, P =.0004). CONCLUSIONS Patients with hypothalamic obesity demonstrate excessive insulin secretion. Octreotide administration promoted weight loss, which correlated with reduction in insulin secretion on OGTT and with reduction in leptin levels. Pre-study biochemical glucose tolerance improved in several patients while they were receiving octreotide. These results suggest that normalization of insulin secretion may be an effective therapeutic strategy in this syndrome.

Model of Associations Between Psychosocial Variables and Health-Outcome Measures of Adolescents with IDDM

The purpose of this study was to develop a model that describes the contributions of key psychosocial variables to the health outcome of adolescents with insulin-dependent diabetes mellitus (IDDM). Subjects were 93 adolescents with IDDM and their parents. Health-outcome measures included adherence and metabolic control (HbA1c). Psychosocial variables included adolescent age, chronic life stress, social competence, family relations, and family knowledge about IDDM. Multiple regression analyses showed that adherence (P < .029) and stress (P < .052) were directly related to metabolic control and that knowledge about IDDM (P < .029), family relations (P < .099), and adolescent age (P < .086) had direct effects on adherence. Combined, the independent variables accounted for 14.5% of the variance in predicting HbA1c and 18.5% of the variance in predicting adherence. In general, these findings are consistent with extant theory. The direct link between stress and metabolic control, however, contrasts with the current view that psychosocial variables affect metabolic control indirectly through their influence on adherence behavior. The methodological limitations of the findings are noted, directions for future research are suggested, and the implications for clinical interventions are described.

Risk factors for hyperglycemia in children with leukemia receiving l-asparaginase and prednisone

We determined retrospectively the frequency and risk of hyperglycemia in 421 children with leukemia who had received L-asparaginase and prednisone as part of their remission induction therapy. Forty-one patients (9.7%) developed this complication, 39 within one week after the first dose of L-asparaginase. Hyperglycemia resolved in all patients and in 32 before the end of the four-week induction period. Age, obesity, and Down syndrome each had a significant bearing on the frequency of hyperglycemia. Children 10 years of age or older were more likely to develop the complication than were younger children. When more than one factor was present in a child, the risk of hyperglycemia increased significantly. A family history of diabetes mellitus also appeared related to an increased risk of hyperglycemia. Childhood leukemia patients with any of the risk factors identified here should be closely monitored for glucosuria while receiving prednisone and L-asparaginase for remission induction.

Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: Report of five new cases and review

The neonatal progeroid syndrome (NPS), or Wiedemann-Rautenstrauch, is a rare autosomal recessive disorder comprised of generalized lipoatrophy except for fat pads in the suprabuttock areas, hypotrichosis of the scalp hair, eyebrows, and eyelashes, relative macrocephaly, triangular face, natal teeth, and micrognathia. We report on 5 new patients who demonstrate phenotypic variability and who represent the single largest series of NPS reported to date. Two of the patients are from an African-American kindred, an ethnic occurrence not reported previously. The fact that there are 2 pairs of sibs among the 5 patients further supports that NPS is an autosomal recessive condition. This report also includes a review of the previously reported 16 patients and compares them with the 5 new patients. Abnormalities in endocrine and lipid metabolism were found in 3 of 5 patients. Skeletal findings in 2 of our patients demonstrated some new findings as well as the typical radiological abnormalities previously noted in NPS. It is apparent, based on the 21 cases, that mild to moderate mental retardation is common in NPS. Long term follow-up of patients with NPS should provide more information relative to their ultimate psychomotor development. NPS is usually lethal by 7 months; however, on rare occasions, patients have survived into the teens. Our 3 surviving patients range in age from 16-23 months. Variability in the phenotype of NPS is clear; however, the phenotype remains distinct enough to allow a secure diagnosis.

Preirradiation endocrinopathies in pediatric brain tumor patients determined by dynamic tests of endocrine function

PURPOSE To prospectively evaluate pediatric patients with localized primary brain tumors for evidence of endocrinopathy before radiotherapy (RT). METHODS AND MATERIALS Seventy-five pediatric patients were evaluated with the arginine tolerance test and L-dopa test for growth hormone secretory capacity and activity; thyroid-stimulating hormone surge and thyrotropin-releasing hormone stimulation test for the hypothalamic-thyroid axis; the 1-microg adrenocorticotropin hormone (ACTH) and metyrapone test for ACTH reserve; and, depending on age, a gonadotropin-releasing hormone stimulation test to determine gonadotropin response. The study included 38 male and 37 female patients, age 1-21 years with ependymoma (n = 35), World Health Organization (WHO) Grade I-II astrocytoma (n = 18), WHO Grade III-IV astrocytoma (n = 10), craniopharyngioma (n = 7), optic pathway tumor (n = 4), and germinoma (n = 1). Seven patients receiving dexamethasone at the time of the evaluation were excluded from the final analysis. RESULTS Of 68 assessable patient, 45 (66%) had evidence of endocrinopathy before RT, including 15 of 32 patients (47%) with posterior fossa tumors. Of the 45 patients, 38% had growth hormone deficiency, 43% had thyroid-stimulating hormone secretion abnormality, 22% had an abnormality in ACTH reserve, and 13% had an abnormality in age-dependent gonadotropin secretion. CONCLUSION The incidence of pre-RT endocrinopathy in pediatric brain tumor patients is high, including patients with tumors not adjacent to the hypothalamic-pituitary unit. These data suggest an overestimation in the incidence of radiation-induced endocrinopathy. Baseline endocrine function should be determined for brain tumor patients before therapy. The potential for radiation-induced endocrinopathy alone cannot be used as an argument for alternatives to RT for most patients. Pre-RT endocrinopathy may be an early indicator of central nervous system damage that will influence the functional outcome unrelated to RT.

Hypothalamic Dysfunction After Chemotherapy

Cranial irradiation with or without chemotherapy can cause hypothalamic-pituitary dysfunction. Chemotherapy without cranial irradiation has not been thought to cause such deficiency. In order to determine whether chemotherapy without cranial irradiation can lead to hormonal deficiency, we reviewed the medical records of 362 childhood cancer patients who underwent full hypothalamic-pituitary evaluation because of altered growth and development after oncological therapy (1987-2002). Of these, 31 received chemotherapy but no cranial or total body irradiation and had no CNS tumor: 18 had hematological malignancy and 13 had a solid tumor of the torso or extremity. Duration of follow-up was 13.0 +/- 4.1 years (mean +/- SD). Growth hormone deficiency (GHD) was identified in 15 (48%), central hypothyroidism (TSH-D) in 16 (52%), and pubertal abnormalities in 10 (32%). Pubertal abnormalities included precocious puberty in two (6%), gonadal failure in five of 27 who were old enough to assess puberty (19%), and gonadotropin deficiency in three of 27 (11%). GHD and TSH-D were co-existent in eight patients (26%). Overall, 81% (n = 25) had GHD, TSH-D, precocious puberty, and/or gonadotropin deficiency. None had ACTH or ADH deficiency or primary hypothyroidism. Of note, this was not a study of prevalence, but rather an evaluation of clinically referred patients. In conclusion, hypothalamic dysfunction may occur in survivors of non-CNS tumors who receive chemotherapy but do not receive cranial irradiation. We recommend at least annual observation of growth rate and pubertal development of all children treated for pediatric malignancies, with evaluation for GHD, TSH-D, pubertal abnormalities, and other hypothalamic dysfunction in all poorly-growing cancer survivors, even those not treated with cranial irradiation.

Diagnosis of ACTH Deficiency

Test sensitivity and accuracy of 250 μg/m2 ACTH test, 1 μg/m2 ACTH test, and overnight metyrapone test were evaluated in 158 children at risk for ACTH deficiency. Of 38 given high-dose ACTH, 20 had normal responses to metyrapone and to high-dose ACTH. 14 had low response to metyrapone; of these only 2 had low cortisol response (<550 nmol/l) to high-dose ACTH. Of 120 given low-dose ACTH, 64 had normal responses to metyrapone and to low-dose ACTH. All 24 with low metyrapone response had low or borderline response to low-dose ACTH. The remaining children had an inconclusive metyrapone response. In conclusion, high-dose ACTH misses most diagnoses of ACTH deficiency (21% sensitivity, 100% specificity, 63% accuracy). In contrast, the low dose ACTH test accurately diagnoses 90% of patients with ACTH deficiency (100% sensitivity, 68% specificity). The low-dose ACTH test can serve as an accurate and practical screening test for adequacy of ACTH reserve.

Comparison of High-Dose and Low-Dose Insulin by Continuous Intravenous Infusion in the Treatment of Diabetic Ketoacidosis in Children

We studied the efficacy of low-dose (0.1 U/kg/h) and high-dose (1.0 U/kg/h) insulin, given randomly to children with diabetic ketoacidosis (DKA) by continuous intravenous infusion without a loading dose. Plasma glucose reached 250 mg/dl in 3.4 ± 0.4 h with the high-dose insulin group compared with 5.4 ± 0.5 h with the low-dose insulin group (P < 0.01). During the first 12 h of therapy, plasma glucose fell below 100 mg/dl in 2 of 16 in the low-dose compared with 12 of 16 in the high-dose patients. The decrement of ketone bodies, cortisol, and glucagon was similar in both groups. The number of hours required for HCO3– ≥ 15 meq/l and arterial blood pH ≥ 7.30 were not significantly different in the two groups. Hypokalemia (K < 3.4 meq/L) occurred in 3 of 16 low-dose and 10 of 16 high-dose patients. The data show that low-dose insulin, with a slower rate of glucose decrease, is as effective as a high dose for the treatment of DKA in children with less incidence of hypokalemia and decreased potential for hypoglycemia.

ACTH deficiency in childhood cancer survivors

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.

Racial differences in glucagon-like peptide-1 (GLP-1) concentrations and insulin dynamics during oral glucose tolerance test in obese subjects

Obese African-American (AA) subjects have higher resting and stimulated insulin concentrations than obese Caucasians (C), which could not be explained by the severity of obesity or the degree of insulin sensitivity. We investigated whether differences in glucagon-like peptide-1 (GLP-1), the most potent incretin that regulates insulin secretion, might explain racial differences in insulin response. Accordingly, we measured fasting and stimulated glucose, insulin, and GLP-1 levels during a 3-h oral glucose tolerance test (OGTT) in 26 obese C (age 38±2 y, body mass index 44±1 kg/m2) and 16 obese AA (age 36±2 y, BMI 46±2 kg/m2) subjects. Corrected insulin response (CIR30), a measure of β-cell activity, whole body insulin sensitivity index (WBISI), and area under the curve (AUC) for insulin, GLP-1, and C-peptide/insulin ratio were computed from the OGTT.Glucose levels, fasting and during the OGTT, were similar between racial groups; 32% of the C and 31% of the AA subjects had impaired glucose tolerance. With a similar WBISI, AAs had significantly higher CIR30 (2.3±0.4 vs 1.01±0.1), insulin response (IAUC: 23 974±4828 vs 14 478±1463), and lower insulin clearance (0.07±0.01 vs 0.11±0.01) than C (all, P<0.01). Obese AAs also had higher fasting GLP-1 (6.7±2.5 vs 4.5±1.1) and GLP-1AUC (1174.7±412 vs 822.4±191) than C (both, P<0.02). Our results indicate that obese AAs had higher concentrations of GLP-1 both at fasting and during the OGTT than obese C. The increased GLP-1 concentration could explain the greater insulin concentration and the increased prevalence of hyperinsulinemia-associated disorders including obesity and type 2 diabetes in AAs.