Poor growth, thyroid dysfunction and vitamin D deficiency remain prevalent despite reduced intensity chemotherapy for hematopoietic stem cell transplantation in children and young adults.

Myeloablative conditioning regimens for hematopoietic stem cell transplant (HSCT) are known to affect endocrine function, but little is known regarding reduced intensity conditioning (RIC) regimens. We retrospectively reviewed 114 children and young adults after single RIC HSCT. The analysis was grouped by age (<2 and ⩾2 years) and diagnosis (hemophagocytic lymphohistiocystosis/X-linked lymphoproliferative syndrome (HLH/XLP), other immune disorders, metabolic/genetic disorders). All groups displayed short stature by mean height-adjusted Z-score (HAZ) before (-1.29) and after HSCT (HAZ -1.38, P=0.47). After HSCT, younger children with HLH/XLP grew better (HAZ -3.41 vs -1.65, P=0.006), whereas older subjects had decline in growth (HAZ -0.8 vs -1.01, P=0.06). Those with steroid therapy beyond standard GVHD prophylaxis were shorter than those without (P 0.04). After HSCT, older subjects with HLH/XLP became thinner with a mean body mass index (BMI) Z-score of 1.20 vs 0.64, P=0.02, and similar to metabolic/genetic disorders (BMI-Z= 0.59 vs -0.99, P<0.001). BMI increased among younger children in these same groups. Thyroid function was abnormal in 24% (18/76). 25-OH vitamin D levels were insufficient in 73% (49/65), with low bone mineral density in 8 of 19 evaluable subjects. Despite RIC, children and young adults still have significant late endocrine effects. Further research is required to compare post-transplant endocrine effects after RIC to those after standard chemotherapy protocols.

Severe poisoning after self-reported use of 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, a novel substituted amphetamine: a case series.

Significant toxicity from amphetamine and cathinone derivatives is being increasingly reported. We describe a series of self-reported exposures to 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25-I-NBOME or 25-I), a novel amphetamine derivative. Ten patients with an average age of 17 years presented to local emergency departments (EDs) in our community after ingestion and/or insufflation of a drug referred to as "25-I." Of 10 patients, 6 reported taking 25-I alone; other substances included ethanol; 2,5-dimethoxy-4-ethylphenethylamine; marijuana; and ketamine. Most common effects included tachycardia (90%), hypertension (70%), agitation (60%), and hallucinations (50%). The average heart rate was 123 beats per minute. Two patients were found in status epilepticus, and another was found unresponsive. One patient who had a seizure had multiple, discrete intraparenchymal hemorrhages and acute kidney injury. Six patients were admitted to the intensive care unit, two were treated in the ED and released, and 1 each was admitted to psychiatry or managed in a clinical decision unit and subsequently discharged. Three patients required emergent intubation, and all admitted patients (7/10) were given intravenous benzodiazepines for sedation. Urine and blood specimens were obtained from 1 patient, which showed analytic confirmation of 25-I. In addition to sympathomimetic effects, methoxy and other substituent groups impart serotonergic effects, resulting in hallucinogenic properties. 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine appears to be extremely potent with a reported "dose" of 500 µg resulting in increased potential for inadvertent overdose. This case series describes significant morbidity in a local cluster of young patients after self-reported use of 25-I, a newly identified drug of abuse.

Neuropsychological functioning in girls with premature adrenarche.

Contemporary research indicates that brain development occurs during childhood and into early adulthood, particularly in certain regions. A critical question is whether premature or atypical hormone exposures impact brain development (e.g., structure) or function (e.g., neuropsychological functioning). The current study enrolled 40 girls (aged 6-8 years) diagnosed with premature adrenarche (PA) and a comparison group of 36 girls with on-time maturation. It was hypothesized that girls with PA would demonstrate lower IQ and performance on several neuropsychological tasks. The potential for a sexually dimorphic neuropsychological profile in PA was also explored. No significant univariate or multivariate group differences emerged for any neuropsychological instrument. However, effect size confidence intervals contained medium-sized group differences at the subscale level. On-time girls performed better on verbal, working memory, and visuospatial tasks. Girls with PA showed improved attention, but not a sexually dimorphic profile. These results, though preliminary, suggest that premature maturation may influence neuropsychological functioning.

Fluid-containing emphysematous bullae: a spectrum of illness.

Fluid-containing emphysematous bullae are an under-reported complication of chronic obstructive pulmonary disease. The roles of bronchoscopy in the work-up and of antibiotics in the treatment are undefined. This study reports the combined results from the analysis of 16 cases treated at the present authors' institution and 36 previously reported cases. The median age at presentation was 58 yrs and the median duration of follow-up was 60 weeks. A third of the patients were asymptomatic, while two-thirds presented with symptoms, including 10% who had evidence of a severe lung infection. Methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa and Bacteroides melaninogenicus were cultured from the bullae fluid in three symptomatic patients. Sputum and blood cultures were uninformative. Bronchoscopy, performed in two-thirds of the cases, added no diagnostic information. Antibiotic treatment did not result in a more rapid resolution of the air fluid level. Percutaneous drainage was safe and effective in four patients. In conclusion, patients with fluid-containing bullae present with a spectrum of illness. Antibiotic treatment does not hasten radiographic resolution and bronchoscopy has no diagnostic or therapeutic role.

Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development.

We assessed the clinical and treatment factors that predispose survivors of childhood acute lymphoblastic leukemia (ALL) to low bone mineral density (BMD). Using quantitative computed tomography, we determined the frequency of low BMD (defined as >1.645 standard deviations (SD) below the mean) in leukemia survivors treated with multiagent chemotherapy including prednisone and antimetabolite. All participants had completed therapy at least 4 years earlier, remained in continuous complete remission, and had no second malignancies. We statistically correlated BMD results with patient characteristics and treatment histories. Among 141 survivors (median age, 15.9 years; median time after diagnosis, 11.5 years), median BMD z score was -0.78 SD (range, -3.23 to 3.61 SDs). Thirty participants (21%; 95% confidence interval, 15% to 29%) had abnormally low BMD, a proportion significantly (P < 0.0001) greater than the expected 5% in normal populations. Risk factors for BMD decrements included male sex (P = 0.038), Caucasian race (P < 0.0001), and cranial irradiation (P= 0.0087). BMD inversely correlated with cranial irradiation dose. BMD z scores of patients who received higher doses of antimetabolites were lower than those of other patients. Childhood ALL survivors are at risk to have low BMD, especially males, Caucasians, and those who received cranial irradiation.

Cranial irradiation and central hypothyroidism.

Cranial irradiation causes thyrotropin (TSH)-releasing hormone (TRH) secretory abnormalities. TRH deficiency leads to abnormal glycosylation of TSH alpha and beta subunits and loss of the normal circadian pattern of TSH secretion (low in the afternoon, a surge in the evening, higher at night). This disruption results in either mixed hypothyroidism (raised TSH with abnormal secretory kinetics) or central hypothyroidism (abnormal secretory kinetics without raised TSH). Although primary hypothyroidism is more common in the general population and cancer survivors, the cumulative incidence of central and mixed hypothyroidism is high during the ten years after cranial irradiation. Monitoring for decline in free thyroxine (FT(4)) and rise in serum TSH, and early recognition using TSH surge and TRH tests, are clinically valuable. Early thyroid hormone replacement therapy to achieve serum FT(4) in the upper half of the normal range is crucial for maintaining optimal health and growth in cancer survivors.

Effect of growth hormone treatment on testicular function, puberty, and adrenarche in boys with non-growth hormone-deficient short stature: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the effect of growth hormone (GH) therapy on pubertal onset, pubertal pace, adult testicular function, and adrenarche in boys with non-GH-deficient short stature. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. GH (0.074 mg/kg, subcutaneously, 3 times per week) or placebo treatment was initiated in prepubertal or early pubertal boys and continued until near final height was reached (n = 49). Statistical significance was assessed by survival analysis, repeated-measures analysis of variance, and Student t test. RESULTS: GH therapy did not affect the age at pubertal onset, defined either by testicular volume >4 mL or by testosterone concentration >1.0 nmol/L (30 ng/dL). GH treatment also did not affect the pace of puberty, defined either by the rate of change in testicular volume or testosterone concentration during the 4 years after pubertal onset. In boys followed up to age > or =16 years during the study, there were no significant differences in final testicular volume or in plasma testosterone, luteinizing hormone, or follicle-stimulating hormone concentrations. The pace of adrenarche, assessed by change in dehydroepiandrosterone sulfate levels over time, also did not differ significantly between the GH and placebo groups. CONCLUSION: Our findings suggest that GH treatment does not cause testicular damage, alter the onset or pace of puberty, or alter the pace of adrenarche in boys with non-GH-deficient short stature.

Disorders of thyrotropin synthesis, secretion, and function.

Advances related to thyrotropin during 1999 included better understanding of the genetic basis of pituitary development and genetic advances in identifying clinical entities and their mechanisms and enabling new therapies. Initial clinical use of recombinant thyrotropin in evaluation of thyroid cancer recurrence was described. The importance of glycosylation pattern was clarified including the role of thyrotropin-releasing hormone in synthesis of thyrotropin molecules with mature glycosylation, and the impact of abnormal glycosylation in loss-of-function and gain-of-function mutations of the thyrotropin receptor. Causes of excessive thyrotropin secretion were evaluated, including pituitary thyrotropin-secreting adenomas. The fairly common causes of central hypothyroidism including ischemic injury, cranial irradiation, psychiatric conditions, or medical illness were assessed. The action of thyrotropin at the thyroid cell was assessed as a growth factor and as an influence on tyrosine sulfate content of thyroglobulin. Such basic and clinical science advances are rapidly affecting clinical care.

CNS germinoma: disease control and long-term functional outcome for 12 children treated with craniospinal irradiation.

PURPOSE: To provide evidence that radiation therapy alone in the form of craniospinal irradiation (CSI) and a boost to the primary site of disease provides effective disease control and limited additional morbidity for patients with CNS germinoma. METHODS AND MATERIALS: Twelve patients with a median age of 12 years (range 9-16 years) with CNS germinoma were treated with CSI (median 25.6 Gy, range 23.4-32 Gy) and a boost to the primary site of disease (50.4 Gy, range 45-54 Gy) between January 1987 and June 1998. All patients were biopsied prior to radiation therapy and none received chemotherapy. No patients were lost to follow-up and the majority had long-term (> 45 month) pre- and postirradiation endocrine and psychology assessment. RESULTS: All 12 patients are alive and no failures have occurred with a median follow-up of 69 months (range 14-143 months). Preirradiation endocrine deficiencies were present in 6 of 6 suprasellar tumors and 1 of 6 pineal tumors; with follow-up there was no substantial difference between age and gender adjusted pre- and postirradiation stature and weight. With long-term follow-up, there were no significant differences between pre- and postirradiation full-scale, verbal, and performance IQ scores. CONCLUSIONS: This study confirms the ability of radiation therapy alone to achieve disease control with a high rate of success in pediatric patients and demonstrates that the treatment toxicity faced by these patients may be less than anticipated. Because these patients present with substantial preexisting morbidity at diagnosis and may be of an age where the potential for radiation-related side effects is relatively small, the superiority of treatment alternatives may be difficult to prove.

Suppression and recovery of GH secretion after GH injection in non-GH deficient short children.

OBJECTIVE: To identify the effect of exogenous GH on endogenous GH secretion in 48 non-GH deficient short children participating in a placebo-controlled trial of GH therapy on final adult height. DESIGN: Night GH secretion (mean of levels every 20 min from 20.00 to 08.00 h) was evaluated at baseline, 6 months before starting placebo or GH (somatotropin, 0.222 mg/kg/ week, divided into 3 doses each week). At 6 months after starting injections, blood samples for GH were obtained hourly for 24 h after an injection, and every 20 min on each of the next two nights (with no additional placebo or GH injection). RESULTS: IGF-I levels in the treatment group were elevated at 12 and 24 h but not at 36 h compared to the placebo group. Mean GH levels in the placebo group did not vary significantly among the four sampling periods. In the treatment group, the mean serum GH rose to a supraphysiological peak at an average time of 4 h after injection. Subsequently, mean GH level was significantly suppressed compared to placebo on the second night following GH injection, but returned to normal by the third night. CONCLUSION: After 6 months of a thrice weekly GH treatment regimen in non-GH deficient short children, endogenous GH secretion was reduced from 24 to 36 h after injection compared to placebo and returned to control levels by 48 to 60 h after injection.

Diagnosis of hidden central hypothyroidism in survivors of childhood cancer.

To determine how often central hypothyroidism remains undetected by routine out-patient tests of thyroid hormone, we studied 208 pediatric cancer survivors referred for evaluation because of signs of subtle hypothyroidism or hypopituitarism. Of the 208 (68 females and 140 males), 110 had brain tumors, 14 had other head/neck tumors, 11 had solid tumors remote from head and neck, and 73 had leukemia. Patients were evaluated 1-16 yr (mean, 6.1+/-4.1 yr) after tumor diagnosis. The nocturnal TSH surge and response to TRH were measured. Of 160 patients with free T4 in lowest third of normal, 34% had central hypothyroidism (blunted TSH surge or low/delayed TSH peak or delayed TSH decline after TRH); 9% had central hypothyroidism with mild TSH elevation (mixed hypothyroidism). Another 16% had mild primary hypothyroidism (TSH, 5-15 mU/L). Of 48 with free T4 in the upper two thirds of normal, 14% had central hypothyroidism; 17% had mild primary hypothyroidism. Incidence of central, mixed, and mild primary hypothyroidism 10 yr after tumor diagnosis was significantly related to total cranial radiation dose (P < 0.0001). Of 62 patients with central hypothyroidism, 34% had not developed GH deficiency. TSH surge identified 71%, and response to TRH identified 60% of those with central hypothyroidism. More than half of the slowly growing patients who have received cranial or craniospinal radiation for childhood cancer develop subtle hypothyroidism. In our study group, 92% of patients with central hypothyroidism and 27% with mixed hypothyroidism would have remained undiagnosed using baseline thyroid function tests alone. Both TSH surge and response to TRH must be evaluated to identify all of these patients.

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.

Six-hour and four-hour nocturnal sampling for growth hormone.

UNLABELLED: Overnight sampling for growth hormone (GH) is a research tool for quantifying characteristics of spontaneous GH secretion. However, the study is costly in assays and blood volume, particularly that required from a small child. DESIGN AND PATIENTS: Existing overnight GH data from 126 normal children and from 227 children with GH deficiency or short stature were reanalyzed, examining 6-h and 4-h segments of this data for accuracy in representing each child's 12-h GH secretion. The goal was to see whether the test could be made shorter and more practical without losing accuracy. RESULTS: The 6-h segment 2200-0400 h consistently contained the majority of GH peaks. Correlation was high between GH values from 2200-0400 h and from the 12-h period. Normal 95% confidence limits (CL) for GH during 2200-0400 h were derived from data in normal children for gender and each pubertal stage. Data from short children were compared with the normal 6-h 95% CL. In short children, GH values low for 12-h were also low for 6-h. Only a few children with normal 12-h values (1.5% of normals, 0.5% with short stature) had GH values outside 95% CL for 6-h. CONCLUSIONS: Six-hour GH sampling (2200-0400 h) is accurate and cost-efficient compared to the 12-h overnight GH study. These studies are primarily useful in research settings.

Caloric restriction for 24 hours increases mean night growth hormone.

UNLABELLED: In obesity, serum growth hormone (GH) is usually low, confounding GH assessment of short obese children. We evaluated whether 24-h caloric restriction would permit better discrimination between normal GH secretion and GH deficiency (GHD) by elevating night GH levels. DESIGN AND PATIENTS: Serum was obtained every 20 minutes 2000-0800 h before and 2200-0400 h after 24 hours of caloric restriction (8% of usual calories) in 24 normal height children [14 normal (weight for height 10-90th percentile); 10 obese (weight for height > 95th percentile)] and in 31 short children (height shorter than -2.0 SD below mean for age). All samples from both nights per child were assayed for GH simultaneously to eliminate interassay variability. RESULTS: Mean GH increased significantly in all groups after caloric restriction (P < 0.01). Obese children had lower baseline mean GH and GH amplitude compared to normal (P < 0.01); GH increased into normal range after restriction. Basal GH studies in short children were not significantly below normal. Surprisingly, some with low stimulated GH increased their night GH into the normal range after caloric restriction. CONCLUSIONS: Caloric restriction for 24 h enhances night GH similarly in short and in normal children, and thus does not increase the diagnostic utility of night GH studies in non-obese short children. Caloric restriction reverses suppressed GH secretory state of obese children, perhaps by decreasing diet-dependent somatostatin inhibition of GH secretion.

Diagnosis of ACTH deficiency. Comparison of overnight metyrapone test to either low-dose or high-dose ACTH test.

Test sensitivity and accuracy of 250 microg/m(2) ACTH test, 1 microg/m(2) 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.

Glycolate kinetics and hemodialysis clearance in ethylene glycol poisoning. META Study Group.

OBJECTIVE: Toxic manifestations following ethylene glycol exposure are due to accumulation of metabolites, particularly glycolate. We characterized glycolate elimination kinetics and dialysis properties in a series of ethylene glycol poisonings. METHODS: Patients who ingested ethylene glycol and received fomepizole (4-methylpyrazole; 4-MP) +/- hemodialysis were prospectively evaluated. Serial blood samples for ethylene glycol, glycolate, pH, and bicarbonate were drawn to determine glycolate elimination rate, t1/2, and correlations between initial glycolate and initial markers of acidosis. Dialyzer inlet and outlet samples were obtained to measure hemodialysis glycolate clearance. Plasma ethylene glycol and glycolate were determined by gas chromatography. RESULTS: Ten patients, mean age 49 years (range 28-73 years), presented a mean of 10.5 hours (range 3.5-21.5 hours) after ethylene glycol ingestion. Mean initial ethylene glycol was 18.5 mmol/L (range 0.8-62.2 mmol/L) (115 mg/dL; range 5-386 mg/dL) and glycolate was 17.0 mmol/L (range 10.0-23.7 mmol/L). Nine of 10 underwent hemodialysis. Nonhemodialysis (n = 4) elimination rate was 1.08 +/- 0.67 mmol/L/h (mean +/- SD) and t1/2 was 626 +/- 474 minutes. Elimination t1/2 during hemodialysis (n = 8) was 155 +/- 42 minutes. Hemodialysis clearance (n = 5) was 170 +/- 23 mL/min with flow rates 250-400 mL/min. Pearson correlation coefficients were: anion gap vs glycolate r2 = 0.65 (p = 0.005), bicarbonate vs glycolate r2 = 0.10 (NS) and pH vs glycolate r2 = 0.06 (NS). CONCLUSION: Glycolate has a slow elimination rate and long half-life. Hemodialysis effectively clears glycolate. An increased anion gap correlates with the presence of glycolate. Hemodialysis is projected as useful for ethylene glycol-poisoned patients with anion gap acidosis and low ethylene glycol blood levels.

Melatonin accelerates metamorphosis in Xenopus laevis.

Delayed metamorphosis associated with large body size has been observed in Woodhousei fowleri tadpoles reared in continuous dark (DD). To evaluate the mechanism by which DD delayed metamorphosis, light-cycle exposure was controlled and thyroxine (T4), melatonin, or drugs that alter prolactin (Prl) concentrations were given to Xenopus laevis tadpoles. It was hypothesized that exogenous melatonin would delay metamorphosis and increase body size, and that elevation of Prl concentrations would have effects similar to melatonin exposure. Xenopus laevis tadpoles were randomized to three light conditions [light/dark (LD, 12 h/12 h), DD, and continuous light (LL)] and subgroups in each light condition were treated with T4, melatonin, bromocriptine (Bro), haloperidol (Hal), or no drug. Each subgroup included 12 tadpoles. Drugs were administered in the water either continuously or daily from 07.00 to 19.00 h (Intermittent). Measurements of total length, leg length, and stage of metamorphosis were obtained at regular intervals. DD resulted in delayed metamorphosis, while LL did not. T4 accelerated metamorphosis as expected, countering the delaying effects of DD. In contrast to the hypothesis, melatonin accelerated metamorphosis and impaired body size compared to controls. Intermittent Hal also accelerated metamorphosis, while Bro delayed it. In DD, both T4 and melatonin led to increased tadpole size in contrast to their counterparts in LD or LL. Delayed metamorphosis in DD is not caused by increased melatonin production. Melatonin and Hal (as given in this study) accelerate metamorphosis. Melatonin acceleration of metamorphosis may occur through alteration of the concentration of prolactin.