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Introduction: Hypothalamic-pituitary-thyroid axis changes in critical illness result in nonthyroidal illness syndrome (NTIS) characterized by abnormal TSH and thyroid hormone levels. It is unclear whether NTIS is adaptive or maladaptive. Some have suggested that NTIS adversely affects outcome, but there are limited data in children., Objective: Our objective was to determine the natural history of NTIS in children undergoing cardiac bypass surgery and to correlate these changes with outcome and illness severity., Methods: Thyroid function was measured in 21 patients, aged 1-11 yr, preoperatively and postoperatively twice daily on postoperative days (POD) 0-3 and daily thereafter until POD 7. Pediatric Logistic Organ Dysfunction and inotrope scores and pediatric intensive care unit, hospital, and ventilation days were measured and statistically analyzed in relation to thyroid function., Results: All patients exhibited NTIS within the first day postoperatively. TSH recovered by POD 4. Total T(3), free T(3) index, and T(3) uptake were still below preoperative levels on POD 7. NTIS changes correlated to prolonged hospital stays with increased pediatric intensive care unit and mechanical ventilation days and also showed strong relations with Pediatric Logistic Organ Dysfunction and inotrope scores. The T(3) measures drawn within 6-14 h from surgery were predictive of clinical outcome. Alterations in illness severity preceded changes in thyroid function., Conclusion: NTIS was present in this population of critically ill children with some of the biochemical changes not corrected by 8 d postoperatively. The degree of NTIS was related to and predictive of clinical outcome and illness severity.

A male patient with B-cell lymphoma was treated with chemotherapy and allogeneic bone marrow transplant, including preparatory total body irradiation. Ten years later, at age 15 years, the patient developed an autonomous thyroid nodule and an incidental papillary microcarcinoma. This is the first report of an autonomous thyroid nodule after total body irradiation for bone marrow transplant. The case is presented and the literature is reviewed.

Objective: To determine whether administration of bacille Calmette-Guérin (BCG) vaccination to newly diagnosed IDDM patients can help preserve C-peptide secretion over the subsequent 18 months., Research Design and Methods: Twenty-six IDDM patients, all of whom had been diagnosed within the previous year, had basal C-peptide levels >0.06 nmol/l, and had negative reactions to Mantoux's test, were randomized pairwise as they presented and were given either 0.1 ml (100 microg) BCG vaccine or 0.1 ml saline intradermally Both the patients and the investigators were blinded to the treatment. Fasting and glucagon-induced C-peptide levels and HbA1c were measured in all patients at enrollment and at 1, 3, 6, 9, 12, and 18 months after vaccination, and insulin dose was recorded at each visit., Results: At enrollment, there was no significant difference in age, duration of diabetes, insulin dose, HbA1c, or fasting C-peptide levels between the BCG-vaccinated and control groups. The mean basal and stimulated C-peptide levels in the BCG-treated group did not differ significantly from those in the control group at any time during the 18 months of follow-up, and there was no difference in insulin dose or HbA1c at any time between the groups., Conclusions: BCG vaccination in children who have been recently diagnosed with IDDM does not affect the progressive decline in C-peptide levels or alter the clinical course of the disease.

Resistance to thyroid hormone (RTH) is characterized by variable tissue hyporesponsiveness to thyroid hormone caused by mutations of thyroid hormone receptor beta (TRbeta) gene. We found a novel point mutation of the TRbeta gene in a family (F123) with RTH, a transition of a guanine to adenine at nucleotide 1215, which replaced the normal Met-310 with Ile. This substitution was found in only one allele of affected family members. In vitro transcription and translation of this mutant TRbeta demonstrated a 12-fold reduction of the affinity for triiodothyronine (T3) compared with the wild type TRbeta. Thyroid function tests were similar to a previously reported RTH family (F99) who had a different mutation in the same codon (Thr 310).

Objective: To determine the incidence of IDDM among children 0-14 years of age in Edmonton, Alberta, between 1990 and 1995 by means of a population-based registry., Research Design and Methods: Children < 15 years of age diagnosed with IDDM between January 1990 and December 1995 were registered according to criteria of the World Health Organization (WHO) Multinational Project for Childhood Diabetes. The primary source of case ascertainment consisted of office records of pediatricians and endocrinologists. The secondary source consisted of inpatient records from the main city hospitals., Results: Between 1990 and 1995, 211 IDDM patients < 15 years of age were detected by the two sources. All but 15 of them were of European ancestry. The ascertainment-corrected incidence rates of this ethnic group (constituting 77% of the population) for the 6 years were 38.6, 23.5, 23.3, 24.2, 22.0, and 24.3 per 100,000, respectively, with case ascertainment rates of 75-95%. The age-adjusted rate over the 6-year period was 25.7 per 100,000 with a case ascertainment rate of 84.3%. No sex difference was observed. The highest incidence occurred in the 10- to 14-year-old age-group, and more cases were detected between January and March than at other periods in the year., Conclusions: The incidence of IDDM among the European-derived population in Edmonton between 1990 and 1995 is the highest rate over a 6-year period to be reported in North America, comparable to that in Prince Edward Island, Canada, and to the highest rates in the world.

Alström disease is a rare disorder; less than 20 cases have been reported. An 11-year-old girl is described with this condition. She has pigmentary retinopathy, sensory neural deafness, obesity, Type II diabetes mellitus, hyperlipidemia, and acanthosis nigricans. However, in addition she developed hepatic dysfunction, pathologically similar to chronic active hepatitis. This may be a further, previously undescribed systemic manifestation of Alström disease.

Allgrove syndrome (isolated glucocorticoid deficiency, achalasia and alacrima) was found in eight members of an inbred French Canadian/North American Indian pedigree. The high degree of consanguinity supports an autosomal recessive mode of inheritance for this disorder. Six patients presented with hypoglycaemia and other evidence of cortisol deficiency between 2.5 and 8 years of age; however, two others became cortisol deficient after initial testing showed normal cortisol responses to ACTH, evidence that the glucocorticoid insufficiency of this syndrome may not be congenital, but may develop as late as the third decade. No evidence of mineralocorticoid deficiency has been found during 65 patient-years of follow-up. Alacrima was the earliest and most consistent clinical sign of Allgrove syndrome. Other manifestations of peripheral or autonomic neuropathy were found in four patients. The patients showed similar facial features, and three had significant velo-pharyngeal incompetence. All showed oesophageal dysmotility even in the absence of symptomatic dysphagia. In-vitro studies of lymphocyte ACTH binding showed no differences from normal controls. If such lymphocyte binding, as has been suggested, reflects adrenal ACTH receptor activity, these data would suggest that the glucocorticoid deficiency of Allgrove syndrome is not the result of a defect in that receptor. However, the observation that ACTH does not elicit increased adenylate cyclase activity even in normal lymphocytes casts considerable doubt on the physiological significance of ACTH binding to lymphocytes. It seems likely, therefore, that true ACTH receptors are not expressed on peripheral lymphocytes, and any conclusions regarding a possible receptor defect in Allgrove syndrome must await studies of receptor expression on adrenal cell membranes.

Insulin-dependent diabetes mellitus is a relatively common condition affecting children and adolescents. Successful management from the time of diagnosis can help prevent chronic complications of diabetes. This article reviews initial and follow-up management of diabetes in children. Guidelines for management during the remission phase, exercise, hypoglycemia, and illness, and the problems of recurrent ketoacidosis management in adolescence are discussed. The keys to successful management of diabetes mellitus in children and adolescents are patient and family education, continued support and encouragement, and early detection of and counselling for the dysfunctional family.

A brother and a sister presented with a malformation syndrome consisting of facial anomalies, distal arthrogryposis with camptodactyly of fingers and "hammer toes," severe mental retardation, and hypopituitarism. The girl is now 6 1/2 years old and exhibits severe mental retardation. She has abnormal secretion of growth hormone and responded to growth hormone therapy. Her brother was born with the same facial manifestations, distal contractures, and hypopituitarism. He died unexpectedly at age 3 months of no apparent cause. The occurrence of the syndrome in 2 sibs of different sex suggests autosomal recessive inheritance.

We report on 2 patients who were apparently normal at birth but later developed characteristics of Wiedemann-Beckwith syndrome (WBS). Both had hypoglycemia neonatally and gradually developed coarse facial changes, umbilical hernia, and macroglossia. Renal sonography done after the macroglossia developed showed large kidneys in both. The placentas were carefully examined in both cases but findings described as typical of WBS were only found in one. The clinical evolution of these infants suggests that some WBS manifestations may have their onset postnatally in some cases. We postulate that the cellular hyperplasia and hypertrophy characteristic of WBS may be caused by persistent rests of embryonal cells that secrete paracrine and/or endocrine growth factors.

We studied in vivo and in vitro steroidogenesis in six phenotypic female children with 17-hydroxylase deficiency. The diagnosis was suspected as a likely cause of familial low renin hypertension and was confirmed by findings of reduced basal and ACTH-stimulated serum and urinary levels of cortisol and other 17-hydroxysteroids, together with hypergonadotropic hypogonadism in both 46,XY and 46,XX patients, and abnormally increased secretion of 17-desoxysteroids, such as progesterone, 11-deoxycorticosterone, and corticosterone. ACTH stimulation testing demonstrated a lesser degree of 17-hydroxylase deficiency in the obligate heterozygous parents; one father had increased basal serum 17-hydroxyprogesterone values, unresponsive to ACTH, suggesting partial Leydig cell 17,20-desmolase deficiency. In vitro kinetic analysis of testicular microsomal enzymes in the affected 46,XY male pseudohermaphrodites confirmed that both 17-hydroxylase and 17,20-desmolase activities were less than 2% of those in age-matched normal subjects. However, in spite of this virtual absence of both enzymatic activities of cytochrome P450c17, Northern blot analysis demonstrated abundant amounts of RNA in these tests that hybridized to a cDNA specific for this P450 enzyme. Moreover, immunoblot analysis of sodium dodecyl sulfate-polyacrylamide gel electrophoresis-resolved testicular microsomes showed an apparently normal content of an immunoreactive protein with a mol wt similar to that of authentic P450c17. These results suggest that these patients have a point mutation in the gene for P450c17; the mutant gene is transcribed, but gives rise to a protein defective in normal 17-hydroxylase and 17,20-desmolase activities.

Eighteen members of an extended pedigree have been found to have a form of euthyroid adolescent multinodular goiter. Histological examination showed multiple adenomata with areas of epithelial hyperplasia, hemorrhage, and calcification. In two subjects there were focal areas of epithelial hyperplasia reminiscent of low-grade papillary carcinoma, but capsular and vascular invasion was not found. The pattern of inheritance appeared to be autosomal dominant, with diminished penetrance in males. Although the patients were euthyroid, the likely basis for this disorder is an abnormality in thyroglobulin structure and function.

The kinetics of the inhibitory effects of the imidazole antimicrobial ketoconazole on the activities of the steroidogenic enzymes distal to cholesterol side-chain cleavage were studied in human adrenal microsomal and mitochondrial suspensions. Although ketoconazole was a competitive inhibitor of all five enzyme reactions, the effects on 17-hydroxylase, 17,20-desmolase, and 11-hydroxylase activities (Ki = 10(-8) M) were considerably greater than those on 21-hydroxylase and 3 beta-hydroxysteroid dehydrogenase/isomerase activities (Ki = 10(-4) M). These findings explain the clinical endocrine effects of ketoconazole in the usual therapeutic doses, which include inhibition of cortisol and androgen secretion, compensatory ACTH-mediated secretion of 17-desoxysteroids such as progesterone and aldosterone, and suppression of PRA.

Kinetic analyses of 17-hydroxylase and 17,20-desmolase activities have been performed on human adrenal microsomes from 12 individuals, aged 1-60 yr. The median Michaelis constant of 17-hydroxylase for the substrate pregnenolone was 0.09 microM, and that of 17,20-desmolase for the substrate 17-hydroxypregnenolone was 0.12 microM. The median maximum velocity of 17-hydroxylase (0.25 nmol/mg X min) was significantly greater than that of the desmolase (0.13 nmol/mg X min). There was no significant correlation between the age of the adrenal donor and the Michaelis constant, but the maximum velocity for both activities in the single infant donor was lower than the values in older individuals. The inhibitory effects of various steroids on both enzyme activities also were studied. All steroids examined, except cortisol, competitively inhibited both enzymes. In each case the inhibition constant was higher for 17-hydroxylase than for 17,20-desmolase, indicating that C21 side-chain cleavage would be more sensitive to inhibition by endogenous steroids. The results, taken together with those of similar studies of 3 beta-hydroxysteroid dehydrogenase kinetics, are compatible with the suggestion that increased enzyme synthesis mediated by ACTH and differential inhibition by endogenous steroids may, in part, account for developmental changes in adrenal hormone secretion.