Pineal cysts in children.

OBJECTIVE: To describe the prevalence and characteristics of pineal cysts found on MRI in children. METHODS: This is a retrospective monocentric study of all brain magnetic resonance imaging (MRI) examinations performed under the same technical conditions for checking the idiopathic nature of short stature (ISS group, n = 116) and for the investigation of central precocious puberty (CPP) over a 3-year period (n = 56). Dimensions, wall and septal thickness, number of locules, signal intensity, and the presence of a solid component were analysed. Ten of 19 cysts were re-evaluated (follow-up interval 4-28 months). The prevalence of the pineal cysts was compared between the two groups using χ2 and Fisher's exact tests, and a significance threshold of p < 0.05. RESULTS: The prevalence of cysts was comparable in the two groups, CPP (10.7%) and ISS (11.2%). Cyst characteristics were similar in the two groups and 74% had thin septations. None of the cysts changed on follow-up. None of the children with pineal cysts exhibited neurological signs. CONCLUSION: Benign pineal cysts are a common finding in young children. High-resolution MRI demonstrates that these cysts are often septated. This pattern is a normal variant and does not require follow-up MR imaging or IV contrast media.

Pseudotumor of the pituitary due to PROP-1 deletion.

Hypopituitarism associated with pituitary mass in childhood is most frequently the consequence of craniopharyngioma or Rathke's cleft cyst. We report a patient with an intrasellar pseudotumor associated with hypopituitarism, which led us to a misdiagnosis of intrasellar craniopharyngioma. After spontaneous involution of the mass, diagnosis was revised. DNA analysis showed a deletion in the Prophet of Pit-1 (PROP-1) gene, a pituitary transcription factor. It is important to recognize that a PROP-1 deletion can cause pituitary pseudotumor that can be mistaken for a craniopharyngioma or Rathke's pouch cyst.

Effects of prolonged administration of ultralente insulin on fasting and postbreakfast beta-cell function in normal adults.

Treatment with small doses of subcutaneous insulin is being investigated as a possible approach to prevent type 1 diabetes in humans. The mechanism of prophylactic insulin therapy could involve the inhibition of beta-cell secretory activity and/or the initiation of an active immunoregulatory process. To evaluate the pure metabolic effect of exogenous insulin, the present study assessed whether daily subcutaneous administration of ultralente insulin alters beta-cell function in normal adults. Fourteen healthy adults were randomized to receive 0.2 U/kg x d ultralente insulin (Ultratard; Novo Nordisk, Bagsvaerd, Denmark) or placebo subcutaneously once daily for 30 days. Plasma glucose, C-peptide, and insulin concentrations were measured in the fasting state and 1 hour after a standardized breakfast, during treatment and during a recovery period of 10 days. Insulin administration induced a 15% to 40% decrease of fasting plasma C-peptide. In contrast, postbreakfast plasma C-peptide increased by 40% to 90% in subjects receiving insulin. Fasting and postbreakfast C-peptide concentrations were significantly different between groups during the injection period after adjustment for baseline concentrations (P < .05, ANOVA with repeated measures). These alterations disappeared 3 days after cessation of insulin treatment. The present regimen of exogenous insulin alters endogenous insulin secretion in normal subjects. Instead of the expected beta-cell rest, the effect appeared to be dual, with insulin secretion decreasing in the basal state and increasing after meals.

Lack of effect of GnRH agonists on final height in girls with advanced puberty: a randomized long-term pilot study.

GnRH agonists improve final height in girls with "true" precocious puberty. To test if a comparable effect can be obtained in older girls, we performed a long-term controlled study in 30 caucasian girls whose puberty started between 8.4 and 10 yr (9.4 +/- 0.1 yr), a variant of normal called "advanced" puberty. At entry into trial, these girls had clinical, biological, and sonographic manifestations of puberty and a bone age greater than 10.9 yr. They were randomized 2:1 to receive 3.75 mg triptorelin im every 4 weeks for 2 yr (n = 20, group I) or no treatment (n = 10, group II). Mean height at inclusion was 135.2 +/- 4.3 cm (+0.6 SDS) in group I, 136.1 +/- 4.2 cm (+0.8 SDS) in group II, with target height 157.6 +/- 4.3 cm (group I) and 157.8 +/- 4.7 cm (group II), and predicted height (Bayley-Pinneau) 154.1 +/- 3.9 cm and 155.2 +/- 3.7 cm. Although GnRH agonists transiently delayed sexual maturation as well as bone age and growth rate, they had no clear-cut long-standing effect, and final height was comparable in treated (157.6 +/- 4.0 cm) and untreated girls (156.1 +/- 5.3 cm) (NS).

T-cell response to proinsulin and insulin in type 1 and pretype 1 diabetes.

Insulin-dependent diabetes mellitus (IDDM) results from the selective destruction of pancreatic beta cells by a T cell-mediated autoimmune process. Insulin and proinsulin are the only known beta cell-specific autoantigens. Using short-term cultures of freshly isolated peripheral blood mononuclear cells, we evaluated T-cell responses to proinsulin and to insulin in IDDM patients and individuals at risk for IDDM. A proliferative T-cell response to proinsulin was observed in only 2 of 26 recent-onset IDDM subjects and 2 of 12 long-standing IDDM subjects and was associated with a proliferative response to insulin. In contrast, 5 of 13 islet cell autoantibody-positive first-degree relatives of IDDM patients showed a proliferative response to proinsulin alone, 3 of 13 to insulin alone, and 1 of 13 to both insulin and proinsulin. Overall, 9 of 13 ICA-positive first-degree relatives responded to either proinsulin or insulin. We observed an inverse relationship between antiinsulin antibodies and T-cell responses to insulin in ICA-positive first-degree relatives but not in long-standing IDDM patients. Our data indicate that proinsulin is a major antigen in IDDM and, further, illustrate the difference between the autoimmune response to insulin and the immune response to exogenous insulin.

Clinical and prognostic aspects of adrenocortical neoplasms in childhood.

BACKGROUND: A retrospective study of 54 children was undertaken to define the clinical presentation and secretory patterns of adrenal tumors and to evaluate the outcome of surgical resection and medical therapy. PROCEDURES: Different factors were studied in univariate and multivariate analysis by using the Cox proportional hazard model. RESULTS: Median age at diagnosis was 4 years. Boys and girls were affected equally. The disease was revealed by virilization (61%) or by a palpable mass (39%) with a 0.1-5.5 year delay from initial symptoms. At initial examination, we found that 76% of children were virilized. Ninety-four percent of the tested tumors secreted androgens, which were associated with glucocorticoids in 36%. Adrenal tumors in children were smaller than in adults. Half of them measured less than 10 cm. There were recurrences in 40% of children. The survival rate at 5 years was 49%, 70% if resection was microscopically complete and 7% if not (P < 0.001). CONCLUSIONS: In children, rare adrenal tumors have different diagnostic and prognostic characteristics than in adults; however, recurrences remain frequent. The efficacy of chemotherapy, mainly o,p'-DDD (Mitotane), remains to be evaluated in comparative trials.

Prognosis of children with malignant pheochromocytoma. Report of 2 cases and review of the literature.

Malignant pheochromocytomas are rare in childhood and the prognosis of children with this tumor is not well known. We present 2 pediatric observations of malignant pelvic pheochromocytoma. Symptoms in both cases were headache and hypertension. The tumor invaded the sacral bone. Angiogram helped to localize the tumor and metastases, and allowed preoperative embolization of the tumor in 1 case. The first child underwent incomplete surgical resection, (131)I-MIBG therapy and radiotherapy, and is still alive 2 years after diagnosis. The second child died from metastatic invasion a few weeks after discovery of the tumor. We reviewed previous reports of children with malignant pheochromocytomas (30 cases). Primary tumor was extraadrenal in 50% of cases. The 3-year survival rate was 73 +/- 9% (mean +/- SD). Apart from surgical resection, no particular treatment appeared to be more effective than others in reducing mortality.

Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure.

We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.

Low dose linomide in Type I juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial.

The quinoline-3-carboxamide, linomide, protects non-obese diabetic mice from diabetes. The effects of linomide on insulin needs and beta cell function were studied in recent juvenile Type I diabetes in a double-blind trial. Patients with recent onset diabetes were randomly assigned to treatment with a fixed dose of 2.5 mg linomide (42 patients) or placebo (21 patients) for 1 year, in addition to insulin and diet. Glycated haemoglobin was 10-15% lower at 9 months (p = 0.003) and 12 months (p < 0.05) in the linomide group. The insulin dose was 32-40% smaller in the linomide group at 3 (p < 0.03), 6 (p < 0.02), 9 (p < 0.001) and 12 months (p = 0.01). Insulin doses correlated negatively with C peptide values (p = 0.001-0.002). The trend for higher C peptide values in the linomide group did not reach significance. In a post hoc subgroup analysis performed in 40 patients (25 from the linomide group and 15 from the placebo group) who still had detectable residual beta cell function at entry, linomide was associated with 45-59% higher C peptide value at 6 months (p < 0.05), 9 months (p < 0.05) and 12 months (p < 0.05). The main adverse effects of linomide were mild transitory anaemia (45 vs 10% in the linomide and placebo groups), thrombocytopenia (24 vs 10%), and mild joint discomfort (45 vs 5%) with no clinical signs. In conclusion, low-dose linomide reduced the insulin needs in patients with juvenile Type I diabetes of recent onset and improved beta cell function in patients who still had detectable beta cell function at entry. These results support further clinical and experimental studies to define the effects of linomide in Type I diabetes provided the safety of linomide is reliably established.

Factors associated with glycemic control. A cross-sectional nationwide study in 2,579 French children with type 1 diabetes. The French Pediatric Diabetes Group.

OBJECTIVE: To determine on a large scale the multiple medical and nonmedical factors that influence glycemic control in the general population of children with diabetes, we performed a nationwide French cross-sectional study. RESEARCH DESIGN AND METHODS: We enrolled 2,579 patients aged 1-19 years with type 1 diabetes of > 1 year's duration. The study was center based: 270 centers were identified, 206 agreed to participate, and 147 included at least 90% of their patients. Questionnaires were completed by physicians interviewing patients and family, and HbA1c measurements were centralized. To identify explanatory variables for HbA1c level and frequency of severe hypoglycemia, we performed multiple regression analysis using all the quantitative variables collected and stepwise logistic regression for the qualitative variables. RESULTS: Mean HbA1c value for the whole population was 8.97 +/- 1.98% (normal 4.7 +/- 0.7% [SD]). Only 19 children (0.7%) had ketoacidosis during the 6 months before the study, whereas 593 severe hypoglycemia events occurred in 338 children (13.8%). Control was better in university-affiliated hospitals and centers following > 50 patients, reflecting the importance of access to experienced diabetologists. Children had a mean of 2.3 injections, allegedly performed 2.8 glucose measurements per day, and were seen an average of 4.6 times per year at the center. In the multiple regression analysis, 94% of the variance of HbA1c was explained by our pool of selected variables, with the highest regression coefficient between HbA1c and age (Rc = 0.43, P < 0.0001), then with daily insulin dosage per kilogram (Rc = 0.28, P < 0.0001), mother's age (Rc = 0.26, P < 0.0001), frequency of glucose measurements (Rc = 0.21, P < 0.0001), and diabetes duration (Rc = 0.14, P < 0.0001). Logistic regression identified quality of family support and dietary compliance, two related qualitative and possibly subjective variables, as additional explanatory determinants of HbA1c. The frequency of severe hypoglycemia was 45 per 100 patient-years and correlated with diabetes duration, but not with HbA1c levels or other variables. CONCLUSIONS: Although overall results remain unsatisfactory, 33% of studied French children with type 1 diabetes had HbA1c < 8%, the value obtained in Diabetes Control and Complications Trial adolescents treated intensively. Diabetes management in specialized centers should be encouraged.

Gonadotropin receptors and the control of gonadal steroidogenesis: physiology and pathology.

Over the past few years, knowledge of the structure of gonadotropin receptors and their mode of action has rapidly advanced. The cDNA corresponding to the luteinizeng hormone (LH) receptor (LHR) has been cloned, leading to the identification of a novel family of G-protein-coupled receptors. The follicle stimulating hormone (FSH) receptor (FSHR) was thereafter cloned by cross-hybridization with the LHR. Structure-function relationships have been studied by mutagenesis experiments in several laboratories. The cloning and chromosomal localization to chromosome 2p21 of the two human gonadotropin receptor genes has provided insights into their evolutionary relationships. The LHR and FSHR genes are very large and contain 10 and 11 exons respectively. The obtention of monoclonal antibodies against the receptors resulted in the characterization of the receptor proteins. These antibodies also allowed the study of receptor expression in target cells in physiological and pathological conditions. The internalization of the LHR has been studied by electron microscopy. A mechanism of receptor-mediated transcytosis through the endothelial cells of the testes has been described for the LHR. The polarized expression of receptors has been studied. The cloning of gonadotropin receptor genes has opened the field of genetic study of the receptors. Inactivating mutations of the LHR have been described in Leydig cell agenesis or hypoplasia. Different phenotypes, including complete pseudohermaphroditism, ambiguous genitalia and male phenotype, have been described. In the case of the FSHR, only one mutation has been reported in familial ovarian dysgenesis with primary amenorrhea. Related males have variable alterations of spermatogenesis and fertility. Constitutive mutations of the LHR have been reported in familial testotoxicosis. One similar mutation has also been described for the FSHR. Such mutations may lead to the development of a model of receptor activation.

[Severe hypoglycemia in diabetic children and adolescents: frequency and circumstances of occurrence]. / Czestosc i warunki wystepowania ciezkich hipoglikemii u dzieci i mlodziezy z cukrzyca typu I.

In 103 children and adolescents aged 13.6+/-5.5 years with type I diabetes lasting for 5.9+/-3.1 years, we have retrospectively studied the frequency and circumstances of severe hypoglycemic episodes (coma and/or convulsions). There were 71 severe hypoglycemia during the 5 year follow-up period. One third of patients had one or more severe hypoglycemia during the 5 years, therefore 6.4% of patients had at least one severe hypoglycemia every year. 8.7% of patients had 3 or more hypoglycemia within 5 years. Both glycated hemoglobin and insulin dose were comparable in patients with, or without severe hypoglycemia. Only in one third of the hypoglycemic episodes an apparent cause was found. We conclude that, most often, severe hypoglycemia occur in diabetic children without an identifiable cause and without any direct relationship with the level of glycated hemoglobin (HbA1c).

Circulating leptin in normal children and during the dynamic phase of juvenile obesity: relation to body fatness, energy metabolism, caloric intake, and sexual dimorphism.

In 112 obese compared with 42 lean children, we found that serum leptin is elevated early in the evolution of childhood-onset obesity (28.4 +/- 1.4 vs. 4.5 +/- 0.4 ng/ml in lean children, P < 0.0001) and correlates with adiposity. Obese children also had higher serum leptin normalized to fat mass. Despite high serum leptin, obese children ingested 2-3 times more calories than did lean control subjects (P < 0.0001) and gained weight rapidly (10.2 +/- 0.3 vs. 2.9 +/- 0.1 kg/year in control subjects, P < 0.0001). Girls had higher leptin levels than did boys, in obese as well as in nonobese children, and showed a closer correlation between adiposity and serum leptin. Elevation of serum leptin was comparable before and after puberty in obese boys, but puberty further increased leptin levels in obese girls (36 +/- 3 ng/ml), resulting in a clear sexual dimorphism with pubertal obese boys (22 +/- 5 ng/ml, P < 0.005). In conclusion, increased serum leptin reflects but does not halt fat deposition in childhood obesity. After normalization to body adiposity, leptin was found to be increased independently by obesity status, female sex, and female sexual maturation.

Cyclosporine delays but does not prevent clinical onset in glucose intolerant pre-type 1 diabetic children.

We conducted a pilot study of immunosuppression with low dose cyclosporine in first degree relatives of diabetic patients with immunologic and metabolic criteria for preclinical diabetes: islet cell antibodies (ICA) > or = 20 Juvenile Diabetes Foundation (JDF) units, first phase insulin response < 10th percentile and impaired glucose tolerance. Cyclosporine was given at an initial dose of 7.5 mg/kg*d and tapered after the end of the first year. Six cyclosporine-treated relatives were compared to nine historical controls followed at the same or at different centres. All untreated patients developed diabetes within 12 months (5.9 +/- 1.1 months). Four of the cyclosporine-treated subjects developed diabetes at 5, 24, 24 and 47 months while the other two are non diabetic 47 and 57 months after entry into the trial (time to diabetes > 34 +/- 8 months, P < 0.001 vs the control group; Mann-Whitney test). First phase insulin response increased to normal values in two patients. These results suggest that reversible functional impairment, in association with beta-cell destruction, contributes to the failure of insulin secretion in preclinical type 1 diabetes.

Alterations of plasma lactate and glucose metabolism in obese children.

Using a double stable isotope infusion method, we quantified plasma glucose and lactate inter-relationships in five recently obese children. Compared with five age-matched controls, obese children had an approximately 50% increase of total body lactate turnover [167 +/- 20 vs. 111 +/- 20 (SE) mg/min, P < 0.05]. The rate of lactate conversion to glucose was double the normal rate (96 +/- 21 vs. 46 +/- 10 mg/min, P < 0.05). Increased gluconeogenesis from plasma lactate correlated with total glucose production (r = 0.74), with plasma lactate contributing to 58% of glucose production in obese children vs. 38% in normal children (P < 0.05). Conversion into glucose correlated with the rate of lactate release in the circulation (r = 0.76). In turn, the obese children converted a larger fraction (35 +/- 2 vs. 27 +/- 2%, P < 0.02) and amount (58 +/- 10 vs. 34 +/- 5 mg/min, P < 0.05) of glucose into plasma lactate. The amount of lactate originating from plasma glucose correlated (r = 0.70) with lipid oxidation, which was increased in the obese children (58 +/- 4 vs. 23 +/- 5 mg/min, P < 0.02). Our data suggest that increased gluconeogenesis from lactate is associated with increased lipid oxidation and could contribute to the progressive development of insulin resistance and glucose intolerance in juvenile obesity.

[Adrenocortical carcinoma in children: retrospective study of 54 cases]. / Corticosurrénalomes de l'enfant: analyse rétrospective de 54 cas.

BACKGROUND: Adrenal tumors rarely occur in childhood. Their criteria for malignancy, as well as the effects of chemotherapy remain poorly defined. POPULATION: Fourty-five children (median age: 4 years) with an adrenal tumor diagnosed between 1973 and 1993 were included in this study. RESULTS: Seventy-six percent of the children showed various degrees of virilization. Tumor was palpable in 57%. Most patients (80%) had local disease, 7% loco-regional disease and 13% distant metastases. Forty-five children underwent an apparently complete surgical resection. Recurrence occurred 2 to 17 months after surgery in 18 of them (40%). Twenty-four children received medical treatment (o.p'-DDD or chemotherapy) and one-third had a tumoral response. The overall 5 year survival rate was 49%. CONCLUSIONS: Adrenocortical neoplasms have a poor prognosis in childhood. Complete resection is the only effective and potentially curative treatment. Currently no effective chemotherapy exists, and the value of adjuvant therapy remains unproven. Multicentric studies are underway to evaluate the efficacy of therapeutic approaches.

Long-term results of early cyclosporin therapy in juvenile IDDM.

In juvenile IDDM patients, immunosuppression with cyclosporin A allows partial beta-cell function recovery and transient remissions of insulin dependency. The effects of this therapeutic approach, however, have not been evaluated in the long-term, since no reported trial exceeded 1 year. Here we analyze 130 diabetic children followed at our institution during the first years of their disease. Cyclosporin was given to 83 of them at an initial dose of 7.2 +/- 0.1 mg.kg-1.day-1, which was decreased stepwise then interrupted after 6-62 months, depending on the response to therapy. A total of 47 diabetic children, who served as control subjects in two trials, were pooled for comparison. Over 4 years, the cyclosporin-treated group kept plasma C-peptide approximately twice as high as the control group (P < 0.02). It took 5.8 +/- 0.6 years for C-peptide secretion stimulated by glucagon to become undetectable in the cyclosporin group versus 3.2 +/- 0.6 years in the control group (P < 0.02). Average insulin dose remained lower by 0.2-0.4 U.kg-1.day-1 and glycated hemoglobin by approximately 1% in cyclosporin-treated patients (P < 0.02), who also had less hypoglycemia than the diabetic control subjects (P < 0.05). After 4 years, differences between the groups became nonsignificant. We observed no significant secondary effects of cyclosporin. In conclusion, positive effects of low-dose cyclosporin in recently diagnosed clinical IDDM patients are prolonged beyond interruption of the drug. The magnitude and duration of the benefit, however, do not appear sufficient to justify this immunosuppressive treatment in clinical practice.

Treatment of prediabetic patients with insulin: experience and future. European Prediabetes Study Group.

Administration of insulin by a variety of routes can prevent the onset of diabetes and the destruction of pancreatic beta-cells in prediabetic animals. Moreover, intensive insulin therapy improves beta-cell function in patients with recent-onset type 1 diabetes. Preliminary trials have suggested that treatment of high-risk prediabetic patients with insulin can prevent the onset of diabetes. In addition, long-term insulin treatment appears to have no significant side-effects in non-diabetics. However, the mechanism of the protective action of insulin is not yet understood. Several large-scale controlled trials have been organized (e.g. the Diabetes Prevention Trial 1, DPT-1, and the European Paediatric Prediabetes Subcutaneous Insulin Trial, EPP-SCIT), to evaluate the effect of prophylactic insulin therapy in the prevention or delay of diabetes in high-risk paediatric individuals.