Biomedical subjects
Publications and source records attributed to Erica A Eugster.
The incidence of pancreatic enzyme elevations in children with diabetic ketoacidosis (DKA) compared with children with newly diagnosed diabetes without DKA was assessed in a prospective study. Pancreatic enzyme elevations, particularly hyperlipasemia, are common but not associated with significant symptomatology. Acute pancreatitis was diagnosed in 2% of children with DKA.
OBJECTIVE: To compare glycemic control, safety, and parental satisfaction in preschool-aged diabetic children randomized to treatment either with continuous subcutaneous insulin infusion (CSII) or intensive insulin injection therapy. STUDY DESIGN: This clinical trial enrolled 42 patients <5 years of age who had been diagnosed with diabetes for at least 12 months. Children were randomly assigned to CSII (n = 21) or intensive insulin injection therapy (n = 21). Hemoglobin A1c (HbA1c) level was measured at baseline, 3, and 6 months. Secondary outcomes included severe hypoglycemic events, meter-detected hypoglycemia, blood sugar variability, body mass index (BMI), and satisfaction with therapy. RESULTS: Thirty-seven patients completed 6 months of therapy. There was a significant decrease in HbA1c during the study period for both groups (from 8.9% +/- 0.6% to 8.6% +/- 0.6% at 3- and 6-month visits). At 3 months, children using pumps had a significantly lower HbA1c than the injection group (8.4% vs 8.8%); however, by 6 months the two groups were similar (8.5% vs 8.7%). No differences in pre-meal blood sugar variabilities were seen between groups. Children on pumps had increases in the number of meter-detected episodes of hypoglycemia. Pump therapy was safe and well tolerated. No episodes of ketoacidosis occurred in either group, whereas one hypoglycemic seizure occurred in each group. Parents reported satisfaction with CSII, with 95% of families continuing on CSII beyond the 6-month study period. CONCLUSION: Pump therapy in preschool-aged children was not associated with clinically significant differences in glycemic control as compared with intensive injection therapy. The rationale for initiating CSII in this age group should be based on patient selection and lifestyle preference.
We sought to determine the prevalence of ACTH deficiency in children with GH deficiency (GHD) of unknown etiology with and without TSH deficiency and to correlate the structural characteristics of the hypothalamic-pituitary region on magnetic resonance imaging (MRI) with TSH and ACTH status. The electronic medical records system of a children's hospital was used to identify all patients less than 18 yr of age with GHD. TSH and ACTH deficiency were defined as being present if the patient was prescribed replacement hormone therapy. The medical records of 236 GHD subjects were reviewed, and the results of their MRI scans were recorded. Ninety had hypothalamic-pituitary-adrenal axis testing, and nine were ACTH deficient (10% of those tested; 4% of all subjects). Twenty-one (9%) of 236 were TSH deficient. All of the ACTH-deficient subjects were also TSH deficient: eight of nine had a gross abnormality on MRI, and one did not have an MRI report in the medical record. We conclude that patients with GHD, normal thyroid function, and no gross abnormalities on MRI do not need hypothalamic-pituitary-adrenal testing because no ACTH-deficient subjects would have been missed using this strategy (95% confidence interval, 0-5%).
We analyzed glycemic control and insulin usage patterns of 14 preschoolers and 14 adolescents on continuous subcutaneous insulin infusion (CSII) matched for sex to determine how CSII therapy for type 1 diabetes mellitus (DM1) differs in preschoolers as compared to adolescents. Average hemoglobin A(1c) was lower in the adolescents. The percent of insulin delivered as the basal rate was the same in both groups; however, during the hours after midnight the preschoolers needed a much lower basal rate per kg body weight. There were also significant differences in insulin sensitivity and insulin/carbohydrate ratios. The number of basal rates, number of boluses, and percent of insulin administered as the basal rate were not different between groups. This is the first report of discrete differences in insulin usage patterns for preschoolers and adolescents on insulin pumps. Reasons for these dissimilarities include differences in hormone production, insulin absorption, frequency of food intake, and glycemic targets. Recognizing these variations is essential for safe and efficacious use of CSII in preschoolers with DM1.
Aromatase inhibitors have been used in the treatment of selective forms of precocious puberty since the mid-1980s. The primary aim of therapy is attenuation of the effects of estrogen on growth, skeletal maturation, and secondary sexual development. The first-generation agent, testolactone, has been demonstrated to be tolerable and effective in the treatment of familial male precocious puberty, while mixed results with testolactone have been achieved in girls with McCune-Albright syndrome. A favorable outcome with the use of testolactone in conjunction with conventional therapy in children with congenital adrenal hyperplasia has also been suggested. Although a few anecdotal reports of the use of newer generation aromatase inhibitors in precocious puberty exist, the extreme rarity of the relevant disorders remains a limiting factor in clinical investigation. In this review, the pathophysiology, presentation, and treatment of precocious puberty are described. Particular attention is devoted to the specific disorders in which aromatase inhibitors have been utilized, which are forms of peripheral (gonadotropin-independent) precocious puberty. The impact of untreated precocious puberty on growth and adult stature is discussed, and the actions of estrogen in the human skeleton are summarized. Finally, a detailed description of the existing literature pertaining to aromatase inhibitors in the pediatric population is provided. Emerging potential new indications are discussed. In conclusion, aromatase inhibitors, particularly testolactone, have a proven track record in the treatment of a few forms of precocious puberty. Continued exploration with new generation aromatase inhibitors in these disorders is ongoing. The wider application of aromatase inhibitors for the purposes of delaying skeletal maturation and increasing adult height in several conditions leading to short stature is currently a subject of intense investigation.
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OBJECTIVE: We undertook a 1-year multicenter trial of tamoxifen treatment for precocious puberty in girls with McCune-Albright syndrome (MAS). STUDY DESIGN: Girls < or =10 years with classic or atypical MAS were recruited. Pretreatment history was collected for 6 months. Patients received 20 mg tamoxifen daily. Diaries were used to record bleeding. Evaluations included physical examination, bone age, pelvic ultrasound, hormone levels, and safety assessments. RESULTS: A total of 28 girls (2.9-10.9 years of age) were enrolled from 20 centers, of whom 25 completed 12 months of tamoxifen treatment. Compared with before the study, vaginal bleeding episodes decreased (3.42+/-3.36/year vs 1.17+/-1.41/year), growth velocity slowed (SDS 1.22+/-2.65 vs -0.59+/-3.06, P=.005), and rate of bone maturation decreased (1.21+/-0.78 vs 0.72+/-0.36, P=.02). Ovarian volumes were enlarged and asymmetric throughout the study, and uterine volumes were increased. No adverse events occurred. CONCLUSIONS: Tamoxifen treatment of precocious puberty in MAS results in a reduction of vaginal bleeding and significant improvements in growth velocity and rate of skeletal maturation.
OBJECTIVE: McCune-Albright syndrome (MAS) is characterized by a clinical triad of endocrinopathies, café au lait pigmentation, and polyostotic fibrous dysplasia of bone. We hypothesized that children diagnosed with fibrous dysplasia are not routinely being evaluated for coexisting endocrine dysfunction or MAS. Our objective was to prospectively screen subjects with fibrous dysplasia for endocrine disease and G(s)alpha gene (GNAS1 )-activating mutations. STUDY DESIGN: Nine subjects who presented with fibrous dysplasia and were followed in orthopedic clinics were evaluated for other manifestations of MAS. Genomic DNA was isolated from blood, and mutation analysis of GNAS1 was performed. RESULTS: On physical examination, 5 of 9 subjects were found to have café au lait pigmentation. Three of 9 subjects had TSH levels below the normal range. One of these subjects was found to have hyperthyroidism and was treated by total thyroidectomy. GNAS1 mutations were identified in 5 of 9 subjects with either monostotic or polyostotic fibrous dysplasia of bone. CONCLUSIONS: We conclude that a substantial proportion of children being followed for fibrous dysplasia of bone have unrecognized clinical and laboratory features of MAS. These children are at risk for endocrinopathy and should be screened accordingly.
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Granulosa cell tumors are serious ovarian neoplasms that can occur in women of all ages. While there have been numerous attempts to understand the cause of these malignancies, the pathogenesis of granulosa cell tumors (GCTs) still remains largely unknown. G-protein coupled receptor kinases (GRKs) are important regulators of signal transduction through the process of receptor desensitization and internalization. Receptors that are regulated by GRKs are members of the large family of seven-transmembrane receptors and include the follicle stimulating hormone receptor (FSHR). In granulosa cells, the FSH signaling system is responsible for cell proliferation, differentiation, and steroidogenesis. In the studies presented, we examined GRK mRNA and protein expression in nonmalignant human granulosa cells, in KGN cells, a human GCT cell line, and in a panel of human GCT samples. The KGN tumor cells express significantly less GRK4 alpha/beta protein and higher levels of GRK2 and GRK4 gamma/delta protein as compared to nonmalignant human granulosa cells. In human GCT samples, GRK4 alpha/beta protein was detected in 3 of the 13 tumor samples, whereas gamma/delta proteins expression was detected in all samples. These findings suggest that GRK protein expression is altered in GCTs and may be involved in the pathogenesis of these tumors.
OBJECTIVE: To characterize the development of hypothyroidism in pediatric patients who receive a fixed dose of radioactive iodine (RAI). STUDY DESIGN: Medical records of children treated with fixed-dose RAI for Graves'disease between 1993 and 2001 were reviewed. Multiple variables including sex, age, thyroid hormone levels, thyroid-stimulating immunoglobulin titer, antithyroid medication use, and 24-hour radioiodine uptake were investigated as possible predictive factors for the development of hypothyroidism after treatment. All patients received RAI at a dose of between 13.8 and 15.6 mCi (average, 14.7 mCi; SD, 0.5). RESULTS: Permanent hypothyroidism developed in all 40 patients, although a second dose of RAI was required in one case. The average time to hypothyroidism was 77 days (SD, 32), with a range of 28 to 194 days; 75% of the patients were diagnosed with hypothyroidism between 40 and 90 days. RAI treatment was ineffective in an additional patient, who required subtotal thyroidectomy. CONCLUSIONS: We conclude that a fixed dose of RAI is effective therapy in nearly all pediatric patients with Graves'disease. Factors predicting the time course to hypothyroidism were not identified.
Multiple lines of evidence have implicated the growth hormone (GH) axis in the regulation of erythropoiesis. To test the hypothesis that GH deficiency is associated with hematologic abnormalities, we analyzed pretreatment hemoglobin levels in 100 children with GH deficiency. Hemoglobin levels were decreased in children with GH deficiency compared with age-corrected norms.
Activating mutations of the Gsalpha gene are responsible for McCune-Albright syndrome and have also been identified in sporadic tumors of the pituitary and thyroid. When associated with malignancy, activating Gsalpha mutations are known as gsp-oncogenes. We hypothesized that similar activating mutations might also account for some cases of premature thelarche and/ or granulosa cell tumors. Polymerase chain reaction and DNA sequencing was used to screen for activating mutations of Gsalpha genes in children with premature thelarche and in pathologic specimens from juvenile and adult granulosa cell tumors. Because these disorders involve over-activity of the FSH-signaling pathway, we also screened for activating mutations of the FSH receptor. No mutations were detected in either the Gsalpha or the FSHR fragment studied. Previously reported polymorphisms (Ser680Asn and Ala307Thr) of the FSHR were detected in 25/27 tumor samples and 9/9 premature thelarche samples. We conclude that activating mutations in previously identified mutation 'hot-spots' in the Gsalpha and FSH receptor genes are probably not a major cause of premature thelarche or granulosa cell tumors. In contrast, polymorphisms of the FSH receptor are common.