Lack of association between gestational age adjusted TSH percentiles and neurodevelopmental outcomes among preterm infants.

BACKGROUND: Limited evidence exists on whether subclinical hypothyroidism suggested by mildly elevated TSH levels affect neurodevelopment and growth in preterm infants. The objective of this study was to determine the association between gestational age adjusted TSH percentiles and neurodevelopmental outcomes among preterm infants. METHODS: Univariate linear regression analysis was conducted to determine, in infants born less than thirty-two weeks gestational age, the correlation between the TSH percentile on the last newborn screen and neurodevelopmental assessment scores and growth outcomes at eighteen to twenty-two months of corrected age. RESULTS: Seventy-four patients were enrolled in the study with a mean gestational age of 28.8 weeks. There was no correlation between the last TSH percentile value and Bayley-III cognitive composite score or other neurodevelopmental or growth outcomes. CONCLUSION: In a cohort of preterm infants, higher TSH percentiles suggesting potential subclinical hypothyroidism did not predict any adverse effect on neurodevelopmental or growth outcomes.

Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium.

This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.

Familial and individual predictors of obesity and insulin resistance in urban Hispanic children.

BACKGROUND: High intake of sugar-sweetened beverages (SSB) has been suggested to contribute to the pediatric obesity epidemic, however, how the home food environment influence children's intake of SSB among Hispanic families is still poorly understood. OBJECTIVES: To evaluate the relationships between the home food environment and Hispanic children's diet in relation to weight status and insulin resistance (IR). METHODS: A food frequency questionnaire was administered to 187 Hispanic children (ages 10 to 14 years) and anthropometrics were measured. IR was estimated from fasting insulin and glucose levels using the homeostasis model assessment of insulin resistance (HOMAIR ). Parents reported on family demographics and the home food environment. A structural equation modelling approach was applied to examine the hypothesized relationships among variables. RESULTS: The prevalence of childhood overweight and obesity was 52.8% and it was positively associated with HOMAIR (ß = 0.687, P < .0001). Children's SSB consumption was positively associated with children's body mass index z-score (ß = 0.151, P < 0.05) and subsequently to HOMAIR . Children's SSB consumption was predicted by home availability (ß = 0.191) and parental intake of SSB (ß = 0.419) (P < 0.05). The model fit indices [χ(2) = 45.821 (d.f. = 30, P > 0.01 and < 0.05), χ(2) /d.f. = 1.53, root mean square error of approximation = 0.053 (90% confidence interval = 0.016, 0.082), comparative fit index = 0.904] suggested a satisfactory goodness-of-fit. CONCLUSIONS: The home food environment and parental diet seem to play an important role in the children's access to and intake of SSB, which in turn predicted children's weight status.

GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults.

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.

Lack of increased risk for extracranial, nonleukemic neoplasms in recipients of recombinant deoxyribonucleic acid growth hormone.

This report describes cases of new extracranial nonleukemic neoplasms in recombinant human GH (rhGH) recipients. The data are largely from the National Cooperative Growth Study (NCGS), with over 51,000 patient-years at risk from 12,209 patients treated with Protropin rhGH. In addition to case reports of extracranial tumors from the NCGS enrollees, there have been reports from non-NCGS patients. Ten cases of new extracranial neoplasms have been reported from this total study population, and there have been eight cases whose second neoplasms were extracranial in nature. For the new cases, the number of observed cases is compared with the number of expected cases, as derived from incidence rates published by the National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) Program. The standard morbidity ratio (SMR), defined as the number of observed cases/expected cases, is calculated for males and females separately, with further subgroup analysis based upon age. For the NCGS population, the SMRs were not statistically distinguishable from unity (i.e. 1). When the number of non-NCGS Protropin patients is estimated and SMRs are calculated for the total Protropin-treated group, the SMRs remain statistically indistinguishable from one. At present, these data suggest that rhGH does not increase the risk for developing nonleukemic extracranial neoplasms. Because a small number of additional cases could significantly alter the SMR calculations, meticulous reporting and continued surveillance must continue.

Safety of recombinant deoxyribonucleic acid-derived growth hormone: The National Cooperative Growth Study experience.

The National Cooperative Growth Study has monitored the safety of recombinant human GH (rhGH) since 1985. Data have been collected from more than 19,000 children representing over 47,000 patient-years of rhGH treatment. Children receiving GH for renal disease were more likely to develop problems such as intracranial hypertension than those with GH deficiency (P < 0.01). Children with idiopathic short stature were less likely to develop slipped capital femoral epiphysis than those with GH deficiency or Turner's syndrome (P < 0.01). There was no evidence of an increased recurrence of leukemia or central nervous system tumors. There were 3 new cases of leukemia in children without known risk factors for developing leukemia and 5 cases in children with known risk factors. Growth deceleration associated with high affinity, high capacity antibodies to GH was found in only 2 of 5039 subjects tested (0.04%). Major adverse events in association with rhGH treatment have been rare, and preexisting medical conditions such as renal insufficiency may affect their frequency.

Treatment of glucocorticoid-induced growth suppression with growth hormone. National Cooperative Growth Study.

Growth failure is common during long term treatment with glucocorticoids (GC) due to blunting of GH release, insulin-like growth factor I (IGF-I) bioactivity, and collagen synthesis. These effects could theoretically be reversed with GH therapy. The National Cooperative Growth Study database (n = 22,005) was searched for children meeting the following criteria: 1) pharmacological treatment with GC and GH for more than 12 months, 2) known type and dose of GC, and 3) height measurements for more than 12 months. A total of 83 patients were identified. Monitoring of glucose, insulin, IGF-I, IGF-binding protein-3, type 1 procollagen, osteocalcin, and glycosylated hemoglobin levels was performed in a subset of patients. Stimulated endogenous GH levels were less than 10 microg/L in 51% of patients and less than 7 microg/L in 37% of patients. The mean GC dose, expressed as prednisone equivalents, was 0.5 +/- 0.6 mg/kg day. Baseline evaluation revealed extreme short stature (mean height SD score = -3.7 +/- 1.2), delayed skeletal maturation (mean delay, 3.1 yr), and slowed growth rates (mean, 3.0 +/- 2.5 cm/yr). After 12 months of GH therapy (mean dose, 0.29 mg/kg x weeks), mean growth rate increased to 6.3 +/- 2.6 cm/yr, and height SD score improved by 0.21 +/- 0.4 (P < 0.01). During the second year of GH therapy (n = 44), the mean growth rate was 6.3 +/- 2.0 cm/yr. Prednisone equivalent dose and growth response to GH therapy were negatively correlated (r = -0.264; P < 0.05). Plasma concentrations of IGF-I, IGF-binding protein-3, procollagen, osteocalcin, and glycosylated hemoglobin increased with GH therapy, whereas glucose and insulin levels did not change. The following conclusions were reached. The growth-suppressing effects of GC are counterbalanced by GH therapy; the mean response is a doubling of baseline growth rate. Responsiveness to GH is negatively correlated with GC dose. Glycosylated hemoglobin levels increased slightly, but glucose and insulin levels were not altered by GH therapy.

Defective aldosterone synthesis associated with hyperkalemic periodic paralysis.

OBJECTIVE: To describe defective aldosterone biosynthesis (corticosterone methyl oxidase type II [CMO-II] deficiency) in a kindred with hyperkalemic periodic paralysis. SETTING: Tertiary care hospital in Madison, Wis. PATIENTS: Individuals studied included a female infant with failure to thrive, hyponatremia, and hyperkalemia; the infant's asymptomatic mother and father; and a maternal aunt and grandmother with hyperkalemic periodic paralysis. INTERVENTIONS: Mineralocorticoid synthetic pathways were analyzed with synthetic adrenocorticotropin stimulation. In one patient with hyperkalemic periodic paralysis, acetazolamide sodium therapy was discontinued and replaced with fludrocortisone acetate therapy. MEASUREMENTS/MAIN RESULTS: Impaired aldosterone synthesis with marked accumulation of mineralocorticoid precursors 18-hydroxycorticosterone and corticosterone indicated severe CMO-II deficiency in the infant. In her relatives and parents, baseline aldosterone levels (74 to 111 pmol/L) were low (reference range, 194 to 830 pmol/L, a nonstricted sodium diet). Serum 18-hydroxycorticosterone levels (442 to 1021 pmol/L) were normal (reference range, 138 to 1270 pmol/L), but ratios of 18-hydroxycorticosterone to aldosterone were abnormally elevated (4.5 to 13.7; reference range, 2.65 +/- 1.86), indicating deficient CMO-II enzyme activity. Acetazolamide therapy was substituted with fludrocortisone therapy in the maternal aunt without return of paralytic symptoms. CONCLUSION: This association of hyperkalemic periodic paralysis with CMO-II deficiency and resolution of paralytic episodes with fludrocortisone therapy suggests a contribution of defective mineralocorticoid-mediated potassium homeostasis to the pathogenesis of hyperkalemic periodic paralysis.

Growth suppression by glucocorticoid therapy.

Glucocorticoids exert multiple growth-suppressing effects, interfering with endocrine (e.g., endogenous GH secretion) and metabolic (e.g., bone formation, nitrogen retention, collagen formation) processes essential for normal growth. Relatively small oral doses of daily exogenous GC, alternate-day oral GC therapy, and even IC are capable of slowing growth in some children. These growth-inhibiting and catabolic effects of GC can be variably counterbalanced by GH therapy. With regard to linear growth, GH responsiveness depends on the GC dose and severity of underlying GC-dependent disease. Short-term risks of combined GH and GC therapy are low; longer term risks (e.g., reduced allograft function, survival, or both; increased underlying disease activity; oncologic risk) require further study. GH therapy in GC-dependent children remains experimental; children considered for such treatment should be enrolled in studies that facilitate careful monitoring and collective data analysis.

Issues in the transition from childhood to adult growth hormone therapy.

The consequences of severe growth hormone deficiency (GHD) in adults and the beneficial effects of GH replacement therapy are clear. However, the majority of children who have a diagnosis of GHD and who are treated with GH do not have permanent GHD and will not require treatment during adulthood. Several issues must be considered in selecting candidates for adult GH treatment and transitioning their care from pediatrics to adult medicine. Counseling about possible lifelong treatment should focus on children with panhypopituitarism and those with severe isolated GHD that is associated with central nervous system abnormalities. When to terminate growth-promoting GH therapy should be guided by balancing the high cost of late-adolescent treatment with the attainment of reasonable statural goals. Retesting for GH secretion is appropriate for all candidates for adult GH therapy; the GH axis can be tested within weeks after the cessation of treatment, but confirming an emerging adult GHD state with body composition, blood lipid, and quality-of-life assessments may require 1 year or more of observation. Selecting patients for lifelong adult GH replacement therapy will present diagnostic, therapeutic, and ethical problems similar to those in treating childhood GHD. The experience and expertise of pediatric endocrinologists in diagnosing and treating GHD should be offered and used in identifying and transitioning appropriate patients to adult GH therapy.

Overt glucocorticoid excess due to inhaled corticosteroid therapy.

Inhaled corticosteroids have become an important therapeutic option in the treatment of childhood asthma. The preparations currently available for pediatric use (beclomethasone dipropionate and triamcinolone acetonide) do not, in general, cause significant hypothalamic-pituitary-adrenal axis suppression and physical signs of glucocorticoid excess have not been described with their use. We report an 8-year-old girl with asthma in whom obesity, hirsutism, and growth retardation developed during treatment with inhaled triamcinolone acetonide alone. Laboratory studies showed suppression of endogenous cortisol production but did not demonstrate suppression of the hypothalamic-pituitary-adrenal axis. Cessation of inhaled triamcinolone acetonide therapy resulted in resolution of obesity and hirsutism, resumption of normal growth, and a return to normal of serum cortisol levels and urinary 17-hydroxycorticosteroid excretion. Careful monitoring of growth velocity and (if clinically indicated) morning serum cortisol levels in asthmatic children using inhaled corticosteroids will detect the rare instance of glucocorticoid excess resulting from systemic absorption of these drugs.

Stimulation of collagen synthesis and linear growth by growth hormone in glucocorticoid-treated children.

Impaired linear growth and skeletal maturation associated with chronic glucocorticoid therapy may result from (1) inhibited insulin-like growth factor 1 (IGF-1) activity; (2) impaired type 1 collagen synthesis; or (3) suppressed growth hormone (GH) secretory response to growth hormone-releasing hormone. Each mechanism could potentially be improved by exogenous GH treatment. Seven slowly growing glucocorticoid-treated children received recombinant DNA human GH (0.3 mg/kg/per week) for 6 to 21 (mean 13.1 +/- 4.9) months. Height, weight, IGF-1 activity, glycosylated hemoglobin level, and C-terminal type 1 procollagen level were measured every 3 months and growth velocity was calculated. Skeletal maturation and 2-hour postprandial serum glucose and insulin levels were assessed every 6 months. All patients showed increased growth velocity during treatment with GH. Mean growth velocity increased from 3.43 +/- 0.65 cm/y to 6.72 +/- 0.84 cm/y with GH therapy (P less than .005). Growth velocity standard deviation scores corrected for bone age (P less than .005), IGF-1 levels (P less than .05), and C-terminal type 1 procollagen levels (P less than .005) also increased with GH therapy. C-terminal type 1 procollagen levels correlated well with growth velocity (r = .652) while IGF-1 levels did not (r = .17). Glycosylated hemoglobin levels remained unchanged, but 2-hour postprandial glucose levels rose during GH treatment. Slowly growing glucocorticoid-treated children receiving GH therapy increased growth velocity for 6 to 21 months. Initially diminished C-terminal type 1 procollagen levels rose with GH therapy, a change which corresponded with growth acceleration.(ABSTRACT TRUNCATED AT 250 WORDS)

Social learning approaches to health education: utilization of infant auto restraint devices.

There has been little critical evaluation of which methods achieve the desired results in health education. Using purchase of proper infant auto restraint devices as an objective, we assessed the effectiveness of three educational approaches. Only 37% of control families had purchased an acceptable car seat, compared to 54% of those who received descriptive literature alone, 71% of those that received literature and had been shown a descriptive film, and 60% of those who were given literature, shown the film, and been provided with a demonstration of the seat. Purchase of car seats was positively correlated with social class and knowledge of auto safety, but not with a history of auto accidents. Utilization of auto restraint devices is an example of how social learning theory can be applied in health education.

Persistent infantile hypothyroidism attributable to thyroxine-binding globulin deficiency.

An infant diagnosed with thyroid-binding globulin (TBG) deficiency after newborn screening demonstrated persistent elevation of thyroid-stimulating hormone (TSH) and abnormally low free thyroxine (fT4) levels. Treatment with thyroxine (T4) normalized fT4 and TSH levels during the first 5 years of life, but withdrawal of T4 supplementation at that time was associated with return of hyperthyrotropinemic hypothyroidism. To our knowledge, this patient is the first reported case of TBG deficiency-associated hypothyroidism. In rare instances, TBG deficiency may lead to hypothyroidism requiring hormone supplementation.

Hypomagnesemia masking the appearance of elevated parathyroid hormone concentrations in familial pseudohypoparathyroidism.

A 21-yr-old postpartum woman was found to be hypocalcemic and hypomagnesemic with a normal serum immunoreactive parathormone level (hypomagnesemic hypoparathyroidism). She was treated with calcitriol, calcium and magnesium. Two yr later the patient's son presented with tetany, hypocalcemia and the physical changes of pseudohypoparathyroidism. Subsequently, the patient's niece and nephew were also diagnosed with pseudohypoparathyroidism (low serum calcium, high serum phosphorus, high circulating immunoreactive parathormone). Re-evaluation of the patient on the above medical therapy showed a normal serum calcium, phosphorus and magnesium levels and an abnormally high serum immunoreactive parathormone level. The patient's magnesium supplementation was discontinued. No change in serum calcium, magnesium or parathormone levels resulted. We think that this patient demonstrates that hypomagnesemia can mask the laboratory presentation of pseudohypoparathyroidism by suppressing secretion of parathormone and further demonstrates that in pseudohypoparathyroidism the parathyroid gland retains its physiologic response to hypomagnesemia.

Autoimmune thyroid phenomena are not evidence for human lymphocyte antigen-genetic heterogeneity in insulin-dependent diabetes.

It is well established that there is genetic heterogeneity between a human lymphocyte antigen (HLA)-DR3-associated allele and an HLA-DR4-associated allele in insulin-dependent diabetes mellitus (IDDM). Equally well established are the association of DR3 with Graves' disease and other autoimmune disorders in nondiabetics and the increased prevalence of autoimmune thyroid disease in IDDM. Perhaps in large part because of these facts, it has been postulated that there are two major forms of classical IDDM--one form characterized by coexistent autoimmune disease, such as autoimmune thyroid disease which is associated with DR3, and another form not associated with additional autoimmune disorders, which is associated with DR4. Several studies have repudiated the idea of specific clinical findings in IDDM being associated exclusively with DR4. However, the DR3-thyroid association in IDDM has not been investigated carefully. Therefore, in order to study this putative association, we divided a group of diabetic children into overlapping subgroups based on thyroid enlargement, antithyroid microsomal antibodies, acquired hypothyroidism, and no evidence of thyroid disease. The distributions of HLA-DR3 and -DR4 among these subgroups did not differ from each other; nor did the distribution of the HLA alleles differ from those of randomly selected IDDM individuals. These results suggest that thyroid autoimmunity in IDDM is part of the IDDM "syndrome" and is associated with DR3 and DR4 to the same extent that IDDM without thyroid disease is associated with these two antigens. Thus, although genetic studies are consistent with the heterogeneity between DR3 and DR4 in IDDM, there is no HLA-thyroid disease association to support this heterogeneity.

Wound hypoxia and acidosis limit neutrophil bacterial killing mechanisms.

BACKGROUND: "Respiratory burst" activity, ie, O2- production, is dependent on PO2, temperature, pH, and glucose concentrations within the physiologic range. OBJECTIVES: To determine whether environmental conditions characteristic of wounds may limit human neutrophil respiratory burst metabolism and to clarify the degree to which bactericidal oxidant production depends on local PO2. METHODS: Human blood and wound neutrophils were stimulated with phorbol myristate acetate. Oxygen consumption and superoxide production were measured over a range of 30 to 300 mm Hg PO2, 0 to 40 mmol/L glucose, pH 6.0 to 8.0, and 30 degrees C to 37 degrees C. The apparent Michaelis Menten constant for oxidant production with respect to PO2 was calculated. RESULTS: Oxygen consumption and O2- production were dependent on PO2 throughout the range tested. Half-maximal oxidant production occurred in the range of 45 to 80 mm Hg PO2 and maximal at PO2 higher than 300 mm Hg. These data agree with the highest previous estimates. Oxidant generation was also dependent on pH, temperature, and glucose concentration, but to a lesser extent. CONCLUSIONS: Leukocyte bacterial killing capacity as measured by oxygen consumption and superoxide production are substantially impaired at the low oxygen tensions often found in wounds. Changes in pH, temperature, and glucose concentration have lesser but nonetheless significant consequences. The data provide a plausible mechanism for the vulnerability of some wounds to infection and for the previous finding that increasing oxygen tension at wound sites enhances bactericidal function. Thus, the data serve as a basis for future studies on prevention of wound infection.

Correlation of glycosylated hemoglobin measured by affinity vs ion exchange chromatography with mean blood sugar in pediatric IDDM patients.

Affinity chromatography provides a more specific estimate of glycosylated hemoglobin (GlyHb) than does ion exchange chromatography (HbA1). However, whether GlyHb correlates closer than HbA1 with mean blood glucose has not been established. GlyHb and HbA1 were measured in pediatric IDDM patients attending a clinic (n = 285 visits) over a one year period and correlated with the mean of a patient's blood glucose measurements from records of home blood glucose monitoring. Mean GlyHb was higher than mean HbA1 (10.8% vs 9.6%) as was its standard deviation (2.2% vs 1.5%). While both GlyHb (r = 0.75) and HbA1 (r = 0.65) were strongly correlated with estimates of mean blood glucose, the correlation with GlyHb was significantly stronger than with HbA1 for the entire spectrum of metabolic control (P = 0.03), as well as for a segregated group of 'poorly controlled' patients with mean blood glucose greater than 150 mg/dl (P = 0.04). The results suggest that GlyHb is more accurate than HbA1 for estimating metabolic control and that GlyHb shows greater discriminating power than HbA1, especially at high concentrations of blood sugar. The mean blood glucose can be estimated from the equation: mean blood glucose (mg/dl) = (11.3 x GlyHb) + 32.

Assessment of SNRPN expression as a molecular tool in the diagnosis of Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is associated with lesions of the paternal chromosome 15q11- 13. Recently, loss of expression of a paternally expressed gene in this region, SNRPN, has been proposed as a molecular hallmark of PWS. The goal of this study was to determine the diagnostic accuracy of SNRPN expression in a well-characterized cohort of PWS patients. METHODS: SNRPN expression was analyzed by reverse transcription coupled to polymerase chain reaction (RT-PCR). RNA was isolated from peripheral blood leukocytes and subjected to multiplex RT-PCR in which expression of SNRPN and a constituitively expressed internal control gene were analyzed. The amplified products were electrophoresed in agarose gels and visualized by ethidium bromide staining. RESULTS: Multiplex RT-PCR was applied to RNAs isolated from 30 normal control subjects and 30 well- characterized PWS patients. All control patients expressed the SNRPN and internal control genes. In contrast, all 30 PWS patients demonstrated loss of SNRPN expression, with integrity of RNA being demonstrated by the presence of internal control gene expression. CONCLUSIONS: Loss of SNRPN expression appears to be a consistent finding in PWS. Expression analysis of SNRPN offers a novel approach for the diagnostic evaluation of PWS that is robust and can be performed in a single day.

Can general surgeons perform colonoscopy safely?

The purpose of the current study was to review the safety of colonoscopy performed by nonfellowship-trained general surgeons. To address this issue, we reviewed more than 1,000 consecutive diagnostic and therapeutic colonoscopies and recorded the complications. This was a multi-institutional study involving seven general surgeons, none of whom had had formal fellowship endoscopic training. Perforation was confirmed by laparotomy, bleeding was defined as that requiring hospitalization and/or transfusion, and cardiopulmonary arrest was self-explanatory. There was one perforation in the diagnostic group and none in the therapeutic group, for a rate of 0.10% overall and 0.12% in diagnostic colonoscopy. There were no instances of bleeding or cardiac arrest. This complication rate of 1 per 1,025 colonoscopic procedures by general surgeons compares favorably with that previously reported by other specialties (p less than 0.001). We conclude that postgraduate endoscopy fellowship is not necessary for general surgeons to become safe colonoscopists.