Mary Murray

IGF-1 and IGF-Binding Proteins and Bone Mass, Geometry, and Strength: Relation to Metabolic Control in Adolescent Girls With Type 1 Diabetes

Children and adolescents with poorly controlled type 1 diabetes mellitus (T1DM) are at risk for decreased bone mass. Growth hormone (GH) and its mediator, IGF‐1, promote skeletal growth. Recent observations have suggested that children and adolescents with T1DM are at risk for decreased bone mineral acquisition. We examined the relationships between metabolic control, IGF‐1 and its binding proteins (IGFBP‐1, ‐3, ‐5), and bone mass in T1DM in adolescent girls 12–15 yr of age with T1DM (n = 11) and matched controls (n = 10). Subjects were admitted overnight and given a standardized diet. Periodic blood samples were obtained, and bone measurements were performed. Serum GH, IGFBP‐1 and ‐5, glycosylated hemoglobin (HbA1c), glucose, and urine magnesium levels were higher and IGF‐1 values were lower in T1DM compared with controls (p < 0.05). Whole body BMC/bone area (BA), femoral neck areal BMD (aBMD) and bone mineral apparent density (BMAD), and tibia cortical BMC were lower in T1DM (p < 0.05). Poor diabetes control predicted lower IGF‐1 (r2 = 0.21) and greater IGFBP‐1 (r2 = 0.39), IGFBP‐5 (r2 = 0.38), and bone‐specific alkaline phosphatase (BALP; r2 = 0.41, p < 0.05). Higher urine magnesium excretion predicted an overall shorter, lighter skeleton, and lower tibia cortical bone size, mineral, and density (r2 = 0.44–0.75, p < 0.05). In the T1DM cohort, earlier age at diagnosis was predictive of lower IGF‐1, higher urine magnesium excretion, and lighter, thinner cortical bone (r2 ⩽ 0.45, p < 0.01). We conclude that poor metabolic control alters the GH/IGF‐1 axis, whereas greater urine magnesium excretion may reflect subtle changes in renal function and/or glucosuria leading to altered bone size and density in adolescent girls with T1DM.

Randomized controlled trial evaluating response to metformin versus standard therapy in the treatment of adolescents with polycystic ovary syndrome.

OBJECTIVE We evaluated the hypothesis that metformin would improve signs and symptoms of polycystic ovary syndrome (PCOS) in adolescents as compared to oral contraceptive pills (OCP) and have a favorable effect on obesity. STUDY DESIGN Thirty-five obese, post-menarchal, non-sexually active adolescents aged 12-21 years with PCOS and hyperinsulinism were randomly assigned to receive either OCP or metformin for 6 months. RESULTS There was a significant decrease in BMI in the two groups over time, from 40.1 to 38.6 in the OCP group, and 37.3 to 36.3 in the metformin group, p = 0.0026, but no significant difference in the degree of change between the two groups. Both groups had decreased free testosterone (OCP: 1.8 pg/ml to 0.96 pg/ml; metformin: 2.1 pg/ml to 1.6 pg/ml), p < 0.0001, and improvements in insulin resistance as evidenced by increased glucose/insulin (G/I) ratio (p < 0.005) and increased QUICK1 scores (p < 0.0005). No significant differences in response to treatment were found between the metformin and OCP groups in outcome variables. CONCLUSION Adolescents with PCOS treated with metformin or OCP experienced similar beneficial outcomes including reduction in androgen levels, weight loss, and increased insulin sensitivity. The choice of a treatment agent for long-term use will depend on safety profiles, therapeutic goals and patient adherence.

Use of Steroid Profiling by UPLC-MS/MS as a Second Tier Test in Newborn Screening for Congenital Adrenal Hyperplasia: The Utah Experience

Newborn screening allows the diagnosis of congenital adrenal hyperplasia (CAH) before symptoms appear, preventing the severe and potentially life-threatening crisis associated with this disease in infancy. Traditional screening by enzyme immunoassay results in a large number of false positives. To reduce the number of unnecessary tests, anxiety to families and physicians, and the burden to the newborn screening follow-up program, we implemented a second-tier test for CAH using steroid profiling by an ultra-performance liquid chromatography-tandem mass spectrometry. We measured three steroids: 17-hydroxyprogesterone, androstenedione, and cortisol and correlated them with the age of infant at the time of sample collection and birth weight. Both age at collection and birth weight affected the levels of adrenal steroids, but the use of appropriate cut offs and analyte ratios allowed the identification of infants with CAH. This approach was effective in identifying infants with CAH, with both salt-wasting and simple virilizing forms, while reducing the false-positive rate from 2.6 to 0.09%.

Peripheral Quantitative Computed Tomography of the Tibia: Pediatric Reference Values

Peripheral quantitative computed tomography (pQCT) has been used in a number of pediatric studies. Reference data for children are primarily limited to the radius. The purpose of this study was to establish normal reference ranges for pQCT measurements of the tibia for children. A cross-sectional sample of healthy, white, non-Hispanic children aged 5-18 years (n=416; 197 boys) was measured at the distal tibia metaphysis and diaphysis by pQCT to assess trabecular and cortical bone, respectively. Differences were determined between and within genders by height for bone geometry, density, and strength. Height-specific normal ranges were calculated, and gender-specific centile curves were generated. A positive, linear relationship was found between tibia cortical bone geometry and strength parameters and height (r2 >or=0.58, p<0.001), with mean values greater for boys than girls (p <or=0.05). Trabecular volumetric bone mineral density values were relatively stable, but greater in boys than girls independent of height or age (p <or=0.01). The reference data for pQCT analyses of the tibia provide additional information on bone size, geometry, and strength in children. pQCT technology provides an additional tool for the evaluation of bone health in young subjects.

Evidence of Increased Bone Resorption in Neurofibromatosis Type 1 Using Urinary Pyridinium Crosslink Analysis

Although neurofibromatosis type 1 (NF1) is a neurocutaneous disorder, skeletal abnormalities such as long-bone dysplasia, scoliosis, sphenoid wing dysplasia, and osteopenia are observed. To investigate the role of bone resorption as a mechanism for the bony abnormalities, we selected urinary pyridinium crosslinks (collagen degradation products excreted in urine) as a measure of bone resorption in NF1. Bone resorption was evaluated by quantitative assessment of the urinary excretion of pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Total (free plus peptide-bound) pyridinium crosslinks from the first morning urines from 59 NF1 children (ages 5–19) were extracted and analyzed (17 children with a localized skeletal dysplasia, and 42 without). The data were compared with a healthy reference population without NF1 (n = 99). Multivariate analyses, controlling for age showed statistically significant increases for Dpd (p < 0.001) and the Dpd/Pyd ratio (p < 0.001) in NF1 individuals with and without a skeletal dysplasia. NF1 children have an increase in the urinary excretion of pyridinium crosslinks, reflecting increased bone resorption. The effects of NF1 haploinsufficiency likely contribute to abnormal bone remodeling, either directly or indirectly by aberrant Ras signaling, potentially predisposing NF1 individuals to localized skeletal defects.

Pediatric 25-Hydroxyvitamin D Concentrations in Neurofibromatosis Type 1

Abstract Objective: Low 25-hydroxyvitamin D (25OHD) concentrations have been associated with tumors and osteopenia or fractures in adults with neurofibromatosis type 1 (NF1). We report 25OHD concentrations in 109 children with NF1 and 218 controls matched for age, sex, geographic location, and time of year. Methods: Children with NF1 were recruited (n=109; 2–17 years), and clinical data and dual-energy X-ray absorptiometry measurements were obtained. 25OHD concentrations were measured in subjects and controls. Results: More NF1 individuals (50%) were in the 25OHD insufficient or deficient range (<30 ng/mL) (1 ng/mL=2.496 nmol/L) compared to controls (36%) (p=0.0129). 25OHD concentrations were higher in individuals with neurofibromas after controlling for age (p=0.0393), and were negatively associated with whole-body subtotal bone mineral density (BMD) z-scores (p=0.0385). Conclusions: More children with NF1 had 25OHD concentrations <30 ng/mL, potentially because of increased pigmentation and/or decreased sunlight exposure. In contrast to adults, decreased 25OHD concentrations were not associated with neurofibromas, and there was no positive association between 25OHD and BMD.

Tibial geometry in individuals with neurofibromatosis type 1 without anterolateral bowing of the lower leg using peripheral quantitative computed tomography.

INTRODUCTION Lower leg bowing with tibial pseudarthrosis is associated with neurofibromatosis type 1 (NF1). The objective of the study is to determine if the geometry of the lower limb in individuals with neurofibromatosis type 1 (NF1) differs from controls, and to characterize the osseous components of the tibia in NF1. METHODS Peripheral quantitative computed tomography (pQCT) of the lower limb was performed (90 individuals with NF1 without tibial and/or fibular dysplasia: 474 healthy individuals without NF1). Subjects were 4-18 years of age. Individuals with NF1 were compared to controls using an analysis-of-covariance with a fixed set of covariates (age, weight, height, Tanner stage, and gender). RESULTS Using pQCT, NF1 individuals without bowing of the lower leg have smaller periosteal circumferences (p<0.0001), smaller cortical area (p<0.0001), and decreased tibial cortical and trabecular bone mineral content (BMC) (p<0.0001) compared to controls. DISCUSSION Individuals with NF1 have a different geometry of the lower leg compared to healthy controls suggesting that NF1 haploinsufficiency impacts bone homeostasis although not resulting in overt anterolateral bowing of the lower leg.

Analysis of radiographic characteristics of anterolateral bowing of the leg before fracture in neurofibromatosis type 1.

Background: Anterolateral leg bowing is associated with neurofibromatosis type 1 (NF1) frequently leading to fracture and nonunion of the tibia. The objective of the study was to characterize the radiographic findings of tibial dysplasia in NF1. Methods: This study is a retrospective review of radiographs of tibial dysplasia obtained within 52 years, between 1950 and 2002, from the Shriners Hospitals for Children, Salt Lake City, and of peripheral quantitative computed tomographic images of 3 individuals with anterolateral bowing of the leg without fracture compared with age- and sex-matched controls. Results: Individuals with NF1 with bowing of the leg have the appearance of thicker cortices with medullary narrowing on plain film radiographs. The peripheral quantitative computed tomographic images of individuals with NF1 with anterolateral bowing show an unusual configuration of the tibia. Conclusions: Anterolateral bowing of the leg in NF1 is associated with the appearance of thicker cortices with medullary narrowing rather than thinning of the long bone cortex on plain film radiographs as currently used as a qualifier in the sixth diagnostic criterion for the clinical diagnosis of NF1. Individuals with NF1 who have anterolateral bowing of the leg have differences in tibial geometry compared with age- and sex-matched controls. Clinical Relevance: The characterization of the radiographic findings of long bone bowing in NF1 helps clarify the NF1 clinical diagnostic criteria.

Academic achievement and metabolic control in adolescents with type 1 diabetes

ABSTRACT Management of type 1 diabetes in adolescence is a complex task requiring self-control within individual and interpersonal domains. This is similarly requisite for academic achievement. Grade point average (GPA) was examined as a barometer of diabetes management reflective of self-control in a challenging daily context. Adolescents with type 1 diabetes (n = 172) completed questionnaires on self-control, self-efficacy, parent/peer relationships, and adherence, while mothers reported GPA. Self-control, self-efficacy, and parent/peer relationships predicted GPA, adherence and HbA1c. GPA predicted HbA1c above and beyond adherence and self-control predictors. GPA may be a valuable indicator of individual and interpersonal self-control processes required for diabetes management.

Bone mineral density in children with neurofibromatosis type 1.

To the Editor: We read with interest the recent article by Dulai et al titled, BDecreased Bone Mineral Density in Neurofibromatosis Type 1: Results From a Pediatric Cohort.[ The authors report generalized osteopenia in children with neurofibromatosis type 1 (NF1), suggesting that it may play a role in the development of the localized skeletal defects observed in NF1. Their results complement our study of 84 children with NF1. Although the findings by Dulai et al support our previously published findings, we have some concerns about potential confounders in their report. The reported Z scores were either ageor height-matched with results given separately, making interpretation difficult as individuals with NF1 are shorter than the general population, and height is a predictor of bone mineral density (BMD). If one were to compare BMD with age, then one would expect decreases in BMD in NF1 because of size. In addition, pubertal development was not considered in the analysis. Sex steroid and growth hormone production during puberty are key regulators of bone mineralization and axial and appendicular skeletal growth. Without information on pubertal staging, comparison of NF1 individuals strictly by age or size may be misleading. The authors state that puberty was not assessed in the study, but they also stated that there was no apparent delay in pubertal development clinically. If pubertal development was not assessed, it is difficult to understand how the authors know that there was no pubertal delay. Pubertal development can be difficult to assess without a prospective method applied to the protocol. Given that puberty is an important variable in its effects on axial and appendicular skeletal growth and bone mineralization, the lack of pubertal assessment in a cohort size of 23 subjects with a mean age of 10.8 years may confound the comparison of NF1 subjects strictly on height. The authors stated that raw values were converted to Z scores using an expanded and updated version of a previously published normative data set by Lu et al.5 In the article by Lu et al, only whole body, hip, and lumbar spine data are published. We question the use of unpublished reference data for the comparison of skeletal segments of the arm, leg, mid femoral shaft, and heel. Details regarding the unpublished reference data would be helpful for future studies, especially if other variables have been collected in their control cohort. The collection of appropriate data for pediatric controls that include variables known to influence bone growth and mineralization such as pubertal development, activity, and diet will be essential as we try to evaluate the effects of various diseases on pediatric bone health. The article by Dulai et al gives additional evidence of decreased BMD in NF1 adolescents and further supports disordered bone remodeling in NF1. However, the clinical significance of these observations is still unclear and requires further investigation of factors contributing to the phenotype to select appropriate treatment strategies for the localized skeletal dysplasias of NF1.