Quantitative Ultrasound and Tibial Dysplasia in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with unilateral anterolateral bowing with subsequent fracture and nonunion. In infancy, physiologic bowing of the lower leg can be confused with pathologic tibial dysplasia in NF1. Little is known about the bone physiology of the tibiae prior to fracture or predictors of fracture. The aim of this study was to characterize bone quality of bowed tibiae prior to fracture in NF1 using quantitative ultrasound (QUS). Bone quality was assessed on both tibiae (the non-bowed and bowed tibiae) using QUS to measure speed of sound (SOS) at the mid-shaft in 23 individuals with NF1. SOS (m/s) was determined and Z-scores generated using cross-sectional reference data of the same sex and age. The mean difference in SOS Z-scores when comparing the bowed tibia vs the individual's contralateral unaffected tibia was statistically significant with lower mean Z-scores in the bowed tibia (p = 0.001). Radiographs of all individuals with a clinical diagnosis of anterolateral bowing were reviewed, and in 2 individuals the radiographs showed minimal bowing with absence of characteristic cortical thickening and medullary canal narrowing in NF1-related tibial dysplasia, suggesting physiologic bowing. In both individuals, the Z-scores of the bowed leg were not lower than the unaffected leg supporting the suggestion of physiologic bowing rather than pathologic tibial dysplasia. These data show that dysplastic tibiae in NF1 prior to fracture and nonunion have abnormal bone quality with significant decreases in SOS even though radiographically the tibiae show a thickened cortex. These data also suggest that QUS can help distinguish dysplastic bowing vs physiologic bowing in infancy in NF1. QUS is an effective quantitative outcome measure for trials aimed at improving tibial bowing to prevent fracture, and it is a potential aid in diagnosis and clinical management in NF1.

Mid-arm circumference is a reliable method to estimate adiposity in preterm and term infants.

BACKGROUND: Premature birth is associated with increased adipose deposition after birth. Standard anthropometry (body weight, length, and head circumference) may not adequately assess fat deposition. Validated methods to assess adiposity are needed to optimize growth quality in preterm infants. The purpose of this study was to identify covariates of infant body fat. METHODS: Air displacement plethysmography (ADP), standard anthropometry, and body circumferences were measured at hospital discharge in preterm (n = 28; 31-35 wk postmenstrual age (PMA)) and term (n = 28; 38-41 wks PMA) infants. RESULTS: Body weight, length, and head circumference were lower for preterm infants (P < 0.05) at hospital discharge compared with that of term infants. Despite smaller body size and younger PMA, preterm infant percent body fat (%BF) by ADP was 12.33 ± 4.15% vs. 9.64 ± 4.01% in term infants (P = 0.01). Mid-arm circumference (MAC) is a covariate of %BF in both preterm and term infants (adjusted R(2) = 0.49; P < 0.001). In preterm infants alone, MAC accounted for 60.4% of the variability of percent body fat (%BF) by ADP (P < 0.01). CONCLUSIONS: Preterm infants have increased body fat deposition as they approach term-corrected age, and MAC is a reliable, low-cost measure for monitoring infant body fat deposition in preterm and term infants.

Estimation of length or height in infants and young children using ulnar and lower leg length with dual-energy X-ray absorptiometry validation.

AIM: We compared the accuracy and reproducibility of using ulnar and lower leg length measurements to predict length and height in infants and children aged 0 to 6 years. METHOD: Length/height and ulnar and lower leg length were measured in 352 healthy preterm and term-born children (167 males, 185 females) (Mean age= 2.6±1.6 years). Ulna length was measured as the distance between the proximal olecranon process and the distal styloid process of the ulna. Tibia length was measured as the distance from the proximal aspect of the medial condyle and the most distal aspect of the medial malleolus of the tibia using a segmometer. Length measurements were taken using an infant length board in children less than 24 months of age, whereas a portable stadiometer was used to measure height in older children. Equations were developed using ulnar and lower leg length and age. Intra- and inter-examiner variability (n=167) was calculated, and dual-energy X-ray absorptiometry scans (n=126) were used to determine accuracy of limb lengths. RESULTS: Ulnar and lower leg length explained over 95% of the variability in length/height in term infants and children, but less in preterm infants (R(2) =0.80-0.87). In preterm infants, the limits of agreement (LOA) for males were -2.44 to 2.44cm and -2.88 to 2.88cm for the ulna and lower leg respectively, whereas the LOA for females were -1.90 to 1.90cm and -1.87 to 1.87cm respectively. In older children, the LOA for males were -5.53 to 4.48cm and -5.59 to 4.62cm for the ulna and lower leg respectively, whereas the LOA for females were -5.57 to 5.01cm and -6.02 to 5.02cm respectively. Intra- and inter-examiner variability was low for all measurements in both sexes and age groups. INTERPRETATION: Length and height measurements using infant length board or stadiometer are reproducible. Because of the wide limits of agreement, estimation of length and height in children using ulnar and lower leg length is not an acceptable alternative to traditional methods.

Heart rate variability during caregiving and sleep after massage therapy in preterm infants.

BACKGROUND: Preterm birth impairs the infant's stress response due to interruption of autonomic nervous system (ANS) development. Preterm infants demonstrate a prolonged and aberrant sympathetic response to stressors. ANS development may be promoted by massage therapy (MT), which has been shown to improve stress response in preterm infants. AIMS: The aim of this study was to compare preterm infant ANS function and stress response during sleep and caregiving epochs, as measured by heart rate variability (HRV), after two weeks of twice-daily MT. STUDY DESIGN: A subset of participants from a larger randomized, masked, controlled trial was used. SUBJECTS: Twenty-one infants (8 males and 13 females) from a larger study of 37 medically stable preterm infants were studied. The infants were receiving full volume enteral feedings with a mean post-menstrual age of 31.4 (MT) and 30.9 (control) weeks. OUTCOME MEASURES: Low to high frequency (LF:HF) ratio of HRV was the outcome of interest. RESULTS: There was a significant group×time×sex interaction effect (p<.05). Male control infants demonstrated a significant decline in LF:HF ratio from baseline to the second caregiving epoch, suggesting decreased mobilization of sympathetic nervous system response when exposed to stressors. Male MT infants demonstrated increased LF:HF ratio during caregiving and decreased LF:HF ratio during sleep epochs, suggesting improved ANS function, although this was not statistically significant. LF:HF ratio was similar in female MT and female control infants during caregiving and sleep. CONCLUSIONS: Control males had decreased HRV compared to MT males. There was no difference in HRV between MT and control females.

Mechanical-tactile stimulation (MTS) intervention in a neonatal stress model alters adult adipose tissue deposition and prevents hyperinsulinemia in male rats.

Preterm infants are exposed to numerous stressors during hospitalization and by term corrected gestational age they have lower body weight but a greater proportion of total body as well as abdominal visceral adipose tissue (VAT) accumulation. Greater abdominal VAT stores have a known association with metabolic syndrome. Mechanical-tactile stimulation (MTS) improves modulation of stress response in both humans and rodents. We hypothesize that MTS, administered during an established model of neonatal stress, would decrease stress-driven adiposity and prevent associated metabolic imbalances in adult rats. Neonatal stress, administered to rat pups from postnatal days 5 to P9, consisted of needle puncture and hypoxic/hyperoxic challenge during 60 min of maternal separation (STRESS; n=20). Mechanical-tactile stimulation (MTS; n=20) was administered to rat pups for 10 min during maternal separation in the stress protocol. Control animals received standard care (CTL; n=20). MRI measured adult (P120) abdominal total fat mass, subcutaneous (SAT) and visceral adipose tissue (VAT). Body weight and fasting serum adiponectin, leptin, glucose, insulin, and corticosterone were also measured. STRESS results in elevated VAT/SAT ratio compared to CTL but lower abdominal total fat mass and abdominal SAT. STRESS males experience hyperinsulinemia. Both STRESS and MTS had elevated leptin with lower adiponectin and corticosterone compared to CTL. In summary, neonatal stress promotes greater abdominal VAT accumulation and, in males, caused hyperinsulinemia and hypoadiponectinemia. Importantly, MTS normalized the VAT/SAT ratio and prevented hyperinsulinemia. We speculate that MTS ameliorates some of the negative metabolic consequences of early life perturbations due to neonatal stress exposure.

Massage improves growth quality by decreasing body fat deposition in male preterm infants.

OBJECTIVES: To assess the effect of massage on weight gain and body fat deposition in preterm infants. STUDY DESIGN: Preterm infants (29-32 weeks) were randomized to the massage group (n = 22, 12 girls, 10 boys) or the control group (n = 22, 12 girls, 10 boys). Treatment was masked with massage or control care administered twice-daily by licensed massage therapists (6 d/wk for 4 weeks). Body weight, length, Ponderal Index (PI), body circumferences, and skinfold thickness (triceps, mid-thigh, and subscapular [SSF]) were measured. Circulating insulin-like growth factor I, leptin, and adiponectin levels were determined by enzyme-linked immunosorbent assay. Daily dietary intake was collected. RESULTS: Energy and protein intake as well as increase in weight, length, and body circumferences were similar. Male infants in the massage group had smaller PI, triceps skinfold thickness, mid-thigh skinfold thickness, and SSF and increases over time compared with control male infants (P < .05). Female infants in the massage group had larger SSF increases than control female infants (P < .05). Circulating adiponectin increased over time in control group male infants (group × time × sex interaction, P < .01) and was correlated to PI (r = 0.39, P < .01). CONCLUSIONS: Twice-daily massage did not promote greater weight gain in preterm infants. Massage did, however, limit body fat deposition in male preterm infants. Massage decreased circulating adiponectin over time in male infants with higher adiponectin concentrations associated with increased body fat. These findings suggest that massage may improve body fat deposition and, in turn, growth quality of preterm infants in a sex-specific manner.

Validity and reliability of perinatal biomarkers of adiposity after storage as dried blood spots on paper.

OBJECTIVE: To validate use of chip-based immunoaffinity capillary electrophoresis on dried blood spot samples (DBSS) to measure obesity-related hormones. METHODS: Chip-based immunoaffinity capillary electrophoresis was used to measure adiponectin, leptin and insulin in capillary serum and DBSS in pregnant women and infant heelstick at birth and six weeks. Concordance of measurements was determined with Pearson's correlation and Bland-Altman plots. RESULTS: We report high concordance between results obtained from serum and DBSS. CONCLUSIONS: Ease of sample collection and storage makes DBSS an optimal method for use in studies involving neonates and young children, as well as studies conducted in areas where freezer storage is not available.

Mechanical-tactile stimulation (MTS) during neonatal stress prevents hyperinsulinemia despite stress-induced adiposity in weanling rat pups.

Stress in early life negatively influences growth quality through perturbations in body composition including increased fat mass. At term (40 weeks) preterm infants have greater fat mass and abdominal visceral adipose tissue than term-born infants. Mechanical-tactile stimulation (MTS) attenuates the stress response in preterm infants and rodents. We tested the hypothesis that MTS, administered during an established model of neonatal stress, would decrease stress-driven adiposity and prevent associated metabolic imbalances in rat pups. Pups received one of three treatments from postnatal days 5 to P9: Neonatal Stress (Stress; n=20) = painful stimulus and hypoxic/hyperoxic challenge during 60 min of maternal separation; MTS (n=20) = neonatal stress+10 min of MTS; or Control (n=20). Body weight, DXA whole body fat mass (g), MRI subcutaneous and visceral adipose tissue, and fasting adiponectin, leptin, glucose, insulin, and corticosterone were measured at weaning (P21). Stress and MTS weight gain (g/d) were accelerated following neonatal stress with greater fat mass, abdominal subcutaneous adipose tissue, serum adiponectin, leptin, and fasting glucose at weaning (P21). Male Stress and MTS pups had greater visceral adipose tissue depot. Male and female Stress pups were hyperinsulinemic. In summary, neonatal stress compromised body composition by increasing fat mass and abdominal subcutaneous adipose tissue depot, and in males, visceral adipose tissue depot. Importantly, MTS prevented hyperinsulinemia despite of stress-induced adiposity. We conclude that MTS during neonatal stress has the potential to minimize metabolic consequences associated with stress-driven perturbations in fat mass and abdominal adipose depots.

Validity and reliability of a nutrition knowledge survey for assessment in elementary school children.

Limited surveys are available to assess the nutrition knowledge of children. The goals of this study were to test the validity and reliability of a computer nutrition knowledge survey for elementary school students and to evaluate the impact of the "Fit Kids 'r' Healthy Kids" nutrition intervention via the knowledge survey. During survey development, a sample (n=12) of health educators, elementary school teachers, and registered dietitians assessed the survey. The target population consisted of first- through fourth-grade students from Salt Lake City, UT, metropolitan area schools. Participants were divided into reliability (n=68), intervention (n=74), and control groups (n=59). The reliability group took the survey twice (2 weeks apart); the intervention and control groups also took the survey twice, but at pre- and post-intervention (4 weeks later). Only students from the intervention group participated in four weekly nutrition classes. Reliability was assessed by Pearson's correlation coefficients for knowledge scores. Results demonstrated appropriate content validity, as indicated by expert peer ratings. Test-retest reliability correlations were found to be significant for the overall survey (r=0.54; P<0.001) and for all subscales: food groups, healthful foods, and food functions (r=0.51, 0.65, and 0.49, respectively; P<0.001). Nutrition knowledge was assessed upon program completion with paired samples t tests. Students from the intervention group demonstrated improvement in nutrition knowledge (12.2+/-1.9 to 13.5+/-1.6; P<0.001), while scores for the control group remained unchanged. The difference in total scores from pre- to post-intervention between the two groups was significant (P<0.001). These results suggest that the computerized nutrition survey demonstrated content validity and test-retest reliability for first- through fourth-grade elementary school children. Also, the study results imply that the Fit Kids 'r' Healthy Kids intervention promoted gains in nutrition knowledge. Overall, the computer survey shows promise as an appealing medium for assessing nutrition knowledge in children.

Newborn adiposity measured by plethysmography is not predicted by late gestation two-dimensional ultrasound measures of fetal growth.

Noninvasive measures of fetal and neonatal body composition may provide early identification of children at risk for obesity. Air displacement plethysmography provides a safe, precise measure of adiposity and has recently been validated in infants. Therefore, we explored relationships between term newborn percent body fat (%BF) measured by air displacement plethysmography to 2-dimensional ultrasound (2-D US) biometric measures of fetal growth and maternal and umbilical cord endocrine activity. A total of 47 mother/infant pairs were studied. Fetal biometrics by 2-D US and maternal blood samples were collected during late gestation (35 wk postmenstrual age); infants were measured within 72 h of birth. Fetal biometrics included biparietal diameter, femur length, head circumference, abdominal circumference (AC), and estimated fetal weight (EFW). Serum insulin, insulin-like growth factor (IGF) 1, IGF binding protein-3, and leptin concentrations were measured in umbilical cord and maternal serum. The mean %BF determined by plethysmography was 10.9 +/- 4.8%. EFW and fetal AC had the largest correlations with newborn %BF (R(2) = 0.14 and 0.10, respectively; P < 0.05); however, stepwise linear regression modeling did not identify any fetal biometric parameters as a significant predictor of newborn %BF. Newborn mid-thigh circumference (MTC; cm) and ponderal index (PI; weight, kg/length, cm(3)) explained 21.8 and 14.4% of the variability in %BF, respectively, and gave the best stepwise linear regression model (%BF = 0.446 MTC + 0.347 PI -29.692; P < 0.001). We conclude that fetal growth biometrics determined by 2-D US do not provide a reliable assessment of %BF in term infants.

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.

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.

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 (HbA(1c)), 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 (r(2) = 0.21) and greater IGFBP-1 (r(2) = 0.39), IGFBP-5 (r(2) = 0.38), and bone-specific alkaline phosphatase (BALP; r(2) = 0.41, p < 0.05). Higher urine magnesium excretion predicted an overall shorter, lighter skeleton, and lower tibia cortical bone size, mineral, and density (r(2) = 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 (r(2) >or=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.

Bone mineral density in children and adolescents with neurofibromatosis type 1.

OBJECTIVE: To assess whether children and adolescents with neurofibromatosis type 1 (NF1) have decreased bone mineral density (BMD). STUDY DESIGN: Bone densitometry of the whole body, hip, and lumbar spine was used in a case-to-control design (84 individuals with NF1: 293 healthy individuals without NF1). Subjects were 5 to 18 years old. Subjects with NF1 were compared with control subjects by using an analysis-of-covariance with a fixed set of covariates (age, weight, height, Tanner stage, and sex). RESULTS: Subjects with NF1 had decreased areal BMD (aBMD) of the hip (P <.0001), femoral neck (P <.0001), lumbar spine (P = .0025), and whole body subtotal (P <.0001). When subjects with NF1 were separated in groups with and without a skeletal abnormality, those who did not have a skeletal abnormality still had statistically significant decreases in aBMD compared with control subjects (P <.0001 for whole body subtotal aBMD), although they were less pronounced than in those with osseous abnormalities. CONCLUSIONS: These data suggest that individuals with NF1 have a unique generalized skeletal dysplasia, predisposing them to localized osseous defects. Dual energy x-ray absorptiometry may prove useful in identifying individuals with NF1 who are at risk for clinical osseous complications and monitoring therapeutic trials.