The 2014 Danish references from birth to 20 years for height, weight and body mass index.

AIM: To construct new Danish growth charts for 0- to 20-year-olds and to compare them with Danish references from 1982 and with World Health Organization (WHO) standards for children aged 0-5 years from 2006, by applying similar inclusion and exclusion criteria. METHODS: Anthropometric data from three contemporary Danish population-based studies were combined. References for height were based on healthy Caucasian children born at term. A total of 12,671 height measurements (8055 in boys and 4616 in girls) were included. Reference charts were developed using the generalised additive models for location, scale and shape. RESULTS: From prepubertal ages, a secular increase in height was observed for both genders. The differences were most pronounced in puberty, and final heights were increased by 1.4 cm in boys and 2.9 cm in girls compared to 1982 references. In boys, but not girls an upward shift in body mass index (BMI) above median levels was found. Reference curves for height were superimposable with standard curves based on the selective WHO criteria. Danish children were longer/taller and heavier and they had larger head circumferences than those reported in the recent multiethnic WHO standards. CONCLUSION: We recommend national implementation of these contemporary 2014 Danish references for anthropometric measurements.

Ten-year review of Danish children with chronic non-bacterial osteitis.

OBJECTIVES: To compare clinical characteristics of children with chronic non-infectious osteomyelitis (CNO) with either mono- or multifocal bone lesions, and to report potential advantages of using whole-body MRI. METHODS: A retrospective evaluation of 31 children (19 girls, 12 boys) diagnosed with CNO between 2001 and 2011. CNO was diagnosed as mono-, or multifocal inflammatory bone lesions (osteomyelitis, osteitis, osteosclerosis), duration of complaints more than 6 weeks and exclusion of infection and malignancy. Clinical and radiological data were registered. The definition of mono- or multifocality was based on the description of imaging results. RESULTS: Mean age at disease onset was 10.3 ± 2.6 years. Mean duration of active disease was 44.4 ± 25.6 months. Twenty-two (71.0%) had two or more bone lesions and 9 (29.0%) had one lesion. Of those with multifocal lesions six were initially detected as monofocal. The most frequent location of the bone lesions was in the metaphysis of the lower extremities. MRI/CT discovered most lesions compared to x-ray and scintigraphy. MRI was performed in 93.5% of which 25.8 % had a whole-body-MRI. Whole-body MRI revealed disclosure of several silent lesions. Extra-osseous involvement occurred in 64.5%. In the multifocal group 22.7 % had psoriasis and 13.6 % had pustulosis palmoplantaris but neither was seen in the monofocal group. All were treated with NSAIDs; 54.8% corticosteroids, 29.1 % methotrexate, 9.7 % pamidronate and 3.2 % infliximab. CONCLUSIONS: Monofocal CNO had comparable clinical and radiological characteristics to multifocal disease. We conclude that whole-body MRI is a relevant screening instrument for the diagnosis of CNO.

A Comparison of Radiographic Joint Space Width Measurements Versus Ultrasonographic Assessment of Cartilage Thickness in Children with Juvenile Idiopathic Arthritis.

OBJECTIVE: Joint space narrowing (JSN) is a measurable outcome of tissue degeneration in arthritis. JSN is usually assessed by conventional radiography. Ultrasonographic (US) measurement of joint cartilage thickness has been validated in healthy children, and US measurement of the distal femoral cartilage has been validated in a group of patients with juvenile idiopathic arthritis (JIA). Our aim was to compare the measures of cartilage thickness of the proximal cartilage site in the second metacarpophalangeal (MCP), second proximal interphalangeal (PIP), and knee joints as assessed by US to joint space width (JSW) as measured by computerized radiography in children with JIA. METHODS: The study included 74 children with JIA aged 5-15 years (median 11.3 yrs). MCP and PIP joints were assessed at one midline spot. Knee joints were assessed at the medial and lateral femoral condylar areas. Only the proximal cartilage site in the joints was assessed by US, whereas the complete JSW was assessed by radiography. RESULTS: We assessed 136 second MCP, 138 second PIP, and 146 knee joints. We found a high level of agreement between US and radiographic measures of cartilage thickness and JSW: r = 0.82-0.86 (second MCP), r = 0.50-0.55 (second PIP), and r = 0.52-0.81 (knee); p < 0.001 for all 8 assessed sites. CONCLUSION: US measurements of cartilage thickness of the proximal site of the second MCP, second PIP, and knee joints correlated well with radiographic JSW measurements in the finger and knee joints of children with JIA. However, US does not measure the distal cartilage, which may limit its use in the assessment of JSN.

Prednisolone Effects on Urine Cross-Linked N-Telopeptides of Type I Collagen (Ntx) Diurnal Rhythms in Children.

BACKGROUND: Recently, methods for mimicking endogenous cortisol rhythms hereby potentially reducing the risk of systemic adverse effects of exogenous corticosteroids have been patented. Methods for sensitive detection of adverse effects on bone turnover of various doses, administration routes and regimens of exogenous corticosteroids have been patented. Urine cross-linked Ntelopeptides of Type I collagen (Ntx) have been established as a sensitive bone resorption marker and urine levels of Ntx have been found to exhibit a distinct diurnal rhythm. OBJECTIVE: To assess whether the timing of administration of prednisolone affects the diurnal rhythm of Ntx in urine. METHODS: Four girls and four boys aged 10.6 to 15.8 (mean 13.2) years with normal weight and height and pubertal stages I-IV were studied in an open randomized 2-periods cross-over trial, with a 1-day run in, and two 4-day periods of 5mg prednisolone in the morning and in the evening, respectively, separated by a 3-week washout period. At run in and on the last day of each treatment period, the first sample of urine was collected from 24.00 to 08.00h in the morning of the day of investigation. Thereafter, urine was collected in 4~hour intervals until 24.00 and in another 08.00h interval from 24.00 to 08.00h. RESULTS: Compared to run in and morning prednisolone treatment urine Ntx levels were suppressed from 24.00 to 8.00h during treatment with prednisolone in the evening (P < 0.01 for both comparisons) and no statistically significant circadian rhythm was observed. During morning prednisolone treatment Ntx trough and peak levels occurred from 16.00 to 20.00 and 24.00 to 08.00h, respectively, and the Ntx levels were significantly reduced from 12.00 to 20.00h as compared to run in (P < 0.005) and prednisolone treatment in the evening (P < 0.01). CONCLUSIONS: Depending on the time of administration, prednisolone interferes with diurnal rhythms in urine Ntx.

Gender differences of oligomers and total adiponectin during puberty: a cross-sectional study of 859 Danish school children.

CONTEXT: Pubertal stages have been shown to influence total adiponectin (ADPN) levels. Furthermore, testosterone has been shown to alter the isomer distribution of ADPN. OBJECTIVE: The goal of this study was to investigate whether pubertal stages and testosterone levels influenced total serum ADPN levels and the distribution of ADPN isomers. DESIGN: This is a cross-sectional study. PATIENTS: The study included 859 children and adolescents (396 males) aged 6-20 yr. MAIN OUTCOME MEASURES: Total ADPN and ADPN isomers were measured using a validated in-house immunofluorometric assay. Fractioning of the ADPN into the three major molecular fractions was performed in representative subgroups of pre- and postpubertal males and females (n = 40, 10 in each group) using a validated fast protein liquid chromatography method. RESULTS: Total ADPN levels before puberty were 13.4 (11.1-15.9) mg/liter (median and interquartile range) and 14.7 (12.3-18.1) mg/liter (P = not significant), in males and females, respectively. After puberty, ADPN levels were significantly reduced in males, 9.7 (8.2-12.0) mg/liter but remained unchanged in females, 12.1 (9.7-15.3) mg/liter (P < 0.0001). Concomitantly, a reduction was seen in the ratio of high-molecular-weight (HMW) isomers to total ADPN (HMW ratio) when comparing prepubertal and postpubertal males. Also, postpubertal males had lower HMW ratios than corresponding females (P = 0.038). Finally, a negative correlation was seen between HMW ratio and testosterone (r = -0.430, P = 0.007). CONCLUSION: Serum total ADPN levels decrease through puberty in males. Also, a reduced HMW ratio is seen in males at the onset of puberty. We speculate that the suppression of HMW ADPN may be caused by testosterone.

The timing of administration of exogenous glucocorticoid affects 24hour growth hormone secretion in children.

Exogenous glucocorticoids may suppress linear growth by affecting the diurnal secretory rhythm of GH. OBJECTIVE: To assess whether the timing of exogenous glucocorticoid administration affects GH secretion in children. DESIGN: Four girls and four boys aged 10.6 to 15.8 (mean 13.2) years with normal weight and height and pubertal stages I-IV were studied in an open randomized 2-period cross-over trial, with a 1-day un-in, and two 4-day periods of 5mg prednisolone in the morning or in the evening, respectively, separated by a 3-week washout period. At run-in and on the last day of each treatment period serum was collected every 20min for 24h for assessment of GH. Secondary analyses were serum levels of IGF-I and IGFBP-3 (measured every 8h), and IGFBP-1, insulin, and collagen markers PICP, PINP, ICTP and PIIINP (measured every 2h). RESULTS: Evening prednisolone suppressed 24hour GH secretion (P=0.016), overnight GH secretion (P=0.023) and IGF-I (P=0.024) when compared to morning prednisolone, but not when compared to run-in. Evening prednisolone also increased nocturnal insulin levels as compared to run-in (P=0.010). Irrespective of time of day, prednisolone increased serum collagen markers PICP, PIINP, ICTP and PINP (all P<0.05). CONCLUSIONS: Short-term prednisolone 5mg administered in the morning may alleviate nocturnal GH suppression as compared to evening administration. In analogy, growth rates are less affected by morning as compared to evening administration of exogenous glucocorticoids. In contrast, collagen markers and metabolic indices were not affected by the timing of prednisolone administration.

Joint cartilage thickness and automated determination of bone age and bone health in juvenile idiopathic arthritis.

BACKGROUND: BoneXpert is an automated method to calculate bone maturation and bone health index (BHI) in children with juvenile idiopathic arthritis (JIA). Cartilage thickness can also be seen as an indicator for bone health and arthritis damage. The objective of this study was to evaluate the relation between cartilage thickness, bone maturation and bone health in patients with JIA. METHODS: Patients with JIA diagnosed according ILAR criteria included in a previous ultrasonography (US) study were eligible if hand radiographs were taken at the same time as the US examination. Of the 95 patients 67 met the inclusion criteria. RESULTS: Decreased cartilage thickness was seen in 27% of the examined joints. Decreased BHI was seen in half of the JIA patient, and delayed bone maturation was seen in 33% of patients. A combination of decreased BHI and bone age was seen in 1 out of 5 JIA patients. Decreased cartilage thickness in the knee, wrist and MCP joint was negatively correlated with delayed bone maturation but not with bone health index. CONCLUSION: Delayed bone maturation and decreased BHI were not related to a thinner cartilage, but a thicker cartilage. No relation with JADAS 10 was found. The rheumatologist should remain aware of delayed bone maturation and BHI in JIA patients with cartilage changes, even in the biologic era.

Pubertal Progression and Reproductive Hormones in Healthy Girls With Transient Thelarche.

Context: Detailed evaluation of pubertal progression in girls from longitudinal studies is sparse, and the phenomenon of transient thelarche (TT), defined as the appearance, regression, and subsequent reappearance of breast buds, in healthy girls remains undescribed. Objective: To describe TT in terms of pubertal progression, growth, genotypes, and reproductive hormones and to apply new puberty nomograms for breast stages, pubic hair, and menarche. Design: A prospective, longitudinal population-based study. Patients or Other Participants: Ninety-eight healthy Danish schoolchildren (Caucasian girls) followed longitudinally as part of the COPENHAGEN Puberty Study were included in the evaluation of TT. A total of 1466 girls from 2 cross-sectional studies were included in the creation of the puberty nomograms. Intervention(s): None. Main Outcome Measure(s): Pubertal progression, specifically thelarche, reproductive hormones, genotype, and growth. Results: Twelve of 98 (12%) girls experienced TT. A larger proportion of girls with TT entered puberty by the pubarche pathway (50%) compared with girls with normal progression (15.4%), P = 0.014. Girls with TT progressed through puberty normally when evaluated using puberty nomograms. Reproductive hormones and growth velocity were lower at the first (transient) thelarche than the second (permanent) thelarche. Conclusion: TT is a frequent phenomenon that appears to be a peripheral occurrence independent of central puberty. It does not appear to affect subsequent pubertal progression as evaluated by our new puberty nomograms.

Cartilage thickness of the knee joint in juvenile idiopathic arthritis: comparative assessment by ultrasonography and magnetic resonance imaging.

OBJECTIVE: The functional disability experienced in juvenile idiopathic arthritis (JIA) is primarily caused by joint effusion, synovial membrane hypertrophy, and periarticular soft tissue edema, leading to the degeneration of the osteocartilaginous structures because of the inflammatory process in the synovium. The ability to visualize the inflammatory changes and hence the ensuing osteocartilaginous degeneration is, therefore, of great importance in pediatric rheumatology. Ultrasonography (US) has been validated as a tool for measuring cartilage thickness in healthy children and, previously, we have found good agreement with the measures obtained by magnetic resonance imaging (MRI). Our aim is to validate and compare US with MRI measurements of distal femoral cartilage thickness in the knee joint at the medial condyle, lateral condyle, and intercondylar spots in children with JIA, and to locate the best spot for imaging comparisons. METHODS: One knee from each of 23 children with oligoarticular JIA were investigated by both MRI and US. Outcome measures of imaging procedures were distal femoral cartilage thickness. RESULTS: We found a high level of agreement between MRI and US measurements of mean cartilage thickness, and Rho values between modalities were high (between 0.70 and 0.86, p < 0.05 for all). We found a thinner cartilage thickness at the medial condyle in comparison to the other investigated points. Evaluation of anatomical landmarks for optimal measurement of cartilage thickness was found to be the intercondylar spot, which was easier to locate in addition to a smaller variance around the mean for that anatomical measuring point. CONCLUSION: US measurements of distal femoral cartilage thickness are highly correlated to MRI measurements. The intercondylar notch of the distal femoral cartilage may be the best anatomical point for cartilage thickness measurements of the knee. US is a reliant and nonexpensive, non-invasive modality for visualization of childhood femoral cartilage.

Does vitamin D administered to children with asthma treated with inhaled glucocorticoids affect short-term growth or bone turnover?

Our objective was to assess whether administration of 25-OH-vitamin D to children with asthma treated with inhaled dry-powder budesonide 400 microg daily affects short-term growth or markers of bone turnover. We utilized a randomized, double-blind, two-period crossover trial with run-in and washout periods of 2 weeks and treatment periods of 4 weeks duration. The setting was an Outpatient clinic in a secondary referral center. Subjects included 14 boys and 3 girls with a mean age of 11.7 (range, 6.1-14.4) years. Interventions included 15 microg (600 IU) 25-OH-vitamin D (cholecalciferol) in one tablet ABCDin(R) once daily in the morning. Primary outcome measures were: lower leg growth rate, serum osteocalcin, and serum markers of type I collagen turnover, i.e., the amino terminal propeptide of type I procollagen (PINP), the carboxy terminal propeptide of type I procollagen (PICP) (formation markers), and the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) (degradation markers). Secondary outcome measures were parameters of asthma control and serum 25-OH-vitamin D. Lower leg growth rate was 0.22 mm/week during vitamin D and 0.25 mm/week during placebo treatment (NS). Osteocalcin was 59.9 and 57.8 microg/l during vitamin D and placebo treatment, respectively, PINP 574 and 565 microg/l, PICP 381 and 382 microg/l, and ICTP 11.5 and 11.1 microg/l, respectively (NS). Serum 25-OH-vitamin D was 76.3 nmol/l and 48.2 nmol/l, respectively (P < 0.001). There were no statistically significant differences in measures of pulmonary function. In conclusion, administration of 25-OH-vitamin D does not affect short-term growth or markers of bone turnover in children with asthma treated with inhaled dry-powder budesonide 400 microg daily.

Differential effects of short-term prednisolone treatment on peripheral and abdominal subcutaneous thickness in children assessed by ultrasound.

Long-term glucocorticoid excess decreases peripheral and increases abdominal subcutaneous thickness. Short-term prednisolone treatment is used in the treatment of many acute and chronic conditions in children. The aim of the present study was to elucidate if changes in thickness of cutis, subcutis, or dermal water content may be induced by short-term prednisolone treatment in children. Twenty children with asthma aged 7.7-13.8 years were included in a double-blind, randomized, placebo-controlled crossover trial. Active treatment was 5mg prednisolone daily. Treatment, run-in, and wash-out periods were 1 week. On days 1 and 7 of each treatment period, 20 MHz ultrasound scanning of the skin was performed on the thigh, forearm, and abdomen. Prednisolone treatment was associated with decreases in the total thickness of the cutis and subcutis in the thigh (0.28 mm) and forearm (0.15 mm), and an increase in the abdomen (0.23 mm). During placebo treatment the thickness was increased in the thigh (0.07 mm) and abdomen (0.05 mm), and reduced in the forearm (0.03 mm). The differences between prednisolone and placebo treatment were statistically significant in the thigh (P=0.04). The increase in thickness in the abdomen during prednisolone treatment was statistically significantly different from the reductions in the thigh (P=0.03) and forearm (P=0.05). There were no statistically significant differences in the dermal thickness or water content during prednisolone treatment compared to placebo.Short-term treatment with 5mg prednisolone daily may cause differential effects in peripheral and abdominal subcutaneous thickness in children.

Diurnal leptin rhythms in children treated with prednisolone once daily in the morning or in the evening.

Serum leptin levels exhibit a marked diurnal variation in children. The aim of the present study was to investigate whether the timing of administration of exogenous glucocorticoids, which have been found to increase serum leptin, affects the diurnal rhythm. Four girls and four boys aged 10.6 to 15.8 (mean 13.2) years with asthma were studied. The design was an open 2-period cross-over trial with a 1-day run in, two 4-day periods of prednisolone 5 mg in the morning or in the evening, with a 3-week washout in between treatment periods. During run in and on the last day of the prednisolone periods a fasting blood sample was drawn at 08.00 h, and thereafter samples were obtained every 2 h throughout the day until 08.00 h the next morning. Serum leptin was measured by a specific radioimmunoassay. During all periods, leptin levels were low during the day with a nadir at 10.00 h (run-in [mean +/- SEM]: 3.9+/-1.28; morning prednisolone: 5.2+/-1.58; evening prednisolone: 5.7+/-2.02 microg/l). Increases in leptin levels were detected from 20.00 h with zeniths at 24.00 h (run in: 7.2+/-1.86; evening prednisolone: 9.2+/-2.36 microg/l) and 02.00 h (morning prednisolone: 9.4+/-1.78 microg/l) (F = 115.5; p <0.01). As compared to run in, leptin levels were increased at all time points during prednisolone treatment in the morning (F = 16.0, p = 0.01) and in the evening (F = 12.6, p = 0.01). No statistically significant differences were found in leptin levels during prednisolone in the morning or in the evening (F = 0.44, p = 0.53). Therefore, the timing of administration of exogenous glucocorticoids does not affect diurnal leptin rhythms in children.

Decreased cartilage thickness in juvenile idiopathic arthritis assessed by ultrasonography.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) may result in disability, which is caused primarily by degeneration of the osteocartilaginous structures, due to the synovial inflammatory process. It is essential to closely monitor structural damage during the disease course. We aimed to compare ultrasound (US) measurements of joint cartilage thickness in 5 joints in children with JIA to our findings in an age- and sex-related healthy cohort regarding disease duration, joint activity, JIA subtype, age, and sex. METHODS: We clinically examined joint activity in 95 patients with JIA and collected parent and physician global assessments. Joint cartilage thickness was assessed by greyscale US in knee, ankle, wrist, metacarpophalangeal, and proximal interphalangeal (PIP) joints. Measurements were compared to reference values of a healthy cohort from a previous study. Medical records were reviewed for JIA subtype, treatment, and disease duration. RESULTS: Joint cartilage thickness was decreased in the knee, wrist, and second PIP joint in children with JIA compared with the healthy cohort (p < 0.001 for all). Patients with oligoarticular JIA had thicker cartilage than patients with polyarticular and systemic JIA. We also found decreased joint cartilage thickness in joints not previously affected by arthritis in children with JIA compared to the same joint in the healthy cohort. We found decreasing cartilage thickness with age and thicker cartilage in boys than in girls. CONCLUSION: Children with JIA have reduced cartilage thickness compared with children who do not have JIA, and children with polyarticular and systemic JIA have thinner cartilage than children with oligoarticular JIA.

Prednisolone reduces the ability of serum to activate the IGF1 receptor in vitro without affecting circulating total or free IGF1.

OBJECTIVE: End-point bioassays based on thymidine or sulfate incorporation have demonstrated that glucocorticoid (GC) treatment inhibits serum IGF1 action, but the mechanism is unknown as serum IGF1 concentrations have been reported to either increase or remain unchanged. AIM: To investigate whether GC treatment affects the ability of serum to activate the IGF1 receptor (IGF1R) in vitro (i.e. bioactive IGF1), using a specific cell-based IGF1 kinase receptor activation assay. SUBJECTS AND METHODS: Twenty children with stable asthma (age 7.7-13.8 years) treated for 1 week with 5 mg prednisolone in a randomized, double-blind, placebo-controlled crossover study. Non-fasting serum samples were collected in the afternoon after each 7-day period and assayed for bioactive IGF1, free IGF1, total IGFs, IGF-binding proteins (IGFBPs), and insulin. RESULTS: Prednisolone treatment reduced IGF1 bioactivity by 12.6% from 2.22±0.18 to 1.94±0.15 µg/l (P=0.01) compared with placebo. In contrast, no changes were observed for (µg/l; placebo vs prednisolone) total IGF1 (215±27 vs 212±24), free IGF1 (1.50±0.16 vs 1.43±0.17), total IGF2 (815±26 vs 800±31), IGFBP3 (3140±101 vs 3107±95), IGFBP2 (238±21 vs 220±19), IGFBP1 (32±6 vs 42±10), or IGFBP1-bound IGF1 (24±5 vs 26±7). Insulin remained unchanged as did IGFBP levels as estimated by western ligand blotting. Prednisolone had no direct effects on IGF1R phosphorylation. CONCLUSIONS: Our study gives evidence that GC treatment induces a circulating substance that is able to inhibit IGF1R activation in vitro without affecting circulating free or total IGF1. This may be one of the mechanisms by which GC inhibits IGF1 action in vivo. However, the nature of this circulating substance remains to be identified.

[Carney complex: a syndrome with cardial, cutaneous and neuronal tumours]. / Carney complex: et syndrom med kardielle, kutane og neuronale tumorer.

A 12 year-old boy presented with neurological symptoms and was found to have a left atrial myxoma. Characteristic facial skin pigmentation raised a suspicion of Carney complex, a rare autosomal dominant disease, which includes cutaneous changes, atrial myxomas and neuroendocrine tumours. The boy's mother had similar skin pigmentation and on subsequent cardiac echocardiography she was found to have left and right atrial myxomas. Both mother and child underwent successful surgical resection of the myxomas.

Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency.

BACKGROUND: In a recently described patient with acid-labile subunit (ALS) deficiency, the inability to form ternary complexes resulted in a marked reduction in circulating total insulin-like growth factor (IGF)-I, whereas skeletal growth was only marginally affected. To further study the role of circulating versus locally produced IGF-I in skeletal growth in this patient, we now describe in detail growth changes and their relationship with several components of the circulating IGF system. DESIGN AND METHODS: We followed growth and development up to the final height in a patient with complete ALS deficiency and determined both spontaneous and growth hormone (GH)-stimulated changes in the IGF system, including measurements of total, free and bioactive IGF-I, total IGF-II and insulin-like growth factor binding protein (IGFBP)-1, IGFBP-2 and IGFBP-3. RESULTS: The patient had a delayed growth and pubertal onset. Six months of GH treatment had no effect on growth. At the age of 19.3 years, he spontaneously completed puberty and had a normal growth spurt for a late adolescent (peak height velocity of 8.4 cm/year). A normal final height was attained at 21.3 years (167.5 cm; -0.78 SDS). During as well as after puberty, basal levels of total, free and bioactive IGF-I were low, as were total IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3. GH treatment for 6 months normalized free IGF-I and increased bioactive IGF-I, but had no effect on growth velocity. CONCLUSIONS: This case story shows that in the presence of complete ALS deficiency, a height within normal limits can be obtained despite low levels of all forms of circulating IGF-I. Furthermore, the patient presented a delayed but normal growth spurt without any marked increment of circulating IGF-I.