Windswept Deformity a Disease or a Symptom? A Systematic Review on the Aetiologies and Hypotheses of Simultaneous Genu Valgum and Varum in Children.

OBJECTIVE: The objective of this study is to create an overview of the possible aetiologies of windswept deformity and to emphasize the points of attention when presented with a case. METHODS: A systematic search according to the PRISMA statement was conducted using PubMed, African Journals Online, Cochrane, Embase, Google Scholar, and Web of Science. Articles investigating the aetiology of windswept deformity at the knee in children, and articles with windswept deformity as an ancillary finding were included. The bibliographic search was limited to English-language articles only. The level of evidence and methodological appraisal were assessed. RESULTS: Forty-five articles discussing the aetiology of windswept deformity were included. A variety of aetiologies can be brought forward. These can be divided into the following groups: 'Rickets and other metabolic disorders', 'skeletal dysplasias and other genetic disorders', 'trauma' and 'descriptive articles without specific underlying disorder'. With rickets being the largest group. Interestingly, in the group without a specific underlying disorder, all patients were from African descent, being otherwise healthy and presented with windswept deformity between two and three years of age. CONCLUSION: We have presented an overview that may help identify the underlying disorder in children with windswept deformity. A step-by-step guide for clinicians who see a child with windswept deformity is provided. Even though, according to the Oxford level of evidence, most articles have a low level of evidence.

Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency.

CONTEXT: Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice daily, but there is debate about the optimal timing of the highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening). OBJECTIVE: We aimed to compare 2 standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure (BP), and sleep and activity scores. METHODS: This 6-week crossover study included 39 patients (aged 4-19 years) with 21OHD. Patients were treated for 3 weeks with the highest hydrocortisone dose in the morning, followed by 3 weeks with the highest dose in the evening (n = 21), or vice versa (n = 18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5 am; 7 am; 3 pm; and 11 pm during the last 2 days of each treatment period. The main outcome measure was comparison of saliva 17OHP and A4 levels between the 2 treatment strategies. RESULTS: Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5 am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The 2 treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal BP, and activity and sleep scores. CONCLUSION: No clear benefit for either treatment schedule was established. Given the variation in individual responses, we recommend individually optimizing dose distribution and monitoring disease control at multiple time points.

Is a Two-Year Growth Response to Growth Hormone Treatment a Better Predictor of Poor Adult Height Outcome Than a First-Year Growth Response in Prepubertal Children With Growth Hormone Deficiency?

Objective: The first year response to growth hormone (GH) treatment is related to the total height gain in GH treated children, but an individual poor first year response is a weak predictor of a poor total GH effect in GH deficient (GHD) children. We investigated whether an underwhelming growth response after 2 years might be a better predictor of poor adult height (AH) outcome after GH treatment in GHD children. Design and methods: Height data of GHD children treated with GH for at least 4 consecutive years of which at least two prepubertal and who attained (near) (n)AH were retrieved from the Belgian Register for GH treated children (n = 110, 63% boys). In ROC analyses, the change in height (ΔHt) SDS after the first and second GH treatment years were tested as predictors of poor AH outcome defined as: (1) nAH SDS <-2.0, or (2) nAH SDS minus mid-parental height SDS <-1.3, or (3) total ΔHt SDS <1.0. The cut-offs for ΔHt SDS and its sensitivity at a 95% specificity level to detect poor AH outcome were determined. Results: Eleven percent of the cohort had a total ΔHt SDS <1.0. ROC curve testing of first and second years ΔHt SDS as a predictor for total ΔHt SDS <1.0 had an AUC >70%. First-year ΔHt SDS <0.41 correctly identified 42% of the patients with poor AH outcome at a 95% specificity level, resulting in respectively 5/12 (4.6%) correctly identified poor final responders and 5/98 (4.5%) misclassified good final responders (ratio 1.0). ΔHt SDS after 2 prepubertal years had a cut-off level of 0.65 and a sensitivity of 50% at a 95% specificity level, resulting in respectively 6/12 (5.5%) correctly identified poor final responders and 5/98 (4.5%) misclassified good final responders (ratio 1.2). Conclusion: In GHD children the growth response after 2 prepubertal years of GH treatment did not meaningfully improve the prediction of poor AH outcome after GH treatment compared to first-year growth response parameters. Therefore, the decision to re-evaluate the diagnosis or adapt the GH dose in case of poor response after 1 year should not be postponed for another year.

Criteria for First-Year Growth Response to Growth Hormone Treatment in Prepubertal Children With Growth Hormone Deficiency: Do They Predict Poor Adult Height Outcome?

Objective: Several criteria for first-year growth response (FYGR) to growth hormone (GH) treatment have been proposed. We explored which FYGR criteria predicted best the final height outcome after GH treatment in prepubertal children with GH deficiency (GHD). Design and methods: Height data of 129 GHD children (83 boys) who attained adult height and had been treated with GH for at least 4 consecutive years with at least 1 year before pubertal onset, were retrieved from the Belgian GH Registry. The FYGR parameters were: (1) increase in height (ΔHt) SDS, (2) height velocity (HV) SDS, (3) ΔHV (cm/year), (4) index of responsiveness (IoR) in KIGS prediction models, (5) first-year HV SDS based on the KIGS expected HV curve (HV KIGS SDS), (6) near final adult height (nFAH) prediction after first-year GH treatment. Poor final height outcome (PFHO) criteria were: (1) total ΔHt SDS <1.0, (2) nFAH SDS <-2.0, (3) nFAH minus midparental height SDS <-1.3. ROC curve analyses were performed to define the optimal cut-off for FYGR parameters to predict PFHO. Only ROC curves with an area under the curve (AUC) of more than 70% were further analyzed. Results: Twelve, 22 and 10% of the children had respectively a total ΔHt SDS <1, nFAH SDS <-2, and nFAH minus midparental height SDS <-1.3. The AUC's ranged between 73 and 85%. The highest AUC was found for first-year ΔHt SDS to predict total ΔHt SDS <1, and predicted nFAH SDS to predict nFAH SDS <-2. The currently used FYGR criteria had low specificities and sensitivities to detect PFHO. To obtain a 95% specificity, the cut-off value (and sensitivity) of FYGR parameters were: ΔHt SDS <0.35 (40%), HV SDS <-0.85 (43%), ΔHV <1.3 cm/year (36%), IoR <-1.57 (17%), HV KIGS SDS <-0.83 (40%) to predict total ΔHt SDS <1; predicted nFAH SDS (with GH peak) <-1.94 (25%), predicted nFAH SDS (without GH peak) <-2.02 (25%) to predict nFAH SDS <-2. At these cut-offs, the amount of correctly diagnosed poor final responders equals the amount of false positives. Conclusion: First-year growth response criteria perform poorly as predictors of poor final height outcome after long-term GH treatment in prepubertal GHD children.

Evaluation of the Dutch neonatal screening for congenital adrenal hyperplasia.

BACKGROUND: In 2002, a nationwide screening for congenital adrenal hyperplasia (CAH) was introduced in the Netherlands. The aim of our study is to evaluate the validity of the neonatal screening for CAH and to assess how many newborns with salt-wasting (SW) CAH have already been clinically diagnosed before the screening result was known. METHODS: Retrospective, descriptive study. The following data of patients with positive screening results since implementation of the screening programme were collected (1 January 2002 up until 31 December 2013): gestational age, sex, diagnosis, clinical presentation and contribution of screening to the diagnosis. RESULTS: In the evaluated period, 2 235 931 newborns were screened. 479 children had an abnormal screening result, 133 children were diagnosed with CAH (114 SW, 14 simple virilizing (SV)), five non-classic CAH. During this period, no patients with SW CAH were missed by neonatal screening (sensitivity was 100%). After exclusion of 17 cases with missing information on diagnosis, specificity was 99.98% and positive predictive value was 24.7%. Most false positives (30%) were attributable to prematurity. Of patients with SW CAH, 68% (71/104) patients were detected by neonatal screening and 33 (33/104) were clinically diagnosed. Of girls with SW CAH, 38% (14/37) were detected by neonatal screening and 62% (23/37) were clinically diagnosed. CONCLUSION: The Dutch neonatal screening has an excellent sensitivity and high specificity. Both boys and girls can benefit from neonatal screening.

Effect of growth hormone treatment on energy expenditure and its relation to first-year growth response in children.

PURPOSE: The effects of growth hormone (GH) treatment on linear growth and body composition have been studied extensively. Little is known about the GH effect on energy expenditure (EE). The aim of this study was to investigate the effects of GH treatment on EE in children, and to study whether the changes in EE can predict the height gain after 1 year. METHODS: Total EE (TEE), basal metabolic rate (BMR), and physical activity level (PAL) measurements before and after 6 weeks of GH treatment were performed in 18 prepubertal children (5 girls, 13 boys) born small for gestational age (n = 14) or with growth hormone deficiency (n = 4) who were eligible for GH treatment. TEE was measured with the doubly labelled water method, BMR was measured with an open-circuit ventilated hood system, PAL was assessed using an accelerometer for movement registration and calculated (PAL = TEE/BMR), activity related EE (AEE) was calculated [AEE = (0.9 × TEE) - BMR]. Height measurements at start and after 1 year of GH treatment were analysed. This is a 1-year longitudinal intervention study, without a control group for comparison. RESULTS: BMR and TEE increased significantly (resp. 5% and 7%). Physical activity (counts/day), PAL, and AEE did not change. 11 out of 13 patients (85%) with an increased TEE after 6 weeks of GH treatment had a good first-year growth response (∆height SDS > 0.5). CONCLUSIONS: GH treatment showed a positive effect on EE in prepubertal children after 6 weeks. No effect on physical activity was observed. The increase in TEE appeared to be valuable for the prediction of good first-year growth responders to GH treatment.

Poor growth response during the first year of growth hormone treatment in short prepubertal children with growth hormone deficiency and born small for gestational age: a comparison of different criteria.

BACKGROUND: There is no consensus on the definition of poor growth response after the first year of growth hormone (GH) treatment. We determined the proportion of poor responders identified by different criteria in children with GH deficiency (GHD) and born small for gestational age (SGA). The second aim was to analyze the IGF-1 response in poor growth responders. METHODS: First-year height data of 171 SGA and 122 GHD children who remained prepubertal during the first GH treatment year were retrieved from the BESPEED database and analyzed. Criteria for poor first-year response/responsiveness were: change in height (∆Ht) SDS<0.3 or<0.5, height velocity (HV) SDS<0.5 or <1 based on the population reference, HV SDS<- 1 based on the KIGS expected HV curve (HV Ranke SDS), studentized residual (SR) <- 1 in the KIGS first-year prediction model. RESULTS: ∆Ht SDS<0.5 gave the highest percentage poor responders (37% SGA, 26% GHD). Although % poor responders were comparable for ∆Ht SDS<0.3, HV SDS<+ 0.5, HV SDS<+ 1, SR<- 1, and HV Ranke SDS<- 1, these criteria did not always identify the same patients as poor responders. Among the poor growth responders 24% SGA and 14% GHD patients had an IGF-1 increase < 40%. CONCLUSIONS: The different response criteria yield high but comparable percentages poor responders, but identify different patients. This study does not provide evidence that one criterion is better than another. A limited IGF-1 generation is not the major reason for a poor growth response in the first year of GH treatment in SGA and GHD children. TRIAL REGISTRATION: Retrospectively registered.

Validation of Prediction Models for Near Adult Height in Children with Idiopathic Growth Hormone Deficiency Treated with Growth Hormone: A Belgian Registry Study.

BACKGROUND/AIM: To validate prediction models for near final adult height (nFAH) by Ranke et al. [Horm Res Paediatr 2013;79:51-67]. METHODS: Height data of 127 (82 male) idiopathic growth hormone (GH)-deficient children, treated with GH until nFAH, were retrieved from the database of the Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED). nFAH was predicted after first-year GH treatment, applying prediction models by Ranke et al. Bland-Altman plots and Clarke error grid analyses were performed to assess clinical significance of the differences between observed and predicted nFAH. RESULTS: In males, the predicted nFAH was higher than the observed nFAH (difference: 0.2 ± 0.7 SD; p < 0.01). In females, there was no significant difference. Bland-Altman analyses showed that the means of the differences between observed and predicted nFAH were close but not equal to zero, with overprediction for smaller heights and underprediction for taller heights. Clarke error grid analysis: in males, 59-61% of the predicted nFAH were within 0.5 SDS and 88% within 1.0 SDS from the observed nFAH; in females, 40-44% of the predicted nFAH were within 0.5 SDS and 76-78% within 1.0 SDS from the observed nFAH. CONCLUSION: Ranke's models accurately predicted nFAH in females and overpredicted nFAH in males by about 1.5 cm. In most individuals, the predicted nFAH was within 1 SDS of observed nFAH. These models can be of help in giving realistic expectations of adult height. © 2016 S. Karger AG, Basel.

Pituitary response to thyrotropin releasing hormone in children with overweight and obesity.

Thyroid stimulating hormone (TSH) concentrations in the high normal range are common in children with overweight and obesity, and associated with increased cardiovascular disease risk. Prior studies aiming at unravelling the mechanisms underlying these high TSH concentrations mainly focused on factors promoting thyrotropin releasing hormone (TRH) production as a cause for high TSH concentrations. However, it is unknown whether TSH release of the pituitary in response to TRH is affected in children with overweight and obesity. Here we describe TSH release of the pituitary in response to exogenous TRH in 73 euthyroid children (39% males) with overweight or (morbid) obesity. Baseline TSH concentrations (0.9-5.5 mU/L) were not associated with BMI z score, whereas these concentrations were positively associated with TSH concentrations 20 minutes after TRH administration (r(2) = 0.484, p < 0.001) and the TSH incremental area under the curve during the TRH stimulation test (r(2) = 0.307, p < 0.001). These results suggest that pituitary TSH release in response to TRH stimulation might be an important factor contributing to high normal serum TSH concentrations, which is a regular finding in children with overweight and obesity. The clinical significance and the intermediate factors contributing to pituitary TSH release need to be elucidated in future studies.

Reference curve for the first-year growth response to growth hormone treatment in prepubertal children with idiopathic growth hormone deficiency: validation of the KIGS first-year growth response curve using the Belgian Register for the Study of Growth and Puberty Problems.

BACKGROUND: Comparing observed and expected growth after first-year growth hormone (GH) therapy is useful for identifying a poor growth response to GH. AIM: To generate a first-year, age-specific growth response reference curve for prepubertal Belgian children with idiopathic growth hormone deficiency (iGHD) treated with a standard weight-adjusted GH dose and to compare this national reference with the response references derived from KIGS. SUBJECTS AND METHODS: First-year height data of 357 prepubertal children (240 males) with iGHD were analyzed. Smooth reference curves of first-year height velocity (HV) in relation to age were created. Differences with the KIGS targets were evaluated after z-score transformation. RESULTS: The observed first-year HVs were log-normal distributed by age and decreased significantly with age (p<0.001). No GH dose or gender effect was observed (p=0.5). Distance to target height, severity of GHD and occurrence of multiple pituitary hormone deficiencies had a positive effect (p<0.01) on the calculated HV SDS. When applying the KIGS targets for severe iGHD, mean HV SDS was close to zero (-0.09±0.84). CONCLUSION: The developed age-specific growth response curves enable rapid identification of poor response to first-year GH treatment in prepubertal iGHD children. Our results validate the published growth targets derived from the KIGS database.