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Background & aims: Cancer treatment is known to have impact on nutritional status, and both underweight and overweight have been reported in several studies in survivors. A limitation of most studies is that they relied on retrospective data or were limited to a subgroup of patients. The current study aims to describe changes in body size and body composition prospectively seven years after diagnosis in a heterogeneous sample of childhood cancer survivors and to evaluate associated factors.Methods: The study population consisted of children diagnosed with hematological, solid and brain malignancies aged 0–18 years at diagnosis. Data of body size, body composition, and associated factors were collected at diagnosis, one year and seven years after diagnosis.Results: In the total cohort mean BMI z-score increased during treatment. In children with hematological and brain malignancies BMI z-score continued to increase after end of treatment leading to quadrupling of the prevalence of obesity seven years after diagnosis. BMI at diagnosis (β = −0.34, P = 0.007) and maternal BMI (β = 0.25, P = 0.046) were associated with the increase in BMI z-score. Mean fat mass (FM) z-score, already high at diagnosis, increased during treatment in children with hematological and brain malignancies and evened out during follow-up. Changes in FM z-score were predicted by type of malignancy (hematologic malignancy versus solid tumor β = 0.48, P = 0.008; brain tumor versus solid tumor β = 0.45, P = 0.012). Mean fat free mass (FFM) z-scores started low at diagnosis, particularly in patients with brain tumors, increased during treatment in patients with solid and brain malignancies, though decreased in children with hematological malignancies. At 7 years follow-up a clear increase to normal was seen. Age at diagnosis (β = 0.43, P = 0.004) and initial FFM (β = −0.49, P = 0.001) were found to be significant predictors for changes in FFM z-scores.Conclusions: The finding that the once obtained extra weight and FM during treatment persisted after termination of treatment in children with hematological and brain malignancies, stresses the importance to create awareness about the risk of developing overweight in children during cancer treatment.

Early recognition of osteoporosis in children and adolescents is important in order to establish an appropriate diagnosis of the underlying condition and to initiate treatment if necessary. In this review, we present the diagnostic work-up, and its pitfalls, of pediatric patients suspected of osteoporosis including a careful collection of the medical and personal history, a complete physical examination, biochemical data, molecular genetics, and imaging techniques. The most recent and relevant literature has been reviewed to offer a broad overview on the topic. Genetic and acquired pediatric bone disorders are relatively common and cause substantial morbidity. In recent years, there has been significant progress in the understanding of the genetic and molecular mechanistic basis of bone fragility and in the identification of acquired causes of osteoporosis in children. Specifically, drugs that can negatively impact bone health (e.g. steroids) and immobilization related to acute and chronic diseases (e.g. Duchenne muscular dystrophy) represent major risk factors for the development of secondary osteoporosis and therefore an indication to screen for bone mineral density and vertebral fractures. Long-term studies in children chronically treated with steroids have resulted in the development of systematic approaches to diagnose and manage pediatric osteoporosis.Conclusions: Osteoporosis in children requires consultation with and/or referral to a pediatric bone specialist. This is particularly relevant since children possess the unique ability for spontaneous and medication-assisted recovery, including reshaping of vertebral fractures. As such, pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children. What is Known:• Both genetic and acquired pediatric disorders can compromise bone health and predispose to fractures early in life.• The identification of children at risk of osteoporosis is essential to make a timely diagnosis and start the treatment, if necessary. What is New:• Pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children and children at risk of osteoporosis.• We offer an extensive but concise overview about the risk factors for osteoporosis and the diagnostic work-up (and its pitfalls) of pediatric patients suspected of osteoporosis.

Osteoporosis is a condition of increased bone fragility associated with fractures. Apart from primary genetic osteoporotic conditions, secondary osteoporosis in children is being increasingly recognized. As a result, there is growing interest in its prevention and treatment. Important goals of care are to prevent fractures, increase bone mass and trabecular and cortical thickness, reshape vertebral fractures, prevent (or correct) skeletal deformities, and improve mobility, independence, and quality of life. Secondary pediatric osteoporosis is often of multifactorial origin since affected children frequently have more than one acquired factor that is detrimental to bone health. Typical conditions causing osteoporosis are leukemias, progressive muscle or neurological disorders, as well as chronic inflammatory conditions and their treatment. Management of children with osteoporosis involves a multidisciplinary team involving pediatric experts from different subspecialties. With regard to prevention and early intervention, it is important to provide optimal management of any underlying systemic conditions including avoidance, or dose-reduction, of osteotoxic medications. Basic supporting life-style measures, such as appropriate nutrition, including adequate calcium intake and vitamin D, and physical activity are recommended, where possible. When pediatric treatment criteria for osteoporosis are met, antiresorptive drugs constitute the first pharmacological line treatment. Conclusion: This clinical review focuses on the prevention, treatment, and follow-up of children with, or at risk of developing, osteoporosis and the transition from pediatric to adult care. What is Known: • Osteoporosis and associated fractures can cause significant morbidity and reduce the quality of life. • The developing skeleton has huge potential for recovery and reshaping, thus early detection of fractures, assessment of recovery potential, and treatment of children with osteoporosis can prevent future fractures, deformities, and scoliosis, improve function and mobility, and reduce pain. What is New: • Osteoporosis in children and adolescents requires a multidisciplinary approach with a thorough assessment of recovery potential, and indication for therapy should be personalized. • Although bisphosphonates still represent the drug most commonly used to increase bone mass, improve mobility, and reduce pain and recurrence of fractures, new agents are being developed and could be beneficial in children with specific conditions.

The aim of this study was to identify the genetic basis of two female siblings - born to consanguineous Sudanese parents - diagnosed clinically as having the rare condition of 25-hydroxylase deficiency (vitamin D-dependent rickets type 1B). The initial diagnosis was established based on clinical data, laboratory and radiological findings retrospectively. Primers for all exons (5) of human CYP2R1 (NM_024514) were generated followed by Sanger sequencing on exons 1–5 for both girls and their parents. Homozygosity for a point mutation (c.85C > T) was detected, leading to a nonsynonymous variant at position 29 in exon 1, resulting in a premature stop codon (p.Q29X). This is a previously unknown variant that leads to a severely truncated protein and predicted to be among the 0.1 % most deleterious genomic variants(CADD score 36). To our knowledge, this family represents the first case series from Sudan with a confirmed CYP2R1 gene mutation and the 6th world-wide. With the lack of genetic facilities, diagnosis should be suspected by the persistently low 25 hydroxyvitamin D level in spite of proper treatment and after ruling out liver disease and malabsorption. Patients in this case series showed healing of rickets when treated with high doses of 1,25-dihydroxyvitamin D3 (1,25(OH)D3; calcitriol) and oral calcium.

The European Society for Paediatric Endocrinology (ESPE) interactive website https://www.espe-elearning.org was first published online in 2012. We describe the various applications of the content of the e-Learning website that has been greatly expanded over the last 10 years. A large module on paediatric diabetes was added with the support of the International Society for Paediatric and Adolescent Diabetes (ISPAD). A separate multilingual module was created that focuses on front-line health care providers in limited resource settings. This module has been well received particularly in targeted parts of the world. E-learning may also be an opportunity to expand or tailor educational activities for learners according to their differing learning needs. The e-Learning website provides guidelines for those interested in general pediatrics, neonatology, clinical genetics and pediatric gynecology. We also describe various new applications such as masterclasses in the format of interactive video lectures and joined and complementary e-Learning/e-Consultation webinars. Finally, international certification was recently realized as e-Learning courses were recognized by the European Accreditation Council for Continuing Medical Education (EACCME). As a result of the social distancing measures introduced to control the COVID-19 pandemic digital education, whether individual or in a virtual classroom setting, has become even more important since e-Learning can connect and engage individuals across geographic boundaries as well as those who live in remote areas. The future of education delivery may include hybrid learning strategies, which include in-person and e-Learning platforms . Combined e-Learning and e-Consultation webinars illustrate how international academic institutions, learned medical specialty societies and networks are uniquely placed to deliver balanced, disease oriented and patient-centred e-Learning education and at the same time as providing expert consultation . Moreover, they are well equipped to maintain professional standards and to offer appropriate accreditation

X-linked hypophosphataemia (XLH) is a rare, inherited, phosphate-wasting disorder that elevates fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D (1,25(OH)2D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH)2D supplements. However, these treatments do not correct the primary pathogenic mechanism or treat all symptoms and can be associated with adverse effects. Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody against FGF23, approved for treating XLH in several geographical regions, including Europe and Israel. Burosumab restores normal serum phosphate levels, minimising the clinical consequences of XLH. Safety data on long-term treatment with burosumab are lacking owing to the rarity of XLH. This post-authorisation safety study (PASS) aims to evaluate the safety outcomes in patients aged >1 year. Methods: The PASS is a 10-year retrospective and prospective cohort study utilising data from the International XLH Registry (NCT03193476), which includes standard diagnostic and monitoring practice data at participating centres. The PASS aims to evaluate frequency and severity of safety outcomes, frequency and outcomes of pregnancies in female patients, and safety outcomes in patients with mild to moderate kidney disease at baseline, in children, adolescents and adults treated with burosumab for XLH. It is expected that there will be at least 400 patients who will be administered burosumab. Results: Data collection started on 24 April 2019. The expected date of the final study report is 31 December 2028, with two interim reports. Conclusion: This PASS will provide data on the long-term safety of burosumab treatment for XLH patients and describe safety outcomes for patients receiving burosumab contrasted with those patients receiving other XLH treatments, to help inform the future management of XLH patients. The PASS will be the largest real-world safety study of burosumab, The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Kyowa Kirin International plc is the sponsor of the International XLH Registry and the PASS, and facilitated the development of this document, although its creation was led entirely and independently by the authors. Kyowa Kirin did not provide any direct financial support

Parathyroid hormone-like hormone (PTHLH) plays an important role in bone formation. Several skeletal dysplasias have been described that are associated with disruption of PTHLH functioning. Here we report on a new patient with a 898 Kb duplication on chromosome 12p11.22 including the PTHLH gene. The boy has multiple skeletal abnormalities including chondrodysplasia, lesions radiographically resembling enchondromas and posterior rib deformities leading to a severe chest deformity. Severe pulmonary symptoms were thought to be caused by limited mobility and secondary sputum evacuation problems due to the chest deformity. Imaging studies during follow-up revealed progression of the number of skeletal lesions over time. This case extends the phenotypic spectrum associated with copy number variation of PTHLH.

PURPOSE Childhood brain tumor survivors (CBTS) are at risk for developing obesity, which negatively influences cardiometabolic health. The prevalence of obesity in CBTS may have been overestimated in previous cohorts because of inclusion of children with craniopharyngioma. On the contrary, the degree of weight gain may have been underestimated because of exclusion of CBTS who experienced weight gain, but were neither overweight nor obese. Weight gain may be an indicator of underlying hypothalamic-pituitary (HP) dysfunction. We aimed to study prevalence of and risk factors for significant weight gain, overweight, or obesity, and its association with HP dysfunction in a national cohort of noncraniopharyngioma and nonpituitary CBTS. METHODS Prevalence of and risk factors for significant weight gain (body mass index [BMI] change ≥ +2.0 standard deviation score [SDS]), overweight, or obesity at follow-up, and its association with HP dysfunction were studied in a nationwide cohort of CBTS, diagnosed in a 10-year period (2002-2012), excluding all craniopharyngioma and pituitary tumors. RESULTS Of 661 CBTS, with a median age at follow-up of 7.3 years, 33.1% had significant weight gain, overweight, or obesity. Of the CBTS between 4 and 20 years of age, 28.7% were overweight or obese, compared with 13.2% of the general population between 4 and 20 years of age. BMI SDS at diagnosis, diagnosis of low-grade glioma, diabetes insipidus, and central precocious puberty were associated with weight gain, overweight, or obesity. The prevalence of HP dysfunction was higher in overweight and obese CTBS compared with normal-weight CBTS. CONCLUSION Overweight, obesity, and significant weight gain are prevalent in CBTS. An increase in BMI during follow-up may be a reflection of HP dysfunction, necessitating more intense endocrine surveillance.

Contains fulltext : 245660.pdf (Publisher’s version ) (Closed access) Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up. Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [β-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin). Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers β-CTX and PINP remained stable. Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Trial Registration: This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).

Vitamin D is important for skeletal growth, bone mineralization and dental health. Vitamin D deficiency is reported in many countries, may have several causes and can cause rickets in children. A guideline with recommendations of vitamin D supplementation to prevent nutritional rickets was published recently. The vitamin D receptor is present in many cells of the body including cells of the immune system. Many studies have been published on associations between vitamin D deficiency and extra skeletal effects, mainly without proof of causality in intervention studies. This review aims to summarize available evidence of the skeletal and extra-skeletal effects of vitamin D. For the extra-skeletal effects there is proof that vitamin D supplementation can prevent acute respiratory infections in children with vitamin D deficiency and can reduce the rate of asthma exacerbations requiring corticosteroids in children with vitamin D deficiency. The evidence of benefit of vitamin D supplementation is too limited for pediatric patients with other infectious, inflammatory, and autoimmune diseases.

BACKGROUND Electronic learning (e-learning) is a widely accessible, low-cost option for learning remotely in various settings that allows interaction between an instructor and a learner. OBJECTIVE We describe the development of a free and globally accessible multilingual e-learning module that provides education material on topics in pediatric endocrinology and diabetes and that is intended for first-line physicians and health workers but also trainees or medical specialists in resource-limited countries. METHODS As complements to concise chapters, interactive vignettes were constructed, exemplifying clinical issues and pitfalls, with specific attention to the 3 levels of medical health care in resource-limited countries. The module is part of a large e-learning portal, ESPE e-learning, which is based on ILIAS (Integriertes Lern-, Informations- und Arbeitskooperations-System), an open-source web-based learning management system. Following a review by global experts, the content was translated by native French, Spanish, Swahili, and Chinese–speaking colleagues into their respective languages using a commercial web-based translation tool (SDL Trados Studio). RESULTS Preliminary data suggest that the module is well received, particularly in targeted parts of the world and that active promotion to inform target users is warranted. CONCLUSIONS The e-learning module is a free globally accessible multilingual up-to-date tool for use in resource-limited countries that has been utilized thus far with success. Widespread use will require dissemination of the tool on a global scale.

Background Electronic learning (e-learning) is a widely accessible, low-cost option for learning remotely in various settings that allows interaction between an instructor and a learner. Objective We describe the development of a free and globally accessible multilingual e-learning module that provides education material on topics in pediatric endocrinology and diabetes and that is intended for first-line physicians and health workers but also trainees or medical specialists in resource-limited countries. Methods As complements to concise chapters, interactive vignettes were constructed, exemplifying clinical issues and pitfalls, with specific attention to the 3 levels of medical health care in resource-limited countries. The module is part of a large e-learning portal, ESPE e-learning, which is based on ILIAS (Integriertes Lern-, Informations- und Arbeitskooperations-System), an open-source web-based learning management system. Following a review by global experts, the content was translated by native French, Spanish, Swahili, and Chinese–speaking colleagues into their respective languages using a commercial web-based translation tool (SDL Trados Studio). Results Preliminary data suggest that the module is well received, particularly in targeted parts of the world and that active promotion to inform target users is warranted. Conclusions The e-learning module is a free globally accessible multilingual up-to-date tool for use in resource-limited countries that has been utilized thus far with success. Widespread use will require dissemination of the tool on a global scale.

Contains fulltext : 193237.pdf (Publisher’s version ) (Open Access) PURPOSE: Severe fluctuations in plasma sodium concentration and plasma osmolarity, including central diabetes insipidus (CDI), may have significant influence on postoperative morbidity and mortality after pediatric brain tumor surgery.The aim of this study was to describe the frequency, severity and neurological consequences of these fluctuations in pediatric brain tumor survivors. METHODS: A retrospective, multi-institutional chart review was conducted among all children who underwent brain tumor surgery in the sellar or suprasellar region in seven university hospitals in the Netherlands between January 2004 and December 2013. RESULTS: Postoperative CDI was observed in 67.5% of 120 included children. Fluctuations of plasma sodium concentration >/= 10 mmol/L/24 h during the first ten postoperative days were seen in 75.3% of patients with CDI, with a maximum delta of 46 mmol/L/24 h. When compared to patients without CDI, altered mental status occurred more frequently in patients with postoperative CDI (5.1 vs. 23.5% respectively, p = 0.009). Low plasma sodium concentration was related to altered mental status and the occurrence of seizures. Frequency and severity of fluctuations in plasma sodium concentration during the first ten postoperative days were significantly higher in patients with permanent CDI at last follow-up than in patients with transient CDI or without CDI (p = 0.007). CONCLUSION: Postoperative CDI is a common complication after pediatric brain tumor surgery in the sellar or suprasellar region. Extreme plasma sodium concentrations and large intra-day fluctuations still occur and seem to influence the postoperative neurological course. These results illustrate the need for intensive monitoring in a highly experienced center.

Background Hypothalamic-pituitary (HP) dysfunction after craniospinal irradiation (CSI) is frequently observed in childhood brain tumor survivors (CBTS). The risk increases with higher dose and younger age at time of radiation exposure. Whether radiological alterations of the HP-region or alterations in brain volume are predictive of HP dysfunction remains unknown. Aim The aim of this (retrospective) study was to quantify radiological alterations of the HP-region in time in CBTS after CSI and to correlate these alterations to the occurrence of HP dysfunction. Methods Ninety survivors of childhood medulloblastoma (mean age at diagnosis: 8.3 years) from a previously reported nationwide cohort, treated with CSI between 2002-2012, were included. Sixty CBTS (67%) were diagnosed with HP dysfunction during follow-up (FU). All MRI scans were collected from time of diagnosis, post-neurosurgical intervention, post-radiation and 3 and 5 years of FU. Pituitary height (PH) and width (PW) were measured on mid-sagittal images. The pituitary stalk (PS) width was assessed by measuring the ratio of the PS to basilar artery (BA) on axial images on the same plane in the middle of the PS. Volume measurements of the PG (PGV) were performed. Observers were blinded for outcome of HP function. Separate analyses were performed for children < 6 years at time of CSI. All measurements were corrected for age and gender using Z-scores. Statistical analyses were performed by SPSS (General Linear Model repeated measures with Bonferroni correction). Results Mean PH (p

Background Childhood Brain Tumor Survivors (CBTS) are at increased risk of hypothalamic-pituitary (HP) dysfunction, which may be caused by radiotherapy , be a complication of the tumor itself or due to brain injury. Being overweighted or underweighted (body mass index (BMI) more than 2 SDS or lower than -2 SDS, respectively) at brain tumor diagnosis may reflect early hypothalamic dysfunction and may be a risk factor to develop HP dysfunction during follow-up. This has, to date, not been investigated. The objective of this study was to examine whether BMI at brain tumor diagnosis is associated with the development of HP dysfunction, independent of brain tumor treatment. Methods Children surviving a brain tumor, excluding craniopharyngioma or a pituitary tumor, for minimally two years, in whom BMI at diagnosis of their brain tumor had been recorded were included from a previous cohort study (n=685 of 718). Odds-ratios (OR) for developing HP dysfunction were calculated using multivariable logistic regression, including BMI at diagnosis, gender, age at follow-up, radiotherapy, histology, location of the primary tumor, hydrocephalus and state of disease. Results Of all, 10.8% (n=74) was overweighted and 5.0% (n=34) was underweighted at diagnosis. Median follow-up time was 7.1 years (5.0-9.6). Being overweighted or underweighted at diagnosis was significantly associated with the development of HP dysfunction (anterior or posterior pituitary deficiency or central precocious puberty , OR 2.43, 95% CI 1.46-4.05) and obesity at follow-up (OR 3.75, 95% CI 2.36-5.97).Development of HP dysfunction was also significantly associated with radiotherapy (OR 11.25, 95% CI 6.76-18.72) and location of primary tumor (OR 2.24, 95% CI 1.60-3.13). In children not treated with radiotherapy (n=430), underweight and overweight at brain tumor diagnosis were also both significantly associated with HP dysfunction and precocious puberty (OR 2.91, 95% CI 1.16-7.28 and 3.00 , 95% CI 1.12-8.01, respectively). In this group, other significant risk factors for HP dysfunction included location of primary tumor (OR 8.90, 95% CI 4.11-19.24), hydrocephalus (2.27, 95% CI 1.06-4.88) and state of disease at follow-up (OR 6.38, 95% CI 1.37-29.58). Conclusions Being overweighted or underweighted at brain tumor diagnosis in childhood is associated with the development of anterior pituitary deficiencies, posterior pituitary deficiencies and CPP, independently of given treatment. This suggests that in these children hypothalamic dysfunction may already be present at brain tumor diagnosis. These findings may be used for future studies on hypothalamic dysfunction in CBTS and can be used to develop recommendations on monitoring the development of pituitary disorders in CBTS.

Objective The incidence of cranial radiotherapy (cRT)–induced central hypothyroidism (TSHD) in childhood brain tumor survivors (CBTS) is reported to be low. However, TSHD may be more frequent than currently suspected, as its diagnosis is challenging due to broad reference ranges for free thyroxine (FT4) concentrations. TSHD is more likely to be present when FT4 levels progressively decline over time. Therefore, we determined the incidence and latency time of TSHD and changes of FT4 levels over time in irradiated CBTS. Design Nationwide, 10-year retrospective study of irradiated CBTS. Methods TSHD was defined as ‘diagnosed’ when FT4 concentrations were below the reference range with low, normal or mildly elevated thyrotropin levels, and as ‘presumed’ when FT4 declined ≥ 20% within the reference range. Longitudinal FT4 concentrations over time were determined in growth hormone deficient (GHD) CBTS with and without diagnosed TSHD from cRT to last follow-up (paired t-test). Results Of 207 included CBTS, the 5-year cumulative incidence of diagnosed TSHD was 20.3%, which occurred in 50% (25/50) of CBTS with GHD by 3.4 years (range, 0.9–9.7) after cRT. Presumed TSHD was present in 20 additional CBTS. The median FT4 decline in GH-deficient CBTS was 41.3% (P P = 0.02) in GH-deficient CBTS without diagnosed TSHD. Conclusions FT4 concentrations in CBTS significantly decline over time after cRT, also in those not diagnosed with TSHD, suggesting that TSHD occurs more frequently and earlier than currently reported. The clinical relevance of cRT-induced FT4 decline over time should be investigated in future studies.

Background: Childhood brain tumor survivors (CBTS) are at risk for hypothalamic-pituitary (HP) dysfunction, mainly caused by radiation exposure or tumor involvement of the HP-region. The risk for HP dysfunction (HPD) may vary between different age groups due to maturation of the brain and differences in oncologic treatment protocols. The aim of this study was to determine the prevalence and risk factors of HPD in infant (IBTS) and toddler brain tumor survivors (TBTS) compared to older childhood brain tumor survivors (OCBTS). Patients and Methods: A retrospective analysis in a nationwide cohort of CBTS was performed. Prevalence and risk factors for HPD were compared between IBTS (aged 0-1 years at diagnosis), TBTS (aged 1-3 years at diagnosis) and OCBTS (aged >3-18 years at diagnosis). Results: In 718 included CBTS, with a median follow-up time of 7.9 years, overall no differences in percentage of HPD were found between the three age groups. Treatment with radiotherapy (RT) (OR 15.41; 95%CI 8.33 to 28.48), suprasellar tumor location (OR 46.62; 95%CI 19.64 to 110.66) and younger age (OR 1.09; 95%CI 1.02 to 1.15) were associated with HP dysfunction. Because IBTS were significantly less often treated with RT, subanalyses were performed for all CBTS not treated with radiation (n=459). In non-irradiated CBTS, IBTS and TBTS were significantly more frequently diagnosed with TSH-, ACTH- and ADH deficiency, compared to ECBTS. IBTS and TBTS showed significantly more weight gain (p Conclusion: Infant and toddler brain tumor survivors seem to be more vulnerable to develop HP dysfunction than when compared to older children. These results emphasize the importance of special infant and toddlers brain tumor treatment protocols and endocrine surveillance in children treated for a brain tumor at young age.

Background/Aims: Congenital hyperinsulinism (CHI) is a rare disease characterized by recurrent severe hypoglycemia. In the diffuse form of CHI, pharmacotherapy is the preferred choice of treatment. Long-acting somatostatin analogues have been used in children as off-label medication. However, the efficacy, outcomes, and adverse effect profiles of long-acting somatostatin analogues have not been described in multicentered studies. The aim of this retrospective study is to summarize the experience with long-acting somatostatin analogues in a large group of children with CHI. Methods: Data were obtained retrospectively from 27 patients with CHI who received long-acting somatostatin analogues in 6 different centers in Europe. These included information on glycemic stability, auxology, and adverse effect profile in clinical follow-up assessments. Results: Blood glucose control improved in most patients (89%). No life-threatening side effects occurred. Thirteen patients (48%) experienced side effects; in 3 patients (11%), the side effects were the main reason for discontinuation of the treatment. The most frequent side effect was elevated liver enzymes (n = 10, 37%). Conclusion: Long-acting somatostatin analogues are effective in glycemic control of patients with CHI. However, in 37% of all patients increased liver enzymes were observed. It is important to monitor liver function in all patients receiving long-acting somatostatin analogue therapy.

More than 45 % of long-term childhood cancer survivors (CCS) were diagnosed with osteopenia. Our data suggest that greater awareness for osteopenia is warranted in long-term CCS, especially in survivors who are older than 30 years, male, and underweight and were treated with cranial-spinal radiotherapy and/or steroids.Osteopenia is a potential complication of childhood cancer treatment, but the magnitude of this problem in survivors is unknown. We examined (determinants of) bone mineral density (BMD) status in long-term survivors of adult childhood cancer.This retrospective single-centre cohort study included 346 subjects with the most common types of childhood cancer. Subjects had a median age at diagnosis of 7.0 years (range 0.1-16.8 years), a median age at follow-up of 24.5 years (range 18.0-47.6 years) and a median follow-up time of 16.7 years (range 5.6-39.9 years). Total body BMD (BMDTB) and BMD of the lumbar spine (BMDLS) were measured by dual X-ray absorptiometry. Osteopenia was defined as BMD standardized deviation score (SDS) below -1.Survivors had a lower BMDTB and BMDLS (mean SDS -0.55; p 30 years at follow-up, male gender, underweight at follow-up and treatment with cranial-spinal radiotherapy or prednisone as independent prognostic factors for osteopenia.This large cohort of childhood cancer survivors identified osteopenia in 45 % of CCS. This indicates that greater awareness is warranted, especially in survivors who are older than 30 years, male, have underweight and were treated with cranial-spinal radiotherapy and/or steroids.

Background/Aims: To systematically assess contemporary knowledge regarding the effectiveness and safety of bisphosphonates (BPs) in children with osteogenesis imperfecta (OI). Methods: PubMed/MEDLINE, Embase, and Cochrane were searched for eligible articles up to June 2014. Studies eligible for inclusion were (randomized) controlled trials assessing the effects of BPs in children with OI. Methodological quality was assessed independently by 4 reviewers using the Cochrane Collaboration's tool for risk of bias. Results: Ten studies (519 children) were included. Four studies (40%) showed a low risk of bias. All studies investigating lumbar spine areal bone mineral density indicated a significant increase as a result of BP treatment. Most studies observed a significant decrease in fracture incidence. The most frequently reported adverse events were gastrointestinal complaints, fever, and muscle soreness. A significant decrease in (bone) pain due to BP treatment was observed in more than half of the studies. Most studies measuring urinary markers of bone resorption reported a significant decrease. The majority of studies with intravenous treatment showed a significant increase in lumbar projection area, whereas studies with oral treatment did not. Conclusions: Treatment with oral or intravenous BPs in children with OI results in an increase in bone mineral density and seems to be safe and well tolerated.

Genomic prediction of the extreme forms of adult body height or stature is of practical relevance in several areas such as pediatric endocrinology and forensic investigations. Here, we examine 770 extremely tall cases and 9,591 normal height controls in a population-based Dutch European sample to evaluate the capability of known height-associated DNA variants in predicting tall stature. Among the 180 normal height-associated single nucleotide polymorphisms (SNPs) previously reported by the Genetic Investigation of ANthropocentric Traits (GIANT) genome-wide association study on normal stature, in our data 166 (92.2 %) showed directionally consistent effects and 75 (41.7 %) showed nominally significant association with tall stature, indicating that the 180 GIANT SNPs are informative for tall stature in our Dutch sample. A prediction analysis based on the weighted allele sums method demonstrated a substantially improved potential for predicting tall stature (AUC = 0.75; 95 % CI 0.72-0.79) compared to a previous attempt using 54 height-associated SNPs (AUC = 0.65). The achieved accuracy is approaching practical relevance such as in pediatrics and forensics. Furthermore, a reanalysis of all SNPs at the 180 GIANT loci in our data identified novel secondary association signals for extreme tall stature at TGFB2 (P = 1.8 x 10(-13)) and PCSK5 (P = 7.8 x 10(-11)) suggesting the existence of allelic heterogeneity and underlining the importance of fine analysis of already discovered loci. Extrapolating from our results suggests that the genomic prediction of at least the extreme forms of common complex traits in humans including common diseases are likely to be informative if large numbers of trait-associated common DNA variants are available.

Objective: The aim of this study was to investigate the long-term treatment effects of risperidone on prolactin levels and prolactin-related side effects in pubertal boys with autism spectrum disorders (ASD) and disruptive behavior disorders (DBD).Method: Physical healthy 10-20-year-old males with ASD (n = 89) and/or DBD (n = 9) chronically treated (mean 52 months, range 16-126 months) with risperidone (group 1, n = 51) or not treated with any antipsychotic (group 2, n = 47) were recruited to this observational study from the child psychiatry outpatient clinic. Morning non-fasting serum prolactin levels were measured and prolactin-related side effects were assessed by means of questionnaires and physical examination. Group differences were tested with Student's t, chi(2), Fisher exact, and Mann-Whitney tests, and logistic regression analysis, according to the type and distribution of data.Results: Hyperprolactinemia was present in 47% of subjects in group 1 but only in 2% of subjects in group 2 (odds ratio 71.9; 95% CI, 7.7; 676.3). Forty-six percent of subjects in group1 had asymptomatic hyperprolactinemia. Current risperidone dose and 9-OH risperidone plasma level were significant predictors of hyperprolactinemia (p = 0.035 and p = 0.03, respectively). Gynecomastia and sexual dysfunction were present in 43% and 14% of the subjects in group1, respectively, compared with 21% and 0% of subjects in group 2 (p = 0.05 and p = 0.01). Gynecomastia was not significantly associated with hyperprolactinemia.Conclusions: Hyperprolactinemia is a common side effect in young males treated over the long term with risperidone. Young males treated with risperidone are more likely to report diminished sexual functioning than are those not treated with antipsychotics.

Purpose To evaluate the prevalence of, and risk factors for, early endocrine disorders in childhood brain tumor survivors (CBTS). Patients and Methods This nationwide study cohort consisted of 718 CBTS who were diagnosed between 2002 and 2012, and who survived ≥ 2 years after diagnosis. Patients with craniopharyngeoma or a pituitary gland tumor were excluded. Results of all endocrine investigations, which were performed at diagnosis and during follow-up, were collected from patient charts. Multivariable logistic regression was used to study associations between demographic and tumor- and treatment-related variables and the prevalence of early endocrine disorders. Results After a median follow-up of 6.6 years, 178 CBTS (24.8%) were diagnosed with an endocrine disorder. A total of 159 CBTS (22.1%) presented with at least one endocrine disorder within the first 5 years after diagnosis. The most common endocrine disorders were growth hormone deficiency (12.5%), precocious puberty (12.2%), thyroid-stimulating hormone deficiency (9.2%), and thyroidal hypothyroidism (5.8%). The risk of hypothalamic-pituitary dysfunction (n = 138) was associated with radiotherapy (odds ratio [OR], 15.74; 95% CI, 8.72 to 28.42), younger age at diagnosis (OR, 1.09; 95% CI, 1.04 to 1.14), advanced follow-up time (OR, 1.10; 95% CI, 1.02 to 1.18), hydrocephalus at diagnosis (OR, 1.77; 95% CI, 1.09 to 2.88), and suprasellar (OR, 34.18; 95% CI, 14.74 to 79.29) and infratentorial (OR, 2.65; 95% CI, 1.48 to 4.74) tumor site. Conclusion The prevalence of early endocrine disorders among CBTS is high. The observation that 22.1% of CBTS developed at least one endocrine disorder within the first 5 years after diagnosis stresses the importance of early and regular assessment of endocrine function in CBTS who are at risk for endocrine damage.

Aims: This cross-sectional study investigates the effect of antipsychotic (AP)-induced hyperprolactinemia on testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), inhibin B, and puberty in boys with mainly autism spectrum disorders (ASD). Method: One hundred and four physically healthy 10- to 19-year-old boys with ASD or disruptive behavior disorder (DBD) were recruited between October 2006 and November 2009. Fifty-six adolescents had been treated with AP for >16 months; 48 had never been exposed to AP. Morning non-fasting levels of serum prolactin, testosterone, LH, FSH and inhibin B were obtained and Tanner pubertal stage was determined. Patients with hyperprolactinemia (n = 28) were compared to those without hyperprolactinemia (n = 76) using non-parametric or parametric tests, as appropriate. Results: Patients with AP-induced hyperprolactinemia had significantly lower testosterone levels with adjustment for age (p = 0.035) compared to patients without hyperprolactinemia and without AP treatment. The difference was not significant within the AP-treated group, and the level of testosterone was within the reference range compared to age- and gender-matched normative data. There was no between-group difference for LH, FSH, inhibin B or Tanner stages. Conclusion: AP-induced hyperprolactinemia is related to significantly lower testosterone levels in pubertal boys with ASD and DBD.

Background: The clinical relevance of low IGF-I levels, caused by cranial radiotherapy, in adult childhood cancer survivors has not been studied extensively. We evaluated whether IGF-I is a useful marker for altered body composition and growth hormone deficiency (GHD) in this group. Procedure: We analyzed retrospective data from 610 adult childhood cancer survivors, retrieved from the late effects clinic. Median age at diagnosis was 6 years (interquartile range 3-11) and follow-up time was 18 years (13-24). We assessed IGF-I standard deviation scores (SDS), anthropometrical measures, growth hormone stimulation tests in patients with clinical signs of GHD, and measures of body composition (assessed by dual X-ray absorptiometry, Lunar Prodigy). Results: In 58 cranially irradiated acute leukemia survivors (25 Gy (24-25)) and 56 locally irradiated brain tumor survivors (42 Gy (35-54)) we found significantly lower IGF-I SDS (P

Background/Objective: High-dose estrogen treatment to reduce final height of tall girls has been shown to interfere with fertility. Ovarian function has not been studied. We therefore evaluated fertility and ovarian function in tall women who did or did not receive such treatment in adolescence. Methods: This was a retrospective cohort study of 413 tall women aged 23–48 yr, of whom 239 women had been treated. A separate group of 126 fertile, normoovulatory volunteers aged 22–47 yr served as controls. Results: Fertility was assessed in 285 tall women (157 treated, 128 untreated) who had attempted to conceive. After adjustment for age, treated women were at increased risk of experiencing subfertility [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.38–3.81] and receiving infertility treatments (OR 3.44, 95% CI 1.76–6.73). Moreover, fecundity was notably affected because treated women had significantly reduced odds of achieving at least one live birth (OR 0.26, 95% CI 0.13–0.52). Remarkably, duration of treatment was correlated with time to pregnancy (r = 0.23, P = 0.008). Ovarian function was assessed in 174 tall women (119 treated, 55 untreated). Thirty-nine women (23%) exhibited a hypergonadotropic profile. After adjusting for age category, treated women had significantly higher odds of being diagnosed with imminent ovarian failure (OR 2.83, 95% CI 1.04–7.68). Serum FSH levels in these women were significantly increased, whereas antral follicle counts and serum anti-Müllerian hormone levels were decreased. Conclusion: High-dose estrogen-treated tall women are at risk of subfertility in later life. Their fecundity is significantly reduced. Treated women exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility.

Background/Aims: Genetic variation in several candidate genes has been associated with short stature. Recently, a high-mobility group A2 (HMGA2) gene SNP has been robustly associated with height in the general population. Only few have attempted to study these genes in extremely tall stature. We therefore studied common genetic variation in candidate genes for height in extremely tall Dutch. Methods: We included 116 constitutionally tall cases with height >2 SD and 103 controls with normally distributed height Results: The HMGA2 gene SNP was significantly associated with tall stature. Using a logistic regression model, we calculated that carrying the HMGA2 (rs1042725) C allele significantly increased the odds of being tall (OR = 1.53, 95% CI 1.02–2.28; p = 0.03). In addition, controls with one or two copies of the C allele were significantly taller than controls carrying the TT genotype [TC: mean (SD) +0.61 (0.21) SDS; p = 0.004, and CC: +0.77 (0.25) SDS; p = 0.003]. Conclusion: Our study shows that a common polymorphism in the HMGA2 gene is not only associated with height variation in the general population but also plays an important role in one of the extremes of the height distribution.

Context: Germline and somatic activating mutations in the LH receptor (LHR) gene have been reported.Objective: Our objective was to perform mutation analysis of the LHR gene of patients with Leydig cell adenoma or hyperplasia. Functional studies were conducted to compare the D578H-LHR mutant with the wild-type (WT)-LHR and the D578G-LHR mutant, a classic cause of testotoxicosis. The three main signal transduction pathways in which LHR is involved were studied.Patients: We describe eight male patients with gonadotropin-independent precocious puberty due to Leydig cell adenoma or hyperplasia.Results: The D578H-LHR mutation was found in the adenoma or nodule with hyperplasia in all but two patients. D578H-LHR displayed a constitutively increased but noninducible production of cAMP, led to a very high production of inositol phosphates, and induced a slight phosphorylation of p44/42 MAPK in the absence of human chorionic gonadotropin. The D578G-LHR showed a response intermediate between WT-LHR and the D578H-LHR. Subcellular localization studies showed that the WT-LHR was almost exclusively located at the cell membrane, whereas the D578H-LHR showed signs of internalization. D578H-LHR was the only receptor to colocalize with early endosomes in the absence of human chorionic gonadotropin.Conclusions: Although several LHR mutations have been reported in testotoxicosis, the D578H-LHR mutation, which has been found only as a somatic mutation, appears up until now to be specifically responsible for Leydig cell adenomas. This is reflected by the different activation of the signal transduction pathways, when compared with the WT-LHR or D578G-LHR, which may explain the tumorigenesis in the D578H mutant. (J Clin Endocrinol Metab 96: E1197-E1205, 2011)

Background/Objective: Sex steroid treatment to reduce final height of tall boys has been available since the 1950s. In women, it has been shown to interfere with fertility. In men, no such data are available. We therefore evaluated fertility and gonadal function in tall men who did or did not receive high-dose androgen treatment in adolescence.Methods: We conducted a retrospective cohort study of 116 tall men, of whom 60 had been treated. Reproductive and gonadal function was assessed by standardized interview, semen analysis, endocrine parameters, ultrasound imaging, and fatherhood. Mean age at treatment commencement was 14.2 yr, and mean follow-up was 21.2 yr.Results: Sixty-six men (36 treated and 30 untreated) had attempted to achieve fatherhood. The probability of conceiving their first pregnancy within 1 yr was similar in treated and untreated men (26 vs. 24; Breslow P = 0.8). Eleven treated and 13 untreated men presented with a left-sided varicocele (P = 0.5). Testicular volume, sperm quality, and serum LH, FSH, and inhibin B levels were comparable between treated and untreated men. However, treated men had significantly reduced serum T levels, adjusted for known confounders [mean (SD) 13.3 (1.8) vs. 15.2 (1.9) nmol/liter; P = 0.005). In addition, testicular volume and serum inhibin B and FSH levels in treated men were significantly correlated with age at treatment commencement.Conclusion: At a mean follow-up of 21 yr after high-dose androgen treatment, we conclude that fatherhood and semen quality in tall treated men are not affected. Serum testosterone levels, however, are reduced in androgen-treated men. Future research is required to determine whether declining testosterone levels may become clinically relevant for these men as they age. (J Clin Endocrinol Metab 95: 5233-5240, 2010)

Contains fulltext : 80129.pdf (Publisher’s version ) (Open Access) OBJECTIVE: This review reports the incidence of hyperprolactinemia, its relationship with genotype, and prolactin-related side effects in children and adolescents treated with antipsychotics. METHOD: Data on prolactin levels were available for haloperidol, pimozide, risperidone, olanzapine, clozapine, ziprasidone, and quetiapine. Twenty-nine studies were selected after a literature search in the English Medline/Embase/Psychinfo/EBM databases (1965 to August, 2008). RESULTS: All antipsychotics, except clozapine, ziprasidone, and quetiapine, increase the mean prolactin level from baseline values of 8.0 ng/mL to 25-28 ng/mL after 4 weeks of treatment (reference range 0-15 ng/mL). The most and best data are available for risperidone. Five risperidone studies (n = 577) show an increase of prolactin level from 7.8 ng/mL to 17.7 ng/mL after 1 year of treatment, and two risperidone studies (n = 60) show an increase from 7.4 ng/mL to 24.9 ng/mL after 2 years of treatment. Aggregated over all antipsychotics, prolactin-related side effects, such as gynecomastia, galactorrhea, irregular menses, and sexual dysfunction, were reported by 4.8% of the children and adolescents. No data are available on bone mineral density in relation to antipsychotic-induced hyperprolactinemia in children and adolescents. Prolactin levels may be influenced by the genetic differences that influence prolactin metabolism and D2 dopamine receptor density. CONCLUSION: Persistent elevation of prolactin for periods up to 2 years has been documented in maintenance treatment with risperidone. Very limited long-term data of pimozide, olanzapine, and quetiapine prohibit drawing conclusions for these antipsychotics. Systematic long-term observational studies, including specific questionnaires as well as physical examination, are needed to investigate prolactin-related side effects of antipsychotic treatment in children and adolescents.

Background/Aims: The aim of the present study was to evaluate bone mineral density (BMD) and body composition of patients with childhood-onset growth hormone (GH) deficiency (GHD) treated with GH during the transition period. Methods: BMD and body composition, measured by dual-energy X-ray absorptiometry, were evaluated at final height and yearly thereafter during 2 years. Twenty-nine of the 40 patients had also been measured before start and during GH therapy. Results: Mean lumbar spine BMD and bone mineral apparent density (BMAD) as well as total body BMD and lean body mass (LBM) SD score (SDS) were significantly lower than normal at final height and during the 2 years thereafter for all patients. Final-height SDS was related to the change in height SDS as well as in LBM SDS during the first year of GH treatment. LBM SDS decreased significantly in the group of patients with GHD without GH treatment (p < 0.01, n = 19). Fat mass SDS increased in all patients. Conclusion: Mean BMD, BMAD and LBM SDS were significantly lower than normal in adolescents with childhood-onset GHD at and 2 years after the attainment of final height.

AIM Children with severe cerebral palsy (CP) are at risk for developing low bone mineral density (BMD) and low-impact fractures. The aim of this study was to provide a systematic literature review of the epidemiology of fractures and low BMD in children with severe CP, with an emphasis on risk factors. Gross Motor Function Classification System (GMFCS) levels IV and V were criteria for severe cerebral palsy. METHOD The literature (PubMed) was searched and eligible studies were given a level of evidence score using the Scottish Intercollegiate Guidelines Network criteria. RESULTS Seven studies were found concerning epidemiology of fractures, 11 studies described epidemiology of low BMD, and 14 studies concerned risk factors. The methodological quality of most of these studies was poor. Five studies were considered well-conducted with low risk of confounding and bias. In these studies, the incidence of fractures in children with moderate to severe CP approached 4% per year, whereas the prevalence of low BMD in the femur was 77%. Limited ambulation, feeding difficulties, previous fractures, anticonvulsant use, and lower body fat mass were associated with low BMD z-scores. INTERPRETATION There is only a limited amount of high-quality evidence on low BMD and fractures in children with severe CP.

Context: Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation and short stature. The incidence of submicroscopic deletions is unknown, as is the effect of GH therapy in this condition. Objective: The objective of the study was to describe the use of a novel genetic technique [multiplex ligation probe amplification (MLPA)] to detect haploinsufficiency of the IGF1R gene in a patient suspected of an IGF1R gene defect and evaluate the effect of long-term GH therapy. Patient: A 15-yr-old adolescent, born small for gestational age, showed persistent postnatal growth retardation, microcephaly, and elevated IGF-I levels. She had been treated with GH since the age of 5 yr. Methods: MLPA and array comparative genomic hybridization (aCGH) were performed to examine gene copy number changes. Dermal fibroblast cultures were used for functional analysis. Results: With MLPA, a deletion of one copy of the IGF1R gene was detected, defined by aCGH as a loss of 15q26.2->qter. IGF1R mRNA expression was decreased in fibroblasts. IGF-I binding and type 1 IGF receptor protein expression as well as activation of type 1 IGF receptor autophosphorylation and protein kinase B/Akt by IGF-I tended to be lower, but this did not reach statistical significance. GH treatment resulted in a good growth response and a normal adult height. Conclusions: MLPA and aCGH are useful tools to detect submicroscopic deletions of the IGF1R gene in patients born small for gestational age with persistent growth failure. The phenotype resembles that of a heterozygous inactivating IGF1R mutation. Long-term GH therapy causes growth acceleration in childhood and a normal adult height.

BACKGROUND: In recent years interest in bone densitometry in children has increased.OBJECTIVE: To evaluate the clinical application of digital X-ray radiogrammetry (DXR) and compare the results with those of dual-energy X-ray absorptiometry (DXA).MATERIALS AND METHODS: A total of 41 children with acute lymphoblastic leukaemia (ALL) and 26 children with growth hormone deficiency (GHD) were included in this longitudinal study. Radiographs of the left hand were obtained and used for DXR. DXA of the total body and of the lumbar spine was performed.RESULTS: In both study populations significant correlations between DXR and DXA were found, and, with the exception of the correlation between DXR bone mineral density (DXR-BMD) and bone mineral apparent density in the GHD population, all correlations had a P-value of CONCLUSIONS: Our study showed that DXR in a paediatric population shows a strong correlation with DXA of the lumbar spine and total body and that it is able to detect a change in BMD during treatment.

Idiopathic infantile arterial calcification (IIAC) is a rare disease characterised by extensive depositions of hydroxyapatite in the internal elastic lamina of medium-sized and large arteries, frequently accompanied by periarticular calcifications. We report on three patients with various presenting signs and symptoms. Diagnostic imaging techniques and therapy with bisphosphonates will be discussed. For the first time long-term follow-up of up to 25 years will be reported.

Item does not contain fulltext We have evaluated the applicability of a new Digital X-ray Radiogrammetry (DXR) system in a Dutch Caucasian pediatric population. For this study we enrolled 535 healthy participants who all signed an informed consent form. In addition, 20 children suffering from inflammatory bowel disease (IBD) and juvenile chronic arthritis (JCA) were enrolled. Radiographs of the left hand were obtained from all participants. From the healthy population a subset of children with a history of forearm fractures were separately analyzed. Measurements consisted of DXR (X-posure; Pronosco-Sectra, Linkoping, Sweden). Five hundred thirty-five subjects were enrolled in the study. Twenty-two subjects (4.3%) were discontinued (age 3-10 years), all because of a nonrecognizable radiograph by the DXR system. The short-term coefficient of variation of DXR in this population was 0.59%. Significant differences in DXR-BMD between boys and girls for the ages of 11, 12, 16, 17, and 18 years were found. There were also significant differences in DXR-BMD between the sequential Tanner stages. For 88 subjects repeat radiographs were available (mean interval 1.8 years). In all cases an increase in DXR-BMD was seen. Girls with IBD, JCA, or a history of forearm fractures and boys with IBD showed a significantly lower DXR-BMD compared with healthy controls. We show that DXR is an applicable technique in children. Also, in a small subpopulation it is possible to discriminate children with a high risk of low BMD.

Aims: To obtain normative data on bone mineral density and body composition measured with dual energy x ray absorptiometry (DXA) from early childhood to young adulthood. Methods: Cross sectional results from 444 healthy white volunteers (4–20 years) in the Netherlands were combined with the results from 198 children who agreed to participate in the follow up study approximately four years later. DXA (Lunar, DPXL) of lumbar spine and total body was performed to assess bone density and body composition. Results: Bone density and lean body mass (LBM) increased with age. Maximal increase in bone density and LBM occurred around the age of 13 years in girls and approximately two years later in boys. Bone density of total body and lumbar spine showed an ongoing slight increase in the third decade. Mean fat percentage in boys remained at 10.5% throughout childhood, but increased in girls. Conclusions: Most of the skeletal mass in lumbar spine and total body is reached before the end of the second decade, with a slight increase thereafter. This study provides reference values for bone density and body composition measured with DXA for children and young adults.

We present a brother and sister with severe rickets, alopecia and highly elevated serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D3). Genomic sequencing showed a homozygous point mutation (A133G) in the vitamin D receptor gene, leading to an amino acid change in the DNA binding domain (K45E), which was described previously. Hereditary vitamin D resistant rickets (HVDRR) was diagnosed. Functional studies in skin biopsy fibroblasts confirmed this. 1,25-(OH)2D3 reduced T helper (Th) cell population-specific cytokine expression of interferon γ (Th1), interleukins IL-17A (Th17) and IL-22 (Th17/Th22) in peripheral blood mononuclear cells (PBMCs) from the patient's parents, whereas IL-4 (Th2) levels were higher, reflecting an immunosuppressive condition. None of these factors were regulated by 1,25-(OH)2D3 in PBMCs from the boy. At present, both patients (boy is 23 years of age, girl is 7) have not experienced any major immune-related disorders. Although both children developed alopecia, the girl did so earlier than the boy. The boy showed complete recovery from the rickets at the age of 17 and does not require any vitamin D supplementations to date. In conclusion, we characterized two siblings with HVDRR, due to a mutation in the DNA binding domain of VDR. Despite a defective T cell response to vitamin D, no signs of any inflammatory-related abnormalities were seen, thus questioning an essential role of vitamin D in the immune system. Despite the fact that currently medicine is not required, close monitoring in the future of these patients is warranted for potential recurrence of vitamin D dependence and diagnosis of (chronic) inflammatory-related diseases.

OBJECTIVE Osteopenia has been reported in adult patients with chronic renal failure (CRF). Only a few studies have been performed in children. The objective of this study was to evaluate bone mineral density (BMD), bone turnover, body composition in children with CRF and to study the effect of GH on these variables. DESIGN Two groups were identified: patients with growth retardation who received GH (GH-group) and patients most of whom were not growth retarded who did not receive GH (no-GH-group). After an observation period of 6 months, the patients in the GH-group started GH treatment. Patients were studied every 6 months during 18 months. PATIENTS Thirty-six prepubertal patients (27 boys and 9 girls), mean age 7.9 years, with CRF participated in the study. The GH-group consisted of 17 patients of whom 14 completed one year treatment. The no-GH-group consisted of 19 patients, of whom 16 were followed for 6 months, 14 for 12 months and 13 for 18 months. MEASUREMENTS Lumbar spine BMD, total body BMD and body composition were assessed by dual energy X-ray absorptiometry, compared to age-and sex-matched reference values of the same population and expressed as standard deviation scores (SDS). BMD of appendicular bone was measured by quantitative microdensitometry (QMD). Blood samples were obtained to assess bone metabolism and growth factors. RESULTS Baseline mean lumbar spine and total body BMD SDS of all patients were not significantly different from normal. Mean lumbar spine and total body BMD SDS did not change significantly in the GH-group during GH treatment. The change of QMD at the midshaft during the first 6 months of GH treatment was significantly smaller than during the observation period (P