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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.

Aim: To provide insight into healthcare resource utilization and hospital expenditure of patients treated for diabetes in Dutch hospitals. Materials and methods: We conducted an observational cohort study of 193 840 patients aged ≥18 years and treated for diabetes mellitus in 65 Dutch hospitals in 2019 to 2020, using real-world reimbursement data. Consultations, hospitalizations, technology use, total hospital and diabetes care costs (encompassing all care for diabetes itself) were assessed during 1-year follow-up. In addition, expenditure was compared with that in the general Dutch population. Results: Total hospital costs for all patients with diabetes were €1 352 690 257 (1.35 billion) per year, and 15.9% (€214 963 703) was associated with treatment of diabetes. Mean yearly costs per patient were €6978, with diabetes care costs of €1109. Mean hospital costs of patients exceeded that of the Dutch population three- to sixfold. Total hospital costs increased with age, whereas diabetes expenditure decreased with age (18-40 years, €1575; >70 years, €932). Of all patients with diabetes, 51.3% (n = 99 457) received care related to cardiovascular complications. Micro- and macrovascular complications, or a combination, increased hospital costs (1.4-5.3 times higher). Conclusions: The hospital resource use of Dutch diabetes patients is high, with a large burden of cardiovascular complications. Resource use is rooted mainly in hospital care of diabetes-related complications, not in the treatment of diabetes. Early treatment and prevention of complications remain imperative to taper future healthcare expenditure on patients with diabetes.

Aims/hypothesis Sex differences are present in cardiovascular care and in outcomes among adults with type 1 diabetes mellitus, which typically commences in childhood. Whether sex influences care and outcomes in childhood is not known. This systematic review provides an overview of sex differences in children with type 1 diabetes, focusing on patient and disease characteristics, treatment, comorbidities and complications. Methods Literature in MEDLINE up to 15 June 2021 was searched, using the terms diabetes mellitus, sex characteristics, sex distribution, children and/or adolescents. All primary outcome studies on children with type 1 diabetes that mentioned a sex difference in outcome were included, with the exception of qualitative studies, case reports or case series. Studies not pertaining to the regular clinical care process and on incidence or prevalence only were excluded. Articles reporting sex differences were identified and assessed on quality and risk of bias using Joanna Briggs Institute critical appraisal tools. Narrative synthesis and an adapted Harvest plot were used to summarise evidence by category. Results A total of 8640 articles were identified, rendering 90 studies for review (n=643,217 individuals). Studies were of observational design and comprised cohort, cross-sectional and case–control studies. Most of the included studies showed a higher HbA1c in young female children both at diagnosis (seven studies, n=22,089) and during treatment (20 out of 21 studies, n=144,613), as well as a steeper HbA1c increase over time. Many studies observed a higher BMI (all ages, ten studies, n=89,700; adolescence, seven studies, n=33,153), a higher prevalence of being overweight or obese, and a higher prevalence of dyslipidaemia among the female sex. Hypoglycaemia and partial remission occurred more often in male participants, and ketoacidosis (at diagnosis, eight studies, n=3561) and hospitalisation was more often seen in female participants. Most of the findings showed that female participants used pump therapy more frequently (six studies, n=211,324) and needed higher insulin doses than male participants. Several comorbidities, such as thyroid disease and coeliac disease, appeared to be more common in female participants. All studies reported lower quality of life in female participants (15 studies, n=8722). Because the aim of this study was to identify sex differences, studies with neutral outcomes or minor differences may have been under-targeted. The observational designs of the included studies also limit conclusions on the causality between sex and clinical outcomes. Conclusions/interpretation Sex disparities were observed throughout diabetes care in children with type 1 diabetes. Several outcomes appear worse in young female children, especially during adolescence. Focus on the cause and treatment of these differences may provide opportunities for better outcomes. Registration This systematic review is registered in PROSPERO (CRD42020213640) Graphical abstract

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.

Background: Temple syndrome (TS14) is an imprinting disorder caused by a maternal uniparental disomy of chromosome 14 (UPD(14)mat), paternal deletion of 14q32 or an isolated methylation defect of the MEG3-DMR. Studies on phenotypical characteristics in TS14 are scarce and patients with TS14 often experience delay in diagnosis, which has adverse effects on their health. TS14 is often characterized as either Prader–Willi-like, Silver–Russell-like or as a Silver–Russell spectrum disorder. Methods: This study describes 15 patients with TS14 who visited the Dutch Reference Center for Prader–Willi-like from December 2018 to January 2022. Results: Eight patients had UPD(14)mat and seven a methylation defect. The most common symptoms were intra-uterine growth retardation (IUGR) (100%), hypotonia (100%), precocious puberty (89%), small for gestational age (SGA) birth (67%), tube feeding after birth (53%) and psycho-behavioral problems (53%). Median (interquartile range (IQR)) IQ was 91.5 (84.25; 100.0), whilst many patients were enrolled in special education (54%). The median (IQR) fat mass % (FM%) SDS was 2.53 (2.26; 2.90) and lean body mass (LBM) SDS −2.03 (−3.22; −1.28). There were no significant differences in clinical characteristics between patients with a UPD(14)mat and a methylation defect. Conclusions: Our patients share a distinct phenotype consisting of IUGR, SGA birth, precocious puberty, hypotonia, tube feeding after birth, psycho-behavioral problems and abnormal body composition with a high FM% and low LBM. Whilst similarities with Prader–Willi syndrome (PWS) and Silver–Russell syndrome (SRS) exist, TS14 is a discernible syndrome, deserving a tailored clinical approach. Testing for TS14 should be considered in patients with a PWS or SRS phenotype in infancy if PWS/SRS testing is negative.

Objective Adolescents and young adults (AYA) with common endocrine disorders show a high dropout (up to 50%) after the transfer from paediatric to adult endocrinology. Little is known about transition readiness in rare endocrine conditions (rEC). This study aims to assess medical self-management skills (SMS) among AYA with rEC in relation to age and gender, in order to understand dropout and increase transition readiness. Design Cross-sectional study using web-based medical self-management questionnaires. Methods Questionnaires consisting of 54 questions in seven domains were filled out by the adolescents before the first shared appointment with both paediatric and adult endocrinologist. Results Fifty-seven patients (median age 17 years, 25/57 females) participated and generally scored well on most items. However, one out of seven did not know the name of their disorder, one sixth of the glucocorticoid users did not know that dose should be adapted in case of illness or surgery, over one-fifth had never ordered their repeat prescriptions themselves and two-thirds had never had a conversation alone with their doctor. Conclusions Several SMS among patients with rEC are insufficient, with regard to medical knowledge, practical skills and communication. As SMS are only weakly related to non-modifiable factors, such as age and gender, we recommend focussing on other factors to increase transition readiness. The timing, amount and ‘mode’ of medical information should be individualised. Transition checklists should be used to detect shortcomings in practical skills and communication, which can subsequently be trained with the help of parents, caregivers and/or e-technology.

Background Treatment of diabetes mellitus has majorly improved over the past century, however, the disease burden is high and its prevalence still expanding. Further insight in the diabetes population is imperative to improve the quality of diabetes care by enhancement of knowledge-based diabetes management strategies. To this end, in 2017 a Dutch nationwide consortium of diabetologists, paediatric endocrinologists, and diabetes patients has founded a national outpatient diabetes care registry named Dutch Pediatric and Adult Registry of Diabetes (DPARD). We aim to describe the implementation of DPARD and to provide an overview of the characteristics of patients included during the first 2 years. Methods For the DPARD cohort with long-term follow-up of observational nature, hospital data are gathered directly from electronic health records and securely transferred and stored. DPARD provides weekly updated clinical information on the diabetes population care on a hospital-level benchmarked against the national average. Results Between November 2017 and January 2020, 20,857 patients were included from 8 (11%) Dutch hospitals with a level of care distribution representative of all diabetic outpatients in the Netherlands. Among patients with known diabetes type, 41% had type 1 diabetes, 51% type 2 diabetes, and 8% had diabetes due to other causes. Characteristics of the total patient population were similar to patients with unknown diabetes classification. HbA1c levels decreased over the years, while BMI levels showed an increase over time. Conclusions The national DPARD registry aims to facilitate investigation of prevalence and long-term outcomes of Dutch outpatients with diabetes mellitus and their treatment, thus allowing for quality improvement of diabetes care as well as allowing for comparison of diabetes care on an international level.

OBJECTIVE To evaluate the efficacy of aluminum-formulated intralymphatic glutamic acid decarboxylase (GAD-alum) therapy combined with vitamin D supplementation in preserving endogenous insulin secretion in all patients with type 1 diabetes (T1D) or in a genetically prespecified subgroup. RESEARCH DESIGN AND METHODS In a multicenter, randomized, placebo-controlled, double-blind trial, 109 patients aged 12–24 years (mean ± SD 16.4 ± 4.1) with a diabetes duration of 7–193 days (88.8 ± 51.4), elevated serum GAD65 autoantibodies, and a fasting serum C-peptide >0.12 nmol/L were recruited. Participants were randomized to receive either three intralymphatic injections (1 month apart) with 4 μg GAD-alum and oral vitamin D (2,000 IE daily for 120 days) or placebo. The primary outcome was the change in stimulated serum C-peptide (mean area under the curve [AUC] after a mixed-meal tolerance test) between baseline and 15 months. RESULTS Primary end point was not met in the full analysis set (treatment effect ratio 1.091 [CI 0.845–1.408]; P = 0.5009). However, GAD-alum–treated patients carrying HLA DR3-DQ2 (n = 29; defined as DRB1*03, DQB1*02:01) showed greater preservation of C-peptide AUC (treatment effect ratio 1.557 [CI 1.126–2.153]; P = 0.0078) after 15 months compared with individuals receiving placebo with the same genotype (n = 17). Several secondary end points showed supporting trends, and a positive effect was seen in partial remission (insulin dose–adjusted HbA1c ≤9; P = 0.0310). Minor transient injection site reactions were reported. CONCLUSION Intralymphatic administration of GAD-alum is a simple, well-tolerated treatment that together with vitamin D supplementation seems to preserve C-peptide in patients with recent-onset T1D carrying HLA DR3-DQ2. This constitutes a disease-modifying treatment for T1D with a precision medicine approach.

Objective: We hypothesized that modelling catch-up growth (CUG) as developed for coeliac disease (CD), might also fit CUG in adequately treated children with juvenile hypothyroidism (JHT) or growth hormone deficiency (GHD). Methods: We used a monomolecular function for all available prepubertal data on height standard deviation score (HSDS) minus target height SDS (adjHSDS) in children with JHT (n=20) and GHD (n=18) on a conventional (CoD) or high GH dose (HD), based either on a national height reference with an age cut-off of 10 (girls) and 12 (boys) years (model 1) or prepubertal height reference values, if age (0) was ≥3, with no upper age limit (model 2). Results: The models could be fitted in 83-90% of cases; in other cases the HSDS decreased after several measurements, which violated the assumption of an irreversible growth process. In JHT, the rate constant (k) and adjHSDS (0) were lower than in CD (p=0.02), but adjHSDS (end) was similar. In GHD (model 1), k was lower than for CD (p=0.004) but similar to JHT, while adjHSDS (0) and adjHSDS (end) were similar to CD and JHT. Thus, the shape of CUG is similar for children with JHT and GHD, while children with CD had less growth deficit at start and a faster CUG. The differences in CUG parameters between GH dose subgroups did not reach statistical significance. Conclusion: Modelling CUG of prepubertal children with JHT and GHD can be used for assessing the adequacy of CUG and the influence of clinical treatment modalities on its speed and magnitude.

Introduction Transition from paediatric to adult endocrinology is a challenge for adolescents, their families and their healthcare professionals. Previous studies show that up to 25% of young adults with endocrine disorders are lost to follow-up once they move out of paediatric care. This poses a health risk for young adults, as lack of medical treatment and surveillance can have both psycho-social and physical consequences. Apart from absenteeism from school or work, this can lead to serious and expensive medical complications like Addison crisis. Methods In 2019 we studied electronic medical records of 387 patients who were over 15 years old when they attended the paediatric endocrine outpatient clinic (OPC) of our medical centre in 2013-2014. We collected data from medical charts, the hospital digital agenda and medical correspondence. Results Of 387 adolescents, 161 (42%) did not need adult endocrine follow-up because paediatric endocrine care was only puberty- or growth-related. Forty-six patients did not enter regular transition because they 1) participated in a pilot to improve transition (N=10), 2) had intellectual disability (ID) and transferred to ID care (N=28), or 3) died (N=8, mostly cancer-related). Hundred-and-eighty patients entered regular transition: 49 (27%) to a regional hospital and 131 (73%) within our university hospital. Of these 131 patients, 33 (25%) were lost to follow up; in 24 of them (73%), the invitation for the adult OPC had never been sent. Loss to follow up occurred when three subsequent critical steps failed: 1) the adult endocrinologist had not received or read the paediatrician’s referral letter and/or had not invited the patient; 2) the paediatrician had not checked whether the appointment was really made and received by the patient and 3) the patients and/or caregivers had not alarmed the hospital when no invitation for an appointment was received. Conclusion We found a 25% dropout during transfer from paediatric to adult tertiary endocrine care. Starting the transition process early and in a structured manner, as well as assigning a transition coordinator, can prevent part of the dropouts. However, 73% of all dropouts appeared to be attributable to failure of practical, logistic steps. In order to prevent this part of the dropouts, we provide practical recommendations for all three parties involved: 1) the adult endocrinologist should carefully read paediatricians’ letters and check whether action is required (i.e. check whether an appointment is requested) 2) the paediatrician should ascertain whether the appointment is really made and received by the patient 3) the patients and/or caregivers should be instructed to alarm the hospital when they do not receive the appointment. These actions require relatively little effort and may prevent the part of drop-outs that is caused by logistic failures.

Most girls with Turner syndrome have hypergonadotropic hypogonadism and need hormonal replacement – for induction of puberty and later maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at 11–12 years old, with a very low dose and increase over 2–3 years. Initiation with low doses of estradiol is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. We suggest transdermal estrogen and oral progestin and discuss other approaches. We also discuss linear growth, metabolic markers, neurocognition, socialization, and bone and uterine health as related to hormonal replacement.

Background Type 1 diabetes (T1D) is a chronic metabolic condition requiring intensive daily self-care to avoid both high and low blood glucose levels. Self-care and glycemic outcomes are particularly problematic in adolescence, a period known for its increased risk of emotional problems. However, the true scope of mood and anxiety disorders in adolescents with T1D is unknown. Earlier studies are limited by a small sample size, lack of diagnostic interview data, a focus on depression only, non-adolescent specific estimates, lack of information about parental emotional problems and/or a cross-sectional design. Diabetes LEAP is a two-year prospective observational cohort study examining (a) the prevalence and course of depression and anxiety in adolescents with T1D and their parents/caregivers, (b) the risk factors predicting the presence of these emotional problems, (c) their longitudinal relation with diabetes outcomes, and (d) the psychosocial care currently in place. Methods Adolescents (12–18 years) from 8 Dutch pediatric diabetes clinics are interviewed using the DISC-IV to establish the presence of mood and anxiety disorders in the previous 4 weeks, the previous 12 months, and lifetime. They also complete questionnaires, including CDI-2, GAD-7, and PAID-T. Parents/caregivers complete PHQ-9, GAD-7, and PAID-PR. Follow-up assessments take place after 1 and 2 years. Discussion This longitudinal study with diagnostic interviews in a large cohort of adolescents with T1D in the Netherlands will provide much needed information regarding the prevalence and course of depression and anxiety in this group, thereby opening avenues for proper recognition, prevention and timely treatment.

Context: Most girls with Turner syndrome (TS) have hypergonadotropic hypogonadism and need hormonal replacement for induction of puberty and then for maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The optimal estrogen replacement regimen is still being studied.Evidence Acquisition: We conducted a systematic search of PubMed for studies related to TS and puberty.Evidence Synthesis: The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at age 11 to 12 years, with dose increases over 2 to 3 years. Initiation with low-dose estradiol (E2) is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. For adults who have undergone pubertal development, we suggest transdermal estrogen and oral progestin and discuss other approaches. We discuss linear growth, lipids, liver function, blood pressure, neurocognition, socialization, and bone and uterine health as related to hormonal replacement.Conclusion: Evidence supports the effectiveness of starting pubertal estrogen replacement with low-dose transdermal E2. When transdermal E2 is unavailable or the patient prefers, evidence supports use of oral micronized E2 or an intramuscular preparation. Only when these are unavailable should ethinyl E2 be prescribed. We recommend against the use of conjugated estrogens. Once progestin is added, many women prefer the ease of use of a pill containing both an estrogen and a progestin. The risks and benefits of different types of preparations, with examples, are discussed.

Contains fulltext : 177474.pdf (Publisher’s version ) (Open Access) BACKGROUND: Raising a child with type 1 diabetes (T1D) means combining the demands of the disease management with everyday parenting, which is associated with increased levels of distress. A Web-based patient portal, Sugarsquare, was developed to support parents, by providing online parent-professional communication, online peer support and online disease information. OBJECTIVE: The first aim of this study was to assess the feasibility of conducting a multicenter, randomized controlled trial in Dutch parents of a child with T1D. The second aim was to assess the feasibility of implementing Sugarsquare in clinical practice. METHODS: The parents of 105 children (N=105) with T1D below the age of 13 participated in a 6-month multicenter randomized controlled feasibility trial. They were randomly assigned to an experimental (n=54, usual care and Sugarsquare) or a control group (n=51, usual care). Attrition rates and user statistics were gathered to evaluate feasibility of the trial and implementation. To determine potential efficacy, the parenting stress index (PSI-SF) was assessed at baseline (T0) and after 6 months (T1). RESULTS: Of a potential population of parents of 445 children, 189 were willing to participate (enrollment refusal=57.5%, n=256), 142 filled in the baseline questionnaire (baseline attrition rate=25%, n=47), and 105 also filled in the questionnaire at T1 (post randomization attrition rate during follow-up=26%, n=32). As such, 24% of the potential population participated. Analysis in the experimental group (n=54) revealed a total of 32 (59%) unique users, divided into 12 (38%) frequent users, 9 (28%) incidental users, and 11 (34%) low-frequent users. Of the total of 44 professionals, 34 (77%) logged in, and 32 (73%) logged in repeatedly. Analysis of the user statistics in the experimental group further showed high practicability and integration in all users, moderate acceptability and demand in parents, and high acceptability and demand in health care professionals. Baseline parenting stress index scores were related to the parents' frequency of logging on (rho=.282, P=.03) and page-views (rho=.304, P=.01). No significant differences in change in parenting stress between experimental and control group were found (F3,101=.49, P=.49). CONCLUSIONS: The trial can be considered feasible, considering the average enrollment refusal rate, baseline attrition rate and postrandomization attrition rate, compared to other eHealth studies, although lower than hypothesized. Implementing Sugarsquare in clinical practice was partly feasible, given moderate demand and acceptability in parent users and lack of potential efficacy. Parents who reported higher levels of parenting stress used Sugarsquare more often than other parents, although Sugarsquare did not reduce parenting stress. These results indicate that Web-based interventions are a suitable way of providing parents of children with T1D with additional support. Future studies should determine how Sugarsquare could reduce parenting stress, for instance by adding targeted interventions. Factors potentially contributing to successful implementation are suggested. TRIAL REGISTRATION: Nederlands Trial Register Number: NTR3643; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3643 (Archived by WebCite at http://www.webcitation.org/6qihOVCi6).

Background/Aims: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost-effectiveness of GH treatment dosed per m2 BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS). Methods: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies. Results: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m2 equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m2 BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m2 BSA. Conclusion: Dosing GH per m2 BSA is at least as efficacious as dosing per kg BW, and is more cost-effective.

The ZAC1 gene, mapped to the 6q24 region, is part of a network of co-regulated imprinted genes involved in the control of embryonic growth. Loss of methylation at the ZAC1 differentially methylated region (DMR) is associated with transient neonatal diabetes mellitus, a developmental disorder involving growth retardation and diabetes in the first weeks of post-natal life. We assessed whether the degree of methylation of the ZAC1 DMR in leukocytes DNA extracted from cord blood is associated with fetal, birth and post-natal anthropometric measures or with C-peptide concentrations in cord serum. We also searched for an influence of dietary intake and maternal parameters on ZAC1 DMR methylation. We found positive correlations between the ZAC1 DMR methylation index (MI) and estimated fetal weight (EFW) at 32 weeks of gestation, weight at birth and weight at one year of age (respectively, r = 0.15, 0.09, 0.14; P values = 0.01, 0.15, 0.03). However, there were no significant correlations between the ZAC1 DMR MI and cord blood C-peptide levels. Maternal intakes of alcohol and of vitamins B2 were positively correlated with ZAC1 DMR methylation (respectively, r = 0.2 and 0.14; P = 0.004 and 0.04). The influence of ZAC1 seems to start in the second half of pregnancy and continue at least until the first year of life. The maternal environment also appears to contribute to the regulation of DNA methylation.

Neonatal encephalitis caused by herpes simplex virus (HSV) is a familiar disease with a high mortality and morbidity rate. Isolated skin-eye-mouth infection is less familiar among professionals. In this article we present two neonates with an isolated skin lesion caused by an HSV infection. Of the neonates infected with HSV, 40-45% show isolated skin-eye-mouth disease. With correct treatment, the risk of spread to the central nervous system will decrease from 50-60% to 5-10%. Typical HSV skin lesions may present at a late stage of the disease or may be masked by a secondary bacterial infection. When a neonate presents with atypical skin lesions starting 7-12 days after the birth, immediate testing for HSV and immediate treatment are required, to decrease the risk of further progression of the disease.

Objectives/Hypothesis. Oxandrolone (Ox) increases height gain but may also cause voice deepening in growth hormone (GH)-treated girls with Turner syndrome (TS). We assessed the effect of Ox on objective and subjective speaking voice frequency in GH-treated girls with TS. Study Design. A multicenter, randomized, placebo (Pl)-controlled, double-blind study was conducted. Methods. One hundred thirty-three patients were included and treated with GH (1.33 mg/m(2)/d) from baseline, combined with Pl or Ox in a low (0.03 mg/kg/d) or conventional (0.06 mg/kg/d) dose from the age of 8 years and estrogens from the age of 12 years. Yearly from starting Ox/Pl until 6 months after discontinuing GH + Ox/Pl, voices were recorded and questionnaires were completed. Results. At start, mean (+/- standard deviation [SD]) voice frequency SD score (SDS) was high for age (1.0 +/- 1.2, P < 0.001) but normal for height. Compared with GH + Pl, voices tended to lower on GH + Ox 0.03 (P = 0.09) and significantly lowered on GH + Ox 0.06 (P = 0.007). At the last measurement, voice frequency SDS was still relatively high in OH + PI group (0.6 +/- 0.7, P = 0.002) but similar to healthy girls in both OH + Ox groups. Voice frequency became lower than 2 SDS in one patient (3%) on OH + Ox 0.03 and three patients (11%) on GH + Ox 0.06. The percentage of patients reporting subjective voice deepening was similar between the dosage groups. Conclusions. Untreated girls with TS have relatively high-pitched voices. The addition of Ox to GH decreases voice frequency in a dose-dependent way. Although most voice frequencies remain within the normal range, they may occasionally become lower than -2 SDS, especially on OH + Ox 0.06 mg/kg/d.

Item does not contain fulltext There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3-4.6 cm. If Ox dosages

Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens.van Pareren YK, de Muinck Keizer-Schrama SM, Stijnen T, Sas TC, Jansen M, Otten BJ, Hoorweg-Nijman JJ, Vulsma T, Stokvis-Brantsma WH, Rouwe CW, Reeser HM, Gerver WJ, Gosen JJ, Rongen-Westerlaken C, Drop SL.Department of Pediatrics, Division of Endocrinology, Erasmus University MC/Sophia Children's Hospital, 3015 GJ Rotterdam, The Netherlands. vanpareren@zonnet.nlAlthough GH treatment for short stature in Turner syndrome is an accepted treatment in many countries, which GH dosage to use and which age to start puberty induction are issues of debate. This study shows final height (FH) in 60 girls with Turner syndrome treated in a randomized dose-response trial, combining GH treatment with low dose estrogens at a relatively young age. Girls were randomly assigned to group A (4 IU/m(2).d; approximately 0.045 mg/kg/d), group B (first year, 4 IU/m(2).d; thereafter 6 IU/m(2).d), or group C (first year, 4 IU/m(2).d; second year, 6 IU/m(2).d; thereafter, 8 IU/m(2).d). After a minimum of 4 yr of GH treatment, at a mean age of 12.7 +/- 0.7 yr, low dose micronized 17beta-estradiol was given orally. After a mean duration of GH treatment of 8.6 +/- 1.9 yr, FH was reached at a mean age of 15.8 +/- 0.9 yr. FH, expressed in centimeters or SD score, was 157.6 +/- 6.5 or -1.6 +/- 1.0 in group A, 162.9 +/- 6.1 or -0.7 +/- 1.0 in group B, and 163.6 +/- 6.0 or -0.6 +/- 1.0 in group C. The difference in FH in centimeters, corrected for height SD score and age at start of treatment, was significant between groups A and B [regression coefficient, 4.1; 95% confidence interval (CI), 1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3, 7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI, -1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD score, more than -2). After starting estrogen treatment, the decrease in height velocity (HV) changed significantly to a stable HV, without affecting bone maturation (change in bone age/change in chronological age). The following variables contributed significantly to predicting FH SD score: GH dose, height SD score (ref. normal girls), chronological age at start of treatment, and HV in the first year of GH treatment. GH treatment was well tolerated. In conclusion, GH treatment leads to a normalization of FH in most girls, even when puberty is induced at a normal pubertal age. The optimal GH dosage depends on height and age at the start of treatment and first year HV

In dit overzichtsartikel worden de recente inzichten besproken betreffende effectiviteit en veiligheid van groeibevorderende behandelingen bij meisjes met het syndroom van Turner (ts). Tegenwoordig betekent dit vooral behandeling met biosynthetisch groeihormoon (gh). Het doel van de behandeling met groeihormoon is het verbeteren van de lengte tijdens de kinderjaren en de volwassen lengte, om daarmee de praktische problemen en de psychosociale belasting van het klein zijn te verminderen. Volgens de huidige kennis kan de behandeling met de standaard-gh-dosis van 1,4 mg/m2/dag (= 4 ie/m2/dag) resulteren in normale lengtegroei tijdens de kinderjaren met als gevolg het bereiken van een normale volwassen lengte, mits de behandeling op jonge leeftijd, dat wil zeggen voor het 8e-9e jaar, wordt gestart. Er zijn aanwijzingen dat hogere gh-doses of toevoegen van het anabole steroid oxandrolon nog effectiever zijn, maar de definitieve resultaten van dergelijke onderzoeken dienen te worden afgewacht. gh-behandeling heeft geen evidente negatieve effecten op de lichaamsverhoudingen, veroorzaakt geen linkerventrikelhypertrofie van het hart en leidt niet tot verslechtering van de reeds bestaande relatief hoge bloeddruk bij meisjes met ts. gh-behandeling leidt wel tot toename van de insulinewaarden, echter zonder effect op de glucosewaarden, wat duidt op relatieve insulineresistentie. Na het staken van de gh-behandeling dalen de insulinewaarden weer naar waarden die vergelijkbaar zijn met die van voor de behandeling. Tijdens de gh-behandeling neemt het hdl-cholesterol toe, terwijl totaal cholesterol en ldl-cholesterol afnemen. De botdichtheid neemt toe. Het uitstellen van puberteitsinductie om daarmee een betere volwassen lengte te bewerkstelligen, is niet noodzakelijk als de gh-behandeling op een jonge leeftijd en met een adequate dosis gestart wordt. gh-behandeling lijkt een effectieve en veilige behandeling te zijn, maar voorzichtigheid blijft geboden en follow-up van behandelde meisjes is daarom essentieel.

Turner syndrome occurs in women who are missing one X chromosome. The most obvious symptoms are small stature and ovarian failure. Turner patients have an increased risk of a large number of disorders, and should therefore have lifelong medical supervision. Recent insights into patient management have been incorporated into the guidelines. Patients are increasingly involved in their own treatment. In patients with 45,X karyotype, Y-chromosomal material is actively sought in a larger number of cells and/or other tissues, using FISH. Pubertal induction therapy, if required, is initiated at an appropriate age. Egg donation or vitrification are new therapeutic options for fertility treatment. Monitoring for cardiac and vascular disease using cardiac ultrasound and MRI is performed more often, partly in connection with the risk of aortal dissection. The coordination of care of patients with Turner syndrome is concentrated in specialized centres in the Netherlands and Belgium.

Item does not contain fulltext OBJECTIVE: To evaluate karyotype-specific ear and hearing problems in young-adult patients with Turner syndrome (TS) and assess the effects of previous treatment with oxandrolone (Ox). STUDY DESIGN: Double-blind follow-up study. SETTING: University hospital. PATIENTS: Sixty-five TS patients (mean age, 24.3 yr) previously treated with growth hormone combined with placebo, Ox 0.03 mg/kg per day, or Ox 0.06 mg/kg per day from the age of 8 years and estrogen from the age of 12 years. INTERVENTION: Ear examination was performed according to standard clinical practice. Air- and bone conduction thresholds were measured in decibel hearing level. MAIN OUTCOME MEASURES: We compared patients with total monosomy of the short arm of the X chromosome (Xp), monosomy 45,X and isochromosome 46,X,i(Xq), with patients with a partial monosomy Xp, mosaicism or other structural X chromosomal anomalies. We assessed the effect of previous Ox treatment. RESULTS: Sixty-six percent of the patients had a history of recurrent otitis media. We found hearing loss in 66% of the ears, including pure sensorineural hearing loss in 32%. Hearing thresholds in patients with a complete monosomy Xp were about 10 dB worse compared with those in patients with a partial monosomy Xp. Air- and bone conduction thresholds were not different between the placebo and Ox treatment groups. CONCLUSION: Young-adult TS individuals frequently have structural ear pathology, and many suffer from hearing loss. This indicates that careful follow-up to detect ear and hearing problems is necessary, especially for those with a monosomy 45,X or isochromosome 46,X,i(Xq). Ox does not seem to have an effect on hearing.

OBJECTIVE To assess possible side-effects of long-term continuous growth hormone (GH) treatment on carbohydrate (CH) metabolism in children with short stature born small for gestational age. DESIGN In a prospective, randomised double-blind, dose–response multicentre trial, the effect of GH treatment on CH metabolism was evaluated, comparing two GH dosages [3 vs. 6 IU/(m2 body surface·day)]. PATIENTS Seventy-eight children with short stature (height SD-score

The aim of this study was to assess body proportions in children with short stature born small for gestational age (SGA) before and during 6 years of growth hormone (GH) treatment. A prospective randomised double-blind dose-response study comparing the effects of 3 vs. 6 IU GH/m2/day. Seventy-nine children with short stature (height SD-score < -1.88) born small for gestational age (birth length SD-score < -1.88). Before and during GH treatment, height, sitting height (SH), hand (Hand) and foot length (Foot), biacromial (Biac) and biiliacal diameter (Biil) were measured. All results were adjusted for age and sex, and expressed as SD-scores (SDS) using reference values for healthy Dutch children. To describe the size of SH, Hand, Foot, Biac, and Biil in relation to height, these values were adjusted for the SDS of height. At baseline, these short children had small hands and feet and narrow shoulders and pelvis compared to healthy peers. Height and SH, were, however, even more affected. Consequently, on average, these children had relatively large hands and feet, and relatively broad shoulders and pelvis compared to their height, but a normal sitting height in proportion to height. In most of the individuals, the values for body proportions were, however, within the normal range. During 6 years of GH treatment the SD-scores of all measurements increased significantly towards values more close to zero. The mean size of Hand, Foot, and Biil decreased in proportion to height. The mean SH increased relatively more than height, however, to values well within the normal range. The mean Biac in relation to height had not changed after 6 years of GH treatment. No differences in the 6-year changes in body proportions were found between the two GH dosage groups. Untreated short children born small for gestational age have, on average, relatively large hands and feet, and broad shoulders and pelvis, but a normal sitting height compared to height. The increase in height during 6 years of GH treatment is accompanied by an improvement of the proportions of the size of hands, feet, and biiliacal diameter, in relation to height. The increase in height appeared to be the result of the increase in sitting height as well as leg length, but the sitting height SD-score increased slightly more than that of leg length. The changes in body proportion during GH treatment were dose-independent. Thus, 6-year continuous GH treatment with either 3 or 6 IU/m2/day in children with short stature born small for gestational age does not negatively influence body proportions.

To assess the effects of long-term continuous GH treatment on body composition, blood pressure (BP), and lipid metabolism in children with short stature born small for gestational age (SGA), body mass index (BMI), skinfold thickness measurements, systemic BP measurements, and levels of blood lipids were evaluated in 79 children with a baseline age of 3‐11 yr with short stature (height SD-score, ,21.88) born SGA (birth length SD-score, ,21.88). Twenty-two of the 79 children were GH deficient (GHD). All children participated in a randomized, double-blind, dose-response multicenter GH trial. Fourand 6-yr data were compared between two GH dosage groups (3 vs. 6 IU/m 2 body surface/day). Untreated children with short stature born SGA are lean (mean BMI SD-score, 21.3; mean SD-score skinfolds, 20.8), have a higher systolic BP (SD-score, 0.7) but normal diastolic BP (SD-score, 20.1), and normal lipids (total cholesterol, 4.7 mmol/L; low-density lipoprotein, 2.9 mmol/L; high-density lipoprotein, 1.3 mmol/L) compared with healthy peers. During long-term continuous GH treatment, the BMI normalized without overall changes in sc fat compared with age-matched references, whereas the BP SD-score and the atherogenic index decreased significantly. Although the mean 6-yr increase in height SD-score was significantly higher in the children receiving GH treatment with 6 IU/m 2 zday (2.7) than in those receiving treatment with 3 IU/m 2 zday (2.2), no differences in the changes in BMI, skinfold measurements, BP, and lipids were found between the GH dosage groups. The pretreatment SD-scores for BMI, skinfold, and BP, as well as the lipid levels, were not significantly different between GHD and non-GHD children, but after 6 yr of GH treatment the skinfold SD-score and BP SD-score had decreased significantly more in the GHD than in the non-GHD children. Our data indicate that GH treatment has at least up to 6 yr positive instead of negative effects on body composition, BP, and lipid metabolism. In view of the reported higher risk of cardiovascular diseases in later life in children born SGA, further research into adulthood remains warranted. (J Clin Endocrinol Metab 85: 3786 ‐3792, 2000)

OBJECTIVE To assess possible side-effects of treatment with supraphysiological GH dosages on carbohydrate (CH) metabolism in girls with Turner syndrome (TS) during GH treatment until adult height is reached as well as after discontinuation of GH treatment. DESIGN In a prospective, randomized injection frequency-response study, the effect of GH treatment in combination with low dose ethinyl oestradiol on CH metabolism was evaluated, comparing twice daily (BID) with once daily (OD) injections of a total GH dose of 6 U/m2/day until adult height was reached. PATIENTS Nineteen untreated girls with TS, mean (SD) pretreatment age 13.3 (1.7) (range 11.0–17.6) year. MEASUREMENTS Glucose and insulin concentrations during oral glucose tolerance tests (OGTT) were measured before and during GH treatment, as well as at 6 months after discontinuation of GH treatment. RESULTS GH treatment was discontinued after a mean of 43 (range 27–57) months. In one of the 19 girls, a different girl at each time point before, during and after discontinuation of GH treatment, the glucose response to OGTT after 120 minutes was above 7.8 mmol/l but below 11.1 mmol/l, indicating impaired glucose tolerance. None of the girls developed diabetes mellitus. Fasting glucose levels did not significantly change during, or after discontinuation of GH treatment. The 3 h area under the curve for time–concentration adjusted for fasting levels during the OGTT for glucose showed a significant decrease during GH treatment. In contrast to the glucose levels, GH treatment induced considerably higher insulin levels compared to pretreatment values. After discontinuation of GH insulin levels decreased to values comparable with pretreatment levels. None of these observed changes were different between the GH injection frequency groups. The changes in CH variables during and after discontinuation of GH were not related to changes in body mass index. CONCLUSIONS GH treatment with 6 U/m2/day in combination with low dose ethinyl oestradiol in girls with Turner syndrome aged ≥ 11 years did not negatively influence glucose levels, but induced higher levels of insulin indicating relative insulin resistance. These changes in insulin levels were independent of the frequency of the GH injections (once vs. twice daily). After discontinuation of GH treatment, insulin values decreased to baseline levels.

OBJECTIVE The aim of this study was to assess the volumetric bone mineral density (BMD) in girls with Turner's syndrome (TS) before and during growth hormone (GH) treatment in combination with low dose oestrogens as well as three years after discontinuation of GH treatment. DESIGN In a prospective, randomized injection frequency-response study, the effect of GH treatment in combination with low dose ethinyl oestradiol (starting with 0.05 μg/kg/day), on BMD was evaluated, comparing twice daily (BID) with once daily (OD) injections of a total GH dose of 6 IU/m2/day until adult height was reached. After discontinuation of GH treatment, the dosage of oestrogens was further increased to adult supplementation levels. PATIENTS Nineteen untreated girls with TS, mean (SD) baseline pretreatment age 13.3 (1.7) (range 11.0–17.6) year. MEASUREMENTS Before and during GH treatment, measurements of volumetric BMD were performed using phalangeal radiographic absorptiometry. In addition, the BMD measurements were repeated three years after discontinuation of GH treatment. BMD results were adjusted for bone age and sex, and expressed as SD-scores (SDS) using reference values of healthy Dutch girls. RESULTS At baseline, most individual BMD values of cortical bone as well as those of trabecular bone were within the normal range of healthy girls. However, the mean BMD SDS of the trabecular bone was significantly lower than zero. During treatment, the BMD SDS showed a significant increment to values equal or higher than zero after mean (SD) GH treatment period of 36.6 (7.5) months. The increase in BMD of the cortical bone was significantly higher in the OD group than in the BID group. The BMD SDS in the last year of GH treatment was not significant different between the two injection frequency groups. Three years after discontinuation of GH treatment, the BMD values had increased further similar as in healthy girls, resulting in BMD values all within normal range or even higher. CONCLUSIONS Most untreated girls with Turner syndrome, age ≥ 11 years, have a normal volumetric BMD of the cortical, as well as of the trabecular bone compared to healthy girls. During GH treatment with 6 IU/m2/day in combination with low dose oestrogens, the BMD SDS increases significantly. After discontinuation of GH treatment and the use of oestrogens in an adult dosage, the BMD was as high as in young healthy women.

To assess possible side-effects of GH treatment with supraphysiological doses on carbohydrate (CH) metabolism in girls with Turner syndrome (TS) during long term GH treatment and after discontinuation of GH treatment, the results of oral glucose tolerance tests and hemoglobin A1c measurements were analyzed in 68 girls with TS participating in a randomized dose-response trial. These previously untreated girls, aged 2–11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m2·day (∼0.045 mg/kg·day); group B, first year ,4 IU/m2·day; thereafter, 6 IU/m2·day (∼0.0675 mg/kg·day); group C, first year, 4 IU/m2·day; second year, 6 IU/m2·day; thereafter, 8 IU/m2·day (∼0.090 mg/kg·day). After the first 4 yr, girls 12 yr of age or older started with 5 μg/kg BW·day 17β-estradiol for induction of puberty. To assess the effects of long term high dose GH treatment on CH metabolism, the 7-yr data from the oral glucose tolerance tests in 9 girls of group C were evaluated (group C1). To determine whether th...

Prenatal exposure to polychlorinated biphenyls (PCBs) and dioxins is associated with changes in the T-cell lymphocyte population in healthy Dutch infants. We investigated whether these changes persist into later childhood and whether background exposure to PCBs and dioxins is associated with the prevalence of infectious or allergic diseases and humoral immunity at preschool age. The total study group consisted of 207 healthy mother-infant pairs. We estimated prenatal exposure to PCBs and dioxins by the sum of PCBs 118, 138, 153, and 180 (sigmaPCB) in maternal and cord plasma and in breast-fed infants by the dioxin, planar, and mono-ortho PCB toxic equivalent (TEQ) levels in human milk. At 42 months of age, current body burden was estimated by the PCB in plasma. We assessed the prevalence of infectious and allergic diseases by parent questionnaire, and measured humoral immunity by antibody levels for mumps, measles, and rubella after primary vaccination. We performed immunologic marker analyses of lymphocytes in a subgroup of 85 children. Prenatal PCB exposure was associated with an increased number of lymphocytes, T-cells, and CD3CD8(+) (cytotoxic), CD4(+)CD45RO(+) (memory), T-cell receptor (TcR) [alpha]ss(+), and CD3(+)HLA-DR(+) (activated) T cells and lower antibody levels to mumps and measles at preschool age. Adjusted for confounders, prenatal PCB exposure was associated with less shortness of breath with wheeze, and current PCB body burden was associated with a higher prevalence of recurrent middle-ear infections and of chicken pox and a lower prevalence of allergic reactions. A higher dioxin TEQ was associated with a higher prevalence of coughing, chest congestion, and phlegm. We conclude that in Dutch preschool children the effects of perinatal background exposure to PCBs and dioxins persist into childhood and might be associated with a greater susceptibility to infectious diseases. Common infections acquired early in life may prevent the development of allergy, so PCB exposure might be associated with a lower prevalence of allergic diseases.

Short stature and ovarian failure are the main features in Turner syndrome (TS). To optimize GH and estrogen treatment, we studied 68 previously untreated girls with TS, age 2–11 yr, who were randomly assigned to one of three GH dosage groups: group A, 4 IU/m2·day (≈0.045 mg/kg·day); group B, first yr 4, thereafter 6 IU/m2·day (≈0.0675 mg/kg/day); group C, first yr 4, second yr 6, thereafter 8 IU/m2·day (≈0.090 mg/kg·day). In the first 4 yr of GH treatment, no estrogens for pubertal induction were given to the girls. Thereafter, girls started with 17β-estradiol (5 μg/kg bw·day, orally) when they had reached the age of 12 yr. Subjects were followed up until attainment of adult height or until cessation of treatment because of satisfaction with the height achieved. Seven-year data of all girls were evaluated to compare the growth-promoting effects of three GH dosages during childhood. After 7 yr, 85% of the girls had reached a height within the normal range for healthy Dutch girls. The 7-yr increment in hei...

To assess body proportions in girls with Turner syndrome (TS) during long term GH treatment, height, sitting height (SH), hand (Hand) and foot (Foot) lengths, and biacromial (Biac) and biiliacal (Biil) diameters were measured in 68 girls with TS participating in a GH dose-response trial. These previously untreated girls with TS, aged 2‐11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m 2 zday; group B, first year 4 and thereafter 6 IU/m 2 zday; group C, first year 4, second year 6, and thereafter 8 IU/m 2 zday. Seven-year data were evaluated to assess the effect of GH treatment on body proportions during childhood. In addition, data from all girls who had reached adult height were evaluated to determine the effect on the adult body proportions. All results were adjusted for age and sex and expressed as SD scores using reference values of healthy Dutch girls. To describe the proportions of SH, Hand, Foot, Biac, and Biil to height, these values were adjusted for the SD score of height and were expressed as shape values, using the formula, e.g. for SH: shape SH 5 (SH SD score 2 height SD score)/=(2 2 2 3 correlation coefficient between SH and height in the reference population). Furthermore, SD scores using references of untreated girls with TS were calculated for height and SH. Values less than 22 or more than 12 were considered outside the normal range. At baseline, the shape values of all measurements were significantly higher than zero, but most mean shape values were still within the normal range. Seven-year data of 64 girls and adult height data of 32 girls showed that an increase in height was accompanied by an even higher increase in Foot, resulting in mean SD scores above zero and shape values of 12 and higher. The increase in the shape value of Foot was significantly higher in groups B and C compared to that in group A after 7 yr of GH treatment, but there were no significant differences between the GH dosage groups in the girls who had reached adult height. The shape values of SH had decreased to values closer to zero after reaching adult height, especially in group A. A similar pattern in the relationship of SH to height was seen using references of girls with TS. No significant changes in the other proportions were found after reaching adult height. In conclusion, on the average, untreated girls with TS have relatively large trunk, hands, and feet, and broad shoulders and pelvis compared to height. The increase in height after long term GH treatment is accompanied by an even higher increase in Foot and a moderate improvement of the disproportion between height and SH. Recently published reference data from untreated adults with TS and the results of a different patient group receiving a comparable GH dosage suggest that the disproportionate growth of feet has to be considered a part of the natural development in TS, but might be influenced by higher GH dosages. The development of large feet can play a role in the decision of the girl to discontinue GH treatment in the last phase of growth. (J Clin Endocrinol Metab 84: 4622‐4628, 1999)

Objective: To assess the effects of long-term growth hormone (GH) treatment for short stature on left ventricular (LV) dimensions and systemic blood pressure (BP) in girls with Turner's syndrome without clinically relevant cardiac abnormalities. Study design: LV dimensions measured by echocardiography and systemic BP were assessed before and during 7 years of GH treatment in 68 girls with Turner's syndrome participating in a randomized dose-response study. These previously untreated girls, age 2 to 11 years, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m 2 /d; group B, first year 4 IU/m 2 /d, thereafter 6 IU/m 2 /d; group C, first year 4 IU/m 2 /d, second year 6 IU/m 2 /d, thereafter 8 IU/m 2 /d. After the first 4 years, girls ≥12 years of age began receiving 17β-estradiol, 5 μg/kg body weight per day, for induction of puberty. Results: At baseline the LV dimensions of almost every girl were within the normal range, and the mean SD scores were close to zero. During 7 years of GH treatment, the growth of the left ventricle was comparable to that of healthy girls. No signs of LV hypertrophy were found. Before the start of GH treatment, mean BP was within the normal range but significantly higher than in healthy control subjects. Diastolic BP and systolic BP were above the 90th percentile in 23% and 28% of the girls, respectively. After 7 years of treatment, these percentages were 14% and 36%, respectively (not significantly different from baseline). The SD score of the diastolic BP showed a small decrease after 7 years of treatment. The growth of the left ventricle and the development of BP were not different between the GH dosage groups. Conclusions: Long-term GH treatment, even at dosages up to 8 IU/m 2 /d, does not result in LV hypertrophy or hypertension in girls with Turner's syndrome. Continued observation into adulthood is recommended to monitor the further development of the relatively high BP and to ensure that GH treatment has no long-term negative effect on the heart. (J Pediatr 1999;135:470-76)

The growth-promoting effect of continuous GH treatment was evaluated over 5 yr in 79 children with short stature (height SD score, less than -1.88) born small for gestational age (SGA; birth length SD score, less than -1.88). Patients were randomly and blindly assigned to 1 of 2 GH dosage groups (3 vs. 6 IU/m2 body surface-day). GH deficiency was not an exclusion criterium. After 5 yr of GH treatment almost every child had reached a height well within the normal range for healthy Dutch children and in the range of their target height SD score. Only in children who remained prepubertal during the study period was the 5-yr increase in height SD score (HSDS) for chronological age significantly higher in the study group receiving 6 compared to 3 IU GH/m2 x day. Remarkably, the 5-yr increment in HSDS for chronological age was not related to spontaneous GH secretion, maximum GH levels after provocation, or baseline insulin-like growth factor I levels. GH treatment was associated with an acceleration of bone maturation regardless of the GH dose given. The HSDS for bone age and predicted adult height increased significantly. GH treatment was well tolerated. In conclusion, our 5-yr data show that long term continuous GH treatment at a dose of 3 or 6 IU/m2 x day in short children born SGA results in a normalization of height during childhood followed by growth along the target height percentile.

In the Dutch growth hormone (GH) registration database there are currently 552 GH-deficient children being treated, subcutaneously, with recombinant human GH six to seven times per week. Of those, 112 who have been treated for at least 2 years have reached final height. Mean age at start of therapy was 11.70 years. Mean GH dose was 15.5 IU/m2 body surface per week. Mean final height was 173.2 cm (boys) and 159.7 cm (girls) and –1.36 SD of the population mean. Of the patients, 73.2% and 63.4%, respectively, reached a final height above –2 SD of the population or within target limits. FH-SDS was higher compared with the results of earlier cohorts with different treatment regimens. Target height, GH peak value at diagnosis, age at start of GH therapy, height SDS (HSDS) at start of puberty, and duration of GH therapy were significantly correlated with final height. These results, combined with those of a prospective GH dose-response study, suggest that better long-term results can be obtained with early and prolonged treatment and if the GH dose is individually adapted to the short-term growth response. In an ongoing dose-response study, 68 girls with Turner’s syndrome, aged 2–11 years, were randomized into three dosage groups with a daily GH dose of: (group A) 4 IU/m2 body surface; (group B) 4 IU/m2 in the first year of therapy and 6 IU/m2 thereafter; (group C) 4 IU/m2 in the first year, 6 IU/m2 in the second year, and 8 IU/m2 thereafter. After 4 years of GH therapy, girls aged 12 years or older started low-dose oestrogen therapy. After 7 years of GH therapy, mean HSDS in all three groups had increased to values above the third percentile for healthy girls. Mean final height and final height gain of 25 girls was 159.1 and 12.5 cm, 161.8 and 14.6 cm, and 162.7 and 16.0 cm in groups A, B and C respectively. These long-term and final height results are more favourable than the results of earlier Dutch Turner’s syndrome studies. Possible explanations are the higher GH doses and/or the younger age at start of GH therapy.

ObjectiveShort stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment.Design and methodsDuring the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl,n=23; Ox 0.03,n=27; and Ox 0.06,n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition.ResultsHeight gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency.ConclusionOx 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.

The treatment of children with type 1 diabetes mellitus has improved dramatically over the last few decades. The maintenance of acceptable metabolic control, nevertheless, remains challenging because the success of treatment is so dependent on patient compliance. Children with type 1 diabetes and poor metabolic control are at risk of developing Mauriac syndrome, a condition characterised by hepatomegaly, growth retardation and cushingoid features. A similar complication may occur in type-1 or type-2 adult diabetics; namely, glycogenic hepatopathy. We describe two children, a 12-year-old girl and a 16-year-old boy, who presented with classic symptoms of Mauriac syndrome. After metabolic control was achieved, reduction of hepatomegaly and the disappearance of cushingoid features were observed, proving the reversibility of the syndrome. Awareness that this syndrome still exists despite improved insulin therapy is crucial for earlier recognition and treatment.

F rom embryogenesis to young adulthood, growth rate declines dramatically. This deceleration in growth velocity is most extreme in infancy with a more subtle slowing in growth velocity throughmid-childhood, interrupted by the pubertal growth spurt, after which the growth rate gradually declines to zero. While in the first years of life the length of healthy infants can cross the percentiles toward their genetic target height (TH) SDS, height tends to remain within a narrow “channel” on the growth charts between 3 years and the onset of puberty, close to the same percentile or SDS position. The tendency to keep to this narrow and predictable track of growth is called “canalization.” An SDS change of >0.25/year is rarely seen in longitudinal growth studies on normal children. A large variety of growth-retarding illnesses, including hypothyroidism, celiac disease (CD), malnutrition, Cushing syndrome or chronic steroid treatment, and growth hormone (GH) deficiency, can lead to a slowing in growth with a downward deviation from the standard growth curve. After release from these growth-inhibiting conditions, exaggerated acceleration in linear growth can occur. In 1963, Prader et al and Tanner introduced the term “catch-up growth” to describe this period of rapid linear growth in children that followed a period of growth inhibition, leading toward their original growth channel. The term catch-up growth is also used for the growth acceleration seen in 85% of infants born small for gestational age (SGA), although in these cases there is usually no information about the foregoing downward deviation. The term catch-up growth is mostly used for height. Catch-up growth has been defined as “a height velocity above the statistical limits of normality for age or maturity during a defined period of time, following a transient period of growth inhibition; the effect of catch-up growth is to take the child towards his/her pre-retardation growth curve.” Even though this definition would imply that for a proper assessment of catch-up growth the full growth trajectory has to be evaluated (up to adult height), only few studies on catch-up growth have included all parts of this trajectory (the phases of growth inhibition, growth acceleration, growth maintenance, and puberty and the achieved adult height in comparison with the genetic growth potential). Furthermore, several alternative definitions of catch-up growth have been used, for example (in children born SGA) reaching an SDS of > 2 for the reference population or a cut-off of a change

The diagnosis of Turner syndrome (TS) requires the presence of characteristic physical features in phenotypic females coupled with complete or partial absence of the second sex chromosome, with or without cell line mosaicism. Most girls with Turner syndrome (TS) are short in childhood as well as in adulthood. Short stature is mainly caused by haploinsufficiency of the short-stature homeobox-containing gene (SHOX) located on the X chromosome, but the precise mechanism is still unknown. Although girls with TS are not growth hormone (GH) deficient, treatment with biosynthetic recombinant human GH accelerates height velocity and increases adult height. A younger starting age, taller parents, a higher GH dose, daily GH injections, good compliance, good short-term effect, and the addition of low dose (0.03 mg/kg per day) of oxandrolone are associated with a higher gain in adult height during GH treatment. In most girls with TS, ovarian failure results in an absence of puberty. If growth-promoting therapy has been optimized, it is desirable and possible to start with low-dose estrogens at a pubertal age to induce puberty. Long-term GH treatment, even using a 1.5–2 times higher dose than the standard GH dose for TS, seems to be safe: no negative effect on heart contractility and ventricular function, aorta diameter and distensibility, blood pressure, glucose levels, blood lipids, and bone mineral density has been found. During GH treatment, a disproportionately greater increase of foot size than height is found in girls with TS, which has to be considered mainly a part of the natural development in TS, albeit influenced by higher GH dosages. Continued observation into adulthood is, however, required to assess possible long-term side effects of the increased insulin and IGF-I levels during GH treatment. Concerning the addition of Ox to GH, especially the higher (0.06 mg/kg per day) Ox dose results in abnormal voice deepening and other forms of virilization in a part of the girls. Growth promotion in TS aims to improve well-being and quality of life and decrease practical and psychosocial problems related to short stature. However, conclusive evidence for a beneficial effect of GH treatment on well-being in patients with TS is lacking. Consequently, clinicians should not only focus on height improvement but also consider other health-related problems (including infertility) in Turner patients.

McArdle disease is a hereditary myopathy caused by muscle phosphorylase deficiency. Patients experience painful muscle cramps after strenuous exercise; the condition is sometimes associated with rhabdomyolysis, myoglobinuria and resulting acute renal failure.A 12-year-old boy visited the Paediatric and Neurology outpatients' departments with symptoms of leg myalgia, occurring during the warming-up phase of soccer practice, which disappeared after a short rest. Detailed history-taking revealed that he already experienced pain while walking during early childhood. An elevated serum creatine kinase concentration in combination with the typical presentation led to the presumptive diagnosis 'McArdle disease', which was confirmed by molecular genetic analysis.There is no effective gene therapy; a multidisciplinary approach by a neurologist, paediatrician, physiotherapist and nutritionist is advised.

Background: The weak androgen oxandrolone (Ox) may increase height but may also affect glucose metabolism in girls with Turner syndrome (TS). Methods: In a randomized, placebo-controlled, double-blind study, we assessed the effect of Ox at a dosage of either 0.06 or 0.03 mg/kg/day on glucose metabolism in 133 growth hormone (GH)-treated girls with TS. Patients were treated with GH (1.33 mg/m2/day) from baseline, combined with placebo (Pl) or Ox from the age of 8, and estrogens from the age of 12. Oral glucose tolerance tests (OGTT) were performed, and HbA1c levels were measured before, during, and after discontinuing Ox/Pl therapy. Results: Insulin sensitivity, assessed by the whole-body insulin sensitivity index (WBISI) decreased during GH+Ox/Pl (p = 0.003) without significant differences between the dosage groups. Values returned to pre-treatment levels after discontinuing GH+Ox/Pl. On GH+Ox, fasting glucose was less frequently impaired (Ox 0.03, p = 0.001; Ox 0.06, p = 0.02) and HbA1c levels decreased more (p = 0.03 and p = 0.001, respectively) than on GH+Pl. Conclusions: We conclude that in GH-treated girls with TS, Ox at a dosage of 0.03 or 0.06 mg/kg/day does not significantly affect insulin sensitivity. Insulin sensitivity decreases during GH therapy, to return to a pre-treatment level after discontinuing therapy.