Geoffrey Ambler

The re-emerging burden of rickets: a decade of experience from Sydney

Aim: To define the demographics and clinical characteristics of cases presenting with nutritional rickets to paediatric centres in Sydney, Australia. Methods: Retrospective descriptive study of 126 cases seen from 1993 to 2003 with a diagnosis of vitamin D deficiency and/or confirmed rickets defined by long bone x ray changes. Results: A steady increase was seen in the number of cases per year, with a doubling of cases from 2002 to 2003. Median age of presentation was 15.1 months, with 25% presenting at less than 6 months of age. The most common presenting features were hypocalcaemic seizures (33%) and bowed legs (22%). Males presented at a younger age, with a lower weight SDS, and more often with seizures. The caseload was almost exclusively from recently immigrated children or first generation offspring of immigrant parents, with the region of origin predominantly the Indian subcontinent (37%), Africa (33%), and the Middle East (11%). Seventy nine per cent of the cases were born in Australia. Eleven cases (all aged <7 months) presented atypically with hyperphosphataemia. Conclusions: This large case series shows that a significant and increasing caseload of vitamin D deficiency remains, even in a developed country with high sunlight hours. Cases mirror recent immigration trends. Since birth or residence in Australia does not appear to be protective, screening of at risk immigrant families should be implemented through public health policies.

Congenital idiopathic growth hormone deficiency associated with prenatal and early postnatal growth failure

To assess the role of growth hormone in fetal and infant growth, we analyzed the pretreatment data on 52 patients with a diagnosis of congenital growth hormone deficiency before 2 years of age, obtained from the Kabi Pharmacia International Growth Study. These infants had reduced birth-length standard deviation scores, an excess of birth weight relative to length, and progressive growth failure. We conclude that congenital growth hormone deficiency may cause impaired growth in utero and early infancy, and that growth hormone plays an important role in perinatal and infantile growth.

Growth Hormone Research Society Workshop Summary: Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome

Context: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥ 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Conclusions: Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks.

Continuous Glucose Monitoring–Guided Insulin Adjustment in Children and Adolescents on Near-Physiological Insulin Regimens A randomized controlled trial

OBJECTIVE—This randomized controlled trial assesses the effect on glycemic control of continuous glucose monitoring system (CGMS)-guided insulin therapy adjustment in young people with type 1 diabetes on intensive diabetes treatment regimens with continuous subcutaneous insulin infusion (CSII) or glargine. RESEARCH DESIGN AND METHODS—Pediatric subjects were recruited if they had an HbA1c (A1C) <10% and had been on CSII or glargine for at least 3 months. Thirty-six subjects were randomized to insulin adjustment on the basis of 72 h of CGMS every 3 weeks or intermittent self-monitoring of blood glucose (SMBG) for 3 months. A1C and fructosamine were measured at baseline and 6 and 12 weeks. Follow-up A1C was measured at 6 months. Mean baseline A1C was 8.2% (n = 19) in the CGMS group and 7.9% (n = 17) in the control group. RESULTS—There was a significant improvement in A1C from baseline values in both groups, but there was no difference in the degree of improvement in A1C at 12 weeks between the CGMS (−0.4% [95% CI −0.7 to −0.1]) and the control group (−0.4% [−0.8 to 0.2]). In the CGMS group, improved A1C was at the cost of increased duration of hypoglycemia. CONCLUSIONS—CGMS is no more useful than intermittent fingerstick SMBG and frequent review in improving diabetes control in reasonably well-controlled patients on near-physiological insulin regimens when used in an outpatient clinic setting.

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma

Inhaled corticosteroids (ICS) remain a vital part of the management of persistent asthma, but concerns have been raised about their potential adverse effects in children. This review examines the safety data on three new ICS — fluticasone propionate, mometasone, and extrafine beclomethasone in hydrofluoroalkane (HFA-134a) propellant (QVAR®1 formulation) in relation to the older corticosteroids.Topical adverse effects such as thrush and dysphonia are rare, but dental erosion is a possibility with powder forms of ICS because of their low pH. Thus, it is important to stress mouth rinsing after administration and maintaining good dental hygiene to minimize this risk.Biochemical adrenal suppression can be readily demonstrated, particularly with high doses of all ICS. The clinical relevance of this was uncertain in the past, but there have now been >50 reported cases of acute adrenal crises in children receiving ICS, most of whom were on fluticasone propionate. In order to minimize the risk of symptomatic adrenal suppression, it is important to back-titrate the ICS dose and alert families of children receiving high-dose ICS of this potential adverse effect. A pediatric endocrine opinion should be sought if adrenal suppression is suspected. The older ICS cause temporary slowing of growth velocity, but the limited data available do not show any significant compromise of final adult height. The effect on growth of fluticasone propionate may not be as great as with the older ICS, but the studies have been short term and only used low doses of fluticasone propionate. There have been case reports of growth suppression in children receiving high doses of fluticasone propionate. The limited studies performed on the effect of ICS on bone mineral density in children did not show any adverse effects, but there may be an increased risk of fractures.Hydrofluoroalkane beclomethasone (QVAR) is essentially the same drug as chlorofluorocarbon beclomethasone, but with double the lung deposition owing to the smaller particle size. Thus, it could be expected that any adverse effects seen with chlorofluorocarbon beclomethasone would be the same with hydrofluoroalkane beclomethasone. However, some of the published data, particularly in adults, suggest that hydrofluoroalkane beclomethasone may be less systemically active than chlorofluorocarbon beclomethasone, even at equipotent doses. As yet, there are no long-term data on mometasone, but initial studies in adults suggest there may be less suppression of the hypothalamic-pituitary-adrenal axis, although further studies are required, particularly in children.ICS will remain a cornerstone in the management of persistent pediatric asthma, provided that the diagnosis of asthma is secure. It is very important to use ICS appropriately and to ensure the lowest possible doses are used to achieve symptom control, thus minimizing the risk of serious adverse effects.

Fluticasone propionate 750 μg/day versus beclomethasone dipropionate 1500 μg/day: comparison of efficacy and adrenal function in paediatric asthma

BACKGROUND Previous studies have suggested a 2:1 efficacy advantage of fluticasone propionate (FP) over beclomethasone dipropionate (BDP) in adults on high dose inhaled steroids and children on low dose inhaled steroids. The lower doses of FP required to provide equivalent efficacy to BDP also appear to have fewer systemic effects as measured by adrenal function. METHODS The efficacy and safety of FP 750 μg/day and BDP 1500 μg/day were compared in 30 children with persistent asthma (requiring 1000–2000 μg/day of inhaled corticosteroids) in a 12 week randomised double blind crossover study. Medication was delivered by a spacer device in two divided doses. Primary efficacy variables were peak expiratory flows (PEF). Adrenal function was assessed by 24 hour urinary free cortisol levels at eight and 12 weeks and ACTH and low dose synacthen tests (LDST) at 12 weeks. The results were adjusted for sequence and period differences. RESULTS There was no difference in the primary efficacy variables over the two 12 week treatment periods (difference in adjusted means for morning PEF 1.3 l/min (95% CI –6.1 to 8.8), p = 0.112) and symptom scores (cough, tachypnoea, wheeze, shortness of breath; difference in adjusted means of night time scores: –0.06 (95% CI –0.14 to 0.03); p = 0.136). Similar degrees of mild adrenal dysfunction were found during BDP and FP treatment phases. Identical height gain velocities were shown during the corresponding periods. CONCLUSIONS FP 750 μg/day is as effective as BDP 1500 μg/day in children with persistent asthma. At these very high doses we were unable to demonstrate a safety advantage of FP over BDP as assessed by adrenal function. However, measures of adrenal function may have been influenced by concurrent and previous systemic steroid usage, and possibly by effects of disease activity.

Fludrocortisone Therapy in Cerebral Salt Wasting

Cerebral salt wasting is an increasingly recognized condition in pediatrics and is characterized by inappropriate natriuresis and volume contraction in the presence of cerebral pathology. Diagnosis can be difficult and therapy challenging. A few single case reports of the successful use of fludrocortisone exist. We report 4 patients with cerebral salt wasting, all of whom presented with hyponatremia in the presence of known intracerebral pathology. All had clinically significant hyponatremia, and 3 had hyponatremic seizures. Two of the patients also satisfied clinical criteria for diabetes insipidus. They all were treated with regimens using increased sodium and fluid administration but experienced ongoing salt wasting. Fludrocortisone was instituted in all 4 patients and in 3 resulted in rapid improvement in net sodium balance, enabling the weaning of hypertonic fluids and stabilization of serum electrolytes. In 3 patients, fludrocortisone treatment was complicated by hypokalemia, and in 1 patient by hypertension, which necessitated a dose reduction or brief cessation of therapy. Duration of therapy was 4 to 125 days. Cerebral salt wasting presents considerable management challenges; however, fludrocortisone therapy can be an effective adjunct to treatment.

Coeliac disease in Type 1 diabetes from 1990 to 2009: higher incidence in young children after longer diabetes duration

Diabet. Med. 29, e286‐e289 (2012)

Screening for Celiac Disease in Type 1 Diabetes: A Systematic Review

BACKGROUND AND OBJECTIVES: Prevalence rates of type 1 diabetes (T1D) and celiac disease (CD) vary from 1.6% to 16.4% worldwide. Screening guidelines are variable and not evidence based. Our aim was to conduct a systematic review of CD in T1D. METHODS: Medline, Embase, and the Cochrane Library were searched. Studies were limited to those in English and in humans. We selected longitudinal cohort studies screening for CD in T1D with at least 5 years of follow-up. Screening rates, characteristics, and prevalence of biopsy-proven CD in people with T1D were extracted. RESULTS: We identified 457 nonduplicate citations; 48 were selected for full-text review. Nine longitudinal cohort studies in 11 157 children and adolescents with 587 cases of biopsy-proven CD met the inclusion criteria. Median follow-up was 10 years (range: 5–18 years). The weighted pooled prevalence of CD was 5.1% (95% confidence interval: 3.1–7.4%). After excluding 41 cases with CD onset before T1D, CD was diagnosed in 218 of 546 (40%) subjects within 1 year, in 55% within 2 years, and in 79% within 5 years of diabetes duration. Two studies (478 cases) reported higher rates of CD in children aged <5 years at T1D diagnosis. The duration of follow-up varied across the included studies. CD screening frequency progressively decreased with increased T1D duration. CONCLUSIONS: Because most cases of CD are diagnosed within 5 years of T1D diagnosis, screening should be considered at T1D diagnosis and within 2 and 5 years thereafter. CD screening should be considered at other times in patients with symptoms suggestive of CD. More research is required to determine the screening frequency beyond 5 years of diabetes duration.

Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers - RESIST. A randomised control trial investigating the effects of two different diets on insulin sensitivity in young people with insulin resistance and/or pre-diabetes.

BackgroundConcomitant with the rise in childhood obesity there has been a significant increase in the number of adolescents with clinical features of insulin resistance and prediabetes. Clinical insulin resistance and prediabetes are likely to progress to type 2 diabetes and early atherosclerosis if not targeted for early intervention. There are no efficacy trials of lifestyle intervention in this group to inform clinical practice. The primary aim of this randomised control trial (RCT) is to determine the efficacy and effectiveness of two different structured lifestyle interventions differing in diet composition on insulin sensitivity, in adolescents with clinical insulin resistance and/or prediabetes treated with metformin.Methods/designThis study protocol describes the design of an ongoing RCT. We are recruiting 108 (54 each treatment arm) 10 to 17 year olds with clinical features of insulin resistance and/or prediabetes, through physician referral, into a multi-centred RCT. All participants are prescribed metformin and participate in a diet and exercise program. The lifestyle program is the same for all participants except for diet composition. The diets are a high carbohydrate, low fat diet and a moderate carbohydrate, increased protein diet.The program commences with an intensive 3 month dietary intervention, implemented by trained dietitians, followed by a 3 month intensive gym and home based exercise program, supervised by certified physical trainers. To measure the longer term effectiveness, after the intensive intervention trial participants are managed by either their usual physician or study physician and followed up by the study dietitians for an additional 6 months. The primary outcome measure, change in insulin sensitivity, is measured at 3, 6 and 12 months.DiscussionClinical insulin resistance and prediabetes in the paediatric population are rapidly emerging clinical problems with serious health outcomes. With appropriate management these conditions are potentially reversible or at least their progression can be delayed. This research study is the first trial designed to provide much needed data on the effective dietary management for this cohort. This study will inform clinical practice guidelines for adolescents with clinical insulin resistance and may assist in preventing metabolic complications, type 2 diabetes and early cardiovascular disease.Trial registrationAustralian and New Zealand Clinical Trials Registration Number ACTRN12608000416392