Clinical practice guidelines for paediatric X-linked hypophosphataemia in the era of burosumab.

X-linked hypophosphataemia (XLH), the most common inherited form of rickets, is caused by a PHEX gene mutation that leads to excessive serum levels of fibroblast growth factor 23 (FGF23). This leads to clinical manifestations such as rickets, osteomalacia, pain, lower limb deformity and overall diminished quality of life. The overarching aims in the management of children with XLH are to improve quality of life by reducing overall burden of disease, optimise an individual's participation in daily activities and promote normal physical and psychological development. Burosumab, a monoclonal antibody targeting FGF23, has been shown to improve biochemistry, pain, function and radiological features of rickets in children with XLH and has transformed management of XLH around the world. Burosumab has been recently approved for clinical use in children with XLH in Australia. This manuscript outlines a clinical practice guideline for the use of burosumab in children with XLH to assist local clinicians, encourage consistency of management across Australia and suggest future directions for management and research. This guideline also strongly advocates for all patients with XLH to have multidisciplinary team involvement to ensure optimal care outcomes and highlights the need to consider other aspects of care for XLH in the era of burosumab, including transition to adult care and the effective coordination of care between local health-care providers and specialist services.

Risk of Fractures and Other Injuries in Children Treated with Antiseizure Medications for Epilepsy.

This study aimed to investigate the prevalence of fractures and non-fracture injuries, including associated risk factors, in children with epilepsy prescribed antiseizure medications (ASM). A controlled, cross-sectional study was conducted in a hospital outpatient setting, comparing children with epilepsy prescribed ASMs with their non-epileptic siblings. Information was collected by questionnaire included history of fractures, non-fracture injuries and epilepsy, comorbidities and ASM use. 261 participants completed the questionnaire, 133 children with epilepsy (aged 10.7 ± 3.5 years, mean ± SD) and 128 siblings (10.1 ± 3.7 years). There were 49 non-seizure-related fractures in 34 ASM patients while prescribed ASMs, compared with 21 lifetime fractures in 15 controls, giving a 2.7 (95% CI 1.3-5.3, p = 0.007) times greater fracture prevalence in children treated with ASMs compared to healthy siblings. The rates of non-fracture injuries were similar across groups, except that concussion was more common in children taking ASMs (9.0% vs 1.6%, p = 0.026). Duration of ASM use and generalized tonic-clonic seizures (GTCS) were independent predictors of fractures (OR 1.55; 95% CI 1.03-2.31, p = 0.03; OR 2.50; 95% CI 1.05-5.94, p = 0.04, respectively). Fewer than 20% of participants and/or their families were aware that ASM use was related to bone health. Children with epilepsy treated with ASMs had a higher fracture prevalence than their sibling controls. Duration of ASM treatment and GTCS were associated with fracture risk. Longitudinal prospective studies are required to further explore risk and the direct impact of epilepsy on bone health.

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-ß-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.

Outcomes of standardised approach to metabolic bone disease of prematurity.

AIM: To assess the current protocol of metabolic bone disease (MBD) at three Monash Health neonatal units (Melbourne, Australia). METHODS: Retrospective audit of 171 infants born at <32 weeks' gestation over 18 months. Mean gestational age was 28.6 ± 2.1 weeks, and birthweight was 1190 ± 374 g. Risk factors of MBD include intra-uterine growth retardation (n = 33, 19.3%), maternal pre-eclampsia (n = 17, 9.9%), necrotising enterocolitis (n = 9, 5.4%) and medications like methylxanthines (94.2%; mean 54.8 days), diuretics (38.6%; mean 49.2 days) and glucocorticoids (5.3%; mean 35 days). RESULTS: In total, 84.8% infants had an initial MBD screen (mean age 36.3 days), with 45% having repeated monitoring (mean age 71.9 days), and 14.2% had initial alkaline phosphatase levels >500 U/L, decreasing to 10.1% on follow-up. All infants received additional vitamin D supplementation of 400 IU/day, phosphate of 25.1% (n = 43) and calcium of 19.9% (n = 34). Fractures were identified from clinical documentation in 2.9% (n = 5) of infants. Stratifying into phosphate-treated and untreated groups revealed significant differences (P < 0.001) for gestational age and birthweight: 26.7 ± 1.7 weeks/918 ± 272 g for treated versus 29.2 ± 1.9 weeks/1283 ± 359 g for untreated. In the phosphate-treated group, improvement was seen in mean alkaline phosphatase (pre-treatment 467 ± 204 U/L and post-treatment 342 ± 221 U/L, P < 0.01) and mean phosphate levels (1.8 ± 0.4 vs. 2.2 ± 1.0 mmol/L, P < 0.01). Linear growth difference between phosphate-treated (n = 10) and untreated groups (n = 24) was insignificant at >6 months of age (P = 0.13), although this may reflect limited data. CONCLUSION: Adequate first-line supplementation with vitamin D and phosphate appeared to improve biochemical markers of MBD, but given the observational nature of this study, further longitudinal/prospective studies are required to confirm these findings.

Consensus guidelines on the use of bisphosphonate therapy in children and adolescents.

Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence-based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non-fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence-based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.

Impaired bone and muscle development in young people treated with antiepileptic drugs.

OBJECTIVE: Antiepileptic drugs (AEDs) are associated with reduced bone density, balance impairment, and increased fracture risk in adults. However, pediatric data are limited. Therefore, we aimed to examine bone, muscle, and balance outcomes in young patients taking AEDs. METHODS: We undertook a case-control study utilizing an AED exposure-discordant matched-pair approach. Subjects were aged 5-18 years with at least 12 months of AED exposure. Pairs were twins, nontwin siblings and first cousins, sex- and age-matched (to within 2 years), allowing for greater power than with unrelated control subjects. Dual energy x-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and muscle force/balance were tested, with questionnaires were administered for bone health and epilepsy details. RESULTS: Twenty-three pairs were recruited, (median age 12.9 years [subjects] and 13.5 years [controls])-7 twin, 14 sibling, and 2 cousin pairs. Those taking AEDs had an increased prevalence of fractures (15 fractures in 8 subjects, compared with 4 fractures in 3 controls, p < 0.01). Trabecular volumetric bone mineral density (vBMD) measured by pQCT at the 4% site (tibia) was reduced by 14% (p = 0.03) in subjects. Subjects exerted a decreased maximum force compared to body weight (Fmax total/g) at the tibia. There were no differences seen in either bone mineral parameters measured by DXA or balance measures. SIGNIFICANCE: Young people taking AEDs reported more fractures and had reductions in tibial vBMD and lower limb muscle force compared to their matched controls. These findings suggest that further exploration of bone health issues of young patients on AED therapy is required. Longitudinal studies are required to confirm these changes in the muscle-bone unit and to further explore the clinical outcomes.

Growth disorders in adolescents.

BACKGROUND: Growth is one of the fundamental processes of adolescent development. Careful history and examination, and relevant tar-geted investigations, can streamline the referral process, highlighting the important role of primary healthcare clinicians. OBJECTIVE: This article will provide a guide for clinicians to categorise growth patterns in adolescents, and recognise patients who may have a growth disorder. It will assist clinicians in considering appropriate investigations, and provide guidance for when to refer the adolescent to appropriate paediatric specialists. DISCUSSION: Causes of tall and short stature can often be distinguished on history, physical examination, and accurate pubertal staging. The height of the adolescent should always be considered in the context of their genetic potential. Physiological variants re-main the most common reason for short stature, but awareness of the features of pathological causes is critical. One of the most common presentations is maturational delay in males, and an approach to this issue is discussed.

Bone density assessment in a tertiary paediatric centre over 13 years: Referral patterns and limitations.

AIM: This study aims to examine the referral practices for the Royal Children's Hospital (RCH) bone density service over the past 13 years and to demonstrate referral patterns and possible limitations to accessing paediatric bone densitometry. METHODS: All patients attending the RCH Healthy Bones Unit for bone densitometry from 1 July 1999 to 30 June 2012, aged under 18 years of age, were included. Densitometry results were downloaded directly from the Hologic scanner into an Excel document. However, the referring unit and indication for referral were collected manually from either the referral card or the hospital's scanned medical records system. RESULTS: A total of 5767 bone densitometry scans were performed over the study period on 3004 patients. The majority of referrals were made by the Endocrinology department, followed by Adolescent Medicine, Gastroenterology and Neurology. Relatively few referrals were made by general paediatrics. The most common indication for bone density test overall was eating disorders, followed by steroid use, osteogenesis imperfecta and other collagen disorders and inflammatory bowel disease. The lowest lumbar spine z-scores by indication were for cerebral palsy and other causes of immobility. CONCLUSIONS: Multiple childhood diseases predispose to low bone density; however, paediatric bone densitometry is still underutilised and not appropriately supported by subsidies.

Low vitamin D is associated with hypertension in paediatric obesity.

AIM: The aim of this paper was to investigate the relationship between circulating 25-hydroxyvitamin D (25(OH)D) and cardio-metabolic risk factors in a large cohort of obese youth attending tertiary paediatric obesity services. METHODS: We conducted a retrospective cross-sectional study. Data were retrospectively collected from all new consultations of children and adolescents attending obesity outpatient clinics between 2008 and 2011 at the two major paediatric hospitals in Melbourne, Australia. Information collected included demographics, anthropometry, blood pressure, pubertal staging, body composition and fasting serum levels of 25(OH)D, glucose, insulin, cholesterol, triglyceride, high-density lipoprotein, liver function, calcium and phosphate. RESULTS: 25(OH)D data were available in 229 patients (age 3-18 years; 116 men; mean (standard deviation) body mass index ( BMI) Z-score 2.5 (0.5) ). One hundred four (45%) participants were 25(OH)D deficient (<50 nmol/L). Lower serum 25(OH)D levels were associated with higher BMI Z-score (P-trend = 0.001), total fat mass (P-trend = 0.009), systolic (P-trend = 0.03) and diastolic blood pressures(P-trend = 0.009). In multivariable-adjusted regression analysis, 25(OH)D was significantly lower in those with elevated blood pressure after adjustment for BMI(P-trend = 0.004) or total fat mass (P-trend = 0.01). CONCLUSION: Overweight and obese youth attending specialist obesity services have a high prevalence of vitamin D deficiency. In this population, lower levels of vitamin D were seen in those with greater adiposity, and independent of this, in those who had higher blood pressure.

Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis.

Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.

Childhood insulinoma masquerading as seizure disorder.

A 9 year old girl presented with seizures, weight gain and early morning behavioural changes. She had been commenced on anticonvulsants and was subsequently diagnosed with hyperinsulinaemic hypoglycaemia. This case demonstrates the importance of blood glucose monitoring in children presenting with new-onset seizures and/or with early morning or fasting behavioural changes, the challenges in localizing the lesion, as well as the difficulties in achieving normoglycaemia prior to, and immediately following, surgery.

Geography does not limit optimal diabetes care: use of a tertiary centre model of care in an outreach service for type 1 diabetes mellitus.

AIM: Young people with type 1 diabetes mellitus living in rural and regional Australia have previously been shown to have limited access to specialised diabetes services. The Royal Children's Hospital Melbourne has been running diabetes outreach clinics to Western Victoria, Australia, for over 13 years. We aim to evaluate this service by comparing the outcomes of three outreach clinics with our urban diabetes clinic at the Royal Children's Hospital Melbourne. METHODS: We examine our tertiary, multidisciplinary team-based model of care, where visiting specialist medical staff work alongside local allied health teams. The local teams provide interim care between clinics utilising the same protocols and treatment practices as the tertiary centre. Longitudinal data encapsulating the years 2005-2010, as a cohort study with a control group, are reviewed. RESULTS: A total of 69 rural patients were compared with 1387 metropolitan patients. Metabolic control was comparable, with no difference in mean HbA1c (8.3%/67 mmol/mol for both groups). Treatment options varied slightly at diagnosis, while insulin pump usage was comparable between treatment settings (20.3% rural compared with 27.6% urban, P = 0.19). Of note was that the number of visits per year was higher in the rural group (3.3 per year rural compared with 2.7 urban, P < 0.001). CONCLUSIONS: We conclude that the outreach service is able to provide a comparable level of care when the urban model is translated to a rural setting. This model may be further able to be extrapolated to other geographic areas and also other chronic health conditions of childhood.

Successful treatment of a sacral aneurysmal bone cyst with zoledronic acid.

BACKGROUND: Aneurysmal bone cysts (ABCs) in the sacrum pose a management challenge as their location usually means that surgical excision is not possible. Strategies such as embolization have been used previously but have the potential for significant side effects. We report the successful use of bisphosphonate treatment (zoledronic acid) in an 8-year-old boy who presented with an ABC that did not respond to embolization. METHODS: The patient presented with pain and progressive limp. After radiologic and histologic confirmation of the diagnosis, embolization therapy was trialed, which was unsuccessful. At this point, he had severe pain and extremely limited mobility, requiring the use of a wheelchair. His ability to lie flat or sit erect was limited by the pain. Zoledronic acid therapy was subsequently commenced at 0.04 mg/kg per dose by intravenous infusion, at 4 monthly intervals, for a total of 2 years (7 doses). RESULTS: The infusions were well tolerated, with rapid reduction in pain and resolution of previously severe immobility, from being bed and chair bound at baseline to normal independent ambulation over several months. This was associated with marked radiologic improvement. We postulate that the effect of treatment is a combination of the anti-inflammatory effect of zoledronic acid and the antiresorptive effect of osteoclast inhibition. CONCLUSIONS: We conclude that bisphosphonates should be considered as possible second-line agents for ABCs. Further, study of a larger cohort would help to establish their efficacy in this setting. LEVEL OF EVIDENCE: Level IV (case report, no comparator/control arm).

Incidence of vitamin D deficiency rickets among Australian children: an Australian Paediatric Surveillance Unit study.

OBJECTIVE: To determine the incidence of and factors associated with vitamin D deficiency rickets in Australian children. DESIGN: 18-month questionnaire-based prospective observational study, using Australian Paediatric Surveillance Unit (APSU) data. SETTING: Australian paediatricians and child health workers, January 2006 - July 2007. PARTICIPANTS: Children aged ≤ 15 years with vitamin D deficiency rickets (25-hydroxyvitamin D [25OHD] ≤ 50 nmol/L, and elevated alkaline phosphatase levels [> 229 IU/L] and/or radiological rickets). MAIN OUTCOME MEASURES: Incidence of vitamin D deficiency rickets. Description of demographics, clinical presentation, identification and further analysis of overrepresented groups, and treatment regimens compared with best-practice guidelines. RESULTS: We identified 398 children with vitamin D deficiency (55% male; median age, 6.3 years [range, 0.2-15 years]). The overall incidence in children ≤ 15 years of age in Australia was 4.9/100 000/year. All had a low 25OHD level (median, 28 nmol/L [range, 5-50 nmol]) and an elevated alkaline phosphatase level (median, 407 IU/L [range, 229-5443 IU/L]), and 48 (12%) were hypocalcaemic. Ninety-five children had wrist x-rays, of whom 67 (71%) had rachitic changes. Most (98%) had dark or intermediate skin colour and 18% of girls were partially or completely veiled. Most children were born in Africa (252; 63%) and 75% of children were refugees. Duration of exclusive breastfeeding was inversely related to serum vitamin D levels in children < 3 years of age. Empirical vitamin D treatment was given to 4% of children before diagnosis. CONCLUSIONS: Vitamin D deficiency rickets is a significant problem in Australia among known high-risk groups. Public health campaigns to prevent, identify and tre@vitamin D deficiency, especially in high-risk groups, are essential.

The clinical features that contribute to poor bone health in young Australians living with cystic fibrosis: A recommendation for BMD screening.

BACKGROUND: For Australians living with cystic fibrosis (CF), increased longevity means greater consideration needs to be given to long-term endocrine sequelae such as CF-related bone disease. Deficits in bone mass accrual are most likely to occur during childhood and adolescence. Current guidelines in Australia suggest repeat dual-energy X-ray absorptiometry (DXA) scans every 2 years. This study aims to stratify clinical factors that determine future bone health in the Australian CF population and use this to guide a more streamlined approach to bone health screening. METHODS: This study was a retrospective audit of all patients diagnosed with CF who were treated at the Royal Children's Hospital Melbourne, Australia from 2000 to 2016 (n = 453). Two hundred and two patients had a DXA scan in the study period (191 with height-adjusted data) and 111 patients had more than one scan (108 with height-adjusted data). An investigation into the associations between bone mineral density (BMD) Z score and potential risk factors was conducted using DXA and historical data. RESULTS: The main predictor of future BMD was the previous BMD Z score (p < .001). Other factors found to be determinants of BMD included nutritional status, lung function (FEV1 ), age, history of previous fracture, oral corticosteroid use, and the number of hospital admissions. However, after adjusting for previous BMD, evidence of an association remained only with nutritional status, FEV1 , and number of hospital admissions. CONCLUSION: Second yearly scans may be unnecessary in children with an adequate DXA score on the initial scan who remain clinically stable. However, clinical deterioration in those whose BMD was previously normal, may require closer monitoring of bone health. We propose a guideline for the frequency of DXA monitoring in relation to clinical risk factors.

Randomized Controlled Trial Evaluating the Use of Zoledronic Acid in Duchenne Muscular Dystrophy.

CONTEXT: Patients with glucocorticoid-dependent Duchenne muscular dystrophy (DMD) have increased fracture risk and reduced bone mineral density (BMD), often precipitating mobility loss. OBJECTIVE: To investigate use of zoledronic acid (ZA) in DMD in improving BMD. METHODS: Two arm, parallel, randomized controlled trial, set in pediatric hospitals across Australia and New Zealand. Sixty-two (31 per arm) boys with glucocorticoid-dependent DMD between 6 and 16 years were included. Five ZA infusions (0.025 mg/kg at months 0, and 3, and 0.05 mg/kg at months 6, 12, and 18), plus calcium and vitamin D, were compared with calcium and vitamin D alone. The main outcome measures were change in lumbar spine (LS) BMD raw and Z-score by dual energy absorptiometry x-ray (DXA) at 12 and 24 months, secondary outcomes assessing mobility, fracture incidence, bone turnover, peripheral quantitative computerized (pQCT) and pain scores. RESULTS: At 12 and 24 months, mean difference in changes of LS BMD Z-score from baseline was 1.2 SD (95% CI 0.9-1.5), higher by 19.3% (14.6-24.0) and 1.4 SD (0.9-1.9), higher by 26.0% (17.4-34.5) in ZA than control arms respectively (both P < .001). Five controls developed Genant 3 vertebral fractures, 0 in the ZA arm. Mobility, pain, and bone turnover markers were similar between arms at 12 and 24 months. Trabecular BMC and vBMD pQCT at radius and tibia were greater at 12 months in the ZA cohort than control; the evidence for this difference remained at 24 months for radius but not tibia. CONCLUSION: ZA improved BMD in glucocorticoid-dependent DMD boys. Although the small cohort precluded demonstrable fracture benefit, improved BMD might reduce incident vertebral fracture.

Effect of Testosterone Treatment for Delayed Puberty in Duchenne Muscular Dystrophy.

OBJECTIVE: To evaluate the impact of pubertal induction with testosterone on bone health, body composition, and motor function in boys with Duchenne muscular dystrophy (DMD) receiving long-term glucocorticoid. STUDY DESIGN: A retrospective, observational, pre-post study investigating the impact of testosterone therapy on bone mass accrual, vertebral fracture incidence, body composition, motor function, and quality of life in boys with DMD. All those boys aged ≥14 years, on chronic steroid therapy, who had delayed puberty, and were receiving oral testosterone or oral and then transitioned to intramuscular testosterone, to complete virilization, were included. Prior/concomitant zoledronic acid use was included. The primary outcome was lumbar spine areal bone mineral density (BMD LS). RESULTS: Puberty was induced, using oral testosterone undecanoate in 16 individuals, 10 of whom had transited to intramuscular testosterone at time of assessment. Median age at testosterone onset was 14.5 years (range 14-17.7). Median duration of testosterone therapy was 2.5 years (range 1.0-4.5). There was statistically significant increase in median BMD LS (0.523-0.700, p < 0.001) and median annualized percentage change of BMD LS (-1.34 to +10.08%, p < 0.001), with median Tanner stage 4 at evaluation (range 2-4). Ten of 14 assessed had no progression in vertebral fractures. Fat mass index (FMI) standard deviation score (SDS), lean body mass index (LBMI) SDS, and percentage change of FMI and LBMI were statistically unchanged. Cardiac function remained stable. Motor function in non-ambulatory individuals with Egen Klassifikation scores improved in 7 of 8. CONCLUSION: Testosterone for delayed puberty acted as an adjunct to bisphosphonates to increase bone density and stabilize vertebral fracture in most boys with DMD.