Prevalence and characteristics of paediatric X-linked hypophosphataemia in Australia and New Zealand: Results from the Australian and the New Zealand Paediatric Surveillance Units survey.

BACKGROUND: X-linked hypophosphataemia (XLH) is the most common heritable form of rickets. Prevalence data varies across the literature between 1 in 20,000 and 1 in 200,000 per population. METHODS: Australian and New Zealand Paediatric Surveillance Units collected cross-sectional data from paediatricians on existing cases to estimate prevalence and characteristics of paediatric XLH in Australia and New Zealand. RESULTS: Seventy-five cases in Australia and 18 cases in New Zealand were identified. Estimated minimum prevalence based on these cases was 1.33 (1.04-1.66) per 100,000 and 1.60 per 100,000 (95%CI 0.97-2.58) in Australia and New Zealand respectively, with actual prevalence likely higher due to incomplete ascertainment. Despite a family history in most cases, delayed diagnosis was common, with 49 % diagnosed after 2 years of age. Delayed diagnosis was more common in sporadic versus familial cases. Most common clinical characteristics included leg bowing (89 %), bone and joint pain (68 %), abnormal gait (57 %) and short stature (49 %). There was a significant burden of orthopaedic disease and surgeries and a high rate of complications of nephrocalcinosis and hyperparathyroidism (32 % and 20 % respectively). Additionally, while guidelines stress the importance of multidisciplinary care, many did not have access to recommended health professionals, with only 3 % seeing a psychologist and 68 % seeing a dentist. This is despite the high psychological burden of XLH and a significant proportion (41 %) of this cohort having dental issues (tooth abscess, dental capping, tooth extraction). There were two cases from NZ without data available. Of the 91 cases with data collected, 46 % were on burosumab therapy. Consistent with clinical trials, those on burosumab had a higher serum phosphate levels (p < 0.001) at most recent follow-up. Three cases reported cancellation of orthopaedic surgery due to improvement in lower limb deformity after commencement of burosumab. CONCLUSION: These data describe the multisystem burden of disease for children with XLH with care impacted by delayed diagnosis and a lack of access to many health professionals, especially psychological support.

Feasibility and acceptability of an online guided self-determination program to improve diabetes self-management in young adults.

Objective: Evaluate the feasibility and acceptability of an online guided self-determination (GSD) program to improve diabetes self-management skills among young adults with type 1 diabetes (YAD). Methods: An online program comprising seven structured interactive conversations was designed. A pre- and post- interventional study used a sequential, two-phase multiple method design. Phase one comprised a training program for diabetes educators (DEs). In Phase two YAD participated in program and completed pre- and post-surveys assessing motivation to self-manage, perceived competence in diabetes and communication with DEs. Both YAD and DEs provided a program evaluation. Results: The online GSD program was acceptable, feasible and effective in improving autonomous motivation in self-management and communication with DEs. Easy access and program flexibility were highly appreciated by both participant groups and perceived to assist YAD to stay motivated. Conclusion: The program had a significant impact on the diabetes self-management of YAD and was a feasible and acceptable way to engage and communicate with DEs. The GSD platform contributes to age appropriate and person-centred diabetes self-management. It can potentially reach geographically distanced populations, or with social circumstances or other barriers impeding in-person service provision.

Prevalence of type 2 diabetes risk factors, including overweight and obesity, among youth attending hospital-based paediatric care in Western Melbourne.

AIM: To determine the prevalence of risk factors for type 2 diabetes in overweight and obese adolescents attending hospital-based paediatric care in Western Melbourne. METHODS: One hundred overweight and obese adolescents (aged 10-17 years) who attended an outpatient clinic at Sunshine Hospital between May 2019 and May 2020 were randomly selected following a retrospective chart review of 10-17 years old for whom a height and weight had been documented. Additional risk factors for type 2 diabetes were ascertained via structured telephone interview. Data were analysed to determine the overall prevalence of risk factors for type 2 diabetes, and to evaluate for associations between each parameter with body mass index and the number of risk factors. RESULTS: Of the 487 adolescents who had height and weight data recorded, 45% were overweight or obese. 77% of those who were interviewed had an additional risk factor for type 2 diabetes. No association between the number of risk factors and body mass index standard deviation score was found. Additionally, there was no association between the number of risk factors for type 2 diabetes and either family history of type 2 diabetes or ethnicity. CONCLUSIONS: This paediatric subpopulation had a high rate of risk factors for type 2 diabetes in addition to overweight and obesity, and are at risk of premature mortality and chronic morbidity should they develop type 2 diabetes.

Accelerometer-based osteogenic indices, moderate-to-vigorous and vigorous physical activity, and bone traits in adolescents.

OBJECTIVES: We investigated the associations of accelerometry-derived osteogenic indices (OIs), moderate-to-vigorous (MVPA), and vigorous intensity physical activity (VPA) with peripheral quantitative computed tomography (pCQT) parameters in 99 adolescents aged 10-13 years. METHODS: Bone parameters were assessed at the distal (4%) and shaft (66%) of the tibia using pQCT. Accelerometers were worn on the right hip for 7 consecutive days. OIs were calculated based on acceleration peak histograms either using all of the peaks (OI) or peaks with acceleration ≥5.2 g (HOI). MVPA and VPA were defined using previously published cut-points. RESULTS: HOI was positively associated with total area (Partial correlation= 0.22, 95% CI=0.01 to 0.41), cortical area (CoA) (0.33, 95% CI=0.13 to 0.50), and stress strain index (SSI) (0.29, 95% CI=0.09 to 0.47) of tibial shaft and with total density at the distal tibia (0.23, 95% CI=0.02 to 0.42). OI was positively associated with CoA (0.31, 95% CI=0.11 to 0.49) and SSI (0.26, 95% CI=0.05 to 0.44) of tibial shaft. MVPA was positively associated with CoA (0.28, 95% CI=0.07 to 0.46) of the tibial shaft. CONCLUSIONS: OI and HOI were positively associated with pQCT parameters while MVPA and VPA demonstrated less consistent associations with them.

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.

Universal Subsidized Continuous Glucose Monitoring Funding for Young People With Type 1 Diabetes: Uptake and Outcomes Over 2 Years, a Population-Based Study.

OBJECTIVE: Continuous glucose monitoring (CGM) is increasingly used in type 1 diabetes management; however, funding models vary. This study determined the uptake rate and glycemic outcomes following a change in national health policy to introduce universal subsidized CGM funding for people with type 1 diabetes aged <21 years. RESEARCH DESIGN AND METHODS: Longitudinal data from 12 months before the subsidy until 24 months after were analyzed. Measures and outcomes included age, diabetes duration, HbA1c, episodes of diabetic ketoacidosis and severe hypoglycemia, insulin regimen, CGM uptake, and percentage CGM use. Two data sources were used: the Australasian Diabetes Database Network (ADDN) registry (a prospective diabetes database) and the National Diabetes Service Scheme (NDSS) registry that includes almost all individuals with type 1 diabetes nationally. RESULTS: CGM uptake increased from 5% presubsidy to 79% after 2 years. After CGM introduction, the odds ratio (OR) of achieving the HbA1c target of <7.0% improved at 12 months (OR 2.5, P < 0.001) and was maintained at 24 months (OR 2.3, P < 0.001). The OR for suboptimal glycemic control (HbA1c ≥9.0%) decreased to 0.34 (P < 0.001) at 24 months. Of CGM users, 65% used CGM >75% of time, and had a lower HbA1c at 24 months compared with those with usage <25% (7.8 ± 1.3% vs. 8.6 ± 1.8%, respectively, P < 0.001). Diabetic ketoacidosis was also reduced in this group (incidence rate ratio 0.49, 95% CI 0.33-0.74, P < 0.001). CONCLUSIONS: Following the national subsidy, CGM use was high and associated with sustained improvement in glycemic control. This information will inform economic analyses and future policy and serve as a model of evaluation diabetes technologies.

The skeletal maturity of Australian children aged 10-13 years in 2016.

Skeletal maturity can be used as a biological indicator of the tempo of growth in children and adolescents. We present a description of skeletal maturity from a cohort of white Australian children and describe variation in skeletal maturity based on child age. Participants (n = 71; age 10.5-13.9 years) were recruited from the 'Healthy, Active Preschool & Primary Years (HAPPY)' study. Left hand-wrist radiographs were used to determine skeletal maturity using the Tanner-Whitehouse III (TW3) RUS technique. In boys, the mean skeletal maturity offset (bone age - chronological age) was -0.12 ± 0.19 years and 57.9% had delayed skeletal maturity compared to chronological age. Among those with delayed skeletal maturity, the average delay was 0.99 years (range 0.02-2.54 years). In girls, skeletal age was advanced, on average, compared to chronological age by 0.32 ± 0.20 years. Among the 39.4% of girls with delayed skeletal maturity, the average delay was 0.48 years (range: 0.01-2.28). Four children in the sample exhibited a delay in skeletal maturity greater than 2 years. In the context of secular trends towards advanced skeletal maturity observed globally, delayed skeletal maturation in this white, economically privileged cohort are surprising and warrant further exploration.

Global consensus on nutritional rickets: Implications for Australia.

In 2016, a global consensus on the prevention, diagnosis and management of nutritional rickets was published. The bone and mineral working group of the Australasian Paediatric Endocrine Group provides a summary and highlights differences to previous Australian and New Zealand (ANZ) guidelines on vitamin D deficiency and their implications for clinicians. Key points are: (i) The International Consensus document is focused on nutritional rickets, whereas the ANZ guidelines were focused on vitamin D deficiency. (ii) Definitions for the interpretation of 25-hydroxy vitamin D (25OHD) levels do not differ between statements. (iii) The global consensus recommends that routine 25OHD screening should not be performed in healthy children and recommendations for vitamin D supplementation are not based solely on 25OHD levels. The Australasian Paediatric Endocrine Group bone and mineral working group supports that screening for vitamin D deficiency should be restricted to populations at risk. (iv) Recommendations from the global consensus for vitamin D dosages for the therapy of nutritional rickets (diagnosed based on history, physical examination, biochemical testing and a confirmation by X-rays) are higher than in ANZ publications. (v) The global consensus recommends the implementation of public health strategies such as universal supplementation with vitamin D from birth to 1 year of age and food fortification. We conclude that updated global recommendations for therapy of nutritional rickets complement previously published position statements for Australia and New Zealand. Screening, management and the implementation of public health strategies need to be further explored for Australia.

Reply to Comment on Di Marco, N., Kaufman, J., Rodda, C.P. Shedding Light on Vitamin D Status and Its Complexities during Pregnancy, Infancy and Childhood: An Australian Perspective. Int. J. Environ. Res. Public Health 2019, 16 (4), 538, doi:10.3390/ijerph16040538.

We thank the author(s) for their most informative letter in response to our article [...].

Shedding Light on Vitamin D Status and Its Complexities during Pregnancy, Infancy and Childhood: An Australian Perspective.

Ensuring that the entire Australian population is Vitamin D sufficient is challenging, given the wide range of latitudes spanned by the country, its multicultural population and highly urbanised lifestyle of the majority of its population. Specific issues related to the unique aspects of vitamin D metabolism during pregnancy and infancy further complicate how best to develop a universally safe and effective public health policy to ensure vitamin D adequacy for all. Furthermore, as Australia is considered a "sunny country", it does not yet have a national vitamin D food supplementation policy. Rickets remains very uncommon in Australian infants and children, however it has been recognised for decades that infants of newly arrived immigrants remain particularly at risk. Yet vitamin D deficiency rickets is entirely preventable, with the caveat that when rickets occurs in the absence of preexisting risk factors and/or is poorly responsive to adequate treatment, consideration needs to be given to genetic forms of rickets.

Proinsulin C-peptide is an autoantigen in people with type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells, found within the islets of Langerhans in the pancreas, are destroyed by islet-infiltrating T cells. Identifying the antigenic targets of beta-cell reactive T cells is critical to gain insight into the pathogenesis of T1D and develop antigen-specific immunotherapies. Several lines of evidence indicate that insulin is an important target of T cells in T1D. Because many human islet-infiltrating CD4+ T cells recognize C-peptide-derived epitopes, we hypothesized that full-length C-peptide (PI33-63), the peptide excised from proinsulin as it is converted to insulin, is a target of CD4+ T cells in people with T1D. CD4+ T cell responses to full-length C-peptide were detected in the blood of: 14 of 23 (>60%) people with recent-onset T1D, 2 of 15 (>13%) people with long-standing T1D, and 1 of 13 (<8%) HLA-matched people without T1D. C-peptide-specific CD4+ T cell clones, isolated from six people with T1D, recognized epitopes from the entire 31 amino acids of C-peptide. Eighty-six percent (19 of 22) of the C-peptide-specific clones were restricted by HLA-DQ8, HLA-DQ2, HLA-DQ8trans, or HLA-DQ2trans, HLA alleles strongly associated with risk of T1D. We also found that full-length C-peptide was a much more potent agonist of some CD4+ T cell clones than an 18mer peptide encompassing the cognate epitope. Collectively, our findings indicate that proinsulin C-peptide is a key target of autoreactive CD4+ T cells in T1D. Hence, full-length C-peptide is a promising candidate for antigen-specific immunotherapy in T1D.

Validity of hip-worn inertial measurement unit compared to jump mat for jump height measurement in adolescents.

Jump tests assess lower body power production capacity, and can be used to evaluate athletic ability and development during growth. Wearable inertial measurement units (IMU) seem to offer a feasible alternative to laboratory-based equipment for jump height assessments. Concurrent validity of these devices for jump height assessments has only been established in adults. Therefore, the purpose of this study was to evaluate the concurrent validity of IMU-based jump height estimate compared to contact mat-based jump height estimate in adolescents. Ninety-five adolescents (10-13 years-of-age; girls N = 41, height = 154 (SD 9) cm, weight = 44 (11) kg; boys N = 54, height = 156 (10) cm, weight = 46 (13) kg) completed 3 counter-movement jumps for maximal jump height on a contact mat. Inertial recordings (accelerations, rotations) were concurrently recorded with a hip-worn IMU (sampling at 256 Hz). Jump height was evaluated based on flight time. The mean IMU-derived jump height was 27.1 (SD 3.8) cm, and the corresponding mean jump-mat-derived value was 21.5 (3.4) cm. While a significant 26% mean difference was observed between the methods (5.5 [95% limits of agreement 2.2 to 8.9] cm, P = 0.006), the correspondence between methods was excellent (ICC = 0.89). The difference between methods was weakly positively associated with jump height (r = 0.28, P = 0.007). Take-off velocity-derived jump height was also explored but produced only fair congruence. In conclusion, IMU-derived jump height exhibited excellent congruence to contact mat-based jump height and therefore presents a feasible alternative for jump height assessments in adolescents.

Higher parental occupational social contact is associated with a reduced risk of incident pediatric type 1 diabetes: Mediation through molecular enteroviral indices.

We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008-2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples. Parent occupational social contact was assessed by the number of well or sick children, adults or animals contacted daily through work. Higher parental occupational social contact was strongly associated with reduced T1D risk with evidence of dose response (contact with the well or sick score, Adjusted odds ratio (AOR) per category: 0.73 (95% Confidence Interval (CI): 0.66, 0.81); P<0.001 or AOR 0.63 (95% CI: 0.53, 0.75); P<0.001) respectively). Nine of the ten parental social contact indices, were significant mediated through one or more enteroviral indices. The strength of association between enterovirus presence and T1D onset increased with child age (1.2 fold increase per year; P = 0.05). Lower child hand hygiene enhanced the adverse effect of low parental occupational contact with the sick; Synergy Index 5.16 (95% CI: 3.61, 7.36). The interaction between hand washing and parental occupational contact is more consistent with protection against parental enteroviral shedding than the sharing of a protective infectious agent or microbiome.

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.

CYP3A4 mutation causes vitamin D-dependent rickets type 3.

Genetic forms of vitamin D-dependent rickets (VDDRs) are due to mutations impairing activation of vitamin D or decreasing vitamin D receptor responsiveness. Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D. Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4). In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites. As CYP3A4 mutations have not previously been linked to rickets, these findings provide insight into vitamin D metabolism and demonstrate that accelerated inactivation of vitamin D metabolites represents a mechanism for vitamin D deficiency.

Comparison of the moulding ability of Plaster of Paris and polyester cast material in the healthy adult forearm.

OBJECTIVES: To quantify the moulding ability of Plaster of Paris and polyester cast materials as assessed by the novel use of peripheral quantitative computed tomography. METHODS: A prospective crossover study was performed in 25 healthy volunteers aged 18-65 years. Participants' non-dominant wrist was immobilized using a synthetic polyester cast followed by a Plaster of Paris cast with three point moulding to simulate reduction of a dorsally angulated distal radius fracture. The novel use of peripheral quantitative computed tomography was used to measure the closeness of fit of each cast on an axial tomographic slice. RESULTS AND CONCLUSIONS: Plaster of Paris casts were able to achieve a closer mould than polyester when measured between the bone and the cast (p=0.002), as well as between the skin and the cast (p=0.001). There was no difference when stratified on BMI. Using pQCT assessment, a closely moulded fit was able to be more consistently achieved when using Plaster of Paris when compared to polyester casts of the distal radius. LEVEL OF EVIDENCE: III.

Conjunctival Ultraviolet Autofluorescence as a Measure of Past Sun Exposure in Children.

Background: Conjunctival ultraviolet autofluorescence (CUVAF) area detected from UVAF photographs is a recently developed potential marker for past sun exposure, but its relationship with sun-related factors has not been fully investigated.Methods: The study included 339 healthy children ages 5 to 15 years in Melbourne, Australia. Data were collected by questionnaire and examination at school. CUVAF area was measured using a computer program and analyzed as a continuous and dichotomous outcome (any/none).Results: Fifty-three children (15.6%) had detectable CUVAF, and the youngest age at which a child showed sun damage was 8 years. Compared with silicone skin cast score, there was good inter-grader agreement on CUVAF grading, with Cohen kappa 0.85 [95% confidence interval (CI), 0.65-1.00] for total CUVAF area using both eye photographs. Perfect intra-grader agreement was achieved. Fairer pigmentation, including medium/fair skin color [adjusted odds ratio (AOR), 3.42; 95% CI, 1.02-11.48 vs. dark/olive] and blue/gray eye color (AOR, 4.07; 95% CI, 1.73-9.55 vs. brown) was associated with increased odds of CUVAF. Increasing lifetime sunburn number (e.g., AOR, 2.89; 95% CI, 1.14-7.35 and 4.29; 1.04-17.76 for sunburns 2 to 4 and ≥ 5 times, respectively, vs. no sunburns, trend P = 0.004) and freckling by the end of last summer were associated with increased odds of CUVAF.Conclusions: CUVAF area can be an a priori objective measure of past sun exposure in pediatric populations for future research.Impact: To our knowledge, this is the first pediatric study that evaluated associations of sun-related risk factors with CUVAF. Cancer Epidemiol Biomarkers Prev; 26(7); 1146-53. ©2017 AACR.