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. <i>Int. J. Environ. Res. Public Health</i> 2019, <i>16</i> (4), 538, doi:10.3390/ijerph16040538

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

A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH):Mutational analysis, phenotypic variability and treatment challenges

Autosomal dominant hypocalcaemia with hypercalciuria (ADHH) is an intriguing syndrome, in which activating mutations of the calcium sensing receptor (CaSR) have recently been recognised. We describe a kindred with seven affected individuals across three generations, including patients affected in the first decade of life. Age at diagnosis varied from birth to 50 years. Affected members had hypocalcaemia (1.53-1.85 mmol/l), hypercalciuria, low but detectable parathyroid hormone (PTH) and hypomagnesaemia. Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia. Additional complications include nephrocalcinosis (n = 3) and basal ganglia calcification, identified by CT scanning in all five individuals. Symptomatic individuals were treated with calcium and calcitriol to reduce the risk of hypocalcaemic seizures. DNA sequence analysis, identified a mutation in exon 3, codon 129 (TGC-->TAC) of the CaSR gene of seven affected family members, resulting in loss of a conserved cysteine residue, potentially disrupting CaSR receptor dimerisation. Thus, a novel mutation was identified in this family, who demonstrate variability of ADHH phenotype and also illustrate the complexities of clinical management. Optimal management of ADHH is difficult and we recommend judicious treatment to avoid an increased risk of nephrocalcinosis

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.peerReviewe

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\u27s 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

Near normalisation of lumbar spine bone density in young women with osteopenia recovered from adolescent onset anorexia nervosa: a longitudinal study

To investigate the effect of the progression of adolescent onset anorexia nervosa (AN) on bone parameters we followed two cohorts (Disease cohort and recovered cohort) of adolescents for a total of 5.2 years. In the \u27Disease\u27 cohort (n = 18), lumbar spine bone density (BMD) was reduced by 0.6 SD after 0.8 years of disease and was reduced a further 1.0 SD after a total 2.5 years of disease (p &lt; 0.001). At the third lumbar vertebra there was bone loss (-3.7%, p &lt; 0.05) resulting in reduced volumetric BMD (-5.1%, p &lt; 0.08). In the \u27recovered\u27 cohort, lumbar spine BMD was reduced by 1.9 SD after 1.7 years of disease, and increased by 1.5 SD after 2.7 years of recovery (p &lt; 0.001). At the third lumbar vertebra there was an increase in bone mass (20.5%, p &lt; 0.001) and bone volume (14.1%, p &lt; 0.001), resulting in increased volumetric BMD (6.3%, p &lt; 0.08). Normalisation of lumbar spine BMD may be achieved in patients with adolescent onset AN when the successful recovery of body weight is combined with the return of regular menses.<br /

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

Prevention and treatment of infant and childhood vitamin D deficiency in Australia and New Zealand : a consensus statement

&bull; Vitamin D deficiency has re-emerged as a significant paediatric health issue, with complications including hypocalcaemic seizures, rickets, limb pain and fracture. &bull; A major risk factor for infants is maternal vitamin D deficiency. For older infants and children, risk factors include dark skin colour, cultural practices, prolonged breastfeeding, restricted sun exposure and certain medical conditions. &bull; To prevent vitamin D deficiency in infants, pregnant women, especially those who are dark-skinned or veiled, should be screened and treated for vitamin D deficiency, and breastfed infants of dark-skinned or veiled women should be supplemented with vitamin D for the first 12 months of life. &bull; Regular sunlight exposure can prevent vitamin D deficiency, but the safe exposure time for children is unknown. &bull; To prevent vitamin D deficiency, at-risk children should receive 400 IU vitamin D daily; if compliance is poor, an annual dose of 150 000 IU may be considered. &bull; Treatment of vitamin D deficiency involves giving ergocalciferol or cholecalciferol for 3 months (1000 IU/day if &lt; 1 month of age; 3000 IU/ day if 1-12 months of age; 5000 IU/day if &gt; 12 months of age). &bull; High-dose bolus therapy (300 000-500 000 IU) should be considered for children over 12 months of age if compliance or absorption issues are suspected.<br /