Publications by authors named "Craig F Munns"

78 Publications

Serum 25-hydroxyvitamin D requirements to prevent nutritional rickets in Nigerian children on a low-calcium diet-a multivariable reanalysis.

Am J Clin Nutr 2021 Mar 19. Epub 2021 Mar 19.

Department of Family Medicine, Mayo Clinic, Rochester, MN, USA.

Background: Nutritional rickets is believed to result from the interaction of inadequate serum 25-hydroxyvitamin D [25(OH)D] concentration and dietary calcium intake, but this interaction has not been confirmed in children with rickets. Determining the vitamin D requirements to prevent nutritional rickets has been thwarted by inconsistent case definition, inadequate adjustment for calcium intake and other confounders, and 25(OH)D assay variability.

Objectives: To model the 25(OH)D concentration associated with nutritional rickets in calcium-deprived Nigerian children, adjusted for confounding factors, and develop a general approach to define vitamin D status while accounting for calcium intake.

Methods: Logistic regression was used to model the association of serum 25(OH)D with having rickets adjusted for calcium intake in a reanalysis of a case-control study in Nigerian children. The matching variables age, sex, weight-for-age z score, and 4 additional significant variables were selected [religion, age began walking, phosphorus intake, and the 25(OH)D × calcium intake interaction] using a rigorous 7-step algorithm.

Results: Cases had significantly (P < 0.0001) lower mean ± SD 25(OH)D than controls (33 ± 13 compared with 51 ± 16 nmol/L, respectively), whereas cases and controls had similarly (P = 0.81) low mean dietary calcium intakes (216 ± 88 and 213 ± 95 mg/d, respectively). There was a significant interaction between 25(OH)D and calcium intake [coefficient (95% CI): -0.0006 (-0.0009, -0.0002)]. Accordingly, as calcium intake increased from 130 to 300 mg/d, the adjusted odds of having rickets decreased dramatically with increasing 25(OH)D such that at 200 mg/d, the adjusted odds of having rickets at 47.5 nmol/L was 0.80, whereas it was 0.2 at 62.5 nmol/L. Moreover, at a calcium intake of 300 mg/d, the adjusted odds was 0.16 at a 25(OH)D concentration of 47.5 nmol/L and 0.02 at 62.5 nmol/L.

Conclusions: The vitamin D requirement to prevent nutritional rickets varies inversely with calcium intake and vice versa. Also, application of multivariable modeling is essential in defining vitamin D requirements.
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http://dx.doi.org/10.1093/ajcn/nqab048DOI Listing
March 2021

Acute illness in children with secondary adrenal insufficiency.

Clin Endocrinol (Oxf) 2021 Feb 5. Epub 2021 Feb 5.

Endocrine and Metabolic Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, SA, Australia.

Objective And Background: Secondary adrenal insufficiency (SAI) is a rare condition in childhood which can be associated with high levels of morbidity in some patients. The causes of increased levels of illness are not well defined and warrant further investigation.

Methods: A retrospective cohort of patients with SAI was constructed by examining records of all attendances for acute illness by SAI patients at the emergency department of the two specialist paediatric hospitals in Sydney, Australia between 2004 and 2016. Demographic, clinical, and physiological characteristics together with pre-hospital illness management strategies were assessed.

Results: There were 168 presentations for an acute illness by 47 children with SAI. Comorbid diabetes insipidus (DI) was present in 46.8% (n = 22), 77.3% (n = 17) of whom were male (P < .05). Patients with comorbid DI were more likely to be admitted (86.7%, n = 65 vs 60.2%, n = 56 for non-DI, P < .01); had a longer hospital stay (6.5 (8.7) vs 2.5 (2.6) days, P < .001); and higher rates of IV HC administration (56.0%, n = 42 vs 35.5%, n = 33), P < .01). The medically-diagnosed adrenal crisis (AC) rate was 3.68 ACs/100PY. Stress dose use was reported by fewer DI patients (58.7%, n = 44) than non-DI patients (78.5%, n = 73, P < .01). Previous attendance at hospital was positively associated with stress dose use (OR = 1.08, 95% CI 1.00, 1.16).

Conclusion: Secondary adrenal insufficiency can cause significant morbidity in children. Comorbid DI is associated with higher levels of hospitalisation, longer hospital stays and lower levels of pre-emergent stress dose use. Educational interventions in this subgroup of SAI patients may reduce the burden of morbidity.
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http://dx.doi.org/10.1111/cen.14427DOI Listing
February 2021

Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of Burosumab Versus Conventional Therapy in Children with X-Linked Hypophosphatemia.

Calcif Tissue Int 2021 Jan 23. Epub 2021 Jan 23.

Department of Medicine and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.

Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vitamin D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1-12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (- 5.02, 95% CI - 9.29 to - 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline.Trial registration: ClinicalTrials.gov NCT02915705.
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http://dx.doi.org/10.1007/s00223-020-00797-xDOI Listing
January 2021

Editorial: Childhood Rickets-New Developments in Epidemiology, Prevention, and Treatment.

Front Endocrinol (Lausanne) 2020 23;11:621734. Epub 2020 Nov 23.

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

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http://dx.doi.org/10.3389/fendo.2020.621734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719773PMC
November 2020

Impact of heritable disorders of connective tissue on daily life of children: Parent perspectives.

J Paediatr Child Health 2020 Nov 26. Epub 2020 Nov 26.

Faculty of Medicine and Health Sydney, The University of Sydney, Sydney, New South Wales, Australia.

Aim: The aim of this study was to investigate parent perspectives on how heritable disorders of connective tissue (HDCT) affect a child's everyday life. In addition, this study aimed to determine if parents seeking health professional services perceive their children with HDCT to have difficulties with activities reliant on hand function.

Methods: This cross-sectional study used a questionnaire for parents to explore the impact of an HDCT on a child's ability to carry out everyday activities. Parents of children (8-18 years) attending a tertiary connective tissue dysplasia clinic, over a 12-month period, were invited to participate.

Results: We analysed 100 surveys completed by parents. Children with Ehlers-Danlos syndrome-hypermobile type, joint hypermobility syndrome (48%) and osteogenesis imperfecta (42%) were the largest diagnostic groups represented. Pain (73%) and fatigue (68%) were the most common symptoms parents perceived to affect day-to-day activities. More parents were satisfied with their child's self-care (61%) than school participation (33%). Keeping up with handwriting (71%) and gross motor activities (70%) were the most frequently reported difficulties at school. Most parents (65%) reported leisure activity difficulties, with pain (64%) and fatigue (60%) as the main contributing factors.

Conclusions: This study has provided new knowledge about the concerns of parents with their child's engagement in everyday life including the impact of HDCT on hand function. Further research is needed on effective management strategies to reduce symptoms and improve hand function for these children.
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http://dx.doi.org/10.1111/jpc.15284DOI Listing
November 2020

High Bone Mineral Density Osteogenesis Imperfecta in a Family with a Novel Pathogenic Variant in COL1A2.

Horm Res Paediatr 2020 11;93(4):263-271. Epub 2020 Sep 11.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.

Osteogenesis imperfecta (OI) is a heterogenous group of heritable bone dysplasias characterized by bone fragility, typically low bone mass, joint laxity, easy bruising, and variable short stature. Classical OI is caused by autosomal dominant pathogenic variants in COL1A1 or COL1A2 that result in either reduced production of normal type 1 collagen or structurally abnormal collagen molecules. Pathogenic variants in these genes generally result in low bone mass. Here, we report a family that had 2 affected individuals who presented with minimal trauma fractures and were found to have elevated bone mineral density (BMD) and a previously unreported variant in COL1A2 c.3356C>T p.(Ala1119Val). We report the change in BMD using dual-energy X-ray and peripheral quantitative computed tomography over a 2.3-year period in the proband. This case report highlights the importance of BMD studies and genetic testing in the diagnostic process for brittle bone disorders.
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http://dx.doi.org/10.1159/000510463DOI Listing
September 2020

Screening of vitamin D and calcium concentrations in neonates of mothers at high risk of vitamin D deficiency.

BMC Pediatr 2020 07 4;20(1):332. Epub 2020 Jul 4.

Department of Paediatric Endocrinology, The Children's Hospital at Westmead, Westmead, NSW, Australia.

Objective: The aim of this study was to determine, retrospectively, the serum 25OHD and calcium concentrations of screened neonates of mothers at high risk of 25OHD deficiency and examine whether their measurement contributes to the management of these neonates.

Methods: Serum 25OHD and calcium concentrations from 600 samples of umbilical cord blood or venous blood collected from neonates over a 12-month period were analysed.

Results: There was a high prevalence of vitamin D insufficiency (27.6%, 30-50 nmol/L) and deficiency (21.3%, < 30 nmol/L) in neonates from high-risk maternal groups. There was a statistically positive but weak correlation (ρ = 0.22, P < 0.0001) between 25OHD and serum calcium. Only 7 neonates out of 569 (1.2%) had calcium concentrations in the hypocalcaemic range; however, a significant number (47.6%) were reported to be in the hypercalcaemic range. Nearly all of these were venous samples collected in first 24 h after birth.

Conclusion: Vitamin D deficiency is prevalent in neonates of high-risk mothers but the risk of hypocalcaemia due to vitamin D deficiency at birth is low. Screening neonates entails blood testing which can cause distress to neonates and their parents, substantial imposition on staff and financial burden on the health care system. Vitamin D supplementation of these neonates from birth without routine screening appears more reasonable. Also, the data from this study suggest that the paediatric reference range for corrected calcium concentrations in neonates should be re-evaluated.
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http://dx.doi.org/10.1186/s12887-020-02204-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334853PMC
July 2020

Global consensus on nutritional rickets: Implications for Australia.

J Paediatr Child Health 2020 06;56(6):841-846

Institute of Endocrinology and Diabetes, Children's Hospital Westmead, Sydney, New South Wales, 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.
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http://dx.doi.org/10.1111/jpc.14941DOI Listing
June 2020

Clinical Evidence for the Benefits of Burosumab Therapy for X-Linked Hypophosphatemia (XLH) and Other Conditions in Adults and Children.

Front Endocrinol (Lausanne) 2020 28;11:338. Epub 2020 May 28.

Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW, Australia.

Burosumab (KRN23) is an FGF23 neutralizing antibody that has been the subject of several recent clinical trials principally focused on the treatment of hypophosphatemic rickets in patients with X-linked hypophosphatemia (XLH). Since the first publications in 2014, these trials have demonstrated efficacy with minimal safety concerns in both adult and pediatric cohorts. These studies have used dose-escalation to establish a dosing regimen that is well-tolerated in clinical use. This review summarizes the clinical trial data with respect to burosumab treatment in adults and children as well as noting several clinical trials currently underway. While burosumab appears transformative for the treatment of XLH, long term follow-up studies would be required to allay concerns over the potential for nephrocalcinosis and cardiac calcification. While these do not appear to be problematic in current trials, the effects of chronic or lifelong treatment have yet to be established.
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http://dx.doi.org/10.3389/fendo.2020.00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271822PMC
May 2020

Safety, feasibility and efficacy of side-alternating vibration therapy on bone and muscle health in children and adolescents with musculoskeletal disorders: A pilot trial.

J Paediatr Child Health 2020 Aug 21;56(8):1257-1262. Epub 2020 May 21.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Aims: A pilot study was performed to establish the safety, feasibility and efficacy of vibration therapy (VT) on bone and muscle health in children and adolescents with a range of musculoskeletal disorders.

Methods: Seventeen participants (15.7 years ± 2.9 years), with conditions that impacted on their musculoskeletal health, completed 20 weeks of side-alternating VT for 9 min/session, 4 times/week at 20 Hz. Data were collected at baseline and after 20 weeks of intervention. Assessments included whole-body dual-energyX-ray absorptiometry, muscle function (force plate) and 6-min walk test.

Results: Compliance with the prescribed VT training protocol was relatively high overall at 78% and there were no adverse events reported. After 20 weeks intervention, functional assessments showed time taken to perform the chair test was reduced by 15% (P = 0.018), leg balance improved with standard ellipse area decreasing by 88% (P = 0.006) and distance walked in the 6-min walk test improved by 9% (P = 0.002). Participants displayed increased total body mass (1.94 kg; P = 0.018) with increased lean mass (1.20 kg; P = 0.019) but not fat mass (P = 0.19). There was no change in total body bone mineral density (P = 0.44) or bone mineral content (P = 0.07).

Conclusions: Twenty weeks of side-alternating VT was a feasible protocol that was associated with improvements in physical function and no detrimental effects on lean mass, bone mass or density in children and adolescents with musculoskeletal disorders.
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http://dx.doi.org/10.1111/jpc.14913DOI Listing
August 2020

The Effects of 20 Weeks of Side-Alternating Vibration Therapy on Physical Function, Bone and Muscle Health in Adolescents with Down Syndrome.

Phys Occup Ther Pediatr 2021 28;41(1):44-55. Epub 2020 Apr 28.

Liggins Institute, University of Auckland, Auckland, New Zealand.

Aims: To evaluate the effects of side-alternating vibration therapy on physical function and body composition in adolescents with Down syndrome.

Methods: Fourteen adolescents (8 males) with Down syndrome (mean ± SD age: 15.5 ± 2.3 years) performed vibration treatment nine minutes daily, four times per week, for 20 weeks on a Galileo vibration platform. Data were collected at baseline and after 20 weeks of intervention. Assessments included six-minute walk test, muscle function (force plate), whole-body dual-energy X-ray absorptiometry and peripheral quantitative computed tomography of the non-dominant tibia.

Results: After 20 weeks, participants increased their distance walked in the six-minute walk test ( = 0.009), 2-leg single jump efficiency ( = 0.024) and jump velocity ( = 0.046). Participants also increased their power ( = 0.034) and reduced the time taken during the chair rise test ( < 0.001). At the total body level, increases were seen in bone mineral density ( = 0.004), bone mineral content ( = 0.043), fat free mass ( = 0.013) and lean mass ( = 0.021).

Conclusion: Side-alternating vibration therapy was associated with increases in physical function and muscle mass with no effects on bone health in adolescents with Down syndrome.

Clinical Trial Registration Number: Australian New Zealand Clinical Trial Registry (ACTRN12615000092594) - registered on 4 February 2015.
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http://dx.doi.org/10.1080/01942638.2020.1758983DOI Listing
April 2020

The effect of patient-managed stress dosing on electrolytes and blood pressure in acute illness in children with adrenal insufficiency.

Clin Endocrinol (Oxf) 2020 08 2;93(2):97-103. Epub 2020 Jun 2.

School of Medicine Sydney, The University of Notre Dame, Darlinghurst, NSW, Australia.

Background: Adrenal crises (AC) are acute episodes of adrenal insufficiency (AI). Manifestations include hypotension and electrolyte disturbances. Glucocorticoid stress dosing (SD) can prevent AC progression, but its effect on physiological parameters has not been assessed in a 'real world setting'.

Aims: To assess the effect of prior self-managed glucocorticoid dose escalation on physiological markers in children with congenital adrenal hyperplasia (CAH) presenting to hospital for an acute illness.

Methods: An audit of records of all children with CAH presenting to paediatric referral hospital between 2000 and 2015. Potassium, sodium and glucose levels, and hypotension were compared between children who had and had not used SD.

Results: There were 321 attendances by patients with CAH and an acute illness during the study period. Any form of SD was used by 64.2% (n = 206); intramuscular (IM) hydrocortisone was used by 22.1% (n = 71) and oral only by 41.7% (n = 134). Use of SD (oral and/or IM) was associated with a significantly lower mean potassium level (4.02 ± 0.71 vs. 4.27 ± 0.79 mmol/l, P < .05). Linear regression analysis showed that age (beta: -0.04 years (95% CI -0.06, -0.02)), diarrhoea (beta: -0.41 (95% CI -0.06, -0.02)) and any form of stress dosing (oral, IM or both) (beta: -0.29 (95% CI -0.55, -0.04)) were each independently and significantly associated with potassium levels. SD was not significantly associated with sodium or glucose concentrations or with estimates of hypotension.

Conclusion: Patient-initiated SD resulted in a significant reduction in hyperkalaemia and lowered mean potassium levels in paediatric patients with CAH but did not alter significantly sodium and glucose concentrations or incidences of hypotension.
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http://dx.doi.org/10.1111/cen.14196DOI Listing
August 2020

A Contemporary View of the Definition and Diagnosis of Osteoporosis in Children and Adolescents.

J Clin Endocrinol Metab 2020 05;105(5)

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

The last 2 decades have seen growing recognition of the need to appropriately identify and treat children with osteoporotic fractures. This focus stems from important advances in our understanding of the genetic basis of bone fragility, the natural history and predictors of fractures in chronic conditions, the use of bone-active medications in children, and the inclusion of bone health screening into clinical guidelines for high-risk populations. Given the historic focus on bone densitometry in this setting, the International Society for Clinical Densitometry published revised criteria in 2013 to define osteoporosis in the young, oriented towards prevention of overdiagnosis given the high frequency of extremity fractures during the growing years. This definition has been successful in avoiding an inappropriate diagnosis of osteoporosis in healthy children who sustain long bone fractures during play. However, its emphasis on the number of long bone fractures plus a concomitant bone mineral density (BMD) threshold ≤ -2.0, without consideration for long bone fracture characteristics (eg, skeletal site, radiographic features) or the clinical context (eg, known fracture risk in serious illnesses or physical-radiographic stigmata of osteoporosis), inappropriately misses clinically relevant bone fragility in some children. In this perspective, we propose a new approach to the definition and diagnosis of osteoporosis in children, one that balances the role of BMD in the pediatric fracture assessment with other important clinical features, including fracture characteristics, the clinical context and, where appropriate, the need to define the underlying genetic etiology as far as possible.
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http://dx.doi.org/10.1210/clinem/dgz294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121121PMC
May 2020

P450 Oxidoreductase Deficiency: A Systematic Review and Meta-analysis of Genotypes, Phenotypes, and Their Relationships.

J Clin Endocrinol Metab 2020 03;105(3)

School of Medicine, Sydney, The University of Notre Dame Australia, Darlinghurst, NSW, Australia.

Context: P450 oxidoreductase deficiency (PORD) is a rare genetic disorder that is associated with significant morbidity. However there has been limited analysis of reported PORD cases.

Objective: To determine, based on the cohort of reported PORD cases, genotype-phenotype relationships for skeletal malformations, maternal virilisation in pregnancy, adrenal insufficiency, and disorders of sexual development (DSD).

Data Sources: PubMed and Web of Science from January 2004 to February 2018.

Study Selection: Published case reports/series of patients with PORD. Eligible patients were unique, had biallelic mutations, and their clinical features were reported.

Data Extraction: Patient data were manually extracted from the text of case reports/series. A malformation score, representing the severity of skeletal malformations, was calculated for each patient.

Data Synthesis: Of the 211 patients published in the literature, 90 were eligible for inclusion. More than 60 unique mutations were identified in this cohort. Four groups of mutations were identified, through regression modeling, as having significantly different skeletal malformation scores. Maternal virilization in pregnancy, reported for 21% of patients, was most common for R457H mutations. Adrenal insufficiency occurred for the majority of patients (78%) and was typically mild, with homozygous R457H mutations being the least deficient. DSD affected most patients (72%), but were less common for males (46XY) with homozygous R457H mutations.

Conclusions: PORD is a complex disorder with many possible mutations affecting a large number of enzymes. By analyzing the cohort of reported PORD cases, this study identified clear relationships between genotype and several important phenotypic features.
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http://dx.doi.org/10.1210/clinem/dgz255DOI Listing
March 2020

Targeting Adeno-Associated Virus Vectors for Local Delivery to Fractures and Systemic Delivery to the Skeleton.

Mol Ther Methods Clin Dev 2019 Dec 5;15:101-111. Epub 2019 Sep 5.

Orthopaedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Westmead, NSW, Australia.

A panel of 18 recombinant adeno-associated virus (rAAV) variants, both natural and engineered, constitutively expressing Cre recombinase under the cytomegalovirus early enhancer/chicken β actin (CAG) promoter, were screened for their ability to transduce bone in Ai9 fluorescent reporter mice. Transgenic Cre-induced tdTomato expression served as a measure of transduction efficiency and alkaline phosphatase (AP) activity as an osteoblastic marker. Single injections of AAV8, AAV9, and AAV-DJ into midshaft tibial fractures yielded robust tdTomato expression in the callus. Next, the bone cell-specific promoters Sp7 and Col2.3 were tested to restrict Cre expression in an alternate model of systemic delivery by intravenous injection. Although CAG promoter constructs packaged into AAV8 produced high levels of tdTomato in the bone, liver, heart, spleen, and kidney, bone-specific promoter constructs restricted Cre expression to osseous tissues. AAV variants were further tested in a human osteoblast cell line (hFOB1.19), measuring GFP reporter expression by flow cytometry after 72 h. AAV2, AAV5, and AAV-DJ showed the highest transduction efficiency. In summary, we produced AAV vectors for selective and high-efficiency gene delivery to murine bone. The AAV8-Sp7-Cre vector has significant practical applications for inducing gene deletion postnatally in mouse models.
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http://dx.doi.org/10.1016/j.omtm.2019.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804917PMC
December 2019

Pretreatment with Pamidronate Decreases Bone Formation but Increases Callus Bone Volume in a Rat Closed Fracture Model.

Calcif Tissue Int 2020 02 1;106(2):172-179. Epub 2019 Oct 1.

Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia.

Clinical concerns have been raised over prior exposure to bisphosphonates impairing fracture healing. To model this, groups of male Wistar rats were assigned to saline control or treatment groups receiving 0.15 mg/kg (low dose), 0.5 mg/kg (medium dose), and 5 mg/kg (high dose) Pamidronate (PAM) twice weekly for 4 weeks. At this point, closed fractures were made using an Einhorn apparatus, and bisphosphonate dosing was continued until the experimental endpoint. Specimens were analyzed at 2 and 6 weeks (N = 8 per group per time point). Twice weekly PAM dosing was found to have no effect on early soft callus remodeling at 2 weeks post fracture. At this time point, the highest dose PAM group gave significant increases in bone volume (+ 10%, p < 0.05), bone mineral content (+ 30%, p < 0.01), and bone mineral density (+ 10%, p < 0.01). This PAM dosing regimen showed more substantive effects on hard callus at 6 weeks post fracture, with PAM treatment groups showing + 46-79% increased bone volume. Dynamic bone labeling showed reduced calcein signal in the PAM-treated calluses (38-63%, p < 0.01) and reduced MAR (32-49%, p < 0.01), suggesting a compensatory reduction in bone anabolism. These data support the concept that bisphosphonates lead to profound decreases in bone turnover in fracture repair, however, this does not affect soft callus remodeling.
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http://dx.doi.org/10.1007/s00223-019-00615-zDOI Listing
February 2020

FGF23, Hypophosphatemia, and Emerging Treatments.

JBMR Plus 2019 Aug 13;3(8):e10190. Epub 2019 May 13.

The University of Sydney Children's Hospital Westmead Clinical School, University of Sydney Sydney Australia.

FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co-receptor Klotho, it modulates phosphate reabsorption and both 1α-hydroxylation and 24-hydroxylation in the renal proximal tubules. The most common FGF23-mediated hypophosphatemia is X-linked hypophosphatemia (XLH), caused by mutations in the gene. FGF23-mediated forms of hypophosphatemia are characterized by phosphaturia and low or low-normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23-mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor-induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23-mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715782PMC
August 2019

Abnormal Cortical and Trabecular Bone in Youth With Type 1 Diabetes and Celiac Disease.

Diabetes Care 2019 08 4;42(8):1489-1495. Epub 2019 Jun 4.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Westmead, New South Wales, Australia

Objective: This study compared bone health in youth with type 1 diabetes and celiac disease (CD) versus type 1 diabetes alone.

Research Design And Methods: This was a case-control study of 42 youth with coexisting type 1 diabetes and CD and 40 with type 1 diabetes matched for age, sex, diabetes duration, and HbA. Bone mineral density (BMD), bone mineral content (BMC), and BMC-to-lean tissue mass (LTM) ratio were measured using DXA and reported as -scores for height. Total, trabecular, and cortical bone and muscle parameters were measured using peripheral quantitative computed tomography (pQCT) and reported as -scores for age.

Results: Mean age at assessment was 14.3 ± 3.1 years; diabetes duration, 8.0 ± 3.5 years; HbA, 8.2 ± 1.5% (66 ± 5 mmol/mol); and 25-hydroxy vitamin D, 71 ± 21 nmol/L. Comparing youth with coexisting CD versus type 1 diabetes alone, DXA showed lower BMC-to-LTM ratio (0.37 ± 1.12 vs. 0.73 ± 2.23, = 0.007) but no difference in total BMD. Youth with coexisting CD also had lower BMC-to-LTM ratio versus the general population ( = 0.04). Radial pQCT showed lower total BMC (-0.92 ± 1.40 vs. -0.26 ± 1.23, = 0.03) despite similar bone and muscle cross-sectional area. In multivariable linear regression, lower BMC was associated with higher insulin dose ( = 0.03) but not HbA.

Conclusions: Youth with both type 1 diabetes and CD have lower BMC relative to LTM and lower BMC, indicating abnormal trabecular and cortical bone development despite similar bone and muscle size. These findings suggest that the two conditions confer a lower bone turnover state. We recommend further examination of bone health in this population; future research should examine early interventions to improve bone health.
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http://dx.doi.org/10.2337/dc18-2376DOI Listing
August 2019

Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.

Lancet 2019 06 16;393(10189):2416-2427. Epub 2019 May 16.

Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.

Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.

Findings: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.

Interpretation: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.

Funding: Ultragenyx Pharmaceutical and Kyowa Kirin International.
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http://dx.doi.org/10.1016/S0140-6736(19)30654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179969PMC
June 2019

Bone Marrow Transplantation for Treatment of the Col1a2 Osteogenesis Imperfecta Mouse Model.

Calcif Tissue Int 2019 04 8;104(4):426-436. Epub 2018 Dec 8.

Orthopaedic Research and Biotechnology Unit, Kids Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia.

Bone marrow transplantation (BMT) of healthy donor cells has been postulated as a strategy for treating osteogenesis imperfecta (OI) and other bone fragility disorders. The effect of engraftment by tail vein injection and/or marrow ablation by 6 Gy whole body irradiation were tested in Col1a2 (OI) mice as a model of mild-moderate OI. Dual-emission X-ray absorptiometry, microCT, and 4-point bending were used to measure bone volume (BV), bone mineral density (BMD), and biomechanical strength. BV, BMD, and mechanical strength were reduced in OI mice compared to wild type (WT) controls. BMT with and without irradiation yielded no difference in BV and BMD outcomes for both OI and WT mice, at 3 weeks. Transplantation of OI cells into OI mice to test for paracrine effects of BMT also showed no difference with non-transplanted OI mice. In a parallel cell tracking study, donor marrow was taken from transgenic mice constitutively expressing tdTomato and transplanted into WT mice. Lineage tracking demonstrated that irradiation considerably enhanced engraftment of tdTomato+ cells. However, tdTomato+ cells predominantly expressed TRAP and not AP, indicating engrafted donor cells were chiefly from the hematopoietic lineages. These data show that whole marrow transplantation fails to rescue the bone phenotype of Col1a2 (OI) mice and that osteopoietic engraftment is not significantly enhanced by irradiation. These findings are highly relevant to modern approaches focused on the gene repair of patient cells ex vivo and their subsequent reintroduction into the osteopoietic compartment via the circulation.
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http://dx.doi.org/10.1007/s00223-018-0504-3DOI Listing
April 2019

Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions.

Endocr Rev 2019 08;40(4):1109-1151

Department of Endocrinology, Columbia University College of Physicians and Surgeons, New York, New York.

The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D-deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
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http://dx.doi.org/10.1210/er.2018-00126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626501PMC
August 2019

A novel CASR mutation (p.Glu757Lys) causing autosomal dominant hypocalcaemia type 1

Endocrinol Diabetes Metab Case Rep 2018 Sep 25;2018. Epub 2018 Sep 25.

University of Sydney, Sydney, New South Wales, Australia.

Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members. Learning points: •• ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia. •• In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients. •• CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members. •• Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.
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http://dx.doi.org/10.1530/EDM-18-0107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169543PMC
September 2018

Differential diagnosis of perinatal hypophosphatasia: radiologic perspectives.

Pediatr Radiol 2019 01 3;49(1):3-22. Epub 2018 Oct 3.

Aoba Ward, Miyagi Children's Hospital, Sendai, Miyagi Prefecture, Japan.

Perinatal hypophosphatasia (HPP) is a rare, potentially life-threatening, inherited, systemic metabolic bone disease that can be difficult to recognize in utero and postnatally. Diagnosis is challenging because of the large number of skeletal dysplasias with overlapping clinical features. This review focuses on the role of fetal and neonatal imaging modalities in the differential diagnosis of perinatal HPP from other skeletal dysplasias (e.g., osteogenesis imperfecta, campomelic dysplasia, achondrogenesis subtypes, hypochondrogenesis, cleidocranial dysplasia). Perinatal HPP is associated with a broad spectrum of imaging findings that are characteristic of but do not occur in all cases of HPP and are not unique to HPP, such as shortening, bowing and angulation of the long bones, and slender, poorly ossified ribs and metaphyseal lucencies. Conversely, absent ossification of whole bones is characteristic of severe lethal HPP and is associated with very few other conditions. Certain features may help distinguish HPP from other skeletal dysplasias, such as sites of angulation of long bones, patterns of hypomineralization, and metaphyseal characteristics. In utero recognition of HPP allows for the assembly and preparation of a multidisciplinary care team before delivery and provides additional time to devise treatment strategies.
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http://dx.doi.org/10.1007/s00247-018-4239-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313373PMC
January 2019

Variations in the management of acute illness in children with congenital adrenal hyperplasia: An audit of three paediatric hospitals.

Clin Endocrinol (Oxf) 2018 11 24;89(5):577-585. Epub 2018 Sep 24.

School of Medicine, Sydney, The University of Notre Dame Australia, Darlinghurst, New South Wales, Australia.

Objective: Episodes of acute adrenal insufficiency (AI)/adrenal crises (AC) are a serious consequence of congenital adrenal hyperplasia (CAH). This study aimed to assess morbidity from acute illness in CAH and identify factors associated with use of IV hydrocortisone, admission and diagnosis of an AC.

Method: An audit of acute illness presentations among children with CAH to paediatric hospitals in New South Wales, Australia, between 2000 and 2015.

Results: There were 321 acute presentations among 75 children with CAH. Two-thirds (66.7%, n = 214) of these resulted in admission and 49.2% (n = 158) of the patients received intravenous (IV) hydrocortisone. An AC was diagnosed in (9.0%). Prior to presentation, 64.2% (n = 206) had used oral stress dosing and 22.1% (n = 71) had been given intramuscular (IM) hydrocortisone. Vomiting was recorded in 61.1% (n = 196), 32.7% (n = 64) of whom had used IM hydrocortisone. Admission, AC diagnosis and use of stress dosing varied significantly between hospitals. IM use varied from 7.0% in one metropolitan hospital to 45.8% in the regional hospital. Children aged up to 12 months had the lowest levels of stress dosing and IV hydrocortisone administration. Higher numbers of prior hospital attendances for acute illness were associated with increased use of IM hydrocortisone.

Conclusion: Prehospital and in-hospital management of children with CAH can vary between health services. Children under 12 months have lower levels of stress dosing prior to hospital than other age groups. Experience with acute episodes improves self-management of CAH in the context of acute illness in educated patient populations.
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http://dx.doi.org/10.1111/cen.13826DOI Listing
November 2018

Vitamin D assays and the definition of hypovitaminosis D: results from the First International Conference on Controversies in Vitamin D.

Br J Clin Pharmacol 2018 10 17;84(10):2194-2207. Epub 2018 Jul 17.

Osteoporosis Clinical Research Program and Institute on Aging, University of Wisconsin-Madison, Madison, WI, USA.

The First International Conference on Controversies in Vitamin D was held in Pisa, Italy, 14-16 June 2017. The meeting's purpose was to address controversies in vitamin D research, review the data available, to help resolve them, and suggest a research agenda to clarify areas of uncertainty. The serum 25-hydroxyvitamin D [25(OH)D] concentration [i.e. the sum of 25(OH)D and 25(OH)D ] remains the critical measurement for defining vitamin D status. Assay variation for 25(OH)D has contributed to the current chaos surrounding efforts to define hypovitaminosis D. An essential requirement to develop a consensus on vitamin D status is that measurement of 25(OH)D and, in the future, other potential vitamin D biomarkers [e.g. 1α,25(OH) D , 3-epi-25(OH)D, 24,25(OH) D vitamin D-binding protein, free/bioavailable 25(OH)D and parathyroid hormone] be standardized/harmonized, to allow pooling of research data. Vitamin D Standardization Program tools are described and recommended for standardizing 25(OH)D measurement in research. In the future, similar methodology, based on National Institute for Standards and Technology standard reference materials, must be developed for other candidate markers of vitamin D status. Failure to standardize/harmonize vitamin D metabolite measurements is destined to promulgate continued chaos. At this time, 25(OH)D values below 12 ng ml (30 nmol l ) should be considered to be associated with an increased risk of rickets/osteomalacia, whereas 25(OH)D concentrations between 20 ng ml and 50 ng ml (50-125 nmol l ) appear to be safe and sufficient in the general population for skeletal health. In an effort to bridge knowledge gaps in defining hypovitaminosis D, an international study on rickets as a multifactorial disease is proposed.
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http://dx.doi.org/10.1111/bcp.13652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138489PMC
October 2018

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

J Paediatr Child Health 2018 Mar;54(3):223-233

Institute of Endocrinology and Diabetes, Children's Hospital at Westmead, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1111/jpc.13768DOI Listing
March 2018

Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment.

Bone 2018 05 31;110:66-75. Epub 2018 Jan 31.

Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by low bone density and recurrent fractures with a wide genotypic and phenotypic spectrum. Common features include short stature, opalescent teeth, blue sclerae and hearing impairment. The majority (>90%) of patients with OI have autosomal dominant variants in COL1A1/COL1A2, which lead to defects in type 1 collagen. More recently, numerous recessive variants involving other genes have also been identified. Sp7/Osx gene, is a protein coding gene that encodes a zinc finger transcription factor, osterix, which is a member of the Sp subfamily of sequence-specific DNA-binding proteins. Osterix is expressed primarily by osteoblasts and has been shown to be vital for bone formation and bone homeostasis by promoting osteoblast differentiation and maturation. In animal models, Sp7/Osx has also been shown to regulate biomineralization of otoliths, calcium carbonate structures found in the inner ear of vertebrates. Until recently, only one report of a boy with an Sp7/Osx pathogenic variant presenting with bone fragility, limb deformities and normal hearing has been described in the literature. We have identified a novel Sp7/Osx variant in another sibship that presented with osteoporosis, low-trauma fractures and short stature. Progressive moderate-to-severe and severe-to-profound hearing loss secondary to otospongiosis and poor mineralization of ossicles and petrous temporal bone was also noted in two of the siblings. A homozygous pathogenic variant in exon 2 of the Sp7/Osx gene was found in all affected relatives; c.946C>T (p.Arg316Cys). Bone biopsies in the proband and his male sibling revealed significant cortical porosity and high trabecular bone turnover. This is the second report to describe children with OI associated with an Sp7/Osx variant. However, it is the first to describe the bone histomorphometry associated with this disorder and identifies a significant hearing loss as a potential feature in this OI subtype. Early audiology screening in these children is therefore warranted.
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http://dx.doi.org/10.1016/j.bone.2018.01.031DOI Listing
May 2018

Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa.

Mol Genet Metab 2017 09 25;122(1-2):4-17. Epub 2017 Jul 25.

Department of Pediatrics, Osaka University, Suita, Osaka 565-0871, Japan.

Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures. Asfotase alfa is a human, recombinant enzyme replacement therapy that is approved in many countries for the treatment of patients with HPP. To address the unmet need for guidance in the monitoring of patients receiving asfotase alfa, an international panel of physicians with experience in diagnosing and managing HPP convened in May 2016 to discuss treatment monitoring parameters. The panel discussions focused on recommendations for assessing and monitoring patients after the decision to treat with asfotase alfa had been made and did not include recommendations for whom to treat. Based on the consensus of panel members, this review provides guidance on the monitoring of patients with HPP during treatment with asfotase alfa, including recommendations for laboratory, efficacy, and safety assessments and the frequency with which these should be performed during the course of treatment. Recommended assessments are based on patient age and include regular monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life. Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving asfotase alfa. Monitoring of efficacy and safety outcomes must be tailored to the individual patient, depending on medical history, clinical manifestations, availability of resources in the clinical setting, and the clinician's professional judgment.
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http://dx.doi.org/10.1016/j.ymgme.2017.07.010DOI Listing
September 2017

Nutritional rickets in immigrant and refugee children.

Public Health Rev 2016 22;37. Epub 2016 Jul 22.

3Department of Endocrinology & Diabetes, Birmingham Children's Hospital, Birmingham, UK.

Immigrant and refugee populations bring public health challenges to host nations. In the current global refugee crisis, children are the most vulnerable subpopulation. Diseases that were considered rare in the host nation may be highly prevalent among immigrant children. The prevalence of nutritional rickets is increasing in high-income countries, largely driven by an influx of immigrant populations. Nutritional rickets is a bone disease in early childhood resulting in bone pain, delayed motor development, and bending of the bones, caused by vitamin D deficiency and/or inadequate dietary calcium intake. The consequences of nutritional rickets include stunted growth, developmental delay, lifelong bone deformities, seizures, cardiomyopathy, and even death. Nutritional rickets is most commonly seen in children from the Middle East, Africa, and South Asia in high-income countries. Dark skin pigmentation, sun avoidance, covering the skin, and prolonged breast feeding without vitamin D supplementation, are important risk factors for vitamin D deficiency, and combined with a lack of dairy products in the diet, these deficiencies can result in insufficient calcium supply for bone mineralization. We recommend screening all immigrant and refugee children under 5 years of age from these ethnic groups for nutritional rickets, based on clinical features, and confirming the diagnosis with radiographs of the wrists and knees. Because nutritional rickets is entirely preventable, public health policies must address the need for universal vitamin D supplementation and adequate dietary calcium to protect children from this scourge. Vitamin D supplementation of all infants and children with 400 IU/d during the first year of life and dietary or supplemental intakes of at least 600 IU/d of vitamin D and 500 mg/d of calcium thereafter, will effectively prevent nutritional rickets. We call on national health authorities of host countries to implement health check lists and prevention programs that include screening for micronutrient deficiencies, in addition to assessing infections and vaccination programs. Due to their high prevalence of vitamin D deficiency, refugee children of all ages from these ethnic groups should be supplemented with vitamin D, beginning upon arrival.
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http://dx.doi.org/10.1186/s40985-016-0018-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810111PMC
July 2016

Central Adrenal Insufficiency Is Not a Common Feature in CHARGE Syndrome: A Cross-Sectional Study in 2 Cohorts.

J Pediatr 2016 09 16;176:150-5. Epub 2016 Jun 16.

Department of Pediatrics, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Objective: To evaluate whether central adrenal insufficiency (CAI) is present in CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital hypoplasia, and Ear abnormalities, including deafness) syndrome, a complex malformation disorder that includes central endocrine dysfunction.

Study Design: Two cross-sectional studies were performed in Dutch (September 2013-February 2015) and Australian (January 2012-January 2014) CHARGE syndrome clinics. Twenty-seven Dutch and 19 Australian patients (aged 16 months-18 years) with genetically confirmed CHARGE syndrome were included. The low-dose adrenocorticotropin (ACTH) test was used to assess CAI in the Dutch cohort. A peak cortisol response less than 18.1 μg/dL (500 nmol/L) was suspected for CAI, and a glucagon stimulation test was performed for confirmation. Australian patients were screened by single measurements of ACTH and cortisol levels. If adrenal dysfunction was suspected, a standard-dose ACTH test was performed.

Results: The low-dose ACTH test was performed in 23 patients (median age 8.4 [1.9-16.9] years). Seven patients showed an insufficient maximum cortisol level (10.3-17.6 μg/dL, 285-485 nmol/L), but CAI was confirmed by glucagon stimulation test in only 1 patient (maximum cortisol level 15.0 μg/dL, 415 nmol/L). In the Australian cohort, 15 patients (median age 9.1 [1.3-17.8] years) were screened, and none had CAI.

Conclusions: CAI was not common in our cohorts, and routine testing of adrenal function in children with CHARGE syndrome is not indicated.
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http://dx.doi.org/10.1016/j.jpeds.2016.05.065DOI Listing
September 2016