Introduction: X-linked hypophosphataemia (XLH) is conventionally managed with oral phosphate and active vitamin D analogues. Objectives: To evaluate long term treatment response by assessing biochemical disease activity [serum alkaline phosphatase (ALP)], radiological rickets severity score (RSS), growth and morbidity in patients with XLH on conventional therapy and assess the correlation between serum ALP and RSS. Methods: XLH patients from 3 UK tertiary centres with >= 3 radiographs one year apart were included. Data was collected retrospectively. The RSS was assessed from routine hand and knee radiographs and ALP z scores were calculated using age-specific reference data. Results: Thirty-eight (male = 12) patients met the inclusion criteria. The mean +/- SD knee, wrist and total RSS at baseline (median age 1.2 years) were 2.0 +/- 1.2, 1.9 +/- 1.2 and 3.6 +/- 1.3 respectively; and at the most recent clinic visit (median age 9.0 years, range 3.3-18.9) were 1.6 +/- 1.0, 1.0 +/- 1.0 and 2.5 +/- 1.5 respectively. The mean +/- SD serum ALP z scores at baseline and the most recent visit were 4.2 +/- 2.3 and 4.0 +/- 3.3. Median height SDS at baseline and most recent visit were -1.2 and -2.1 (p = 0.05). Dental abscess, craniosynostosis, limb deformity requiring orthopaedic intervention and nephrocalcinosis were present in 31.5%, 7.9%, 31.6% and 42.1% of the cohort respectively. There was no statistically significant (p > 0.05) correlation between ALP z scores and knee (r = 0.07) or total (r = 0.12) RSS. Conclusions: Conventional therapy was not effective in significantly improving biochemical and radiological features of disease. The lack of association between serum ALP and rickets severity on radiographs limits the value of ALP as the sole indicator of rickets activity in patients receiving conventional therapy.

Judith Elizabeth Adams Professor Judith Elizabeth Adams, “Judy” to her friends, an eminent skeletal radiologist, passed away after a short illness on September 30, 2017. Judy was born May 16, 1945, in Liverpool, UK, and grew up in Northern Rhodesia (now Zambia). She trained at University College Hospital, London, UK, with her radiology career beginning in 1972. Her mentors included Sir Godfrey Hounsfield, the inventor of X-ray computed tomography, and Sir Charles Dent, a pioneer of metabolic bone disease in the UK. She joined The University of Manchester in 1976 and became a Professor of Radiology and Head of Clinical Radiology in 1993. She served as Dean, member of council, and Vice President of the Royal College of Radiologists. Judy was a member of many societies, including the American Society for Bone and Mineral Research, European Calcified Tissue Society, National Osteoporosis Society, and Bone Research Society (UK), in addition to the International Skeletal Society and European Society for Skeletal Radiologists. She traveled the world attending the International Bone Densitometry Workshops and hosting the 1987 Workshop in the UK. Her clinical and research expertise lay particularly in the field of bone densitometry, quantitative computed tomography, and vertebral fracture recognition. She contributed greatly to the development and application of bone densitometry in children and adults. She led and coauthored several national and international guidance documents for clinical application of bone densitometry in pediatric and adult fields. In addition to her clinical expertise, she carried out extensive research in the field of osteoporosis and bone densitometry throughout her career, with more than £5.5 million awarded from research councils, charity, and industry, with £750,000 still in active research. This research resulted in more than 200 peer-reviewed publications, 24 invited reviews, and 34 book chapters, the last proofread only 3 weeks ago. For her contribution to research of note was her role in the collection of one of the first and largest UK reference data sets in children, which has transformed pediatric practice in the UK. She championed the clinical application of quantitative computed tomography in adults and also for research since the early days of its use, being for a long time the only UK center that used the method. As part of this, she worked closely with Professor Harry Genant at UCSF. Judy worked tirelessly to emphasize the importance of identifying the presence of osteoporotic vertebral fractures. She subsequently worked on creating active appearance models for the semi-automated assessment of vertebral fracture from dual-energy X-ray absorptiometry (DXA) and from clinical CT scans. She was a champion of the International Osteoporosis Foundation Vertebral Fracture initiative. Through her role in the European Society for Skeletal Radiology, Judy provided a bridge between the radiology and bone fields. Besides focusing on osteoporosis in adults and children today, Judy also used her expertise to elucidate skeletal pathologies in ancient Egyptian mummies, both human and animal. This included making a diagnosis of a case of osteogenesis imperfecta type V 3000 years later! She always loved new challenges in the application of imaging. The UK Bone Research Society honored Judy by inviting her to co-present the annual BRS Dent Lecture in 2015 with Professor Ignac Fogelman, recognizing her contribution to developments in clinical imaging. In 2016, she was awarded the Linda Edwards Award from the National Osteoporosis Society, UK, in recognition of her outstanding contribution to the field of osteoporosis. For radiology, she was most recently awarded the gold medal from the Royal College of Radiologists (2016), as well as a gold medal from the International Skeletal Society (2007). Judy was a tireless supporter of the UK National Osteoporosis Society, bringing her expertise as a radiologist to the charity. She served as a trustee, member of the Medical Board, conference planning committee, and Bone Densitometry Training Scheme along with other advisory roles. Judy was a warm, thoughtful, and loyal friend. She was a great mentor to both of us and many other clinicians and scientists who are indebted to her mentorship and tutelage. Her collaborations spanned the globe. She will be remembered by all for her elegance, her smile and her laugh, her bright clothes, and her endless energy and enthusiasm. Judy was wonderful company both professionally and personally. Outside of work, she loved culture, from Manchester United to opera, flowers, gardening, and travel. Sadly, Judy's husband of 45 years, Professor Peter Adams, an Emeritus Professor of Medicine at the University of Manchester, passed away a week later. They are survived by their two sons, Charles and James, their three grandchildren on whom they doted, and by Judy's sister Jane and family. Kate Ward Associate Professor, MRC Lifecourse Epidemiology University of Southampton, Southampton General Hospital Southampton, UK Zulf Mughal Consultant in Pediatric Bone Disorders & Honorary Clinical Professor of Child Health Department of Pediatric Endocrinology Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust Manchester, UK

Oral glucocorticoids (GC) preserve muscle strength and prolong walking in boys with Duchenne muscular dystrophy (DMD). Although vertebral fractures have been reported in boys taking GC, fracture rates for different GC regimes have not been investigated. The aim of this pragmatic longitudinal study was to compare growth, body mass, bone mineral density (BMD), vertebral fractures (VF) and ambulatory status in boys with DMD on daily (DAILY) or intermittent (INTERMITTENT), oral GC regimens. A convenience sample of 50 DMD boys from two centres was included in the study; 25 boys each were on the DAILY or INTERMITTENT regimen. Size adjusted lumbar spine BMD (LS BMAD), total body less head BMD (TBLH), by DXA and distal forearm bone densities by pQCT, GC exposure, VF assessment and ambulatory status were analysed at three time points; baseline, 1 and 2 years. At baseline, there were no differences in age, GC duration or any bone parameters. However, DAILY boys were shorter (height SDS DAILY = -1.4(0.9); INTERMITTENT = -0.8(1.0), p = 0.04) with higher BMI (BMI SDS DAILY = 1.5(0.9); INTERMITTENT = 0.8(1.0), p = 0.01). Over 2 years, DAILY boys got progressively shorter (delta height SDS DAILY = -0.9(1.1); INTERMITTENT = +0.1(0.6), p < 0.001). At their 2 year assessment, 5 DAILY and 10 INTERMITTENT boys were non-ambulant. DAILY boys had more VFs than INTERMITTENT boys (10 versus 2; chi(2) p = 0.008). BMAD SDS remained unchanged between groups. TBLH and radius BMD declined significantly but the rate of loss was not different. In conclusion, there was a trend for more boys on daily GCs to remain ambulant but at the cost of more VFs, greater adiposity and markedly diminished growth. In contrast, boys on intermittent GCs had fewer vertebral fractures but there was a trend for more boys to loose independent ambulation.

Background Hypoparathyroidism is characterised by hypocalcaemia, and standard management is with an active vitamin D analogue and adequate oral calcium intake (dietary and/or supplements). Little is described in the literature about the impact of intercurrent illnesses on calcium homeostasis in children with hypoparathyroidism. Methods We describe three children with hypoparathyroidism in whom intercurrent illnesses led to hypocalcaemia and escalation of treatment with alfacalcidol (1-hydroxycholecalciferol) and calcium supplements. Results Three infants managed with standard treatment for hypoparathyroidism (two with homozygous mutations in GCMB2 gene and one with Sanjad-Sakati syndrome) developed symptomatic hypocalcaemia (two infants developed seizures) following respiratory or gastrointestinal illnesses. Substantial increases in alfacalcidol doses (up to three times their pre-illness doses) and calcium supplementation were required to achieve acceptable serum calcium concentrations. However, following resolution of illness, these children developed an increase in serum calcium and hypercalciuria, necessitating rapid reduction to pre-illness dosages of alfacalcidol and oral calcium supplementation. Conclusion Intercurrent illness may precipitate symptomatic hypocalcaemia in children with hypoparathyroidism, necessitating increase in dosages of alfacalcidol and calcium supplements. Close monitoring is required on resolution of the intercurrent illness, with timely reduction of dosages of active analogues of vitamin D and calcium supplements to prevent hypercalcaemia, hypercalciuria and nephrocalcinosis.

Background Higher 25(OH)D3 levels are associated with lower HbA1c, but there are limited UK interventional trials assessing the effect of cholecalciferol on HbA1c. Aims (1) To assess the baseline 25(OH)D3 status in a Manchester cohort of children with type 1 diabetes (T1D). (2) To determine the effect of cholecalciferol administration on HbA1c. Methods Children with T1D attending routine clinic appointments over three months in late winter/early spring had blood samples taken with consent. Participants with a 25(OH)D3 level <50 nmol/L were treated with a one-off cholecalciferol dose of 100,000 (2–10 years) or 160,000 (>10 years) units. HbA1c levels before and after treatment were recorded. Results Vitamin D levels were obtained from 51 children. 35 were Caucasian, 11 South Asian and 5 from other ethnic groups. 42 were vitamin D deficient, but 2 were excluded from the analysis. All South Asian children were vitamin D deficient, with mean 25(OH)D3 of 28 nmol/L. In Caucasians, there was a negative relationship between baseline 25(OH)D3 level and HbA1c (r = −0.484, P < 0.01). In treated participants, there was no significant difference in mean HbA1c at 3 months (t = 1.010, P = 0.328) or at 1 year (t = −1.173, P = 0.248) before and after treatment. One-way ANCOVA, controlling for age, gender, ethnicity, BMI and diabetes duration showed no difference in Δ HbA1c level. Conclusion We report important findings at baseline, but in children treated with a stat dose of cholecalciferol, there was no effect on HbA1c. Further studies with larger sample sizes and using maintenance therapy are required.

Background Intensive glycaemic control in type one diabetes (T1D) reduces progression of complications (DCCT and EDIC). In clinical practice, glycosylated haemoglobin (Hba1c) levels reflect control. Previous studies show that higher 25(OH)D3 levels are associated with lower Hba1c (US SEARCH study). However, there are limited interventional trials assessing the effect of cholecalciferol on Hba1c. Aims. 1. To assess the baseline 25(OH)D3 status in a paediatric cohort of patients with T1D. 2. To determine the effect of cholecalciferol administration on Hba1c. Methods Children with T1D attending routine clinic appointments from February to April 2011 had blood samples taken with consent, and patients with a 25(OH)D3 level <20ng/ml were treated with a one-off stat cholecalciferol dose of 100 000 (2–10 years) or 160 000 (>10 years) units. Hba1c levels from the year preceding treatment and the year after treatment were recorded. Results Vitamin D levels were obtained from 51 patients (30 male, 21 female). 35 were Caucasian, 11 South Asian and 5 from other ethnic groups. 42 subjects were vitamin D deficient, but 2 were excluded from the analysis (one moved away, one was non-compliant). All South Asian patients were vitamin D deficient, with mean 25(OH)D3 of 11.2 ng/ml. In Caucasians, there was a negative relationship between baseline 25(OH)D3 level and HbA1C (r= –0.484, p < 0.01), but not in South Asians. In treated patients, paired t tests showed no significant difference in mean Hba1c at 3 months (t=1.010, p 0.328) or at 1 year (t=-1.173, p = 0.248) before and after treatment. One way ANCOVA, controlling for age, gender, ethnicity, BMI and diabetes duration showed no difference in change in Hba1c level between those treated and not treated, at 3m and at 1 year before and after treatment. Conclusion We confirmed a high prevalence of vitamin D deficiency in this clinic cohort of children with T1D, and found a negative relationship between baseline 25(OH)D3 level and HbA1C in Caucasians. However, in patients treated with a stat dose of cholecalciferol there was no effect on Hba1c. Further studies with larger sample sizes, and using maintenance 25(OH)D3 therapy rather than stat therapy are required.

OBJECTIVES 1) To update the 2006 systematic review and meta-analysis by Nnoaham & Clarke exploring the association between serum vitamin D and risk of active tuberculosis (TB) following discrepant evidence; and 2) to identify whether TB and vitamin D are associated in rural Afghanistan. METHODS Systematic review and meta-analysis of studies published between January 1980 and June 2014 using Nnoaham & Clarke's methodology. For this case-control study, 90 age- and sex-matched pairs were recruited from rural provinces, and blood 25-hydroxyvitamin D concentrations were measured using enzyme-linked immunosorbent assay. RESULTS Sixteen studies were eligible for review. Eleven showed differences between vitamin D levels in TB patients and controls, two showed partial differences and three showed none. Studies on African and European populations show lower vitamin D levels in TB patients, but results from Asia vary. No significant differences were found in vitamin D levels in our rural Afghan population. Controls had a higher body mass index (BMI) (mean control BMI 21.50 kg/m(2), mean case BMI 18.86 kg/m(2), P < 0.001), and were more likely to have been employed (40% of controls, 15.6% of cases, P = 0.002). CONCLUSION Genetic differences may account for the differences among study results in the systematic review. Vitamin D levels are not associated with TB among Afghans living in these rural provinces.

To the Editor : Fractures are the most common injuries during growing years; around 10 to 25 % of all pediatric injuries are fractures [1]. The WHO describes fractures as the most common category of unintentional injuries suffered by children below 15 y and requiring hospital admission in developing countries [2]. To the best of our knowledge, there are no data on prevalence of fractures in childhood in India. As a part of a nationwide multicentre study to collect anthropometric data in 2–18 y old children (July 2010 January 2012) [3], we also collected data on history of fractures. In 9496 children, information about fractures and sports activity was collected from parents by a self administered questionnaire. Mean age of children was 10.4±3.3 y. In all, 9 % children (Boys: 6 %, Girls: 3 %) had suffered from at least one fracture till date. The percentage of fracture was significantly higher (p<0.05) in children from 10 to 14 y of age (53 % of the total fractures) than other age-groups. However, boys from 10 to 14 and 15 to 18 y of age had significantly greater (p<0.05) number of fractures than girls from the similar age group. Majority of children played football, basketball, volley ball, dodge ball, badminton, table tennis and cricket. The mean sports activity minutes were 307±280 min/wk in boys and 216±218 min/wk in girls. Percentage of fractures increased with the increase in the sports activity in boys from 2 to 5, 6 to 9 and 15 to 18 y of age. High level of sports activity may increase the risk of fractures. The increased fracture incidence during adolescence may also be due to the greater rate of increase in bone area than bone mineralization during adolescence. The present study provides a valuable snapshot of fracture incidence in Indian school going children. Fracture is an important cause of morbidity and so calls for a higher quality study from all the classes of society so as to improve safety and preventive measures to avoid fractures in school going children.

In 1987, Cole and Carpenter reported two unrelated infants with multiple fractures and deformities of bone, with a skeletal phenotype similar to severe osteogenesis imperfecta. In addition, these patients also had proptosis, blue sclerae, hydrocephalus, and a distinct facial gestalt. They were reported to be of normal intelligence. Radiologically, these patients had characteristic skeletal manifestations including craniosynostosis and deformities similar to severe progressive osteogenesis imperfecta. Since the first description, there have only been a few other reports of patients with a similar phenotype. Collagen studies performed in reported patients have been normal. The molecular basis of this syndrome has not been elucidated and the inheritance pattern is still unknown. We report on a child with Cole‐Carpenter syndrome phenotype who has a homozygous c.118G>T mutation in exon 1 of theCRTAPgene. We describe the clinical features and correlate this with her molecular results. This is the first report towards elucidating the molecular basis of Cole‐Carpenter syndrome. © 2015 Wiley Periodicals, Inc.

BackgroundSun exposure has positive and negative effects on health, yet little is known about the sun exposure behaviour of UK adolescents, including those more prone or less prone to sunburn.ObjectiveTo examine sun exposure behaviour of UK white Caucasian adolescents including time spent outdoors, holiday behaviour, use of sunscreen and clothing, with assessment for differences between sun-reactive skin type groups.MethodsWhite Caucasian adolescents (12-15years) attending schools in Greater Manchester completed a two-page questionnaire to assess sun exposure and photoprotective behaviour.ResultsA total of 133 adolescents (median age 13.4years; 39% skin type I/II, 61% skin type III/IV) completed the questionnaire. In summer, adolescents spent significantly longer outdoors at weekends (median 4h/day, range 0.25-10) than on weekdays (2, 0.25-6; P<0.0001). When at home in the UK during summer, 44% reported never wearing sunscreen compared to just 1% when on a sunny holiday. Sunscreen use was also greater (frequency/coverage) when on a sunny holiday than at home in the UK summer (P<0.0001). Adolescents of skin types I/II (easy burning) spent significantly less time outdoors than skin types III/IV (easy tanning) on summer weekends (P<0.001), summer weekdays (P<0.05) and on a sunny holiday (P=0.001). Furthermore, skin types I/II reported greater sunscreen use during summer in the UK and on sunny holiday (both P<0.01), and wore clothing covering a greater skin area on a sunny holiday (P<0.01) than skin types III/IV. There was no difference in sun exposure behaviour/protection between males and females.ConclusionThe greater sun-protective measures reported by adolescents of sun-reactive skin type group I/II than III/IV suggest those who burn more easily are aware of the greater need to protect their skin. However, use of sunscreen during the UK summer is low and may need more effective promotion in adolescents.

Objectives: The aim of this cross-sectional study was to assess the vitamin D status and muscle function in children with NF1 compared with their unaffected siblings. Methods: NF1 children between 5 and 18 years of age and who had at least one unaffected sibling were identified. Serum concentrations of 25-hydroxyvitamin D (25(OH) D), calcium, inorganic phosphate, alkaline phosphate, parathyroid hormone and 1,25-dihydroxyvitamin D were measured. The Leonardo Mechanography Ground Reaction Force Platform (GRFP) was used to measure EFI, jump power, force and height. Results: There was no significant difference in 25(OH) D between NF1 subjects and unaffected siblings. Relative jump power and force were found to be significantly different. The adjusted means (95% confidence limits) of non-NF1 and NF1 children for relative jump power (W/kg), controlling for body mass and age, were 37.31 (34.14, 40.49) and 32.51 (29.34, 35.68), respectively (P=0.054); and force (N/kg), controlling for body mass, age and gender, were 25.79 (24.28, 27.30) and 21.12 (19.61, 22.63), respectively (P<0.0001). Jumping parameters were not related to serum 25(OH) D. Conclusions: There was no significant relationship between vitamin D status and NF1 status in children. NF1 children had significantly impaired jumping power and force, when compared to their unaffected siblings.

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

We read Professor Nussey’s response to our position statement with interest.1 2 We are not a committee but a current comprehensive group of clinicians who manage children with bone disease in the UK. Our opinions are based on our combined clinical experience of vitamin D deficiency in infants, children, and adolescents across the UK. Our statement was a concise expression of our position rather than an exposition of the evidence. However, careful consideration of the extant literature underpins our statement (although we acknowledge the paucity of studies that examine clinical outcomes in …

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ObjectiveLoss-of-function calcium-sensing receptor (CAR) mutations cause elevated parathyroid hormone (PTH) secretion and hypercalcaemia. Although full Car deletion is possible in mice, most human CAR mutations result from a single amino acid substitution that maintains partial function. However, here, we report a case of neonatal severe hyperparathyroidism (NSHPT) in which the truncated CaR lacks any transmembrane domain (CaRR392X), in effect a full CAR ‘knockout’.Case reportThe infant (daughter of distant cousins) presented with hypercalcaemia (5.5–6 mmol/l corrected calcium (2.15–2.65)) and elevated PTH concentrations (650–950 pmol/l (12–81)) together with skeletal demineralisation. NSHPT was confirmed by CAR gene sequencing (homozygous c.1174C-to-T mutation) requiring total parathyroidectomy during which only two glands were located and removed, resulting in normalisation of her serum PTH/calcium levels.Design and methodsThe R392X stop codon was inserted into human CAR and the resulting mutant (CaRR392X) expressed transiently in HEK-293 cells.ResultsCaRR392X expressed as a 54 kDa dimeric glycoprotein that was undetectable in conditioned medium or in the patient's urine. The membrane localisation observed for wild-type CaR in parathyroid gland and transfected HEK-293 cells was absent from the proband's parathyroid gland and from CaRR392X-transfected cells. Expression of the mutant was localised to endoplasmic reticulum consistent with its lack of functional activity.ConclusionsIntriguingly, the patient remained normocalcaemic throughout childhood (2.5 mM corrected calcium, 11 pg/ml PTH (10–71), age 8 years) but exhibited mild asymptomatic hypocalcaemia at age 10 years, now treated with 1-hydroxycholecalciferol and Ca2+ supplementation. Despite representing a virtual CAR knockout, the patient displays no obvious pathologies beyond her calcium homeostatic dysfunction.

Because of the lack of well designed studies on vitamin D and health,1 the British Paediatric and Adolescent Bone Group has produced a position statement based on current expert opinion. This statement is supported by the British Society of Paediatric Radiology and child protection and nutrition committees of the Royal College of Paediatrics …

Aims To assess the incidence of Avascular Necrosis (AVN) in Children receiving treatment for all. Methods The notes of patients who developed AVN due to treatment for ALL were reviewed. Patients were male and females, aged 3-14 years and received regimens A, B or C as per UKALL. 2, 8 and 3 patients received these regimens respectively. Types of ALL included Common ALL, Pre-B cell and T cell ALL. Two of the patients reviewed relapsed with ALL. Patients were of different ethnic backgrounds, The majority were white British. The time between initial diagnosis of ALL and an initial symptom suggesting AVN was recorded as was the timing of the first radiological diagnosis of AVN. AVN was confirmed by XR and or MRI scan. The location of the AVN was also noted in each patient and any intervention carried out or medication given to alleviate the AVN was also recorded. Results Incidence of AVN: 18.57%(13/70 patients) (figure 1). The mean age of diagnosis with ALL of those who developed AVN: 12 years. –Females 11.75 Years. –Males 12.4 years. Mean time from initial diagnosis of ALL to first symptom of AVN*: 19.23 Months. –Females 21.5 Months. –Males 15.6 Months. Mean time from Initial diagnosis of ALL to radiological diagnosis*: 30 months. –Females 32.13 Months. –Males 26.6 Months. *This included 2 patients who relapsed with leukaemia. Incidence of AVN in Females Vs Males (figure 2): The most common area for occurrence of AVN was the hips, followed by the knees and shoulders equally, and then the wrist and pelvis. 9/13 patients with a radiological diagnosis of AVN received an intervention. Interventions Carried out for AVN (figure 3): Oral Medications Given to Relieve AVN (figure 4): Conclusions –Dexamethasone increases incidence of AVN-The majority of AVN patients had dexamethasone reduced or replaced with prednisolone to reduce AVN. –Females developed AVN earlier than males. –Receiving chemotherapy and the intensity of treatment increased incidence of AVN. –Older the age of the child at diagnosis greater the risk for development of AVN. –The majority of patients who developed AVN required an intervention.