Sunshine and vitamin D Saraff, Vrinda; Shaw, Nick
Archives of Disease in Childhood,
02/2016, Volume:
101, Issue:
2
Journal Article, Book Review
Peer reviewed
Vitamin D is vital for bone health and its deficiency deemed as a disease of the past has re-emerged as an important health concern. Exposure of the skin to solar ultraviolet B radiation is the major ...source of vitamin D and only a small proportion is derived from dietary intake. We review the various factors that influence the cutaneous synthesis of vitamin D and the recommendations regarding safe sun exposure and dietary supplementation to achieve adequate vitamin D levels proposed for optimal bone health.
Abstract
Background
X-linked hypophosphatemia (XLH) is a rare multisystemic disease with a prominent musculoskeletal phenotype. We aim here to improve understanding of the prevalence of XLH across ...the life course and of overall survival among people with XLH.
Methods
This was a population-based cohort study using a large primary care database in the United Kingdom (UK) from 1995 to 2016. XLH cases were matched by age, gender, and practice to up to 4 controls. Trends in prevalence over the study period were estimated (stratified by age) and survival among cases was compared with that of controls.
Findings
From 522 potential cases, 122 (23.4%) were scored as at least possible XLH, while 62 (11.9%) were classified as highly likely or likely (conservative definition). In main analyses, prevalence (95% CI) increased from 3.1 (1.5–6.7) per million in 1995–1999 to 14.0 (10.8–18.1) per million in 2012–2016. Corresponding estimates using the conservative definition were 3.0 (1.4–6.5) to 8.1 (5.8–11.4). Nine (7.4%) of the possible cases died during follow-up, at median age of 64 years. Fourteen (2.9%) of the controls died at median age of 72.5 years. Mortality was significantly increased in those with possible XLH compared with controls (hazard ratio HR 2.93; 95% CI, 1.24–6.91). Likewise, among those with likely or highly likely XLH (HR 6.65; 1.44–30.72).
Conclusions
We provide conservative estimates of the prevalence of XLH in children and adults within the UK. There was an unexpected increase in mortality in later life, which may have implications for other fibroblast growth factor 23–related disorders.
Current guidelines use differing definitions of vitamin D deficiency based on serum 25-hydroxyvitamin D (25OHD) levels, which complicates clinical decision making on vitamin D doses used for the ...prevention and treatment. This study examined the natural relationship between serum 25OHD, parathyroid hormone (PTH), calcium, phosphate, and alkaline phosphatase.
Two-hundred and fourteen children routinely admitted without conditions affecting the natural relationship among metabolites, including 17 with radiologically confirmed vitamin D deficiency rickets, were studied. The frequency of abnormal bone metabolites was examined for different 25OHD thresholds.
The best fitting intersection point where PTH levels increased was a 25OHD level of 34 nmol/l (R(2) = 0.454; 95% confidence interval: 27-41 nmol/l). Seventy-three and 86% of the children demonstrated some biochemical abnormality below 25OHD levels of 41 and 27 nmol/l, respectively. All patients with rickets had 25OHD levels < 34 nmol/l. The vast majority of children with abnormal bone metabolites had 25OHD levels < 34 nmol/l and PTH levels > 50 ng/l.
Vitamin D deficiency, based on PTH elevation, was best defined by a 25OHD level of < 34 nmol/l. Because deficient calcium supply often coexists with vitamin D deficiency and both can independently cause nutritional rickets, a threshold for the skeletal effects of vitamin D should not be based purely on 25OHD levels.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Fibrous Dysplasia / McCune Albright syndrome (FD/MAS) represents a wide spectrum of diseases due to somatic gain-of-function mutations of the GNAS gene. The mutation leads to overactivity in the ...target tissues and to a wide phenotype of clinical features that vary in severity and age of onset. The rarity of the disease and its variable presentation to multiple specialities often leads to misdiagnosis and inappropriate variability in investigations and treatments. To address this, our international consortium of clinicians, researchers, and patients' advocates has developed pragmatic clinical guidelines for best clinical practice for the definition, diagnosis, staging, treatment and monitoring for FD/MAS to empower patients and support clinical teams in both general and specialised healthcare settings. With the lack of strong evidence to inform care, the guidelines were developed based on review of published literature, long-standing extensive experience of authors, input from other healthcare professionals involved in the care of FD/MAS patients and feedback from patients and patient groups across the globe. This has led to the formulation of a set of statements to inform healthcare professionals, patients, their families, carers and patient groups of the best practice of care. It is anticipated the implementation of these recommendations will lead to improvement in the care of patients with FD/MAS internationally.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Vitamin D is a key hormone in the regulation of calcium and phosphorus metabolism and plays a pivotal role in bone health, particularly during pediatric age when nutritional rickets and impaired bone ...mass acquisition may occur. Great interest has been placed in recent years on vitamin D’s extraskeletal actions. However, while recent data suggest a possible role of vitamin D in the pathogenesis of several pathological conditions, including infectious and autoimmune diseases, the actual impact of vitamin D status on the global health of children and adolescents, other than bone, remains a subject of debate. In the meantime, pediatricians still need to evaluate the determinants of vitamin D status and consider vitamin D supplementation in children and adolescents at risk of deficiency. This review is the result of an expert meeting that was held during the congress “Update on vitamin D and bone disease in childhood” convened in Pisa, Italy, in May 2013.
Conclusion
: The collaboration of the international group of experts produced this “state of the art” review on vitamin D in childhood and adolescence. After dealing with vitamin D status and its determinants, the review outlines the current debate on vitamin D’s health benefits, concluding with a practical approach to vitamin D supplementation during childhood and adolescence.
What is Known
:
•
Vitamin D deficiency is a worldwide health problem.
•
Vitamin D deficiency affects not only musculoskeletal health but also a potentially wide range of acute and chronic diseases.
What is New
:
•
We reviewed the literature focusing on randomized controlled trials of vitamin D supplementation during childhood and adolescence.
•
This review will help pediatricians to appreciate the clinical relevance of an adequate vitamin D status and it will provide a practical approach to vitamin D supplementation
.
Full text
Available for:
DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Abstract
Objectives
X-Linked hypophosphataemic rickets (XLH) is a rare multi-systemic disease of mineral homeostasis that has a prominent skeletal phenotype. The aim of this study was to describe ...additional comorbidities in XLH patients compared with general population controls.
Methods
The Clinical Practice Research Datalink (CPRD) GOLD was used to identify a cohort of XLH patients (1995–2016), along with a non-XLH cohort matched (1 : 4) on age, sex and GP practice. Using the CALIBER portal, phenotyping algorithms were used to identify the first diagnosis (and associated age) of 273 comorbid conditions during patient follow-up. Fifteen major disease categories were used and the proportion of patients having ≥1 diagnosis was compared between cohorts for each category and condition. Main analyses were repeated according to the Index of Multiple Deprivation (IMD).
Results
There were 64 and 256 patients in the XLH and non-XLH cohorts, respectively. There was increased prevalence of endocrine OR 3.46 (95% CI: 1.44, 8.31) and neurological OR 3.01 (95% CI: 1.41, 6.44) disorders among XLH patients. Across all specific comorbidities, four were at least twice as likely to be present in XLH cases, but only depression met the Bonferroni threshold: OR 2.95 (95% CI: 1.47, 5.92). Distribution of IMD among XLH cases indicated greater deprivation than the general population.
Conclusion
We describe a higher risk of mental illness in XLH patients compared with matched controls, and greater than expected deprivation. These findings may have implications for clinical practice guidelines and decisions around health and social care provision for these patients.
To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children in Great Britain.
A nationally representative cross-sectional study survey of children (1102) aged 4-18 years ...(999 white, 570 male) living in private households (January 1997-1998). Interventions provided information about dietary habits, physical activity, socio-demographics, and blood sample. Outcome measures were vitamin D insufficiency (<50 nmol/L).
Vitamin D levels (mean = 62.1 nmol/L, 95%CI 60.4-63.7) were insufficient in 35%, and decreased with age in both sexes (p<0.001). Young People living between 53-59 degrees latitude had lower levels (compared with 50-53 degrees, p = 0.045). Dietary intake and gender had no effect on vitamin D status. A logistic regression model showed increased risk of VDI in the following: adolescents (14-18 years old), odds ratio (OR) = 3.6 (95%CI 1.8-7.2) compared with younger children (4-8 years); non white children (OR = 37 95%CI 15-90); blood levels taken December-May (OR = 6.5 95%CI 4.3-10.1); on income support (OR = 2.2 95%CI 1.3-3.9); not taking vitamin D supplementation (OR = 3.7 95%CI 1.4-9.8); being overweight (OR 1.6 95%CI 1.0-2.5); <1/2 hour outdoor exercise/day/week (OR = 1.5 95%CI 1.0-2.3); watched >2.5 hours of TV/day/week (OR = 1.695%CI 1.0-2.4).
We confirm a previously under-recognised risk of VDI in adolescents. The marked higher risk for VDI in non-white children suggests they should be targeted in any preventative strategies. The association of higher risk of VDI among children who exercised less outdoors, watched more TV and were overweight highlights potentially modifiable risk factors. Clearer guidelines and an increased awareness especially in adolescents are needed, as there are no recommendations for vitamin D supplementation in older children.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glucocorticoids (GCs) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures.
This study aims to determine the efficacy and safety of intravenous (IV) zoledronic acid ...(ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO).
Children aged 5 to 17 years with GIO were enrolled in this multinational, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov NCT00799266). Eligible children were randomly assigned 1:1 to 6 monthly IV ZA 0.05 mg/kg or IV placebo. The primary end point was the change in lumbar spine bone mineral density z score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed.
Thirty-four children were enrolled (mean age 12.6 ± 3.4 years 18 on ZA, 16 on placebo), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from -2.13 ± 0.79 to -1.49 ± 1.05 on ZA, compared with -2.38 ± 0.90 to -2.27 ± 1.03 on placebo (least squares means difference 0.41 95% CI, 0.02-0.81; P = .04); when corrected for height z score, the least squares means difference in LBMDZ was 0.75 95% CI, 0.27-1.22; P = .004. Two children on placebo had new low-trauma VF vs none on ZA. Adverse events (AEs) were reported in 15 of 18 children (83%) on ZA, and in 12 of 16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths or treatment discontinuations due to treatment-emergent AEs.
LSBMDZ increased significantly on ZA compared with placebo over 1 year in children with GIO. Most AEs occurred after the first infusion.
Background
Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of osteosclerosis of the ...metaphyseal margins of long tubular bones. To date, only thirteen cases have been reported (eight molecularly confirmed). Five homozygous sequence variants in the leucine-rich repeat kinase 1 (
LRRK1
) gene have been identified to cause OSMD. We present two male siblings with OSMD with a novel
LRRK1
variant.
Cases
The index case, now aged 6 years, was referred aged 9 months when diffuse sclerosis of the ribs and vertebral bodies, suggestive of osteopetrosis, was incidentally identified on a chest radiograph for suspected lower respiratory tract infection. Parents were consanguineous and of Pakistani origin. Further evaluation revealed developmental delay, nystagmus with bilateral optic nerve hypoplasia and severe visual impairment. Skeletal survey confirmed typical changes of OSMD, with widespread diffuse sclerosis and Erlenmeyer flask deformity of long bones. His older sibling, now aged 12 years, was 7 years at the time of referral and had similar clinical course and skeletal findings. Additionally, he had a chronic progressive osteonecrosis of the left mandible that required debridement, debulking and long-term antibiotics. Skeletal survey revealed findings similar to his sibling. Neither sibling had significant skeletal fractures or seizures. Unlike most previous reports suggesting sparing of the skull and lack of visual impairment, our patients had evidence of osteosclerosis of the cranium. Genetic screening for the common autosomal recessive and dominant pathogenic variants of osteopetrosis was negative. Whole Exome Sequencing (WES) followed by Sanger sequencing, identified a novel homozygous
LRRK1
c.2506C>T p. (Gln836Ter) nonsense variant predicted to result in premature truncation of LRRK1 transcript.
Conclusion
Our cases confirm the autosomal recessive inheritance and expand the spectrum of genotype and phenotype of OSMD reported in the literature. Increasing reports of
LRRK1
variants in this phenotype raise the question of whether
LRRK1
should be included in targeted osteopetrosis panels. Bone histology in previous cases has shown this to be an osteoclast rich form of osteopetrosis raising the possibility that haematopoietic stem cell transplantation may be an appropriate treatment modality.
Abstract
Context:
Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI) by dysregulating intracellular calcium flux.
Objectives:
Clinical and bone material phenotype description ...and osteoblast differentiation studies.
Design and Setting:
Natural history study in pediatric research centers.
Patients:
Eight patients with type XIV OI.
Main Outcome Measures:
Clinical examinations included bone mineral density, radiographs, echocardiography, and muscle biopsy. Bone biopsy samples (n = 3) were analyzed using histomorphometry, quantitative backscattered electron microscopy, and Raman microspectroscopy. Cellular differentiation studies were performed on proband and control osteoblasts and normal murine osteoclasts.
Results:
Type XIV OI clinical phenotype ranges from asymptomatic to severe. Previously unreported features include vertebral fractures, periosteal cloaking, coxa vara, and extraskeletal features (muscular hypotonia, cardiac abnormalities). Proband lumbar spine bone density z score was reduced median −3.3 (range −4.77 to +0.1; n = 7) and increased by +1.7 (1.17 to 3.0; n = 3) following bisphosphonate therapy. TMEM38B mutant bone has reduced trabecular bone volume, osteoblast, and particularly osteoclast numbers, with >80% reduction in bone resorption. Bone matrix mineralization is normal and nanoporosity low. We demonstrate a complex osteoblast differentiation defect with decreased expression of early markers and increased expression of late and mineralization-related markers. Predominance of trimeric intracellular cation channel type B over type A expression in murine osteoclasts supports an intrinsic osteoclast defect underlying low bone turnover.
Conclusions:
OI type XIV has a bone histology, matrix mineralization, and osteoblast differentiation pattern that is distinct from OI with collagen defects. Probands are responsive to bisphosphonates and some show muscular and cardiovascular features possibly related to intracellular calcium flux abnormalities.
We describe the clinical and bone material phenotype in type XIV OI. Bone histology, matrix composition, and the osteoblast differentiation pattern is distinct from OI due to collagen defects.
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