Growth and Body Composition in PKU Children-A Three-Year Prospective Study Comparing the Effects of L-Amino Acid to Glycomacropeptide Protein Substitutes.

Protein quality and quantity are important factors in determining lean body (muscle) mass (LBM). In phenylketonuria (PKU), protein substitutes provide most of the nitrogen, either as amino acids (AA) or glycomacropeptide with supplementary amino acids (CGMP-AA). Body composition and growth are important indicators of long-term health. In a 3-year prospective study comparing the impact of AA and CGMP-AA on body composition and growth in PKU, 48 children were recruited. N = 19 (median age 11.1 years, range 5-15 years) took AA only, n = 16 (median age 7.3 years, range 5-15 years) took a combination of CGMP-AA and AA, (CGMP50) and 13 children (median age 9.2 years, range 5-16 years) took CGMP-AA only (CGMP100). A dual energy X-ray absorptiometry (DXA) scan at enrolment and 36 months measured LBM, % body fat (%BF) and fat mass (FM). Height was measured at enrolment, 12, 24 and 36 months. No correlation or statistically significant differences (after adjusting for age, gender, puberty and phenylalanine blood concentrations) were found between the three groups for LBM, %BF, FM and height. The change in height z scores, (AA 0, CGMP50 +0.4 and CGMP100 +0.7) showed a trend that children in the CGMP100 group were taller, had improved LBM with decreased FM and % BF but this was not statistically significant. There appeared to be no advantage of CGMP-AA compared to AA on body composition after 3-years of follow-up. Although statistically significant differences were not reached, a trend towards improved body composition was observed with CGMP-AA when it provided the entire protein substitute requirement.

Nutritional rickets under 16 years: UK surveillance results.

OBJECTIVE: The UK national incidence of nutritional rickets is unknown. We aimed to describe the incidence, presentation and clinical management of children under 16 years with nutritional rickets in the UK presenting to secondary care. METHODS: Prospective data were collected monthly between March 2015 and March 2017 from 3500 consultant paediatricians using British Paediatric Surveillance Unit methodology. Clinicians completed online clinical questionnaires for cases fitting the surveillance case definition. RESULTS: 125 cases met the case definition, an annual incidence of 0.48 (95% CI 0.37 to 0.62) per 100 000 children under 16 years. 116 children were under 5 years (annual incidence of 1.39 (95% CI 1.05 to 1.81) per 100 000. Boys (70%) were significantly more affected than girls (30%) (OR 2.17, 95% CI 1.25 to 3.78). The majority were of Black (43%) or South Asian (38%) ethnicity. 77.6% of children were not taking vitamin D supplements despite being eligible. Complications included delayed gross motor development (26.4%), fractures (9.6%), hypocalcaemic seizures (8%) and dilated cardiomyopathy (3%). Two children died (1.6%). In eight cases, rickets was confirmed radiologically and biochemically [raised serum alkaline phosphatase (ALP) and parathyroid hormone (PTH) levels ] but were excluded from the incidence analysis for not meeting the case definition of 25-hydroxyvitamin D of <25 nmol/L. CONCLUSION: The incidence of nutritional rickets in the UK is lower than expected. Serious complications and unexpected deaths, particularly in Black and South Asian children under 5 years, occurred. Both vitamin D deficiency and dietary calcium deficiency are role players in pathogenesis. Uptake of vitamin D supplementation remains low.

Rickets.

Rickets is a bone disease associated with abnormal serum calcium and phosphate levels. The clinical presentation is heterogeneous and depends on the age of onset and pathogenesis but includes bowing deformities of the legs, short stature and widening of joints. The disorder can be caused by nutritional deficiencies or genetic defects. Mutations in genes encoding proteins involved in vitamin D metabolism or action, fibroblast growth factor 23 (FGF23) production or degradation, renal phosphate handling or bone mineralization have been identified. The prevalence of nutritional rickets has substantially declined compared with the prevalence 200 years ago, but the condition has been re-emerging even in some well-resourced countries; prematurely born infants or breastfed infants who have dark skin types are particularly at risk. Diagnosis is usually established by medical history, physical examination, biochemical tests and radiography. Prevention is possible only for nutritional rickets and includes supplementation or food fortification with calcium and vitamin D either alone or in combination with sunlight exposure. Treatment of typical nutritional rickets includes calcium and/or vitamin D supplementation, although instances infrequently occur in which phosphate repletion may be necessary. Management of heritable types of rickets associated with defects in vitamin D metabolism or activation involves the administration of vitamin D metabolites. Oral phosphate supplementation is usually indicated for FGF23-independent phosphopenic rickets, whereas the conventional treatment of FGF23-dependent types of rickets includes a combination of phosphate and activated vitamin D; an anti-FGF23 antibody has shown promising results and is under further study.

EFFECT OF PASTEURISATION ON THE CONCENTRATIONS OF VITAMIN D COMPOUNDS IN DONOR BREAST MILK.

AIM: Breastmilk is considered the most important nutrient and source of supplementation for both term and preterm infants.1 It is composed of many important nutrients, including vitamin D.2 The content of this vitamin in breast milk is usually low, even for lactating mothers with adequate vitamin D status.2 3 Preterm infants are at the great risk of vitamin D deficiency due to decreased transplacental transfer.4 Premature infants are the main recipients of pasteurised donor human milk (PDHM), when their mothers are unable to provide their own.This study aims to evaluate the effect of pasteurisation on the concentrations of vitamin D compounds in donor breast milk. METHOD: A total of 16 participants, who donated breast milk to the RBWH milk bank, were recruited in this study. Milk samples were obtained pre- and post-Holder pasteurisation. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to analyse the samples for vitamins D2 and D3 and 25-hydroxyvitamins D2 and D3 (25(OH)D2 and 25(OH)D3). The significance of differences in vitamin D concentrations between the two groups of milk samples was assessed using the Wilcoxon matched-pairs signed rank test, in which P<0.05 was considered significant. RESULTS: Pasteurisation resulted in a significant reduction (P<0.05) in the content of D2, D3, 25(OH)D2 and 25(OH)D3, with P values of 0.0001 for all targeted analytes. The concentrations of the vitamin D analogues in non-pasteurised milk ranged from 3.6 to 5.0 pM (D2), 1.0 to 9.8 pM (D3), 1.4 to 2.1 pM (25(OH)D2) and 1.2 to 9.3 pM (25(OH)D3). The concentrations of the vitamin D analogues in post-pasteurised milk ranged from 3.0 to 4.0 pM (D2), 0.6 to 9.5 pM (D3), 1.2 to 1.7 pM (25(OH)D2) and 1.1 to 9.1 pM (25(OH)D3). Losses of vitamin D compounds resulting from the pasteurisation process ranged from 10% to 20%. CONCLUSION: Pasteurisation significantly affected the concentration of vitamin D compounds in pasteurised donor breast milk.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.

BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.

BACKGROUND: Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. EVIDENCE: A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. PROCESS: Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. RESULTS: This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. CONCLUSION: Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

Nutritional rickets in immigrant and refugee children.

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.

Sunshine and vitamin D.

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.

Vitamin D in childhood and adolescence: an expert position statement.

UNLABELLED: 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.

Vitamin D deficiency and insufficiency after pediatric liver transplantation.

Vitamin D deficiency and insufficiency are increasingly recognized in the general population, including healthy children. There is also an increasing emphasis on the importance of vitamin D status following pediatric liver transplantation and specifically its relationship to metabolic bone disease and growth retardation. Vitamin D insufficiency has also been associated with multiple immunological and metabolic disorders in adults. To our knowledge, this has not been systematically evaluated in children undergoing liver transplantation to date. Between October 2004 and August 2008, serum 25-(OH)-vitamin D levels were measured in 199 children who had undergone liver transplantation at Birmingham Children's Hospital. Potential factors contributing to vitamin D levels were evaluated. Additionally, we evaluated a possible relationship between vitamin D levels and immunological phenomena and metabolic complications. Median 25-(OH)-vitamin D level was 19.5 ng/mL (range: 4.4-71.4 ng/mL). A total of 105 children (53%) had insufficient vitamin D levels and 28 children (14%) showed vitamin D deficiency. The only factors found to be associated with vitamin D deficiency were season of sample, ethnicity, and PTH levels. Vitamin D deficiency was more prevalent during the first year after transplantation. We did not find a significant relationship between vitamin D levels and graft function or any other immunological and metabolic complications. Vitamin D insufficiency and deficiency are common in children after liver transplantation, especially in winter and spring and in non-white patients. Initial post-transplant period and high PTH are significantly associated with vitamin D deficiency. Vitamin D status should be monitored following pediatric liver transplantation and vitamin D supplementation provided as required.

Vitamin D and child health: part 2 (extraskeletal and other aspects).

The first part of this review focused on the skeletal aspects of vitamin D. This second part reviews some of the available evidence that vitamin D may have a physiological extraskeletal role beyond its traditional effect on the skeleton. This aspect has influenced the definition of vitamin D deficiency and what level of vitamin D should be regarded as optimal. The recognition of the prevalence of vitamin D deficiency and insufficiency has led to debate as to whether and how we should be treating asymptomatic individuals. This review discusses the potential extraskeletal effects of vitamin D, the definition of vitamin D deficiency and our thoughts on indications for measurement and treatment.

Vitamin D and child health part 1 (skeletal aspects).

Currently, there is considerable clinical and academic interest in vitamin D as a consequence of a number of developments over the past decade. This was initially related to a recognised resurgence of symptomatic vitamin D deficiency in children in the UK and other countries. The potential importance of maternal vitamin D status on bone mass in early childhood and the effect of vitamin D supplementation on peak bone mass has been the subject of much research. An additional development has been the recognition that vitamin D may have a physiological extraskeletal role. This aspect has influenced the definition of vitamin D deficiency, and what level should be regarded as optimal. The recognition of the prevalence of vitamin D deficiency and insufficiency has led to debate as to whether and how we should be treating asymptomatic individuals. This review consists of two parts, the first focuses on the skeletal aspects of vitamin D, while the second will review some of the potential extraskeletal aspects, the definition of vitamin D deficiency, and our thoughts on indications for measurement and treatment.

Prevalence and predictors of vitamin D insufficiency in children: a Great Britain population based study.

OBJECTIVES: To evaluate the prevalence and predictors of vitamin D insufficiency (VDI) in children in Great Britain. DESIGN: 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). RESULTS: 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 = 1.6[95%CI 1.0-2.4]). CONCLUSION: 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.