Evidence of a significant vitamin D deficiency among 9-13-year-old Polish children: results of a multicentre study.

PURPOSE: To evaluate the extent to which the population of Polish preadolescents is vitamin D deficient and to assess seasonal variations in vitamin D status. PARTICIPANTS AND METHODS: A total of 720 healthy children aged 9-13 years (409 girls, 311 boys) residing in 6 representative geographical locations in Poland were studied. A parental-assisted questionnaire provided data on nutritional habits, vitamin D supplements and sun exposure. Serum concentration of 25-hydroxyvitamin was determined twice, after the winter in March and after the summer in October. RESULTS: In March, vitamin D deficiency (25-50 nmol/L) was found in 64%, and severe deficiency (< 25 nmol/L) in 20.2% of children. In October, the deficiency and severe deficiency were still noticed in 25.9 and 0.1% of children, respectively. The mean serum concentration of 25-OHD was 52% higher in October (55.4 ± 14.0 nmol/L) than in March (36.4 ± 13.5 nmol/L), (p < 0.01). In children with 25-OHD < 50 nmol/L in March, their 25-OHD concentration increased by 64% through March to October (32.5 ± 8.2 vs. 53.2 ± 7.9 nmol/L, p < 0.01). An association was found between 25-OHD concentration and regular consumption of vitamin D supplements, cod-liver oil and fish. CONCLUSIONS: The majority of preadolescent Polish boys and girls show vitamin D deficiency after the winter period, although a distinct amelioration over summertime is found in this age group. There is a need to implement effective prevention and intervention strategies in the management of vitamin D deficiency among schoolchildren in Poland, with the supplementation throughout the entire year.

NGS analysis of collagen type I genes in Polish patients with Osteogenesis imperfecta: a nationwide multicenter study.

Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue. It presents with a wide spectrum of skeletal and extraskeletal features, and ranges in severity from mild to perinatal lethal. The disease is characterized by a heterogeneous genetic background, where approximately 85%-90% of cases have dominantly inherited heterozygous pathogenic variants located in the COL1A1 and COL1A2 genes. This paper presents the results of the first nationwide study, performed on a large cohort of 197 Polish OI patients. Variants were identified using a next-generation sequencing (NGS) custom gene panel and multiplex ligation probe amplification (MLPA) assay. The following OI types were observed: 1 (42%), 2 (3%), 3 (35%), and 4 (20%). Collagen type I pathogenic variants were reported in 108 families. Alterations were observed in α1 and α2 in 70% and 30% of cases, respectively. The presented paper reports 97 distinct causative variants and expands the OI database with 38 novel pathogenic changes. It also enabled the identification of the first glycine-to-tryptophan substitution in the COL1A1 gene and brought new insights into the clinical severity associated with variants localized in "lethal regions". Our results contribute to a better understanding of the clinical and genetic aspects of OI.

[Brittle bone disease type III in neonates--own experience]. / Wrodzona lamliwosc kosci typu III u noworodków--obserwacje wlasne.

UNLABELLED: Fractures of long bone and ribs in the neonatal period may be expression of genetic disturbances of collagen type I production. The aim of the study was to present clinical symptoms, results of radiological, biochemical and densitometric examinations in 11 newborns with osteogenesis imperfecta type III. METHODS: In all children accurate medical history, clinical examination and radiograph were performed. We measured concentration of 25-hydroxyvitamin D (25OHD) and osteocalcin (bone formation marker) in serum. Urinary excretion of bone resorption marker type I collagen N-telopeptide related to creatinine were made. In 5/11 children densitometric examination in Infant programme by DXA method (dual-X-ray absorptiometry) were done. RESULTS: In all family osteogenesis imperfecta occurred by the first. In clinical examination deformities in body proportion, shortness of the extremities, sabre shanks, flabbily of skull bones and reduction of activity were diagnosed. 8/11 newborns had blue sclera. In all X-ray (baby-gram) bone fractures occurring in utero as well as after birth were founded. In biochemical indices a small numbers of abnormality were described. In 5/11 newborns with results of densitometric examination normal bone mineral density adequate to body mass were demonstrated, in 3/5 bone mineral content (BMC) were decreased. CONCLUSION: 1.Osteogens esis imperfecta is the one of reasons of bone fractures in neonates and its diagnosis is based on family history, clinical manifestation and X-ray examination. 2. In newborns with bone fractures dual X-ray absorptiometry are recomendated.

The Clinical Picture of Patients Suffering from Hypophosphatasia-A Rare Metabolic Disease of Many Faces.

Hypophosphatasia (HPP) is a rare, and usually diagnosed with delay, genetic disease caused by a mutation in the alkaline phosphatase liver/bone/kidney type (ALPL) gene. Low activity of the alkaline phosphatase (ALP) impairs the hydroxyapatite formation, reducing skeletal mineralization. The aim of the study was to present patients diagnosed with HPP. The data from the history and medical records of patients were analyzed. In the study group, one patient was diagnosed with perinatal type of HPP, three were diagnosed with infant variant, eight were diagnosed with children variant, two were diagnosed with odontohypophosphatasia, and two were diagnosed with the adult type of the disease. The most frequently presented symptoms included premature loss of teeth in 11/16 (68.75%) patients, bone deformities in 10/16 (62.5%) patients, chronic bone pain in 9/16 (56.25%) patients, and fractures in 8/16 (50%) patients. Reduction in bone mineral density in at least one examined projection has been found in 11/14 patients. Conclusions: The correct diagnosis of HPP is difficult due to the variety of types and clinical symptoms, as well as the very rare occurrence of this disease. Both lower and upper reference values of the determined biochemical parameters may be important in HPP diagnostics.

Bone Turnover Markers and Bone Mineral Density in Children with Hypophosphatemic Rickets.

Hypophosphatemic rickets is a rare disease that results in bone deformities. However, little is known about bone turnover and bone mass disorders in this disease. This retrospective study included 12 children aged 1-16 years diagnosed with hypophosphatemic rickets. Parameters of calcium-phosphate metabolism and bone turnover markers were analysed. Bone mineral density was assessed with the use of dual-energy X-ray absorptiometry, and indices of quantitative ultrasound examination of tibiae and radial bones were analysed. In the majority of patients, hypophosphatemia and hyperphosphaturia were present. The assessed bone turnover markers showed increased bone formation. Increased pyridinoline levels were found in 5 out of 12 patients. Bone mineral density was decreased only in one patient. Decreased values of quantitative ultrasound examination were observed in all the analysed patients. Conclusions: (1) Bone metabolism disturbances, reflected in the increased values of bone turnover markers and worse bone quality, were found in the group of patients with hypophosphatemic rickets. (2) It is crucial to determine bone turnover markers, dual-energy X-ray absorptiometry findings and indices of quantitative ultrasound examination in order to monitor progress of the disease, as well as treatment effects.

The first glycine-to-tryptophan substitution in the COL1A1 gene identified in a patient with progressively-deforming Osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue with variable phenotype and heterogeneous genetic background. Majority of reported mutations are glycine substitutions, whose clinical outcome ranges from mild to perinatal lethal. The phenotype appears to be influenced by the properties of amino acid side chain and the degree of structural aberration of collagen molecules. Since the genotype-phenotype correlation remains unclear, the severity of mutation is mostly predicted according to previously-reported cases. Although the number of OI variants is constantly expanding, no glycine-to-tryptophan substitutions have been reported in COL1A1 gene. METHODS: A sample from a 15-year-old girl presenting with progressively-deforming OI type III was tested using an NGS custom gene panel. Multiple bioinformatic and interpretation tools, including mutation databases and conservation analysis, were used for variant classification. The presence of the mutation was verified by Sanger sequencing. RESULTS: A novel heterozygous mutation c.733G>T was identified in the COL1A1 gene (p.Gly245Trp). CONCLUSIONS: The discovery of this novel glycine-to-tryptophan substitution located in the COL1A1 gene broadens the spectrum of mutations underlying this rare disease and provides useful information on the clinical outcome of such substitutions.

Novel Mutations Within Collagen Alpha1(I) and Alpha2(I) Ligand-Binding Sites, Broadening the Spectrum of Osteogenesis Imperfecta - Current Insights Into Collagen Type I Lethal Regions.

Osteogenesis imperfecta (OI) is a rare genetic disorder demonstrating considerable phenotypic and genetic heterogeneity. The extensively studied genotype-phenotype correlation is a crucial issue for a reliable counseling, as the disease is recognized at increasingly earlier stages of life, including prenatal period. Based on population studies, clusters in COL1A1 and COL1A2 genes associated with the presence of glycine substitutions leading to fatal outcome have been distinguished and named as "lethal regions." Their localization corresponds to the ligand-binding sites responsible for extracellular interactions of collagen molecules, which could explain high mortality associated with mutations mapping to these regions. Although a number of non-lethal cases have been identified from the variants located in lethal clusters, the mortality rate of mutations has not been updated. An next generation sequencing analysis, using a custom gene panel of known and candidate OI genes, was performed on a group of 166 OI patients and revealed seven individuals with a causative mutations located in the lethal regions. Patients' age, ranging between 3 and 25 years, excluded the expected fatal outcome. The identification of non-lethal cases caused by mutations located in lethal domains prompted us to determine the actual mortality caused by glycine substitutions mapping to lethal clusters and evaluate the distribution of all lethal glycine mutations across collagen type I genes, based on records deposited in the OI Variant Database. Finally, we identified six glycine substitutions located in lethal regions of COL1A1 and COL1A2 genes, of which four are novel. The review of all mutations in the dedicated OI database, revealed 33 distinct glycine substitutions in two lethal domains of COL1A1, 26 of which have been associated with a fatal outcome. Similarly, 109 glycine substitutions have been identified in eight lethal clusters of COL1A2, of which 51 have been associated with a fatal manifestation. An analysis of all glycine substitutions leading to fatal phenotype, showed that their distribution along collagen type I genes is not regular, with 17% (26 out of 154) of mutations reported in COL1A1 and 64% (51 out of 80) in COL1A2 corresponding to localization of the lethal regions.

Metabolic bone markers can be related to preserved insulin secretion in children with newly diagnosed type 1 diabetes.

INTRODUCTION: Type 1 diabetes (T1D) may be associated with numerous complications including bone metabolism disorders. The aim of the study was to evaluate the bone metabolism markers twice in children with a newly diagnosed T1D and after an average of seven months of its duration in relation to parameters of the clinical course of diabetes. MATERIAL AND METHODS: In 100 T1D patients and 52 control subjects, the following bone turnover markers were evaluated: osteocalcin - OC, osteoprotegerin - OPG, sRANKL, and deoxypyridoline in urine - DPD and DXA examination was also performed. RESULTS: Lower OC concentration at T1D onset in comparison to controls (p < 0.001) and its increase during follow-up (p < 0.001) was ob-served. The OPG concentration was elevated at T1D onset as compared to the control group (p = 0.024) and decreased thereafter (p < 0.001). The s-RANKL level increased during follow-up (p < 0.001) and was lower than in controls (p < 0.001). Urine DPD con-centration also increased during follow-up in the T1D patient group (p < 0.001) and was higher in comparison to the control group (p = 0.021). BMD-TBLH was higher in the control group as compared to patients both at T1D onset (p = 0.025) and in follow-up ob-servation (p = 0.034). Moreover, OPG correlated positively with glycated haemoglobin (HbA1c) (p = 0.004) and negatively with fasting C-peptide level (p = 0.046) and BMI Z-score (p = 0.003), whereas s-RANKL correlated positively with both fasting (p < 0.001) and stimulated C-peptide levels (p < 0.001). CONCLUSIONS: Bone metabolism disorders observed at T1D onset in children and modified after reaching the metabolic control of the disease seem to be most strongly associated with preserved insulin secretion.

Evaluation of bone mineral density and bone metabolism in children with multiple bone fractures.

BACKGROUND: The aim of the study was to carry out a comprehensive analysis of determinants of multiple bone fractures in children with regard to densitometric indices and markers of bone metabolism. MATERIAL AND METHODS: The study involved 112 children aged 5-18 years, including 81 patients with a history of at least 3 bone fractures and 31 healthy patients in a control group. Total body and spinal DXA densitometry of the skeleton (DPX-L apparatus, Lunar) was carried out in all children. Laboratory assays comprised the determination of calcium, phosphorus, magnesium (in the serum and 24-hour urine collection), parathormone, liver metabolite of vitamin D, osteocalcin, bone alkaline phosphatase, and N-terminal cross-linked telopeptide of collagen type I (NTx). RESULTS: Mean values of DXA Z-score, both in total body and in spinal scans, were significantly lower in children with multiple fractures as compared to controls. In children with multiple fractures, there was a higher prevalence of hypercalciuria, hypermagnesuria and hyperphosphaturia. Decreased levels of the liver metabolite of vitamin D were observed in 20/81 (24.7%) patients in this group and in 6/31 controls. Other findings included a higher level of NTx in 38/75 (50.7%) patients with fractures, an increased activity of bone alkaline phosphatase in 29, and of osteocalcin in 12 patients. In this group, there was a significant negative correlation between biochemical bone turnover markers and low bone mass. Also, lower DXA Z-scores were found in children with higher urinary calcium excretion. CONCLUSIONS: 1. Decreased bone mineral density was the most frequent risk factor for bone fractures in children; it was found in about 2/3 of the patients with multiple bone fractures. 2. Accelerated bone turnover, and, particularly, increased bone resorption, indicates a derangement of bone metabolism in children with multiple fractures. 3. Repeated fractures during the body growth period are an indication for a quantitative evaluation of bone mass, calcium-phosphate metabolism and bone turnover markers.

Vitamin D Supplementation Guidelines for General Population and Groups at Risk of Vitamin D Deficiency in Poland-Recommendations of the Polish Society of Pediatric Endocrinology and Diabetes and the Expert Panel With Participation of National Specialist Consultants and Representatives of Scientific Societies-2018 Update.

INTRODUCTION: Vitamin D deficiency is an important public health problem worldwide. Vitamin D deficiency confers a significant risk for both skeletal and non-skeletal disorders and a number of lifelong negative health outcomes. The objectives of this evidence-based guidelines document are to provide health care professionals in Poland, an updated recommendation for the prevention, diagnosis and treatment of vitamin D deficiency. METHODS: A systematic literature search examining the prevention and treatment strategies for vitamin D deficiency was conducted. Updated recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation system describing the strength of the recommendation and the quality of supporting evidence. Twenty-seven contributors representing different areas of expertise and medical specialties, including pediatricians, geriatricians, endocrinologists, epidemiologists, nephrologists, gynecologists and obstetricians evaluated the available published evidence related to vitamin D, formulated the goals of this document and developed a common consolidated position. The consensus group, representing six national specialist consultants and eight Polish and international scientific organizations/societies, participated in the process of grading evidence and drawing up the general and specific recommendations. RESULTS: The updated recommendations define the diagnostic criteria for the evaluation of vitamin D status and describe the prevention and treatment strategies of vitamin D deficiency in the general population and in groups at increased risk of the deficiency. Age- and weight-specific recommendations for prevention, supplementation and treatment of vitamin D deficiency are presented, and detailed practice guidance is discussed regarding the management in primary and specialized health care. CONCLUSION: Vitamin D deficiency remains still highly prevalent in Poland, in all age groups. Currently, there is a great necessity to implement a regular supplementation with recommended doses and to develop an effective strategy to alleviate vitamin D deficiency in the population. These updated recommendations are addressed to health professionals and the authorities pursuing comprehensive health policies and should also be included in public health programs aimed at preventing a broad spectrum of chronic diseases.

Vertebral fractures in children with osteoporosis.

Background. The aim of our study was to analyze the results of biochemical, densitometic and calcaneous ultrasound examination in children with vertebral fractures. Material and methods. The study involved 19 patients (7 girls, 12 boys) with pathological vertebral fractures diagnosed radiologically. Bone mineral densitometry (DXA method) and ultrasound examinations of the calcaneous bone were performed. The biochemical examinations including serum concentration and diurnal elimination of calcium, phosphorus and magnesium. Concentrations of parathormon (PTH) were assessed by radioimmunometry, and 25OHD by the Elisa method. Results. Fifteen children had back pain complaints; in 5 cases there had been vertebral trauma before diagnosis, and in 12 at least one fracture of a long bone. The most common fractures occurred at Th6-L1 and L4- L5. Fractures of only one vertebra appeared in 3 children. In 10 patients the DXA Z-score was below -2.0, and in 7 from -1.0 to -2.0. In 11 patients at least one of the ultrasound parameters fell below -2.0. Seven patients had a low concentration of 25OHD and PTH, and there were 5 cases of hypomagnesemia. Conclusions. In children with pain complaints from the vertebral region and a significant quantitative decrease of bone mineral density (even without clinical symptoms), lateral X-rays of the lower thoracic and lumbar region are indicated. Pathological vertebral fractures (after exclusion of local changes and metastases) should be an important diagnostic criterion for osteoporosis regardless of quantitative bone examination results.

[The vitamin D and calcium consumption and bone quality in children of lódZ (Poland) at the age 9-13 years]. / Spozycie witaminy D i wapnia a jakosc kosci dzieci lódzkich w wieku 9-13 lat.

INTRODUCTION: Only few publications concern the influence of the vitamin D and calcium consumption on the bone mineralization in the developmental age. AIM OF THE STUDY: The aim of the study was the analysis of the vitamin D and calcium diet supply in relation to the bone status assessed with Quantitative Ultrasound (QUS) in growing children. MATERIAL AND METHODS: The study comprised 643 pupils (384 girls and 259 boys) at the age 9-13 years from primary schools in lódZ. The medium daily consumption of vitamin D and calcium was estimated with the computer program Dieta 2. In all children the QUS was performed. RESULTS: Extreme deficiency of vitamin D was found in the diet of nearly all examined children (in 96,7% schoolgirls and 95,7% schoolboys). Girls consumed on average 25,5% of recommended values, boys 33,3%. Considerable deficiency of diet calcium was observed in 92% schoolgirls and 81,9% of schoolboys. The medium daily consumption of calcium was higher than vitamin D and reached 59,2% of recommended values in girls and 66,2% in boys. In 48% of children an decrease of at least one of the QUS parameters was observed. The statistical analysis showed positive, significant correlation between QUS parameters and calcium consumption, it was not observed for vitamin D. CONCLUSIONS: 1. The deficiency of diet vitamin D and calcium is common in children in lódZ. 2. The extremely low supply of diet vitamin D does not meet the recommended values. 3. The lowering of the QUS parameters observed in 48% of children indicates for worse bone mineralization and bone quality. 4. The results of this study indicate for the necessity of changes in nutritional habits of children and adolescence and if it is not possible the supplementation of vitamin D and calcium.