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1.
Artigo em Inglês | MEDLINE | ID: mdl-31618689

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely performed in children and adolescents with hematologic diseases, including very high-risk leukemia. With increasing success and survival rates, the long-term sequelae of HSCT have become important. Here, we provide guidance to the prevention and treatment of the most common bone morbidities-osteoporosis and osteonecrosis-emerging in the context of HSCT in children and adolescents. We give an overview on definitions, symptoms, and diagnostics and propose an algorithm for clinical practice based on discussions within the International Berlin Frankfurt Münster (BFM) Stem Cell Transplantation Committee and the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, our expert knowledge, and a literature review.

2.
J Clin Densitom ; 22(4): 567-589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31421951

RESUMO

Dual-energy X-ray absorptiometry (DXA) is widely used in the evaluation of bone fragility in children. Previous recommendations emphasized total body less head and lumbar spine DXA scans for clinical bone health assessment. However, these scan sites may not be possible or optimal for all groups of children with conditions that threaten bone health. The utility of DXA scans of the proximal femur, forearm, and radius were evaluated for adequacy of reference data, precision, ability of predict fracture, and applicability to all, or select groups of children. In addition, the strengths and limitations of vertebral fracture assessment by DXA were evaluated. The new Pediatric Positions provide guidelines on the use of these additional measures in the assessment of skeletal health in children.

3.
Bone ; 127: 9-16, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31146036

RESUMO

BACKGROUND: Hypophosphatasia (HPP) is an inherited metabolic bone disease characterized by reduced mineralization due to mutations in the tissue non-specific alkaline phosphatase (ALPL) gene. HPP is clinically variable with extensive allelic heterogeneity in the ALPL gene. We report the findings of in vitro functional studies following site-directed mutagenesis in bi-allelic mutations causing extreme clinical phenotypes; severe perinatal and asymptomatic HPP. AIMS: Elucidate genotype-phenotype correlation using in vitro functional studies and 3 dimensional (3D) ALP modelling. METHODS: Clinical, biochemical and radiological features were recorded in two children with extreme HPP phenotypes: Subject 1 (S1): Perinatal HPP with compound heterozygous mutations (c.110T>C; c.532T>C); Subject 2 (S2): asymptomatic with homozygous missense mutation (c.715G>T). Plasmids created for mutants 1 c.110T>C (L37P), 2 c.532T>C (Y178H) and 3 c.715G>T (D239Y) using in vitro mutagenesis were transfected into human osteosarcoma (U2OS) cells and compared to wildtype (WT) and mock cDNA. ALP activity was measured using enzyme kinetics with p-nitrophenylphosphate. Mineral deposition was evaluated photometrically with Alizarin Red S staining after culture with mineralization medium. Western blot analysis was performed to identify the mature type protein expression (80 kDa). Mutations were located on a 3D ALP model. Co-transfection was performed to identify dominant negative effect of the mutants. RESULTS: Phenotype: S1, had typical perinatal HPP phenotype at birth; extremely under-mineralized bones and pulmonary hypoplasia. S2, diagnosed incidentally by laboratory tests at 4 years, had normal growth, development, dentition and radiology. All S2's siblings (3 homozygous, 1 heterozygous) were asymptomatic. All subjects had typical biochemical features of HPP (low ALP, high serum pyridoxal-5'-phosphate), except the heterozygous sibling (normal ALP). Functional assay: Mutants 1 and 2 demonstrated negligible ALP activity and mineralization was 7.9% and 9.3% of WT, respectively. Mutant 3 demonstrated about 50% ALP activity and 15.5% mineralization of WT. On Western blot analysis, mutants 1 and 2 were detected as faint bands indicating reduced expression and mutant 3 was expressed as mature form protein with 50% of WT expression. Mutant 1 was located near the Glycosylphosphatidylinositol anchor, 2 at the core structure of the ALP protein and 3 at the periphery of the protein structure. Co-transfection did not reveal a dominant negative effect in any of the mutants. CONCLUSION: Our findings expand the current knowledge of functional effect of individual mutations and the importance of their location in the ALP structure.

4.
Lancet ; 393(10189): 2416-2427, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31104833

RESUMO

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.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Estatura , Criança , Desenvolvimento Infantil , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Feminino , Humanos , Lactente , Masculino , Índice de Gravidade de Doença , Resultado do Tratamento
5.
Metabolism ; : 153892, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30928313

RESUMO

Early diagnosis, optimal therapeutic management and regular follow up of children with X-linked hypophosphatemia (XLH) determine their long term outcomes and future quality of life. Biochemical screening of potentially affected newborns in familial cases and improving physician's knowledge on clinical signs, symptoms and biochemical characteristics of XLH for de novo cases should lead to earlier diagnosis and treatment initiation. The follow-up of children with XLH includes clinical, biochemical and radiological monitoring of treatment (efficacy and complications) and screening for XLH-related dental, neurosurgical, rheumatological, cardiovascular, renal and ENT complications. In 2018, the European Union approved the use of burosumab, a humanized monoclonal anti-FGF23 antibody, as an alternative therapy to conventional therapy (active vitamin D analogues and phosphate supplements) in growing children with XLH and insufficiently controlled disease. Diagnostic criteria of XLH and the principles of disease management with conventional treatment or with burosumab are reviewed in this paper.

6.
Minerva Pediatr ; 71(3): 229-234, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017381

RESUMO

BACKGROUND: The 6-minute walk test (6MWT) in children can be performed in the conventional way, or by using a measuring wheel. This study aimed to compare these test modalities and to determine influencing factors. METHODS: The study included 317 healthy children (172 boys) between 6 and 15 years from elementary schools and high schools, who were randomly assigned to perform a 6MWT either with or without a measuring wheel according to the guidelines of the American Thoracic Society. The 6-minute walk distance (6MWD) was compared between the two measuring modalities as well as different school types. RESULTS: The use of a measuring wheel during the 6MWT led to a significantly greater 6MWD compared to conventional walking. Students of sports schools walked substantially farther than those attending general high schools, irrespective of test modality. In multivariate regression analysis height, post-test heart rate, male sex and the measuring wheel itself were all independently associated with greater 6MWD. CONCLUSIONS: The use of a measuring wheel during a 6MWT reflects physical performance in children and adolescents more accurately as it includes the stretch of way around the cones during lap turns. Test modalities and sports background should be taken into account, especially when performing longitudinal monitoring and multicenter studies.


Assuntos
Frequência Cardíaca/fisiologia , Instituições Acadêmicas , Teste de Caminhada/métodos , Caminhada/fisiologia , Adolescente , Criança , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto , Fatores Sexuais
7.
J Clin Endocrinol Metab ; 104(7): 2735-2747, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811537

RESUMO

CONTEXT: Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited. OBJECTIVE: To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years. DESIGN: Phase 2 open-label study (July 2010 to September 2016). SETTING: Twenty-two sites; 12 countries. PARTICIPANTS: Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months. INTERVENTION: Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously. MAIN OUTCOME MEASURES: Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2). RESULTS: During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment. CONCLUSIONS: Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.

8.
BMC Musculoskelet Disord ; 20(1): 80, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764793

RESUMO

BACKGROUND: Hypophosphatasia (HPP) is a rare, systemic disease caused by mutation(s) within the ALPL gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP has a heterogeneous presentation, which coupled with its rarity, often leads to missed/delayed diagnosis and an incomplete understanding of its natural history. To better understand the epidemiology and clinical course of HPP, including timing of diagnosis after first reported manifestation, we present baseline data for patients enrolled in the Global HPP Registry. METHODS: Data were analyzed from patients with an HPP diagnosis confirmed by low serum ALP activity and/or an ALPL pathogenic variant, regardless of prior or current treatment, according to age at enrollment (children: < 18 y; adult: ≥18 y). All analyses were descriptive. RESULTS: Of 269 patients from 11 countries enrolled January 2015-September 2017, 121 (45.0%) were children and 148 (55.0%) were adults. The majority of children and adults were female (61.2 and 73.0%, respectively) and white (57.7 and 90.0%, respectively). Children had a median (min, max) age at earliest reported HPP manifestation of 7.2 months (- 2.3 mo, 16.0 y), which was > 12 months before diagnosis at age 20.4 months (- 0.2 mo, 16.0 y). In adults, the earliest reported manifestation occurred at a median (min, max) age of 37.6 years (0.2 y, 75.2 y), which preceded age at diagnosis (47.5 years [0.2 y, 75.2 y]) by ~ 10 years. Premature loss of deciduous teeth (48.2%, age ≥ 6 mo), bone deformity (32.5%), and failure to thrive (26.7%) were most commonly reported in the HPP-related disease history of children. Pain (74.5%), orthopedic procedures and therapies (44.6%), and recurrent and poorly healing fractures (36.5%) were most commonly reported in the HPP-related disease history of adults. CONCLUSIONS: The Global HPP Registry represents the largest observational study of patients with HPP, capturing real world data. This analysis shows that diagnostic delay is common, reflecting limited awareness of HPP, and that HPP is associated with systemic manifestations across all ages. Many patients diagnosed in adulthood had HPP manifestations in childhood, highlighting the importance of taking thorough medical histories to ensure timely diagnosis. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02306720 , December 2014; ENCePP.eu: EUPAS13526 , May 2016 (retrospectively registered).


Assuntos
Diagnóstico Tardio , Hipofosfatasia/diagnóstico , Adolescente , Adulto , Fatores Etários , Idoso , Fosfatase Alcalina/genética , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Hipofosfatasia/tratamento farmacológico , Hipofosfatasia/epidemiologia , Hipofosfatasia/genética , Lactente , Japão/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mutação , América do Norte/epidemiologia , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Sistema de Registros , Fatores de Tempo , Adulto Jovem
9.
Public Health Nutr ; : 1-8, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30744725

RESUMO

OBJECTIVE: To explore the extent to which micronutrient deficiencies (MND) affect children's health-related quality of life (HRQoL), using vitamin D deficiency (VDD) as a case study. DESIGN: Proxy valuation study to estimate the impact of VDD on the HRQoL of younger (0-4 years) and older (>4 years) children. We used the Child Health Utility 9 Dimension (CHU9D) questionnaire to estimate HRQoL for children within six VDD-related health states: 'hypocalcaemic cardiomyopathy', 'hypocalcaemic seizures', 'active rickets', 'bone deformities', 'pain and muscle weakness' and 'subclinical VDD'. SETTING: Sampling was not restricted to any particular setting and worldwide experts were recruited.ParticipantsRespondents were paediatric bone experts recruited through network sampling. RESULTS: Thirty-eight experts completed the survey. The health state with the largest detrimental impact (mean score (se)) on children's HRQoL was hypocalcaemic cardiomyopathy (0·47 (0·02)), followed by hypocalcaemic seizures (0·50 (0·02)) and active rickets (0·62 (0·02) in young children; 0·57 (0·02) in older children). Asymptomatic VDD had a modest but noticeable negative impact on HRQoL, attributed mostly to tiredness in both age groups and pain in the older paediatric population. CONCLUSIONS: Elicitation of HRQoL from clinical experts suggests a negative impact of VDD on HRQoL, even if there is no recognizable clinical manifestation. HRQoL data from populations of patients with MND will inform public health policy decisions. In some settings, routine collection of HRQoL data alongside national nutrition surveys may help capture the full burden of MND and prioritize resources towards effective prevention.

10.
J Steroid Biochem Mol Biol ; 188: 141-146, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30654108

RESUMO

Osteomalacia and rickets result from defective mineralization when the body is deprived of calcium. Globally, the main cause of osteomalacia is a lack of mineral supply for bone modeling and remodeling due to solar vitamin D and/or dietary calcium deficiency. Osteomalacia occurs when existing bone is replaced by unmineralized bone matrix (osteoid) during remodeling in children and adults, or when newly formed bone is not mineralized in time during modeling in children. Rickets occurs when hypomineralization affects the epiphyseal growth plate chondrocytes and adjacent bone metaphysis in growing children. Hence, osteomalacia co-exists with rickets in growing children. Several reports in the last decade highlight the resurgence of so-called "nutritional" rickets in the dark-skinned population living in high-income countries. However, very few studies have ever explored the hidden iceberg of nutritional osteomalacia in the population. Rickets presents with hypocalcaemic (seizures, tetany, cardiomyopathy), or hypophosphataemic complications (leg bowing, knock knees, rachitic rosary, muscle weakness) and is diagnosed on radiographs (cupping and fraying of metaphyses). In contrast, osteomalacia lacks distinctive, non-invasive diagnostic laboratory or imaging criteria and the clinical presentation is non-specific (general fatigue, malaise, muscle weakness and pain). Hence, osteomalacia remains largely undiagnosed, as a hidden disease in millions of dark-skinned people who are at greatest risk. Radiographs may demonstrate Looser's zone fractures in those most severely affected, however to date, osteomalacia remains a histological diagnosis requiring a bone biopsy. Biochemical features of high serum alkaline phosphatase (ALP), high parathyroid hormone (PTH) with or without low 25 hydroxyvitamin D (25OHD) concentrations are common to both rickets and osteomalacia. Here, we propose non-invasive diagnostic criteria for osteomalacia. We recommend a diagnosis of osteomalacia in the presence of high ALP, high PTH, low dietary calcium intake (<300 mg/day) and/or low serum 25OHD (<30 nmol/L). Presence of clinical symptoms (as above) or Looser's zone fractures should be used to reaffirm the diagnosis. We call for further studies to explore the true prevalence of nutritional osteomalacia in various populations, specifically the Black and Asian ethnic groups, in order to identify the hidden disease burden and inform public health policies for vitamin D/calcium supplementation and food fortification.


Assuntos
Osteomalacia/diagnóstico , Fosfatase Alcalina/sangue , Animais , Cálcio/deficiência , Humanos , Osteomalacia/sangue , Osteomalacia/epidemiologia , Osteoporose/diagnóstico , Hormônio Paratireóideo/sangue , Prevalência , Raquitismo/diagnóstico , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/diagnóstico
11.
Eur J Endocrinol ; 180(3): 213-221, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30566905

RESUMO

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (>20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.


Assuntos
Androgênios/sangue , Doenças do Sistema Endócrino/epidemiologia , Doenças do Sistema Endócrino/etiologia , Puberdade/sangue , Adolescente , Androstenodiona/sangue , Criança , Pré-Escolar , Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/sangue , Doenças do Sistema Endócrino/sangue , Doenças do Sistema Endócrino/patologia , Feminino , Humanos , Masculino , Puberdade Precoce/sangue , Puberdade Precoce/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Maturidade Sexual/fisiologia , Testosterona/sangue
12.
Bone ; 114: 252-256, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29960081

RESUMO

OBJECTIVES: To estimate the cumulative effective dose of radiation (E) and additional lifetime attributable risk (LAR) of cancer from ionizing radiation in children with osteogenesis imperfecta (OI), who require frequent imaging for fractures and bone densitometry (DXA) surveillance. Also, to evaluate the pattern of long bone fractures. METHODS: We reviewed all imaging (x-rays, DXA and computed tomography [CT]) conducted in a cohort of children with OI with a minimum observation period of 5 years. For each image, E was estimated using age-dependent local data, and LAR of cancer was extrapolated. LAR and fracture data were compared among children with mild, moderate and severe OI. LAR was allocated to cancer risk categories, and the moderate risk group (1 in 1000 to 1 in 100) was evaluated further. RESULTS: Results from 106 children with OI (50% females, 5747 images) are presented, with a median (range) observation period of 11.7 (5.2-15.6) years. CT accounted for 0.8% of total imaging procedures but contributed to 66% of total E. The overall LAR of cancer was minimal, averaging an additional 8.8 cases per 100,000 exposed patients (0.8-403). LAR was significantly lower in children with mild OI compared to those with moderate (p = 0.006) and severe OI (p = 0.001). All patients with a moderate LAR of cancer (n = 8) had undergone CT scans and 88% had scoliosis or vertebral fractures. The cohort experienced 412 long bone fractures, with the most common site being the femur (26.5%). OI severity correlated positively with long bone fracture rates (p < 0.001). CONCLUSIONS: When compared to baseline LAR of cancer (50%) the additional cancer risk from ionizing radiation imaging in our paediatric OI cohort was small (0.0088%). To reduce additional cancer risk, we recommend replacing spinal x-rays with vertebral fracture assessments on DXA and exercising caution with CT imaging.

13.
BMC Pediatr ; 18(1): 183, 2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29940979

RESUMO

BACKGROUND: Whilst hypocalcemic complications from vitamin D deficiency are considered rare in high-income countries, they are highly prevalent among Black, Asian and Minority Ethnic (BAME) group with darker skin. To date, the extent of osteomalacia in such infants and their family members is unknown. Our aim was to investigate clinical, cardiac and bone histomorphometric characteristics, bone matrix mineralization in affected infants and to test family members for biochemical evidence of osteomalacia. CASE PRESENTATION: Three infants of BAME origin (aged 5-6 months) presented acutely in early-spring with cardiac arrest, respiratory arrest following seizure or severe respiratory distress, with profound hypocalcemia (serum calcium 1.22-1.96 mmol/L). All infants had dark skin and vitamin D supplementation had not been addressed during child surveillance visits. All three had severely dilated left ventricles (z-scores + 4.6 to + 6.5) with reduced ejection fraction (25-30%; normal 55-70), fractional shortening (7 to 15%; normal 29-40) and global hypokinesia, confirming hypocalcemic dilated cardiomyopathy. They all had low serum levels of 25 hydroxyvitamin D (25OHD < 15 nmol/L), and elevated parathyroid hormone (PTH; 219-482 ng/L) and alkaline phosphatase (ALP; 802-1123 IU/L), with undiagnosed rickets on radiographs. One infant died from cardiac arrest. At post-mortem examination, his growth plate showed a widened, irregular zone of hypertrophic chondrocytes. Histomorphometry and backscattered electron microscopy of a trans-iliac bone biopsy sample revealed increased osteoid thickness (+ 262% of normal) and osteoid volume/bone volume (+ 1573%), and extremely low bone mineralization density. Five of the nine tested family members had vitamin D deficiency (25OHD < 30 nmol/L), three had insufficiency (< 50 nmol/L) and 6/9 members had elevated PTH and ALP levels. CONCLUSIONS: The severe, hidden, cardiac and bone pathology described here exposes a failure of public health prevention programs, as complications from vitamin D deficiency are entirely preventable by routine supplementation. The family investigations demonstrate widespread deficiency and undiagnosed osteomalacia in ethnic risk groups and call for protective legislation.

14.
N Engl J Med ; 378(21): 1987-1998, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29791829

RESUMO

BACKGROUND: X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia. METHODS: In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events. RESULTS: The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity. CONCLUSIONS: In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ).


Assuntos
Anticorpos Monoclonais/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Fosfatase Alcalina/sangue , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/metabolismo , Raquitismo Hipofosfatêmico Familiar/fisiopatologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Crescimento/efeitos dos fármacos , Humanos , Túbulos Renais/metabolismo , Articulação do Joelho/diagnóstico por imagem , Masculino , Manejo da Dor , Fósforo/sangue , Radiografia , Índice de Gravidade de Doença
15.
Arch Dis Child ; 103(9): 901-906, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29661756

RESUMO

The consequences of vitamin D and dietary calcium deficiency have become a huge public health concern in the UK. The burden of disease from these deficiencies includes rickets, and hypocalcaemic seizures, dilated cardiomyopathy and mostly occult myopathy and osteomalacia. The increasing burden of the disease is intrinsically linked to ethnicity and the population demographic changes in the UK. Three facts have led to the resurfacing of the English disease: (1) the UK has no ultraviolet sunlight for at least 6 months of the year, (2) dark skin produces far less vitamin D than white skin per unit ultraviolet light exposure, and (3) non-European Union immigration over the last century. To date, the UK government demonstrates incomplete understanding of these three facts, and its failure to adjust its prevention programmes to changing demographics is endangering the health and life of UK residents with dark skin, of whom infants are the most vulnerable. Establishing accountability through the implementation of monitored antenatal and infantile supplementation programmes and mandatory food fortification is overdue.

16.
Horm Res Paediatr ; 89(4): 271-277, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28926829

RESUMO

BACKGROUND/AIMS: Hypoparathyroidism associated with malabsorption can be particularly challenging to manage due to limited and erratic intestinal absorption of calcium and vitamin D analogues, resulting in episodes of hypo- or hypercalcaemia. We evaluated the role of continuous subcutaneous recombinant parathyroid hormone (rhPTH 1-34) infusion (CSPI) in children with hypoparathyroidism associated with intestinal malabsorption resistant to conventional therapy. METHOD: Four patients (8-13 years of age), with symptomatic hypocalcaemia resistant to conventional therapy, were started on CSPI (follow-up 3-8 years) in two paediatric endocrinology units in Europe. RESULTS: Serum calcium normalized within 48 h of commencing treatment in all 4 patients. An average rhPTH 1-34 dose of 0.4 µg/kg/day resulted in a substantial reduction in symptomatic hypocalcaemia and hypo-/hypercalcaemia-related hospital admissions. An increased alkaline phosphatase activity was noted in the first 6 months on CSPI, indicating an increase in bone turnover. In 2 patients with elevated urinary calcium excretion before CSPI, this normalized in the first year on treatment. No significant side effects were noticed in the short or long term, with patient-reported preference of CSPI over conventional treatment. CONCLUSION: CSPI is a promising and effective treatment option for managing hypocalcaemia and hyperphosphataemia in children with hypoparathyroidism associated with intestinal malabsorption.


Assuntos
Hipoparatireoidismo , Síndromes de Malabsorção , Hormônio Paratireóideo/administração & dosagem , Adolescente , Adulto , Fosfatase Alcalina/sangue , Cálcio/urina , Criança , Seguimentos , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/tratamento farmacológico , Hiperfosfatemia/urina , Hipocalcemia/sangue , Hipocalcemia/tratamento farmacológico , Hipocalcemia/urina , Hipoparatireoidismo/sangue , Hipoparatireoidismo/complicações , Hipoparatireoidismo/tratamento farmacológico , Hipoparatireoidismo/urina , Infusões Subcutâneas , Síndromes de Malabsorção/sangue , Síndromes de Malabsorção/complicações , Síndromes de Malabsorção/tratamento farmacológico , Síndromes de Malabsorção/urina , Masculino
17.
J Clin Endocrinol Metab ; 103(2): 596-603, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29211870

RESUMO

Context: Denosumab, an inhibitor of receptor activator of nuclear factor κ-B ligand, is an approved treatment of giant cell tumor of bone (GCTB) in adults and "skeletally mature" adolescents. Safety concerns include oversuppression of bone remodelling, with risk of osteonecrosis of the jaw (ONJ) and atypical femur fractures during treatment in adults and rebound hypercalcemia after treatment cessation in children. To date, ONJ has never been reported in children or adolescents. Objectives: To describe serious adverse effects during and following high-dose denosumab therapy in GCTB patients. Patients: Two adolescents (14 and 15 years) and a young adult (40 years) received fixed-dose denosumab for GCTB for 1.3 to 4 years (cumulative dose, 47 to 98 mg/kg), which was stopped because of development of ONJ in one adolescent and bilateral femoral cortical stress reactions in the young adult. All three patients developed rebound hypercalcemia with acute kidney injury 5.5 to 7 months after denosumab cessation. Results: The ONJ necessitated surgical debridement. Rebound hypercalcemia (serum calcium, 3.1 to 4.3 mmol/L) was unresponsive to hyperhydration alone, requiring repeated doses of calcitonin or intravenous bisphosphonate treatment. Hypercalcemia recurred in two patients within 4 weeks, with normal serum calcium profiles thereafter. All patients were naive to chemotherapy, radiotherapy, bisphosphonates, and corticosteroids and were metastases free, confirming the causative role of denosumab in these complications. Conclusion: These suppression-release effects of high-dose denosumab on bone remodeling raise questions about safety of fixed dosing and treatment duration. In young people, weight-adjusted dosing and safety monitoring during and after antiresorptive therapy is required.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Neoplasias Ósseas/tratamento farmacológico , Denosumab/uso terapêutico , Tumor de Células Gigantes do Osso/tratamento farmacológico , Hipercalcemia/patologia , Adolescente , Adulto , Neoplasias Ósseas/patologia , Denosumab/efeitos adversos , Feminino , Tumor de Células Gigantes do Osso/patologia , Humanos , Hipercalcemia/induzido quimicamente , Masculino
18.
Arch Dis Child ; 103(1): 92-94, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28988216

RESUMO

Intravenous pamidronate has been used in the treatment of osteogenesis imperfecta (OI) in children for over 20 years. The more potent zoledronate is an attractive alternative as it is administered less frequently. This study compares the clinical efficacy of intravenous pamidronate (1.5 mg/kg/day over 2 days, every 3 months) versus zoledronate (0.05 mg/kg/dose every 6 months) in 40 children (20 per group) with mild to moderate OI and the treatment costs of the two drugs in a tertiary centre for children with osteoporosis. Lumbar spine bone mineral density and fracture rate did not differ between drug groups following 1 and 2 years of treatment, respectively. Total cost per treatment course per patient was £1157 for pamidronate and £498 for zoledronate. Therefore, zoledronate is a considerably cheaper alternative to pamidronate with comparable efficacy, resulting in substantial annual savings for healthcare providers and a more convenient option for patients due to fewer hospital visits.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Imidazóis/uso terapêutico , Osteoporose/tratamento farmacológico , Administração Intravenosa , Densidade Óssea , Conservadores da Densidade Óssea/economia , Criança , Difosfonatos/economia , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Imidazóis/economia , Masculino , Pamidronato , Estudos Retrospectivos , Ácido Zoledrônico
19.
Endocr Connect ; 6(8): 667-675, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28924002

RESUMO

BACKGROUND: Nutritional rickets is a growing global public health concern despite existing prevention programmes and health policies. We aimed to compare infant and childhood vitamin D supplementation policies, implementation strategies and practices across Europe and explore factors influencing adherence. METHODS: European Society for Paediatric Endocrinology Bone and Growth Plate Working Group members and other specialists completed a questionnaire on country-specific vitamin D supplementation policy and child health care programmes, socioeconomic factors, policy implementation strategies and adherence. Factors influencing adherence were assessed using Kendall's tau-b correlation coefficient. RESULTS: Responses were received from 29 of 30 European countries (97%). Ninety-six per cent had national policies for infant vitamin D supplementation. Supplements are commenced on day 1-5 in 48% (14/29) of countries, day 6-21 in 48% (14/29); only the UK (1/29) starts supplements at 6 months. Duration of supplementation varied widely (6 months to lifelong in at-risk populations). Good (≥80% of infants), moderate (50-79%) and low adherence (<50%) to supplements was reported by 59% (17/29), 31% (9/29) and 10% (3/29) of countries, respectively. UK reported lowest adherence (5-20%). Factors significantly associated with good adherence were universal supplementation independent of feeding mode (P = 0.007), providing information at neonatal unit (NNU) discharge (P = 0.02), financial family support (P = 0.005); monitoring adherence at surveillance visits (P = 0.001) and the total number of factors adopted (P < 0.001). CONCLUSIONS: Good adherence to supplementation is a multi-task operation that works best when parents are informed at birth, all babies are supplemented, and adherence monitoring is incorporated into child health surveillance visits. Implementation strategies matter for delivering efficient prevention policies.

20.
J Clin Endocrinol Metab ; 102(11): 4163-4172, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28938420

RESUMO

Context: Hajdu-Cheney syndrome (HJCYS) is a rare, multisystem bone disease caused by heterozygous mutations in the NOTCH2 gene. Histomorphometric and bone ultrastructural analyses in children have not been reported and sparse evidence exists on response to bisphosphonate (BP) therapy. Objective: To investigate clinical and bone histomorphometric characteristics, bone matrix mineralization, and the response of bone geometry and density to BP therapy. Patients: Five children with HJCYS (three males) between 6.7 and 15.3 years of age. Interventions: Various BP regimens (pamidronate, zoledronic acid, and alendronate) were used for between 1 and 10 years. Main Outcome Measures: Pretreatment transiliac bone biopsy specimens and peripheral quantitative computed tomography results were available in four and three subjects, respectively. Bone histomorphometry and quantitative backscattered electron imaging were performed in two patients. The response to BP was monitored using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Results: Three patients had previously unreported NOTCH2 mutations. Histomorphometry demonstrated increased bone resorption and osteoclast numbers, increased heterogeneity of mineralization, and immature, woven bone. Trabecular bone formation was normal or elevated. Radius cortical thickness and density and lumbar spine bone mineral density were reduced at baseline and increased in response to BP therapy, which was not sustained after therapy discontinuation. Conclusions: Increased bone resorption and low cortical thickness are consistent with the effect of activating NOTCH2 mutations, which stimulate osteoclastogenesis. The increase in lumbar spine bone density and radial cortical thickness and density by BP therapy provides evidence of beneficial treatment effects in children with HJCYS.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Difosfonatos/uso terapêutico , Síndrome de Hajdu-Cheney/tratamento farmacológico , Adolescente , Alendronato/uso terapêutico , Osso e Ossos/fisiologia , Calcificação Fisiológica/efeitos dos fármacos , Estudos de Casos e Controles , Criança , Feminino , Síndrome de Hajdu-Cheney/genética , Síndrome de Hajdu-Cheney/metabolismo , Síndrome de Hajdu-Cheney/fisiopatologia , Humanos , Imidazóis/uso terapêutico , Masculino , Mutação , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Receptor Notch2/genética , Ácido Zoledrônico
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