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1.
Am J Med Genet A ; 179(8): 1585-1590, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31175705

RESUMO

Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain-of-function mutations in the regulatory (SUR2) and pore-forming (Kir6.1) subunits of KATP channels, respectively, suggesting that channel-blocking sulfonylureas could be a viable therapy. Here we report a neonate with CS, carrying a heterozygous ABCC9 variant (c.3347G>A, p.Arg1116His), born prematurely at 32 weeks gestation. Initial echocardiogram revealed a large patent ductus arteriosus (PDA), and high pulmonary pressures with enlarged right ventricle. He initially received surfactant and continuous positive airway pressure ventilation and was invasively ventilated for 4 weeks, until PDA ligation. After surgery, he still had ongoing bilevel positive airway pressure (BiPAP) requirement, but was subsequently weaned to nocturnal BiPAP. He was treated for pulmonary hypertension with Sildenafil, but failed to make further clinical improvement. A therapeutic glibenclamide trial was commenced in week 11 (initial dose of 0.05 mg-1 kg-1 day-1 in two divided doses). After 1 week of treatment, he began to tolerate time off BiPAP when awake, and edema improved. Glibenclamide was well tolerated, and the dose was slowly increased to 0.15 mg-1 kg-1 day-1 over the next 12 weeks. Mild transient hypoglycemia was observed, but there was no cardiovascular dysfunction. Confirmation of therapeutic benefit will require studies of more CS patients but, based on this limited experience, consideration should be given to glibenclamide as CS therapy, although problems associated with prematurity, and complications of hypoglycemia, might limit outcome in critically ill neonates with CS.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31136042

RESUMO

AIM: Paediatric vitamin D (25-hydroxyvitamin D (25OHD)) deficiency can lead to nutritional rickets and extra-skeletal complications. Compliance with daily therapy can be difficult, making high-dose, short-term vitamin D (stoss) therapy attractive to correct vitamin D deficiency. We compared the effectiveness and safety of standard versus stoss therapy in treating childhood 25OHD deficiency. METHODS: Children aged 2-16 years with 25OHD <50 nmol/L were randomised to either standard (5000 IU daily for 80 days) or stoss (100 000 IU weekly for 4 weeks) cholecalciferol. Participants underwent an evaluation of effectiveness and safety. The 25OHD level, random spot calcium: creatinine ratio (Ca:Cr) and compliance were measured at 12 weeks. RESULTS: A total of 151 children were enrolled in the study (68 standard and 83 stoss), median age 9 years (inter-quartile range (IQR): 6-12 years). Baseline 25OHD levels were 26 nmol/L (IQR: 19-35 nmol/L) and 32 nmol/L (IQR: 24-39 nmol/L) in the standard and stoss groups, respectively. At 12 weeks, the median 25OHD level was significantly greater in the standard versus stoss group (81 vs. 67 nmol/L; P = 0.005); however, >80% of participants in both groups achieved sufficiency (25OHD > 50 nmol/L) and had normal urinary Ca:Cr, with no significant difference seen between groups. Compliance was similar in the two groups. CONCLUSIONS: Compared to stoss, standard therapy achieved higher 25OHD levels at 12 weeks; however, in both groups, there was a similar proportion of participants who achieved 25OHD sufficiency, with no evidence of toxicity. Unlike other studies, simplifying the treatment regimen did not improve compliance. These results support stoss therapy as an effective and safe alternative therapy for the treatment of paediatric vitamin D deficiency.

3.
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
4.
J Adolesc Health ; 64(3): 305-310, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30819332

RESUMO

PURPOSE: Anorexia nervosa (AN) is a chronic and life-threatening eating disorder that can have a considerable negative impact on the growing skeleton. We hypothesized that the long-term impact on bone health may persist even after normalization of body weight. METHODS: 41 females (mean age 21.2 ± 2.9 years) with a history of adolescent-onset AN attended a follow-up bone health assessment at 5 years (T5, n = 28) or 10 years (T10, n = 13) after their first AN-related hospital admission. Assessment included dual-energy x-ray absorptiometry measurements of the total body, lumbar spine, and proximal femur, peripheral quantitative computed tomography at the radius and tibia, anthropometric measurements, serum biochemistry, fracture history, and a patient questionnaire. RESULTS: A recovery in body weight and BMI was seen for both the T5 and T10 cohorts (BMI at intake 16.6, BMI at T5-T10 21.2-21.3). Dual-energy x-ray absorptiometry body composition indicated a recovery of fat mass and lean tissue mass. Total BMD was unaffected, but reductions were seen at the femoral neck and arms. Peripheral quantitative computed tomography showed reduced trabecular and cortical bone in the radius, and cortical thinning in the tibia. AN patients showed a statistically significant reduction in measures of radiographic bone health at follow up, although not to a degree that necessitated clinical intervention. Serum insulin-like growth factor 1 was also positively correlated with total BMD and BMC measures. While fracture risk was not increased, a subset of participants (8%) showed multiple (>4) fractures. CONCLUSION: A longitudinal study of adolescent AN showed persisting negative effects on bone health.

5.
J Paediatr Child Health ; 54(12): 1292-1293, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30198119

RESUMO

Modern medicine has eradicated smallpox, contained polio and is making significant advances in personalised/genetic medicine. However, we are facing a pandemic of apocalyptic proportions, and there is currently no vaccine or United Nations Charter to help address this issue. Following its insidious spread in the 1980s, the full impact of this phenomenon on civilisation has not been fully appreciated. It has slipped under the radar of the International Classification of Diseases (ICD-10) and Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classification systems. We all know someone who is affected by this condition, and society is struggling to cope with the acute and chronic morbidity that has ensued. I am, of course, referring to the problem of the workplace email. This article examines the problems associated with workplace email and aims to offer some strategies to help contain it.

6.
J Paediatr Child Health ; 54(3): 223-233, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29504223

RESUMO

Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence-based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non-fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence-based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.

8.
Bone ; 110: 66-75, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29382611

RESUMO

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by low bone density and recurrent fractures with a wide genotypic and phenotypic spectrum. Common features include short stature, opalescent teeth, blue sclerae and hearing impairment. The majority (>90%) of patients with OI have autosomal dominant variants in COL1A1/COL1A2, which lead to defects in type 1 collagen. More recently, numerous recessive variants involving other genes have also been identified. Sp7/Osx gene, is a protein coding gene that encodes a zinc finger transcription factor, osterix, which is a member of the Sp subfamily of sequence-specific DNA-binding proteins. Osterix is expressed primarily by osteoblasts and has been shown to be vital for bone formation and bone homeostasis by promoting osteoblast differentiation and maturation. In animal models, Sp7/Osx has also been shown to regulate biomineralization of otoliths, calcium carbonate structures found in the inner ear of vertebrates. Until recently, only one report of a boy with an Sp7/Osx pathogenic variant presenting with bone fragility, limb deformities and normal hearing has been described in the literature. We have identified a novel Sp7/Osx variant in another sibship that presented with osteoporosis, low-trauma fractures and short stature. Progressive moderate-to-severe and severe-to-profound hearing loss secondary to otospongiosis and poor mineralization of ossicles and petrous temporal bone was also noted in two of the siblings. A homozygous pathogenic variant in exon 2 of the Sp7/Osx gene was found in all affected relatives; c.946C>T (p.Arg316Cys). Bone biopsies in the proband and his male sibling revealed significant cortical porosity and high trabecular bone turnover. This is the second report to describe children with OI associated with an Sp7/Osx variant. However, it is the first to describe the bone histomorphometry associated with this disorder and identifies a significant hearing loss as a potential feature in this OI subtype. Early audiology screening in these children is therefore warranted.

9.
Sci Data ; 4: 170068, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28534869

RESUMO

State-of-the-art measurements of the direction and intensity of Earth's ancient magnetic field have made important contributions to our understanding of the geology and palaeogeography of Precambrian Earth. The PALEOMAGIA and PINT(QPI) databases provide thorough public collections of important palaeomagnetic data of this kind. They comprise more than 4,100 observations in total and have been essential in supporting our international collaborative efforts to understand Earth's magnetic history on a timescale far longer than that of the present Phanerozoic Eon. Here, we provide an overview of the technical structure and applications of both databases, paying particular attention to recent improvements and discoveries.

10.
Endocr Dev ; 28: 210-25, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26138844

RESUMO

As many as 50% of children will sustain a fracture before 18 years of age, and up to 20% will have two or more fractures. A small proportion of children who experience multiple fractures have osteoporosis, either from a genetic bone disorder (primary osteoporosis) or secondary to another underlying medical condition (secondary osteoporosis). Fracture history, together with bone mineral density assessment and vertebral radiographs, help clinicians to identify children with osteoporosis. Its aetiology can usually be determined through the combination of a detailed medical history and physical examination, laboratory investigations to assess mineral homeostasis, evaluation of secondary causes of osteoporosis and genetic studies to identify the underlying cause of the disorder. Transiliac bone biopsy with histology and histomorphometry should not be overlooked as valuable tools for the investigation of a child with osteoporosis of uncertain aetiology. Optimal management of osteoporosis requires a multidisciplinary team to address physical activity, nutrition, pubertal progression, the management of any underlying medical condition, pharmacotherapy (bisphosphonates) and orthopaedic surgery. This chapter outlines an approach to the evaluation and treatment of children with recurrent fractures and describes three common scenarios involving infants, children with chronic illness and children without chronic illness.


Assuntos
Fraturas Ósseas/diagnóstico , Osteogênese Imperfeita/diagnóstico , Osteoporose/diagnóstico , Fraturas por Osteoporose/diagnóstico , Absorciometria de Fóton , Biópsia , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/terapia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Criança , Difosfonatos/uso terapêutico , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Humanos , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/terapia , Osteoporose/complicações , Osteoporose/terapia , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/prevenção & controle , Recidiva , Vitamina D/uso terapêutico
11.
Am J Hum Genet ; 96(6): 971-8, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-26027496

RESUMO

Heparan and chondroitin/dermatan sulfated proteoglycans have a wide range of roles in cellular and tissue homeostasis including growth factor function, morphogen gradient formation, and co-receptor activity. Proteoglycan assembly initiates with a xylose monosaccharide covalently attached by either xylosyltransferase I or II. Three individuals from two families were found that exhibited similar phenotypes. The index case subjects were two brothers, individuals 1 and 2, who presented with osteoporosis, cataracts, sensorineural hearing loss, and mild learning defects. Whole exome sequence analyses showed that both individuals had a homozygous c.692dup mutation (GenBank: NM_022167.3) in the xylosyltransferase II locus (XYLT2) (MIM: 608125), causing reduced XYLT2 mRNA and low circulating xylosyltransferase (XylT) activity. In an unrelated boy (individual 3) from the second family, we noted low serum XylT activity. Sanger sequencing of XYLT2 in this individual revealed a c.520del mutation in exon 2 that resulted in a frameshift and premature stop codon (p.Ala174Profs(∗)35). Fibroblasts from individuals 1 and 2 showed a range of defects including reduced XylT activity, GAG incorporation of (35)SO4, and heparan sulfate proteoglycan assembly. These studies demonstrate that human XylT2 deficiency results in vertebral compression fractures, sensorineural hearing loss, eye defects, and heart defects, a phenotype that is similar to the autosomal-recessive disorder spondylo-ocular syndrome of unknown cause. This phenotype is different from what has been reported in individuals with other linker enzyme deficiencies. These studies illustrate that the cells of the lens, retina, heart muscle, inner ear, and bone are dependent on XylT2 for proteoglycan assembly in humans.


Assuntos
Catarata/genética , Catarata/patologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/patologia , Mutação da Fase de Leitura/genética , Homozigoto , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Pentosiltransferases/genética , Descolamento Retiniano/genética , Descolamento Retiniano/patologia , Sequência de Bases , Catarata/tratamento farmacológico , Anormalidades Craniofaciais/tratamento farmacológico , Difosfonatos/uso terapêutico , Exoma/genética , Oftalmopatias Hereditárias/tratamento farmacológico , Transtornos da Audição/genética , Transtornos da Audição/patologia , Humanos , Imuno-Histoquímica , Masculino , Dados de Sequência Molecular , Osteocondrodisplasias/tratamento farmacológico , Osteoporose/diagnóstico por imagem , Osteoporose/genética , Pamidronato , Linhagem , Pentosiltransferases/sangue , Radiografia , Reação em Cadeia da Polimerase em Tempo Real , Descolamento Retiniano/tratamento farmacológico , Análise de Sequência de DNA
12.
Horm Res Paediatr ; 83(3): 183-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25676713

RESUMO

BACKGROUND/AIMS: Intravenous bisphosphonate therapy is the first-line treatment in moderate-to-severe osteogenesis imperfecta (OI), but there are varied treatment protocols with little data on long-term efficacy. This study evaluates the clinical outcomes when transitioning from active bisphosphonate treatment to maintenance therapy. METHODS: A retrospective review was conducted on 17 patients before treatment, following active treatment (zoledronate 0.05 mg/kg 6-monthly or pamidronate 6-9 mg/kg/year) and after establishment on maintenance treatment for more than 2 years (zoledronate 0.025 mg/kg 6-monthly or pamidronate <4 mg/kg/year). RESULTS: There was a significant reduction in mean fracture rate from 1.5 ± 1.1 fractures/year at baseline to 0.7 ± 0.7 fractures/year on active treatment. Z-scores for lumbar spine bone mineral density, bone mineral content, volumetric bone mineral density and bone mineral content for lean tissue mass increased during active treatment. These improvements were maintained during the period of maintenance treatment. Vertebral height improved in fractured thoracic vertebrae from pre-treatment to active therapy and improved further during maintenance treatment. Metacarpal cortical thickness and relative cortical area also increased over the treatment periods. CONCLUSION: Maintenance intravenous bisphosphonate therapy preserved the beneficial effects of active treatment at the doses stated above. Further studies are required to determine the optimal bisphosphonate treatment regimen in the management of children with OI.


Assuntos
Difosfonatos/administração & dosagem , Substituição de Medicamentos , Imidazóis/administração & dosagem , Osteogênese Imperfeita/tratamento farmacológico , Administração Intravenosa , Densidade Óssea/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/metabolismo , Pamidronato , Radiografia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/metabolismo , Ácido Zoledrônico
13.
J Am Soc Nephrol ; 25(10): 2366-75, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24700880

RESUMO

Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P<0.001). Renal calcifications were also more frequent in het carriers (16%; P=0.003 compared with the general population) and were more likely to occur in comp/hom and het individuals with decreased serum phosphate (odds ratio [OR], 0.75, 95% confidence interval [95% CI], 0.59 to 0.96; P=0.02), decreased tubular reabsorption of phosphate (OR, 0.41; 95% CI, 0.23 to 0.72; P=0.002), and increased serum 1,25(OH)2 vitamin D (OR, 1.22; 95% CI, 1.05 to 1.41; P=0.008). Additional studies are needed to determine whether these biochemical parameters are independent of genotype and can guide therapy to prevent nephrocalcinosis, nephrolithiasis, and potentially, CKD.


Assuntos
Cálculos Renais/genética , Nefrocalcinose/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo IIc/genética , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto
14.
Horm Res Paediatr ; 81(3): 204-10, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24356182

RESUMO

BACKGROUND/AIMS: Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. METHODS: An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. RESULTS: Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. CONCLUSION: There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Difosfonatos/efeitos adversos , Imidazóis/efeitos adversos , Osteogênese Imperfeita , Fraturas do Rádio , Conservadores da Densidade Óssea/administração & dosagem , Criança , Pré-Escolar , Difosfonatos/administração & dosagem , Feminino , Humanos , Imidazóis/administração & dosagem , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/metabolismo , Fraturas do Rádio/induzido quimicamente , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/metabolismo , Tomografia Computadorizada por Raios X , Ácido Zoledrônico
15.
Horm Res Paediatr ; 80(3): 179-84, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24052046

RESUMO

AIM: To evaluate the safety and efficacy of 12 months of zoledronic acid (ZA) administered every 6 months to children with osteoporosis. METHODS: Retrospective cohort study of 27 patients (16 male, 11 female) treated with ZA (0.05 mg/kg/dose) every 6 months for 1 year. 20 were immobile, 4 steroid-induced osteoporosis, 2 idiopathic osteoporosis and 1 neurofibromatosis type 1. 16 had long bone fractures and 12 had vertebral wedging at baseline. Mineral homeostasis, bone mineral density (BMD) and vertebral morphometry were evaluated at baseline and 12 months. Results were compared to published data on 3-monthly ZA treatment. RESULTS: Median age at ZA start was 10.5 years (range 6.2-13.3). Following the first infusion, 2 developed asymptomatic hypocalcemic, 14 developed temperature > 38°C, 13 aches/pain and 6 nausea. At 12 months, there was reduction in bone turnover and improvement in BMD and vertebral shape. No patient fractured after starting ZA. Growth was normal. Outcomes were similar to 3-monthly ZA. CONCLUSION: ZA administered 6-monthly was associated with acute phase reaction to the first dose and improvement in BMD, reduction in bone turnover and improved vertebral shape at 12 months.


Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Difosfonatos/administração & dosagem , Imidazóis/administração & dosagem , Osteoporose/tratamento farmacológico , Adolescente , Conservadores da Densidade Óssea/efeitos adversos , Criança , Difosfonatos/efeitos adversos , Feminino , Fraturas Ósseas/sangue , Fraturas Ósseas/patologia , Fraturas Ósseas/fisiopatologia , Fraturas Ósseas/prevenção & controle , Humanos , Imidazóis/efeitos adversos , Masculino , Osteoporose/sangue , Osteoporose/patologia , Osteoporose/fisiopatologia , Estudos Retrospectivos , Fatores de Tempo , Ácido Zoledrônico
16.
Dev Neurorehabil ; 16(6): 391-7, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23477616

RESUMO

OBJECTIVE: To evaluate the effects of spinal cord injury (SCI) on bone density and morphology in children using peripheral quantitative computer tomography (pQCT). DESIGN: Retrospective cohort study of 19 paediatric patients with SCI (9 paraplegics and 10 tetraplegics). RESULTS: There was significant reduction in tibial metaphysial volumetric bone mineral density (vBMD), diaphysial cortical cross-sectional area (CSA), cortical thickness and polar strength-strain index. There was a significant loss of calf muscle CSA. Those who were able to stand had greater trabecular vBMD, tibial cortical thickness and tibial muscle CSA Z-scores. Lower limb fractures did not occur if tibial trabecular vBMD was greater than 100 mg/cm³. Tibial geometry following SCI was more circular compared to controls. CONCLUSIONS: pQCT provides a valuable insight into the regional changes in bone and muscle development in children following SCI. Residual muscle function with the ability to weight bear provides a significant benefit to bone development.


Assuntos
Densidade Óssea/fisiologia , Paraplegia/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Tíbia/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Paraplegia/diagnóstico por imagem , Estudos Retrospectivos , Traumatismos da Medula Espinal/diagnóstico por imagem , Tíbia/diagnóstico por imagem
18.
Mol Genet Metab ; 84(1): 61-74, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15639196

RESUMO

Over 170 known mutations of the mitochondrial genome are responsible for disease. Due to the unique features of mitochondrial genetics, such patients are clinically diverse and difficult to diagnose. As pathogenic mitochondrial DNA (mtDNA) mutations are mostly heteroplasmic, denaturing high-performance liquid chromatography (DHPLC) could be used to detect these heteroplasmic species and therefore act as a rapid screening test for mtDNA mutations. The entire mitochondrial genome was amplified by PCR in 40 overlapping regions. In addition, known mtDNA mutants were constructed for each of these regions using a PCR-based site-directed mutagenesis approach. These mutants were used as positive controls and showed a detection limit of 3-10% heteroplasmy by DHPLC (depending on the specific mutation) compared to 40% for conventional sequencing. To further validate the screening test, mtDNA from 17 patients with seven different pathogenic mutations was used to compare mutation detection by DHPLC and conventional sequencing. DHPLC had a sensitivity of 88% compared to 82% for sequencing. This increased to 100% sensitivity for DHPLC when excluding the m.8993T>G mutation. DHPLC analysis is therefore a sensitive, rapid and cost-effective method to screen for mutations in the mitochondrial genome. The role of pyrosequencing in the quantitation of mutant load for known mtDNA mutations was highlighted using the m.3243A>G mutation as an illustrative example. Pyrosequencing analysis was able to discriminate samples containing as little as 5% heteroplasmy and proved to be an accurate and reproducible method for estimation of mutant load.


Assuntos
Análise Mutacional de DNA/métodos , DNA Mitocondrial/genética , Mutação/genética , Sequência de Bases , Cromatografia Líquida de Alta Pressão/métodos , Primers do DNA , Humanos , Mutagênese Sítio-Dirigida , Reação em Cadeia da Polimerase , Análise de Sequência de DNA
19.
Hum Mutat ; 23(1): 99, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14695540

RESUMO

Marfan syndrome (MFS) is a disorder of the extracellular matrix caused by mutations in the gene encoding fibrillin-1 (FBN1). Recent studies have illustrated the variability in disease severity and clinical manifestations of MFS. Useful genotype-phenotype correlations have been slow to emerge. We screened 57 unrelated patients with MFS or a Marfan-like phenotype using a combination of SSCP and/or DHPLC. We detected 49 different FBN1 mutations, 30 (62%) of which were novel. The mutations comprised 38 substitutions (78%), 10 deletions (20%), and one duplication (2%). There were 28 missense (57%), nine frameshift (18%), eight splice site (16%), and four nonsense mutations (8 %). Genotype-phenotype analysis revealed that patients with an identified FBN1 mutation were more likely to have ectopia lentis and cardiovascular complications compared to those without an identifiable mutation (relative risks of 4.6 and 1.9, respectively). Ectopia lentis was also found to be more prevalent in patients whose mutations involved a cysteine substitution (relative risk 1.6) and less prevalent in those with premature termination mutations (relative risk 0.4). In our hands, we achieved 93% mutation detection for DHPLC analysis of patients who fulfilled the Ghent criteria. Further analysis of detailed clinical information and mutation data may help to anticipate the clinical consequences of specific FBN1 mutations.


Assuntos
Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Fibrilina-1 , Fibrilinas , Genótipo , Humanos , Lactente , Síndrome de Marfan/diagnóstico , Fenótipo
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