RESUMO
BACKGROUND: Osteogenesis imperfecta (OI) is associated with short stature, which is mild, severe and moderate in OI types I, III and IV, respectively. Standardized OI type- and sex-specific growth charts across all pediatric ages do not exist. METHODS: We assessed 573 individuals with OI (type I, III or IV), each with at least one height measurement between ages 3 months and 20 years (total 6523 observations). Analogous to the Centers for Disease Control pediatric growth charts, we generated OI type- and sex-specific growth charts for infants (ages 3-36 months) as well as children and adolescents (ages 2-20 years). Growth curves were fitted to the data using the LMS method and percentiles were smoothed. RESULTS: Age was associated with a decline in height z-scores (p < 0.001 for all OI types), which was more pronounced in females. Height multiplier curves were produced to predict adult height in children with OI. Among individuals with OI type I, those with COL1A1 pathogenic variants leading to haploinsufficiency were taller than those with COL1A1 or COL1A2 pathogenic variants not leading to haploinsufficiency. CONCLUSION: Our standardized OI type- and sex-specific growth charts can be used to assess the growth of individuals with OI from infancy to adulthood. IMPACT: Standardized osteogenesis imperfecta (OI) type- and sex-specific growth charts across all pediatric ages do not exist. Our study is the first to generate OI type- and sex-specific growth charts across all pediatric ages. Our height multiplier curves can be utilized to predict adult height in children with OI.
Assuntos
Osteogênese Imperfeita , Masculino , Lactente , Adulto , Feminino , Adolescente , Humanos , Criança , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/complicações , Gráficos de Crescimento , Colágeno Tipo I/genética , Estatura , MutaçãoRESUMO
Loss- and gain-of-function mutations in the broadly expressed gene Lrp5 affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of beta-Catenin does not affect bone formation. Instead, we show here that Lrp5 inhibits expression of Tph1, the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a beta-Catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation. By identifying duodenum-derived serotonin as a hormone inhibiting bone formation in an Lrp5-dependent manner, this study broadens our understanding of bone remodeling and suggests potential therapies to increase bone mass.
Assuntos
Duodeno/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Osteogênese , Serotonina/metabolismo , Animais , Proteína de Ligação a CREB/metabolismo , Feminino , Proteínas Relacionadas a Receptor de LDL/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Camundongos , Receptor 5-HT1B de Serotonina/metabolismo , Triptofano Hidroxilase/metabolismoRESUMO
PURPOSE: Short stature is common in osteogenesis imperfecta (OI) and is usually severe in OI types III and IV. The characteristics of pubertal growth in OI have not been studied in detail. METHODS: We assessed 82 individuals with OI caused by pathogenic variants in COL1A1 or COL1A2 who had annual height data between 6 and 16 years of age at a minimum. Height velocity curves were fitted to each individual's height data to describe the pubertal growth spurt. RESULTS: Curve fitting was successful in 30 of the 33 individuals with OI type I (91%), in 23 of the 32 individuals with OI type IV (72%), and in 4 of the 17 participants with OI type III (24%). Pubertal growth spurt could be identified in most individuals with OI types I and IV, but rarely in OI type III. The timing of the pubertal growth spurt was similar between OI types I and IV in both sexes. However, height velocity was consistently higher in OI type I, leading to a widening height gap between OI types I and IV. CONCLUSION: A pubertal growth spurt was present in most individuals with OI types I and IV, but rarely in OI type III.
Assuntos
Osteogênese Imperfeita , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Humanos , Masculino , Mutação , Osteogênese Imperfeita/genéticaRESUMO
Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vitamin D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1-12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (- 5.02, 95% CI - 9.29 to - 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline.Trial registration: ClinicalTrials.gov NCT02915705.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Criança , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Humanos , Medidas de Resultados Relatados pelo PacienteRESUMO
Maximizing ambulation is a key treatment aim in moderate to severe osteogenesis imperfecta (OI). Here we investigated which early clinical characteristics predicted ambulation function at skeletal maturity. We assessed Bleck ambulation scores in 88 individuals with OI at 5 to 6 years of age and again at final height (at 15 to 24 years of age). At 5 to 6 years of age, 33 (38%) children were non-ambulators, 32 (36%) were fully independent ambulators, and 23 (26%) had intermediate ambulation skills. At skeletal maturity, 58% of the study participants had the same mobility level as at first assessment. The ability to ambulate independently at skeletal maturity was predicted by independent ambulation at 5 to 6 years (odds ratio [OR] 22.6, 95% confidence interval [CI] 4.9-105; P < 0.001), height z score at 5 to 6 years (OR 3.1, CI 1.6-6.3; P = 0.001) and weight z score at 5 to 6 years (OR 0.44, CI 0.19-0.99; P = 0.04).Conclusion: Independent ambulation at 5 to 6 years was the main determinant of independent ambulation at skeletal maturity. This highlights the importance of maximizing ambulation in children below 5 years of age. What is Known: â¢walking ability varies markedly between OI types. The highest level of mobility was found in OI type I, the lowest in OI type III who require mobility aids; intermediate levels were reported for OI type IV. ⢠OI type is a key predictor of ultimate ability to ambulate, whereas the timing of developmental milestones was not associated with walking ability What is New: ⢠overall key predictors of mobility function at skeletal maturity were mobility status and height z-score at 5-6 years of age ⢠Childrenwho were non-ambulators at 5 to 6 years of age had a higher chance of having better mobility at skeletal maturity if they had good upper extremity function, as expressed in the PEDI Self Care Score.
Assuntos
Osteogênese Imperfeita , Adulto , Peso Corporal , Densidade Óssea , Criança , Pré-Escolar , Humanos , Autocuidado , CaminhadaRESUMO
Osteocytes are terminally differentiated osteoblasts embedded within the bone matrix and key orchestrators of bone metabolism. However, they are generally not characterized by conventional bone histomorphometry because of their location and the limited resolution of light microscopy. OI is characterized by disturbed bone homeostasis, matrix abnormalities and elevated bone matrix mineralization density. To gain further insights into osteocyte characteristics and bone metabolism in OI, we evaluated 2D osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging in transiliac bone biopsy samples from children with OI type I (n = 19) and age-matched controls (n = 24). The OLS characteristics were related to previously obtained, re-visited histomorphometric parameters. Moreover, we present pediatric bone mineralization density distribution reference data in OI type I (n = 19) and controls (n = 50) obtained with a field emission scanning electron microscope. Compared to controls, OI has highly increased OLS density in cortical and trabecular bone (+50.66%, +61.73%; both p < 0.001), whereas OLS area is slightly decreased in trabecular bone (-10.28%; p = 0.015). Correlation analyses show a low to moderate, positive association of OLS density with surface-based bone formation parameters and negative association with indices of osteoblast function. In conclusion, hyperosteocytosis of the hypermineralized OI bone matrix associates with abnormal bone cell metabolism and might further impact the mechanical competence of the bone tissue.
Assuntos
Osteócitos/metabolismo , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/patologia , Densidade Óssea/fisiologia , Desenvolvimento Ósseo/fisiologia , Matriz Óssea/patologia , Osso e Ossos/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Osteoblastos/patologia , Osteócitos/patologia , Osteócitos/fisiologia , Osteogênese/fisiologiaRESUMO
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 , Anticorpos Monoclonais Humanizados , Estatura , Criança , Desenvolvimento Infantil , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Lactente , Masculino , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Hearing loss (HL) is an extra-skeletal manifestation of the connective tissue disorder osteogenesis imperfecta (OI). Systematic evaluation of the prevalence and characteristics of HL in COL1A1/COL1A2-related OI will contribute to a better clinical management of individuals with OI. We collected and analyzed pure-tone audiometry data from 312 individuals with OI who were enrolled in the Linked Clinical Research Centers and the Brittle Bone Disorders Consortium. The prevalence, type, and severity of HL in COL1A1/COL1A2-related OI are reported. We show that the prevalence of HL in OI is 28% and increased with age in Type I OI but not in Types III and IV. Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I. We also show that the prevalence of SNHL is higher in females with OI compared to males. This study reveals new insights regarding prevalence of HL in OI including a lower general prevalence of HL in COL1A1/COL1A2-related OI than previously reported (28.3 vs. 65%) and high prevalence of SNHL in females. Our data support the need in early routine hearing evaluation in all types of OI that can be adjusted to the severity of the skeletal disease.
Assuntos
Colágeno Tipo I/genética , Perda Auditiva/epidemiologia , Mutação , Osteogênese Imperfeita/fisiopatologia , Adolescente , Adulto , Criança , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Genótipo , Perda Auditiva/genética , Perda Auditiva/patologia , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Fenótipo , Adulto JovemRESUMO
PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. METHODS: Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. RESULTS: In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). CONCLUSION: From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.
Assuntos
Estatura/fisiologia , Peso Corporal/fisiologia , Osteogênese Imperfeita/epidemiologia , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Feminino , Humanos , Masculino , América do Norte , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/uso terapêutico , Adulto JovemRESUMO
PURPOSE: Osteogenesis imperfecta (OI) is a genetic connective tissue disorder that causes bone fragility. Phenotypic severity influences ability to walk, however, little is known about ambulatory characteristics of individuals with OI, especially in more severe forms. The purpose of this work was to characterize mobility in OI using standard clinical assessment tools and determine if patient characteristics could be used to predict mobility outcomes. METHODS: We collected mobility data at five clinical sites to analyze the largest cohort of individuals with OI (n = 491) to date. Linear mixed models were developed to explore relationships among subject demographics and mobility metrics. RESULTS: Results showed minor limitations in the mild group while the more severe types showed more significant limitations in all mobility metrics analyzed. Height and weight were shown to be the most significant predictors of mobility. Relationships with mobility and bisphosphonates varied with OI type and type used (oral/IV). CONCLUSION: These results are significant to understanding mobility limitations of specific types of OI and beneficial when developing rehabilitation protocols for this population. It is important for physicians, patients, and caregivers to gain insight into severity and classification of the disease and the influence of disease-related characteristics on prognosis for mobility.
Assuntos
Limitação da Mobilidade , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/reabilitação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Fenótipo , PrognósticoRESUMO
Pulmonary complications are a significant cause for morbidity and mortality in osteogenesis imperfecta (OI). However, to date, there have been few studies that have systematically evaluated pulmonary function in individuals with OI. We analyzed spirometry measurements, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1 ), in a large cohort of individuals with OI (n = 217) enrolled in a multicenter, observational study. We show that individuals with the more severe form of the disease, OI type III, have significantly reduced FVC and FEV1 which do not follow the expected trends of the normal population. We also show that "normalization" of FVC and FEV1 using general population data to generate percent predicted values underestimates the pulmonary involvement in OI. Within each subtype of OI, we used linear mixed models to find potential correlations between FEV1 and FVC with the clinical variables including mobility, bisphosphonate use, and scoliosis. Our results are an important step in understanding the extent of pulmonary involvement in individuals with OI and for developing pulmonary endpoints for use in the routine patient care as well as in the investigation of new therapies.
Assuntos
Pulmão/fisiopatologia , Osteogênese Imperfeita/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese Imperfeita/diagnóstico , Testes de Função Respiratória , Índice de Gravidade de Doença , Espirometria , Capacidade Vital , Adulto JovemRESUMO
We had previously published the clinical characteristics of a bone fragility disorder in children that was characterized mainly by lower extremity fractures and a mineralization defect in bone tissue but not on the growth plate level. We have now performed whole-exome sequencing on four unrelated individuals with this phenotype. Three individuals were homozygous for a nucleotide change in BMP1, affecting the polyadenylation signal of the transcript that codes for the short isoform of BMP1 (BMP1-1) (c.*241T>C). In skin fibroblasts of these individuals, we found low levels of BMP1-1 transcript and protein. The fourth individual was compound heterozygous for the c.*241T>C variant in BMP1-1 and a variant in BMP1 exon 15 (c.2107G>C) that affected splicing in both BMP1-1 and the long isoform of BMP1 (BMP1-3). Both the homozygous 3'UTR variant and the compound heterozygous variants were associated with impaired procollagen type I C-propeptide cleavage, as the amount of free C-propeptide in the supernatant of skin fibroblasts was less than in controls. Peripheral quantitative computed tomography showed that all individuals had elevated volumetric cortical bone mineral density. Assessment of iliac bone samples by histomorphometry and quantitative backscattered electron imaging indicated that the onset of mineralization at bone formation sites was delayed, but that mineralized matrix was hypermineralized. These results show that isolated lack of BMP1-1 causes bone fragility in children.
Assuntos
Doenças Ósseas/genética , Proteína Morfogenética Óssea 1/genética , Fraturas Ósseas/genética , Regiões 3' não Traduzidas , Doenças Ósseas/metabolismo , Proteína Morfogenética Óssea 1/deficiência , Criança , Pré-Escolar , Colágeno Tipo I/metabolismo , Éxons , Feminino , Fraturas Ósseas/metabolismo , Humanos , Lactente , Masculino , PoliadenilaçãoRESUMO
Results of previous studies suggest that children and adolescents with osteogenesis imperfecta (OI) type IV have muscle force deficits. However, muscle function remains to be objectively quantified in this population. This study aimed to assess upper and lower extremity muscle function in patients with OI type IV. It was carried out in the outpatient department of a pediatric orthopedic hospital; 27 individuals with OI type IV (7-21 years; 13 males), 27 age- and sex-matched individuals with OI type I, and 27 age- and sex-matched controls. Upper extremity muscle force was assessed with hydraulic hand dynamometry, and lower extremity muscle function (peak force per body weight and peak power per body mass) was measured by mechanography through five tests: multiple two-legged hopping, multiple one-legged hopping, single two-legged jump, chair-rise test, and heel-rise test. Upper-limb grip force was normal for patients with OI type IV when compared to height and sex reference data (average z-score = 0.17 ± 1.30; P = 0.88). Compared to age- and sex-matched controls, patients with OI type IV had approximately 30% lower-limb peak force and 50% peak power deficits (P values <0.05). At the lower-limb level, they had a 50% lower peak power than age- and sex-matched patients with OI type I (P < 0.05). Patients with OI type IV have normal upper-limb muscle force but a muscle function deficit at the lower-limb level. These results suggest that lower-limb muscle weakness may contribute to functional deficits in these individuals.
Assuntos
Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Osteogênese Imperfeita/fisiopatologia , Adolescente , Criança , Feminino , Humanos , Masculino , Adulto JovemRESUMO
Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly (MDMHB) is an autosomal-dominant bone dysplasia characterized by metaphyseal flaring of long bones, enlargement of the medial halves of the clavicles, maxillary hypoplasia, variable brachydactyly, and dystrophic teeth. We performed genome-wide SNP genotyping in five affected and four unaffected members of an extended family with MDMHB. Analysis for copy-number variations revealed that a 105 kb duplication within RUNX2 segregated with the MDMHB phenotype in a region with maximum linkage. Real-time PCR for copy-number variation in genomic DNA in eight samples, as well as sequence analysis of fibroblast cDNA from one subject with MDMHB confirmed that affected family members were heterozygous for the presence of an intragenic duplication encompassing exons 3 to 5 of RUNX2. These three exons code for the Q/A domain and the functionally essential DNA-binding runt domain of RUNX2. Transfection studies with murine Runx2 cDNA showed that cellular levels of mutated RUNX2 were markedly higher than those of wild-type RUNX2, suggesting that the RUNX2 duplication found in individuals with MDMHB leads to a gain of function. Until now, only loss-of-function mutations have been detected in RUNX2; the present report associates an apparent gain-of-function alteration of RUNX2 function with a distinct rare disease.
Assuntos
Braquidactilia/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Duplicação Gênica/genética , Osteocondrodisplasias/genética , Adolescente , Braquidactilia/diagnóstico por imagem , Cromossomos Humanos Par 6/genética , Éxons/genética , Fácies , Família , Feminino , Dedos/anormalidades , Dedos/diagnóstico por imagem , Genoma Humano/genética , Humanos , Masculino , Maxila/anormalidades , Maxila/diagnóstico por imagem , Osteocondrodisplasias/diagnóstico por imagem , Linhagem , Radiografia , Adulto JovemRESUMO
OBJECTIVE: To use peripheral quantitative computed tomography to determine the cross-sectional area (CSA) of subcutaneous fat and muscle (fat CSA, muscle CSA) in transverse forearm scans in patients with osteogenesis imperfecta (OI). STUDY DESIGN: Fat and muscle CSA were quantified in 266 individuals (142 female) aged 5-20 years who had a diagnosis of OI type I, III, or IV and who had mutations in COL1A1 or COL1A2. Results were compared with those of 255 healthy controls. RESULTS: In a subgroup of 39 patients with OI type I, % fat CSA correlated closely with total body percentage fat mass as determined by dual-energy x-ray absorptiometry (R(2) = 0.69; P < .001). In the entire study cohort, muscle CSA adjusted for age, sex, and forearm length was lower in OI type I and III than in controls (P < .05 each), but fat CSA was similar between OI types and controls. No relationship between the type of disease-causing mutation in the COL1A1 or COL1A2 genes and fat CSA or muscle CSA was found. CONCLUSIONS: Children and adolescents with OI have low muscle size but a normal amount of subcutaneous fat at the forearm.
Assuntos
Composição Corporal , Osteogênese Imperfeita/metabolismo , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
Osteogenesis imperfecta (OI) type I is usually caused by COL1A1 stop or frameshift mutations, leading to COL1A1 haploinsufficiency. Here we report on 12 individuals from 5 families who had OI type I due to an unusual causeheterozygous deletions of the entire COL1A1 gene. The deletions were initially detected by semiconductor-based sequencing of genomic DNA and confirmed by quantitative PCR. Array comparative genomic hybridization in DNA of the index patient in each family showed that deletion size varied from 18.5 kb to 2.23 Mb between families, encompassing between 1 and 47 genes (COL1A1 included). The skeletal phenotype of the affected individuals was similar to that of patients with haploinsufficiency caused by COL1A1 stop or frameshift mutations. However, one individual with a deletion that included also DLX3 and DLX4 had tooth discoloration and bone fragility. Three individuals from 2 families had deletions that included also CACNA1G, and these individuals had learning disabilities. These features are not usually observed in COL1A1 haploinsufficiency, but are in accordance with previously described individuals in whom deletions included the same genes. In summary, we found deletions of COL1A1 in 5 out of 161 families (3 %) with OI type I that were evaluated. Deletions encompassing not only COL1A1 but also neighboring genes can lead to contiguous gene syndromes that may include dental involvement and learning disability.
Assuntos
Colágeno Tipo I/genética , Deleção de Genes , Osteogênese Imperfeita/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cadeia alfa 1 do Colágeno Tipo I , Hibridização Genômica Comparativa , Família , Feminino , Humanos , Lactente , Masculino , Osteogênese Imperfeita/epidemiologia , Linhagem , Polimorfismo Genético , Adulto JovemRESUMO
Osteogenesis imperfecta (OI) type VI is a recessively inherited form of OI that is caused by mutations in SERPINF1, the gene coding for pigment-epithelium derived factor (PEDF). Here, we report on two apparently unrelated children with OI type VI who had the same unusual homozygous variant in intron 6 of SERPINF1 (c.787-10C>G). This variant created a novel splice site that led to the in-frame addition of three amino acids to PEDF (p.Lys262_Ile263insLeuSerGln). Western blotting showed that skin fibroblasts with this mutation produced PEDF but failed to secrete it. Both children were treated with intravenous bisphosphonates, but the treatment of Individual 1 was switched to subcutaneous injections of denosumab (dose 1 mg per kg body weight, repeated every 3 months). An iliac bone sample obtained after 5 denosumab injections (and 3 months after the last injection) showed no change in the increased osteoid parameters that are typical of OI type VI, but the number of osteoclasts in trabecular bone was markedly increased. This suggests that the effect of denosumab on osteoclast suppression is of shorter duration in children with OI type VI than what has previously been reported on adults with osteoporosis.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Proteínas do Olho/genética , Fatores de Crescimento Neural/genética , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Serpinas/genética , Adolescente , Western Blotting , Canadá , Criança , Pré-Escolar , Denosumab/uso terapêutico , Feminino , Humanos , Lactente , Masculino , MutaçãoRESUMO
Intravenous pamidronate is widely used to treat children with osteogenesis imperfecta (OI). In a well-studied protocol ('standard protocol'), pamidronate is given at a daily dose of 1 mg per kg body weight over 4 h on 3 successive days; infusion cycles are repeated every 4 months. Here, we evaluated renal safety of a simpler protocol for intravenous pamidronate infusions (2 mg per kg body weight given in a single infusion over 2 h, repeated every 4 months; 'modified protocol'). Results of 18 patients with OI types I, III, or IV treated with the modified protocol for 12 months were compared to 18 historic controls, treated with standard protocol. In the modified protocol, mild transient post-infusion increases in serum creatinine were found during each infusion but after 12 months serum creatinine remained similar from baseline [0.40 mg/dl (SD: 0.13)] to the end of the study [0.41 mg/dl (SD: 0.11)] (P = 0.79). The two protocols led to similar changes in serum creatinine during the first pamidronate infusion [modified protocol: +2% (SD: 21%); standard protocol: -3% (SD: 8%); P = 0.32]. Areal lumbar spine bone mineral density Z-scores increased from -2.7 (SD: 1.5) to -1.8 (SD: 1.4) with the modified protocol, and from -4.1 (SD: 1.4) to -3.1 (SD: 1.1) with standard protocol (P = 0.68 for group differences in bone density Z-score changes). The modified pamidronate protocol is safe and may have similar effects on bone density as the standard pamidronate protocol. More studies are needed with longer follow-up to prove anti-fracture efficacy.
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Difosfonatos/administração & dosagem , Osteogênese Imperfeita/tratamento farmacológico , Administração Intravenosa , Adolescente , Densidade Óssea/efeitos dos fármacos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/prevenção & controle , Estudo Historicamente Controlado , Humanos , Injeções Intramusculares , Masculino , Osteogênese Imperfeita/epidemiologia , PamidronatoRESUMO
OBJECTIVE: To determine the functional outcomes associated with long-term multidisciplinary treatment, intravenous bisphosphonate treatment, orthopedic surgery, and rehabilitation in children with severe osteogenesis imperfecta (OI) (diagnosed clinically as OI types III or IV). DESIGN: Retrospective study where outcomes were measured prospectively. SETTING: Pediatric orthopedic hospital. PARTICIPANTS: Adolescents (N=41; age range, 15-21y) with severe OI (OI type III: n=17; OI type IV: n=24) who had started therapy before the age of 6 years, had received treatment for at least 10 years, and had achieved final height. INTERVENTIONS: Intravenous bisphosphonate treatment, orthopedic surgery, and rehabilitation. MAIN OUTCOME MEASURE: Pediatric Evaluation of Disability Inventory. RESULTS: At the time of the last available follow-up examination, none of the individuals diagnosed with OI type III (most severely affected group) was able to ambulate without ambulation aids, whereas 20 (83%) patients with OI type IV were able to ambulate without ambulation aids. Regarding self-care, we specifically assessed 8 skills that we deemed essential for living independently (grooming; dressing; toileting; bed, chair, toilet, tub, and car transfers). Only 6 (35%) of the youths with OI type III were able to complete all 8 items, whereas 23 (96%) individuals with OI type IV managed to perform all tasks. Teens with OI type III often needed assistance for the transfer to toilet, tub, and car and for personal hygiene and clothing management associated with toileting, usually because of limitations in upper-extremity function. CONCLUSIONS: These observations suggest that further improvements in the functional status of the most severely affected children with OI are contingent on advances in the clinical management of upper-extremity issues.
Assuntos
Osteogênese Imperfeita/terapia , Adolescente , Conservadores da Densidade Óssea/uso terapêutico , Terapia Combinada , Difosfonatos/uso terapêutico , Avaliação da Deficiência , Feminino , Humanos , Masculino , Procedimentos Ortopédicos , Amplitude de Movimento Articular , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Metabolic bone disorders in children frequently are heritable, but the expanding number of genes associated with these conditions makes it difficult to perform molecular diagnosis. In the present study, we therefore evaluated a semiconductor (SC)-based sequencing system for this purpose. A total of 65 DNA samples were analyzed comprising 24 samples from patients with 27 known pathogenic mutations, 6 samples from patients with prior negative Sanger sequencing, and 35 consecutive samples from patients with suspected heritable metabolic bone disorders who had not had prior molecular diagnosis. In the samples with known pathogenic mutations, 26 of 27 mutations were identified by SC sequencing. All single nucleotide variants were correctly identified, but a 7-nucleotide duplication in CYP27B1 was not detected. SC sequencing revealed two pathogenic mutations in the six samples where prior Sanger sequencing had failed to identify a mutation. Finally, pathogenic mutations were found in 27 samples of patients with unknown mutation status (15 in COL1A1, 9 in COL1A2, 1 in LEPRE1, 1 in LRP5, 1 in PHEX). Subsequent Sanger sequencing confirmed the mutations in all 27 samples. In conclusion, we found that SC sequencing is suitable for the diagnosis of heritable metabolic bone disorders in children.