Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation

Osteogenesis imperfecta (OI) is a heritable disorder characterized by osteoporosis and increased susceptibility to fracture. All children with severe OI have extreme short stature and some have "popcorn" calcifications, areas of disorganized hyperdense lines in the metaphysis and epiphysis around the growth plate on lower limb radiographs. Popcorn calcifications were noted on radiographs of two children with non-lethal type VIII OI, a recessive form caused by P3H1 deficiency. To determine the incidence, progression, and molecular correlations of popcorn calcifications, we retrospectively examined serial lower limb radiographs of 45 children with type III or IV OI and known dominant mutations in type I collagen. Popcorn calcifications were present in 13 of 25 type III (52%), but only 2 of 20 type IV (10%), OI children. The mean age of onset was 7.0 years, with a range of 4-14 years. All children with popcorn calcifications had this finding in their distal femora, and most also had calcifications in proximal tibiae. While unilateral popcorn calcification contributes to femoral growth deficiency and leg length discrepancy, severe linear growth deficiency, and metaphyseal flare do not differ significantly between type III OI patients with and without popcorn calcifications. The type I collagen mutations associated with popcorn calcifications occur equally in both COL1A1 and COL1A2, and have no preferential location along the chains. These data demonstrate that popcorn calcifications are a frequent feature of severe OI, but do not distinguish cases with defects in collagen structure (primarily dominant type III OI) or modification (recessive type VIII OI).     

Pediatric Outcomes Data Collection Instrument is a Useful Patient-Reported Outcome Measure for Physical Function in Children with Osteogenesis Imperfecta

PurposePatient-reported outcome measures (PROMs) are increasingly recognized as valuable endpoints in clinical trials. The Pediatric Outcomes Data Collection Instrument (PODCI) is a PROM utilized in children with musculoskeletal disorders. We evaluated the validity and reliability of PODCI in children with osteogenesis imperfecta (OI).MethodsPhysical functioning and psychological well-being were assessed using PODCI in a large cohort of children enrolled in a multicenter study conducted by the Brittle Bone Disorders Consortium. Physical function scores were correlated with a validated, observer-rated scale, Brief Assessment of Motor Function (BAMF), and with psychological well-being scores. We calculated sample sizes required to detect clinically meaningful differences in physical function.ResultsFour hundred seventeen children with OI types I, III, and IV were enrolled. Physical function scores in OI type III were significantly lower than those in OI types I and IV. There were no significant differences in psychological well-being. PODCI physical function scores showed moderate-to-strong correlation with BAMF. The Global Functioning Scale, a composite of physical function, did not consistently correlate with psychological well-being.ConclusionPODCI can be a reliable measure of physical functioning in children with OI and offers valuable information about patient-reported health status and new ways to examine the utility of interventions in this population.     

Testing for osteogenesis imperfecta in cases of suspected non-accidental injury

To evaluate if laboratory testing for osteogenesis imperfecta (OI) identifies children unrecognised by clinical examination in instances where non-accidental injury (NAI) is suspected as the likely cause of fracture, we carried out a retrospective review of available medical records and biochemical test results from 262 patients. Cultured fibroblasts were received for biochemical testing for OI from children in whom the diagnosis of NAI was suspected. Eleven of the samples had alterations in the amount or structure of type I collagen synthesised, consistent with the diagnosis of OI, and in 11 others we could not exclude OI. Referring physicians correctly identified children with OI in six of the 11 instances established by biochemical studies, did not identify OI by clinical examination in three, and there was inadequate clinical information to know in two others. Biochemical testing was inconclusive in 11 infants in whom the diagnosis of OI could not be excluded, none of whom were thought to be affected by the referring clinicians. Four children believed to have OI by clinical examination had normal biochemical studies, a false positive clinical diagnosis attributed, in large part, to the use of scleral hue (a feature that is age dependent) as a major diagnostic criterion.

Given the inability to identify all children with OI by clinical examination in situations of suspected NAI, laboratory testing for OI (and other genetic predispositions for fractures) is a valuable adjunct in discerning the basis for fractures and may identify a small group of children with previously undiagnosed OI.

     

The development of callous-unemotional traits and antisocial behavior in children: are there shared and/or unique predictors?

Callous and unemotional (CU) traits have been linked to severe antisocial behavior in youth, but studies examining the etiology of CU traits are lacking. Based on prior research, it was hypothesized that childhood anxiety and parenting practices would interact to predict changes in CU traits over time. Hypotheses were tested using a sample of 120 moderate to highly aggressive fifth graders followed over a 1-year period. Although CU traits displayed moderate temporal stability and predicted increases in antisocial behavior, evidence suggested that these features were not immutable. Children exposed to lower levels of physical punishment showed decreases in CU traits over time, whereas higher levels of child-reported parental warmth and involvement predicted decreases in both CU traits and antisocial behavior over time. Lower levels of anxiety were uniquely related to increased CU traits for children who described their primary caregiver as exhibiting low warmth and involvement.     

Clinical management of osteogenesis imperfecta

Knowledge of the natural history of different types of OI permits planning of rehabilitation goals for children with OI. Notwithstanding this knowledge, rehabilitation will need to be modified to accommodate unexpected fractures and the highly variable chance of deformity in each individual. Immobilisation should be minimized to avoid immobilization osteoporosis. New rehabilitation issues include basilar impression, recommencement of fractures in postmenopausal women with OI, pregnancy related bone loss and sleep apnoea.     

Mobility in osteogenesis imperfecta: a multicenter North American study

PurposeOsteogenesis 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.MethodsWe 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.ResultsResults 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).ConclusionThese 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.     

Osteogenesis imperfecta: an overview of general pediatric rehabilitation

The unique biological changes associated with Osteogenesis Imperfecta (OI) result in a dramatic reduction in a child's functional capacity. Successful adaptation and optimal functioning for the child and family, the over-arching goal of comprehensive rehabilitation, are dependent upon the complex interactions between biological processes and a host of behavioral, psychosocial, and environmental factors. This article reviews the premises underlying the need for rehabilitation; general rehabilitation strategies; the aims and outcomes to be achieved through the provision of rehabilitation; and the broad-based issues and variables that affect outcome. Because of the multifactorial and complex nature of the pediatric disability, advances in the rehabilitation of children with OI will require long-term, multivariant, and multicenter studies that will capture health-related, psychosocial, environmental, and functional variables.     

Heritable dentin defects: Nosology,pathology, and treatment

Heritable dentin defects have been divided into 2 main categories: dentinogenesis imperfecta (DI) and dentin dysplasia (DD). Recent studies have shown that they share many features in common. Of the connective tissue diseases, only osteogenesis imperfecta (OI) has been linked to these disorders. So far, no definitive relation between the type of OI and the dental involvement can be established. Familial occurrence of DI with OI cannot be comprehensively explained by mutations in type I collagen genes. No information about the gene defects in DD is available. At the ultrastructural level, the organization of the normally cross-striated collagen fibers in the dentin matrix varies markedly in patients affected by DI.     

Triadic communication in the primary care paediatric consultation: a review of the literature.

BACKGROUND: Children aged 6-12 years are usually seen in primary care with an adult carer. It is a government and professional priority for doctors to try and involve these children in their medical consultations. AIM: To ascertain the evidence available on the amount and type of involvement that children in the 6-12 year age group have in their primary care consultations when the consultation was held with a child, a GP, and an adult. DESIGN OF THE STUDY: Literature review. METHOD: Data sources included MEDLINE, CINAHL, EMBASE, and ERIC, The Cochrane library, PsychINFO, Web of Science and Wilson's Social Science abstracts, hand searching for references, and contact with authors. RESULTS: Twenty-one studies were selected for inclusion in the study. Children were found to have little quantitative involvement in their own consultations. They may take part during information gathering but are unlikely to participate in the treatment planning and discussion parts of the consultation. CONCLUSION: Children in the 6-12 year age group have little meaningful involvement in their consultations.     

Osteogenesis imperfecta and achievements in cell and gene therapy

Osteogenesis imperfecta (OI) or "brittle bone" disease is characterized by fragile bones, skeletal deformity, and growth retardation. Depending on the mutation and related phenotype, O1 is classified into types I-IV, which are caused by different mutations in collagen genes, and types V-VIII, which are indirectly but not directly collagen related. The most common cause of this inheritable disorder of connective tissue are mutations affecting the COL1A1 and COL1A2 genes of type I collagen. There is no cure for OI and current treatments include surgical intervention, use of prostheses and physical therapy. Pharmacological agents have also been tried with limited success, with the exception of recent use of bisphosphonates, which have been shown to have some effect in bone mass acquisition. Since OI is a genetic disease, these agents are not expected to alter the course of collagen mutations. Recent technology in molecular biology has led to the development of transgenic models of OI, which are necessary for development of cell and gene therapies as potential treatments for OI and are currently being actively investigated. However, the design of gene therapies for OI is complicated by genetic heterogeneity of the disease and by the fact that most of OI mutations are dominant negative where the mutant allele product interferes with the function of the normal allele. Therefore, therapy needs to include suppression of the mutant allele and introduction of the wild type allele. The present review will discuss the classification of OI and molecular changes seen in different types of OI and transgenic murine models that mimic different types of OI. Cell therapy, gene therapy, and a combination of both represent new approaches in OI therapy development that are being investigated as potential future treatments for OI. Modest success of cell therapy, encouraging results of gene therapy in vitro and in animal models as well as their problems and limitations for use in humans will be presented.     

New directions in the evaluation and education of handicapped children.

The Education for All Handicapped Children Act of 1975, which went into effect last October, ensures the right of handicapped children to free appropriate public education. State and local education agencies are required to identify, evaluate and provide services for all disabled children. This multibilliondollar program will guarantee special education resources for up to 12 per cent of American children. A role for physicians in the program is implied rather than defined in the law. Their involvement will vary somewhat from state to state, but will at a minimum involve counseling parents whose children are under evaluation. The law assumes a sophistication of diagnostic ability and curriculum design that does not yet exist, and therefore places a special burden upon physicians to deal effectively with patients now, while developing better training programs and assessment tools, and makes essential the enhancement of the communication between doctors and educators.     

Osteogenesis imperfecta type III. Delineation of the phenotype with reference to genetic heterogeneity

The existence of a rare form of osteogenesis imperfecta, OI type III, has been postulated. This is characterized by autosomal recessive inheritance with neonatal manifestations of bone fragility or deformability. It is usually nonlethal. Studies of some 345 pedigrees of OI in the last 8 years confirm that patients falling into this group are rare. They should be distinguished as a special group within the group of OI subjects with a progressively deforming OI phenotype delineated in previous publications [Sillence et al, 1979a, b]. The OI type III phenotype does not necessarily equate with progressively deforming OI, and probably only a proportion of cases with severe deformity and normal sclerae have OI type III. On the other hand, distinction between these patients and those with a milder form of perinatally lethal OI type II might be difficult. Whereas the natural history of skeletal deformity and fractures in patients with OI type III has certain similarities, variable severity between families indicates that OI type III is likely to be genetically heterogeneous.     

早期干预对高危新生儿智能发育的影响

目的探讨早期干预对高危儿智能发育的效果。方法选择高危儿69例随机分为干预组与未干预组,并设正常新生儿对照组,干预组按计划采用一对一智能发育评估及训练指导,个体化早教方案的制定、亲子活动、家庭康复训练和健康教育等综合方法进行早期干预。未干预组按儿童保健常规进行体格检查和育儿指导。结果干预组在1岁、2岁智力发育指数和运动发育指数明显高于未干预组,差异有显著性（P均〈0.05）,可达正常儿对照组水平。结论早期干预可促进高危儿的智能发育,可降低脑瘫的发生率,对提高人口素质具有重要意义。     

Non-invasive prenatal diagnosis of osteogenesis imperfecta

The main mode of non-invasive prenatal diagnosis of osteogenesis imperfecta (OI) is fetal imaging, either by radiography or detailed ultrasonography. Radiography is more of historical interest and ultrasonography is in practice virtually exclusively used for non-invasive second trimester diagnosis of OI. Both methods have also been reported later in pregnancy when diagnosis allows the most appropriate method of delivery to be planned. For example, a caesarean section can be avoided if the fetus is shown to have a form of OI associated with limited survival. Ultrasonography is useful mainly for prenatal diagnosis of the severe forms of OI, especially the perinatally lethal forms (Sillence type II) and to a lesser extent for the severe progressively deforming forms (Sillence types III and III/IV). For the milder varieties of OI (Sillence types I and IV), many cases will be missed by scans. Invasive methods of prenatal diagnosis of OI (principally chorion villous sampling) are used for families with the milder dominant forms of OI and in severe forms of OI in which the actual biochemical or molecular defect in type I collagen is known. Many cases of type II OI and a few of type III have now been reported which were detected by scans before 20 weeks gestation, the earliest being at 15 weeks, for type IIA OI. These include cases not only at genetic risk but also sporadic cases in which scans were done either routinely or for obstetric indications. The ultrasonic abnormalities which are found include reduced echogenicity, multiple fractures, and deformity of the long bones, ribs and skull. There is a marked reduction of long bone length on measurement. The abnormalities are more severe in type II OI than in type III. No false negative diagnoses have yet been reported for severe OI. Ultrasonography is a reliable mode of prenatal diagnosis for a pregnancy at risk of type II OI and probably also for type III, although more reports for the latter are needed to give more information about the likelihood of false negative diagnoses in this form of OI. For pregnancies at risk of types II and III OI, serial scans from 14 weeks gestation can be offered. An experienced operator, using a good realitime scanner should be able to detect type II OI by at least 17 weeks gestation, and type III OI by 19 to 20 weeks. In future, it may be possible to diagnose type II OI in the first trimester by ultrasound using an intravaginal transducer.     

Child and context characteristics in trajectories of physical and relational victimization among early elementary school children

Transactional models suggest that peer victimization results from both individual and context differences, and understanding these differences may point to important targets for prevention and interventions that reduce victimization. Multilevel modeling was used to examine within-person (aggression and emotional dysregulation), between-person (sex and age), and between-school (participation in a victimization prevention program) factors that influence changes in physical and relational victimization over the first three years of elementary school. Children (n = 423) reported their experiences of peer victimization at entry into Grade 1 and at the end of Grade 1, Grade 2, and Grade 3. On average, trajectories of both physical and relational victimization declined. However, for individual children, teacher-rated aggression was associated with increases in physical and relational victimization, while emotional dysregulation was associated with attenuation of longitudinal declines in physical victimization and increases in relational victimization. Individual differences in sex and age at entry into Grade 1 did not significantly influence victimization trajectories over Grades 1 to 3. Children who participated in the WITS? victimization prevention program showed significant declines in physical and relational victimization. Levels of victimization among nonparticipants remained stable. Implications of child and context characteristics for preventing peer victimization in elementary school are discussed.     

Posttraumatic stress symptoms in children following orthopedic or traumatic brain injury

Examined posttraumatic stress (PTS) symptoms in children following pediatric traumatic brain injury (TBI). Children (ages 6-12) with TBI (n = 81) and orthopedic injury (01; n = 59) were assessed 6 and I2 months postinjury. Parents of children with severe TBI reported higher levels of child PTS symptoms than did parents of children with moderate TBI or 0 1 at the 6- and 12-month follow-ups. Group differences in child-reported PTS symptoms emerged at the 12-month follow-up with higher symptom levels reported by children with severe TBI than by those with moderate TBI or OI. At both follow-ups, rates of clinically significant symptom levels were higher in the severe TBI group than in the moderate TBI or OI groups. The group differences in parent and child reports were significant even after taking ethnicity, social disadvantage, and age at injury into account. Parent and child reports of child PTS symptoms were related to family socioeconomic status. Implications for clinical intervention with children and families following pediatric TBI are discussed.     

Social, emotional, and behavioral functioning of children with NF1

Children with neurofibromatosis type 1 (NF1) can have varying degrees of cognitive impairment, and are at risk for social, emotional, and behavioral dysfunction. We undertook an evaluation of social, emotional, and behavioral functioning of youth with NF1 and peers from multiple perspectives. We hypothesized that children with NF1 would have more psychosocial difficulties, which would be positively associated with neurological involvement. We compared 58 children with NF1, ages 7-15, with comparison classroom peers, classmates who were same race/gender and closest date of birth. Peer relationships, emotional well-being, and behavior were evaluated from multiple perspectives in multiple settings. Results showed that teachers perceived children with NF1 as more prosocial (i.e., polite, helpful to others). Teachers and peers viewed children with NF1 as displaying less leadership behavior and as more socially sensitive-isolated (i.e., often left out, trouble making friends). Children with NF1 had fewer friendships and were less well liked by peers. Mothers and fathers reported more problems with social functioning among children with NF1. Few group differences in emotional well-being and behavior were identified according to child and father report. However, mothers perceived children with NF1 to have more emotional problems relative to comparison peers, predominantly among older children. Neurological involvement was significantly related to psychosocial problems. We conclude that children with NF1 are frequently socially isolated and rejected by peers; and that greater neurological involvement is associated with more emotional problems. Central nervous system involvement appears to play a key role in identifying children at risk for problems with friendships, social acceptance, and emotional functioning (i.e., depression).     

Mental state attributions and diffusion tensor imaging after traumatic brain injury in children

We studied social cognition in 49 children 3 months after moderate to severe traumatic brain injury (TBI) and in 39 children with orthopedic injury (OI). Children underwent diffusion tensor imaging (DTI) and a mental attribution task showing two triangles. Mental state attributions increased when one triangle reacted to intentions of the other, but less so in the TBI than the OI group. DTI identified injury to white matter microstructure in the TBI group, but the relation of DTI to mental attributions did not differ between groups. Moderate to severe TBI produces white matter disconnections that may affect social cognitive networks.     

Mental State Attributions and Diffusion Tensor Imaging After Traumatic Brain Injury in Children

We studied social cognition in 49 children 3 months after moderate to severe traumatic brain injury (TBI) and in 39 children with orthopedic injury (OI). Children underwent diffusion tensor imaging (DTI) and a mental attribution task showing two triangles. Mental state attributions increased when one triangle reacted to intentions of the other, but less so in the TBI than the OI group. DTI identified injury to white matter microstructure in the TBI group, but the relation of DTI to mental attributions did not differ between groups. Moderate to severe TBI produces white matter disconnections that may affect social cognitive networks.     

Family background characteristics and school adjustment problems

Primary grade children identified by teachers as having selected family characteristics were compared on teacher ratings of school maladjustment. Children pressured to achieve academic success coped with school demands in a significantly more shy, anxious, and immature fashion than children from homes lacking educational stimulation. The latter group experienced greater difficulty in mastering basic academic skills. Children from rejecting parents had more serious acting out, aggressive problems than did children from overprotective parents. The latter group, however, experience anxiety and interpersonal discomfort. Treatment implications of these data focus primarily upon increased involvement of parents and families in school mental health programs.