Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review.

BACKGROUND: Secreted protein, acidic, cysteine rich (SPARC)-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARC is located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape. METHODS: We describe a further two patients with previously unreported homozygous SPARC variants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et al and Hayat et al with clinical descriptions of patients with SPARC variants. RESULTS: From the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup. CONCLUSION: Common phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of 'myopathy'.

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial.

BACKGROUND: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH). METHODS: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records. RESULTS: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode. CONCLUSIONS: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD.

A Prospective Cohort Study of Racial/Ethnic Variation in the Association between Change in Cystatin C and Dietary Quality in Older Americans.

Using a sample of U.S. adults aged 65 and older, we examined the role of dietary quality in cystatin C change over 4 years and whether this association varied by race/ethnicity. The Health and Retirement Study provided observations with biomarkers collected in 2012 and 2016, participant attributes measured in 2012, and dietary intake assessed in 2013. The sample was restricted to respondents who were non-Hispanic/Latino White (n = 789), non-Hispanic/Latino Black (n = 108), or Hispanic/Latino (n = 61). Serum cystatin C was constructed to be equivalent to the 1999-2002 NHANES scale. Dietary intake was assessed by a semi-quantitative food frequency questionnaire (FFQ) with diet quality measured using an energy-adjusted form of the Alternative Healthy Eating Index-2010 (AHEI-2010). Statistical analyses were conducted using autoregressive linear modeling adjusting for covariates and complex sampling design. Cystatin C slightly increased from 1.2 mg/L to 1.3 mg/L over the observational period. Greater energy-adjusted AHEI-2010 scores were associated with slower increase in cystatin C from 2012-2016. Among respondents reporting moderately low to low dietary quality, Hispanic/Latinos had significantly slower increases in cystatin C than their non-Hispanic/Latino White counterparts. Our results speak to the importance of considering racial/ethnic determinants of dietary intake and subsequent changes in health in aging populations. Further work is needed to address measurement issues including further validation of dietary intake questionnaires in diverse samples of older adults.

Cognitive Function Among Noncustodial Grandparents in China and the United States: A Cross-National Perspective.

The current study aimed to investigate the association between grandparenting and cognitive function over time in noncustodial grandparents in China and the United States. Lagged dependent variable (LDV) approach and linear regression models were applied to analyze a sample of 1,411 Chinese and 6,579 American adults aged 65 and above from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2013) and the U.S. Health and Retirement Study (HRS, 2012-2014). Grandparenting involvement was associated with less decline in episodic memory for grandparents and greater level of grandparenting had no negative effect on mental status and global cognitive function in noncustodial grandparents in China and the United States. The impact of grandparenting on cognitive function was conditioned on caregiving intensity, gender, urban/rural residence, and nation. Findings of the study suggest that greater attention on grandparenting facilitation might yield improved research, social support, policy, and interventions on cognitive health for the general older population.

Marital Transitions, Change in Depressive Symptomology, and Quality of Social Relationships in Midlife and Older U.S. Adults: An Analysis of the Health and Retirement Study.

Preventing negative health outcomes following marital transitions can promote personal recovery and well-being. We used the Health and Retirement Study (HRS) (2012, 2014) to test whether social relationship quality moderated the association between marital transition and change in depressive symptomology among U.S. adults aged 50 and older (n = 3,705). Marital status transitions between 2012 and 2014 included remained married/partnered, divorced/separated, and widowed. Depressive symptomology was measured using the Center for Epidemiological Studies Depression Scale 8 Short Form (CES-D 8). Social support, social contact, and social strain were indicators of social relationship quality. Change in depressive symptomology was modeled using autoregressive multiple regression. Social relationship quality appeared to influence depressive symptomatology for those experiencing divorce/separation. Compared to individuals who remained married/partnered, depressive symptomatology in those experiencing separation/divorce decreased among those reporting low social support, increased among those reporting high social support, and increased among those who reported low social strain. Limitations and clinical implications are discussed.

Dietary quality modifies the association between multimorbidity and change in mobility limitations among older Americans.

To identify potentially modifiable risk-factors in the age-related disablement process, we examined the association between change in mobility limitations and multimorbidity and how dietary quality moderates this association. Information from 3320 adults aged 65 and older in 2012 was drawn from the Health and Retirement Study and the Health Care and Nutrition Study. Mobility limitations reported in 2012 and change in mobility limitations from 2012 to 2014 were regressed on multimorbidity measured as number of chronic conditions in 2012, dietary quality measured in 2013 using the Alternative Healthy Eating Index-2010 (AHEI-2010), and their interaction term using Poisson regression. Respondents reported an average of 2.9 (SD, 2.9) mobility limitations in 2012 and 3.1 (SD, 3.0) mobility limitations in 2014, an average of 2.64 (SD, 1.4) chronic conditions in 2012, and mean AHEI-2010 score in 2013 of 57.1 (SD, 10.9). Greater AHEI-2010 scores were associated with fewer mobility limitations at baseline (p < .001) and slower progression of mobility limitations over the two-year observational window (p < .001). For those with AHEI-2010 scores ≥48.4, dietary quality appeared to moderate the association between multimorbidity and change in mobility limitations. These results suggest that improving dietary quality may be an effective means of reducing the progression of mobility limitations among older adults and that dietary quality may modify the effect of multimorbidity on progressive disablement. Our work adds to research supporting dietary quality as a potentially intervenable factor in the reduction of disablement in aging populations.

Investigating walnut consumption and cognitive trajectories in a representative sample of older US adults.

OBJECTIVE: Existing research suggests walnut intake may be associated with better cognitive function in older adults, yet few studies utilise longitudinal data from observational studies of ageing populations. Our objective was to estimate the association between whole walnut intake and cognitive change in a representative sample of older Americans. DESIGN: Secondary analysis of the Health and Retirement Study and Health Care and Nutrition Study. Walnut consumption was defined as a categorical measure (none, low intake (0·01-0·08 1 oz. servings per day) and moderate intake (>0·08 1 oz. servings per day)) and cognitive function was measured using the Telephone Interview for Cognitive Status. Latent growth modelling estimated the association between walnut consumption and trajectories of cognitive status over a 4-year observational period. Sensitivity analyses assessing non-random dropout and Monte Carlo power analyses were conducted to contextualise results. SETTING: The USA. PARTICIPANTS: A sample of 3632 US adults aged 65 years and older. RESULTS: Those reporting any walnut consumption had greater cognitive scores at baseline than those not consuming walnuts (low walnut consumption, b = 1·53, se = 0·21, P < 0·001; moderate walnut consumption, b = 2·22, se = 0·27, P < 0·001), but walnut consumption was not associated with cognitive change. Walnut consumption was positively associated with socioeconomic status and health behaviours as well as intake of nutrients identified to have neuroprotective benefits. CONCLUSIONS: We identified an association between walnut consumption and cognitive function in older adults, although we did not find that walnut consumption was protective against age-related cognitive decline.

Dietary lutein and zeaxanthin are associated with working memory in an older population.

OBJECTIVE: The purpose of the study was to examine the association between dietary lutein and zeaxanthin (L + Z) intake and immediate word recall (IWR) and delayed word recall (DWR), and to identify the major contributors to dietary L + Z intake in a recent and representative sample of the older US population. DESIGN: In this cross-sectional analysis, multivariate path analytic models estimated the association between L + Z consumption and cognitive performance while adjusting for covariates. SETTING: Observations were drawn from the 2014 Health and Retirement Study, a nationally representative panel study of older US adults, and the 2013 Health Care and Nutrition Study, which assessed dietary intake via FFQ in a subsample of respondents. PARTICIPANTS: The analytic sample included 6390 respondents aged ≥50 years. RESULTS: L + Z intake was 2·44 ± 2·32 mg/d on average, and L + Z intake differed significantly across quartiles (P < 0·001). For example, average L + Z intake in Q1 was 0·74 ± 0·23 mg/d and in Q4 was 5·46 ± 2·88 mg/d. In covariate adjusted models, older adults in the highest quartiles of L + Z intake had significantly greater IWR and DWR scores than those in the lowest quartile. Leafy vegetables, cruciferous vegetables, dark yellow vegetables, fish and seafood, legumes, eggs and fruit were significant and meaningful predictors of dietary L + Z intake. CONCLUSION: A high consumption of vegetables, fish and seafood, legumes, eggs and fruit is associated with a higher intake of L + Z and greater word recall among older adults.

Latent profile analysis of dietary intake in a community-dwelling sample of older Americans.

OBJECTIVE: To estimate latent dietary profiles in a community-dwelling sample of older Americans and identify associations between dietary profile membership and individual demographic, socio-economic and health characteristics. DESIGN: Secondary analysis of the 2012 Health and Retirement Study (HRS) and linked 2013 Health Care and Nutrition Study (HCNS). Latent profile analysis identified mutually exclusive subgroups of dietary intake and bivariate analyses examined associations between dietary profile membership, participant characteristics and nutrient intakes. SETTING: USA. PARTICIPANTS: An analytic sample of 3558 adults aged 65 years or older. RESULTS: Four dietary profiles were identified with 15·5 % of the sample having a 'Healthy' diet, 42·0 % consuming a 'Western' diet, 29·7 % having a diet consisting of high intake of all food groups and 12·7 % reporting relatively low intake of all food groups. Members of the 'Healthy' profile reported the greatest socio-economic resources and health, and members of the 'Low Intake' profile had the fewest resources and worst health outcomes. Macronutrient and micronutrient intakes varied across profile although inadequate and excessive intakes of selected nutrients were observed for all profiles. CONCLUSIONS: We identified dietary patterns among older Americans typified by either selective intake of foods or overall quantity of foods consumed, with those described as 'Low Intake' reporting the fewest socio-economic resources, greatest risk of food insecurity and the worst health outcomes. Limitations including the presence of measurement error in dietary questionnaires are discussed. The causes and consequences of limited dietary intake among older Americans require further study and can be facilitated by the HRS and HCNS.

Socioeconomic correlates of adherence to mineral intake recommendations among pregnant women in north China: Findings from a cross-sectional study.

BACKGROUND AND OBJECTIVES: The purpose of the present study is to examine the socioeconomic correlates of adherence to minimum mineral intake recommended by the Chinese Dietary Guidelines during each trimester of pregnancy among Chinese women. METHODS AND STUDY DESIGN: A total of 567 pregnant women with foetal age of 6 - 12 weeks were recruited from nine community health centres and three hospitals. Cross-sectional survey data were collected using structured interviews and questionnaires. Mineral intake was calculated from food consumption reported on 24-hour dietary reviews using the Chinese Food Composition Metrics. Logistic regression models were estimated to assess the relationship between sociodemographic factors and adherence to mineral intake recommendations for each trimester. RESULTS: Significant predictors of adherence to mineral intake recommendations include: (1) age (zinc: OR=1.09, p<0.05; copper: OR=1.11, p<0.05), having bachelor's degree (copper: OR=2.23, p<0.05; phosphorus: OR=2.23, p<0.01), and household income ≥5,000RMB (potassium: OR=2.51, p<0.001; phosphorus: OR=1.91, p<0.05) during the first trimester, (2) being employed (zinc: OR=0.54, p<0.001; selenium: OR=0.53, p<0.05) and household income ≥5,000 RMB (zinc: OR=1.86, p<0.05) during the second trimester, and (3) husband/partner with associate degree or vocational school education (selenium: OR=3.26, p<0.01) and household income of 3,000-4,999 RMB (potassium: OR=1.71, p<0.05; zinc: OR=1.48, p<0.05) during the third trimester. CONCLUSIONS: To our knowledge, this is the first study that examines the relationship between socioeconomic factors and mineral intake among Chinese pregnant women at three trimesters. Findings highlight the importance of considering individuals' socioeconomic status to develop personalized interventions to prevent undernutrition among this population.

Egg Consumption, Multi-Domain Cognitive Performance, and Short-Term Cognitive Change in a Representative Sample of Older U.S. Adults.

Objective: Existing research supports a positive relationship between egg intake and cognitive function in older populations, although the impact of whole egg consumption on multi-domain cognitive function and cognitive decline in representative samples of older adults has not been described. We examined the association between egg consumption, cognitive performance, and cognitive change in a representative sample of U.S. adults aged 65 and older. Methods: We drew observations from the 2012 and 2014 Health and Retirement Study and the recently released 2013 Health Care and Nutrition Study. The analytic sample contained 3835 respondents, representing a weighted population of 37,806,082 community-dwelling adults aged 65 and older in 2013. Multivariate path analytic models were used to estimate the association between egg consumption groups (none, ≤ 1 serving per week, 2-6 servings per week, ≥ 7 servings per week) and cognitive performance across domains of working memory, executive function, and global mental status. First-order autoregressive models were used to estimate cognitive change over the 2-year observational period. Follow-up analyses examined associations between egg consumption group, dietary patterns, and nutrient intake. Results: On average, older adults consumed 0.34 eggs per day (SD = 0.36). Although bivariate analyses suggested that moderate egg consumers had the best cognitive performance at baseline assessment, egg consumption was not associated with cognitive performance or cognitive change when adjusting models for covariates known to have a robust association with cognitive health. Conclusions: Our results suggest that egg consumption does not benefit, nor is detrimental to, the cognitive health of older adults. Further studies of whole egg consumption and cognitive performance would benefit from controlled experimental settings, longer follow-up periods to measure cognitive change, and assessment of both community-dwelling and institutionalized older adults.

P4HB recurrent missense mutation causing Cole-Carpenter syndrome.

BACKGROUND: Cole-Carpenter syndrome (CCS) is commonly classified as a rare Osteogenesis Imperfecta (OI) disorder. This was following the description of two unrelated patients with very similar phenotypes who were subsequently shown to have a heterozygous missense mutation in P4HB. OBJECTIVES: Here, we report a 3-year old female patient with severe OI who on exome sequencing was found to carry the same missense mutation in P4HB as reported in the original cohort. We discuss the genetic heterogeneity of CCS and underlying mechanism of P4HB in collagen production. METHODS: We undertook detailed clinical, radiological and molecular phenotyping in addition, to analysis of collagen in cultured fibroblasts and electron microscopic examination in the patient reported here. RESULTS: The clinical phenotype appears consistent in patients reported so far but interestingly, there also appears to be a definitive phenotypic clue (crumpling metadiaphyseal fractures of the long tubular bones with metaphyseal sclerosis which are findings that are uncommon in OI) to the underlying genotype (P4HB variant). DISCUSSION: P4HB (Prolyl 4-hydroxylase, betasubunit) encodes for PDI (Protein Disulfide isomerase) and in cells, in its tetrameric form, catalyses formation of 4-hydroxyproline in collagen. The recurrent variant in P4HB, c.1178A>G, p.Tyr393Cys, sits in the C-terminal reactive centre and is said to interfere with disulphide isomerase function of the C-terminal reactive centre. P4HB catalyses the hydroxylation of proline residues within the X-Pro-Gly repeats in the procollagen helical domain. Given the inter-dependence of extracellular matrix (ECM) components in assembly of a functional matrix, our data suggest that it is the organisation and assembly of the functional ECM that is perturbed rather than the secretion of collagen type I per se. CONCLUSIONS: We provide additional evidence of P4HB as a cause of a specific form of OI-CCS and expand on response to treatment with bisphosphonates in this rare disorder.

Novel PLS3 variants in X-linked osteoporosis: Exploring bone material properties.

BACKGROUND: Idiopathic Juvenile Osteoporosis (IJO) refers to significantly lower than expected bone mass manifesting in childhood with no identifiable aetiology. IJO classically presents in early pubertal period with multiple fractures including metaphyseal and vertebral crush fractures, and low bone-mass. METHODS: Here we describe two patients and provide information on their clinical phenotype, genotype and bone material analysis in one of the patients. RESULTS: Patient 1: 40-year old adult male diagnosed with IJO in childhood who re-presented with a hip fracture as an adult. Genetic analysis identified a pathogenic PLS3 hemizygous variant, c.1765del in exon 16. Patient 2: 15-year old boy with multiple vertebral fractures and bone biopsy findings suggestive of IJO who also has a diagnosis of autism spectrum disorder. Genetic analysis identified a maternally inherited PLS3 pathogenic c.1295T>A variant in exon 12. Analyses of the transiliac bone sample revealed severe reduction of trabecular volume and bone turnover indices and elevated bone matrix mineralisation. DISCUSSION: We propose that genetic testing for PLS3 should be undertaken in patients presenting with a current or previous history of IJO as this has implications for genetic counselling and cascade screening. The extensive evaluation of the transiliac biopsy sample of Patient 2 revealed a novel bone phenotype. CONCLUSION: This report includes a review of IJO and genetic causes of osteoporosis, and suggests that existing cases of IJO should be screened for PLS3. Through analysis of bone material properties in Patient 2, we can conclude that PLS3 does have a role in bone mineralisation.

Food insecurity, comorbidity, and mobility limitations among older U.S. adults: Findings from the Health and Retirement Study and Health Care and Nutrition Study.

Both food insecurity and comorbidity have been identified as precursors to functional limitation in older adults, yet whether food insecurity modifies the progression from chronic disease to disability has not been assessed. We examined 5986 respondents age 50 and older drawn from the 2012-2014 Health and Retirement Study (HRS) and 2013 Health Care and Nutrition Study (HCNS). Mobility limitations reported in 2014 and change in mobility limitations from 2012 to 2014 were regressed on measures of food insecurity, number of chronic conditions, and their interaction terms using Poisson regression. Around 17.3% of the sample was identified as food insecure. In 2012, respondents reported an average of 1.9 (SD = 1.5) chronic conditions and 2.4 mobility limitations (SD = 3.0). In 2014, individuals reported an average of 2.5 (SD = 3.1) mobility limitations. Food insecurity was associated with a greater number of mobility limitations (IRR = 1.20, 95% CI: 1.11-1.29, p < .001) and more rapid increase in mobility limitations over the two-year observational period (IRR = 1.06, 95% CI: 1.00-1.11, p = .047). Food security status also modified the association between comorbidity and both mobility limitation outcomes, with the food secure exhibiting a stronger positive association between chronic conditions and mobility limitations than the food insecure. The food insecure tended to have more mobility limitations than the food secure when few chronic conditions were reported. Our results suggest that food insecurity is associated with prevalence and change in mobility limitations among older adults.

Clinical practice recommendations for native vitamin D therapy in children with chronic kidney disease Stages 2-5 and on dialysis.

Vitamin D deficiency is widely prevalent and often severe in children and adults with chronic kidney disease (CKD). Although native vitamin D {25-hydroxyvitamin D [25(OH)D]} is thought to have pleiotropic effects on many organ systems, its skeletal effects have been most widely studied. The 25(OH)D deficiency is causally linked with rickets and fractures in healthy children and those with CKD, contributing to the CKD-mineral and bone disorder (MBD) complex. There are few studies to provide evidence for vitamin D therapy or guidelines for its use in CKD. A core working group (WG) of the European Society for Paediatric Nephrology (ESPN) CKD-MBD and Dialysis WGs have developed recommendations for the evaluation, treatment and prevention of vitamin D deficiency in children with CKD. We present clinical practice recommendations for the use of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) in children with CKD Stages 2-5 and on dialysis. A parallel document addresses treatment recommendations for active vitamin D analogue therapy. The WG has performed an extensive literature review to include meta-analyses and randomized controlled trials in healthy children as well as children and adults with CKD, and prospective observational studies in children with CKD. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system has been used to develop and grade the recommendations. In the absence of applicable study data, the opinion of experts from the ESPN CKD-MBD and Dialysis WGs is provided, but clearly GRADE-ed as such and must be carefully considered by the treating physician, and adapted to individual patient needs as appropriate.

The Influence of Contamination and Cleaning on the Strength of Modular Head Taper Fixation in Total Hip Arthroplasty.

BACKGROUND: Intraoperative interface contamination of modular head-stem taper junctions of hip implants can lead to poor fixation strength, causing fretting and crevice corrosion or even stem taper fracture. Careful cleaning before assembly should help to reduce these problems. The purpose of this study was to determine the effect of cleaning (with and without drying) contaminated taper interfaces on the taper fixation strength. METHODS: Metal or ceramic heads were impacted onto titanium alloy stem tapers with cleaned or contaminated (fat or saline solution) interfaces. The same procedure was performed after cleaning and drying the contaminated interfaces. Pull-off force was used to determine the influence of contamination and cleaning on the taper strength. RESULTS: Pull-off forces after contamination with fat were significantly lower than those for uncontaminated interfaces for both head materials. Pull-off forces after application of saline solution were not significantly different from those for uncontaminated tapers. However, a large variation in taper strength was observed, pull-off forces for cleaned and dried tapers were similar to those for uncontaminated tapers for both head materials. CONCLUSION: Intraoperative contamination of taper interfaces may be difficult to detect but has a major influence on taper fixation strength. Cleaning of the stem taper with saline solution and drying with gauze directly before assembly allows the taper strength of the pristine components to be achieved. Not drying the taper results in a large variation in pull-off forces, emphasizing that drying is essential for sufficient and reproducible fixation strength.

The Influence of Cement Morphology Parameters on the Strength of the Cement-Bone Interface in Tibial Tray Fixation.

BACKGROUND: The strength of the cement-bone interface in tibial component fixation depends on the morphology of the cement mantle. The purpose of this study was to identify thresholds of cement morphology parameters to maximize fixation strength using a minimum amount of cement. METHODS: Twenty-three cadaveric tibiae were analyzed that had been implanted with tibial trays in previous studies and for which the pull-out strength of the tray had been measured. Specimens were separated into a group failing at the cement-bone interface (INTERFACE) and one failing in the bulk bone (BULK). Maximum pull-out strength corresponds to the ultimate strength of the bulk bone if the cement-bone interface is sufficiently strong. 3D models of the cement mantle in situ were reconstructed from computed tomography scans. The influences of bone mineral density and 6 cement morphology parameters (reflecting cement penetration, bone-cement interface, cement volume) on pull-out strength of the BULK group were determined using multiple regression analysis. The threshold of each parameter for classification of the specimens into either group was determined using receiver operating characteristic analysis. RESULTS: Cement penetration exceeding a mean of 1.1 mm or with a maximum of 5.6 mm exclusively categorized all BULK bone failure specimens. Failure strength of BULK failure specimens increased with bone mineral density (R2 = 0.67, P < .001) but was independent of the cement morphology parameters. CONCLUSION: To maximize fixation strength, a mean cement penetration depth of at least 1.1 mm should be achieved during tibial tray cementing.

Copy number variants in association with type 1 collagenopathy: Atypical osteogenesis imperfecta.

We report a sibling-pair and a 4-year old child from two families with an atypical presentation in Osteogenesis imperfecta (OI). In the sib-pair, the older sibling initially came to medical attention due to a fracture history (Patient 1) and she was shown to have a COL1A2 mutation. In addition, she also had developmental delay, facial dysmorphism, and a history of frequent infections which led to a search for an alternate diagnosis. ArrayCGH revealed a 4.3 Mb duplication on chromosome 19q13.42q13.43, which was confirmed by FISH analysis. On further familial analysis, the younger sibling who had no previous fracture history was also found to have the COL1A2 mutation and tested positive for the 19q13.42q13.43 duplication (Patient 2). The 19q13 duplication appears to be the cause of intellectual disability in these siblings but given that this is a chromosomal duplication, it is still possible that there is an as yet unidentified cause that may account for the combined phenotype in this family. Patient 3 was a 4-year old child presenting with a femoral fracture, blue sclerae, developmental delay, and joint hypermobility. Genetic analyses confirmed a COL1A2 mutation but also revealed an 8.8 Mb deletion of 11q24.2q25, confirmed by G-band chromosome analysis. We discuss the differing phenotypes in patients presenting with atypical OI and stress the need to consider ancillary investigations in individuals presenting with heterogeneous phenotypic symptoms, not entirely attributable to OI.

Diagnostic conundrums in antenatal presentation of a skeletal dysplasia with description of a heterozygous C-propeptide mutation in COL1A1 associated with a severe presentation of osteogenesis imperfecta.

Prompt and accurate diagnosis of skeletal dysplasias can play a crucial role in ensuring appropriate counseling and management (both antenatal and postnatal). When a skeletal dysplasia is detected during the antenatal period, especially early in the pregnancy, it can be associated with a poor prognosis. It is important to make a diagnosis in antenatal presentation of skeletal dysplasias to inform diagnosis, predict prognosis, provide accurate recurrence risks, and options for prenatal genetic testing in future pregnancies. Prenatal ultrasound scanning is a useful tool to detect several skeletal dysplasias and sonographic measurements serve as reliable indicators of lethality. The lethality depends on various factors including gestational age at which features are identified, size of the chest and progression of malformations. Although, it is important to type the skeletal presentation as accurately as possible, this is not always possible in an antenatal presentation and it is important to acknowledge this uncertainty. In the case of a live birth, it is always important to reassess the infant. Osteogenesis imperfecta (OI) is a heterogeneous group of disorders characterized by fragile bones. Here, we report an infant with severe OI born following a twin pregnancy in whom the bone disease is caused by a heterozygous pathogenic mutation, c.4160C >T, p.(Ala1387Val) located in the C-propeptide region of COL1A1. An assumption of lethality antenatally complicated his management in early life. We discuss this patient with particular emphasis on the neonatal presentation of a severe skeletal dysplasia and the lessons that may be learned in such situations. © 2016 Wiley Periodicals, Inc.

Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations.

Osteogenesis Imperfecta (OI) is an inherited bone fragility disorder most commonly associated with autosomal dominant mutations in the type I collagen genes. Autosomal recessive mutations in a number of genes have also been described, including the BMP1 gene that encodes the mammalian Tolloid (mTLD) and its shorter isoform bone morphogenic protein-1 (BMP1). To date, less than 20 individuals with OI have been identified with BMP1 mutations, with skeletal phenotypes ranging from mild to severe and progressively deforming. In the majority of patients, bone fragility was associated with increased bone mineral density (BMD); however, the full range of phenotypes associated with BMP1 remains unclear. Here, we describe three children with mutations in BMP1 associated with a highly variable phenotype: a sibship homozygous for the c.2188delC mutation that affects only the shorter BMP1 isoform and a further patient who is compound heterozygous for a c.1293C>G nonsense mutation and a c.1148G>A missense mutation in the CUB1 domain. These individuals had recurrent fractures from early childhood, are hypermobile and have no evidence of dentinogenesis imperfecta. The homozygous siblings with OI had normal areal BMD by dual energy X-ray absorptiometry whereas the third patient presented with a high bone mass phenotype. Intravenous bisphosphonate therapy was started in all patients, but discontinued in two patients and reduced in another due to concerns about increasing bone stiffness leading to chalk-stick fractures. Given the association of BMP1-related OI with very high bone material density, concerns remain whether anti-resorptive therapy is indicated in this ultra-rare form of OI.© 2016 Wiley Periodicals, Inc.