Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period.

In a randomized, open-label phase 3 study of 61 children aged 1-12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64-88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.

Diagnosis and Management of Thoracic Myelopathy.

Thoracic myelopathy can be a challenging condition to diagnose and treat. Successful outcomes depend on early recondition of the pathology and appropriate surgical referral in cases of progressive neurologic deterioration. The thoracic cord is tethered in kyphosis by the dentate ligaments and contains a tenuous blood supply. These conditions make the thoracic cord particularly susceptible to external compression and ischemic damage. Careful preoperative planning with specific attention to the location and source of thoracic stenosis is critical to successful decompression and complication avoidance. The purpose of this discussion is to outline the common sources of thoracic myelopathy and current recommendations regarding diagnosis and management. The review concludes with an overview of the most up-to-date literature regarding clinical outcomes.

Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression.

Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal ( https://cseminer.stjude.org/ ), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.

Dosing of Convalescent Plasma and Hyperimmune Anti-SARS-CoV-2 Immunoglobulins: A Phase I/II Dose-Finding Study.

BACKGROUND AND OBJECTIVE: During the COVID-19 pandemic, trials on convalescent plasma (ConvP) were performed without preceding dose-finding studies. This study aimed to assess potential protective dosing regimens by constructing a population pharmacokinetic (popPK) model describing anti-SARS-CoV-2 antibody titers following the administration of ConvP or hyperimmune globulins (COVIg). METHODS: Immunocompromised patients, testing negative for anti-SARS-CoV-2 spike antibodies despite vaccination, received a range of anti-SARS-CoV-2 antibodies in the form of COVIg or ConvP infusion. The popPK analysis was performed using NONMEM v7.4. Monte Carlo simulations were performed to assess potential COVIg and ConvP dosing regimens for prevention of COVID-19. RESULTS: Forty-four patients were enrolled, and data from 42 were used for constructing the popPK model. A two-compartment elimination model with mixed residual error best described the Nab-titers after administration. Inter-individual variation was associated to CL (44.3%), V1 (27.3%), and V2 (29.2%). Lean body weight and type of treatment (ConvP/COVIg) were associated with V1 and V2, respectively. Median elimination half-life was 20 days (interquartile range: 17-25 days). Simulations demonstrated that even monthly infusions of 600 mL of the ConvP or COVIg used in this trial would not achieve potentially protective serum antibody titers for > 90% of the time. However, as a result of hybrid immunity and/or repeated vaccination, plasma donors with extremely high antibody titers are now readily available, and a > 90% target attainment should be possible. CONCLUSION: The results of this study may inform future intervention studies on the prophylactic and therapeutic use of antiviral antibodies in the form of ConvP or COVIg. CLINICAL TRIAL REGISTRATION NUMBER: NL9379 (The Netherlands Trial Register).

A Matched-Cohort Analysis of Outcomes in Patients with Hereditary Hemochromatosis After Anterior Cervical Discectomy and Fusion.

BACKGROUND: Hereditary hemochromatosis (HH) is a common autosomal recessive disorder. This disease affects gut iron transport, leading to iron overload, which affects immune function, coagulation mechanics, and bone health. Within the spine, HH contributes to decreased bone mineral density and accelerated intervertebral disc degeneration. The purpose of this study was to discover the differences in the rates of common 90-day postoperative complications and 1-year and 2-year surgical outcomes in patients with and without HH after anterior cervical discectomy and fusion (ACDF). METHODS: Using the PearlDiver database, patients with active diagnoses of HH before ACDF were matched to patients without HH using a 1:5 ratio on the basis of age, sex, body mass index, and comorbidities. Postoperative complications were assessed at 90 days, and 1-year and 2-year surgical outcomes were assessed. All outcomes and complications were analyzed using multivariate logistic regression with significance achieved at P < 0.05. RESULTS: Patients with HH had significantly higher rates of 1-year and 2-year reoperation rates compared with patients without HH (29.19% vs. 3.94% and 37.1% vs. 5.93%, respectively; P < 0.001). The rates of 90-day postoperative complications significantly increased in patients with HH including dysphagia, pneumonia, cerebrovascular accident, deep vein thrombosis, acute kidney injury, urinary tract infection, hyponatremia, surgical site infection, iatrogenic deformity, emergency department visit, and hospital readmission. CONCLUSIONS: Patients with HH undergoing ACDF showed increased 90-day postoperative complications and significantly increased rates of 1-year and 2-year reoperation compared with patients without HH. These findings suggest that iron overload may contribute to adverse outcomes in patients with HH undergoing 1-level and 2-level ACDF.

A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

Southern Hemisphere dominates recent decline in global water availability.

Global land water underpins livelihoods, socioeconomic development, and ecosystems. It remains unclear how water availability has changed in recent decades. Using an ensemble of observations, we quantified global land water availability over the past two decades. We show that the Southern Hemisphere has dominated the declining trend in global water availability from 2001 to 2020. The significant decrease occurs mainly in South America, southwestern Africa, and northwestern Australia. In the Northern Hemisphere, the complex regional increasing and decreasing trends cancel each other, resulting in a negligible hemispheric trend. The variability and trend in water availability in the Southern Hemisphere are largely driven by precipitation associated with climate modes, particularly the El Niño-Southern Oscillation. This study highlights their dominant role in controlling global water availability.

Early Resveratrol Treatment Mitigates Joint Degeneration and Dampens Pain in a Mouse Model of Pseudoachondroplasia (PSACH).

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 signaling, shutting down autophagy and blocking ER clearance, resulting in premature loss of chondrocytes that negatively impacts linear growth and causes early joint degeneration in MT-COMP mice and PSACH. Previously, we have shown that resveratrol treatment from birth to 20 weeks prevents joint degeneration and decreases the pathological processes in articular chondrocytes. Resveratrol's therapeutic mechanism of action in the mutant-COMP pathology was shown to act by primarily stimulating autophagy and reducing inflammation. Importantly, we demonstrated that MT-COMP mice experience pain consistent with PSACH joint pain. Here, we show, in the MT-COMP mouse, that resveratrol treatment must begin within 4 weeks to preserve joint health and reduce pain. Resveratrol treatment started at 6 or 8 weeks (to 20 weeks) was not effective in preventing joint degeneration. Collectively, our findings in MT-COMP mice show that there is a postnatal resveratrol treatment window wherein the inevitable mutant-COMP joint degeneration and pain can be prevented.

Pathologic Findings in Severe Coal Workers' Pneumoconiosis in Contemporary US Coal Miners.

CONTEXT.­: The pathology of coal workers' pneumoconiosis (CWP) and its most severe form-progressive massive fibrosis (PMF)-in US coal miners has changed in recent years. Severe disease is occurring in younger miners and has been linked to an increase in silica dust exposure. OBJECTIVE.­: To update the description of the pathologic features of CWP in contemporary miners compared to historical miners. DESIGN.­: This study is a retrospective expert classification of lung tissue from 85 historical and contemporary coal miners with PMF. Significant pathologic features were scored by using a standardized instrument with consensus achieved for major findings, including newly defined categories of PMF as coal-type, mixed-type, and silica-type. RESULTS.­: Pathologic features associated with silica dust exposure, including silica-type PMF, mineral dust alveolar proteinosis (MDAP), and immature (early stage) silicotic nodules were increased in contemporary miners. Detailed descriptions of the pathology of contemporary CWP with illustrative figures are provided. CONCLUSIONS.­: Silica-related pathologies are more common in contemporary miners. Severe forms of CWP can be detected by subtyping PMF lesions (if present) or by identification of mature and immature silicotic nodules, coal mine dust-related alveolar proteinosis, and severe inflammation in coal miners' lungs. Silica-type PMF cases showed significantly higher levels of MDAP than either mixed- or coal-type PMF (P < .001). High profusion of birefringent silica/silicate particles was observed more frequently in cases with immature (early stage) silicotic nodules (P = .04). Severe inflammation was also significantly increased in contemporary miners (P = .03). Our findings underscore the urgent need to revise current exposure limits and monitoring of respirable crystalline silica in US coal mines.

Historical shift in pathological type of progressive massive fibrosis among coal miners in the USA.

BACKGROUND: Pneumoconiosis among coal miners in the USA has been resurgent over the past two decades, despite modern dust controls and regulatory standards. Previously published studies have suggested that respirable crystalline silica (RCS) is a contributor to this disease resurgence. However, evidence has been primarily indirect, in the form of radiographic features. METHODS: We obtained lung tissue specimens and data from the National Coal Workers' Autopsy Study. We evaluated specimens for the presence of progressive massive fibrosis (PMF) and used histopathological classifications to type these specimens into coal-type, mixed-type and silica-type PMF. Rates of each were compared by birth cohort. Logistic regression was used to assess demographic and mining characteristics associated with silica-type PMF. RESULTS: Of 322 cases found to have PMF, study pathologists characterised 138 (43%) as coal-type, 129 (40%) as mixed-type and 55 (17%) as silica-type PMF. Among earlier birth cohorts, coal-type and mixed-type PMF were more common than silica-type PMF, but their rates declined in later birth cohorts. In contrast, the rate of silica-type PMF did not decline in cases from more recent birth cohorts. More recent year of birth was significantly associated with silica-type PMF. CONCLUSIONS: Our findings demonstrate a shift in PMF types among US coal miners, from a predominance of coal- and mixed-type PMF to a more commonly encountered silica-type PMF. These results are further evidence of the prominent role of RCS in the pathogenesis of pneumoconiosis among contemporary US coal miners.

Consumers decrease variability across space and turnover through time during coral reef succession.

Consumers play an integral role in mediating ecological succession-the change in community composition over time. As consumer populations are facing rapid decline in ecosystems around the world, understanding of their ecological role is becoming increasingly urgent. Increased understanding of how changes in consumer populations may influence community variability across space and turnover through time during succession is particularly important for coral reefs, which are among the most threatened ecosystems globally, and where fishes play vital roles in structuring benthic succession. Here, we examine how consumers influence coral reef succession by deploying 180 paired settlement tiles, caged (to exclude fishes larger than approximately 15 cm) and uncaged, within Palmyra Atoll, a remote marine wildlife refuge with previously documented high fish abundance, and monitored benthic community development one and three years after deployment. We found that excluding large fishes lead to lower alpha diversity and divergent community states across space (i.e.,, high beta diversity among caged tiles), suggesting that benthic fish feeding maintains local diversity but tends to homogenize community composition with dominance by crustose coralline algae. In addition, when fish were experimentally excluded, the developing benthic community exhibited a greater change in species composition over time (i.e., high temporal beta diversity), indicating that fish feeding tends to canalize community successional trajectories. Finally, the caged and uncaged tiles became more similar over time, suggesting that fish feeding plays a more important role during early succession. Our results demonstrate that the loss of large fishes, for example from overfishing, may result in benthic communities that are more variable across space and time. Increased variability could have important implications for ecosystem function and coral reef resilience in the face of escalating global stressors.

Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders.

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.

Burosumab vs Phosphate/Active Vitamin D in Pediatric X-Linked Hypophosphatemia: A Subgroup Analysis by Dose Level.

CONTEXT: In an open-label, randomized, controlled, phase 3 trial in 61 children aged 1 to 12 years with X-linked hypophosphatemia (XLH), burosumab improved rickets vs continuing conventional therapy with active vitamin D and phosphate. OBJECTIVE: We conducted an analysis to determine whether skeletal responses differed when switching to burosumab vs continuing higher or lower doses of conventional therapy. METHODS: Conventional therapy dose groups were defined as higher-dose phosphate [greater than 40 mg/kg] (HPi), lower-dose phosphate [40 mg/kg or less] (LPi), higher-dose alfacalcidol [greater than 60 ng/kg] or calcitriol [greater than 30 ng/kg] (HD), and lower-dose alfacalcidol [60 ng/kg or less] or calcitriol [30 ng/kg or less] (LD). RESULTS: At week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomly assigned to burosumab vs conventional therapy for all prebaseline dose groups: HPi (+1.72 vs +0.67), LPi (+2.14 vs +1.08), HD (+1.90 vs +0.94), LD (+2.11 vs +1.06). At week 64, the RGI-C for rickets was also higher in children randomly assigned to burosumab (+2.06) vs conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase (ALP) also decreased in the burosumab-treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses. CONCLUSION: Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum ALP more than continuing either higher or lower doses of phosphate or active vitamin D.

SOX5: Lamb-Shaffer syndrome-A case series further expanding the phenotypic spectrum.

To delineate further the clinical phenotype of Lamb-Shaffer Syndrome (LSS) 16 unpublished patients with heterozygous variation in SOX5 were identified either through the UK Decipher database or the study team was contacted by clinicians directly. Clinical phenotyping tables were completed for each patient by their responsible clinical geneticist. Photos and clinical features were compared to assess key phenotypes and genotype-phenotype correlation. We report 16 SOX5 variants all of which meet American College of Medical Genetics/Association for Clinical Genomic Science ACMG/ACGS criteria class IV or V. 7/16 have intragenic deletions of SOX5 and 9/16 have single nucleotide variants (including both truncating and missense variants). The cohort includes two sets of monozygotic twins and parental gonadal mosaicism is noted in one family. This cohort of 16 patients is compared with the 71 previously reported cases and corroborates previous phenotypic findings. As expected, the most common findings include global developmental delay with prominent speech delay, mild to moderate intellectual disability, behavioral abnormalities and sometimes subtle characteristic facial features. We expand in more detail on the behavioral phenotype and observe that there is a greater tendency toward lower growth parameters and microcephaly in patients with single nucleotide variants. This cohort provides further evidence of gonadal mosaicism in SOX5 variants; this should be considered when providing genetic counseling for couples with one affected child and an apparently de novo variant.

Leadership Lessons Learned from the Military.

The military provides a valuable resource for the civilian medical education sector to potentially model or adopt strategies used to train emerging leaders. The Department of Defense has a long tradition of cultivating leaders, espousing a culture that emphasizes a value system that promotes selfless service and integrity. In addition to leadership training, and a fostered value system, the military additionally trains leaders to use a defined military decision-making process. This article identifies and shares lessons learned in how the military structures and focuses to accomplish the mission, and develops and invests in military leadership training.

Pathology and Mineralogy of the Pneumoconioses.

Pneumoconioses represent the spectrum of lung diseases caused by inhalation of respirable particulate matter small enough (typically <5-µm diameter) to reach the terminal airways and alveoli. Pneumoconioses primarily occur in occupational settings where workers perform demanding and skilled manual labor including mining, construction, stone fabrication, farming, plumbing, electronics manufacturing, shipyards, and more. Most pneumoconioses develop after decades of exposure, though shorter latencies can occur from more intense particulate matter exposures. In this review, we summarize the industrial exposures, pathologic findings, and mineralogic features of various well-characterized pneumoconioses including silicosis, silicatosis, mixed-dust pneumoconiosis, coal workers' pneumoconiosis, asbestosis, chronic beryllium disease, aluminosis, hard metal pneumoconiosis, and some less severe pneumoconioses. We also review a general framework for the diagnostic work-up of pneumoconioses for pulmonologists including obtaining a detailed occupational and environmental exposure history. Many pneumoconioses are irreversible and develop due to excessive cumulative respirable dust inhalation. Accurate diagnosis permits interventions to minimize ongoing fibrogenic dust exposure. A consistent occupational exposure history coupled with typical chest imaging findings is usually sufficient to make a clinical diagnosis without the need for tissue sampling. Lung biopsy may be required when exposure history, imaging, and testing are inconsistent, there are unusual or new exposures, or there is a need to obtain tissue for another indication such as suspected malignancy. Close collaboration and information-sharing with the pathologist prior to biopsy is of great importance for diagnosis, as many occupational lung diseases are missed due to insufficient communication. The pathologist has a broad range of analytic techniques including bright-field microscopy, polarized light microscopy, and special histologic stains that may confirm the diagnosis. Advanced techniques for particle characterization such as scanning electron microscopy/energy dispersive spectroscopy may be available in some centers.

Carbon fiber lumbopelvic reconstruction following sacral giant cell tumor resection: illustrative case.

BACKGROUND: The use of carbon fiber or polyetheretherketone spine constructs has proven to be a safe and effective alternative to standard metal alloy. The mechanical properties of carbon fiber while unique provide a construct that is comparable in strength to previous titanium-based constructs and have additionally shown greater fatigue resistance. These constructs have been especially useful for the mechanical stabilization of the spine following tumor resection. The subsequent interference seen when imaging a patient with a traditional metallic construct is reduced and allows for improved tumor surveillance after the procedure, and a more accurate delivery of radiotherapy when indicated. OBSERVATIONS: This case report details the treatment of a 25-year-old female diagnosed with a sacral giant cell tumor. The authors discuss the use of a carbon fiber-reinforced polyetheretherketone for lumbopelvic reconstruction. LESSONS: Carbon fiber-reinforced polyetheretherketone with its radiolucency and rigidity is a reliable option for complex spinal reconstruction after tumor resection.

Standardized growth charts for children with osteogenesis imperfecta.

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.

Expanding the phenotypic spectrum of Chromosome 16p13.11 microduplication: A multicentric analysis of 206 patients.

INTRODUCTION: Recurrent chromosome 16p13.11 microduplication has been characterised in the literature as a cause of developmental delay, learning difficulties and behavioural abnormalities. It is a neurosusceptibility locus and has incomplete penetrance and variable expression. Other clinical features, such as cardiac abnormalities have also been reported. The duplicated region contains the MYH11 gene, which encodes the protein myosin-11 and is a component of the myosin heavy chain in smooth muscle. Recent literature has suggested 16p13.11 microduplication as one of the possible risk factors for thoracic aortic aneurysms and dissection (TAAD). Therefore, we studied the detailed phenotype of cases of chromosome 16p13.11 microduplication from seven centres in the United Kingdom (UK) to expand the phenotype, focusing on the cardiac abnormalities. METHODS: All individuals with a chromosome 16p13.11 microduplication seen in Clinical Genetics prior to June 2017 in 6 centres (prior to 2018 in the seventh centre) were identified through the regional genetics laboratory databases. A Microsoft Excel® proforma was created and clinical data was collected retrospectively from clinical genetics databases from the seven genetics services in the UK. The data was collated and analysed collectively. RESULTS: The majority of the individuals presented with (72%) developmental delay and (62%) behavioural abnormalities, in keeping with the published literature. 27% had some dysmorphic features, 14% had visual impairment and 8% had congenital cardiac abnormalities. Echocardiograms were performed in 50% of patients, and only 3.8% patients had aortic dilatation and no one had aortic dissection. 9.7% of patients were found to have a second genetic/chromosomal diagnosis, especially where there were additional phenotypic features. CONCLUSION: 16p13.11 microduplication is a neurosusceptibility locus and is associated with variable expression. It may be helpful to refer children with 16p13.11 microduplication for a cardiac review for congenital cardiac abnormalities and also for ophthalmological assessment. Further prospective studies with cardiac assessments are recommended in this cohort of patients to determine whether ongoing aortic surveillance is indicated. Guidelines about the frequency of surveillance are indicated, especially in individuals with normal cardiac findings. We also highlight the importance of considering a second diagnosis if the phenotype is inconsistent with that reported.