Premature Fusion Of Cranial Sutures Research Articles

Whole genome sequencing identifies associations for nonsyndromic sagittal craniosynostosis with the intergenic region of BMP2 and noncoding RNA gene LINC01428

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

Yoda1 opens the lymphatic path for craniosynostosis therapy.

The rediscovery of meningeal lymphatic vessels (MLVs) has sparked research interest in their function in numerous neurological pathologies. Craniosynostosis (CS) is caused by a premature fusion of cranial sutures during development. In this issue of the JCI, Matrongolo and colleagues show that Twist1-haploinsufficient mice that develop CS exhibit raised intracranial pressure, diminished cerebrospinal fluid (CSF) outflow, and impaired paravascular CSF-brain flow; all features that were associated with MLV defects and exacerbated pathology in mouse models of Alzheimer's disease. Activation of the mechanosensor Piezo1 with Yoda1 restored MLV function and CSF perfusion in CS models and in aged mice, opening an avenue for further development of therapeutics.

Insights into craniosynostosis management in low- and middle-income countries: A narrative review of outcomes, shortcomings and paediatric neurosurgery capacity.

Craniosynostosis, marked by premature cranial suture fusion, necessitates prompt intervention to avert developmental, neurological, and aesthetic issues. While high-income countries have advanced in managing this condition, low- and middle-income countries grapple with substantial healthcare access disparities. This narrative review explores current craniosynostosis management in low- and middle-income countries. The review focused on studies published between 2008 and 2023. The focus was neurosurgical outcomes, and the search utilised databases like PubMed, EMBASE, Google Scholar, the Cochrane Library and Scopus, incorporating specific keywords and phrases. An in-depth analysis of 21 included studies reveals noteworthy positive outcomes, including low mortality, successful corrections and sustained efficacy. These advancements stem from enhanced pre-operative strategies, surgical techniques and postoperative care. Nonetheless, challenges persist, encompassing complications, mortality, reoperations, and treatment disparities, particularly in low- and middle-income countries constrained by financial and expertise limitations. The enhancement of clinical practice and the formulation of effective policies in the future entail several key strategies. These include the reinforcement of specialised healthcare infrastructure and diagnostic capabilities, the ongoing training and retention of neurosurgeons, the improvement of funding mechanisms, and the promotion of equitable access. Additionally, a crucial focus is placed on fortifying paediatric neurosurgical care in low- and middle-income countries. The recommendations underscore the importance of collaborative initiatives, the development of specialised healthcare infrastructure, and the implementation of strategic policies to not only advance pediatric neurosurgical care but also to address existing gaps in management.

Ribosome biogenesis controls cranial suture MSC fate via the complement pathway in mouse and human iPSC models

Disruption of global ribosome biogenesis selectively affects craniofacial tissues with unclear mechanisms. Craniosynostosis is a congenital craniofacial disorder characterized by premature fusion of cranial suture(s) with loss of suture mesenchymal stem cells (MSCs). Here we focused on ribosomopathy disease gene Snord118, which encodes a small nucleolar RNA (snoRNA), to genetically disturb ribosome biogenesis in suture MSCs using mouse and human induced pluripotent stem cell (iPSC) models. Snord118 depletion exhibited p53 activation, increased cell death, reduced proliferation, and premature osteogenic differentiation of MSCs, leading to suture growth and craniosynostosis defects. Mechanistically, Snord118 deficiency causes translational dysregulation of ribosomal proteins and downregulation of complement pathway genes. Further complement pathway disruption by knockout of complement C3a receptor 1 (C3ar1) exacerbated MSC and suture defects in mutant mice, whereas activating the complement pathway rescued MSC cell fate and suture growth defects. Thus, ribosome biogenesis controls MSC fate via the complement pathway to prevent craniosynostosis.

Meningeal lymphatics stem cognitive decline in craniosynostosis.

Craniosynostosis is a congenital craniofacial disorder where premature fusion of cranial sutures causes elevated intracranial pressure and neurological deficits. In this issue of Cell Stem Cell, Ma etal. demonstrate that replenishing skull progenitor cells alleviates intracranial pressure elevations in craniosynostosis by restoring the meningeal lymphatic system, improving neurocognitive function.

Evaluating Tranexamic Acid Administration in Cranial Vault Reconstruction: The Experience of an Academic Center in the Deep South

Background: In infants with craniosynostosis, cranial vault reconstruction is performed to prevent sequela of premature fusion of cranial sutures. Open correction puts patients at risk for complications of major blood loss. We evaluated the impact of tranexamic acid (TXA) in children undergoing open surgical repair of a variety of types of craniosynostosis. Methods: A retrospective review of 102 infants who underwent open cranial vault reconstruction between January 2015 and December 2020 at a tertiary referral hospital was performed. The patients were stratified into TXA or non-TXA based on usage. Outcome measures included volume of blood transfused, perioperative blood loss and any adverse effects were noted. Results: In this cohort 42% of patients were treated with TXA. There was no significant difference between the patient demographics of TXA and non-TXA cohorts with the majority classified as Sagittal Craniosynostosis ( P = .1062), an average weight of 8.89 ± 1.37 kg, and age of 9.02 ± 2.02 months at time of surgery. The non-TXA cohort had longer length of hospital stay ( P = .04). The TXA cohort had an average 100 ml decrease in surgical drain output over the course of their hospital stay ( P = .02). Overall surgical complication was 14% ( P = .18) and clinical outcomes were not significantly different between the cohorts. Conclusions: The receipt of TXA in the interoperative period in patients with craniosynostosis undergoing cranial vault remodeling was associated with a decreased surgical drain output and length of stay.

FRI285 Evidence For ZIC1 As A Novel Gene For Isolated Hypogonadotropic Hypogonadism With Phenotypic Pleiotropic Intersection With Cerebellar Malformation

Abstract Disclosure: J. Cassin: None. D.L. Keefe: None. K.E. Sung: None. C.C. Bojo: None. G. Santiago: None. L. Plummer: None. K.B. Salnikov: None. S.B. Seminara: None. R. Balasubramania: None. P.L. Mellon: None. Isolated Hypogonadotropic Hypogonadism (IHH) is a condition marked by absent pubertal development and low sex steroids in the setting of low/normal gonadotropins. Mutations in known IHH genes only explain <50% of the genetic etiology suggesting significant missing heritability in IHH. To explore this missing IHH heritability, we examined whole exome sequencing data from approximately 1400 IHH probands for rare genetic variants in novel genes that are enriched in IHH patients. We identified four IHH probands with rare, novel heterozygous variants in ZIC1 (p.H134Rfs*21, p.Y287X, p.E299K, p.S413Y), a gene encoding C2H2-type zinc finger protein (rare variant enrichment p <0.0001 for both truncating and missense alleles). Prior literature review show that heterozygous deletions affecting the ZIC1 gene have been linked to Dandy Walker malformation [DWM], a cerebellar malformation, while gain-of-function ZIC1 single nucleotide variants have been linked to coronal craniosynostosis (premature cranial suture fusion). Notably, two IHH subjects with novel ZIC1 variants in our cohort exhibited posterior fossa abnormalities (DWM [p.H134Rfs*21] and ventriculomegaly [E299K]) but none had any cranial suture defects. Given the above genetic enrichment, phenotypic overlap between DWM and IHH, and ZIC1’s known high expression in the hypothalamus, we explored whether ZIC1 regulates the expression of hypothalamic releasing factors. We determined that ZIC1 overexpression increases GNRH1 luciferase expression in the immortalized GnRH cell line, GT1-7. We next explored whether the rare ZIC1 variants identified in the four IHH probands would affect this phenotype. We discovered that three of the four ZIC1 variants significantly reduced GNRH1-luciferase expression. Of those, one truncating mutation, p.H134Rfs*21, resulted in lower ZIC1 protein content in the cell and failure to localize to the nucleus, suggesting a hypomorphic mechanism of action. These findings implicate ZIC1 variants as putatively causal for IHH. Further studies will define the precise ZIC1 transcriptional targets that relate to ZIC1’s pleotropic effects on GnRH transcription, neuronal function, cerebellar development, and cranial suture fusion. Presentation: Friday, June 16, 2023

Concurrent impact of de novo mutations on cranial and cortical development in nonsyndromic craniosynostosis.

Nonsyndromic craniosynostosis (nsCS), characterized by premature cranial suture fusion, is considered a primary skull disorder in which impact on neurodevelopment, if present, results from the mechanical hindrance of brain growth. Despite surgical repair of the cranial defect, neurocognitive deficits persist in nearly half of affected children. Therefore, the authors performed a functional genomics analysis of nsCS to determine when, where, and in what cell types nsCS-associated genes converge during development. The authors integrated whole-exome sequencing data from 291 nsCS proband-parent trios with 29,803 single-cell transcriptomes of the prenatal and postnatal neurocranial complex to inform when, where, and in what cell types nsCS-mutated genes might exert their pathophysiological effects. The authors found that nsCS-mutated genes converged in cranial osteoprogenitors and pial fibroblasts and their transcriptional networks that regulate both skull ossification and cerebral neurogenesis. Nonsyndromic CS-mutated genes also converged in inhibitory neurons and gene coexpression modules that overlapped with autism and other developmental disorders. Ligand-receptor cell-cell communication analysis uncovered crosstalk between suture osteoblasts and neurons via the nsCS-associated BMP, FGF, and noncanonical WNT signaling pathways. These data implicate a concurrent impact of nsCS-associated de novo mutations on cranial morphogenesis and cortical development via cell- and non-cell-autonomous mechanisms in a developmental nexus of fetal osteoblasts, pial fibroblasts, and neurons. These results suggest that neurodevelopmental outcomes in nsCS patients may be driven more by mutational status than surgical technique.

Delineation of craniosynostosis in Saudi Arabia

Craniosynostosis (CS) is defined as an early premature fusion of cranial sutures resulted to congenital skull deformity and affecting approximately 1 in 2500 children.

Application and development of orthognathic surgery in treatment of syndromic craniosynostosis

To summarize the application and recent development of orthognathic surgery in treating syndromic craniosynostosis. The related literature at home and abroad in recent years was extensively reviewed, and the indications, routine procedures, and protocols of orthognathic surgery in the treatment of syndromic craniosynostosis were summarized and analyzed. Craniosynostosis is a common congenital craniofacial malformation. Syndromic craniosynostosis usually involves premature fusion of multiple cranial sutures and is associated with other deformities. Orthognathic surgery is the necessary and effective means to improve the midfacial hypoplasia and malocclusion. Le Fort I osteotomy combined with sagittal split ramus osteotomy are the common surgical options. Orthognathic surgery should combine with craniofacial surgery and neurosurgery, and a comprehensive long-term evaluation should be conducted to determine the best treatment plan. Orthognathic surgery plays an important role in the comprehensive diagnosis and treatment of syndromic craniosynostosis. The development of digital technology will further promote the application and development of orthognathic surgery in the treatment of syndromic craniosynostosis.

Craniosynostosis in Patients With X-Linked Hypophosphatemia: A Review.

Craniosynostosis is a rare condition of skull development, manifesting during fetal and early infant development, and is usually congenital. Craniosynostosis secondary to metabolic disorders, such as X-linked hypophosphatemia (XLH), is less common and is typically diagnosed later than congenital craniosynostosis. XLH is a rare, progressive, and lifelong hereditary phosphate-wasting disorder characterized by loss of function of the phosphate-regulating endopeptidase homologue, X-linked gene, which is associated with premature fusion of cranial sutures due to abnormal phosphate metabolism (hypophosphatemia) and altered bone mineralization or elevated levels of fibroblast growth factor 23. This targeted literature review of 38 articles seeks to provide an overview of craniosynostosis in individuals with XLH. The objectives of this review are to increase awareness of the prevalence, presentation, and diagnosis of craniosynostosis in XLH; examine the spectrum of craniosynostosis severity in XLH; discuss the management of craniosynostosis in those with XLH; recognize the complications for patients with XLH; and identify what is known about the burden of craniosynostosis for individuals with XLH. The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes. Consequently, craniosynostosis in patients with XLH is an underreported and potentially underrecognized condition. There have been no studies investigating the effects of craniosynostosis on the quality of life of people with XLH. Despite a growing awareness among researchers and experienced clinicians, there are still improvements to be made in general awareness and timely diagnosis of craniosynostosis in XLH. The XLH community would benefit from further study into the prevalence of craniosynostosis, the effect of XLH medical therapy on the development of craniosynostosis, and the effects of craniosynostosis on quality of life. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Augmentation of BMP Signaling in Cranial Neural Crest Cells Leads to Premature Cranial Sutures Fusion through Endochondral Ossification in Mice.

Craniosynostosis is a congenital anomaly characterized by the premature fusion of cranial sutures. Sutures are a critical connective tissue that regulates bone growth; their aberrant fusion results in abnormal shapes of the head and face. The molecular and cellular mechanisms have been investigated for a long time, but knowledge gaps remain between genetic mutations and mechanisms of pathogenesis for craniosynostosis. We previously demonstrated that the augmentation of bone morphogenetic protein (BMP) signaling through constitutively active BMP type 1A receptor (caBmpr1a) in neural crest cells (NCCs) caused the development of premature fusion of the anterior frontal suture, leading to craniosynostosis in mice. In this study, we demonstrated that ectopic cartilage forms in sutures prior to premature fusion in caBmpr1a mice. The ectopic cartilage is subsequently replaced by bone nodules leading to premature fusion with similar but unique fusion patterns between two neural crest-specific transgenic Cre mouse lines, P0-Cre and Wnt1-Cre mice, which coincides with patterns of premature fusion in each line. Histologic and molecular analyses suggest that endochondral ossification in the affected sutures. Both in vitro and in vivo observations suggest a greater chondrogenic capacity and reduced osteogenic capability of neural crest progenitor cells in mutant lines. These results suggest that the augmentation of BMP signaling alters the cell fate of cranial NCCs toward a chondrogenic lineage to prompt endochondral ossification to prematurely fuse cranial sutures. By comparing P0-Cre;caBmpr1a and Wnt1-Cre;caBmpr1a mice at the stage of neural crest formation, we found more cell death of cranial NCCs in P0-Cre;caBmpr1a than Wnt1-Cre;caBmpr1a mice at the developing facial primordia. These findings may provide a platform for understanding why mutations of broadly expressed genes result in the premature fusion of limited sutures. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Spectrum of ocular manifestations in apert syndrome

Apert syndrome is a congenital type 1 acrocephalosyndactyly characterized by craniosynostosis, dysmorphic facial features and symmetrical syndactyly. There is premature fusion of cranial sutures which leads to restriction of intracranial and orbital space expansion giving characteristic dysmorphic facial appearance. We are reporting two cases of Apert syndrome of different age groups from ophthalmic point of view, and with different sets of ocular manifestation. Of the two cases, the one who presented early had a better visual prognosis. Apert Syndrome has a social stigma and the patients often suffers social and psychological disturbances. Patient counselling, timely management by multidisciplinary approach and regular follow ups are an important aspect which can offer a better quality of life.

Augmentation of bone morphogenetic protein signaling in cranial neural crest cells in mice deforms skull base due to premature fusion of intersphenoidal synchondrosis.

Craniofacial anomalies (CFAs) are a diverse group of disorders affecting the shapes of the face and the head. Malformation of the cranial base in humans leads CFAs, such as midfacial hypoplasia and craniosynostosis. These patients have significant burdens associated with breathing, speaking, and chewing. Invasive surgical intervention is the current primary option to correct these structural deficiencies. Understanding molecular cellular mechanism for craniofacial development would provide novel therapeutic options for CFAs. In this study, we found that enhanced bone morphogenetic protein (BMP) signaling in cranial neural crest cells (NCCs) (P0-Cre;caBmpr1a mice) causes premature fusion of intersphenoid synchondrosis (ISS) resulting in leading to short snouts and hypertelorism. Histological analyses revealed reduction of proliferation and higher cell death in ISS at postnatal day 3. We demonstrated to prevent the premature fusion of ISS in P0-Cre;caBmpr1a mice by injecting a p53 inhibitor Pifithrin-α to the pregnant mother from E15.5 to E18.5, resulting in rescue from short snouts and hypertelorism. We further demonstrated to prevent premature fusion of cranial sutures in P0-Cre;caBmpr1a mice by injecting Pifithrin-α through E8.5 to E18.5. These results suggested that enhanced BMP-p53-induced cell death in cranial NCCs causes premature fusion of ISS and sutures in time-dependent manner.

Maternal hyperthyroidism increases the synthesis activity and the osteogenic markers expression of calvarial osteoblasts from offspring in a murine model

To evaluate the characteristics and synthesis activity of osteoblasts extracted from the calvaria of offspring of rats exposed to maternal hyperthyroidism. Twelve adult Wistar rats were divided into two groups, one control and one treated with daily administration of L-thyroxine by an orogastric tube (50 µg/animal/day) during pregnancy. Three days after delivery and confirmation of the mothers’ hyperthyroidism, the offspring were euthanized for the extraction of osteoblasts from the calvaria. At 7, 14, and 21 days, proliferation activity was assessed using MTT assay, while alkaline phosphatase (ALP) activity was assessed by the BCIP/NBT method. At 21 days, the total area of the mineralized matrix stained by von Kossa was evaluated by morphometry. The expression of gene transcripts for Runx2, Bmp2, Fgfr1, collagen type 1 (Col1), osteocalcin (Oc), and osteopontin (Op) were evaluated by real-time RT-PCR. Means were compared using the Student’s t-test. FA activity was significantly higher at 14 and 21 days in cultures of osteoblasts extracted from offspring exposed to maternal hyperthyroidism, while MTT conversion was significantly lower at 21 days in this group. Osteoblast cultures of neonates exposed to maternal hyperthyroidism also showed a larger total area of mineralized matrix and greater expression of gene transcripts for Oc and Op. Maternal hyperthyroidism increases the activity of matrix synthesis, alkaline phosphatase activity, and expression of gene transcripts for osteocalcin and osteopontin in the osteoblasts, extracted from the calvaria of the offspring, which may be one of the mechanisms of premature fusion of cranial sutures.

A Retrospective Study: ABO and Rh Phenotype Blood Group Distribution Amongst Different Types of Craniosynostosis Patients

Background: Craniosynostosis refers to the premature fusion of cranial sutures. Premature closure can impair brain development and cognitive problems. Only available treatment of craniosynostosis is through surgical intervention which is associated with excessive blood loss. Objectives: In this study, we investigate the prevalence of each ABO/Rh blood group amongst patients with different types of craniosynostosis. Methods: We included 163 patients, under craniosynostosis treatment, in Imam Hossein children’s hospital at Isfahan, Iran. A retrospective analysis was performed and the frequency of blood groups as well as types of craniosynostosis were reported. Moreover, the connection between ABO/Rh blood groups and the types of craniosynostosis was examined by chi-square test. Results: Of 163 cases reviewed; The majority of participants had blood group A positive (32.5%), followed by O positive (31.3%). The rest of the blood groups were reported in order: B positive (22.1%), B negative (4.9%), AB positive (4.3%), O negative (2.5%), A negative (1.8%), AB negative (0.6%). Also, the most common type of craniosynostosis was metopic (27%) and the other types were pansynostosis (23.9%), sagittal (21.5%), coronal (16.6%), multisuture (10.4%) and lambdoid (0.6%) respectively. Due to connection between ABO/Rh blood groups and the types of craniosynostosis, no significant relationship was observed. Conclusion: Based on the results of the present study, it was found that the frequency of ABO blood groups in children with craniosynostosis can be different from the population of the same area. Also, the ratio of different types of craniosynostosis was different from previous data.

Mechanical loading of cranial joints minimizes the craniofacial phenotype in Crouzon syndrome

Children with syndromic forms of craniosynostosis undergo a plethora of surgical interventions to resolve the clinical features caused by the premature fusion of cranial sutures. While surgical correction is reliable, the need for repeated rounds of invasive treatment puts a heavy burden on the child and their family. This study explores a non-surgical alternative using mechanical loading of the cranial joints to prevent or delay craniofacial phenotypes associated with Crouzon syndrome. We treated Crouzon syndrome mice before the onset of craniosynostosis by cyclical mechanical loading of cranial joints using a custom designed set-up. Cranial loading applied to the frontal bone partially restores normal skull morphology, significantly reducing the typical brachycephalic appearance. This is underpinned by the delayed closure of the coronal suture and of the intersphenoidal synchondrosis. This study provides a novel treatment alternative for syndromic craniosynostosis which has the potential to be an important step towards replacing, reducing or refining the surgical treatment of all craniosynostosis patients.

Retrospective Investigation of Cranial Volume and Cephalic Index in Patients with Nonsyndromic Sagittal Synostosis Operated by Total Vault Remodeling

Background: Premature fusion of cranial sutures affects skull development and leads to head deformity. Intracranial pressure increase and brain growth restriction can occur in untreated craniosynostosis. Operative treatment aims to achieve an immediate and long-lasting correction of skull shape that is close to the average and to prevent or release possible increased intracranial pressure by increasing the intracranial volume (ICV) or normalizing the ICV if it is already below the standards. This study was designed to evaluate the effect of a total calvarial reconstruction on skull development in patients with nonsyndromic sagittal synostosis. Material and Methods: The study population included 19 male and 5 female patients with isolated nonsyndromic sagittal suture synostosis. During the operation, temporarily fixed prebent metal plates provided an intraoperative reference for the desired cranial expansion gain of height and shortening. Preoperative and postoperative ICVs and cephalic indices were measured on computed tomography datasets using the software program ImageJ and were compared with one another and with normative data. Results: The male population presented with a preoperative mean ICV of 863.3 cm³. A postoperative mean ICV increase of 243.5 cm³ (p < 0.001) and a further ICV enlargement (p < 0.001) was measured. The mean CI changed from 71.0% preoperatively to 75.4% postoperatively (p = 0.002) and decreased insignificantly in the follow-up (p = 0.546). The female population had a preoperative mean ICV of 804.9 cm³. Postoperatively, the mean ICV increased by 211.1 cm³ (p = 0.043) and also increased in the follow-up (p = 0.043). Their mean CI values increased from 66.5% preoperatively to 72.8% (p = 0.043) postoperatively and decreased insignificantly in the follow-up (p = 0.345). Conclusion: This method of total vault remodeling provides reliable ICV increase and improvement in length and width of skull proportions beyond the immediate postoperative period together with an ICV increase.

Posterior vault distraction osteogenesis in Apert syndrome

Apert syndrome is an uncommon autosomal dominant condition with a varied clinical spectrum which includes premature cranial and facial suture fusion and complex upper and lower limb syndactilies. In this manuscript, we share our posterior vault distraction osteogenesis (PVDO) experience regarding Apert syndrome patients so that a larger patient population may benefit. In addition, we aimed to determine an onset of elevated intracranial pressure in the long term follow up.&#x0D; A retrospective study was performed on consecutive patients with syndromic craniosynostosis who were diagnosed with Apert syndrome, underwent PVDO between 2012 and 2019, and received at least 2 years of follow-up care. Demographic data, diagnosis, surgery related data, and outcome data (perioperative and mid-term complications and need for additional surgery), were verified by means of medical records, clinical photographs, radiographic images, and interviews with all included patients and/or their parents.&#x0D; The present study included 14 patients who were diagnosed respectively with Apert syndrome (n = 14). The average posterior advancement distance achieved was 19.37 ± 3.0 mm. Two patients included in this study presented major complications, but neither experienced permanent sequelae or a lethal course. Two Apert patients presented cerebral spinal fluid (CSF) leakage (Clavien–Dindo type II). One patient presented a onset of elevated intracranial pressure at 4 years of follow up.&#x0D; PVDO is an effective procedure at alleviating intracranial pressure and present a low complication rate.&#x0D; &#x0D; &#x0D;

Thyroxine Metabolism in an Avian Model of Induced Thyrotoxicosis

Craniosynostosis (CS) is the premature fusion of cranial sutures which leads to abnormal cranial structure and causes abnormal neurocognition and behavior. Maternal thyroid disorders are associated with incidence of CS in infants. However, the mechanism of TH-induced CS is still obscure. Thyroxine (T4) metabolism is regulated by the expression of deiodinases. Type I and type II deiodinases (DIO1 and DIO2) remove iodine from T4 producing active triiodothyronine (T3). Deiodinase III (DIO3) inactivates both T4 and T3. Our lab is establishing a model to study the effects of thyrotoxicosis induced CS using fertilized chicken eggs. Eggs were injected into the air cell with either saline or 25 ng T4 on days E11 and E15 of embryonic development. Heart rates were measured daily from EKG recordings and on E19, tissue samples were collected for qRT-PCR analysis. The main objective was to validate the induced state of thyrotoxicosis by evaluating negative feedback mechanisms of thyroid hormone regulation following exposure by measuring expression of DIO1 and DIO3 in embryonic livers. Since livers are the main site of metabolism, we hypothesize that levels of DIO3 will increase following thyroxine exposure. Results demonstrated a significant upregulation of DIO3 2 days after exposure and a significant downregulation 4 days following exposure. No significant differences were observed in DIO1 on any of the days after exposure. These results, along with correlating heart rates, support our model by of induced thyrotoxicosis by demonstrating the metabolism of thyroxine in response to our treatment regimen.&#x0D; &#x0D; &#x0D; Acknowledgment of NASA West Virginia Space Grant Consortium (Grant #80NSSC20M0055) and the Genomics Core Facility and WV-INBRE (NIH grant P20GM103434).&#x0D;