Materiały źródłowe

• #1 Craniosynostosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544366/

  Craniosynostosis, the premature fusion of one or more cranial sutures, presents a spectrum of challenges ranging from altered skull morphology to potential neurodevelopmental impairment. […] Craniosynostosis occurs due to the premature in-utero fusion of one or more cranial sutures. These sutures allow for passage through the birth canal and, later in development, allow the expansion and growth of the underlying brain. When these sutures close prematurely, the head shape becomes altered depending on the sutures involved. […] Almost 20% of all craniosynostoses have a genetic basis, most of which are inherited in an autosomal dominant fashion. […] Some of the risk factors identified to contribute to the development of craniosynostosis include: Environmental factors: Advanced parental age, maternal smoking (15 cigarettes/day), in vitro fertilization, and specific medications, such as valproic acid, nitrofurantoin, and sertraline.

• #1 The clinical manifestations, molecular mechanisms and treatment of craniosynostosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9044212/

  Craniosynostosis can result from mutations, chromosomal abnormalities or adverse environmental effects, and can occur in isolation or in association with numerous syndromes. […] Based on studies from animal models, we present a framework for understanding the pathogenesis of craniosynostosis, with an emphasis on the loss of postnatal suture mesenchymal stem cells as an emerging disease-driving mechanism. […] Overall, there is a strong unmet medical need for effective therapies to treat craniosynostosis and to prevent re-synostosis. […] The premature fusion of cranial sutures restricts brain growth, leading to abnormal brain structure (i.e. microcephaly) and to abnormal cognitive functions in craniosynostosis. […] However, neurocognitive deficits have been largely neglected in basic research on craniosynostosis.

• #2 Craniosynostosis – Wikipedia

  https://en.wikipedia.org/wiki/Craniosynostosis

  Craniosynostosis is a condition in which one or more of the fibrous sutures in a young infant’s skull prematurely fuses by turning into bone (ossification), thereby changing the growth pattern of the skull. Because the skull cannot expand perpendicular to the fused suture, it compensates by growing more in the direction parallel to the closed sutures. Sometimes the resulting growth pattern provides the necessary space for the growing brain, but results in an abnormal head shape and abnormal facial features. In cases in which the compensation does not effectively provide enough space for the growing brain, craniosynostosis results in increased intracranial pressure leading possibly to visual impairment, sleeping impairment, eating difficulties, or an impairment of mental development combined with a significant reduction in IQ.

• #3 Craniosynostosis | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg2010235

  Craniosynostosis, defined as the premature fusion of the cranial sutures, presents many challenges in classification and treatment. At least 20% of cases are caused by specific single gene mutations or chromosome abnormalities. […] Both environmental factors (especially intrauterine fetal head constraint) and genes (single gene mutations, chromosome abnormalities and polygenic background) predispose to craniosynostosis. Most genetically determined craniosynostosis is characterised by autosomal dominant inheritance, but around half of cases are accounted for by new mutations. […] Genes most commonly mutated in craniosynostosis are FGFR2, FGFR3, TWIST1 and EFNB1. […] The genes most frequently mutated were FGFR2 (32% of all genetic cases), FGFR3 (25%), TWIST1 (19%) and EFNB1 (7%). […] The cellular consequences of mutation are complex, including enhancement of proliferation, differentiation and apoptosis of osteoblasts bordering the cranial suture mesenchyme; premature differentiation is probably the most important factor leading to craniosynostosis.

• #4 Molecular Mechanisms Involved in Craniosynostosis | In Vivo

  https://iv.iiarjournals.org/content/37/1/36

  Craniosynostosis refers to the early fusion of one or many cranial sutures, causing craniofacial abnormalities observed in 1:2,500 births worldwide. […] The main gene mutations in craniosynostosis involve FGFR1, FGFR2, FGFR3, TWIST1 and MSX2, which encode key factors influencing cranial bone morphogenesis. […] In recent decades, the progress in mapping human genes has revealed that many of the syndromic craniosynostoses have a genetic origin. For example, mutations in the genes of three of the four fibroblast growth factor receptors (FGFR-1, FGFR-2, FGFR-3) have been associated with the onset of Apert, Crouzon, Jackson-Weiss, Muenke and Pfeiffer syndromes. […] Fibroblast growth factor receptors (FGFRs) are a subset of receptor tyrosine kinases, which are activated when fibroblast growth factor (FGF), heparin sulfate proteoglycans (HSPGs), and FGFR form a trimolecular complex, resulting in receptor dimerization, autophosphorylation, and downstream signaling.

• #5 Craniosynostosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK544366/

  Genetic factors: Around 15% of SSC cases involve causal variants in 29 genes, with mutations being autosomal dominant in 8% of cases. Gene associations vary by suture type and familial patterns. […] If left untreated, craniosynostosis can affect development due to the growth restriction of the brain and increased intracranial pressure.

• #6 Craniosynostosis | ACNR Journal

  https://acnr.co.uk/articles/craniosynostosis/

  FGFR mutation results in gain of function causing abundant activation of the FGF/FGFR signalling pathway, which is then leading to expression of runt-related transcription-factor 2 (RUNX2). The result is early onset differentiation of mesenchyme cells into osteoblasts that deposit bone and eventually lead to premature suture closure. […] Therefore, the authors showed that Gli1+ cells in the suture mesenchyme form the osteogenic stem cells of the craniofacial sutures and that pathogenesis of craniosynostosis may be due to reduced numbers of Gli1+ cells.

• #7 Molecular signaling in pathogenesis of craniosynostosis: the role of fibroblast growth factor and transforming growth factor–β in: Neurosurgical Focus Volume 31 Issue 2 (2011) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/31/2/2011.5.focus1197.xml

  The interplay of signals between dura mater, suture mesenchyme, and brain is essential in determining the fate of cranial sutures and the pathogenesis of premature suture fusion leading to craniosynostosis. At the forefront of research into suture fusion is the role of fibroblast growth factor and transforming growth factor, which have been found to be critical in the cell-signaling cascade involved in aberrant suture fusion. […] Regulation of suture fusion in craniosynostosis is a complex process involving the interplay of multiple signaling pathways, which results in premature and aberrant fusion of cranial sutures. Ongoing research in recent years has shown that most important among these pathways are those involving signaling mediated by fibroblast growth factor (FGF) and transforming growth factor (TGF).

• #8 Molecular Mechanisms Involved in Craniosynostosis | In Vivo

  https://iv.iiarjournals.org/content/37/1/36

  The TWIST1 gene encodes a transcription factor that is a primary regulator of many genes expressed in specific cell types, resulting in a tissue-specific phenotype. […] The genetic and biochemical information regarding suture formation and closure, combined with detailed clinical studies can lead to a pathophysiological hypothesis for craniosynostosis that will focus on processes playing a critical role on tissue boundary formation and the balance between bone cell proliferation and differentiation. […] Molecular studies of Msx2 have revealed that it is necessary for the normal closure of sutures. […] The transforming growth factor (TGF-) is responsible for osteoblastic differentiation and matrix producing potential. […] What is clear, however, is that the bones of the dome of the skull do not develop separately, but in a close and complex interaction with the developing brain and the underlying meninges. […] Future research may take into account the environmental factors (such as smoking or taking certain medication during pregnancy) of craniosynostosis and its clinical variability.

• #9 Molecular signaling in pathogenesis of craniosynostosis: the role of fibroblast growth factor and transforming growth factor–β in: Neurosurgical Focus Volume 31 Issue 2 (2011) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/31/2/2011.5.focus1197.xml

  A model has been proposed for downstream regulation of suture fusion whereby TGF-2 induces suture closure through phosphorylation of Erk1/2. […] The primacy of the TGF-2 isoform in regulating suture fusion has been shown in studies in which treatment with TGF-2 neutralizing antibodies inhibited postoperative resynostosis and enhanced growth of the cranial vault following surgical removal of the coronal suture in a craniosynostotic rabbit model. […] Understanding how growth factors influence suture fusion allows development of new therapies for treatment.

• #10 Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis

  https://www.mdpi.com/2073-4425/12/7/1073

  Taking into account the wide genetic heterogeneity of the disease, Twigg and Wilkie provided an interesting overview of the main pathogenic mechanisms involved in cranial suture biology and development, considering the known disease-associated genes. […] Indeed, several genes can be categorised within a number of partially overlapping pathways, which allow defining the corresponding CS syndromes as pathway disorders, such as Fibroblast Growth Factor Receptor (FGFR) syndromes, RASopathies, Transforming Growth Factor β (TGFβ)-related syndromes, and Hedgehog (HH) signalling-related developmental disorders, among others. […] In this developmental context, HH signalling is essential for mesodermal tissue patterning and differentiation, thereafter, in later stages, it is also needed for cranial suture morphogenesis and intramembranous ossification.

• #11 Signaling mechanisms implicated in cranial sutures pathophysiology: Craniosynostosis · 研飞ivySCI

  https://www.ivysci.com/articles/681739__Signaling_mechanisms_implicated_in_cranial_sutures_pathophysiology_Craniosynostosis

  Normal extension and skull expansion is a synchronized process that prevails along the osteogenic intersections of the cranial sutures. […] Premature fusion of one or more cranial sutures can trigger craniosynostosis, a birth defect characterized by dramatic manifestations in appearance and functional impairment. […] Clinical studies have identified several genes implicated in the pathogenesis of craniosynostosis syndromes with useful insights into the underlying molecular signaling events that determine suture fate. […] In this review, we exploit the intracellular signal transduction pathways implicated in suture pathobiology, in an attempt to identify key signaling molecules for therapeutic targeting.

• #12 The clinical manifestations, molecular mechanisms and treatment of craniosynostosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9044212/

  Numerous mutations can contribute to dysregulation of suture mesenchymal cells and subsequent premature suture fusion. […] Heterozygous loss-of-function mutations in TWIST1 lead to Saethre-Chotzen syndrome in humans. […] Twist1 haploinsufficiency leads to a loss of the osteogenic-non-osteogenic boundary and subsequent ossification of the coronal suture. […] Gain-of-function mutation in RUNX family transcription factor 2 (RUNX2) is also responsible for craniosynostosis. […] The cranial suture harbors an MSC niche that is crucial for craniofacial homeostasis and repair. […] Suture MSC loss is a newly identified disease-driving mechanism. […] This discovery calls for a unique time window for therapeutic intervention. […] Overall, pathophysiological studies will no doubt provide a better understanding of suture development, stem cell biology and tissue regeneration, and disease mechanism-based therapeutic efforts will help bring improved treatment for patients with craniosynostosis.

• #13 Cranial Neural Crest Cells and Their Role in the Pathogenesis of Craniofacial Anomalies and Coronal Craniosynostosis

  https://www.mdpi.com/2221-3759/8/3/18

  Therefore, the role of neural crest cell defects in the pathogenesis of coronal craniosynostosis is of particular interest. […] Cranial neural crest cell defects underpin many craniofacial anomalies. […] Defects in cranial neural crest cells and their cell lineages also contribute to the pathogenesis of craniosynostosis. […] Craniosynostosis is the pediatric condition in which cranial suture tissue is prematurely lost and cranial bone fusion occurs. […] Approximately 80% of individuals with craniosynostosis are non-syndromic, occurring with no additional anomalies or identified genetic abnormality, while approximately 20% of infants develop craniosynostosis as part of an established genetic syndrome. […] Studies utilizing genetic mouse models of syndromic craniosynostosis have shown that the pathogenesis can include pre-ossification development defects, such as insufficient differentiation of migrating cranial neural crest cells into mesenchymal cells, deficient neural crest cell renewal, and inappropriate mesoderm and/or neural crest cell localization to sites of bone and suture formation.

• #14 Cranial Neural Crest Cells and Their Role in the Pathogenesis of Craniofacial Anomalies and Coronal Craniosynostosis

  https://www.mdpi.com/2221-3759/8/3/18

  Craniosynostosis pathogenesis can also include post-ossification defects in cranial bone/suture boundary maintenance, premature cranial progenitor cell lineage commitment and suture osteogenesis, diminished proliferation, and/or apoptosis of suture stem or cranial bone progenitor cells. […] Mechanisms differ, depending upon the genetic abnormality and involved suture.

• #15 Overactive autophagy is a pathological mechanism underlying premature suture ossification in nonsyndromic craniosynostosis | Scientific Reports

  https://www.nature.com/articles/s41598-018-24885-z

  Nonsyndromic craniosynostosis (NSC) is the most common craniosynostosis with the primary defect being one or more fused sutures. […] In contrast to syndromic craniosynostosis, the etiopathogenesis of NSC is largely unknown. […] Here we show that autophagy, a major catabolic process required for the maintenance of bone homeostasis and bone growth, is a pathological change associated with NSC. […] Our findings suggest that autophagy is essential for the osteogenic differentiation of SMCs and that overactive autophagy is a molecular abnormality underlying premature calvarial ossification in NSC. […] Although significant advances have been achieved in understanding the molecular pathogenesis of NSC, much has yet to be revealed. […] Therefore, it is likely that overactive autophagy is a pathological mechanism of premature suture ossification in NSC.

• #16 Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis

  https://www.mdpi.com/2073-4425/12/7/1073

  Indeed, the dysregulation of this pathway results in a wide array of craniofacial developmental defects. […] The primary cilium serves as a signalling hub and a mechanotransduction relay among the forebrain neuroectoderm, the surface ectoderm, the endoderm and cranial neural crest cells. […] The involvement of the primary cilium in osteogenic mechanosensing has been also proposed in non-syndromic sagittal CS. […] This suggests that the pathogenic events leading to premature suture fusion involve the reduced primary cilium expression on osteogenic precursors, which are thus unable to properly sense and respond to osteogenic stimuli from the surrounding environment. […] The primary cilium acts as a cellular antenna, to bridge abnormal mechanical stimuli from the environment to defective developmental paths due to the underlying genetic background.

• #17 The mechanobiology of craniosynostosis in Crouzon syndrome | bioRxiv

  https://www.biorxiv.org/content/10.1101/2021.08.31.458360v2.full

  While our understanding of the pathogenesis of syndromic craniosynostosis has increased significantly -mainly through the use of genetically manipulated mouse models-this has not resulted in any clinically applicable non-surgical treatment alternatives. […] Our hypothesis is that in vivo mechanical loading of calvarial bone can significantly delay premature, pathogenic suture closure in a mouse model for craniosynostosis. […] This study has shown that the application of external mechanical loading on the skull of a syndromic craniosynostosis mouse model can prevent the complete closure of the coronal suture and of the anterior synchondrosis, which in turn reduces the damaging effects on skull shape and size, partially restoring normal skull appearance. […] Overall we identified a significant effect on the size and shape of Crouzon skulls after frontal loading only.

• #18 The mechanobiology of craniosynostosis in Crouzon syndrome | bioRxiv

  https://www.biorxiv.org/content/10.1101/2021.08.31.458360v2.full-text

  Studies showing an association between intrauterine constraint and increased incidence of craniosynostosis indicate a role for external mechanical forces on the formation and/or homeostasis of cranial sutures. […] Our hypothesis is that in vivo mechanical loading of calvarial bone can significantly delay premature, pathogenic suture closure in a mouse model for craniosynostosis. […] This study has shown that the application of external mechanical loading on the skull of a syndromic craniosynostosis mouse model can prevent the complete closure of the coronal suture and of the anterior synchondrosis, which in turn reduces the damaging effects on skull shape and size, partially restoring normal skull appearance. […] While we anticipated the effect to be more pronounced on the loaded side compared to the unloaded side, analysis showed only a small number of samples that presented with an asymmetric presentation of coronal synostosis rescue.

• #19 The biomechanics of chewing and suckling in the infant: A potential mechanism for physiologic metopic suture closure | PLOS Computational Biology

  https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1011227

  In this study, we use patient-specific FEA to examine the role of physiologic forces, specifically muscle forces associated with chewing and suckling, in the closure of the metopic suture in humans. […] Our results show that during physiologic chewing and suckling in humans, the patent metopic suture experiences strain regimes that may correlate with its unique physiologic fate, i.e. early closure. […] Studies of animal models support this hypothesis: during mastication in pigs the interfrontal (i.e. equivalent to human metopic) suture experiences larger strain magnitudes than other cranial vault sutures. […] Our results raise some interesting questions. […] Our conclusions are limited by a set of factors common to finite-element analysis and computational experiments, such as a limited ability to include thin or small structures due to CT scan resolution and a relative inability to fully discern causation from correlation.

• #20 The biomechanics of chewing and suckling in the infant: A potential mechanism for physiologic metopic suture closure | PLOS Computational Biology

  https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1011227

  Craniosynostosis is a condition with neurologic and aesthetic sequelae requiring invasive surgery. Understanding its pathobiology requires familiarity with the processes underlying physiologic suture closure. […] Animal studies have shown that cyclical strain from chewing and suckling influences the closure of cranial vault sutures, especially the metopic, an important locus of craniosynostosis. […] In summary, our work provides human evidence that bone strain patterns from chewing and suckling correlate with the physiologically early closure pattern of the metopic suture, and that deviations from physiologic strain regimes may contribute to clinically observed craniofacial dysmorphism. […] The relative timing of cranial vault suture closure is important for normal calvarial development.

• #21 An Axin2 mutation and perinatal risk factors contribute to sagittal craniosynostosis: evidence from a Chinese female monochorionic diamniotic twin family | Hereditas | Full Text

  https://hereditasjournal.biomedcentral.com/articles/10.1186/s41065-021-00182-0

  Our findings corroborate another well-established gene-environment interaction model of NCS, which substantiates the same environmental insults ultimately determining phenotype. […] Based on the results of monochorionic twins, we demonstrated Axin2 (c.1181GA, p.R394H, rs200899695) mutation led to haploinsufficiency with incomplete penetrance in female, and additional prenatal risk factors (intrauterine growth restriction and breech position) were indispensable to trigger the occurrence of sagittal craniosynostosis in this Chinese female monochorionic diamniotic twin family. These findings provide new evidence for the gene-environment interplay in understanding etiologies of NCS.

• #22 The clinical manifestations, molecular mechanisms and treatment of craniosynostosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9044212/

  Increased ICP on the cerebral cortex is thought to contribute to impaired neurocognition and intelligence. […] Historically, elevated ICP is mainly assumed to result from the premature fusion of the skull, reducing the volume that the brain can occupy and leading to its compression. […] However, patients continue to have chronic elevated ICP even after surgical skull expansion, which suggests that there are other causes of ICP elevation in craniosynostosis. […] Accumulating evidence suggests that ICP elevation might partly result from venous malformations that lead to CSF accumulation and to elevated ICP. […] The loss of boundary integrity between cranial neural crest- and mesoderm-derived cells, abnormal specification of suture cells during embryonic development and premature loss of mesenchymal stem cells in the suture at a later stage may constitute the cellular mechanisms of craniosynostosis.

• #23 Neuro-Ophthalmological Manifestations of Craniosynostosis: Current Per | EB

  https://www.dovepress.com/neuro-ophthalmological-manifestations-of-craniosynostosis-current-pers-peer-reviewed-fulltext-article-EB

  A variety of mechanisms have been proposed to explain the prominence of elevated ICP in craniosynostosis. Classically, elevated ICP was thought to arise from a mismatch between cerebral growth and synostotic cranial volume (termed craniocerebral disproportion or CCD). […] Numerous studies have explored the role of a number of entities including hydrocephalus, respiratory pathologies, and venous hypertension in the development of elevated ICP and optic neuropathy. […] Recently, it has been increasingly posited that respiratory obstruction and venous hypertension may account for the majority of elevated ICP in children with craniosynostosis. […] Abnormal patterns of intracranial venous drainage arising from anomalous or stenotic venous sinuses may also contribute to elevated ICP, particularly in syndromic craniosynostosis.

• #24 Current and Future Perspectives in Craniosynostosis

  https://www.jkns.or.kr/journal/view.php?number=802

  Recent clinical and genetic studies have identified multiple forms of human craniosynostosis, each associated with mutations within various growth factor signaling pathways. […] Knowledge gathered from these investigations may result in the future development of alternative strategies to enhance or perhaps even replace current approaches for the treatment of craniosynostosis. […] Several investigations have evaluated the roles of various growth factors and cytokines in determining the fate of sutures. […] Fibroblast growth factors (FGFs) are particularly important, as mutations in their receptors have been implicated in many craniosynostosis syndromes. […] Mutations in three of the four known FGF receptors have been associated with premature pathologic suture fusions. […] Recent advances in developmental biology and genetics have identified some of the events governing suture fate, highlighting multiple axes of cellular signaling with the potential for clinical manipulation. […] Such knowledge and comprehension may facilitate therapeutic translations, ultimately enhancing or perhaps even replacing contemporary modalities for treating craniosynostosis.

• #25 Signaling Mechanisms Underlying Genetic Pathophysiology of Craniosynostosis

  https://www.ijbs.com/v15p0298.htm

  Therefore, the understanding of genetic pathophysiological framework and its underlying molecular mechanisms are of vital importance for our comprehension of the etiology of craniosynostosis, and the development of effective pharmacological treatment. […] The etiology of craniosynostosis includes both genetic factors and environmental interference. […] The majority of mutations occurred in FGFRs were gain-of-function mutations, which would excessive activate the downstream signals, thus disturb the physiological processes and induce craniosynostosis. […] The complex and interacted signaling pathways make it difficult to manipulate the pathogenic processes via targeted regulate typical molecular. […] In summary, the etiology of craniosynostosis is complicated and further studies are need to clarify the specific roles of each parameter.

• #26 Molecular signaling in pathogenesis of craniosynostosis: the role of fibroblast growth factor and transforming growth factor–β in: Neurosurgical Focus Volume 31 Issue 2 (2011) Journals

  https://thejns.org/focus/view/journals/neurosurg-focus/31/2/2011.5.focus1197.xml

  The exact mechanism by which mutations in FGFR result in aberrant suture fusion is as yet unclear. In vitro studies have shown that under different culture conditions FGF signaling leads to either increased osteoblast differentiation or decreased osteoblast differentiation with subsequent apoptosis. […] Other pathways have been implicated in pathogenesis of abnormal suture fusion downstream of FGFR. Noggin, an antagonist of bone morphogenetic proteins, has been found to be expressed in suture mesenchyme of patent but not fusing cranial sutures, with noggin expression suppressed by FGF2 and syndromic FGFR signaling. […] Transforming growth factor- consists of a superfamily of growth factors, 3 of which have been found to be relevant in cranial suture fusion and craniosynostosis. These growth factors include TGF-1, TGF-2, and TGF-3.

• #27 Craniosynostosis – Wikipedia

  https://en.wikipedia.org/wiki/Craniosynostosis

  Multiple potential causes of premature suture closure have been identified, such as the several genetic mutations that are associated with syndromic craniosynostosis. The cause of nonsyndromic craniosynostosis however, is still greatly unknown. Most likely, a role is played by biomechanical factors, as well as environmental, hormonal and genetical factors. […] Hyperthyroid induced craniosynostosis is a hormone mediated premature closure. It is thought that the bone matures faster due to high levels of thyroid hormone. […] A relation between the mutations in these genes and craniosynostosis is therefore possible. Moloney et al. observed a FGFR3 mutation in as many as 31% of the cases with nonsyndromic coronal synostosis, thus showing that FGFR abnormalities play an important role in nonsyndromic craniosynostosis. Craniosynostosis is therefore likely the result of a disturbance in the fine balance that regulates the multiplication and maturation of the precursor bone cells in the cranial sutures.

• #28 Overactive autophagy is a pathological mechanism underlying premature suture ossification in nonsyndromic craniosynostosis | Scientific Reports

  https://www.nature.com/articles/s41598-018-24885-z

  Our findings indicate that overactive autophagy is a novel pathological mechanism resulting in premature ossification in NSC patients. […] Our work suggests that mutations or epigenetic changes in autophagy-related genes should be explored to understand NSC etiology. […] Overall, our data revealed the existence of autophagy during the osteogenic differentiation of human calvarial SMCs and that overactive autophagy in pathological calvarial SMCs is associated with premature calvarial ossification in NSC.

• #29 Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles | eLife

  https://elifesciences.org/articles/20125

  Collectively, the significant burden of both de novo and rare transmitted mutations, along with significant association results in case-control analysis provide extremely strong evidence that rare damaging SMAD6 alleles impart large effects on risk of non-syndromic midline craniosynostosis. SMAD6 mutations were significantly more frequent in kindreds with any metopic craniosynostosis (10 of 78, 12.8%) compared to those with isolated sagittal craniosynostosis (3 of 113, 2.7%; p=8.1 103 by Fishers exact test, odds ratio 5.3). These results suggest that mutations in SMAD6 confer greater risk for metopic suture closure. We found no significant correlation between the type of mutation (LOF vs. D-mis) or location within the gene of SMAD6 mutation and phenotypic class. […] These findings implicate a two locus model of inheritance in non-syndromic midline craniosynostosis via epistatic interactions of rare heterozygous SMAD6 mutations and common risk alleles near BMP2. There is extremely strong evidence implicating each locus independently, along with highly significant evidence from both analysis of association and linkage that the risk of craniosynostosis is markedly increased in individuals carrying risk alleles at both loci compared to those with only a single risk allele at either locus. Rare damaging variants in SMAD6 alone impart very large effects on disease risk with low penetrance, with inheritance at BMP2 explaining nearly all of the variation in occurrence of craniosynostosis seen among SMAD6 mutation carriers. The results support a threshold effect model, with quantitative increases in SMAD signaling resulting from reduced inhibition of SMAD signaling by SMAD6, owing to haploinsufficiency (strongly supported by a plethora of LOF variants distributed across SMAD6), along with a putative increase in SMAD signaling owing to increased BMP2 expression via the risk SNP rs1884302 leading to accelerated closure of midline sutures.

• #30 An Axin2 mutation and perinatal risk factors contribute to sagittal craniosynostosis: evidence from a Chinese female monochorionic diamniotic twin family | Hereditas | Full Text

  https://hereditasjournal.biomedcentral.com/articles/10.1186/s41065-021-00182-0

  In our study, we found that a heterozygous mutation of Axin2(c.1181GA, p.R394H, rs200899695) exist in Chinese female monochorionic sisters and their father. However, only the proband, suffering a persistent breech presentation and intrauterine growth restriction, was diagnosed with sagittal craniosynostosis. […] We assume that this Axin2 mutation predisposes to sagittal craniosynostosis but extra environmental insults are needed to initiate the disease. […] Prenatal risk factors, including intrauterine constraint, twin gestation, premature delivery, maternal thyroid disorders, gestational diabetes, malnutrition, virus infectious, increase the susceptibility of craniosynostosis in genetically predisposed infants. […] In this study, an Axin2 heterozygous missense mutation (c.1181GA: p.R394H, rs200899695) was identified in peripheral blood samples of subjects I-1, II-1 and II-2, suggesting that the proband inherits the mutation from her father.

• #31 The role of bone centers in the pathogenesis of craniosynostosis

  https://repub.eur.nl/pub/55088/

  This paper describes the role of the displacement of bone centers, i.e., the tubers, in the pathogenesis of craniosynostosis. […] The results showed a significantly more occipital localization of the frontal bone center and a more frontal localization of the parietal bone center at the side of a synostotic coronal suture in the isolated form as well as in Apert syndrome. […] In contrast, this was not the case in Crouzon syndrome, thus showing that these two syndromes have a different pathogenesis. […] For trigonocephaly, a more anteromedial localization of the frontal bone centers was found.

• #32

  https://journals.lww.com/plasreconsurg/abstract/1996/07000/the_role_of_bone_centers_in_the_pathogenesis_of.4.aspx

  This paper describes the role of the displacement of bone centers, i.e., the tubers, in the pathogenesis of craniosynostosis. This displacement was studied in 54 patients with isolated or syndromic craniosynostosis in the form of CT scans as well as in two dry neonate skulls with Apert syndrome. […] The results showed a significantly more occipital localization of the frontal bone center and a more frontal localization of the parietal bone center at the side of a synoslotic coronal suture in the isolated form as well as in Apert syndrome. In contrast, this was not the case in Crouzon syndrome, thus showing that these two syndromes have a different pathogenesis. […] For trigonocephaly, a more anteromedial localization of the frontal bone centers was found.

• #33 Assessment of paediatric head shape and management of craniosynostosis

  https://www1.racgp.org.au/ajgp/2022/january-february/paediatric-head-shape-and-craniosynostosis

  Craniosynostosis is the most common paediatric skull deformity requiring specialist craniofacial intervention and often initially presents as an abnormal head shape. Craniosynostosis is the premature fusion of one or more cranial sutures, which causes skull growth restriction in the plane perpendicular to the involved suture, with compensatory overgrowth parallel planes. This results in distinctive head shapes, which can help determine the involved suture(s) and lead to a diagnosis. […] The cause of craniosynostosis is incompletely understood, but the condition is believed to occur early in gestation. The pathogenesis may involve developmental errors during embryogenesis, intrauterine skull compression, genetic factors and/or teratogens. […] Syndromic craniosynostosis is rarer and accounts for between 9.9% and 18.3% of all craniosynostosis cases. It frequently involves multiple sutures, and children present with a wide range of affected extracranial organ systems.

• #34 Craniosynostosis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/craniosynostosis/symptoms-causes/syc-20354513

  Craniosynostosis (kray-nee-o-sin-os-TOE-sis) is a disorder present at birth in which one or more of the fibrous joints between the bones of your baby’s skull (cranial sutures) close prematurely (fuse), before your baby’s brain is fully formed. Brain growth continues, giving the head a misshapen appearance. […] Craniosynostosis usually involves premature fusion of a single cranial suture, but it can involve more than one of the sutures in a baby’s skull (multiple suture craniosynostosis). In rare cases, craniosynostosis is caused by certain genetic syndromes (syndromic craniosynostosis). […] Often the cause of craniosynostosis is not known, but sometimes it’s related to genetic disorders. […] Nonsyndromic craniosynostosis is the most common type of craniosynostosis. Its cause is unknown, although it’s thought to be a combination of genes and environmental factors. […] Syndromic craniosynostosis is caused by certain genetic syndromes, such as Apert syndrome, Pfeiffer syndrome or Crouzon syndrome, which can affect a baby’s skull development. These syndromes usually also include other physical features and health problems.

• #35 Nonsyndromic craniosynostosis [Neurosurgery Education Wiki]

  https://neurosurgery.education/wiki/doku.php?id=nonsyndromic_craniosynostosis

  Nonsyndromic Craniosynostosis Pathogenesis. […] The study reveals that metopic suture is the most frequent craniosynostosis within nonsyndromic types. […] Nonsyndromic craniosynostosis in about 14.7% of patients was familial.

• #36 Frontiers in Medical Case ReportsMedical Research Online Library-Open Access

  https://www.jmedicalcasereports.org/article_html.php?did=6909&issueno=0

  Craniosynostosis, represents the fusion, ossification and sclerosis of one or more cranial sutures, either of the vault or of the base, which cause different degrees of cerebral compression, intracranial hypertension, cognitive deterioration and visual alterations. […] Craniosynostosis can be non-syndromic or be associated with some syndrome; they are classified as primary and secondary. Primary craniosynostosis occurs in the prenatal period due to developmental disorders. […] Different classifications of craniosynostosis are used depending on the mechanism, the presence of other disorders or the number of fused sutures. For example, if a craniosynostosis develops due to a primary defect of the ossification process, it is called primary craniosynostosis. […] On the other hand, secondary craniosynostosis is the result of known systemic diseases, with hematological and/or metabolic dysfunction, such as rickets and hypothyroidism.

• #37 Pediatric Craniosynostosis: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1281182-overview

  Craniosynostosis is a birth defect in which premature fusion of one or more cranial sutures occurs, often resulting in an abnormal head shape. It may result from a primary defect of ossification (primary craniosynostosis) or, more commonly, from a failure of brain growth (secondary craniosynostosis). […] The primary factor that maintains suture patency is ongoing brain growth and that the expanding dura is very osteogenic. […] When one or more sutures fuse prematurely, skull growth can be restricted perpendicular to the suture. If multiple sutures fuse while the brain is still increasing in size, intracranial pressure can increase. […] More frequent than the primary type, secondary craniosynostosis can result from early fusion of sutures due to primary failure of brain growth. Since brain growth drives the bony plates apart at the sutures, a primary lack of brain growth allows premature fusion of all the sutures. […] Intrauterine space constraints may play a role in the premature fusion of sutures in the fetal skull.

• #38 Pediatric Craniosynostosis: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1175957-overview

  Craniosynostosis is a birth defect in which premature fusion of one or more cranial sutures occurs, often resulting in an abnormal head shape. It may result from a primary defect of ossification (primary craniosynostosis) or, more commonly, from a failure of brain growth (secondary craniosynostosis). […] When one or more sutures fuse prematurely, skull growth can be restricted perpendicular to the suture. If multiple sutures fuse while the brain is still increasing in size, intracranial pressure can increase. […] More frequent than the primary type, secondary craniosynostosis can result from early fusion of sutures due to primary failure of brain growth. Since brain growth drives the bony plates apart at the sutures, a primary lack of brain growth allows premature fusion of all the sutures. […] Intrauterine space constraints may play a role in the premature fusion of sutures in the fetal skull. […] Other secondary causes of craniosynostosis include systemic disorders that affect bone metabolism such as rickets and hypercalcemia.

• #39 Recently-identified genetic forms of craniosynostosis | Great Ormond Street Hospital

  https://www.gosh.nhs.uk/conditions-and-treatments/conditions-we-treat/new-genetic-forms-craniosynostosis/

  Craniosynostosis is a condition where the plates of bone that make up the skull fuse too early, leading to a misshapen head. […] In the past few years, researchers have identified two new genetic mutations that cause craniosynostosis. […] Around 25 per cent of all cases of craniosynostosis are thought to have a genetic basis. In many cases, a mutation (change) of a specific gene leads to a child developing craniosynostosis in the womb. […] Research has identified two new genetic mutations on the genes called ERF and TCF12. Both are thought to play a part in how certain cells in the body including bone cells grow, divide and die. […] It is not yet clear how the mutation is passed on from parent to child. In time, further research will identify this mechanism. […] As these two new genetic mutations are recently identified, it is possible that children with the mutations have previously been diagnosed with other forms of craniosynostosis.

• #40 Altered bone growth dynamics prefigure craniosynostosis in a zebrafish model of Saethre-Chotzen syndrome | eLife

  https://elifesciences.org/articles/37024

  Cranial sutures separate the skull bones and house stem cells for bone growth and repair. In Saethre-Chotzen syndrome, mutations in TCF12 or TWIST1 ablate a specific suture, the coronal. This suture forms at a neural-crest/mesoderm interface in mammals and a mesoderm/mesoderm interface in zebrafish. Despite this difference, we show that combinatorial loss of TCF12 and TWIST1 homologs in zebrafish also results in specific loss of the coronal suture. Sequential bone staining reveals an initial, directional acceleration of bone production in the mutant skull, with subsequent localized stalling of bone growth prefiguring coronal suture loss. Mouse genetics further reveal requirements for Twist1 and Tcf12 in both the frontal and parietal bones for suture patency, and to maintain putative progenitors in the coronal region. These findings reveal conservation of coronal suture formation despite evolutionary shifts in embryonic origins, and suggest that the coronal suture might be especially susceptible to imbalances in progenitor maintenance and osteoblast differentiation.

• #41 Craniosynostosis: Causes, Symptoms, Diagnosis and Treatment | Nationwide Children’s Hospital

  https://www.nationwidechildrens.org/conditions/craniosynostosis

  Craniosynostosis occurs when one or more of the sutures closes early. Early suture closure can cause the skull to grow in an unusual shape. Sometimes, early suture closure can also restrict overall skull growth which may be harmful to the brain inside which is trying to grow. […] Left untreated, craniosynostosis can result in further cranial deformity and potentially an overall restriction in head growth, with secondary increased intracranial pressure. […] In most infants, the cause of craniosynostosis is unknown and the child is otherwise healthy. Sometimes the cause is familial or genetic – a change occurs in one or more genes to result in the condition. […] Treating craniosynostosis usually involves surgery to unlock and bones and reshape the skull. Historically, craniosynostosis has been treated using surgical methods that involve an incision from ear to ear and the removal, reshaping, and reattachment of affected bones. […] Minimally invasive surgery produces the most successful outcomes when performed on children before the age of six months. […] Cranial distraction can be used to create more space inside of the skull. After the bones are unlocked, distractors are implanted across the bone cut.

• #42 Craniosynostosis | Symptoms, Diagnosis & Treatment

  https://www.cincinnatichildrens.org/health/c/craniosynostosis

  Craniosynostosis, or simply synostosis, is the early growing together (or fusion) of two or more bones of the skull. […] Synostosis interferes with normal growth of the brain and skull. […] If a suture the seam between two skull bones is fused, it cannot grow. This causes the bones with open sutures to grow more than usual to allow enough room for brain growth. […] Children who have multiple suture craniosynostosis, have a higher risk of increased brain pressure. They can experience head pain, damage to the eyes, and developmental delays because of this. […] Craniosynostosis can happen on its own without other related abnormalities (non-syndromic). It may stem from an underlying genetic condition (syndromic). The type of craniosynostosis a child has depends on which skull sutures fuse. The childs head shape looks different based on which sutures fuse. […] Craniosynostosis is treated by surgery that opens the fused sutures. This creates space for brain growth.

• #43

  https://journals.lww.com/co-neurology/abstract/1996/04000/craniosynostosis__novel_insights_into_pathogenesis.16.aspx

  The identification in craniosynostosis syndromes of mutations in genes belonging to the fibroblast growth factor signalling pathway and the transcriptional regulator MSX2 provides important clues to the pathogenesis of these disorders. […] Although surgery continues to be the mainstay of treatment, new animal models and improved understanding of cranial suture biology and pathology may lead to complementary therapies.

• #44 A review of the management of single-suture craniosynostosis, past, present, and future in: Journal of Neurosurgery: Pediatrics Volume 24 Issue 6 (2019) Journals

  https://thejns.org/pediatrics/view/journals/j-neurosurg-pediatr/24/6/article-p622.xml

  Craniosynostosis is a condition in which 2 or more of the skull bones fuse prematurely. […] The common mechanism for craniosynostosis involving upregulated osteoblastic activity and downregulated osteoclastic activity leads to overgrowth and fusion of the bone at the cranial sutures during gestation at a point when apoptosis should have occurred. […] It appears that the abnormal closure of the suture is a consequence of a genetic predisposition, although other theories have been espoused. […] The genetic pathophysiology of synostosis is becoming increasingly well understood. […] There may come a time when nonsurgical treatment options will be available that are based on a more comprehensive understanding of the genetic etiopathogenesis of craniosynostosis.

• #45 Assessment of paediatric head shape and management of craniosynostosis

  https://www1.racgp.org.au/ajgp/2022/january-february/paediatric-head-shape-and-craniosynostosis

  While the effect of surgery in reducing raised ICP risk is unknown, it is generally accepted that surgery reduces the overall risk. Despite this, a minority of patients may later develop raised ICP, which can, if untreated, lead to optic nerve atrophy, failure to thrive and associations with neurodevelopmental delay. […] There is a wide range of surgical approaches for craniosynostosis, with no consensus on an optimal method. Surgical approaches generally can be divided into early, more limited procedures and later, more extensive remodelling procedures. […] Optimal treatment time and the ideal operative window is debatable. Surgery before 12 months of age can reduce potential impacts on crucial brain development, raised ICP risk and skull base deformities. Bone is also easily remodelled, and infants are able to ossify craniectomy defects that occur with surgery.

• #46 Assessment of paediatric head shape and management of craniosynostosis

  https://www1.racgp.org.au/ajgp/2022/january-february/paediatric-head-shape-and-craniosynostosis

  Exciting future advances such as machine-learning applications have the potential to be able to aid in the diagnosis of craniosynostosis, especially when combined with three-dimensional photography. […] The accuracy of three-dimensional photogrammetry lessens with age as children develop more hair and thicker skin. There is also no visualisation of cranial vault and brain, impairing its usefulness in assessing intracranial pathology.

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