RARE DISEASE
Saethre-Chotzen syndrome
Saethre-Chotzen syndrome
Saethre-Chotzen syndrome
Synonyms: ACS3, Acrocephalosyndactyly type 3, SCS
Synonyms: ACS3, Acrocephalosyndactyly type 3, SCS
Synonyms: ACS3, Acrocephalosyndactyly type 3, SCS
Drug discovery
68
papers
On emerging therapies
Overview
Saethre-Chotzen syndrome (SCS) is an autosomal dominant disorder caused by TWIST1 gene mutations, characterized by coronal craniosynostosis, facial asymmetry, ptosis, syndactyly, and varied skeletal anomalies. Clinical features include hypertelorism, low-set hairline, and potential cleft palate. While most patients have normal intelligence, 10-25% exhibit developmental delays, particularly with chromosomal deletions [1][2][6][18]. Management requires lifelong multidisciplinary care to address cranial, ocular, dental, and psychosocial needs [1][2][8].
Therapies
Early cranial vault remodeling (6–12 months) to relieve intracranial pressure [4][7][11][15].
Midface advancement or orthognathic surgery for airway/occlusion issues [3][11][17].
Adjuvant care: Ptosis repair, syndactyly correction, speech/orthodontic therapy, and emerging epigenetic therapies (e.g., KDM6A/B inhibitors in preclinical studies) [3][7][12][17].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
68 drug discovery papers about Saethre-Chotzen syndrome. Recent publications:
68 drug discovery papers about Saethre-Chotzen syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | A mini-review of the molecular mechanisms, mutational landscape, and therapeutic opportunities of TWIST1 in oncology.
TWIST1 is a deeply conserved basic helix-loop-helix (bHLH) transcription factor that has emerged as a central transcriptional regulator bridging developmental biology and cancer pathogenesis. This key regulator orchestrates mesoderm formation, neural crest migration, and craniofacial morphogenesis through precise dimerization-dependent mechanisms. The TWIST1 bHLH domain mediates DNA binding at E-box motifs (CANNTG), with its regulatory role determined by homodimer versus E-protein heterodimer formation. Recent reports demonstrate that post-translational modifications (PTMs) are critical for TWIST1 activity: diacetylation at K73/K76 by TIP60 recruits BRD8 to activate mesenchymal and MYC targets, whereas non-acetylated TWIST1 recruits the NuRD repressor complex to silence epithelial genes. Aurora kinase A (AURKA) phosphorylation at three sites stabilizes TWIST1, promotes homodimerization, and drives chemoresistance, while SETD6-mediated K33 methylation enhances EZH2 occupancy and H3K27me3 deposition at the LINC-PINT locus. Germline loss-of-function mutations clustered in the bHLH domain cause Saethre-Chotzen syndrome (SCS), an autosomal dominant craniosynostosis disorder characterized by protein degradation or impaired nuclear localization. Therapeutic targeting TWIST1 remains challenging due to the absence of deep binding pockets, but emerging strategies include harmine (a β-carboline alkaloid)-mediated proteasomal degradation, BRD4/TIP60/BRD8 axis inhibition, and transcription factor-targeted proteolysis-targeting chimeras (TF-PROTACs) employing DNA oligonucleotide warheads linked to E3 ligase ligands. This review summarizes classic and recent findings on structural biology, PTM networks, mutation landscapes, oncogenic mechanisms, and therapeutic frontiers, highlighting TWIST1 as a target for precision oncology and therapy.
2026-05-20 | TGFβ-mediated dural progenitor cell migration into the coronal suture is crucial for preventing craniosynostosis.
Cranial sutures are essential for skull growth and tissue homeostasis. Among them, the coronal suture is most frequently affected in syndromic craniosynostosis, yet the mechanisms underlying this preferential involvement remain unclear. Here, we show that the coronal suture mesenchyme undergoes a postnatal lineage transition from mesodermal to cranial neural crest origin, facilitated by dural cell migration into the suture. Mechanistically, this migration is regulated by suture TGFβ signals to Tgfbr2+ dural cells. Loss of dural Tgfbr2 impairs this cell migration into the suture, reduces the Gli1+ suture progenitor pool, and causes premature coronal suture fusion. Furthermore, in Twist1+/- mice recapitulating human Saethre-Chotzen syndrome, upregulated decorin leads to compromised TGFβ signaling, which impairs dural cell migration, leading to craniosynostosis. Significantly, restoring TGFβ signaling rescues coronal suture patency in Twist1+/- mice. These findings identify the critical role of TGFβ-mediated dural-suture interactions, particularly dural cell migration, in maintaining coronal suture patency and provide an explanation for the preferential coronal fusion in syndromic craniosynostosis.
2024-05-09 | Targeting of C-ROS-1 Activity Using a Controlled Release Carrier to Treat Craniosynostosis in a Preclinical Model of Saethre-Chotzen Syndrome
Saethre-Chotzen syndrome (SCS) is one of the most prevalent craniosynostosis, caused by a loss-of-function mutation in the TWIST-1 gene, with current treatment options relying on major invasive transcranial surgery. TWIST-1 haploinsufficient osteogenic progenitor cells exhibit increased osteogenic differentiation potential due to an upregulation of the transmembrane tyrosine kinase receptor, C-ROS-1, a TWIST-1 target gene known to promote bone formation. The present study assessed the efficacy of suppressing C-ROS-1 activity using a known chemical inhibitor to C-ROS-1, crizotinib, to halt premature coronal suture fusion in a preclinical mouse model of SCS. Crizotinib (1 μM, 2 μM, or 4 μM) was administered locally over the calvaria of Twist‐1del/+ heterozygous mice prior to coronal suture fusion using either a nonresorbable collagen sponge (quick drug release) or a resorbable sodium carboxymethylcellulose microdisk (slow sustained release). Coronal suture fusion rates and bone parameters were determined by μCT imaging and histomorphometric analysis of calvaria postcoronal suture fusion. Results demonstrated a dose-dependent increase in the efficacy of crizotinib to maintain coronal suture patency, with no adverse effects to brain, kidney, liver, and spleen tissue, or blood cell parameters. Moreover, crizotinib delivered on microdisks resulted in a greater efficacy at a lower concentration to reduce bone formation at the coronal suture sites compared to sponges. However, the bone inhibitory effects were found to be diminished by over time following cessation of treatment. Our findings lay the foundation for the development of a pharmacological nonsurgical, targeted approach to temporarily maintain open coronal sutures in SCS patients. This study could potentially be used to develop similar therapeutic strategies to treat different syndromic craniosynostosis conditions caused by known genetic mutations.
2021-05-14 | A novel therapeutic hypothesis for craniosynostosis syndromes: Clover to clever.
Cloverleaf skull is a complex skull deformity named after its cloverleaf shape. The primary pathogenic factor is craniosynostosis. Craniosynostosis could result in limited development of skull, brain, maxillofacial and nervous system, thus arising a series of complex syndromes, including Crouzon, Apert, Pfeiffer, Saethre-Chotzen and Muenke syndromes. Craniosynostosis syndromes exhibit a group of similar symptoms because of the mutual cause, craniosynostosis, with Crouzon syndrome being the most common one. At present, the surgical approach for Craniosynostosis syndromes has been established and generally accepted, including a series of surgical interventions in stages according to patients' age, severity and function of skull malformation. It's a large, complex, long time span deformity correcting procedure with formidable limitations, including high risk, expensive cost, quantity shortage of qualified surgeons and unsatisfactory successful rate for complicated cases. Hence, a new nonsurgical therapy for patients with craniosynostosis syndromes is seriously needed. A concept of Dynamic Cranial Suture Management (DCSM) was introduced. It includes objective and evaluable monitoring tools and craniosynostosis patent modifying drugs or medications tools which consist of regulatory factors for osteoclasts, osteoblasts and mesenchymal stem cells. By using these tools alternatively in different skull developing stages, DCSM is designed to prevent craniosynostosis. A Crouzon syndrome case was also presented.
2020-12-01 | Pharmacological targeting of KDM6A and KDM6B, as a novel therapeutic strategy for treating craniosynostosis in Saethre-Chotzen syndrome
Abstract Background During development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or craniosynostosis, leading to craniofacial and cognitive issues. Saethre-Chotzen syndrome (SCS) is a common form of craniosynostosis, caused by TWIST-1 gene mutations. Currently, the only treatment option for craniosynostosis involves multiple invasive cranial surgeries, which can lead to serious complications. Methods The present study utilized Twist-1 haploinsufficient ( Twist-1 del/+ ) mice as SCS mouse model to investigate the inhibition of Kdm6a and Kdm6b activity using the pharmacological inhibitor, GSK-J4, on calvarial cell osteogenic potential. Results This study showed that the histone methyltransferase EZH2 , an osteogenesis inhibitor, is downregulated in calvarial cells derived from Twist-1 del/+ mice, whereas the counter histone demethylases, Kdm6a and Kdm6b , known promoters of osteogenesis, were upregulated. In vitro studies confirmed that siRNA-mediated inhibition of Kdm6a and Kdm6b expression suppressed osteogenic differentiation of Twist-1 del/+ calvarial cells. Moreover, pharmacological targeting of Kdm6a and Kdm6b activity, with the inhibitor, GSK-J4, caused a dose-dependent suppression of osteogenic differentiation by Twist-1 del/+ calvarial cells in vitro and reduced mineralized bone formation in Twist-1 del/+ calvarial explant cultures. Chromatin immunoprecipitation and Western blot analyses found that GSK-J4 treatment elevated the levels of the Kdm6a and Kdm6b epigenetic target, the repressive mark of tri-methylated lysine 27 on histone 3, on osteogenic genes leading to repression of Runx2 and Alkaline Phosphatase expression. Pre-clinical in vivo studies showed that local administration of GSK-J4 to the calvaria of Twist-1 del/+ mice prevented premature suture fusion and kept the sutures open up to postnatal day 20. Conclusion The inhibition of Kdm6a and Kdm6b activity by GSK-J4 could be used as a potential non-invasive therapeutic strategy for preventing craniosynostosis in children with SCS. Graphical abstract Pharmacological targeting of Kdm6a/b activity can alleviate craniosynostosis in Saethre-Chotzen syndrome. Aberrant osteogenesis by Twist-1 mutant cranial suture mesenchymal progenitor cells occurs via deregulation of epigenetic modifiers Ezh2 and Kdm6a/Kdm6b. Suppression of Kdm6a- and Kdm6b-mediated osteogenesis with GSK-J4 inhibitor can prevent prefusion of cranial sutures.
gene therapies
2025-09-27 | RNA Polymerase I Dysfunction Underlying Craniofacial Syndromes: Integrated Genetic Analysis Reveals Parallels to 22q11.2 Deletion Syndrome.
POLR1A and related gene variants cause craniofacial and developmental syndromes, including Acrofacial Dysostosis-Cincinnati, Treacher-Collins types 2-4, and TWIST1-associated disorders. Using a patient case integrated with molecular analyses, we aimed to clarify shared pathogenic mechanisms and propose these conditions as part of a spectrum of RNA polymerase I (Pol I)-related ribosomopathies. A patient with a heterozygous POLR1A variant underwent clinical evaluation. Findings were integrated with a literature review of craniofacial syndromes to identify overlapping fea tures. Protein-protein and gene-gene interactions were analyzed with STRING and Pathway Commons, a structural modeling of POLR1A assessed the mutation's impact. The patient exhibited features overlapping with Sweeney-Cox, Saethre-Cox, Robinow-Sorauf, and Treacher-Collins types 2-4, supporting a shared spectrum. Computational analyses identified POLR1A-associated partners and pathways converging on Pol I function, ribosomal biogenesis, and nucleolar processes. Structural modeling of the Met496Ile variant suggested disruption of DNA binding and polymerase activity, linking molecular dysfunction to the clinical phenotype. Significant clinical and genetic overlap exists among Saethre-Chotzen, Sweeney-Cox, Treacher-Collins types 2-4, and Acrofacial Dysostosis-Cincinnati. POLR1A and related Pol I subunits provide a mechanistic basis through impaired nucleolar organization and rRNA transcription, contributing to abnormal craniofacial development. Integrative protein, gene, and structural analyses support classifying these syndromes as Pol I-related ribosomopathies, with implications for diagnosis, counseling, and future mechanistic or therapeutic studies.
2025-04-24 | SP26. Chiari 1 Malformation in Non-Syndromic and Syndromic Craniosynostoses: A Meta-Analysis
PURPOSE: Chiari I malformation (CM) is typically the result of either caudal traction or craniocerebral disproportion. Craniosynostosis (CS), the premature fusion of cranial sutures, can result in craniocerebral disproportion and thus has been associated with CM. Although there are studies with small sample sizes evaluating the association between CM and CS, a comprehensive meta-analysis of the cumulative data has not been reported. Moreover, most patients with CS who develop CM are diagnosed incidentally and have asymptomatic presentations [1]. For this reason, knowing the distribution of CM among different phenotypic presentations of CS will help in clinical evaluation. We aim to highlight the prevalence of CM amongst diverse phenotypic presentations of CS. METHODS: A meta-analysis via PRISMA guidelines was conducted with keywords for Chiari malformation OR terms related to Chiari malformation AND craniosynostosis OR multi-sutural craniosynostosis OR single-suture craniosynostosis OR related terms. These terms were applied to databases OVID (Medline), Cumulated Index to Nursing and Allied Health Literature (CINAHL), Scopus, and the register Cochrane Trials on 1/11/24, with the yield of 688 articles with 264 duplicates. Records were further screened by three independent reviewers with perusal of individual abstracts, with the inclusion criteria of specific discussion of craniosynostosis (single suture, multi-suture, or syndromic) and CM as diagnosed by cerebellar tonsillar herniation at or below 5 mm. Logistic regression analyses were performed for suture types and syndromes independently. The coronal suture and Saethre-Chotzen syndrome served as the reference categories for regression analysis, respectively. RESULTS: Based on the inclusion criteria, 23 reports were sought for retrieval. Based on the cumulative data in all reports, 30.2% of single-suture CS was associated with CM. Specifically, 43.9% of lambdoid, 6.7% of coronal, 6.5% of sagittal, 0.8% of metopic, and 20.5% of multi-sutural CS were associated with CM. Additionally, 22.2% of all syndromic cases presented with CM. By specific syndrome, 73.0% of Pfeiffer, 43.0% of Crouzon, 30.6% of Crouzon-Pfeiffer, 17.2% of Apert, 7.7% of Muenke, and 1.2% of Saethre-Chotzen presented with CM.The results highlight a significant positive association between CM and lambdoid CS (β = 2.38, p < 0.001) and multi-suture CS (β = 1.28, p = 0.001). Conversely, metopic suture involvement demonstrated a negative association with CM (β = -2.20, p = 0.038), while sagittal CS showed no significant association (β = -0.034, p = 0.932). There was a significantly greater association of CM with the syndromes Apert (β = 2.81, p = 0.00579), Crouzon (β = 4.10, p < 0.0001), Crouzon-Pfeiffer (β = 3.56, p = 0.000495), and Pfeiffer (β = 5.38, p < 0.000001). CONCLUSION: Based on this meta-analysis, the rates of CM are significantly associated with lambdoid CS and with multisutural CS. Additionally, there is a significant association between CM and the syndromes Apert, Crouzon, Pfeiffer, and Crouzon-Pfeiffer. These data emphasize the importance of careful evaluation of at-risk phenotypes of CS for CM.
2010-08-08 | Pivotal role of Twist in skeletal biology and pathology
Basic Helix–loop–Helix (bHLH) factors play important roles in development and disease. Recent functional and genetic analyses revealed that the bHLH factor Twist1 is a critical modulator of mesenchymal cell fate during skeletal development. Specifically, studies in mice and humans showed that Twist1 controls mesenchymal stem cell differentiation into chondrocytes, osteoblasts or adipocytes via direct and indirect mechanisms. In a physiological context, Twist1 targets several molecular mechanisms to induce positive or negative effects on osteoblastic cell growth, differentiation and survival. In a pathological context, Twist1 loss-of-function mutations induce premature cranial suture fusion (craniosynostosis) in the Saethre–Chotzen syndrome. In this syndrome, expansion of cranial osteogenesis at the suture level results from alterations in the balance between osteoprogenitor cell proliferation, differentiation and apoptosis. These studies provide mechanisms by which Twist1 plays a pivotal role in skeletal cell fate in normal and pathologic conditions, which may offer therapeutic perspectives in conditions where mesenchymal cell behaviour is compromised.
2007-09-01 | Generation of a Twist1 conditional null allele in the mouse.
Twist1 is the mouse ortholog of TWIST1, the human gene mutated in Saethre-Chotzen syndrome. Previously, a Twist1 null allele was generated by gene targeting in mouse embryonic stem cells. Twist1 heterozygous mice develop polydactyly and a craniofacial phenotype similar to Saethre-Chotzen patients. Mice homozygous for the Twist1 null allele die around embryonic day 11.5 (E11.5) with cranial neural tube closure and vascular defects, hindering in vivo studies of Twist1 function at later stages of development. Here, we report the generation of a Twist1 conditional null allele in mice that functions like a wild-type allele but can be converted to a null allele upon Cre-mediated recombination.
cell therapies
2023-11-06 | Skull progenitor cell-driven meningeal lymphatic restoration improves neurocognitive functions in craniosynostosis.
The meninges lie in the interface between the skull and brain, harboring lymphatic vasculature and skull progenitor cells (SPCs). How the skull and brain communicate remains largely unknown. We found that impaired meningeal lymphatics and brain perfusion drive neurocognitive defects in Twist1+/- mice, an animal model of craniosynostosis recapitulating human Saethre-Chotzen syndrome. Loss of SPCs leads to skull deformities and elevated intracranial pressure (ICP), whereas transplanting SPCs back into mutant mice mitigates lymphatic and brain defects through two mechanisms: (1) decreasing elevated ICP by skull correction and (2) promoting the growth and migration of lymphatic endothelial cells (LECs) via SPC-secreted vascular endothelial growth factor-C (VEGF-C). Treating Twist1+/- mice with VEGF-C promotes meningeal lymphatic growth and rescues defects in ICP, brain perfusion, and neurocognitive functions. Thus, the skull functionally integrates with the brain via meningeal lymphatics, which is impaired in craniosynostosis and can be restored by SPC-driven lymphatic activation via VEGF-C.
small molecules
2026-09-24 | A mini-review of the molecular mechanisms, mutational landscape, and therapeutic opportunities of TWIST1 in oncology.
TWIST1 is a deeply conserved basic helix-loop-helix (bHLH) transcription factor that has emerged as a central transcriptional regulator bridging developmental biology and cancer pathogenesis. This key regulator orchestrates mesoderm formation, neural crest migration, and craniofacial morphogenesis through precise dimerization-dependent mechanisms. The TWIST1 bHLH domain mediates DNA binding at E-box motifs (CANNTG), with its regulatory role determined by homodimer versus E-protein heterodimer formation. Recent reports demonstrate that post-translational modifications (PTMs) are critical for TWIST1 activity: diacetylation at K73/K76 by TIP60 recruits BRD8 to activate mesenchymal and MYC targets, whereas non-acetylated TWIST1 recruits the NuRD repressor complex to silence epithelial genes. Aurora kinase A (AURKA) phosphorylation at three sites stabilizes TWIST1, promotes homodimerization, and drives chemoresistance, while SETD6-mediated K33 methylation enhances EZH2 occupancy and H3K27me3 deposition at the LINC-PINT locus. Germline loss-of-function mutations clustered in the bHLH domain cause Saethre-Chotzen syndrome (SCS), an autosomal dominant craniosynostosis disorder characterized by protein degradation or impaired nuclear localization. Therapeutic targeting TWIST1 remains challenging due to the absence of deep binding pockets, but emerging strategies include harmine (a β-carboline alkaloid)-mediated proteasomal degradation, BRD4/TIP60/BRD8 axis inhibition, and transcription factor-targeted proteolysis-targeting chimeras (TF-PROTACs) employing DNA oligonucleotide warheads linked to E3 ligase ligands. This review summarizes classic and recent findings on structural biology, PTM networks, mutation landscapes, oncogenic mechanisms, and therapeutic frontiers, highlighting TWIST1 as a target for precision oncology and therapy.
2026-05-20 | TGFβ-mediated dural progenitor cell migration into the coronal suture is crucial for preventing craniosynostosis.
Cranial sutures are essential for skull growth and tissue homeostasis. Among them, the coronal suture is most frequently affected in syndromic craniosynostosis, yet the mechanisms underlying this preferential involvement remain unclear. Here, we show that the coronal suture mesenchyme undergoes a postnatal lineage transition from mesodermal to cranial neural crest origin, facilitated by dural cell migration into the suture. Mechanistically, this migration is regulated by suture TGFβ signals to Tgfbr2+ dural cells. Loss of dural Tgfbr2 impairs this cell migration into the suture, reduces the Gli1+ suture progenitor pool, and causes premature coronal suture fusion. Furthermore, in Twist1+/- mice recapitulating human Saethre-Chotzen syndrome, upregulated decorin leads to compromised TGFβ signaling, which impairs dural cell migration, leading to craniosynostosis. Significantly, restoring TGFβ signaling rescues coronal suture patency in Twist1+/- mice. These findings identify the critical role of TGFβ-mediated dural-suture interactions, particularly dural cell migration, in maintaining coronal suture patency and provide an explanation for the preferential coronal fusion in syndromic craniosynostosis.
2024-05-09 | Targeting of C-ROS-1 Activity Using a Controlled Release Carrier to Treat Craniosynostosis in a Preclinical Model of Saethre-Chotzen Syndrome
Saethre-Chotzen syndrome (SCS) is one of the most prevalent craniosynostosis, caused by a loss-of-function mutation in the TWIST-1 gene, with current treatment options relying on major invasive transcranial surgery. TWIST-1 haploinsufficient osteogenic progenitor cells exhibit increased osteogenic differentiation potential due to an upregulation of the transmembrane tyrosine kinase receptor, C-ROS-1, a TWIST-1 target gene known to promote bone formation. The present study assessed the efficacy of suppressing C-ROS-1 activity using a known chemical inhibitor to C-ROS-1, crizotinib, to halt premature coronal suture fusion in a preclinical mouse model of SCS. Crizotinib (1 μM, 2 μM, or 4 μM) was administered locally over the calvaria of Twist‐1del/+ heterozygous mice prior to coronal suture fusion using either a nonresorbable collagen sponge (quick drug release) or a resorbable sodium carboxymethylcellulose microdisk (slow sustained release). Coronal suture fusion rates and bone parameters were determined by μCT imaging and histomorphometric analysis of calvaria postcoronal suture fusion. Results demonstrated a dose-dependent increase in the efficacy of crizotinib to maintain coronal suture patency, with no adverse effects to brain, kidney, liver, and spleen tissue, or blood cell parameters. Moreover, crizotinib delivered on microdisks resulted in a greater efficacy at a lower concentration to reduce bone formation at the coronal suture sites compared to sponges. However, the bone inhibitory effects were found to be diminished by over time following cessation of treatment. Our findings lay the foundation for the development of a pharmacological nonsurgical, targeted approach to temporarily maintain open coronal sutures in SCS patients. This study could potentially be used to develop similar therapeutic strategies to treat different syndromic craniosynostosis conditions caused by known genetic mutations.
2021-05-14 | A novel therapeutic hypothesis for craniosynostosis syndromes: Clover to clever.
Cloverleaf skull is a complex skull deformity named after its cloverleaf shape. The primary pathogenic factor is craniosynostosis. Craniosynostosis could result in limited development of skull, brain, maxillofacial and nervous system, thus arising a series of complex syndromes, including Crouzon, Apert, Pfeiffer, Saethre-Chotzen and Muenke syndromes. Craniosynostosis syndromes exhibit a group of similar symptoms because of the mutual cause, craniosynostosis, with Crouzon syndrome being the most common one. At present, the surgical approach for Craniosynostosis syndromes has been established and generally accepted, including a series of surgical interventions in stages according to patients' age, severity and function of skull malformation. It's a large, complex, long time span deformity correcting procedure with formidable limitations, including high risk, expensive cost, quantity shortage of qualified surgeons and unsatisfactory successful rate for complicated cases. Hence, a new nonsurgical therapy for patients with craniosynostosis syndromes is seriously needed. A concept of Dynamic Cranial Suture Management (DCSM) was introduced. It includes objective and evaluable monitoring tools and craniosynostosis patent modifying drugs or medications tools which consist of regulatory factors for osteoclasts, osteoblasts and mesenchymal stem cells. By using these tools alternatively in different skull developing stages, DCSM is designed to prevent craniosynostosis. A Crouzon syndrome case was also presented.
2020-12-01 | Pharmacological targeting of KDM6A and KDM6B, as a novel therapeutic strategy for treating craniosynostosis in Saethre-Chotzen syndrome
Abstract Background During development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or craniosynostosis, leading to craniofacial and cognitive issues. Saethre-Chotzen syndrome (SCS) is a common form of craniosynostosis, caused by TWIST-1 gene mutations. Currently, the only treatment option for craniosynostosis involves multiple invasive cranial surgeries, which can lead to serious complications. Methods The present study utilized Twist-1 haploinsufficient ( Twist-1 del/+ ) mice as SCS mouse model to investigate the inhibition of Kdm6a and Kdm6b activity using the pharmacological inhibitor, GSK-J4, on calvarial cell osteogenic potential. Results This study showed that the histone methyltransferase EZH2 , an osteogenesis inhibitor, is downregulated in calvarial cells derived from Twist-1 del/+ mice, whereas the counter histone demethylases, Kdm6a and Kdm6b , known promoters of osteogenesis, were upregulated. In vitro studies confirmed that siRNA-mediated inhibition of Kdm6a and Kdm6b expression suppressed osteogenic differentiation of Twist-1 del/+ calvarial cells. Moreover, pharmacological targeting of Kdm6a and Kdm6b activity, with the inhibitor, GSK-J4, caused a dose-dependent suppression of osteogenic differentiation by Twist-1 del/+ calvarial cells in vitro and reduced mineralized bone formation in Twist-1 del/+ calvarial explant cultures. Chromatin immunoprecipitation and Western blot analyses found that GSK-J4 treatment elevated the levels of the Kdm6a and Kdm6b epigenetic target, the repressive mark of tri-methylated lysine 27 on histone 3, on osteogenic genes leading to repression of Runx2 and Alkaline Phosphatase expression. Pre-clinical in vivo studies showed that local administration of GSK-J4 to the calvaria of Twist-1 del/+ mice prevented premature suture fusion and kept the sutures open up to postnatal day 20. Conclusion The inhibition of Kdm6a and Kdm6b activity by GSK-J4 could be used as a potential non-invasive therapeutic strategy for preventing craniosynostosis in children with SCS. Graphical abstract Pharmacological targeting of Kdm6a/b activity can alleviate craniosynostosis in Saethre-Chotzen syndrome. Aberrant osteogenesis by Twist-1 mutant cranial suture mesenchymal progenitor cells occurs via deregulation of epigenetic modifiers Ezh2 and Kdm6a/Kdm6b. Suppression of Kdm6a- and Kdm6b-mediated osteogenesis with GSK-J4 inhibitor can prevent prefusion of cranial sutures.
gene therapies
2025-09-27 | RNA Polymerase I Dysfunction Underlying Craniofacial Syndromes: Integrated Genetic Analysis Reveals Parallels to 22q11.2 Deletion Syndrome.
POLR1A and related gene variants cause craniofacial and developmental syndromes, including Acrofacial Dysostosis-Cincinnati, Treacher-Collins types 2-4, and TWIST1-associated disorders. Using a patient case integrated with molecular analyses, we aimed to clarify shared pathogenic mechanisms and propose these conditions as part of a spectrum of RNA polymerase I (Pol I)-related ribosomopathies. A patient with a heterozygous POLR1A variant underwent clinical evaluation. Findings were integrated with a literature review of craniofacial syndromes to identify overlapping fea tures. Protein-protein and gene-gene interactions were analyzed with STRING and Pathway Commons, a structural modeling of POLR1A assessed the mutation's impact. The patient exhibited features overlapping with Sweeney-Cox, Saethre-Cox, Robinow-Sorauf, and Treacher-Collins types 2-4, supporting a shared spectrum. Computational analyses identified POLR1A-associated partners and pathways converging on Pol I function, ribosomal biogenesis, and nucleolar processes. Structural modeling of the Met496Ile variant suggested disruption of DNA binding and polymerase activity, linking molecular dysfunction to the clinical phenotype. Significant clinical and genetic overlap exists among Saethre-Chotzen, Sweeney-Cox, Treacher-Collins types 2-4, and Acrofacial Dysostosis-Cincinnati. POLR1A and related Pol I subunits provide a mechanistic basis through impaired nucleolar organization and rRNA transcription, contributing to abnormal craniofacial development. Integrative protein, gene, and structural analyses support classifying these syndromes as Pol I-related ribosomopathies, with implications for diagnosis, counseling, and future mechanistic or therapeutic studies.
2025-04-24 | SP26. Chiari 1 Malformation in Non-Syndromic and Syndromic Craniosynostoses: A Meta-Analysis
PURPOSE: Chiari I malformation (CM) is typically the result of either caudal traction or craniocerebral disproportion. Craniosynostosis (CS), the premature fusion of cranial sutures, can result in craniocerebral disproportion and thus has been associated with CM. Although there are studies with small sample sizes evaluating the association between CM and CS, a comprehensive meta-analysis of the cumulative data has not been reported. Moreover, most patients with CS who develop CM are diagnosed incidentally and have asymptomatic presentations [1]. For this reason, knowing the distribution of CM among different phenotypic presentations of CS will help in clinical evaluation. We aim to highlight the prevalence of CM amongst diverse phenotypic presentations of CS. METHODS: A meta-analysis via PRISMA guidelines was conducted with keywords for Chiari malformation OR terms related to Chiari malformation AND craniosynostosis OR multi-sutural craniosynostosis OR single-suture craniosynostosis OR related terms. These terms were applied to databases OVID (Medline), Cumulated Index to Nursing and Allied Health Literature (CINAHL), Scopus, and the register Cochrane Trials on 1/11/24, with the yield of 688 articles with 264 duplicates. Records were further screened by three independent reviewers with perusal of individual abstracts, with the inclusion criteria of specific discussion of craniosynostosis (single suture, multi-suture, or syndromic) and CM as diagnosed by cerebellar tonsillar herniation at or below 5 mm. Logistic regression analyses were performed for suture types and syndromes independently. The coronal suture and Saethre-Chotzen syndrome served as the reference categories for regression analysis, respectively. RESULTS: Based on the inclusion criteria, 23 reports were sought for retrieval. Based on the cumulative data in all reports, 30.2% of single-suture CS was associated with CM. Specifically, 43.9% of lambdoid, 6.7% of coronal, 6.5% of sagittal, 0.8% of metopic, and 20.5% of multi-sutural CS were associated with CM. Additionally, 22.2% of all syndromic cases presented with CM. By specific syndrome, 73.0% of Pfeiffer, 43.0% of Crouzon, 30.6% of Crouzon-Pfeiffer, 17.2% of Apert, 7.7% of Muenke, and 1.2% of Saethre-Chotzen presented with CM.The results highlight a significant positive association between CM and lambdoid CS (β = 2.38, p < 0.001) and multi-suture CS (β = 1.28, p = 0.001). Conversely, metopic suture involvement demonstrated a negative association with CM (β = -2.20, p = 0.038), while sagittal CS showed no significant association (β = -0.034, p = 0.932). There was a significantly greater association of CM with the syndromes Apert (β = 2.81, p = 0.00579), Crouzon (β = 4.10, p < 0.0001), Crouzon-Pfeiffer (β = 3.56, p = 0.000495), and Pfeiffer (β = 5.38, p < 0.000001). CONCLUSION: Based on this meta-analysis, the rates of CM are significantly associated with lambdoid CS and with multisutural CS. Additionally, there is a significant association between CM and the syndromes Apert, Crouzon, Pfeiffer, and Crouzon-Pfeiffer. These data emphasize the importance of careful evaluation of at-risk phenotypes of CS for CM.
2010-08-08 | Pivotal role of Twist in skeletal biology and pathology
Basic Helix–loop–Helix (bHLH) factors play important roles in development and disease. Recent functional and genetic analyses revealed that the bHLH factor Twist1 is a critical modulator of mesenchymal cell fate during skeletal development. Specifically, studies in mice and humans showed that Twist1 controls mesenchymal stem cell differentiation into chondrocytes, osteoblasts or adipocytes via direct and indirect mechanisms. In a physiological context, Twist1 targets several molecular mechanisms to induce positive or negative effects on osteoblastic cell growth, differentiation and survival. In a pathological context, Twist1 loss-of-function mutations induce premature cranial suture fusion (craniosynostosis) in the Saethre–Chotzen syndrome. In this syndrome, expansion of cranial osteogenesis at the suture level results from alterations in the balance between osteoprogenitor cell proliferation, differentiation and apoptosis. These studies provide mechanisms by which Twist1 plays a pivotal role in skeletal cell fate in normal and pathologic conditions, which may offer therapeutic perspectives in conditions where mesenchymal cell behaviour is compromised.
2007-09-01 | Generation of a Twist1 conditional null allele in the mouse.
Twist1 is the mouse ortholog of TWIST1, the human gene mutated in Saethre-Chotzen syndrome. Previously, a Twist1 null allele was generated by gene targeting in mouse embryonic stem cells. Twist1 heterozygous mice develop polydactyly and a craniofacial phenotype similar to Saethre-Chotzen patients. Mice homozygous for the Twist1 null allele die around embryonic day 11.5 (E11.5) with cranial neural tube closure and vascular defects, hindering in vivo studies of Twist1 function at later stages of development. Here, we report the generation of a Twist1 conditional null allele in mice that functions like a wild-type allele but can be converted to a null allele upon Cre-mediated recombination.
cell therapies
2023-11-06 | Skull progenitor cell-driven meningeal lymphatic restoration improves neurocognitive functions in craniosynostosis.
The meninges lie in the interface between the skull and brain, harboring lymphatic vasculature and skull progenitor cells (SPCs). How the skull and brain communicate remains largely unknown. We found that impaired meningeal lymphatics and brain perfusion drive neurocognitive defects in Twist1+/- mice, an animal model of craniosynostosis recapitulating human Saethre-Chotzen syndrome. Loss of SPCs leads to skull deformities and elevated intracranial pressure (ICP), whereas transplanting SPCs back into mutant mice mitigates lymphatic and brain defects through two mechanisms: (1) decreasing elevated ICP by skull correction and (2) promoting the growth and migration of lymphatic endothelial cells (LECs) via SPC-secreted vascular endothelial growth factor-C (VEGF-C). Treating Twist1+/- mice with VEGF-C promotes meningeal lymphatic growth and rescues defects in ICP, brain perfusion, and neurocognitive functions. Thus, the skull functionally integrates with the brain via meningeal lymphatics, which is impaired in craniosynostosis and can be restored by SPC-driven lymphatic activation via VEGF-C.
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