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Introduction: While several literature reports have been published about patients with microdeletions within chromosome 7p, only a small fraction of those reports is specific to deletions that encompass the TWIST gene and HOXA gene cluster. The large-span deletions within this cluster result in haploinsufficiency of six genes known to have a role in different autosomal dominant genetic disorders: TWIST1, GSDME (DFNA5), CYCS, HOXA11, HOXA13, and GARS. Deletion of TWIST1 gene on 7p21 and deletion of HOXA cluster on 7pl5.2 lead to Saethre-Chotzen syndrome and to hand-foot-genital syndrome, respectively. Objectives: Our patient presented with a phenotype combining Saethre-Chotzen syndrome (SCS) and hand-foot-genital syndrome (HFS), which is similar to previously reported cases with a deletion spanning 7p21– p14.3. The objective of our report is to correlate the clinical observations with the patient’s genetic test result, namely 46,XY,del(7)(p14p21). Patient and Methods: We describe a patient who had manifestations of SCS and HFU, caused by an interstitial deletion of chromosome 7p21–p14 detected by RHG band. Results and Conclusion: We therefore confirm previous reports that microdeletions of 7p spanning the TWIST gene and HOXA gene cluster lead to a clinically recognizable ‘haploinsufficiency syndrome’. All of the features of this patient could be accounted for by combined effect of the deletion of the TWIST and HOXA cluster.

Aim: To assess the long-term outcomes of our management protocol for Saethre–Chotzen syndrome, which includes one-stage fronto-orbital advancement. Method: All patients born with Saethre–Chotzen syndrome between January 1992 and March 2017 were included. Evaluated parameters included occipital frontal head circumference (OFC), fundoscopy, neuroimaging (ventricular size, tonsillar position, and the presence of collaterals/an abnormal transverse sinus), polysomnography, and ophthalmological outcomes. The relationship between papilledema and its associated risk factors was evaluated with Fisher’s exact test. Results: Thirty-two patients (21 females, 11 males) were included. Median (SD) age at first surgery was 9.6 months (3.1mo) for patients who were primarily referred to our center (range: 3.6–13.0mo), the median (SD) age at last follow-up was 13 years (5y 7mo; range: 3–25y). Seven patients had papilledema preoperatively, which recurred in two. Two patients had papilledema solely after first surgery. Second cranial vault expansion was indicated in 20%. Thirteen patients had an OFC deflection, indicating restricted skull growth, one patient had ventriculomegaly, and none developed hydrocephalus. Eleven patients had emissary veins, while the transverse sinus was aberrant unilaterally in 13 (hypoplastic n=10 and absent n=3). Four patients had mild tonsillar descent, one of which was a Chiari type I malformation. Four patients had obstructive sleep apnoea (two mild, one moderate, and one severe). An aberrant transverse sinus was associated with papilledema (p=0.01). Interpretation: Single one-stage fronto-orbital advancement was sufficient to prevent intracranial hypertension for 80% of our patients with Saethre–Chotzen syndrome. Follow-up should focus on OFC deflection and venous anomalies.

Objectives To determine whether dental maturity (dental development) was delayed in patients with Muenke syndrome, Saethre-Chotzen syndrome, and TCF12-related craniosynostosis, compared with a Dutch control group without syndromes. Materials and methods This study included 60 patients (38 patients with Muenke syndrome, 17 patients with Saethre-Chotzen syndrome, and 5 with TCF12-related craniosynostosis), aged 5.8–16.8 years that were treated at the Department of Oral Maxillofacial Surgery, Special Dental Care, and Orthodontics, in Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands. Dental age was calculated according to Demirjian’s index of dental maturity. The control group included 451 children without a syndrome. Results Compared with the control group, dental development was delayed by an average of one year in 5- to 8-year-old patients with Muenke syndrome (P = 0.007) and in 8- to 10-year-old patients with Saethre-Chotzen syndrome (P = 0.044), but not in patients with TCF12-related craniosynostosis. Conclusions Our results indicated that dental development was delayed by one year, on average, in patients with Muenke syndrome and Saethre-Chotzen syndrome, compared with a Dutch control group without syndromes. Implications Our findings have improved the understanding of dental development in patients with Muenke and Saethre-Chotzen syndrome. These results can provide guidance on whether the orthodontist needs to consider growth disturbances related to dental development.

ALX4 is a homeobox gene expressed in the mesenchyme of developing bone and is known to play an important role in the regulation of osteogenesis. Enlarged parietal foramina (EPF) is a phenotype of delayed intramembranous ossification of calvarial bones due to variants of ALX4. The contrasting phenotype of premature ossification of sutures is observed with heterozygous loss-of-function variants of TWIST1, which is an important regulator of osteoblast differentiation. Here, we describe an individual with a large cranium defect, with dominant transmission from the mother, both carrying disease causing heterozygous variants in ALX4 and TWIST1. The distinct phenotype of absent superior and posterior calvarium in the child and his mother was in sharp contrast to the other affected maternal relatives with a recognizable ALX4-related EPF phenotype. This report demonstrates comorbid disorders of Saethre-Chotzen syndrome and EPF in a mother and her child, resulting in severe skull defects reminiscent of calvarial abnormalities observed with bilallelic ALX4 variants. To our knowledge this is the first instance of ALX4 and TWIST1 variants acting synergistically to cause a unique phenotype influencing skull ossification.

Objective: Descriptions of the craniofacial morphology in Saethre-Chotzen syndrome (SCS) are primarily based on case reports or visual assessments of affected families. The aim of this study was to compare cephalometric measurements of the craniofacial skeleton in a cohort of individuals with SCS and age- and sex-matched individuals without craniofacial anomalies. Design: Retrospective case series. Patients: Eight girls and 4 boys with SCS (age range, 7.0-19.2 years). Methods: Cephalometric measurements were performed using lateral and frontal cephalograms. Results: Most of the individuals with Saethre-Chotzen syndrome exhibited lower values for SNA, SNB, s-n and s-ar, while their NSL/NL, NSL/ML, NL/ML, and n-s-ba values were higher than the respective mean reference values for healthy individuals. In comparison with age- and sex-matched individuals without craniofacial anomalies, the individuals with SCS showed higher values for the maxillary and mandibular angular measurements, as well as for the menton midline angle. Conclusions: This sample of 12 unrelated individuals with SCS is the largest collected to date for cephalometric measurements. We found that the syndrome is associated with bimaxillary retrognathism, posterior maxillary and mandibular inclination, neutral sagittal relation as well as a tendency toward an open vertical skeletal relation, a short and flattened skull base, and facial asymmetry, as compared to individuals without the syndrome.

The Saethre-Chotzen syndrome is a craniofacial malformation syndrome characterized by synostosis of coronal sutures and limb anomalies. The estimated prevalence of this syndrome is 1 in 25 000-50 000 live births. We present a case report of a neonate, without relevant family history, who presented craniofacial alterations at birth. Given the phenotypic features, a cranial computed tomography scan was performed, showing partial fusion of the coronal suture, evidencing the presence Sindrome de Saethre-Chotzen: a proposito de un caso Saethre-Chotzen syndrome: a case report of wormian bones in the metopic and right lambdoid location. With the clinical suspicion of craniofacial malformation syndrome, an analysis of the directed exome was requested confirming that the patient is a heterozygous carrier of the pathogenic variant c.415C>A, which induces a change of proline to threonine at position 139 of the TWIST1 gene, responsible for Saethre-Chotzen syndrome. The presence of wormian bones, a finding not described so far in the literature, extends the well-known phenotypic variability of this syndrome.

Purpose Syndromic craniosynostosis is a rare genetic disease caused by premature fusion of one or multiple cranial sutures combined with malformations of other organs. The aim of this publication is to investigate sonographic signs of different syndromic craniosynostoses and associated malformations to facilitate a precise and early diagnosis. Methods We identified in the period of 2000–2019 thirteen cases with a prenatal suspected diagnosis of syndromic craniosynostosis at our department. We analyzed the ultrasound findings, MRI scans, genetic results as well as the mode of delivery, and postnatal procedures. Results Eight children were diagnosed with Apert Syndrome, two with Saethre Chotzen syndrome, one with Crouzon syndrome, and one with Greig cephalopolysyndactyly syndrome. One child had a mutation p.(Pro253Leu) in the FGFR2 gene. We identified characteristic changes of the head shape as well as typical associated malformations. Conclusion Second trimester diagnosis of syndromic craniosynostosis is feasible based on the identified sonographic signs. In case of a suspected diagnosis a genetic, neonatal as well as surgical counseling is recommended. We also recommend to offer a fetal MRI. The delivery should be planned in a perinatal center.

Premature closure of cranial sutures (i.e., craniosynostosis) suppresses bone growth, promotes growth in open cranial sutures, and leads to abnormal morphogenesis and craniofacial deformation, which impairs the growth of the viscerocranium, neurocranium, and brain tissue itself. Craniosynostosis can be divided into primary (of genetic origin) and secondary forms, which are extremely rare. The classification of primary intrauterine craniosynostosis distinguishes between syndromic and non-syndromic forms. Non-syndromic forms of craniosynostosis are mainly sporadic, and monogenetic mutations are responsible for 85% of cases. However, some patients have chromosomal disorders, i.e., numerical and structural aberrations. A variety of mutations in different genes (e.g., MSX2, FGFR1-3, TWIST1, EFNB1, SMAD6, TCF12, ERF) are responsible for the development of craniosynostoses, and pathway analysis has identified similar signaling pathways as common causes of both syndromic and non-syndromic craniosynostoses. Secondary craniosynostoses are an extremely rare form with a great etiological diversity that includes teratogenic, metabolic, hematological, and developmental disorders. Surgical treatment of craniosynostoses, however, is based on the deformity itself and is not affected by the categorization of a particular syndrome.

BackgroundDuring 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 byTWIST-1gene mutations. Currently, the only treatment option for craniosynostosis involves multiple invasive cranial surgeries, which can lead to serious complications.MethodsThe present study utilizedTwist-1haploinsufficient (Twist-1del/+) 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.ResultsThis study showed that the histone methyltransferaseEZH2, an osteogenesis inhibitor, is downregulated in calvarial cells derived fromTwist-1del/+mice, whereas the counter histone demethylases,Kdm6aandKdm6b, known promoters of osteogenesis, were upregulated. In vitro studies confirmed that siRNA-mediated inhibition ofKdm6aandKdm6bexpression suppressed osteogenic differentiation ofTwist-1del/+calvarial cells. Moreover, pharmacological targeting of Kdm6a and Kdm6b activity, with the inhibitor, GSK-J4, caused a dose-dependent suppression of osteogenic differentiation byTwist-1del/+calvarial cells in vitro and reduced mineralized bone formation inTwist-1del/+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 ofRunx2andAlkaline Phosphataseexpression. Pre-clinical in vivo studies showed that local administration of GSK-J4 to the calvaria ofTwist-1del/+mice prevented premature suture fusion and kept the sutures open up to postnatal day 20.ConclusionThe 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 abstractPharmacological 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.

Introduction Saethre-Chotzen syndrome is a genetic condition characterized by craniofacial and limb anomalies, with craniosynostosis (mainly coronal) being the most frequent craniofacial finding. Cranial and facial deformities can be extremely variable requiring individualization of treatment strategies. We present our case series to highlight clinical findings, treatment philosophy, and challenges facing Saethre-Chotzen patients. Methods A retrospective review was performed on records of patients given a diagnosis of Saethre-Chotzen syndrome at the University of California Los Angeles (UCLA) Craniofacial Clinic (n = 7) between 1980 and 2010. Patients with complete records were included in this study, and review of demographic data, clinical findings, surgical interventions and postoperative follow-up, and stability were performed. Results Seven patients (1 male and 6 female) were included in this study. The average age at which the patients were first seen was 6.5 years. Suture involvement was bicoronal (n = 6) and unicoronal (n = 1). There was 1 patient having superimposed metopic synostosis, and there was another patient having Kleeblattschadel deformity. Previous procedures performed for patients before establishing care at UCLA were strip craniectomy (n = 2) and fronto-orbital advancement (n = 2). All patients (n = 7) had fronto-orbital advancements at UCLA. Other skeletal operations included the following: redo forehead advancement and contouring (n = 3), monobloc advancement (n = 1), and LeFort III distraction (n = 1). Five patients reached skeletal maturity, and 2 patients received LeFort I advancement for class III malocclusion, one of which also required a bilateral sagittal split osteotomy of the mandible. Conclusion Clinical presentation and severity of deformity in Saethre-Chotzen syndrome are variable. Our current report reviews our treatment strategies and illustrates the predominance of cranial and upper face deformities and frequent need for redo surgeries to address forehead asymmetry in this group of syndromic craniosynostosis patients.

Saethre-Chotzen syndrome (SCS) belongs to a group of rare congenital disorders connected with craniosynostosis and syndactyly. The purpose of this paper is to provide a review of the literature, to collect all reported symptoms and to describe the case of an 11-year-old female with SCS. The electronic databases PubMed and Scopus were searched to gain all symptoms of SCS described in the literature. The most common features of SCS described in the literature are synostosis of the coronal suture, syndactyly, facial asymmetry, low hairline, prominent ear crus, prominent nasal bridge, eyelid ptosis, and ocular hypertelorism. Less common symptoms include hearing loss, renal abnormalities and cardiac defects. Intraoral manifestations of SCS include maxillary hypoplasia, mandibular prognathism and high arched palate. Moreover, in some patients mental disability is observed, which may be connected with the size of the deletion in the Twist gene. There are no pathognomonic symptoms of SCS, which would indicate a diagnostic problem. Our patient displayed small dysmorphic changes within the skull and limbs and proper intellectual development. On the basis of an intraoral, extraoral examination and X-rays, she was diagnosed with relative mandibular prognathism. Currently, she is treated with a removable appliance. This report emphasizes a considerable variability of symptoms in SCS and highlights the most common features.

Saethre-Chotzen Syndrome (SCS) is an autosomal dominant syndrome that occurs due to a mutation or deletion of the Twist1 gene at chromosome 7p21. Our aim was to conduct a morphometric analysis of the craniofacial features in the mouse associated with a Twist1Micro-computed imaging was conducted for the skulls of forty skeletally mature mice, equally distributed by sex (male and female) and two genotypes (Twist1Compared with wild-type, the murine model of SCS showed these trends: (1) maxillary-zygomatico-temporal region, significantly shorter length and width posteriorly (p0.05), (2) mandible, significantly reduced height and width (p0.05), and (3) teeth, significantly shorter height, shorter mesio-distal width but longer bucco-lingual width (p0.05). In the murine model of SCS, the key morphological variations included incomplete ossification of the temporal bone and zygomatic arch, twisting and/or incomplete ossification of the palatal process of the maxilla, premaxilla and the ventral nasal concha, as well as bifid coronoid processes.The skeletal and dental alterations in the height, length and width provide a foundation for large-scale phenomics studies, which will improve existing knowledge of the Twist1 signalling cascade. This is relevant given the predicted shift towards minimally invasive molecular medical treatment for craniosynostosis.

Saethre-Chotzen syndrome (SCS) is an autosomal dominant condition defined by mutations affecting the TWIST1 gene on chromosome 7p21.1. Previous research has identified an elevated prevalence of intracranial hypertension and hearing impairment associated with this syndrome. This study aimed to investigate the influence of hearing history and presence of intracranial hypertension on language development in children with SCS. A retrospective study note analysis was performed for all patients with a confirmed TWIST1 gene abnormality who attended the Oxford Craniofacial Unit and underwent a language assessment over a 22-year period. Intracranial pressure monitoring, hearing status, and language outcomes were examined in detail. Thirty patients with genetically confirmed SCS and language assessment data were identified. Twenty-eight patients underwent surgical intervention; 10 presented with intracranial hypertension (5 prior to, and 5 after primary surgical intervention). Language data coinciding with the presentation of intracranial hypertension were available for 8 children. About 44% of children with intracranial hypertension presented with concurrent receptive and expressive language delay (n = 4/8). For both children (n = 2) with longitudinal language data available, the onset of intracranial hypertension reflected a concurrent decline in language skills. Audiometric data were available for 25 children, 80% (n = 20/25) had a history of hearing loss. About 50% of these had confirmed conductive hearing loss with middle ear effusion and the other 50% had presumed conductive hearing loss with middle ear effusion. About 100% of the children with available hearing data in our study had evidence of middle ear effusion in at least 1 ear. Results also indicated that 43% (n = 13/30) of the children presented with receptive and/or expressive language delay during childhood. Given the importance of hearing for language development and the preliminary findings of a potential decline in language skills in children during periods of intracranial hypertension, regular follow-up of hearing, language, and intracranial hypertension are indicated in children with SCS.

Acrocephaly is a common neonatal craniofacial malformation. Saethre-Chotzen syndrome (SCS) is one of the acrocephaly related syndromes less frequently described in the literature. A female newborn term was admitted to our Neonatal Unit to study craniofacial dysmorphia without family history of interest. Pregnancy, childbirth and the neonatal period were uneventful. She had exotropia, short anterior-posterior cranial diameter, flat occiput and wide normotensive anterior fontanelle (beginning at the nose root, continuing through the sagittal suture with the posterior fontanelle) without syndactyly. The scanner imaging confirmed an acrocephaly with fusion of bilateral coronal sutures. We initially suspected a cranyosinostosis due to a Crouzon syndrome or SCS. After differential diagnosis and genetic study the patient was diagnosed as having SCS due to a de novo TWIST1 gene mutation. The craniofacial dysmorphias were corrected early by neurosurgical with good results. This case shows a new example of the phenotypic and genotypic variability of these TWIST1 gene mutations.

Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostotic disorder characterized by coronal synostosis, facial asymmetry, ptosis, and limb abnormalities. Haploinsufficiency of TWIST1, a basic helix-loop-helix transcription factor is responsible for SCS. Here, we report a 15-month-old male patient with typical clinical features of SCS in addition to developmental delay, which is a rare complication in SCS. He showed a de novo 0.9-Mb microdeletion in 7p21, in which TWIST1, NPMIP13, FERD3L, TWISTNB, and HDAC9 were included. In comparison with previously reported patients, HDAC9 was suggested to contribute to developmental delay in SCS patients with 7p21 mirodeletions.

Saethre-Chotzen syndrome (SCS), one of the most common forms of syndromic craniosynostosis (premature fusion of the cranial sutures), results from haploinsufficiency of TWIST1, caused by deletions of the entire gene or loss-of-function variants within the coding region. To determine whether non-coding variants also contribute to SCS, we screened 14 genetically undiagnosed SCS patients using targeted capture sequencing, and identified novel single nucleotide variants (SNVs) in the 5' untranslated region (UTR) of TWIST1 in two unrelated SCS cases. We show experimentally that these variants, which create translation start sites in the TWIST1 leader sequence, reduce translation from the main open reading frame (mORF). This is the first demonstration that non-coding SNVs of TWIST1 can cause SCS, and highlights the importance of screening the 5' UTR in clinically diagnosed SCS patients without a coding mutation. Similar 5' UTR variants, particularly of haploinsufficient genes, may represent an under-ascertained cause of monogenic disease. This article is protected by copyright. All rights reserved.

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., eLife digest Some of the most common birth defects involve improper development of the head and face. One such birth defect is called craniosynostosis. Normally, an infant’s skull bones are not fully fused together. Instead, they are held together by soft tissue that allows the baby’s skull to more easily pass through the birth canal. This tissue also houses specialized cells called stem cells that allow the brain and skull to grow with the child. But in craniosynostosis these stem cells behave abnormally, which fuses the skull bones together and prevents the skull and brain from growing properly during childhood. One form of craniosynostosis called Saethre-Chotzen syndrome is caused by mutations in one of two genes that ensure the proper separation of two bones in the roof of the skull. Mice with mutations in the mouse versions of these genes develop the same problem and are used to study this condition. Mouse studies have looked mostly at what happens after birth. Studies looking at what happens in embryos with these mutations could help scientists learn more. One way to do so would be to genetically engineer zebrafish with the equivalent mutations. This is because zebrafish embryos are transparent and grow outside their mother’s body, making it easier for scientists to watch them develop. Now, Teng et al. have grown zebrafish with mutations in the zebrafish versions of the genes that cause Saethre-Chotzen syndrome. In the experiments, imaging tools were used to observe the live fish as they developed. This showed that the stem cells in their skulls become abnormal much earlier than previous studies had suggested. Teng et al. also showed that similar stem cells are responsible for growth of the skull in zebrafish and mice. Babies with craniosynostosis often need multiple, risky surgeries to separate their skull bones and allow their brain and head to grow. Unfortunately, these bones often fuse again because they have abnormal stem cells. Teng et al. provide new information on what goes wrong in these stem cells. Hopefully, this new information will help scientists to one day correct the defective stem cells in babies with craniosynostosis, thus reducing the number of surgeries needed to correct the problem.

This article reports the surgical management of a 3-month-old girl with Saethre-Chotzen syndrome, who presented with bicoronal synostosis and a large midline sinus pericranii with abnormal cerebral venous drainage via scalp veins. Raised intracranial pressure was demonstrated on monitoring, indicating the need for calvarial expansion necessitating a coronal access incision. A 2-staged delayed raising of the coronal flap was performed to reduce the potential risk of cerebral venous infarction. Monitoring for clinical sequelae and a computerised tomography venogram followed each of these procedures, demonstrating successful redirection of the venous drainage of the brain posteriorly. Finally, a successful fronto-orbital advancement and remodeling procedure was performed with no complications.