Premature Fusion Of Cranial Sutures Research Articles

Identification of differentially expressed proteins between fused and open sutures in sagittal nonsyndromic craniosynostosis during suture development by quantitative proteomic analysis.

Nonsyndromic craniosynostosis (NCS), the premature fusion of cranial sutures, results in an abnormal skull shape and is associated with a significant morbidity. Proteomics is a promising tool for disease characterization and biomarker discovery; we aimed to identify biologically relevant differentially expressed proteins for NCS. Label-based quantitative proteomic profiling using TMT was performed on protein extracted from mesenchymal stem cells, osteoblasts and bone tissue of five open and five fused sutures of sagittal NCS (sNCS) and analyzed using quantitative LC-MS/MS based bottom-up proteomics. Differential protein abundance between open and fused sutures was determined to identify biologically relevant proteins of interest. Proteins were validated in an independent sample set by western blot and immunohistochemistry. We observed 838 differentially expressed proteins between open and fused sutures of sNCS. Decorin, lumican, and asporin were significantly downregulated while COL4A1 and TGFβ1|1 were upregulated in fused compared to open sutures. The majority of significantly differentially expressed proteins between open and fused sutures were observed in the proteomes of osteoblasts suggesting that protein changes contributing to premature sagittal suture fusion occur predominantly at the osteoblast level. Our findings suggest a possible ineffective ECM deposition at the osteoblast cell stage.

Realistic simulator for craniosynostosis endoscopic approach.

Craniosynostosis is a premature fusion of cranial sutures, and it requires surgery to decrease cranial pressure and remodel the affected areas. However, mastering these procedures requires years of supervised training. Several neurosurgical training simulators have been created to shorten the learning curve. Laboratory training is fundamental for acquiring familiarity with the necessary techniques and skills to properly handle instruments. This video presents a novel simulator for training on the endoscopic treatment for scaphocephaly and trigonocephaly, covering all aspects of the procedure, from patient positioning to performing osteotomies.The video can be found here: https://vimeo.com/512526147.

Neuro-Ophthalmological Manifestations of Craniosynostosis: Current Perspectives.

Craniosynostosis, a premature fusion of cranial sutures that can be isolated or syndromic, is a congenital defect with a broad, multisystem clinical spectrum. The visual pathway is prone to derangements in patients with craniosynostosis, particularly in syndromic cases, and there is a risk for permanent vision loss when ocular disease complications are not identified and properly treated early in life. Extensive advancements have been made in our understanding of the etiologies underlying vision loss in craniosynostosis over the last 20 years. Children with craniosynostosis are susceptible to interruptions in visual input arising from strabismus, refractive errors, and corneal damage; any of these aberrations can result in understimulation of the visual cortex during childhood neurodevelopment and permanent amblyopia. Elevated intracranial pressure resulting from abnormal cranial shape or volume can lead to papilledema and, ultimately, optic atrophy and vision loss. A pediatric ophthalmologist is a crucial component of the multidisciplinary care team that should be involved in the care of craniosynostosis patients and consistent ophthalmologic follow-up can help minimize the risk to vision posed by such entities as papilledema and amblyopia. This article aims to review the current understanding of neuro-ophthalmological manifestations in craniosynostosis and explore diagnostic and management considerations for the ophthalmologist taking care of these patients.

Craniosynostosis

Craniosynostosis is a condition of one or more of the fibrous sutures in an infant skull prematurely fuses by turning into bone (ossification).1 Premature fusion of cranial sutures may have an effect on cranial shape an less frequently on brain growth.2 There is a changing in the growth pattern of the skull and the skull can’t expand perpendicular to the fused suture, craniosynostosis can lead to abnormal head shape and abnormal facial features and results in increased intracranial pressure leading possibly to visual difficulty, sleeping impairment, eating problem, or impaired mental status with a significant reduction in IQ. Keywords: Preterm labor, IUGR, Hydrocephalus, Fetal anomalies, Increase intracranial pressure.

Isolation and Characterization of Human Suture Mesenchymal Stem Cells In Vitro.

Background and ObjectivesCranial sutures play a critical role in adjustment of skull development and brain growth. Premature fusion of cranial sutures leads to craniosynostosis. The aim of the current study was to culture and characterize human cranial suture mesenchymal cells in vitro.MethodsThe residual skull tissues, containing synostosed or contralateral suture from three boys with right coronal suture synostosis, were used to isolate the suture mesenchymal cells. Then, flow cytometry and multilineage differentiation were performed to identify the typical mesenchymal stem cell (MSC) properties. Finally, we used quantitative real-time polymerase chain reaction (RT-PCR) to detect the mRNA expression of osteogenesis and stemness related genes.ResultsAfter 3 to 5 days in culture, the cells migrated from the tissue explants and proliferated parallelly or spirally. These cells expressed typical MSC markers, CD73, CD90, CD105, and could give rises to osteocytes, adipocytes and chondrocytes. RT-PCR showed relatively higher levels of Runx2, osteocalcin and FGF2 in the fused suture MSCs than in the normal cells. However, BMP3, the only protein of BMP family that inhibits osteogenesis, reduced in synostosed suture derived cells. The expression of effector genes remaining cell stemness, including Bmi1, Gli1 and Axin2, decreased in the cells migrated from the affected cranial sutures.ConclusionsThe MSCs from prematurely occlusive sutures overexpressed osteogenic related genes and down-regulated stemness-related genes, which may further accelerate the osteogenic differentiation and suppress the self-renewal of stem cells leading to craniosynostosis.

Glycosylation of DMP1 maintains cranial sutures in mice.

Craniosynostosis, a severe craniofacial developmental disease, can only be treated with surgery currently. Recent studies have shown that proteoglycans are involved in the suture development. For the bone matrix protein, dentin matrix protein 1 (DMP1), glycosylation on the N-terminal of it could generate a functional proteoglycan form of DMP1 during osteogenesis. We identified that the proteoglycan form of DMP1 (DMP1-PG) is highly expressed in mineralisation front of suture. But, the potential role of DMP1-PG in suture fusion remain unclear. To investigate the role of DMP1-PG in cranial suture fusion and craniofacial bone development. By using a DMP1 glycosylation site mutation mouse model, DMP1-S89G mice, we compared the suture development in it with control mice. We compared the suture phenotypes, bone formation rate, expression levels of bone formation markers in vivo between DMP1-S89G mice and wild-type mice. Meanwhile, cell culture and organ culture were performed to detect the differences in cell differentiation and suture fusion in vitro. Finally, chondroitin sulphate (CHS), as functional component of DMP1-PG, was employed to test whether it could delay the premature suture fusion and the abnormal differentiation of bone mesenchymal stem cells (BMSCs) of DMP1-PG mice. DMP1-S89G mice had premature closure of suture and shorter skull size. Lack of DMP1-PG accelerated bone formation in cranial suture. DMP1-PG maintained the essential stemness of BMSCs in suture through blocking the premature differentiation of BMSCs to osteoblasts. Finally, chondroitin sulphate, a major component of DMP1-PG, successfully delayed the premature suture fusion by organ culture of skull in vitro. DMP1-PG could inhibit premature fusion of cranial suture and maintain the suture through regulating the osteogenic differentiation of BMSCs.

Wound Healing Complications After Cranial Vault Reconstruction for Craniosynostosis.

Craniosynostosis is a congenital cranial malformation involving premature fusion of cranial sutures. Indications for surgical repair of craniosynostosis include elevation of intracranial pressure, which can result in impaired vision and mental disability, as well as correction of abnormal skull shape. Resorbable plating systems have become the preferred technique for bony fixation in the repair of craniosynostosis. Multiple studies demonstrate the safety and low complication rate of resorbable plating systems.However, there is no consensus on which plating system is superior for patient outcomes. This study aims to investigate how the polymer composition of resorbable plating systems utilized in cranial vault reconstruction contributes to wound healing complications. A retrospective chart review was performed at the institution between January 1, 2005 and December 31, 2015. About 202 patients who underwent surgical repair of craniosynostosis were identified. The results showed that patients receiving the Biomet Lactosorb plating system were over twice as likely to have a wound complication within a year of surgery compared to other plating systems used at the institution. Wound complications continued to occur in the Biomet Lactosorb group at ≥180 days after surgery, whereas complications among the other plating systems occurred ≤80 days postoperatively. Half of all patients with wound complications had to undergo reoperation. These data demonstrate the effect of unique polymer compositions on wound healing, and will help to guide future clinical practice and industry development of resorbable plating systems.

The importance of physical treatment in children underwent craniosynostosis surgery in the first year of life

Background/Aim. Craniosynostosis is a condition that occurs intrauterine or develops in the infant period, and represents premature fusion of cranial sutures. This fusion of sutures limits the normal cranium development and leads to disorder in the phase of rapid growth and development of the brain. Creation of craniosynostoses is associated with an increased incidence of developmental delay during the breastfeeding period. Craniosynostoses are treated by surgery. The role of a physiatrist is to postoperatively assess psychomotor development and implement habilitation treatment. The aim of this study was to determine distribution of the type of craniosynostoses according to the age and gender of patients, effectiveness of habilitation treatment and to estimate the somatosensory evoked potential in the preoperative and postoperative period in children who underwent craniosynostosis surgery in the first year of life. Methods. The study was designed as a retrospective research. The data were collected from medical records of 51 children with craniosynostoses and delay in psychomotor development who underwent surgical intervention. The children included in this study, during follow-up, were involved in the habilitation treatment. Results. An early diagnosis and surgical intervention had a favorable effect on the development of motor function in children with craniosynostoses. The importance of stimulation treatment in the postoperative period was also proved for achievement of an adequate degree of motor development in children in relation to age. The results of our study confirmed the results obtained in previously published studies that the children who did not undergo surgery and start with the habilitation treatment immediately after it, had delay in psychomotor development of moderate degree. Conclusion. Habilitation treatment significantly reduced the deviations in psychomotor development of children with craniosynostoses if it started immediately after the surgical procedure.

S14-09 SESSION 14: FACIOCRANIOSYNOSTOSIS – PART III MITIGATION OF SHP2 ACTIVATION PREVENTS FGFR2 SIGNALING INDUCED CRANIOSYNOSTOSIS

Introduction: Activating-dominant mutations in the fibroblast growth factor receptor IIIc splice variant gene (Fgfr2c) cause premature cranial suture fusion (craniosynostosis), which can restrict growth of the craniofacial complex. Fgfr2c signaling is mediated via the docking protein Frs2a, which interacts with both Shp2, a tyrosine phosphatase, and Grb2, an adapter protein, to induce ERK-MAPK activation. The role of both Shp2 and Grb2 in craniosynostosis and craniofacial growth remains unknown; however, it is known that gain-of-function Fgfr2c mutant mice demonstrate hyperactivation of the ERK-MAPK signaling cascade and osteoblast activity. The objective of the current study is to determine the role Shp2 and Grb2 may play in Fgfr2-induced craniosynostosis and craniofacial growth. Methods: Gain-of-function Fgfr2c mice were crossed with mice deficient in two Shp2- or four Grb2-specific tyrosine phosphorylation sites within Frs2a. Skull morphology and sutures were analyzed grossly, histologically, and by micro-Computed Tomography. Coronal sutures were analyzed for ERK protein activation and whole calvaria were cultured and analyzed for alkaline phosphatase activity. Fluorescence-lifetime imaging microscopy – Fluorescence Resonance Energy Transfer (FLIM-FRET) was performed to study the interactions between FRS2a, Shp2, and Grb2 within WT or gain-of-function Fgfr2c mutant HEK293T cells. Analysis of Variance was used to compare three or more groups. An observed P value ≤ 0.05 was considered statistically significant. Results: Reduction of Shp2 activation prevents coronal suture fusion and restores normal craniofacial growth (P < 0.05), ERK-MAPK signaling (P < 0.05), and osteoblast activity (P < 0.05) in a mouse model of Fgfr2c-induced craniosynostosis via an Frs2a-dependent mechanism. Complete uncoupling of Grb2 from Frs2a resulted in only partial rescue of normal suture formation and growth. FLIM-FRET analysis revealed a complex interplay between FRS2a, Shp2, and Grb2 in the setting of dysregulated Fgfr2c signaling. Conclusion: This study provides mechanistic insight into craniofacial development and identifies Shp2 as a key regulator of craniofacial growth and development and highlights the therapeutic potential of Shp2 modulation for the treatment of Fgfr2c-related disorders.

Characterization of Perinatal Risk Factors and Complications Associated With Nonsyndromic Craniosynostosis.

Certain intrauterine risk factors are known to increase the risk of premature cranial suture fusion and may cause complications during birth. Some of these risk factors may be modifiable. Therefore, the authors sought to characterize the institutional patterns of prenatal risk factors and perinatal complications in nonsyndromic craniosynostosis patients compared to normal births from the surrounding area to identify areas for possible intervention or prevention. The medical records of all infants with nonsyndromic craniosynostosis and full birth records born at Duke University Health System from 2006 to 2017 were retrospectively reviewed. Maternal comorbidities, prenatal risk factors, and perinatal complications were collected. The North Carolina State Center for Health Statistics was queried for perinatal statistics from Durham county and the Northeastern Perinatal Care Region to represent a control cohort of normal births from the same time period and region. The primary outcome investigated was the incidence of prenatal risk factors and complications at birth associated with premature fusion of cranial sutures. Eighty births with nonsyndromic craniosynostosis were included in this study. The majority of these patients were males (61.7%) and born via cesarean section (55.0%). Intrauterine growth restriction occurred in 10.0% and head trauma during delivery occurred in 2.5%. Twinning (14.8% vs 3.6%, P < 0.0001), cesarean births (55.5% vs 30.0%, P < 0.0001), and breech presentation (17.3% vs 3.2%, P < 0.0001) were significantly more common in craniosynostosis patients. Prenatally, mothers of craniosynostosis infants had higher incidence of gestational diabetes (13.5% vs 5.0%, P < 0.0001) and oligohydramnios (6.1% vs 1.3%, P < 0.0001) compared to regional controls. This study demonstrates that premature suture fusion is associated with prenatal risk factors such as gestational diabetes and oligohydramnios. Continued research into potentially modifiable prenatal risk factors and more refined prenatal diagnostic tools has the potential to reduce both the incidence of premature suture fusion and the sequelae of birth complications in this population.

Perioperative management of patients undergoing craniosynostosis repair

Craniosynostosis is a type of craniofacial malformation because of premature fusion of cranial suture. The primary treatment is surgical correction which is usually done in stages over years to get best possible outcome. We did a retrospective analysis of five years from 1st August 2011 to 30th July 2016 in which we included twelve patients of craniosynostosis requiring corrective surgeries under general anaesthesia in our institution.

PLGA-based control release of Noggin blocks the premature fusion of cranial sutures caused by retinoic acid

Craniosynostosis (CS), the premature and pathological fusion of cranial sutures, is a relatively common developmental disorder. Elucidation of the pathways involved and thus therapeutically targeting it would be promising for the prevention of CS. In the present study, we examined the role of BMP pathway in the all-trans retinoic acid (atRA)–induced CS model and tried to target the pathway in vivo via PLGA-based control release. As expected, the posterior frontal suture was found to fuse prematurely in the atRA subcutaneous injection mouse model. Further mechanism study revealed that atRA could repress the proliferation while promote the osteogenic differentiation of suture-derived mesenchymal cells (SMCs). Moreover, BMP signal pathway was found to be activated by atRA, as seen from increased expression of BMPR-2 and pSMAD1/5/9. Recombinant mouse Noggin blocked the atRA-induced enhancement of osteogenesis of SMCs in vitro. In vivo, PLGA microsphere encapsulated with Noggin significantly prevented the atRA-induced suture fusion. Collectively, these data support the hypothesis that BMP signaling is involved in retinoic acid–induced premature fusion of cranial sutures, while PLGA microsphere–based control release of Noggin emerges as a promising strategy for prevention of atRA-induced suture fusion.

Locally Affine Diffeomorphic Surface Registration and Its Application to Surgical Planning of Fronto-Orbital Advancement.

Metopic craniosynostosis is a condition caused by the premature fusion of the metopic cranial suture. If untreated, it can result into brain growth restriction, increased intra-cranial pressure, visual impairment, and cognitive delay. Fronto-orbital advancement is the widely accepted surgical approach to correct cranial shape abnormalities in patients with metopic craniosynostosis, but the outcome of the surgery remains very dependent on the expertise of the surgeon because of the lack of objective and personalized cranial shape metrics to target during the intervention. We propose in this paper a locally affine diffeomorphic surface registration framework to create an optimal interventional plan personalized to each patient. Our method calculates the optimal surgical plan by minimizing cranial shape abnormalities, which are quantified using objective metrics based on a normative model of cranial shapes built from 198 healthy cases. It is guided by clinical osteotomy templates for fronto-orbital advancement, and it automatically calculates how much and in which direction each bone piece needs to be translated, rotated, and/or bent. Our locally affine framework models separately the transformation of each bone piece while ensuring the consistency of the global transformation. We used our method to calculate the optimal surgical plan for 23 patients, obtaining a significant reduction of malformations (p < 0.001) between 40.38% and 50.85% in the simulated outcome of the surgery using different osteotomy templates. In addition, malformation values were within healthy ranges (p > 0.01).

Rapamycin rescues BMP mediated midline craniosynostosis phenotype through reduction of mTOR signaling in a mouse model.

Craniosynostosis is defined as congenital premature fusion of one or more cranial sutures. While the genetic basis for about 30% of cases is known, the causative genes for the diverse presentations of the remainder of cases are unknown. The recently discovered cranial suture stem cell population affords an opportunity to identify early signaling pathways that contribute to craniosynostosis. We previously demonstrated that enhanced BMP signaling in neural crest cells (caA3 mutants) leads to premature cranial suture fusion resulting in midline craniosynostosis. Since enhanced mTOR signaling in neural crest cells leads to craniofacial bone lesions, we investigated the extent to which mTOR signaling is involved in the pathogenesis of BMP-mediated craniosynostosis by affecting the suture stem cell population. Our results demonstrate a loss of suture stem cells in the caA3 mutant mice by the newborn stage. We have found increased activation of mTOR signaling in caA3 mutant mice during embryonic stages, but not at the newborn stage. Our study demonstrated that inhibition of mTOR signaling via rapamycin in a time specific manner partially rescued the loss of the suture stem cell population. This study provides insight into how enhanced BMP signaling regulates suture stem cells via mTOR activation.

Tyrosine kinase receptor c-ros-oncogene 1 inhibition alleviates aberrant bone formation of TWIST-1 haploinsufficient calvarial cells from Saethre-Chotzen syndrome patients.

Saethre-Chotzen syndrome (SCS), associated with TWIST-1 mutations, is characterized by premature fusion of cranial sutures. TWIST-1 haploinsufficiency, leads to alterations in suture mesenchyme cellular gene expression patterns, resulting in aberrant osteogenesis and craniosynostosis. We analyzed the expression of the TWIST-1 target, Tyrosine kinase receptor c-ros-oncogene 1 (C-ROS-1) in TWIST-1 haploinsufficient calvarial cells derived from SCS patients and calvaria of Twist-1del/+ mutant mice and found it to be highly expressed when compared to TWIST-1 wild-type controls. Knock-down of C-ROS-1 expression in TWIST-1 haploinsufficient calvarial cells derived from SCS patients was associated with decreased capacity for osteogenic differentiation in vitro. Furthermore, treatment of human SCS calvarial cells with the tyrosine kinase chemical inhibitor, Crizotinib, resulted in reduced C-ROS-1 activity and the osteogenic potential of human SCS calvarial cells with minor effects on cell viability or proliferation. Cultured human SCS calvarial cells treated with Crizotinib exhibited a dose-dependent decrease in alkaline phosphatase activity and mineral deposition, with an associated decrease in expression levels of Runt-related transcription factor 2 and OSTEOPONTIN, with reduced PI3K/Akt signalling in vitro. Furthermore, Crizotinib treatment resulted in reduced BMP-2 mediated bone formation potential of whole Twist-1del/+ mutant mouse calvaria organotypic cultures. Collectively, these results suggest that C-ROS-1 promotes osteogenic differentiation of TWIST-1 haploinsufficient calvarial osteogenic progenitor cells. Furthermore, the aberrant osteogenic potential of these cells is inhibited by the reduction of C-ROS-1. Therefore, targeting C-ROS-1 with a pharmacological agent, such as Crizotinib, may serve as a novel therapeutic strategy to alleviate craniosynostosis associated with aberrant TWIST-1 function.

Genetic Analysis of Syndromic and Nonsyndromic Patients With Craniosynostosis Identifies Novel Mutations in the TWIST1 and EFNB1 Genes.

Craniosynostosis, the premature fusion of cranial sutures, is usually divided into 2 major categories: syndromic and nonsyndromic. Mutations in the FGFR1, FGFR2, FGFR3, TWIST1, and EFNB1 genes cause the common craniosynostosis syndromes Muenke, Crouzon and Crouzon with acanthosis nigricans, Apert, Pfeiffer, Saethre-Chotzen, and Craniofrontonasal. Overlapping features among craniosynostosis syndromes, phenotypic heterogeneity even within the same syndrome, especially in the case of Muenke syndrome, and inadequate clinical evaluation can lead to misdiagnosis, which molecular testing can help clarify. The aim of this study is to investigate the underlying genetic cause in 46 patients with syndromic or nonsyndromic craniosynostosis by direct sequencing and/or microdeletion/microduplication analysis of the FGFR1-3, TWIST1, and EFNB1 genes. Genetic analysis identified 3 novel mutations, c.413T>C - p.(Leu138Pro) [p.(L138P)] in TWIST1, the previously reported c.373G>A - p.(Glu125Lys) [p.(E125K)], and c.717dupA - p.(Leu240IlefsTer79) [p.(L240fs)] mutation in EFNB1 gene as well as 6 previously known mutations and a heterozygous TWIST1 gene deletion. The 2 novel mutations within EFNB1 gene arose de novo, but the novel mutation p.(L138P) within TWIST1 gene was inherited from the patient's father, who was found to be mosaic for the mutation. To our knowledge, this is the first case of mosaicism described for TWIST1 gene. The contribution of molecular genetic analysis to the diagnosis of patients with syndromic craniosynostosis was useful because some were originally misdiagnosed. Conversely, thorough clinical evaluation can guide molecular testing and result in a correct diagnosis.

Craniosynostosis as a clinical and diagnostic problem: molecular pathology and genetic counseling.

Craniosynostosis (occurrence: 1/2500 live births) is a result of premature fusion of cranial sutures, leading to alterations of the pattern of cranial growth, resulting in abnormal shape of the head and dysmorphic facial features. In approximately 85% of cases, the disease is isolated and nonsyndromic and mainly involves only one suture. Syndromic craniosynostoses such as Crouzon, Apert, Pfeiffer, Muenke, and Saethre-Chotzen syndromes not only affect multiple sutures, but are also associated with the presence of additional clinical symptoms, including hand and feet malformations, skeletal and cardiac defects, developmental delay, and others. The etiology of craniosynostoses may involve genetic (also somatic mosaicism and regulatory mutations) and epigenetic factors, as well as environmental factors. According to the published data, chromosomal aberrations, mostly submicroscopic ones, account for about 6.7-40% of cases of syndromic craniosynostoses presenting with premature fusion of metopic or sagittal sutures. The best characterized is the deletion or translocation of the 7p21 region containing the TWIST1 gene. The deletions of 9p22 or 11q23-qter (Jacobsen syndrome) are both associated with trigonocephaly. The genes related to the pathogenesis of the craniosynostoses itself are those encoding transcription factors, e.g., TWIST1, MSX2, EN1, and ZIC1, and proteins involved in osteogenic proliferation, differentiation, and homeostasis, such as FGFR1, FGFR2, RUNX2, POR, and many others. In this review, we present the clinical and molecular features of selected craniosynostosis syndromes, genotype-phenotype correlation, family genetic counseling, and propose the most appropriate diagnostic algorithm.

A RARE CASE OF NEONATAL APERT SYNDROME

Apert syndrome is a rare Type I acrocephalosyndactyly syndrome. It is a congenital disorder characterized by premature fusionof cranial sutures (craniosynostosis), malformation of skull, hands, face, and feet. Apert syndrome has an incidence of 1/50,000to 1/80,000 live births. It is classified as a branchial arch syndrome, affecting the first branchial or pharyngeal arch, the precursorof the maxilla and mandible. Disturbances in the development of branchial arches in the fetal development create lasting andwidespread effects. It is inherited as an autosomal dominant and occurs due to the gene mutations in the receptors of the fibroblastgrowth factor. Management of Apert syndrome requires multidisciplinary approach. We, hereby, report a case of a 5‑h‑old neonatewith Apert syndrome.

Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples.

Craniosynostosis is a heterogeneous condition caused by the premature fusion of cranial sutures, occurring mostly as an isolated anomaly. Pathogenesis of non-syndromic forms of craniosynostosis is largely unknown. In about 15–30% of cases craniosynostosis occurs in association with other physical anomalies and it is referred to as syndromic craniosynostosis. Syndromic forms of craniosynostosis arise from mutations in genes belonging to the Fibroblast Growth Factor Receptor (FGFR) family and the interconnected molecular pathways in most cases. However it can occur in association with other gene variants and with a variety of chromosome abnormalities as well, usually in association with intellectual disability (ID) and additional physical anomalies. Evaluating the molecular properties of the genes undergoing intragenic mutations or copy number variations (CNVs) along with prevalence of craniosynostosis in different conditions and animal models if available, we made an attempt to define two distinct groups of unusual syndromic craniosynostosis, which can reflect direct effects of emerging new candidate genes with roles in suture homeostasis or a non-specific phenotypic manifestation of pleiotropic genes, respectively. RASopathies and 9p23p22.3 deletions are reviewed as examples of conditions in the first group. In particular, we found that craniosynostosis is a relatively common component manifestation of cardio-facio-cutaneous (CFC) syndrome. Chromatinopathies and neurocristopathies are presented as examples of conditions in the second group. We observed that craniosynostosis is uncommon on average in these conditions. It was randomly associated with Kabuki, Koolen-de Vries/KANSL1 haploinsufficiency and Mowat–Wilson syndromes and in KAT6B-related disorders. As an exception, trigonocephaly in Bohring-Opitz syndrome reflects specific molecular properties of the chromatin modifier ASXL1 gene. Surveillance for craniosynostosis in syndromic forms of intellectual disability, as well as ascertainment of genomic CNVs by array-CGH in apparently non-syndromic craniosynostosis is recommended, to allow for improvement of both the clinical outcome of patients and the accurate individual diagnosis.

Imaging of Skeletal Disorders Caused by Fibroblast Growth Factor Receptor Gene Mutations.

Fibroblast growth factors and fibroblast growth factor receptors (FGFRs) play important roles in human axial and craniofacial skeletal development. FGFR1, FGFR2, and FGFR3 are crucial for both chondrogenesis and osteogenesis. Mutations in the genes encoding FGFRs, types 1-3, are responsible for various skeletal dysplasias and craniosynostosis syndromes. Many of these disorders are relatively common in the pediatric population, and diagnosis is often challenging. These skeletal disorders can be classified based on which FGFR is affected. Skeletal disorders caused by type 1 mutations include Pfeiffer syndrome (PS) and osteoglophonic dysplasia, and disorders caused by type 2 mutations include Crouzon syndrome (CS), Apert syndrome (AS), and PS. Disorders caused by type 3 mutations include achondroplasia, hypochondroplasia, thanatophoric dysplasia (TD), severe achondroplasia with developmental delay and acanthosis nigricans, Crouzonodermoskeletal syndrome, and Muenke syndrome. Most of these mutations are inherited in an autosomal dominant fashion and are gain-of-function-type mutations. Imaging plays a key role in the evaluation of these skeletal disorders. Knowledge of the characteristic imaging and clinical findings can help confirm the correct diagnosis and guide the appropriate molecular genetic tests. Some characteristics and clinical findings include premature fusion of cranial sutures and deviated broad thumbs and toes in PS; premature fusion of cranial sutures and syndactyly of the hands and feet in AS; craniosynostosis, ocular proptosis, and absence of hand and foot abnormalities in CS; rhizomelic limb shortening, caudal narrowing of the lumbar interpediculate distance, small and square iliac wings, and trident hands in achondroplasia; and micromelia, bowing of the femora, and platyspondyly in TD. ©RSNA, 2017.