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We present the first comprehensive study, to our knowledge, on genomic chromosomal analysis in syndromic craniosynostosis. In total, 45 patients with craniosynostotic disorders were screened with a variety of methods including conventional karyotype, microsatellite segregation analysis, subtelomeric multiplex ligation-dependent probe amplification)...
Citations
... Nonsyndromic craniosynostosis constitutes about 80% of all known cases [4]. The syndromic craniosynostosis (SC) is considerably rarer -20 % of all repoted cases. ...
... The syndromic craniosynostosis (SC) is considerably rarer -20 % of all repoted cases. About 30% of the SC are mainly attributed to pathogenic variants in certain genes (FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2, RAB23, RUNX2) [4]. They are inherited in an autosomal dominant pattern (except for RAB23) with variable penetrance and expressivity. ...
... They are inherited in an autosomal dominant pattern (except for RAB23) with variable penetrance and expressivity. Chromosomal anomalies account for about 16% of syndromic craniosynostosis cases [4]. MLPA and array CGH offer similar diagnostic value in literature and can be used in tandem to confirm a certain finding [4]. ...
Syndromic craniosynostosis (SC) is a genetically determined premature closure of one or more of the cranial sutures, which may result in severe dysmorphism, increased intracranial pressure along with many other clinical manifestations. The considerable risk of complications along with their significant incidence makes these cranial deformations an important medical problem.
Aiming to elucidate the complex genetic etiology of syndromic craniosynostosis, we investigated 39 children, screened systematically with a combination of conventional cytogenetic analysis, multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridisation (aCGH).
Pathological findings were established in 15.3% (6/39) of the cases using aCGH, in 7.7% (3/39) using MLPA and 2.5% (1/39) using conventional karyotyping. About 12.8% (5/39) of the patients with normal karyotype carried submicroscopic chromosomal rearrangements. Duplications were found to be more common than deletions.
Conclusion : The systematic genetic evaluation of children with SC revealed a high prevalence of submicrosopic chromosomal rearrangements (most commonly duplications). This suggests the leading role of those defects in the pathogenesis of syndromic craniosynostosis. The genetic complexity of SC was reaffirmed by the dis Bulgaria covery of pathological findings in various chromosomal regions. Certain genes were discussed in conjunction with craniosynostosis.
... The chromosomal array testing seems to be suitable for patients having severe developmental retardation and several abnormalities. The presence of chromosomal abnormalities in patients might require the investigation of the parents as well (61). In patients that have an isolated coronary suture, genetic tests usually begin with screening for mutations in FGFR3 (Muenke's syndrome). ...
Craniosynostosis refers to the early fusion of one or many cranial sutures, causing craniofacial abnormalities observed in 1:2,500 births worldwide. In most cases (85%), craniosynostosis is presented as sporadic anomaly (non-syndromic craniosynostosis), while in other cases (15%) as part of syndromes (syndromic craniosynostosis). Patients with syndromic disorder usually have more severe symptoms compared to those with single suture synostosis. Most common syndromes of craniosynostosis include Pfeiffer, Apert, Crouzon, Jackson-Weiss, Muenke and Boston type MSX2-related syndrome. The main gene mutations in craniosynostosis involve FGFR1, FGFR2, FGFR3, TWIST1 and MSX2, which encode key factors influencing cranial bone morphogenesis. The main therapeutic approaches are surgical as discussed in this review, and the type of therapy depends on the graveness of the incident.
... CRS can be classi ed as syndromic -when the cranial synostosis is a part of a malformative syndrome or nonsyndromic -when it presents as an isolated feature. Nonsyndromic craniosynostosis (NSC) constitutes about 80% of all cases [4]. Recent studies have shown that genetic variations play a leading role in the pathogenesis of NSC. ...
... Considerably rarer are the syndromic forms of craniosynostosis -20 % of all repoted cases. About 30% of the SC are caused by pathogenic variants in certain genes (FGFR1, FGFR2, FGFR3, TWIST1, EFNB1, MSX2, RAB23, RUNX2) [4]. These are called "monogenic" or "mendelian" forms of craniosynostosis. ...
... They are inherited in an autosomal dominant pattern (except for RAB23) with a variable degree of expression and penetration that yields a large array of clinical manifestations. Chromosomal anomalies account for about 16% of syndromic craniosynostosis cases [4]. MLPA and array CGH offer similar diagnostic value in literature and can be used in tandem to con rm a certain nding [4]. ...
Syndromic craniosynostosis (SC) is a genetically determined premature closure of one or more of the cranial sutures, which may result in severe dysmorphism, increased intracranial pressure along with many other clinical manifestations. The considerable risk of complications along with significant incidence makes these cranial deformations an important medical problem. Despite the efforts to clarify the pathogenesis of SC in recent years, its genetic aspects remain largely unknown.
Aiming to elucidate the complex genetic etiology of syndromic craniosynostosis, we conducted an investigation of 39 children, screened systematically with a combination of conventional cytogenetic analysis, multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridisation (aCGH).
Pathological findings were established in 15.3% (6/39) of the cases using aCGH, in 7.7% (3/39) using MLPA and 2.5% (1/39) using conventional karyotyping. About 12.8% (5/39) of the patients with normal karyotype carried submicroscopic chromosomal rearrangements. Duplications were found to be more common than deletions.
Conclusion: The systematic genetic evaluation of children with SC revealed a high prevalence of submicrosopic chromosomal rearrangements (most commonly duplications and gain-of-function variations). This suggests the leading role of those defects in the pathogenesis of syndromic craniosynostosis. The genetic complexity of SC was reaffirmed by the discovery of pathological findings in various chromosomal regions. Certain genes were discussed in conjunction with craniosynostosis.
... Submicroscopic chromosomal abnormalities are also associated with syndromic craniosynostosis and the prevalence of this alterations shows wide variety, from 6.7% to 28%. 7,8 According to the Oxford study the prevalence of chromosome abnormalities in metopic or sagittal synostosis was 85% and single gene disorders were reported 58% of cases which needs reoperation. 7 The etiology of the disease, clinical presentation and prognosis were based on identification of molecular genetic alterations. ...
... Chromosomal alterations had been identified in 42% of the syndromic craniosynostosis cases and submicroscopic abnormalities identified in 28% of the karyotypically normal cases. 8 Mefford et al. identified rare CNVs in 7.5% of the single-suture synostosis cases. Studies showed that deletion of chromosome 9p22-p24 and 11q23 (Jacobsen syndrome) were related with trigonocephaly. ...
... 14,15 A huge variety of chromosomal alterations have been linked with craniosynostosis cases. 7,8 In this study, we determined NM_001163213.1(FGFR3):c.749C>G (p.Pro250Arg) mutation and NM_000141.4 ...
The early fusion of the cranial sutures was described as a craniosynostosis. The early diagnosis and management of craniosyn-ostosis is very important. Environmental factors and genetic abnormalities plays a key role during the development of craniosynostosis. Syndromic craniosynostosis cases are related with autosomal dominant disorders but nearly half of the affected cases carry a new mutation. In this study, in order to identify the genetic etiology of craniosynostosis the authors analyzed 20 craniosynostosis patients by using conventional karyotype, aCGH, sanger sequencing, next generation sequencing (NGS) and Multiplex ligation-dependent probe amplification (MLPA) techniques. The authors identified mutations on FGFR2 and FGFR3 genes which were associated with Muenke syndrome, Crouzon syndrome and skeletal dysplasia syndromes. NGS applied all of the cases and 7 clinical variations in 5 different gene were detected in %20 of cases. In addition to these abnormalities ; del(11)(q14.1q22.2), del(17)(q21.31), dup(22)(q13.31) and t(2;16)(q37;p13) have been identified in our cohort which are not previously detected in craniosynostosis cases. Our study demonstrates the importance of detailed genetic analysis for the diagnosis, progression and management of the craniosynostosis.
... This finding clearly highlights the importance of gene dosage effect on syndromic craniosynostosis. 82 Interestingly, in at least two cases, it has been shown with multiple chromosomal aberrations that both had deletions in chromosomes 7p21 (ranging in size from 3 to 12 Mb) 83,84 and 22q11.2. 37,85,86 All these genetic and cytogenetic factors make craniosynostosis a highly complex condition. ...
Craniosynostosis is one of the pathologic craniofacial disorders and is defined as the premature fusion of one or more cranial (calvarial) sutures. Cranial sutures are fibrous joints consisting of non-ossified mesenchymal cells that play an important role in the development of healthy craniofacial skeletons. Early fusion of these sutures results in incomplete brain development that may lead to complications of several severe medical conditions including seizures, brain damage, mental delay, complex deformities, strabismus, visual and breathing problems. As a congenital disease, craniosynostosis has a heterogeneous origin that can be affected by genetic and epigenetic alterations, teratogens and environmental factors and make the syndrome highly complex. To date, approximately 200 syndromes are correlated to the craniosynostosis. In addition to being part of a syndrome, craniosynostosis can be seen as nonsyndromic formed without any additional anomalies. More than 50 nuclear genes that are relating to the craniosynostosis have been identified. Besides genetic factors, epigenetic factors like microRNAs and mechanical forces also play important roles in suture fusion. Due to craniosynostosis being a multifactorial disorder, evaluating the craniosynostosis syndrome requires and depends on all the information obtained from clinical findings, genetical analysis, epigenetic or environmental factors or gene modulators. In this review, we will focus on embryologic and genetic studies, as well as epigenetic including environmental studies. We will discuss published studies and correlate the findings with unknown aspects of craniofacial disorders.
... Mefford et al. (2010), in the largest study to date of patients with isolated sagittal, unilateral coronal, metopic, or unilateral lambdoid synostosis confirmed by computed tomography (CT) scanning, and negative screening for certain single-gene defects associated with craniosynostoses, identified 7.5% potentially pathogenic deletions or duplications, including a duplication of a novel gene, RUNX2. Previous work by Jehee et al. (2008) had specifically pointed to the metopic suture as being more frequently affected in patients from syndromic cohorts carrying pathogenic CNVs. ...
The aim of this review is to provide the current state of knowledge about the usefulness of modern genetic technologies in uncovering the causality of isolated and multiple congenital anomalies. Array comparative genomic hybridization and next-generation sequencing have revolutionized the clinical approach to patients with these phenotypes. Both technologies enable early diagnosis, especially in clinically challenging newborn populations, and help to uncover genetic defects associated with various phenotypes. The application of both complementary methods could assist in identifying many variants that may simultaneously be involved in the development of a number of isolated or multiple congenital anomalies. Both technologies carry serious variant misinterpretation risks as well. Therefore, the methods of variant classification and accessible variant databases are mentioned. A useful strategy of clinical genetic testing with the application of both methodologies is presented. Finally, future directions and challenges are briefly commented on in this review.
... Multi-suture craniosynostosis accounts for the remaining 5-15%, and includes well-recognized syndromes such Crouzon, Apert, Pfeiffer, and Saethre-Chotzen, as well as individuals with rare syndromes and uncommon combinations of craniosynostosis. Beyond mutations in classical syndromic craniosynostosis genes, chromosome abnormalities account for 16-22% [2,17]. ...
The craniofacial skeleton is made up of the neurocranium, which encases the brain, and the viscerocranium, which includes the bones of the face and cranial base. At birth, the human craniofacial skeleton is comprised of 44 bones that develop via both endochondral and intramembranous ossification, depending on the bone. Undifferentiated mesenchyme separates the bones for varying periods of postnatal life, playing a key role in regulating cranioskeletal growth. Appositional bone growth at the suture margins is regulated by a complex crosstalk between growth factor signaling pathways, some of which function more prominently in specific sutures. In this chapter, we review the embryology and current understanding of the molecular genetic basis of premature fusions (synostosis) of both the calvarial and facial sutures gleaned from genetic studies in humans and model organisms such as the mouse. In addition, we reassess the spectrum of mutations found in FGFR2, the most prominent factor implicated in craniofacial synostosis, and propose a new model for explaining the impact of many of the common amino acid substitutions that result in pathology. Finally, advancements that promise to enable use of mesenchymal stem cells in tissue engineering-based approaches are discussed with respect to prospects for more effective treatment of these craniofacial conditions.
... Genetics diagnostics was performed with different techniques in the screening of 45 patients with a syndromic craniosynostosis without known mutation. 56 New causal abnormalities were found in 19 patients. ...
This guideline for care of children with craniosynostosis was developed by a national working group with representatives of 11 matrix societies of specialties and the national patients' society. All medical aspects of care for nonsyndromic and syndromic craniosynostosis are included, as well as the social and psychologic impact for the patient and their parents. Managerial aspects are incorporated as well, such as organizing a timely referral to the craniofacial center, requirements for a dedicated craniofacial center, and centralization of this specialized care. The conclusions and recommendations within this document are founded on the available literature, with a grading of the level of evidence, thereby highlighting the areas of care that are in need of high-quality research. The development of this guideline was made possible by an educational grant of the Dutch Order of Medical Specialists. The development of this guideline was supported by an educational grant of the Dutch Order of Medical Specialists.
... These fusions can occur in any suture: sagittal (47.5%), coronal and/or bicoronal (24.5%), metopic (17.7%), lambdoid (4.9%) or multiple (5.4%) [Wilkie et al., 2010]. Several genes have been associated with craniosynostosis [for review see Wilkie et al., 2010], and up to 22% of syndromic cases have been associated with chromosomal rearrangements [Jehee et al., 2008]. As such, the use of molecular chromosomal analysis is recommended for initial investigation of craniosynostosis, especially in syndromic cases [Wilkie et al., 2010]. ...
... This is, to our knowledge, the first report of an unbalanced translocation involving chromosomes 17q and 20q. Since it has been estimated that 22% of craniosynostosis cases are associated with chromosomal rearrangements, a CMA approach was used for this patient, after G-banding had shown an apparently normal karyotype [Jehee et al., 2008]. The advent of molecular cytogenetic techniques has facilitated a 'genotype-first' approach to identifying genetic anomalies in patients for whom the phenotype does not point to an obvious gene or genomic region. ...
Craniosynostosis is defined as a premature fusion of at least one cranial suture, which can be accompanied by other findings. Of syndromic cases, 14-22% have been associated with chromosomal rearrangements. This report describes a Brazilian boy with syndromic craniosynostosis who also presented with intellectual disability, microcephaly, frontal bossing, bitemporal narrowing, short neck, syndactyly, and cardiac defects. Chromosome banding showed an apparently normal male karyotype. Subsequent chromosomal microarray analysis (CMA) using the Affymetrix CytoScan 750 K Array showed a duplication of 2.1 Mb on chromosome 17q and a deletion of 1.4 Mb on chromosome 20q. The data suggested an unbalanced translocation, which was confirmed by fluorescence in-situ hybridization analysis (FISH). While there are several reports in the literature of chromosome 17q duplication syndrome accompanied by partial monosomies of other chromosomes, this is the first case featuring partial monosomy of 20q. The patient́s phenotype is generally consistent with 17q duplication syndrome, however craniosynostosis has rarely been associated with this chromosomal anomaly. © 2014 Wiley Periodicals, Inc.
© 2014 Wiley Periodicals, Inc.
... Mutational targeted genetic testing may be appropriate for patients in whom classical or specific CS syndrome diagnosis is suspected as a first-line test, but high-resolution cytogenetic testing, such as array CGH, may be worthy first in the nontypical syndromic CS phenotype. Array CGH detects chromosomal abnormalities in 6-28 % of cases with syndromic CS of unknown origin [8,30] and should be contemplated in these cases. Despite the clinical diversity of CS, genetic studies may be decisive for genetic counselling. ...
Case report
We describe an unusual clinical case with an 11-Mb deletion at 4q27 (chr4: 123094652-134164491), craniosynostosis (CS), mild psychomotor retardation, and facial dysmorphic features. This deletion involves 18 genes; FGF2, NUDT6, and SPRY1 are primarily or secondarily implicated in human cranial bone and sagittal suture development and could play an important role in CS.
Conclusions
Clinicians should always contemplate genetic studies in patients with syndromic CS. Mutational targeted genetic testing is appropriate for patients with classical or specific CS syndrome. Nevertheless, array comparative genomic hybridization (array CGH) should be considered as a first-line test in nontypical syndromic CS phenotype. Cytogenetic studies are decisive for genetic counseling indeed.
