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Genetic Bases of Craniosynostoses: an Update Neurochirurgie 65 (2019) 196–201 Disponible en ligne sur ScienceDirect www.sciencedirect.com Craniosynostosis: State of the Art 2019 Genetic bases of craniosynostoses: An update a b c a,d e a,d,∗ T. Armand , E. Schaefer , F. Di Rocco , P. Edery , C. Collet , M. Rossi a Service de génétique, Centre de Référence Anomalies du Développement, Hospices Civils de Lyon, 69677 Bron, France b Service de Génétique Médicale, Institut de Génétique Médicale d’Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France c Service de neurochirurgie pédiatrique, Centre de référence des craniosténoses et malformations crânio-faciales, Hospices Civils de Lyon, Bron, France d CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Université Claude Bernard Lyon 1, Inserm U1028, Bron, France e Département de biochimie et de génétique, Hospital Lariboisière, AP–HP, Paris, France a r t i c l e i n f o a b s t r a c t Article history: Craniosynostosis (CS) is defined as the premature fusion of cranial sutures, leading to an abnormal skull Received 28 June 2019 shape. The overall incidence is between 1: 2,000 and 1: 3,000 live births. Genetic causes are found in Received in revised form 20% of cases. CS can be isolated (non-syndromic CS/NSCS) or they can be part of multiple congenital 27 September 2019 abnormalities syndromes (syndromic CS/SCS). A few SCS, such as Crouzon, Pfeiffer, Apert and Saethre- Accepted 2 October 2019 Chotzen syndromes, are very well known and their molecular bases have been clarified in the 90s and early Available online 9 October 2019 2000s, thus showing the major role of the FGF receptors and TWIST signaling pathways in the etiology of these conditions. The recent availability of powerful molecular tools for genetic diagnosis, such as Keywords: whole exome or whole genome sequencing, has led to the characterization of the molecular bases of Craniosynostosis Genes an increasing number of CS, thus emphasizing the significant genetic heterogeneity of these conditions, Syndromes and blurring the limit between SCS and NSCS. The genetic characterization of patients affected by CS leads to appropriate genetic counseling and provides relevant information concerning comorbidity and prognosis. Nevertheless, this can also lead to the detection of susceptibility factors with low penetrance whose interpretation in genetic counseling is difficult and it raises the question of its cost-effectiveness for health systems. These aspects suggest the need of a patient-tailored clear rationale for performing genetic tests. In this study, we reviewed the main molecular etiologies reported in the last 15 years of either SCS or NSCS, and we propose a systematic multidisciplinary approach as well as a diagnostic flowchart for the genetic evaluation of these patients. © 2019 Published by Elsevier Masson SAS. 1. Introduction Following Virchow’s law [1], a premature fusion of a cranial suture is associated with restricted bone perpendicular growth and Craniosynostosis (CS) is defined as the premature fusion of one compensatory parallel growth resulting, ultimately, in an abnormal or more cranial sutures leading to an abnormal skull shape. skull shape. During infancy and childhood, the calvaria expands to accom- Among rare diseases (defined as affecting less than 1 in 2,000 live modate the growing brain. This growth occurs predominantly at the births), CS are relatively common, their incidence being estimated junctions of undifferentiated mesenchyme, named sutures, which between 1: 2,000; 1: 3,000 [2]. lie between cranial bones. The paired frontal and parietal bones Differential diagnosis includes positional plagiocephaly which are separated in the midline by the metopic and sagittal sutures, is characterized by a deformation of skull bones in the absence of respectively; coronal sutures separate frontal and parietal bones; abnormal fusion of the sutures [1]. parietal bones are separated from the occipital bone by lambdoid CS are heterogeneous conditions from a clinical and etiologi- sutures. cal point of view and their classification, diagnosis and treatment represent a challenge for physicians. Various classifications have been proposed, based on different approaches. Firstly, CS can be classified on the basis of the result- ing head-shape (e.g.: scaphocephaly for the premature fusion of ∗ Corresponding author at: Service de Génétique, Centre de Référence des Anoma- sagittal suture; brachycephaly, when coronal sutures are involved; lies du Développement, Hospices Civils de Lyon, 59, boulevard Pinel, Bron cedex, trigonocephaly when metopic suture is involved; plagiocephaly, 69677, France. when lambdoid suture is involved; oxycephaly/turricephaly when E-mail address: [email protected] (M. Rossi). https://doi.org/10.1016/j.neuchi.2019.10.003 0028-3770/© 2019 Published by Elsevier Masson SAS. T. Armand et al. / Neurochirurgie 65 (2019) 196–201 197 multiple sutures such as sagittal, coronal and lambdoid, are MSX2 mutations cause Craniosynostosis 2/Boston type, an auto- involved, sometimes leading to a cloverleaf appearance) as well as somal dominant condition characterized by variable intra-familial the affected cranial suture (sagittal in about 50% of cases, metopic expressivity. The main clinical features include frontal bossing, tur- in about 25%, coronal in about 20%, and lambdoid in < 5% of cases) ricephaly, trigonocephaly, brachycephaly and cloverleaf skull in the [3–5]. most severely affected patients. The craniosynostosis is generally Furthermore, they can be classified on the basis of the possi- “non-syndromic”; brachydactyly can be observed and intelligence ble association with other malformations, syndromic forms (SCS) is usually normal. being rarer (25–30%) than non-syndromic CS (NSCS) (70–75%) [6]. In this respect, a few papers suggest a progressively increasing inci- ERF 3. (ETS2 repressor factor) [OMIM: # 611888] [15,16] dence of NSCS, which currently remains unexplained [3,7,8]. It is well-known that developmental delay can be observed in SCS, but ETS2 is a transcription factor and proto-oncogene involved in increasing evidence suggests that neurodevelopmental problems development, apoptosis, and telomerase regulation. ERF encodes can be observed also in a subset of patients presenting “NSCS”, for an inhibitory ETS transcription factor which directly binds to regardless the type of surgery performed, thus suggesting that a ERK1/2. clear difference between SCS and NSCS is not always possible [6]. Mutations in ERF where initially found in patients with a A further classification is based on the etiology: primary CS Crouzon-like appearance, showing midface-hypoplasia and eye are due to intrinsic genetic causes acting alone or in combina- proptosis (CS 4/Crouzon-like CS, OMIM: # 611888) with possi- tion with environmental factors, while secondary CS are caused by ble multisuture involvement. Associated features include relatively systemic disorders affecting also the developing suture. Systemic frequent learning difficulties and behavioral problems as well as diseases possibly associated with CS include skeletal dysplasias non-specific brain abnormalities, such as Chiari type 1 and dilated such as acrodysostosis [OMIM: # 101800], hypophosphatasia ventricles. Subsequently, it has been shown that mutations in ERF [OMIM: # 146300], hypophosphatemic rickets [OMIM: # 307800]; can cause also NSCS. CS4 is inherited with an autosomal dominant inherited metabolic diseases with skeletal involvement such as pattern. mucopolysaccharidoses; ciliopathies, such as Sensenbrenner syn- drome [OMIM: # 218330]. 4. TCF12 (transcription factor 12) [OMIM: # 600480] [17,18] In this respect, CS have been included in the last nosology of skeletal disorders (group 33), a classification based on a combina- TCF12 is a member of the helix-loop-helix family; it forms tion of radiological and molecular criteria [9]. heterodimers with TWIST1 and acts as a SMAD cofactor, thus Various etiologies have been reported for CS. Prenatal exposure playing a major role in coronal suture development [6]. Muta- to some teratogens, such as valproic acid (affecting mainly metopic tions in TCF12 cause Craniosynostosis 3 (OMIM: # 615314), an suture), retinoic acid, hydantoin, and fluconazole, can cause CS [10]. autosomal dominant disorder. Skull involvement can be isolated A genetic cause is found overall in 20% of cases and significant het- (NSCS) or associated with mild dysmorphic features such as eye- erogeneity is observed: on one hand, one clinical picture can be lids ptosis, minor ear anomalies (prominent ear crus), malocclusion, caused by different genetic abnormalities and, on the other hand, brachydactyly, toe syndactyly, clinodactyly, camptodactyly) and one gene can cause different clinical pictures, thus making differ- the possible presence of developmental delay and/or learning dif- ential diagnosis difficult. ficulties. Hence, this condition has to be considered particularly in Currently chromosomal imbalance represents about 20% of the the differential diagnosis of either Saethre–Chotzen [18] or Muenke observed genetic causes. The main chromosomal abnormalities syndromes. Incomplete penetrance (up to 50%) has been reported causing CS have already been extensively reviewed [11]. A chromo- [17]. somal imbalance should be considered in patients presenting with SCS, especially involving metopic or sagittal sutures, and develop- 5. SMAD6 (SMAD family member 6) [OMIM: # 602931] [19] mental delay. The clinical phenotypes and genetic bases of various Mendelian
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