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Metopic and Sagittal Synostosis in Greig Cephalopolysyndactyly Syndrome: five Cases with Intragenic Mutations Or Complete Deletions of GLI3

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Metopic and Sagittal Synostosis in Greig Cephalopolysyndactyly Syndrome: five Cases with Intragenic Mutations Or Complete Deletions of GLI3 European Journal of Human Genetics (2011) 19, 757–762 & 2011 Macmillan Publishers Limited All rights reserved 1018-4813/11 www.nature.com/ejhg ARTICLE Metopic and sagittal synostosis in Greig cephalopolysyndactyly syndrome: five cases with intragenic mutations or complete deletions of GLI3 Jane A Hurst1,2, Dagan Jenkins3, Pradeep C Vasudevan4, Maria Kirchhoff5, Flemming Skovby5, Claudine Rieubland6, Sabina Gallati6, Olaf Rittinger7, Peter M Kroisel8, David Johnson2, Leslie G Biesecker9 and Andrew OM Wilkie*,1,2,3 Greig cephalopolysyndactyly syndrome (GCPS) is a multiple congenital malformation characterised by limb and craniofacial anomalies, caused by heterozygous mutation or deletion of GLI3. We report four boys and a girl who were presented with trigonocephaly due to metopic synostosis, in association with pre- and post-axial polydactyly and cutaneous syndactyly of hands and feet. Two cases had additional sagittal synostosis. None had a family history of similar features. In all five children, the diagnosis of GCPS was confirmed by molecular analysis of GLI3 (two had intragenic mutations and three had complete gene deletions detected on array comparative genomic hybridisation), thus highlighting the importance of trigonocephaly or overt metopic or sagittal synostosis as a distinct presenting feature of GCPS. These observations confirm and extend a recently proposed association of intragenic GLI3 mutations with metopic synostosis; moreover, the three individuals with complete deletion of GLI3 were previously considered to have Carpenter syndrome, highlighting an important source of diagnostic confusion. European Journal of Human Genetics (2011) 19, 757–762; doi:10.1038/ejhg.2011.13; published online 16 February 2011 Keywords: trigonocephaly; metopic synostosis; sagittal synostosis; Greig cephalopolysyndactyly syndrome; GLI3; Carpenter syndrome INTRODUCTION (SHH) pathway. In the presence of SHH, full-length GLI3 functions In 1926, Greig1 first described the condition now known as Greig as a transcriptional activator, whereas in the absence of SHH, cephalopolysyndactyly syndrome (GCPS, MIM 175700) in a mother GLI3 is cleaved to produce a repressor.12 The phenotype of GCPS and daughter with digital malformations and an unusual skull shape. is attributable to functional haploinsufficiency of GLI3; when The syndrome is inherited in an autosomal dominant pattern and this is caused by heterozygous deletion at 7p14.1, additional develop- presents with characteristic limb and craniofacial anomalies. It is mental delay may be attributable to the deletion of contiguous highly penetrant but there is both inter- and intra-familial variability gene(s).13,14 of the features.2,3 In the extremities, there may be both pre-axial and In this study we describe five unrelated individuals (four boys and post-axial polydactyly with broad or duplicated thumbs, broad or a girl) with GLI3 mutation-proven GCPS and a typical pattern of duplicated halluces, post-axial polydactyly of hands and feet and pre- and post-axial polydactyly, all of whom had trigonocephaly cutaneous syndactyly of the fingers or toes. Craniofacial features caused by metopic synostosis, confirming that this is a nonrandom include macrocephaly, prominent or broad forehead with frontal association. The key clinical features and results of molecular genetic bossing, a broad base to the nose and a wide nasal bridge. Some analyses are summarised in Table 1. affected individuals have learning difficulties. Developmental anoma- lies of the corpus callosum and mild cerebral ventriculomegaly are CASE REPORTS recognised associations. To our knowledge, trigonocephaly was Patient 1 described only twice in possible GCPS cases before molecular con- This boy (Figures 1a–c), the third child of healthy unrelated parents, firmation became available.4,5 was tabulated (subject G31) in the report by Johnston et al.15 He was Following the recognition that GCPS was associated with rearran- born at term by normal vaginal delivery weighing 4132 g (95th centile) gements and translocations of 7p14.1, 6–9 heterozygous GLI3 muta- and noted to have a prominent metopic ridge. At 10.5 months his tions and deletions were identified as the cause of GCPS by Vortkamp occipito-frontal circumference (OFC) was 48 cm (90th centile) and et al in 1991.10,11 The GLI3 gene encodes a zinc-finger transcrip- inner canthal distance was 2.9 cm (95th centile). He had bilateral post- tion factor that is a downstream mediator of the sonic hedgehog axial polydactyly type B of the fingers and pre-axial polydactyly of the 1Department of Clinical Genetics, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK; 2Craniofacial Unit, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK; 3Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK; 4Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK; 5Department of Clinical Genetics, University Hospital of Copenhagen, Copenhagen, Denmark; 6Division of Human Genetics, Inselspital, University of Bern, Bern, Switzerland; 7Children’s Hospital, Paracelsus Medical University, Salzburg, Austria; 8Institute of Human Genetics, Medical University of Graz, Graz, Austria; 9National Human Genome Research Institute, Bethesda, MD, USA *Correspondence: Professor AOM Wilkie, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK. Tel: +44 1865 222619; Fax: +44 1865 222500; E-mail: [email protected] Received 6 September 2010; revised 11 January 2011; accepted 12 January 2011; published online 16 February 2011 GLI3 mutations and craniosynostosis JA Hurst et al 758 Table 1 Clinical features and results of GLI3 testing in Patients 1–5 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Sex Male Male Female Male Male GLI3 testing c.1728C4A, p.Y576X c.1793dupA, 8.3-Mb deletion 6.8 Mb-deletion 6.0-Mb deletion pN598KfsX7 7p12.3-p14.1 7p13-p14.1 7p13-p14.1 Family history No No No No No Parental ages Mother 32 years Mother 22 years Mother 25 years Mother 19 years Mother 29 years Father 34 years Father 22 years Father 25 years Father 23 years Father 29 years OFC Before surgery: 48 cm Before surgery: 52 cm Birth: 32.8 cm Birth: 34 cm Birth 33.5 cm at 10.5 months at 4 years 3 months (5th centile) (20th centile) (10th centile) (90th centile) (75th centile) Trigonocephaly Yes Yes Yes Yes and Yes scaphocephaly Craniosynostosis Metopic and Metopic Metopic Metopic and Metopic sagittal sagittal Structural brain No No Bilateral frontal and No Hypoplasia corpus anomaly parietal atrophy callosum Mild cerebral ventricular dilatation Development Normal Normal Delayed Delayed Delayed Sat 1 year 14 months 2 years Walked 2.5 years Not walking 3.5 years independently at 5 years 9 months Speech at 3 years 10–12 words o5 words 15 words Schooling — — At 15 years approx Special schooling — equivalent to average 7years Thumb Normal Partially duplicated Broad Normal Broad Finger Post-axial polydactyly Post-axial polydactyly No No No poly/syndactyly type B type B Hallux Duplicated (separate Duplicated, with Broad Duplicated, with Duplicated, with partial pre-axial digit on left) complete cutaneous partial cutaneous cutaneous syndactyly syndactyly syndactyly Toe cutaneous Complete cutaneous Complete cutaneous Partial cutaneous Partial syndactyly Partial syndactyly poly/syndactyly syndactyly hallux and syndactyly hallux and syndactyly between second/third toes second/third toes second toe. Partial second toe. Partial hallux/second/third syndactyly second/third syndactyly second- toes toes fourth toes Other anomalies No No Short palpebral fissures, Telecanthus, Flat nasal bridge and flat nasal bridge and bilateral ptosis, broad base. DORV with broad base, thick lips anteverted nares, pulmonary stenosis. Hypermetropia and large mouth. squint. Small VSD Laryngomalacia, VSD, (closed spontaneously) ASD and PDA Seizures aged 3 years Abbreviations: VSD, ventricular septal defect; ASD, atrial septal defect; PDA, patent ductus arteriosus; DORV, double outlet right ventricle. feet, with cutaneous syndactyly between the hallux and second Patient 2 toe and partial cutaneous syndactyly of second and third toes. This boy (Figures 1d–f) was included in the series of patients with Cranial computed tomography (CT) scan showed metopic and metopic synostosis reported by Kini et al.17 He was referred for sagittal synostosis. He attained his developmental milestones normally. craniofacial assessment at 3 years with trigonocephaly. He had healthy Corrective surgery was performed on the hands and feet at 10 months unrelated white British parents. He was born at term weighing 3260 g and 1 year, respectively, and trigonocephaly correction at the age (25th centile), and was noted to have limb malformations and a of 2 years. trigonocephalic appearance. He had partially duplicated thumbs, DNA sequencing showed a heterozygous nonsense mutation in bilateral post-axial polydactyly type B of the hands and bilateral pre- exon 12 of GLI3 (c.1728C4A, p.Y576X; GenBank NM_000168.5),15 axial polydactyly of the halluces with cutaneous syndactyly between which was not present in either parent. This mutation is predicted to the duplicated halluces and the second and third toes, which have truncate GLI3 in the zinc-finger motif and falls within the mutation required multiple corrective surgical procedures. At 4.2 years his OFC spectrum previously described as associated with GCPS.15,16 was 52 cm (75th centile) and developmental milestones were normal. European Journal of
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