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The Genetic Landscape and Clinical Implications of Vertebral Anomalies

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The Genetic Landscape and Clinical Implications of Vertebral Anomalies JMG Online First, published on April 15, 2016 as 10.1136/jmedgenet-2015-103554 Review J Med Genet: first published as 10.1136/jmedgenet-2015-103554 on 15 April 2016. Downloaded from The genetic landscape and clinical implications of vertebral anomalies in VACTERL association Yixin Chen,1 Zhenlei Liu,1 Jia Chen,1 Yuzhi Zuo,1 Sen Liu,1,2 Weisheng Chen,1 Gang Liu,1 Guixing Qiu,1,2 Philip F Giampietro,3 Nan Wu,1,2 Zhihong Wu2,4 1Department of Orthopedic ABSTRACT (FA) have birth defects meeting the diagnosis of Surgery, Peking Union Medical VACTERL association is a condition comprising VACTERL association with hydrocephalus College Hospital, Peking Union 910 Medical College and Chinese multisystem congenital malformations, causing severe (VACTERL-H). It is suggested that FA with Academy of Medical Sciences, physical disability in affected individuals. It is typically VACTERL-H should be treated separately from the Beijing, China defined by the concurrence of at least three of the VACTERL association because of the core character- 2 Beijing Key Laboratory for following component features: vertebral anomalies (V), istics of FA such as haematological anomalies and Genetic Research of Skeletal anal atresia (A), cardiac malformations (C), tracheo- skin pigmentary changes, the different frequencies Deformity, Beijing, China fi 3Department of Pediatrics, oesophageal stula (TE), renal dysplasia (R) and limb of VACTERL-associated phenotypes and the prog- 10 11 University of Wisconsin School abnormalities (L). Vertebral anomaly is one of the most nosis and therapeutic intervention. of Medicine and Public Health, important and common defects that has been reported Although the clinical criteria for VACTERL asso- Madison, Wisconsin, USA in approximately 60–95% of all VACTERL patients. ciation appear to be straightforward, the overlap- 4Department of Central Laboratory, Peking Union Recent breakthroughs have suggested that genetic ping in either clinical manifestation or genetic Medical College Hospital, factors play an important role in VACTERL association, finding is challenging for clinicians and geneticists. Peking Union Medical College especially in those with vertebral phenotypes. In this The CHD7 gene mutation, which is proved to be and Chinese Academy of review, we summarised the genetic studies of the associated with CHARGE syndrome, may also be Medical Sciences, Beijing, VACTERL association, especially focusing on the genetic found in patients diagnosed with VACTERL associ- China aetiology of patients with vertebral anomalies. ation, even CHARGE syndrome is clinically 12 Correspondence to Furthermore, genetic reports of other syndromes with excluded. Besides, most of the conditions listed Dr Nan Wu, Department of vertebral phenotypes overlapping with VACTERL are monogenic disorders. Careful genetic evaluation Orthopedic Surgery, Peking association are also included. We aim to provide a may help ruling out these conditions. In this review, Union Medical College Hospital, Peking Union Medical further understanding of the genetic aetiology and a we listed the related monogenic diseases that share College and Chinese Academy better evidence for genetic diagnosis of the association two more overlapping manifestations and their of Medical Sciences, No.1 and vertebral anomalies. genetic findings (table 1). We propose that(1) these Shuaifuyuan, Beijing 100730, syndromes as well as these candidate genes should China; Beijing Key Laboratory be considered in diagnostic and genetic studies in for Genetic Research of Skeletal Deformity, China; OVERVIEW OF VACTERL ASSOCIATION VACTERL association; and (2) VACTERL syndrome [email protected] VACTERL association is a condition with multisys- remains a diagnosis of exclusion following a tem congenital malformations: Vertebral anomalies thoughtful clinical evaluation and consideration of http://jmg.bmj.com/ Dr Zhihong Wu, Department of (V), anal atresia (A), cardiac malformation (C), genetic testing for overlapping syndromes. Central Laboratory, Peking fi Union Medical College tracheo-oesophageal stula (TE) with or without Prior studies have estimated that 90% of the Hospital, Peking Union College oesophageal atresia, renal dysplasia (R) and limb patients diagnosed with VACTERL association had and Chinese Academic of abnormalities (L).12It was first named as VATER three or fewer phenotypes (referred to as Medical Sciences, No 1 (without ‘C’ and ‘L’) association in 1973.3 The VACTERL-like association) and <1% of patients Shuaifuyuan, Beijing 100730, prevalence of VACTERL/VATER association is had all six anomalies.4 Although the frequency of China; Beijing Key Laboratory 45 on September 29, 2021 by guest. Protected copyright. for Genetic Reserach of between 1/7000 and 1/40 000. the six clinical features (CFs) varies, vertebral Skeletal Deformity, China; As there is no available objective laboratory test anomalies is the most common observation in many [email protected] for its diagnosis, VACTERL association is diagnosed cohorts of VACTERL association, which have been totally based on the clinical manifestations men- reported in approximately 60–95% of affected indi- Received 30 November 2015 730–33 Revised 3 March 2016 tioned above. Most clinicians and researchers viduals. Additionally, vertebral anomalies are Accepted 17 March 2016 require the presence of at least three component fea- the most prevalent findings in the first-degree rela- tures for diagnosis. Besides, due to its heterogeneous tives of the probands in some cohorts,34 35 thus phenotype and the abundance of overlapping highlighting the importance of vertebral anomalies defects of other syndromes, VACTERL association is as a major diagnostic feature for VACTERL associ- – typically considered a diagnosis of exclusion5 8 with ation. In this review, we will summarise the genetic no clear evidence for an alternative or overlapping studies of the VACTERL association with an diagnosis such as Coloboma, Heart anomaly, Atresia emphasis on vertebral anomalies. of choanae, Retardation of mental and somatic development, Genital hypoplasia, Ear abnormalities Vertebral anomalies (CHARGE) syndrome, DiGeorge syndrome and Vertebral anomalies in VACTERL association can Pallister–Hall syndrome. The presence of other fea- be classified as (1) failure of formation, such as To cite: Chen Y, Liu Z, tures not typically seen in VACTERL association hemivertebrae, butterfly or wedge-shaped verte- Chen J, et al. J Med Genet Published Online First: may suggest other disorders. Thus, a physical exam- brae; (2) failure of segmentation such as [please include Day Month ination and family history are essential to rule out vertebral bars, fused vertebrae and block vertebrae; Year] doi:10.1136/ potentially overlapping diagnoses. It is worth men- and (3) a combination of these two features, result- jmedgenet-2015-103554 tioning that 5–10% patients with Fanconi anaemia ing in a mixed deformity.36 37 Rib anomalies such Chen Y, et al. J Med Genet 2016;0:1–7. doi:10.1136/jmedgenet-2015-103554 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence. Review J Med Genet: first published as 10.1136/jmedgenet-2015-103554 on 15 April 2016. Downloaded from Table 1 Monogenic diseases overlapping with VACTERL association Overlap Characteristic features beyond Syndrome OMIM Locus Gene Vertebral anomalies malformations VACTERL association Reference Fanconi anaemia 227650; 16q24; Xp22 FANCA; Same phenotype with V, A, C TE, R, L Haematological anomalies; Holden et al13 with VACTERL-H 300514 FANCB,etc.* VACTERL but lower pigmentary changes; frequency hydrocephalus Alagille syndrome 118450 20p12; JAG1; Mostly butterfly vertebra, V, C, R Jaundice with conjugated Turnpenny and 1p12-p11 NOTCH2 occasionally hyperbilirubinemia; dysmorphic Ellard14 hemivertebrae, fusion of facies; posterior embryotoxon and vertebrae retinal pigmentary changes Basal cell nevus 109400 9q22; 1p32; PTCH1; Multiple fusion of V, L Odontogenic keratocysts of the Oostra and Maas;15 syndrome 10q24-q25 PTCH2; SUFU vertebral bodies and ribs jaw; palmar or plantar pits; Pino et al16 bilamellar calcification of the falx cerebri; basal cell tumours Baller–Gerold 218600 8q24 RECQL4 Rib fusion and flat V, A, C, R, L Craniosynostosis; microcephaly Murthy et al17 syndromes vertebrae DiGeorge syndrome 188400 22q11 TBX1 Hemivertebrae V, C, R, L Thymic abnormality;conotruncal Tsirikos et al;18 (22q11.2 deletion cardiac anomaly; facial Maggadottir and syndrome) dysmorphism; hypocalcaemia Sullivan19 Feingold syndrome 164280 2p23-24 N-MYC Absence of the fifth V, C, TE, R, L Microcephaly; Celli et al20 sacral vertebra and brachymesophalangy fusion of C5–C7in a case McKusick–Kaufman 236700 20p12 MKKS Vertebral anomalies in V, C, L Hydrometrocolpos; gastrointestinal Knowles et al21 syndrome one case malformations CHARGE syndrome 214800 8q12 CHD7 Idiopathic scoliosis C, TE, R Coloboma; choanal atresia/ Hsu et al;22 without vertebral stenosis;hypoplasia/aplasia of Verloes23 anomalies semicircular, etc. Pallister–Hall 146510 7p14.1 GLI3 NA A, C, R, L Hypothalamic hamartoma; bifid Demurger et al24 syndrome epiglottis; craniofacial abnormalities Townes–Brocks 107480 16q21.1 SALL1 NA A, C, R, L Dysplastic ears with hearing Sudo et al25 syndrome impairment; intellectual disability Holt–Oram syndrome 142900 12q24 TBX5 NA C, L NA Goldfarb and Wall201426 Hemifacial 164210 14q32 NA Hemivertebrae, fusion of V, C Craniofacial anomalies; central Beleza-Meireles microsomia (OAVS) vertebrae nervous system defects:
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