{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:15:09Z","timestamp":1790399709187,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,22]],"date-time":"2020-06-22T00:00:00Z","timestamp":1592784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, inherited disorder characterized by a congenital absence of conjugate horizontal eye movements with progressive scoliosis developing in childhood and adolescence. Mutations in the Roundabout (ROBO3) gene located on chromosome 11q23\u201325 are responsible for the development of horizontal gaze palsy and progressive scoliosis. However, some studies redefined the locus responsible for this pathology to a 9-cM region. This study carried out a systematic review in which 25 documents were analyzed, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. The search was made in the following electronic databases from January 1995 to October 2019: PubMed, Scopus, Web of Science, PEDRO, SPORT Discus, and CINAHL. HGPPS requires a multidisciplinary diagnostic approach, in which magnetic resonance imaging might be the first technique to suggest the diagnosis, which should be verified by an analysis of the ROBO3 gene. This is important to allow for adequate ocular follow up, apply supportive therapies to prevent the rapid progression of scoliosis, and lead to appropriate genetic counseling.<\/jats:p>","DOI":"10.3390\/ijerph17124467","type":"journal-article","created":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T06:11:02Z","timestamp":1592892662000},"page":"4467","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Mutation in ROBO3 Gene in Patients with Horizontal Gaze Palsy with Progressive Scoliosis Syndrome: A Systematic Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9611-3939","authenticated-orcid":false,"given":"Elena","family":"Pinero-Pinto","sequence":"first","affiliation":[{"name":"Department of Physiotherapy, University of Seville, 41009 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3896-357X","authenticated-orcid":false,"given":"Ver\u00f3nica","family":"P\u00e9rez-Cabezas","sequence":"additional","affiliation":[{"name":"Department of Nursing and Physiotherapy, Spain INDESS (Instituto Universitario para el Desarrollo Social Sostenible), University of Cadiz, 11009 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Tous-Rivera","sequence":"additional","affiliation":[{"name":"Nodo Biobanco Hospital Universitario Virgen del Roc\u00edo (Biobanco del Sistema Sanitario P\u00fablico de Andaluc\u00eda), 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0450-7717","authenticated-orcid":false,"given":"Jos\u00e9-Mar\u00eda","family":"S\u00e1nchez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Physics of Condensed Matter, Optics Area, University of Seville, 41012 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6208-0208","authenticated-orcid":false,"given":"Carmen","family":"Ruiz-Molinero","sequence":"additional","affiliation":[{"name":"Department of Nursing and Physiotherapy, Spain INDESS (Instituto Universitario para el Desarrollo Social Sostenible), University of Cadiz, 11009 Cadiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3358-3305","authenticated-orcid":false,"given":"Jos\u00e9-Jes\u00fas","family":"Jim\u00e9nez-Rejano","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy, University of Seville, 41009 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2058-8799","authenticated-orcid":false,"given":"Mar\u00eda-Luisa","family":"Ben\u00edtez-Lugo","sequence":"additional","affiliation":[{"name":"Department of Physiotherapy, University of Seville, 41009 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9453-8615","authenticated-orcid":false,"given":"Mar\u00eda Carmen","family":"S\u00e1nchez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Physics of Condensed Matter, Optics Area, University of Seville, 41012 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.2106\/00004623-197456080-00034","article-title":"Congenital scoliosis associated with encephalopathy in five children of two families","volume":"56","author":"Dretakis","year":"1974","journal-title":"J. Bone Jt. Surg. Ser. A"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1302\/0301-620X.56B3.484","article-title":"Scoliosis with progressive external ophthalmoplegia in four siblings","volume":"56","author":"Crisfield","year":"1974","journal-title":"J. Bone Jt. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1080\/13816810.2019.1592199","article-title":"Horizontal gaze palsy and progressive scoliosis with two novel ROBO3 gene mutations in two Jordanian families","volume":"40","author":"Rousan","year":"2019","journal-title":"Ophthalmic Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s12031-009-9217-4","article-title":"Allelic ROBO3 heterogeneity in Tunisian patients with horizontal gaze palsy with progressive scoliosis","volume":"39","author":"Amouri","year":"2009","journal-title":"J. Mol. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1212\/01.WNL.0000156349.01765.2B","article-title":"Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3","volume":"64","author":"Bosley","year":"2005","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1136\/jnnp.2006.088435","article-title":"Patients with horizontal gaze palsy and progressive scoliosis due to ROBO3 E319K mutation have both uncrossed and crossed central nervous system pathways and perform normally on neuropsychological testing","volume":"77","author":"Amoiridis","year":"2006","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1126\/science.1096437","article-title":"Mutations in a Human ROBO Gene Disrupt Hindbrain Axon Pathway Crossing and Morphogenesis","volume":"304","author":"Jen","year":"2006","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1212\/WNL.59.3.432","article-title":"Familial horizontal gaze palsy with progressive scoliosis maps to chromosome 11q23-25","volume":"59","author":"Jen","year":"2002","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sabatier, C., Plump, A.S., Ma, L., Brose, K., Tamada, A., Murakami, F., Lee, E.Y.H.P., and Tessier-Lavigne, M. (2004). The divergent robo family protein Rig-1\/Robo3 is a negative regulator of slit responsiveness required for midline crossing by commissural axons. Cell.","DOI":"10.1016\/S0092-8674(04)00303-4"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/dneu.22478","article-title":"The Robo3 receptor, a key player in the development, evolution, and function of commissural systems","volume":"77","author":"Friocourt","year":"2017","journal-title":"Dev. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1161\/STROKEAHA.110.591271","article-title":"Ipsilateral stroke in a patient with horizontal gaze palsy with progressive scoliosis and a subcortical infarct","volume":"42","author":"Ng","year":"2011","journal-title":"Stroke"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1212\/WNL.59.3.462","article-title":"Brainstem hypoplasia in familial horizontal gaze palsy and scoliosis","volume":"59","author":"Pieh","year":"2002","journal-title":"Neurology"},{"key":"ref_13","first-page":"370","article-title":"Horizontal gaze palsy and scoliosis: A case report and review of the literature","volume":"17","author":"Samoladas","year":"2013","journal-title":"Hippokratia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"212","DOI":"10.3109\/13816810.2011.574186","article-title":"Horizontal gaze palsy and progressive scoliosis without ROBO3 mutations","volume":"32","author":"Faletra","year":"2011","journal-title":"Ophthalmic Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1136\/bmj.b2535","article-title":"Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement","volume":"339","author":"Moher","year":"2009","journal-title":"BMJ"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Liberati, A., Altman, D.G., Tetzlaff, J., Mulrow, C., G\u00f8tzsche, P.C., Ioannidis, J.P.A., Clarke, M., Devereaux, P.J., Kleijnen, J., and Moher, D. (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. PLoS Med., 6.","DOI":"10.2427\/5768"},{"key":"ref_17","unstructured":"(2018, December 15). Study Quality Assessment Tools|National Heart; Lung, and Blood Institute (NHLBI), Available online: https:\/\/www.nhlbi.nih.gov\/health-topics\/study-quality-assessment-tools."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1055\/s-2007-973565","article-title":"Familial congenital horizontal gaze paralysis and kyphoscoliosis","volume":"29","author":"Steffen","year":"1998","journal-title":"Neuropediatrics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.0009-9163.2004.00201.x","article-title":"The locus responsible for horizontal gaze palsy\/progressive scoliosis and brainstem hypoplasia is refined to a 9-cM region on chromosome 11q23","volume":"65","author":"Lo","year":"2004","journal-title":"Clin. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1177\/08830738050200011303","article-title":"Two siblings with familial idiopathic scoliosis with conjugate gaze palsy","volume":"20","author":"Incecik","year":"2005","journal-title":"J. Child Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1136\/jmg.2005.035436","article-title":"Horizontal gaze palsy with progressive scoliosis can result from compound heterozygous mutations in ROBO3","volume":"43","author":"Chan","year":"2006","journal-title":"J. Med. Genet."},{"key":"ref_22","first-page":"540","article-title":"Gene symbol: ROBO3. Disease: Gaze Palsy, horizontal, with progressive scoliosis","volume":"123","year":"2008","journal-title":"Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"162","DOI":"10.4103\/0301-4738.77012","article-title":"Synergistic convergence and split pons in horizontal gaze palsy and progressive scoliosis in two sisters","volume":"59","author":"Jain","year":"2011","journal-title":"Indian J. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"203","DOI":"10.3109\/01658107.2012.710920","article-title":"Acquired convergence substitution in horizontal gaze palsy and progressive scoliosis associated with ROBO3 mutations","volume":"36","author":"Bakbak","year":"2012","journal-title":"Neuro-Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/j.ejpn.2013.05.011","article-title":"Early-onset or rapidly progressive scoliosis in children: Check the eyes","volume":"17","author":"Kurian","year":"2013","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1097\/WNO.0000000000000455","article-title":"Horizontal Gaze Palsy and Progressive Scoliosis with ROBO 3 Mutations in Patients from Cape Verde","volume":"37","author":"Marques","year":"2017","journal-title":"J. Neuro-Ophthalmol."},{"key":"ref_27","first-page":"1046","article-title":"MR imaging of brain-stem hypoplasia in horizontal gaze palsy with progressive scoliosis","volume":"25","author":"Rossi","year":"2004","journal-title":"Am. J. Neuroradiol."},{"key":"ref_28","first-page":"1382","article-title":"MR imaging features of brain stem hypoplasia in familial horizontal gaze palsy and scoliosis","volume":"27","author":"Matias","year":"2006","journal-title":"Am. J. Neuroradiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00234-007-0359-1","article-title":"Functional MRI, DTI and neurophysiology in horizontal gaze palsy with progressive scoliosis","volume":"50","author":"Haller","year":"2008","journal-title":"Neuroradiology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1007\/s00247-008-1058-8","article-title":"Horizontal gaze palsy with progressive scoliosis: CT and MR findings","volume":"39","author":"Bomfim","year":"2009","journal-title":"Pediatr. Radiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.mri.2009.10.004","article-title":"Diffusion tensor imaging in horizontal gaze palsywith progressive scoliosis","volume":"28","author":"Avadhani","year":"2010","journal-title":"Magn. Reson. Imaging"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3109\/13816810.2011.580445","article-title":"Horizontal gaze palsy and progressive scoliosis due to a deleterious mutation in ROBO3","volume":"32","author":"Kapoor","year":"2011","journal-title":"Ophthalmic Genet."},{"key":"ref_33","first-page":"1978","article-title":"Horizontal gaze palsy with progressive scoliosis: Three novel ROBO3 mutations and descriptions of the phenotypes of four patients","volume":"17","author":"Volk","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.3928\/01913913-20140521-01","article-title":"Horizontal Gaze Palsy With Progressive Scoliosis and Severe Keratoconus With a Compound Heterozygous Mutation in ROBO3","volume":"51","author":"Pina","year":"2014","journal-title":"J. Pediatr. Ophthalmol. Strabismus"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1080\/13816810.2016.1188123","article-title":"A novel mutation of ROBO3 in horizontal gaze palsy with progressive scoliosis","volume":"38","year":"2017","journal-title":"Ophthalmic Genet."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lin, C.-W., Lo, C.-P., and Tu, M.-C. (2018). Horizontal gaze palsy with progressive scoliosis: A case report with magnetic resonance tractography and electrophysiological study. BMC Neurol., 18.","DOI":"10.1186\/s12883-018-1081-9"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jns.2008.08.026","article-title":"Five new consanguineous families with horizontal gaze palsy and progressive scoliosis and novel ROBO3 mutations","volume":"276","author":"Dhalaan","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.neuron.2004.06.018","article-title":"The slit receptor Rig-1\/Robo3 controls midline crossing by hindbrain precerebellar neurons and axons","volume":"43","author":"Marillat","year":"2004","journal-title":"Neuron"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Chen, Z., Gore, B.B., Long, H., Ma, L., and Tessier-Lavigne, M. (2008). Alternative Splicing of the Robo3 Axon Guidance Receptor Governs the Midline Switch from Attraction to Repulsion. Neuron.","DOI":"10.1016\/j.neuron.2008.02.016"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zelina, P., Blockus, H., Zagar, Y., P\u00e9res, A., Friocourt, F., Wu, Z., Rama, N., Fouquet, C., Hohenester, E., and Tessier-Lavigne, M. (2014). Signaling switch of the axon guidance receptor Robo3 during vertebrate evolution. Neuron.","DOI":"10.1016\/j.neuron.2014.11.004"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Comer, J.D., Pan, F.C., Willet, S.G., Haldipur, P., Millen, K.J., Wright, C.V.E., and Kaltschmidt, J.A. (2015). Sensory and spinal inhibitory dorsal midline crossing is independent of Robo3. Front. Neural Circuits.","DOI":"10.3389\/fncir.2015.00036"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"a001784","DOI":"10.1101\/cshperspect.a001784","article-title":"Human genetic disorders of axon guidance","volume":"2","author":"Engle","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.mcn.2005.07.014","article-title":"Evidence for the existence of two Robo3 isoforms with divergent biochemical properties","volume":"30","author":"Camurri","year":"2005","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1055\/s-0036-1597610","article-title":"Horizontal gaze palsy in two brothers with compound heterozygous ROBO3 gene mutations","volume":"48","author":"Hackenberg","year":"2016","journal-title":"Neuropediatrics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.oftal.2016.05.002","article-title":"Par\u00e1lisis de la mirada horizontal y escoliosis progresiva en un paciente con endotropia cong\u00e9nita y limitaci\u00f3n de abducci\u00f3n. A prop\u00f3sito de un caso","volume":"91","year":"2016","journal-title":"Arch. Soc. Esp. Oftalmol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/WNO.0000000000000603","article-title":"Horizontal Gaze Palsy With Progressive Scoliosis","volume":"38","author":"Ungaro","year":"2018","journal-title":"J. Neuro-Ophthalmol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1016\/j.ophtha.2008.08.010","article-title":"Bilateral synergistic convergence associated with homozygous ROB03 mutation (p.Pro771Leu)","volume":"115","author":"Khan","year":"2008","journal-title":"Ophthalmology"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Yamada, S., Okita, Y., Shofuda, T., Yoshioka, E., Nonaka, M., Mori, K., Nakajima, S., and Kanemura, Y. (2015). Ipsilateral hemiparesis caused by putaminal hemorrhage in a patient with horizontal gaze palsy with progressive scoliosis: A case report. BMC Neurol.","DOI":"10.1186\/s12883-015-0286-4"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1055\/s-0034-1396178","article-title":"Horizontale Blickparese mit progredienter Skoliose","volume":"232","author":"Arlt","year":"2015","journal-title":"Klin. Monbl. Augenheilkd."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.jaapos.2014.02.011","article-title":"Infantile esotropia with cross-fixation, inability to abduct, and underlying horizontal gaze palsy with progressive scoliosis","volume":"18","author":"Khan","year":"2014","journal-title":"J. Am. Assoc. Pediatr. Ophthalmol. Strabismus"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.conb.2012.02.006","article-title":"Human disorders of axon guidance","volume":"22","author":"Nugent","year":"2012","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Bouvier, J., Thoby-Brisson, M., Renier, N., Dubreuil, V., Ericson, J., Champagnat, J., Pierani, A., Ch\u00e9dotal, A., and Fortin, G. (2010). Hindbrain interneurons and axon guidance signaling critical for breathing. Nat. Neurosci.","DOI":"10.1038\/nn.2622"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s10072-018-3567-z","article-title":"Horizontal gaze palsy with progressive scoliosis: Is scoliosis linked to ROBO3 mutations?","volume":"40","author":"Ungaro","year":"2019","journal-title":"Neurol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"187","DOI":"10.4236\/nm.2018.94019","article-title":"The spectrum of ROBO3 mutations in horizontal gaze palsy with progressive scoliosis: An update","volume":"9","author":"Ungaro","year":"2018","journal-title":"Neurosci. Med."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/17\/12\/4467\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:41:30Z","timestamp":1760175690000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/17\/12\/4467"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,22]]},"references-count":54,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijerph17124467"],"URL":"https:\/\/doi.org\/10.3390\/ijerph17124467","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,22]]}}}