{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:36:56Z","timestamp":1790905016811,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T00:00:00Z","timestamp":1689897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec><jats:title>Background and aims<\/jats:title><jats:p>Joubert syndrome (JBTS, OMIM # 213300) is a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosing JBTS. It is a clinically and genetically heterogeneous disorder involving mutations in more than 40 ciliopathy-related genes. However, long-term follow-up data are scarce, and further research is needed to determine the abundant phenotypes and genetics of this disorder. The study aimed to summarize clinical manifestations, particular appearance on cranial imaging, genetic data, and prognostic features of patients with JBTS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A retrospective case review of 36 cases of JBTS from May 1986 to December 2021 was performed. Clinical data of JBTS patients with development retardation and molar tooth sign on cranial imaging as the main features were analyzed. Genetic testing was performed according to consent obtained from patients and their families. The Gesell Developmental Scale was used to evaluate the intelligence level before and after treatment. The children were divided into a purely neurological JBTS (pure JBTS) group and JBTS with multi-organ system involvement group and then followed up every 3\u20136 months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We enrolled 18 males and 18 females. Thirty-four (94.44%) cases had developmental delay, one patient (2.78%) had strabismus, and one patient (2.78%) had intermittent dizziness. There was one case co-morbid with Lesch-Nyhan syndrome. Three-quarters of cases had one or more other organ or system involvement, with a greater predilection for vision and hearing impairment. JBTS could also involve the skin. Thirty-one cases (86.11%) showed a typical molar tooth sign, and five cases showed a bat wing sign on cranial imaging. Abnormal video electroencephalogram (VEEG) result was obtained in 7.69% of cases. We found six JBTS-related <jats:italic>novel<\/jats:italic> gene loci variants: <jats:italic>CPLANE1<\/jats:italic>: c.4189\u2009+\u20091G\u2009&amp;gt;\u2009A, c.3101T\u2009&amp;gt;\u2009C(p.Ile1034Thr), c.3733T\u2009&amp;gt;\u2009C (p.Cys1245Arg), c.4080G\u2009&amp;gt;\u2009A(p.Lys1360=); <jats:italic>RPGRIP1l<\/jats:italic>: c.1351-11A\u2009&amp;gt;\u2009G; <jats:italic>CEP120<\/jats:italic>: c.214 C\u2009&amp;gt;\u2009T(p.Arg72Cys). The <jats:italic>CHD7<\/jats:italic> gene may be potentially related to the occurrence of JBTS. Analysis showed that the prognosis of pure JBTS was better than that of JBTS with neurological and non-neurological involvement after the formal rehabilitation treatment (<jats:italic>P<\/jats:italic>\u2009&amp;lt;\u20090.05). Of the three children with seizures, two cases had epilepsy with a poor prognosis, and another case had breath-holding spells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that early cranial imaging is helpful for the etiological diagnosis of children with unexplained developmental delay and multiple malformations. Patients with JBTS may have coexisting skin abnormalities. The <jats:italic>novel<\/jats:italic> gene loci of <jats:italic>CPLANE1<\/jats:italic>, <jats:italic>RPGRIP1l<\/jats:italic>, and <jats:italic>CEP120<\/jats:italic> were associated with JBTS in our study and provided significant information to enrich the related genetic data. Future works investigating several aspects of the association between <jats:italic>CHD7<\/jats:italic> gene and JBTS merit further investigation. The prognosis of children with pure JBTS is better than that of children with JBTS with non-neurological involvement.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2023.1102639","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T14:30:11Z","timestamp":1689949811000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Clinical and genetic characteristics of 36 children with Joubert syndrome"],"prefix":"10.3389","volume":"11","author":[{"given":"Yan","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianming","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengna","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Falin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiying","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shichao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,21]]},"reference":[{"key":"B1","first-page":"302","article-title":"Familial dysgenesis of the vermis: a syndrome of hyperventilation, abnormal eye movements and retardation","volume":"18","author":"Joubert","year":"1968","journal-title":"Neurology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1136\/jmedgenet-2021-108114","article-title":"Sufu haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum","volume":"59","author":"Serpieri","year":"2022","journal-title":"J Med Genet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1016\/s1474-4422(13)70136-4","article-title":"Joubert syndrome: congenital cerebellar ataxia with the molar tooth","volume":"12","author":"Romani","year":"2013","journal-title":"Lancet Neurol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.spen.2009.06.002","article-title":"Joubert syndrome: insights into brain development, cilium biology, and complex disease","volume":"16","author":"Doherty","year":"2009","journal-title":"Semin Pediatr Neurol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"112450","DOI":"10.1016\/j.envres.2021.112450","article-title":"Association of both prenatal and early childhood multiple metals exposure with neurodevelopment in infant: a prospective cohort study","volume":"205","author":"Liu","year":"2022","journal-title":"Environ Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1289\/ehp196","article-title":"Adverse associations of both prenatal and postnatal exposure to organophosphorous pesticides with infant neurodevelopment in an agricultural area of Jiangsu province, China","volume":"124","author":"Liu","year":"2016","journal-title":"Environ Health Perspect"},{"key":"B7","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1177\/088307389701200703","article-title":"\u201cJoubert syndrome\u201d revisited: key ocular motor signs with magnetic resonance imaging correlation","volume":"12","author":"Maria","year":"1997","journal-title":"J Child Neurol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/s41436-019-0686-8","article-title":"Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American college of medical genetics and genomics (ACMG) and the clinical genome resource (CLINGEN)","volume":"22","author":"Riggs","year":"2020","journal-title":"Genet Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"195","DOI":"10.7326\/0003-4819-28-1-195_3","article-title":"Developmental diagnosis: normal and abnormal child development\u2014clinical methods and pediatric applications","volume":"28","author":"Amatruda","year":"1948","journal-title":"Ann Intern Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1742-4682-10-1","article-title":"A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children","volume":"10","author":"Hou","year":"2013","journal-title":"Theor Biol Med Model"},{"key":"B11","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/jp.2010.75","article-title":"Neurological and developmental disabilities in elbw and vlbw: follow-up at 2 years of age","volume":"31","author":"Stoinska","year":"2011","journal-title":"J Perinatol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2200","DOI":"10.1007\/s43032-022-00898-y","article-title":"Identification of pathogenic variants in Rpgrip1l with Meckel syndrome and preimplantation genetic testing in a Chinese family","volume":"29","author":"Zhang","year":"2022","journal-title":"Reprod Sci"},{"key":"B13","doi-asserted-by":"publisher","first-page":"994412","DOI":"10.3389\/fcell.2022.994412","article-title":"Eyes on charge syndrome: roles of Chd7 in ocular development","volume":"10","author":"Krueger","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/0887-8994(90)90015-s","article-title":"Charge and Joubert syndromes: are they a single disorder?","volume":"6","author":"Menenzes","year":"1990","journal-title":"Pediatr Neurol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"387","DOI":"10.3760\/cma.j.cn511374-20210405-00303","article-title":"Clinical and genetic analysis of two patients with charge syndrome due to de novo variants of Chd7 gene","volume":"39","author":"Yan","year":"2022","journal-title":"Chin J Med Genet"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1195","DOI":"10.1093\/ndt\/gfy333","article-title":"Impaired urinary concentration ability is a sensitive predictor of renal disease progression in Joubert syndrome","volume":"35","author":"Nuovo","year":"2018","journal-title":"Nephrol Dial Transplant"},{"key":"B17","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1038\/gim.2016.204","article-title":"Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center","volume":"19","author":"Vilboux","year":"2017","journal-title":"Genet Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.pediatrneurol.2020.01.012","article-title":"Clinical and molecular diagnosis of Joubert syndrome and related disorders","volume":"106","author":"Radha Rama Devi","year":"2020","journal-title":"Pediatr Neurol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"231","DOI":"10.14802\/jmd.21066","article-title":"Clinical and imaging profile of patients with Joubert syndrome","volume":"14","author":"Surisetti","year":"2021","journal-title":"J Mov Disord"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1016\/b978-0-444-59565-2.00058-7","article-title":"Joubert syndrome and related disorders","volume":"113","author":"Valente","year":"2013","journal-title":"Handb Clin Neurol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.3877\/cma.j.issn.1674-0785.2017.08.035","article-title":"Joubert syndrome","volume":"11","author":"Shanyamei","year":"2017","journal-title":"Chin J Clin"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.3174\/ajnr.A2517","article-title":"Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients","volume":"32","author":"Poretti","year":"2011","journal-title":"Am J Neuroradiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/labinvest.3700253","article-title":"Cilium-generated signaling and cilia-related disorders","volume":"85","author":"Pan","year":"2005","journal-title":"Lab Invest"},{"key":"B24","doi-asserted-by":"publisher","first-page":"500","DOI":"10.3390\/cells4030500","article-title":"Specialized cilia in mammalian sensory systems","volume":"4","author":"Falk","year":"2015","journal-title":"Cells"},{"key":"B25","doi-asserted-by":"publisher","first-page":"5329","DOI":"10.1242\/dev.02153","article-title":"Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus","volume":"132","author":"Banizs","year":"2005","journal-title":"Development"},{"key":"B26","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1038\/nature03494","article-title":"Fgf-induced vesicular release of sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination","volume":"435","author":"Tanaka","year":"2005","journal-title":"Nature"},{"key":"B27","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1136\/jmedgenet-2015-103087","article-title":"Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity","volume":"52","author":"Bachmann-Gagescu","year":"2015","journal-title":"J Med Genet"},{"key":"B28","doi-asserted-by":"publisher","first-page":"a015255","DOI":"10.1101\/cshperspect.a015255","article-title":"Epidermal polarity genes in health and disease","volume":"4","author":"Tellkamp","year":"2014","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.cell.2011.05.030","article-title":"A role for the primary cilium in notch signaling and epidermal differentiation during skin development","volume":"145","author":"Ezratty","year":"2011","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1002\/ajmg.c.31963","article-title":"Genotype-phenotype correlates in Joubert syndrome: a review","volume":"190","author":"Gana","year":"2022","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B31","first-page":"9","article-title":"Joubert syndrome","volume-title":"Genereviews(\u00ae)","author":"Parisi","year":"1993"},{"key":"B32","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1002\/ajmg.c.30229","article-title":"Clinical and molecular features of Joubert syndrome and related disorders","author":"Parisi","year":"2009","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B33","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1136\/jmg.2010.087106","article-title":"Chd7 mutations and charge syndrome: the clinical implications of an expanding phenotype","volume":"48","author":"Bergman","year":"2011","journal-title":"J Med Genet"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1038\/ejhg.2013.10","article-title":"Clinical utility gene card for: Joubert syndrome\u2013update 2013","volume":"21","author":"Valente","year":"2013","journal-title":"Eur J Hum Genet"},{"key":"B35","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jns.2017.02.065","article-title":"Neuroimaging findings in Joubert syndrome with C5orf42 gene mutations: a milder form of molar tooth sign and vermian hypoplasia","volume":"376","author":"Enokizono","year":"2017","journal-title":"J Neurol Sci"},{"key":"B36","doi-asserted-by":"publisher","first-page":"333","DOI":"10.13929\/j.issn.1003-3289.2021.03.004","article-title":"Prenatal imaging findings and genetic abnormalities of Joubert syndrome","volume":"37","author":"Lan","year":"2021","journal-title":"Chin J Magn Reson Imaging"},{"key":"B37","doi-asserted-by":"publisher","first-page":"4298","DOI":"10.1083\/jcb.201804141","article-title":"Proteins that control the geometry of microtubules at the ends of cilia","volume":"217","author":"Louka","year":"2018","journal-title":"J Cell Biol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"77","DOI":"10.22141\/2307-1257.3.17.2016.76542","article-title":"Ciliopathies, the role of wnt-signaling pathway in the course of acute (postinfectious) glomerulonephritis: literature review and own observations","volume":"3","author":"Diadyk","year":"2016","journal-title":"Kidneys"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1002\/ajmg.a.61018","article-title":"A novel pathogenic variant in Ofd1 results in X-linked Joubert syndrome with orofaciodigital features and pituitary aplasia","volume":"179","author":"Aljeaid","year":"2019","journal-title":"Am J Med Genet A"},{"key":"B40","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1111\/cge.12836","article-title":"Molecular genetic analysis of 30 families with Joubert syndrome","volume":"90","author":"Suzuki","year":"2016","journal-title":"Clin Genet"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1962","DOI":"10.2215\/cjn.05660517","article-title":"Prospective evaluation of kidney disease in Joubert syndrome","volume":"12","author":"Fleming","year":"2017","journal-title":"Clin J Am Soc Nephrol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/s00439-014-1508-3","article-title":"Oral-facial-digital syndrome type vi: is C5orf42 really the major gene?","volume":"134","author":"Romani","year":"2015","journal-title":"Hum Genet"},{"key":"B43","doi-asserted-by":"publisher","first-page":"197","DOI":"10.7754\/Clin.Lab.2017.170813","article-title":"Lesch-Nyhan syndrome in a Chinese family with mutation in the hypoxanthine-guanine phosphoribosyltransferase gene","volume":"64","author":"Huang","year":"2018","journal-title":"Clin Lab"},{"key":"B44","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1146\/annurev.me.24.020173.000353","article-title":"The Lesch-Nyhan syndrome","volume":"24","author":"Nyhan","year":"1973","journal-title":"Annu Rev Med"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1016\/j.radcr.2021.02.031","article-title":"A case report of Joubert syndrome with renal involvement and seizures in a neonate","volume":"16","author":"Ahmetgjekaj","year":"2021","journal-title":"Radiol Case Rep"},{"key":"B46","doi-asserted-by":"publisher","first-page":"5339","DOI":"10.1007\/s11033-021-06508-5","article-title":"Identification of a novel truncating variant in Ahi1 gene and a brief review on mutations spectrum","volume":"48","author":"Karamzade","year":"2021","journal-title":"Mol Biol Rep"},{"key":"B47","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1038\/ng2069","article-title":"Mutations in the gene encoding the basal body protein Rpgrip1l, a nephrocystin-4 interactor, cause Joubert syndrome","volume":"39","author":"Arts","year":"2007","journal-title":"Nat Genet"},{"key":"B48","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1136\/jmedgenet-2016-103832","article-title":"Mutations in Cep120 cause Joubert syndrome as well as complex ciliopathy phenotypes","volume":"53","author":"Roosing","year":"2016","journal-title":"J Med Genet"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e2109508119","DOI":"10.1073\/pnas.2109508119","article-title":"The charge syndrome ortholog chd-7 regulates tgf-\u0392 pathways in caenorhabditis elegans","volume":"119","author":"Jofr\u00e9","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B50","doi-asserted-by":"publisher","first-page":"618","DOI":"10.3760\/cma.j.cn112142-20210630-00426","article-title":"A case of charge syndrome confirmed by ophthalmology","volume":"57","author":"Shang","year":"2021","journal-title":"Zhonghua Yan Ke Za Zhi"},{"key":"B51","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1002\/humu.22821","article-title":"Kiaa0586 is mutated in Joubert syndrome","volume":"36","author":"Bachmann-Gagescu","year":"2015","journal-title":"Hum Mutat"},{"key":"B52","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/ajmg.a.61399","article-title":"Healthcare recommendations for Joubert syndrome","volume":"182","author":"Bachmann-Gagescu","year":"2020","journal-title":"Am J Med Genet A"},{"key":"B53","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3233\/trd-190041","article-title":"The molecular genetics of Joubert syndrome and related ciliopathies: the challenges of genetic and phenotypic heterogeneity","volume":"4","author":"Parisi","year":"2019","journal-title":"Transl Sci Rare Dis"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1102639\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T14:30:21Z","timestamp":1689949821000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2023.1102639\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,21]]},"references-count":53,"alternative-id":["10.3389\/fped.2023.1102639"],"URL":"https:\/\/doi.org\/10.3389\/fped.2023.1102639","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,21]]},"article-number":"1102639"}}