Lumbar Hemivertebra Associated with Coronal Craniosynostosis due to TCF12 Mutation: An Expansion of the Axial Skeletal Phenotype.

Lumbar Hemivertebra Associated with Coronal Craniosynostosis due to TCF12 Mutation: An Expansion of the Axial Skeletal Phenotype. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Lumbar Hemivertebra Associated with Coronal Craniosynostosis due to TCF12 Mutation: An Expansion of the Axial Skeletal Phenotype. Miguel Caparrós Calle, Juan Sánchez Palacios, Jesús Gallego Álvarez, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9169519/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Introduction : Mutations in TCF12 are identified in 10–20% of coronal craniosynostoses negative for TWIST1 and FGFR mutations, with autosomal dominant inheritance, incomplete penetrance, and wide phenotypic variability. The recognized phenotypic spectrum includes coronal synostosis, craniofacial dysmorphism, ptosis, strabismus, mild syndactyly, and neurocognitive alterations. However, axial skeletal segmentation anomalies have not been previously reported in association with TCF12 mutations. Case presentation : We present the case of a 9-year-old male with right unicoronal craniosynostosis treated by endoscopic suturectomy at 3 months of age. Genetic testing identified a pathogenic heterozygous variant in TCF12 (c.1691C>G; p.Ser564*). During follow-up, spine evaluation revealed a left lumbar congenital scoliosis (43° Cobb, L1–L5), an L5 hemivertebra, and a posterior sacral fusion deficit, confirmed on radiography and MRI. Cranial MRI showed mild supratentorial ventriculomegaly. Neurocognitive developmental delay with social communication difficulties was also noted. The same TCF12 mutation was identified in the phenotypically asymptomatic father. Over six years of follow-up, the lumbar curve remained stable and was managed conservatively. Conclusion : This case represents the first reported association between coronal craniosynostosis due to a TCF12 mutation and axial skeletal segmentation anomalies. Given the broad embryonic expression of TCF12 and its role in osteoblast differentiation, this finding suggests a wider effect on axial skeletal morphogenesis beyond the cranial vault. We propose that systematic spinal evaluation should be considered in patients with TCF12-related craniosynostosis presenting with signs of trunk asymmetry, and that a multidisciplinary follow-up , including neurosurgery, orthopedics, ophthalmology, and neurodevelopmental assessment is essential to detect and manage the full phenotypic spectrum. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Craniosynostosis is the premature closure of one or more cranial sutures before the brain has completed its growth. This prevents normal skull growth perpendicular to the affected suture, resulting in characteristic deformities and potentially increased intracranial pressure, which may lead to permanent neurological disability [ 1 ]. Literature has described mutations related to premature coronal suture closure, either unilateral or bilateral, with the most frequent being mutations in the FGFR3 and TWIST1 genes, associated with Muenke and Saethre-Chotzen syndromes, respectively [ 2 , 3 ]. Another mutation linked to premature coronal suture synostosis is that of the TCF12 gene, detected in 10–20% of coronal craniosynostoses negative for TWIST1 and FGFRs [ 4 ]. Inheritance is autosomal dominant, with incomplete penetrance and high phenotypic variability. The phenotypic spectrum includes coronal synostosis, eyelid ptosis, mild syndactyly, low frontal hairline implantation, dental malocclusion and other palate abnormalities, and strabismus [ 5 , 6 ]. Recently, mild neurocognitive developmental involvement has also been described, with increased risk of social communication difficulties and behavioral problems [ 7 ]. To date, no axial skeletal segmentation anomalies associated with coronal craniosynostosis due to TCF12 gene mutation have been reported in the literature. Clinical Case We present the case of a 9-year-and-1-month-old male patient with no relevant perinatal history, who underwent surgery for right unicoronal craniosynostosis (Figure 1) via endoscopic suturectomy at 3 months and 15 days of age, and was referred at 7 months of age for suspected congenital muscular torticollis. Initial physical examination was consistent with torticollis secondary to strabismus, which required surgical intervention by ophthalmology, with the rest of the initial orthopedic and neurological examination being normal. No brachydactyly or syndactyly was observed. At the same time, genetic testing of FGFR1 , FGFR2 , FGFR3 , and TWIST genes was initiated, with negative results. The genetic study was expanded, identifying the variant c.1691 C>G; p.(Ser564)* in heterozygosis in the TCF12 gene. During subsequent follow-up, delayed acquisition of motor skills and language associated with neurocognitive developmental delay and social communication difficulties was observed, while the rest of the neurological examination remained normal. Orthopedically, examination highlighted bilateral grade II flat feet with 11° hindfoot valgus, correctable with the Fonseca maneuver, as well as shoulder asymmetry and left lumbar gibbus of 3° on Adams test with no significant lateral displacement on plumb line test, detected at 2 years and 9 months of age. Spine radiography showed a left lumbar curve (L1-L5) of 43° Cobb (Figure 2), and spine MRI revealed a lumbar hemivertebra at L5 and posterior sacral bone fusion deficit (Figure 3). Following this finding, the study was expanded to a clinical exome, without detecting variants in other genes that could justify the patient's axial skeletal phenotype. The genetic study was also extended to the parents, identifying the same heterozygous mutation in the father. Clinical history and physical examination of the father showed no history of craniosynostosis or spinal deformities. Cranial MRI performed at 2 years and 1 month of age showed mild supratentorial ventriculomegaly and widening of subarachnoid spaces in the right frontotemporal region and right Sylvian fissure, with no other radiological abnormalities (Figure 4). Based on this finding and the neurocognitive developmental delay, the option of intracranial pressure monitoring with an epidural sensor was discussed with the parents; a joint decision was made to adopt an expectant attitude with close observation. The patient's neurocognitive evolution was favorable, although behavioral problems and communication difficulties persist. Subsequent MRIs showed stable ventricular size and morphology. Regarding the lumbar hemivertebra and posterior sacral fusion deficit associated with congenital scoliosis with a left lumbar curve, no increase in left lumbar gibbus was observed in orthopedic follow-up examinations, nor progression of the curve in subsequent radiographic controls over 6 years of follow-up (43º Cobb at 9 years and 1 month of age). Conservative management with observation and follow-up was decided based on radiological stability, low lumbar curve location, and absence of postural instability or pain symptoms. Discussion and Conclusions Mutations in TCF12 account for 10–20% of coronal craniosynostoses negative for TWIST1 and FGFRs , with autosomal dominant inheritance, incomplete penetrance, and wide phenotypic variability. The identification of the same mutation in the patient's father, who is phenotypically asymptomatic, is consistent with the incomplete penetrance and variable expressivity described for this gene. The classic phenotype includes coronal synostosis, craniofacial dysmorphism, ptosis, strabismus, mild syndactyly, and mild neurocognitive alterations. However, vertebral segmentation anomalies such as those observed in our patient have not been previously described. In other syndromes, such as Saethre-Chotzen, extracranial skeletal alterations, including vertebral anomalies, have been described, suggesting that genes involved in cranial osteogenesis may exert broader effects on axial skeleton development [ 8 ]. In this context, the association observed in our case between coronal craniosynostosis due to TCF12 mutation and a lumbar hemivertebra with posterior sacral fusion defect is consistent with a possible broader effect on axial skeletal morphogenesis. From an embryological perspective, TCF12 encodes a member of the basic helix–loop–helix family of transcription factors that forms heterodimers with TWIST1 , regulating osteoblast differentiation and bone modeling in multiple regions, particularly the coronal suture [ 9 ]. Experimental data have shown that TCF12 displays a broad expression pattern during embryonic development and participates in the regulation of mesenchyme and early bone differentiation processes [ 10 ]. This provides a plausible biological framework for broader skeletal involvement beyond the skull, although it requires confirmation through functional studies and larger series. The coexistence in our case of coronal craniosynostosis, lumbar hemivertebra, and posterior sacral fusion deficit suggests a broader effect on axial bone morphogenesis, significantly expanding the known phenotypic spectrum. From a clinical standpoint, this finding suggests the need for systematic orthopedic spine evaluation in patients with craniosynostosis due to TCF1 2 mutation, especially in the presence of trunk asymmetry signs. Likewise, a multidisciplinary approach, including neurosurgery follow-up and assessment of neurocognitive development and communication, is essential to detect comorbidities early and optimize functional management. As the main limitation, this is a single clinical case, so additional studies will be necessary to confirm this possible association and more precisely define the axial phenotypic spectrum of TCF12 mutations. Nevertheless, we consider this case to provide novel and clinically relevant information, expanding current knowledge on skeletal manifestations associated with this gene. Declarations Author contribution: MCC conceived the study, collected clinical data, and wrote the original draft. JSP and JGA contributed to clinical data acquisition and critically revised the manuscript. AGP contributed to the analysis and interpretation of findings and reviewed the manuscript. All authors read and approved the final version of the manuscript. Funding: The authors received no financial support for the research and publication of this article. Data availability: No datasets were generated or analysed during the current study. Competing interests: The authors declare no competing interests. Consent to publish: Consent was obtained from the patient´s parents. References Dias MS, Samson T, Rizk EB, Governale LS, Richtsmeier JT, SECTION ON NEUROLOGIC SURGERY, SECTION ON PLASTIC AND RECONSTRUCTIVE SURGERY (2020). Identifying the Misshapen Head: Craniosynostosis and Related Disorders. Pediatrics. ;146(3):e2020015511. 10.1542/peds.2020-015511 . PMID: 32868470 Mulliken JB, Gripp KW, Stolle CA, Steinberger D, Müller U (2004) Molecular analysis of patients with synostotic frontal plagiocephaly (unilateral coronal synostosis). Plast Reconstr Surg. ;113(7):1899 – 909. 10.1097/01.prs.0000122202.26792.bf . PMID: 15253176 Paznekas WA, Cunningham ML, Howard TD, Korf BR, Lipson MH, Grix AW, Feingold M, Goldberg R, Borochowitz Z, Aleck K, Mulliken J, Yin M, Jabs EW (1998) Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations. Am J Hum Genet 62(6):1370–1380. 10.1086/301855 PMID: 9585583; PMCID: PMC1377134 Foss-Skiftesvik J, Larsen CC, Stoltze UK, Kofod T, Hove H, Bøgeskov L, Østergaard E (2024) The role of pathogenic TCF12 variants in children with coronal craniosynostosis-a systematic review with addition of two novel cases. Childs Nerv Syst 40(11):3655–3671. 10.1007/s00381-024-06544-z Epub 2024 Jul 27. PMID: 39060747 Min L, Wei J, Mao W, Wang X (2025) Extended Phenotype of Bilateral Coronal Craniosynostosis Due to Novel TCF12 Mutation. J Craniofac Surg 36(3):e341–e342. 10.1097/SCS.0000000000010971 Epub 2025 May 1. PMID: 40558004 di Rocco F, Baujat G, Arnaud E, Rénier D, Laplanche JL, Daire VC, Collet C (2014) Clinical spectrum and outcomes in families with coronal synostosis and TCF12 mutations. Eur J Hum Genet 22(12):1413–1416. 10.1038/ejhg.2014.57 Epub 2014 Apr 16. PMID: 24736737; PMCID: PMC4231413 Kennedy-Williams P, Care H, Dalton L, Horton J, Kearney A, Rooney N, Hotton M, Pinckston M, Huggons E, Culshaw L, Kilcoyne S, Johnson D, Wilkie AOM, Wall S (2021) Neurodevelopmental, Cognitive, and Psychosocial Outcomes for Individuals With Pathogenic Variants in the TCF12 Gene and Associated Craniosynostosis. J Craniofac Surg. ;32(Suppl 3):1263–1268. 10.1097/SCS.0000000000007535 . PMID: 33904513 Trusen A, Beissert M, Collmann H, Darge K (2003) The pattern of skeletal anomalies in the cervical spine, hands and feet in patients with Saethre-Chotzen syndrome and Muenke-type mutation. Pediatr Radiol 33(3):168–172. 10.1007/s00247-002-0823-3 Epub 2002 Nov 12. PMID: 12612814 Sharma VP, Fenwick AL, Brockop MS, McGowan SJ, Goos JA, Hoogeboom AJ, Brady AF, Jeelani NO, Lynch SA, Mulliken JB, Murray DJ, Phipps JM, Sweeney E, Tomkins SE, Wilson LC, Bennett S, Cornall RJ, Broxholme J, Kanapin A, 500 Whole-Genome Sequences (WGS500) Consortium, Johnson D, Wall SA, van der Spek PJ, Mathijssen IM, Maxson RE, Twigg SR, Wilkie AO (2013) Mutations in TCF12, encoding a basic helix-loop-helix partner of TWIST1, are a frequent cause of coronal craniosynostosis. Nat Genet. ;45(3):304-7. 10.1038/ng.2531 . Epub 2013 Jan 27. Erratum in: Nat Genet. 2013;45(10):1261. PMID: 23354436; PMCID: PMC3647333 Blümel R, Zink M, Klopocki E, Liedtke D (2019) On the traces of tcf12: Investigation of the gene expression pattern during development and cranial suture patterning in zebrafish (Danio rerio). PLoS ONE 14(6):e0218286. 10.1371/journal.pone.0218286 PMID: 31188878; PMCID: PMC6561585 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 07 Apr, 2026 Reviews received at journal 07 Apr, 2026 Reviewers agreed at journal 07 Apr, 2026 Reviews received at journal 03 Apr, 2026 Reviewers agreed at journal 03 Apr, 2026 Reviewers invited by journal 01 Apr, 2026 Editor assigned by journal 24 Mar, 2026 Submission checks completed at journal 24 Mar, 2026 First submitted to journal 19 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9169519","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":616966419,"identity":"d6167956-9eda-4243-8308-c00091d04838","order_by":0,"name":"Miguel Caparrós 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Mar","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"Sánchez","lastName":"Palacios","suffix":""},{"id":616966424,"identity":"e67bc130-17f8-4183-8b6e-82296e3a2636","order_by":2,"name":"Jesús Gallego Álvarez","email":"","orcid":"","institution":"Hospital Universitario Puerta del Mar","correspondingAuthor":false,"prefix":"","firstName":"Jesús","middleName":"Gallego","lastName":"Álvarez","suffix":""},{"id":616966432,"identity":"d2144844-5b4a-4e7a-a8ef-28463f008097","order_by":3,"name":"Ariel Goltzman Peist","email":"","orcid":"","institution":"Hospital Universitario Puerta del Mar","correspondingAuthor":false,"prefix":"","firstName":"Ariel","middleName":"Goltzman","lastName":"Peist","suffix":""}],"badges":[],"createdAt":"2026-03-19 12:38:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9169519/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9169519/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106309966,"identity":"a50c3946-cb90-4c40-aacc-4504e4664a7f","added_by":"auto","created_at":"2026-04-07 10:21:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":180742,"visible":true,"origin":"","legend":"\u003cp\u003e3D computed tomography (CT) reconstruction of the skull showing right-sided unicoronal craniosynostosis.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9169519/v1/8a9d63328e46c794a488a2e8.png"},{"id":106309962,"identity":"7230b98f-d602-409e-819c-24a4ccc5fe54","added_by":"auto","created_at":"2026-04-07 10:21:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":223945,"visible":true,"origin":"","legend":"\u003cp\u003eAnteroposterior spine radiograph showing a 43° Cobb angle left-sided lumbar curve extending from L1 to L5.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9169519/v1/ca34f6a44a9f58800e01cb0a.png"},{"id":106309963,"identity":"58edb034-267b-4a8b-9aae-227aace32283","added_by":"auto","created_at":"2026-04-07 10:21:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":195352,"visible":true,"origin":"","legend":"\u003cp\u003eCoronal T2-weighted magnetic resonance imaging (MRI) of the spine showing an L5 lumbar hemivertebra.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9169519/v1/4d22fcb62a93cbf817cb1842.png"},{"id":106404695,"identity":"ca417287-6369-4568-9fb5-fe70af4c0aa0","added_by":"auto","created_at":"2026-04-08 09:16:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":110740,"visible":true,"origin":"","legend":"\u003cp\u003eAxial T1-weighted cranial MRI showing mild supratentorial ventriculomegaly.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9169519/v1/7dfc4448fd7f870d8f469934.png"},{"id":106405937,"identity":"c8bfe52e-6dba-4148-a361-04e5bc60b383","added_by":"auto","created_at":"2026-04-08 09:29:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1236715,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9169519/v1/397c0ce0-f6e0-4cb7-b1ac-1a0ed662b530.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eLumbar Hemivertebra Associated with Coronal Craniosynostosis due to TCF12 Mutation: An Expansion of the Axial Skeletal Phenotype.\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCraniosynostosis is the premature closure of one or more cranial sutures before the brain has completed its growth. This prevents normal skull growth perpendicular to the affected suture, resulting in characteristic deformities and potentially increased intracranial pressure, which may lead to permanent neurological disability [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLiterature has described mutations related to premature coronal suture closure, either unilateral or bilateral, with the most frequent being mutations in the \u003cem\u003eFGFR3\u003c/em\u003e and \u003cem\u003eTWIST1\u003c/em\u003e genes, associated with Muenke and Saethre-Chotzen syndromes, respectively [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother mutation linked to premature coronal suture synostosis is that of the \u003cem\u003eTCF12\u003c/em\u003e gene, detected in 10\u0026ndash;20% of coronal craniosynostoses negative for \u003cem\u003eTWIST1\u003c/em\u003e and \u003cem\u003eFGFRs\u003c/em\u003e [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Inheritance is autosomal dominant, with incomplete penetrance and high phenotypic variability. The phenotypic spectrum includes coronal synostosis, eyelid ptosis, mild syndactyly, low frontal hairline implantation, dental malocclusion and other palate abnormalities, and strabismus [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Recently, mild neurocognitive developmental involvement has also been described, with increased risk of social communication difficulties and behavioral problems [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, no axial skeletal segmentation anomalies associated with coronal craniosynostosis due to \u003cem\u003eTCF12\u003c/em\u003e gene mutation have been reported in the literature.\u003c/p\u003e"},{"header":"Clinical Case","content":"\u003cp\u003eWe present the case of a 9-year-and-1-month-old male patient with no relevant perinatal history, who underwent surgery for right unicoronal craniosynostosis (Figure 1) via endoscopic suturectomy at 3 months and 15 days of age, and was referred at 7 months of age for suspected congenital muscular torticollis. Initial physical examination was consistent with torticollis secondary to strabismus, which required surgical intervention by ophthalmology, with the rest of the initial orthopedic and neurological examination being normal. No brachydactyly or syndactyly was observed. At the same time, genetic testing of \u003cem\u003eFGFR1\u003c/em\u003e, \u003cem\u003eFGFR2\u003c/em\u003e, \u003cem\u003eFGFR3\u003c/em\u003e, and \u003cem\u003eTWIST\u003c/em\u003e genes was initiated, with negative results. The genetic study was expanded, identifying the variant c.1691 C\u0026gt;G; p.(Ser564)* in heterozygosis in the \u003cem\u003eTCF12\u003c/em\u003e gene.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring subsequent follow-up, delayed acquisition of motor skills and language associated with neurocognitive developmental delay and social communication difficulties was observed, while the rest of the neurological examination remained normal. Orthopedically, examination highlighted bilateral grade II flat feet with 11\u0026deg; hindfoot valgus, correctable with the Fonseca maneuver, as well as shoulder asymmetry and left lumbar gibbus of 3\u0026deg; on Adams test with no significant lateral displacement on plumb line test, detected at 2 years and 9 months of age. Spine radiography showed a left lumbar curve (L1-L5) of 43\u0026deg; Cobb (Figure 2), and spine MRI revealed a lumbar hemivertebra at L5 and posterior sacral bone fusion deficit (Figure 3). Following this finding, the study was expanded to a clinical exome, without detecting variants in other genes that could justify the patient\u0026apos;s axial skeletal phenotype. The genetic study was also extended to the parents, identifying the same heterozygous mutation in the father. Clinical history and physical examination of the father showed no history of craniosynostosis or spinal deformities.\u003c/p\u003e\n\u003cp\u003eCranial MRI performed at 2 years and 1 month of age showed mild supratentorial ventriculomegaly and widening of subarachnoid spaces in the right frontotemporal region and right Sylvian fissure, with no other radiological abnormalities (Figure 4). Based on this finding and the neurocognitive developmental delay, the option of intracranial pressure monitoring with an epidural sensor was discussed with the parents; a joint decision was made to adopt an expectant attitude with close observation. The patient\u0026apos;s neurocognitive evolution was favorable, although behavioral problems and communication difficulties persist. Subsequent MRIs showed stable ventricular size and morphology.\u003c/p\u003e\n\u003cp\u003eRegarding the lumbar hemivertebra and posterior sacral fusion deficit associated with congenital scoliosis with a left lumbar curve, no increase in left lumbar gibbus was observed in orthopedic follow-up examinations, nor progression of the curve in subsequent radiographic controls over 6 years of follow-up (43\u0026ordm; Cobb at 9 years and 1 month of age). Conservative management with observation and follow-up was decided based on radiological stability, low lumbar curve location, and absence of postural instability or pain symptoms.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003cp\u003eMutations in \u003cem\u003eTCF12\u003c/em\u003e account for 10\u0026ndash;20% of coronal craniosynostoses negative for \u003cem\u003eTWIST1\u003c/em\u003e and \u003cem\u003eFGFRs\u003c/em\u003e, with autosomal dominant inheritance, incomplete penetrance, and wide phenotypic variability. The identification of the same mutation in the patient's father, who is phenotypically asymptomatic, is consistent with the incomplete penetrance and variable expressivity described for this gene. The classic phenotype includes coronal synostosis, craniofacial dysmorphism, ptosis, strabismus, mild syndactyly, and mild neurocognitive alterations. However, vertebral segmentation anomalies such as those observed in our patient have not been previously described.\u003c/p\u003e \u003cp\u003eIn other syndromes, such as Saethre-Chotzen, extracranial skeletal alterations, including vertebral anomalies, have been described, suggesting that genes involved in cranial osteogenesis may exert broader effects on axial skeleton development [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In this context, the association observed in our case between coronal craniosynostosis due to \u003cem\u003eTCF12\u003c/em\u003e mutation and a lumbar hemivertebra with posterior sacral fusion defect is consistent with a possible broader effect on axial skeletal morphogenesis.\u003c/p\u003e \u003cp\u003eFrom an embryological perspective, \u003cem\u003eTCF12\u003c/em\u003e encodes a member of the basic helix\u0026ndash;loop\u0026ndash;helix family of transcription factors that forms heterodimers with \u003cem\u003eTWIST1\u003c/em\u003e, regulating osteoblast differentiation and bone modeling in multiple regions, particularly the coronal suture [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Experimental data have shown that \u003cem\u003eTCF12\u003c/em\u003e displays a broad expression pattern during embryonic development and participates in the regulation of mesenchyme and early bone differentiation processes [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This provides a plausible biological framework for broader skeletal involvement beyond the skull, although it requires confirmation through functional studies and larger series. The coexistence in our case of coronal craniosynostosis, lumbar hemivertebra, and posterior sacral fusion deficit suggests a broader effect on axial bone morphogenesis, significantly expanding the known phenotypic spectrum.\u003c/p\u003e \u003cp\u003eFrom a clinical standpoint, this finding suggests the need for systematic orthopedic spine evaluation in patients with craniosynostosis due to \u003cem\u003eTCF1\u003c/em\u003e2 mutation, especially in the presence of trunk asymmetry signs. Likewise, a multidisciplinary approach, including neurosurgery follow-up and assessment of neurocognitive development and communication, is essential to detect comorbidities early and optimize functional management.\u003c/p\u003e \u003cp\u003eAs the main limitation, this is a single clinical case, so additional studies will be necessary to confirm this possible association and more precisely define the axial phenotypic spectrum of \u003cem\u003eTCF12\u003c/em\u003e mutations. Nevertheless, we consider this case to provide novel and clinically relevant information, expanding current knowledge on skeletal manifestations associated with this gene.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor contribution:\u0026nbsp;MCC conceived the study, collected clinical data, and wrote the original draft. JSP and JGA contributed to clinical data acquisition and critically revised the manuscript. AGP contributed to the analysis and interpretation of findings and reviewed the manuscript. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eFunding: The authors received no financial support for the research and publication of this article.\u003c/p\u003e\n\u003cp\u003eData availability: No datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eConsent to publish: Consent was obtained from the patient\u0026acute;s parents.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDias MS, Samson T, Rizk EB, Governale LS, Richtsmeier JT, SECTION ON NEUROLOGIC SURGERY, SECTION ON PLASTIC AND RECONSTRUCTIVE SURGERY (2020). Identifying the Misshapen Head: Craniosynostosis and Related Disorders. 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PMID: 23354436; PMCID: PMC3647333\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBl\u0026uuml;mel R, Zink M, Klopocki E, Liedtke D (2019) On the traces of tcf12: Investigation of the gene expression pattern during development and cranial suture patterning in zebrafish (Danio rerio). PLoS ONE 14(6):e0218286. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pone.0218286\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0218286\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 31188878; PMCID: PMC6561585\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9169519/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9169519/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e: Mutations in TCF12 are identified in 10–20% of coronal craniosynostoses negative for TWIST1 and FGFR mutations, with autosomal dominant inheritance, incomplete penetrance, and wide phenotypic variability. The recognized phenotypic spectrum includes coronal synostosis, craniofacial dysmorphism, ptosis, strabismus, mild syndactyly, and neurocognitive alterations. However, axial skeletal segmentation anomalies have not been previously reported in association with TCF12 mutations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e: We present the case of a 9-year-old male with right unicoronal craniosynostosis treated by endoscopic suturectomy at 3 months of age. Genetic testing identified a pathogenic heterozygous variant in TCF12 (c.1691C\u0026gt;G; p.Ser564*). During follow-up, spine evaluation revealed a left lumbar congenital scoliosis (43° Cobb, L1–L5), an L5 hemivertebra, and a posterior sacral fusion deficit, confirmed on radiography and MRI. Cranial MRI showed mild supratentorial ventriculomegaly. Neurocognitive developmental delay with social communication difficulties was also noted. The same TCF12 mutation was identified in the phenotypically asymptomatic father. Over six years of follow-up, the lumbar curve remained stable and was managed conservatively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: This case represents the first reported association between coronal craniosynostosis due to a TCF12 mutation and axial skeletal segmentation anomalies. Given the broad embryonic expression of TCF12 and its role in osteoblast differentiation, this finding suggests a wider effect on axial skeletal morphogenesis beyond the cranial vault. We propose that systematic spinal evaluation should be considered in patients with TCF12-related craniosynostosis presenting with signs of trunk asymmetry, and that a multidisciplinary follow-up , including neurosurgery, orthopedics, ophthalmology, and neurodevelopmental assessment\u0026nbsp; is essential to detect and manage the full phenotypic spectrum.\u003c/p\u003e","manuscriptTitle":"Lumbar Hemivertebra Associated with Coronal Craniosynostosis due to TCF12 Mutation: An Expansion of the Axial Skeletal Phenotype.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-07 10:21:03","doi":"10.21203/rs.3.rs-9169519/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-07T11:43:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-07T11:41:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"105286881135458632905474147486681681901","date":"2026-04-07T11:34:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-03T06:09:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"268008091534770618488096104858415401079","date":"2026-04-03T06:02:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-01T10:57:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-24T06:10:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-24T06:03:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Child's Nervous System","date":"2026-03-19T12:22:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"353d518d-da0b-4dac-a476-e7f8a1e8fdda","owner":[],"postedDate":"April 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T11:09:16+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-07 10:21:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9169519","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9169519","identity":"rs-9169519","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}