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Cited by 2Craniofacial Disorders and TreatmentsPectus Deformity Diagnosis and TreatmentFetal and Pediatric Neurological Disorders

Genetics versus environment in the pathophysiology of sagittal synostosis

Open access
De Gregorio, Valentina, Tosi, Domiziano D., Vita, Alessia, Salvati, Martina, Massimi, Luca, Tamburrini, Gianpiero, Tiberio, Federica, Lattanzi, Wanda·2026·Child's Nervous System
DOI 10.1007/s00381-026-07396-5PMC PMC13380559
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Abstract

Purpose: This systematic review aims to provide an updated overview of the relative contribution of germline genetic and environmental factors to the pathophysiology of sagittal craniosynostosis (sCS). Methods: Using the PubMed database in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, relevant studies addressing genetic and/or environmental determinants of sCS in paediatric patients were systematically reviewed. Results: A total of 1238 records were identified, of which 97 studies met inclusion criteria after full-text review. Overall, 25,877 patients were included, with 11,086 diagnosed with sCS (42.8%). Germline genetic variants potentially associated with craniosynostosis were reported in 251 patients, accounting for 12.6% of genetically tested individuals with sCS. Identified variants were distributed across 125 genes, with recurrent findings in 25 genes. Environmental and perinatal factors were more consistently reported across large population-based and case-control studies. Frequently associated factors included male sex, advanced maternal age, maternal smoking, thyroid dysfunction, fertility treatments, foetal constraint, prematurity, and abnormal birth weight, although effect sizes varied across studies. Conclusion: Identifiable germline genetic causes appear to account for only a minority of sCS cases, whereas epidemiological evidence suggests that environmental and perinatal influences may also contribute to disease pathogenesis. Nevertheless, most cases lack identifiable germline mutations in key signalling pathways, and the available evidence does not support either genetic or environmental factors as individually deterministic drivers of disease development. Overall, the evidence synthesized in this review supports a multifactorial model for sCS, in which rare genetic susceptibility and non-genetic influences likely interact in the etiopathogenesis of the condition rather than reflecting a single dominant aetiology. However, heterogeneity across studies, differences in genetic testing methodologies, potential bias in exposure assessment, and the limited availability of integrative analyses restrict definitive conclusions regarding the relative contribution of these factors.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review of 97 studies and 11,086 sagittal craniosynostosis (sCS) patients found identifiable germline variants in only 12.6% of genetically tested sCS cases, while environmental and perinatal factors were more consistently reported. The evidence supports a multifactorial model rather than a single dominant genetic or environmental cause.

Key findings

  • Among 97 included studies covering 25,877 patients, 11,086 had sCS (42.8%). Germline genetic variants potentially associated with craniosynostosis were reported in 251 patients, accounting for 12.6% of genetically tested individuals with sCS; variants were distributed across 125 genes, with recurrent findings in 25 genes.
  • Environmental and perinatal factors were more consistently reported in large population-based and case-control studies, including male sex, advanced maternal age, maternal smoking, thyroid dysfunction, fertility treatments, foetal constraint, prematurity, and abnormal birth weight, although effect sizes varied across studies.
  • Male predominance was marked (sum of studies: 5156 male and 1800 female), with odds ratios ranging from 1.46 to 4.5 (geometric mean ~2.7). Advanced maternal age (>35 years) was associated with OR 2.01–2.32; maternal smoking with OR 1.48–5.12; maternal thyroid disease with OR 1.3–2.11.
  • The authors conclude that most cases lack identifiable germline mutations in key signalling pathways and that the evidence supports a multifactorial model in which rare genetic susceptibility and non-genetic influences likely interact.

Methods

  • Systematic review conducted according to PRISMA guidelines using the PubMed database; the search was conducted on 31/12/2025 and identified 1238 records, of which 97 studies met inclusion criteria after full-text review.
  • Included non-randomized observational studies (cohort, case-control, population-based, case series, and case reports); no randomized controlled trials were identified. Quality was assessed with AMSTAR 2 and the Newcastle-Ottawa Scale, with case reports/series narratively assessed.
  • Data were extracted independently by two reviewers; because of clinical and methodological heterogeneity, a narrative synthesis was performed rather than a quantitative meta-analysis, with effect sizes and odds ratios reported where provided by original studies.

Limitations

  • The paper states that heterogeneity across studies, differences in genetic testing methodologies, potential bias in exposure assessment, and limited availability of integrative analyses restrict definitive conclusions about the relative contribution of genetic versus environmental factors.
  • The paper states that many studies were underpowered (only 29 of 96 cohorts included more than 200 participants), that reliance on parental self-report introduces recall bias, and that limiting the search to PubMed may have missed relevant publications.
  • Evident from the text: the included evidence spans heterogeneous designs and risk levels (case reports, cohort studies, GWAS, population-based studies), and the reported genetic diagnostic yield should be interpreted cautiously because of methodological heterogeneity; the text also reports germline variants in 251 patients in the abstract but 259 patients in the Results, indicating an internal inconsistency.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00381-026-07396-5

Cites

122 of 127 references verified5 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

70 of 132 cited sources checked · 26 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Environmental influences, including in utero mechanical constraints, maternal health conditions, medication exposure, and other prenatal risk factors, have been proposed as contributing factors particularly in non-syndromic cases.

    “Environmental influences have also been proposed as contributing factors, particularly in non-syndromic cases. These include in utero mechanical constraints, maternal health conditions, medication exposure, and other prenatal risk factors [1, 2, 11, 22–25].”
    Quote in the paperNot a substantial claim3 of 7 sources checked
    • cites [1] Lattanzi W, Barba M, Di Pietro L, Boyadjiev SA (2017) Genetic advances in craniosynostosis. Am J Med Genet A 173:1406–1429. https://doi.org/10.1002/ajmg.a.38159 source

      The Introduction (page unavailable) discusses proposed risk factors for nonsyndromic craniosynostosis, including intrauterine head constraint, maternal age, prenatal smoking, and medication exposures. It does not identify maternal health conditions as a risk-factor category for nonsyndromic cases; it also describes the evidence for several environmental exposures as mixed or inconclusive. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [2] Boulet SL, Rasmussen SA, Honein MA (2008) A population-based study of craniosynostosis in metropolitan Atlanta, 1989–2003. Am J Med Genet A 146:984–991. https://doi.org/10.1002/ajmg.a.32208 source
    • cites [11] Kajdic N, Spazzapan P, Velnar T (2018) Craniosynostosis - recognition, clinical characteristics, and treatment. Bosn J Basic Med Sci 18:110–116. https://doi.org/10.17305/bjbms.2017.2083 source

      The CRANIOSYNOSTOSIS section (p. 1) identifies intrauterine constraint, maternal smoking, prenatal teratogen exposure, and antiepileptic drugs as possible predisposing factors. It discusses these factors for craniosynostosis generally, however, and does not say they contribute particularly to non-syndromic cases. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [22] Twigg SRF, Wilkie AOM (2015) A genetic-pathophysiological framework for craniosynostosis. Am J Hum Genet 97:359–377. https://doi.org/10.1016/j.ajhg.2015.07.006 source
    • cites [23] Anderson PJ, Netherway DJ, McGlaughlin K, David DJ (2007) Intracranial volume measurement of sagittal craniosynostosis. J Clin Neurosci 14:455–458. https://doi.org/10.1016/j.jocn.2006.07.001 source
    • cites [24] Tamburrini G, Caldarelli M, Massimi L et al (2005) Intracranial pressure monitoring in children with single suture and complex craniosynostosis: a review. Childs Nerv Syst 21:913–921. https://doi.org/10.1007/s00381-004-1117-x source
    • cites [25] Clarke CM, Fok VT, Gustafson JA et al (2018) Single suture craniosynostosis: identification of rare variants in genes associated with syndromic forms. Am J Med Genet A 176:290–300. https://doi.org/10.1002/ajmg.a.38540 source

      The Discussion (page unavailable) suggests that gene–environment interactions may help explain incomplete penetrance in single-suture craniosynostosis, supporting a possible environmental contribution. It does not identify in utero mechanical constraints, maternal health conditions, medication exposure, or other prenatal risk factors as contributors. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    The penetrance of SMAD6 variants appears to be modified by common regulatory variation near BMP2.

    “Strong evidence supports a role for the BMP/SMAD pathway, particularly through SMAD6, whose variants represent one of the most consistent findings in midline NCS [62]; importantly, their penetrance appears to be modified by common regulatory variation near BMP2, supporting a two-locus model rather than a simple monogenic one [76].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [76] Justice CM, Yagnik G, Kim Y et al (2012) A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet 44:1360–1364. https://doi.org/10.1038/ng.2463 source

      The paper reports common variants associated with sagittal craniosynostosis near BMP2 and predicts a regulatory element in that region (association findings and discussion; page unavailable). It does not report SMAD6 variants or show that BMP2-region variation modifies their penetrance. Its discussion treats gene–gene interactions as a possibility, not an established two-locus model. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Strong evidence supports a role for the BMP/SMAD pathway in sCS, particularly through SMAD6.

    “Strong evidence supports a role for the BMP/SMAD pathway, particularly through SMAD6, whose variants represent one of the most consistent findings in midline NCS [62]; importantly, their penetrance appears to be modified by common regulatory variation near BMP2, supporting a two-locus model rather than a simple monogenic one [76].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [62] Di Rocco F, Rossi M, Verlut I et al (2023) Clinical interest of molecular study in cases of isolated midline craniosynostosis. Eur J Hum Genet 31, 621–628 (2023). https://doi.org/10.1038/s41431-023-01295-y source

      The Discussion reports SMAD6 variants in 7 of 43 children with isolated trigonocephaly and concludes that SMAD6 has a major role in metopic nonsyndromic craniosynostosis. That supports the SMAD6 portion of the claim, but our copy does not establish a broader role for the BMP/SMAD pathway. The later two-locus statement is attached to a different citation and is not judged here. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Findingcitation

    SMAD6 variants represent one of the most consistent findings in midline NCS.

    “Strong evidence supports a role for the BMP/SMAD pathway, particularly through SMAD6, whose variants represent one of the most consistent findings in midline NCS [62]; importantly, their penetrance appears to be modified by common regulatory variation near BMP2, supporting a two-locus model rather than a simple monogenic one [76].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [62] Di Rocco F, Rossi M, Verlut I et al (2023) Clinical interest of molecular study in cases of isolated midline craniosynostosis. Eur J Hum Genet 31, 621–628 (2023). https://doi.org/10.1038/s41431-023-01295-y source
  • Interpretationcitation

    Altered gene dosage and disrupted regulation can contribute to sCS even in the absence of pathogenic coding variants.

    “Tandem duplications of upstream IHH enhancers, rare chromosomal microdeletions and microduplications, and CNVs involving regions that include genes such as FGF2, SPRY1, SEMA5A, FBLN2, and TMEM43 support the concept that altered gene dosage and disrupted regulation can contribute to sCS even in the absence of pathogenic coding variants [64, 85, 87, 115, 124].”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [64] Fernández-Jaén A, Fernández-Perrone AL, Fernández-Mayoralas DM et al (2014) Craniosynostosis, psychomotor retardation, and facial dysmorphic features in a Spanish patient with a 4q27q28.3 deletion. Childs Nerv Syst 30:2157–2161. https://doi.org/10.1007/s00381-014-2474-8 source
    • cites [85] Maldžienė Ž, Bulanovaitė E, Aleksiūnienė B et al (2019) 16p13.11-p12.3 Microdeletion identified in a patient with sagittal craniosynostosis and developmental delay. Clin Dysmorphol 28:195–197. https://doi.org/10.1097/MCD.0000000000000285 source
    • cites [87] Mefford HC, Shafer N, Antonacci F et al (2010) Copy number variation analysis in single-suture craniosynostosis: multiple rare variants including RUNX2 duplication in two cousins with metopic craniosynostosis. Am J Med Genet A 152:2203–2210. https://doi.org/10.1002/ajmg.a.33557 source

      The Discussion (page not provided) proposes that changes in gene dosage, including RUNX2 duplication, increase susceptibility to premature suture fusion. The Results table also identifies rare CNVs involving SEMA5A, FBLN2, and TMEM43 in people with single-suture craniosynostosis. The paper does not establish disrupted regulation or show that the affected individuals lacked pathogenic coding variants. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [115] Wentz E, Vujic M, Kärrstedt EL et al (2014) A case report of two male siblings with autism and duplication of Xq13-q21, a region including three genes predisposing for autism. Eur Child Adolesc Psychiatry 23:329–336. https://doi.org/10.1007/s00787-013-0455-1 source
    • cites [124] Yu D, Li S, Liu Q, Zhang K (2017) Novel chromosomal microduplications associated with dolichocephaly craniosynostosis: a case report. Medicine (Baltimore) 96:e8729. https://doi.org/10.1097/MD.0000000000008729 source
  • May combine two claims. 45
  • Classified as probably not a substantial claim. 29

  • May combine two claims.

    Premisecitation

    The relative contribution of genetic and environmental factors in the pathogenesis of sagittal synostosis remains unclear, and current evidence is fragmented and often limited by small sample sizes or investigation of isolated risk factors.

    “Despite these findings, the relative contribution of genetic and environmental factors in the pathogenesis of sagittal synostosis remains unclear. Current evidence is fragmented and often limited by small sample sizes or the investigation of isolated risk factors [10, 29, 31, 36].”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [10] Johnson D, Wilkie AOM (2011) Craniosynostosis. Eur J Hum Genet 19:369–376. https://doi.org/10.1038/ejhg.2010.235 source

      The Clinical Overview (page not specified) identifies both genetic and environmental predispositions to craniosynostosis, while Genetic counselling/risk assessment describes uncertainty in estimates for sagittal synostosis. Genetic testing strategy notes relatively small numbers in some tested groups. The paper does not specifically assess the relative genetic and environmental contributions to sagittal synostosis or characterize the overall evidence as fragmented and focused on isolated risk factors. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [29] Sanchez-Lara PA, Carmichael SL, Graham JM Jr et al (2010) Fetal constraint as a potential risk factor for craniosynostosis. Am J Med Genet A 152:394–400. https://doi.org/10.1002/ajmg.a.33246 source

      The Introduction says no population-based study had directly assessed fetal-constraint factors in nonsyndromic craniosynostosis, and the Discussion says the underlying causes need further investigation. This supports uncertainty and investigation of selected risk factors, but the paper does not characterize the evidence on sagittal synostosis generally as fragmented or often limited by small samples; it describes its own study as the largest population-based study to date. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [31] Carmichael SL, Ma C, Rasmussen SA et al (2008) Craniosynostosis and maternal smoking. Birth Defects Res A Clin Mol Teratol 82:78–85. https://doi.org/10.1002/bdra.20426 source
    • cites [36] Gedzelman E, Meador KJ (2012) Antiepileptic drugs in women with epilepsy during pregnancy. Ther Adv Drug Saf 3:71–87. https://doi.org/10.1177/2042098611433192 source

  • May combine two claims.

    Premisecitation

    Both genetic predisposition and environmental influences contribute to non-syndromic craniosynostosis aetiology.

    “Both genetic predisposition and environmental influences contribute to NCS aetiology [12, 13].”
    • Also stated in: § Introduction · hedged
      “Both genetic predisposition and environmental factors are thought to contribute to the aetiology of non-syndromic sCS [12, 13].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [12] Greenwood J, Flodman P, Osann K et al (2014) Familial incidence and associated symptoms in a population of individuals with nonsyndromic craniosynostosis. Genet Med 16:302–310. https://doi.org/10.1038/gim.2013.134 source

      The Introduction describes nonsyndromic craniosynostosis as hypothesized to involve genetic and environmental influences. It reports evidence for a genetic role and associations with several environmental factors, but says the precise causes are not fully understood. The claim presents their contribution to aetiology more definitively than the source does. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [13] Cohen MM, MacLean RE (2000) Craniosynostosis: diagnosis, evaluation, and management, 2nd ed. Oxford University Press, New York

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Epidemiological studies have identified demographic and environmental associations with sCS, including male sex, advanced maternal age, and specific prenatal exposures such as maternal smoking, hypoxia-related conditions, sodium valproate, retinoic acid, antidepressants, and assisted reproductive technologies.

    “Epidemiological studies have identified several demographic and environmental associations, such as male sex, advanced maternal age, and specific prenatal exposures including maternal smoking, hypoxia-related conditions, sodium valproate, retinoic acid, antidepressants, and assisted reproductive technologies [15, 26–35].”
    Quote in the paperNot a substantial claim4 of 10 sources checked
    • cites [15] Källén K (1999) Maternal smoking and craniosynostosis. Teratology 60:146–150. https://doi.org/10.1002/(sici)1096-9926(199909)60:3%3C146::aid-tera10%3E3.3.co;2-v source
    • cites [26] Zeiger JS, Beaty TH, Hetmanski JB et al (2002) Genetic and environmental risk factors for sagittal craniosynostosis. J Craniofac Surg 13:602–606. https://doi.org/10.1097/00001665-200209000-00002 source
    • cites [27] Reefhuis J, Honein MA, Shaw GM, Romitti PA (2003) Fertility treatments and craniosynostosis: California, Georgia, and Iowa, 1993–1997. Pediatrics 111:1163–1166 source
    • cites [28] Reefhuis J, Honein MA (2004) Maternal age and non-chromosomal birth defects, Atlanta—1968–2000: teenager or thirty-something, who is at risk? Birth Defects Res A Clin Mol Teratol 70:572–579. https://doi.org/10.1002/bdra.20065 source
    • cites [29] Sanchez-Lara PA, Carmichael SL, Graham JM Jr et al (2010) Fetal constraint as a potential risk factor for craniosynostosis. Am J Med Genet A 152:394–400. https://doi.org/10.1002/ajmg.a.33246 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [30] Gill SK, Broussard C, Devine O et al (2012) Association between maternal age and birth defects of unknown etiology - United States, 1997–2007. Birth Defects Res A Clin Mol Teratol 94:1010–1018. https://doi.org/10.1002/bdra.23049 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [31] Carmichael SL, Ma C, Rasmussen SA et al (2008) Craniosynostosis and maternal smoking. Birth Defects Res A Clin Mol Teratol 82:78–85. https://doi.org/10.1002/bdra.20426 source
    • cites [32] Lajeunie E, Barcik U, Thorne JA et al (2001) Craniosynostosis and fetal exposure to sodium valproate. J Neurosurg 95:778–782. https://doi.org/10.3171/jns.2001.95.5.0778 source
    • cites [33] James AW, Levi B, Xu Y et al (2010) Retinoic acid enhances osteogenesis in cranial suture–derived mesenchymal cells: potential mechanisms of retinoid-induced craniosynostosis. Plast Reconstr Surg 125:1352–1361. https://doi.org/10.1097/PRS.0b013e3181d62980 source

      Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [34] Alwan S, Reefhuis J, Rasmussen SA et al (2007) Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med 356:2684–2692. https://doi.org/10.1056/NEJMoa066584 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Sagittal craniosynostosis is the most common form of non-syndromic craniosynostosis, accounting for 40-60% of all craniosynostosis cases, with an estimated incidence of 1:5000 live births.

    “Among NCS, sagittal CS (sCS) is the most common form, accounting for 40–60% of all CS cases, with an estimated incidence of 1:5000 live births [14].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Spazzapan P, Velnar T (2024) Isolated sagittal craniosynostosis: a comprehensive review. Diagnostics 14:435. https://doi.org/10.3390/diagnostics14040435 source

  • May combine two claims.

    Interpretationcitation

    ALX4 may be a potential target of TWIST1 or TCF12, both of which are required for calvarial development and suture closure.

    “ALX4 may be a potential target of TWIST1 or even TCF12, both of which are required for calvarial development and suture closure [127, 128].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [127] Loebel DAF, O’Rourke MP, Steiner KA, Banyer J, Tam PPL (2002) Isolation of differentially expressed genes from wild-type and Twist mutant mouse limb buds. Genesis 33:103–113 source
    • cites [128] Fan X, Waardenberg AJ, Demuth M, Osteil P, Sun JQJ, Loebel DAF et al (2020) TWIST1 homodimers and heterodimers orchestrate lineage-specific differentiation. Mol Cell Biol 40:e00663–19 source

      The Introduction (p. 4) describes TWIST1 as critical for craniofacial development and links altered TWIST1 function to craniosynostosis. The TCF12–TWIST1 section (p. 13) says the two act synergistically in cranial tissue development and discusses skull-suture regulation. Our copy does not identify ALX4 as a potential target of either factor (searched: ALX4), so the central proposed target relationship is unsupported. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Study selection was conducted in two stages by two independent reviewers using Rayyan systematic review software.

    “Study selection was conducted in two stages by two independent reviewers (V. DG and D. D. T.) using Rayyan systematic review software [39]: stage 1, title, and abstract screening: All retrieved citations were independently screened by both reviewers using the prespecified eligibility criteria.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A (2016) Rayyan—a web and mobile app for systematic reviews. Syst Rev 5:210. https://doi.org/10.1186/s13643-016-0384-4 source

  • May combine two claims.

    Interpretationcitation

    Increasing evidence implicates WNT/β-catenin signalling through AXIN1, AXIN2, and RUNX2 in sCS, suggesting that dysregulated osteoblast differentiation may be a recurrent biological mechanism.

    “Similarly, increasing evidence implicates WNT/β-catenin signalling through AXIN1, AXIN2, and RUNX2, suggesting that dysregulated osteoblast differentiation may be a recurrent biological mechanism in sCS [58, 105, 118, 121].”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [58] Cuellar A, Bala K, Di Pietro L et al (2020) Gain-of-function variants and overexpression of RUNX2 in patients with nonsyndromic midline craniosynostosis. Bone 137:115395. https://doi.org/10.1016/j.bone.2020.115395 source

      The Introduction identifies Wnt signalling as one pathway converging on RUNX2, and the Conclusions suggest that RUNX2 overexpression in osteogenic precursors could accelerate differentiation and cause premature suture fusion. This supports the RUNX2 and dysregulated-differentiation part of the claim, but the paper does not establish the specific WNT/β-catenin mechanism through AXIN1 and AXIN2 in nonsyndromic craniosynostosis. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [105] Timberlake AT, Hemal K, Gustafson JA et al (2024) AXIN1 mutations in nonsyndromic craniosynostosis. J Neurosurg Pediatr 34:246–251. https://doi.org/10.3171/2024.5.PEDS24115 source
    • cites [118] Xu J, Yan Q, Song C et al (2021) An Axin2 mutation and perinatal risk factors contribute to sagittal craniosynostosis: evidence from a Chinese female monochorionic diamniotic twin family. Hereditas 158:20. https://doi.org/10.1186/s41065-021-00182-0 source
    • cites [121] Yilmaz E, Mihci E, Guzel Nur B, Alper OM (2018) A novel AXIN2 gene mutation in sagittal synostosis. Am J Med Genet A 176:1976–1980. https://doi.org/10.1002/ajmg.a.40373 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ALX4 is involved in craniofacial development.

    “Particularly, ALX4 is involved in craniofacial development [62], anda variant in ALX4 was found associated with a moderate form of frontonasal dysplasia type 1 with minute parietal foramina [126].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Di Rocco F, Rossi M, Verlut I et al (2023) Clinical interest of molecular study in cases of isolated midline craniosynostosis. Eur J Hum Genet 31, 621–628 (2023). https://doi.org/10.1038/s41431-023-01295-y source

  • May combine two claims.

    Findingcitation

    Variants in TWIST1, FGFR1, and FGFR2 have been described in sCS, although each accounts for only a minor proportion of cases.

    “Variants in TWIST1, FGFR1, and FGFR2 have been described, although each accounts for only a minor proportion of cases [62, 98, 120].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [62] Di Rocco F, Rossi M, Verlut I et al (2023) Clinical interest of molecular study in cases of isolated midline craniosynostosis. Eur J Hum Genet 31, 621–628 (2023). https://doi.org/10.1038/s41431-023-01295-y source

      The Introduction (page unavailable) describes TWIST1 and FGFR2 variants as rare in isolated sagittal craniosynostosis, supporting their description and minor contribution. Neither that passage nor the searched passages on FGFR1 identify FGFR1 variants in these cases, so the claim is unsupported for that gene. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [98] Seto ML, Hing AV, Chang J et al (2007) Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. Am J Med Genet A 143:678–686. https://doi.org/10.1002/ajmg.a.31630 source
    • cites [120] Ye X, Guilmatre A, Reva B et al (2016) Mutation screening of candidate genes in patients with nonsyndromic sagittal craniosynostosis. Plast Reconstr Surg 137:952–961. https://doi.org/10.1097/01.prs.0000479978.75545.ee source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The PRISMA principle was used as an assessment tool, and PubMed was used to collect data.

    “The PRISMA [38] principle was used as an assessment tool, using the PubMed database to collect data.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Page MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71. https://doi.org/10.1136/bmj.n71 source

  • May combine two claims.

    Interpretationcitation

    Additional convergence in sCS is seen in the Hedgehog pathway, involving ALX4, IHH, and RAB23, and in the RAS/MAPK cascade, given the association of sCS with RASopathies and variants in BRAF, PTPN11, and MAP4K4.

    “Additional convergence is seen in the Hedgehog pathway, involving ALX4, IHH, and RAB23 [46, 72, 77], and in the RAS/MAPK cascade, given the association of sCS with RASopathies and variants in BRAF, PTPN11, and MAP4K4 [61, 112, 122].”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [46] Barroso E, Berges-Soria J, Benito-Sanz S et al (2015) Identification of the fourth duplication of upstream IHH regulatory elements, in a family with craniosynostosis Philadelphia type, helps to define the phenotypic characterization of these regulatory elements. Am J Med Genet A 167:902–906. https://doi.org/10.1002/ajmg.a.36811 source
    • cites [72] Jenkins D, Seelow D, Jehee FS et al (2007) RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet 80:1162–1170. https://doi.org/10.1086/518047 source
    • cites [77] Klopocki E, Lohan S, Brancati F et al (2011) Copy-number variations involving the IHH locus are associated with syndactyly and craniosynostosis. Am J Hum Genet 88:70–75. https://doi.org/10.1016/j.ajhg.2010.11.006 source
    • cites [61] Davis AA, Zuccoli G, Haredy MM, et al (2019) RASopathy in patients with isolated sagittal synostosis. Glob Pediatr Health 6:2333794X19846774. https://doi.org/10.1177/2333794X19846774 source

      The Background identifies RASopathies as MAPK-pathway disorders, and the Discussion reports isolated sagittal synostosis in patients with BRAF and PTPN11 variants. The paper does not report a MAP4K4 variant; the Hedgehog-pathway clause is attached to other citations. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [112] Ueda K, Yaoita M, Niihori T et al (2017) Craniosynostosis in patients with RASopathies: accumulating clinical evidence for expanding the phenotype. Am J Med Genet A 173:2346–2352. https://doi.org/10.1002/ajmg.a.38337 source
    • cites [122] Yoon JG, Yu JW, Shim KW et al (2024) Syndromic craniosynostosis caused by a novel missense variant in MAP4K4: expanding the genotype-phenotype relationship in RASopathies. Clin Genet 106:199–203. https://doi.org/10.1111/cge.14539 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    AMSTAR 2 appraisal tool was used to assess systematic review quality.

    “AMSTAR 2 appraisal tool has been used to assess systematic review quality [37].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, Henry DA (2017) AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 358:j4008 source

  • May combine two claims.

    Findingcitation

    Intake of specific micronutrients is associated with reduced risk of sCS: riboflavin OR=0.5, vitamin B6 OR=0.4, vitamin E OR=0.6, and vitamin C OR=0.7.

    “Conversely, intake of specific micronutrients has been associated with a reduced risk of sCS, including riboflavin (OR = 0.5), vitamin B6 (OR = 0.4), vitamin E (OR = 0.6), and vitamin C (OR = 0.7) [55].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [55] Carmichael SL, Rasmussen SA, Lammer EJ et al (2010) Craniosynostosis and nutrient intake during pregnancy. Birth Defects Res A Clin Mol Teratol 88:1032–1039. https://doi.org/10.1002/bdra.20717 source

      The Results report the stated adjusted odds ratios for riboflavin (0.5), vitamin B6 (0.4), and vitamin E (0.6) for sagittal synostosis. They report a vitamin C ratio of ≤0.7, not the exact 0.7 attributed here; its highest-versus-lowest-quartile confidence interval did not exclude 1, although the continuous analysis found an association. These dietary analyses were restricted to mothers who took folic acid–containing supplements in the first trimester. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    A possible explanation for male predominance is sex-specific transcriptional factors that may alter osteoblast differentiation signals mainly in males, while sCS occurrence in females has different genetic risk profiles.

    “A possible explanation of this effect has been linked to possible sex-specific transcriptional factor that may alter osteoblasts differentiation signal mainly on males, while sCS occurrence in females have different genetic risk profiles [91].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [91] Park SS, Beyer RP, Smyth MD et al (2015) Osteoblast differentiation profiles define sex specific gene expression patterns in craniosynostosis. Bone 76:169–176. https://doi.org/10.1016/j.bone.2015.03.001 source

      The Conclusion links sex-specific gene expression correlated with osteoblast differentiation to the possible male predominance of sagittal and metopic craniosynostosis. It also suggests that females with sagittal synostosis may have different genetic risk profiles. It does not establish that sex-specific transcription factors alter differentiation signals; the evidence concerns correlated transcripts, not a demonstrated mechanism. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Susceptibility loci near BMP2 and within BBS9, as well as functional evidence implicating ciliogenesis and primary cilium biology, are relevant to sagittal suture homeostasis.

    “This is further reinforced by the identification of susceptibility loci near BMP2 and within BBS9, as well as functional evidence implicating ciliogenesis and primary cilium biology in sagittal suture homeostasis [44, 76].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [44] Barba M, Di Pietro L, Massimi L et al (2018) BBS9 gene in nonsyndromic craniosynostosis: role of the primary cilium in the aberrant ossification of the suture osteogenic niche. Bone 112:58–70. https://doi.org/10.1016/j.bone.2018.04.013 source
    • cites [76] Justice CM, Yagnik G, Kim Y et al (2012) A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet 44:1360–1364. https://doi.org/10.1038/ng.2463 source

      The Abstract (page unavailable) reports replicated susceptibility loci near BMP2 and within BBS9. It also links BBS9 to ciliary transport and discusses primary-cilium signaling, but says that BBS9’s effect on suture fusion remains unknown. It does not provide functional evidence that ciliogenesis or primary cilia maintain sagittal suture homeostasis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    Discordant phenotypes in genetically identical twins carrying the same variant, as reported for AXIN2 and ERF, suggest that genetic predisposition alone may not fully determine the phenotype and that additional modifiers are likely involved.

    “The observation of discordant phenotypes in genetically identical twins carrying the same variant, as reported for AXIN2 and ERF, further suggests that genetic predisposition alone may not fully determine the phenotype and that additional modifiers are likely involved [63, 118].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [63] Farooq S, Morton J, Lloyd M, Krishna ST (2020) The influence of epigenetic factors in four pairs of twins with non-syndromic craniosynostosis. J Craniofac Surg 31:283–285. https://doi.org/10.1097/SCS.0000000000006064 source
    • cites [118] Xu J, Yan Q, Song C et al (2021) An Axin2 mutation and perinatal risk factors contribute to sagittal craniosynostosis: evidence from a Chinese female monochorionic diamniotic twin family. Hereditas 158:20. https://doi.org/10.1186/s41065-021-00182-0 source

  • May combine two claims.

    Findingcitation

    Maternal thyroid disease is linked to increased risk of CS, with reported ORs ranging from 1.3 to 2.11.

    “Maternal thyroid disease has also been linked to an increased risk of CS, with reported ORs ranging from 1.3 to 2.11 [56, 93], consistent with the well-established role of thyroid hormones in skeletal development.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [56] Carmichael SL, Ma C, Rasmussen SA et al (2015) Craniosynostosis and risk factors related to thyroid dysfunction. Am J Med Genet A 167:701–707. https://doi.org/10.1002/ajmg.a.36953 source

      The Results report an adjusted OR of 1.4 for maternal thyroid disease and craniosynostosis overall, supporting the stated link, although its 95% CI (0.9–1.9) includes 1. The paper does not report the claimed OR range of 1.3 to 2.11; its reported OR for multiple affected sutures is 3.0. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [93] Rasmussen SA, Yazdy MM, Carmichael SL et al (2007) Maternal thyroid disease as a risk factor for craniosynostosis. Obstet Gynecol 110:369–377. https://doi.org/10.1097/01.AOG.0000270157.88896.76 source

      The Results report an association between maternal thyroid disease and craniosynostosis, but the overall adjusted OR is 2.47, outside the stated range. The paper reports an OR of 2.11 only for sagittal craniosynostosis; it does not report 1.3 as an OR for the overall association (Results; page not specified in our copy). (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Thyroid hormones play a well-established role in skeletal development.

  • May combine two claims.

    Findingcitation

    Schraw et al. found increased odds of patients coming from parents residing close to the US-Mexico border (aPR=1.29), and Somolan et al. showed a correlation with patients living in more rural areas.

    “An example of the link between area of living and CS has been shown by Schraw et al., where they found increased changes of patients to come from parents residing close to the US-Mexico border (aPR = 1.29) [96], and by Somolan et al., showing a correlation with patients living in more rural areas [103].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [96] Schraw JM, Woodhouse JP, Langlois PH et al (2021) Risk factors and time trends for isolated craniosynostosis. Birth Defects Res 113:43–54. https://doi.org/10.1002/bdr2.1824 source

      The Results (Risk Factors for Isolated Craniosynostosis by Subtype) report an aPR of 1.29 for sagittal synostosis among offspring of mothers residing in counties adjoining the U.S.–Mexico border. The citing sentence presents that figure as applying to craniosynostosis generally, but the paper reports a different association for coronal synostosis and none for metopic synostosis. The separately cited claim about rural areas is not attributed to Schraw et al. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [103] Somolan CV, Petchesi CD, Jurca C, Bembea M (2022) Clinical-epidemiological study of a cohort of 35 patients with craniosynostosis. Maedica (Bucur) 17:893–901. https://doi.org/10.26574/maedica.2022.17.4.893 source

      The Outcomes section reports that 21 of 35 patients came from rural areas, compared with 14 from urban areas, and the Conclusions identify rural patients among the most frequently affected groups. These descriptive counts do not establish a correlation between rural residence and craniosynostosis; the paper does not list rural residence among its identified risk factors. The Schraw et al. finding is attributed to a different citation and is not assessed here. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Study designs such as case reports, case series, and small observational studies limit generalizability and causal inference, although they are useful for hypothesis generation.

    “Although useful for hypothesis generation, these study designs limit generalizability and causal inference [12, 25].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [12] Greenwood J, Flodman P, Osann K et al (2014) Familial incidence and associated symptoms in a population of individuals with nonsyndromic craniosynostosis. Genet Med 16:302–310. https://doi.org/10.1038/gim.2013.134 source

      The Introduction says prior studies of associated symptoms were limited by small sample sizes, and the Discussion cautions that this study’s findings may not reflect the target population. Those passages support a concern about generalizability, but the paper does not make the broader claim that case reports, case series, and small observational studies limit causal inference while serving as hypothesis generators. Page numbers were not available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [25] Clarke CM, Fok VT, Gustafson JA et al (2018) Single suture craniosynostosis: identification of rare variants in genes associated with syndromic forms. Am J Med Genet A 176:290–300. https://doi.org/10.1002/ajmg.a.38540 source

      The Discussion (page unavailable) says the study identified candidate variants but did not establish causality; further functional studies would be needed. That supports the point about generating leads without establishing causation, but the paper does not discuss case reports, case series, or small observational studies as a class, or their limits on generalizability. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A total of 1238 records were identified through the PubMed search.

    “A total of 1238 records were identified, of which 97 studies met inclusion criteria after full-text review.”
    • Also stated in: § Study selection · plain
      “A total of 1238 articles were initially identified through the PubMed search.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Identified variants were distributed across 125 genes, with recurrent findings in 25 genes.

    “Identified variants were distributed across 125 genes, with recurrent findings in 25 genes.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    97 studies met inclusion criteria after full-text review.

    “of which 97 studies met inclusion criteria after full-text review”
    • Also stated in: § Study selection · plain
      “Full-text assessment then led to a final selection of 97 articles that met the criteria of this review”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Seven included studies presented both genetic and environmental factors.

    “Seven of these studies presented both genetic and environmental factor out of which 4 case-control study, 1 cohort study, 1 clinical and molecular family study, and 1 prospective study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Genetic investigations were reported in the majority of studies, whereas environmental determinants were assessed less consistently and primarily within epidemiological frameworks.

    “Genetic investigations were reported in the majority of studies, whereas environmental determinants were assessed less consistently and primarily within epidemiological frameworks.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Among the included studies, 25 focused on environmental engagement.

    “Studies with a focus on environmental engagement were 25, out of which 2 were reported as case report, 1 case series, 3 as case-control study, 12 as population-based case-control study, 5 as retrospective study, 1 as prospective study, and 1 as twin study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Most reported variants occur in single individuals or small cohorts, whereas only a few genes recur across independent studies.

    “This interpretation is consistent with the observation that most reported variants occur in single individuals or small cohorts, whereas only a few genes recur across independent studies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    128 studies were considered sufficiently relevant after preliminary screening of titles and abstracts.

    “As shown in Fig. 1, only 128 studies were considered sufficiently relevant after the preliminary screening of titles and abstracts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The highest risk for PAH exposure is during the early months of pregnancy, with OR=1.76.

    “The highest risk has been reported during the early months of pregnancy for PAH exposure (OR = 1.76).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Paternal employment as mechanics/repairmen is associated with increased odds across multiple suture types (OR range: 1.8-3.0), whereas no association was observed for sagittal synostosis among fathers working in agriculture/forestry (OR=0.9).

    “In this study, paternal employment as mechanics/repairmen was associated with increased odds across multiple suture types (OR range: 1.8–3.0), whereas no association was observed for sagittal synostosis among fathers working in agriculture/forestry (OR = 0.9) [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Bradley CM, Alderman BW, Williams MA et al (1995) Parental occupations as risk factors for craniosynostosis in offspring. Epidemiology 6:306–310. https://doi.org/10.1097/00001648-199505000-00020 source

  • May combine two claims.

    Findingcitation

    The effect of maternal smoking on sCS risk varies with timing of cessation and number of cigarettes smoked per day, with highest risk in women smoking more than 15 cigarettes/day.

    “The effect can vary depending on both the timing of maternal smoking cessation (e.g. in the first, second, or third trimester) and the number of cigarettes smoked per day (with the highest risk observed in women smoking more than 15 cigarettes/day) [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Honein MA, Rasmussen SA (2000) Further evidence for an association between maternal smoking and craniosynostosis. Teratology 62:145–146. https://doi.org/10.1002/1096-9926(200009)62:3%3C145::AID-TERA1%3E3.0.CO;2-7 source

  • May combine two claims.

    Findingown data

    Most included studies come from North America (34/97) and have 6501 (58.6%) of all sCS patients; Europe has 31/97 studies and 1356 (12.2%) patients; Asia and Oceania have 12/97 and 7/97 studies with 409/2426 (3.7% & 21.9%) sCS patients.

    “Collectively, most of the studies come from North America (34/97) and have 6501 (58.6%) of all sCS patients in this systematic review; secondly, there is Europe with (31/97 studies) and 1356 (12.2%) patients, then Asia and Oceania (12/97 & 7/97 studies) with 409/2426 (3.7% & 21.9%) sCS patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Maternal smoke is one of the first and most documented risk factors for CS, with OR 1.48-5.12 for sagittal suture fusion.

    “Maternal smoke is one of the first and most documented risk factors for the insurgence of CS with OR 1.48–5.12 [15, 63, 69] for sagittal suture fusion.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Källén K (1999) Maternal smoking and craniosynostosis. Teratology 60:146–150. https://doi.org/10.1002/(sici)1096-9926(199909)60:3%3C146::aid-tera10%3E3.3.co;2-v source
    • cites [63] Farooq S, Morton J, Lloyd M, Krishna ST (2020) The influence of epigenetic factors in four pairs of twins with non-syndromic craniosynostosis. J Craniofac Surg 31:283–285. https://doi.org/10.1097/SCS.0000000000006064 source
    • cites [69] Honein MA, Rasmussen SA (2000) Further evidence for an association between maternal smoking and craniosynostosis. Teratology 62:145–146. https://doi.org/10.1002/1096-9926(200009)62:3%3C145::AID-TERA1%3E3.0.CO;2-7 source

  • May combine two claims.

    Findingown data

    The male predominance in sCS has been found consistently from 1980 to 2024 and despite population or region of birth.

    “These data have been found consistently during the years (from 1980 to 2024) and despite the population or region of birth.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Findingnone given

    The scarce evidence of integrative studies simultaneously assessing genetic and environmental variables represents a major limitation in the current literature.

    “However, the scarce evidence of integrative studies simultaneously assessing genetic and environmental variables represents a major limitation in the current literature.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Heterogeneity across studies, differences in genetic testing methodologies, potential bias in exposure assessment, and limited availability of integrative analyses restrict definitive conclusions regarding the relative contribution of genetic and environmental factors.

    “However, heterogeneity across studies, differences in genetic testing methodologies, potential bias in exposure assessment, and the limited availability of integrative analyses restrict definitive conclusions regarding the relative contribution of these factors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A written protocol specifying the research question, population, exposures, inclusion/exclusion criteria, search strategy, and data extraction plan was established prior to data collection.

    “A written protocol specifying the research question, population, exposures of interest (genetic variants and environmental/perinatal factors), inclusion and exclusion criteria, planned search strategy, and data extraction plan was established by the authors prior to the commencement of data collection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Although more than 60 genes have been implicated in craniosynostosis overall, the genetic basis of isolated sagittal synostosis remains less clearly defined.

    “Although more than 60 genes have been implicated in CS overall, including FGFR1–3, TWIST1, EFNB1, and ERF, the genetic basis of isolated sagittal synostosis remains less clearly defined [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Yilmaz E, Mihci E, Nur B et al (2019) Recent advances in craniosynostosis. Pediatr Neurol 99:7–15. https://doi.org/10.1016/j.pediatrneurol.2019.01.018 source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The methodological quality of included studies was independently assessed by two reviewers using the Newcastle-Ottawa Scale (NOS).

    “The methodological quality of included studies was independently assessed by two reviewers (V.DG. and D.D.T.) using the Newcastle-Ottawa Scale (NOS).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    sCS may not always represent a purely isolated developmental anomaly but can also arise as part of broader syndromic or metabolic conditions.

    “The sCS may not always represent a purely isolated developmental anomaly but can also arise as part of broader syndromic or metabolic conditions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A variant in ALX4 was found associated with a moderate form of frontonasal dysplasia type 1 with minute parietal foramina.

    “Particularly, ALX4 is involved in craniofacial development [62], anda variant in ALX4 was found associated with a moderate form of frontonasal dysplasia type 1 with minute parietal foramina [126].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Altunoglu U, Satkin B, Uyguner ZO, Kayserili H (2014) Mild nasal clefting may be predictive for ALX4 heterozygotes. Am J Med Genet Part A 164:2054–2058 source

  • May combine two claims.

    Interpretationreasoning

    sCS has a markedly heterogeneous genetic basis and is unlikely to be explained by a single dominant molecular mechanism.

    “The available evidence indicates that sCS has a markedly heterogeneous genetic basis and is unlikely to be explained by a single dominant molecular mechanism.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Discrepancies between reviewers at either selection stage were resolved through discussion, and if consensus was not reached, a third senior reviewer adjudicated.

    “Any discrepancies between reviewers at either stage were resolved through discussion, and if consensus was not reached, a third senior reviewer adjudicated (F. T.).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Data extraction was performed independently by two reviewers using a standardized form.

    “Data extraction was performed independently by two reviewers (V.DG. and D.D.T.) using a standardized form.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Disagreements in data extraction were resolved through discussion and consensus (>80%).

    “Disagreements were resolved through discussion and consensus (> 80%).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Case reports and case series were not scored using the NOS; instead, they were narratively assessed and classified as inherently carrying a high risk of bias due to absence of a control group, small sample sizes, and limited generalizability.

    “Case reports and case series were not scored using the NOS, as this instrument is not validated for these study designs; instead, they were narratively assessed and classified as inherently carrying a high risk of bias due to the absence of a control group, small sample sizes, and limited generalizability.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Given clinical and methodological heterogeneity across included studies, a narrative synthesis was performed rather than a quantitative meta-analysis.

    “Given the clinical and methodological heterogeneity across the included studies, a narrative synthesis was performed rather than a quantitative meta-analysis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Geographic location and place of birth have been associated with variation in CS risk, suggesting that contextual and environmental factors linked to where individuals are born and parents reside may contribute to disease susceptibility.

    “Geographic location and place of birth have been associated with variation in CS risk, suggesting that contextual and environmental factors linked to where individuals are born, and parents reside may contribute to disease susceptibility.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Across epidemiological studies of NCS, maternal smoking, micronutrient intake, fertility treatment, and exposure to metals emerge as high risk factors, suggesting that alterations in the intrauterine metabolic and endocrine milieu may influence suture patency during critical windows of craniofacial development.

    “Across epidemiological studies of NCS, factors such as maternal smoking, micronutrient intake, fertility treatment, and exposure to metals emerge as high risk factors, suggesting that alterations in the intrauterine metabolic and endocrine milieu may influence suture patency during critical windows of craniofacial development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These birth-related factors are suggested to be correlated with intra-uterine compression of the foetus, which can lead to wrong mechanical stimuli for normal growth of the skull.

    “These factors are suggested to be correlated with intra-uterine compression of the foetus, which ultimately can lead to wrong mechanical stimuli for the normal growth of the skull.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The effects of parental age can be explained by the increase of sperm and oocytes DNA damage and mutation with age, which then leads to birth defects.

    “These effects can be explained by the increase of sperm and oocytes DNA damage and mutation with age, which then leads to birth defects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Overall, sCS exhibits a highly heterogeneous genetic structure, in which rare high-impact variants coexist with a multifactorial/oligogenic contribution.

    “Overall, the evidence gathered confirmed that sCS exhibited a highly heterogeneous genetic structure, in which rare high impact variants coexisted with a multifactorial/oligogenic contribution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    These exposures can alter FGFR2 expression by decreasing methylation in the FGFR2 regulatory region and enhancing access to the Sp1 transcription factor, leading to abnormal FGFR2 upregulation and premature osteogenic differentiation.

    “These exposures can alter FGFR2 expression by decreasing methylation in the FGFR2 regulatory region and enhancing access to the Sp1 transcription factor, leading to abnormal FGFR2 upregulation and premature osteogenic differentiation [114].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Weng Z, Xu C, Chen X et al (2024) Sp1-activated FGFR2 is involved in early-life exposure to nickel-induced craniosynostosis by regulating the ERK1/2 signaling pathway. Environ Int 184:108477. https://doi.org/10.1016/j.envint.2024.108477 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The association between higher parental education and sCS may reflect differences in socioeconomic status, potentially leading to improved access to healthcare services and higher rates of diagnosis in families with higher educational attainment compared to lower-income groups.

    “This association may reflect differences in socioeconomic status, potentially leading to improved access to healthcare services and, consequently, higher rates of diagnosis in families with higher educational attainment compared to lower-income groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The hypothesis that sCS arises from gene-environment interplay is consistent with evidence of shared heritability across syndromic CS and NCS and with models of cranial development emphasizing the integration of molecular signalling and biomechanical forces.

    “This hypothesis is consistent with evidence of shared heritability across syndromic CS and NCS and with models of cranial development emphasizing the integration of molecular signalling and biomechanical forces.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The predominance of negative or heterogeneous genetic findings underscores the complexity of the condition and suggests that genetic susceptibility alone is often insufficient to drive disease onset.

    “The predominance of negative or heterogeneous genetic findings underscores the complexity of the condition and suggests that genetic susceptibility alone is often insufficient to drive disease onset.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Current evidence is limited by heterogeneity across studies, potential biases in exposure assessment, and a lack of integrative analyses combining genetic and environmental data.

    “However, current evidence is limited by heterogeneity across studies, potential biases in exposure assessment, and a lack of integrative analyses combining genetic and environmental data.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    The expanding use of molecular diagnostics is progressively improving our understanding of the genetic architecture of sCS and may help clarify the extent to which genetic predisposition contributes to disease development, either independently or through interaction with environmental factors.

    “This expanding use of molecular diagnostics is progressively improving our understanding of the genetic architecture of sCS and may help clarify the extent to which genetic predisposition contributes to disease development, either independently or through interaction with environmental factors.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: In recent years, there has been a growing trend toward the implementation of comprehensive genetic screening in patients with non-syndromic craniosynostosis.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The 26-year time frame covered by the selected studies provides a comprehensive overview of the existing evidence.

    “The 26-year time frame covered by the selected studies provides a comprehensive overview of the existing evidence.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Restricting the review to a clearly defined CS subtype such as sCS increased the homogeneity of the included studies.

    “Moreover, restricting the review to a clearly defined CS subtype such as sCS increased the homogeneity of the included studies.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The included sSC sample size of more than 11,086 patients is a strength.

    “The main strengths of this study include its stringent and transparent methodology which increases reproducibility and the included sSC sample size of more than 11,086 patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The main strengths of this study include its stringent and transparent methodology which increases reproducibility.

    “The main strengths of this study include its stringent and transparent methodology which increases reproducibility and the included sSC sample size of more than 11,086 patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Underpowered studies may lead to unstable effect estimates and reduced ability to detect true associations.

    “This may lead to unstable effect estimates and reduced ability to detect true associations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The evidence synthesized in this review supports a multifactorial model for sCS, in which neither genetic nor environmental factors appear to act as individually deterministic drivers in the etiopathogenesis of sCS.

    “In conclusion, the evidence synthesized in this review supports a multifactorial model for sCS, in which neither genetic nor environmental factors appear to act as individually deterministic drivers in the etiopathogenesis of sCS, supporting a model in which multiple components likely interact.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Twin observations have been interpreted as consistent with a shared genetic susceptibility combined with non-shared environmental and/or stochastic factors, which may differentially perturb cranial signalling pathways and drive premature osteogenic differentiation in distinct sutures.

    “These observations have been interpreted as consistent with a shared genetic susceptibility combined with non-shared environmental and/or stochastic factors, which may differentially perturb cranial signalling pathways and drive premature osteogenic differentiation in distinct sutures.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Study design and conductnone given

    Limiting the literature search to the PubMed database only may have resulted in a limited number of relevant publications being overlooked, although this is not expected to have had a major impact on the study overall.

    “Limiting the literature search to the PubMed database only may have resulted in a limited number of relevant publications being overlooked, although this is not expected to have had a major impact on the study overall.”
    Quote in the paperNot a substantial claim
65 of 65

  • The paper relies on this without support.

    The germline variants reported by included studies are correctly classified as pathogenic or likely pathogenic and are causally related to sCS.

    “Germline genetic variants potentially associated with craniosynostosis were reported in 251 patients”
    “A pathogenic germline mutation was reported for 259 patients (12.6%) out of 2060 (75.9%) sequenced and genetically tested patients from 2636 identified patients with sCS.”

  • The paper relies on this without support.

    The genetic testing methodologies used in the included studies would have detected pathogenic germline variants in key signalling pathways if present.

    “most cases lack identifiable germline mutations in key signalling pathways”
    “differences in genetic testing methodologies”

  • The paper relies on this without support.

    The included studies are a representative and complete body of evidence on genetic and environmental determinants of sCS.

    “Using the PubMed database in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, relevant studies addressing genetic and/or environmental determinants of sCS in paediatric patients were systematically reviewed.”
    “A total of 1238 records were identified, of which 97 studies met inclusion criteria after full-text review.”

  • The paper relies on this without support.

    sCS is a rare and heterogeneous condition.

    “Overall, the available literature is characterized by a predominance of descriptive and observational study designs, reflecting the rarity and heterogeneity of the condition.”

  • The paper relies on this without support.

    Thyroid hormones play a well-established role in skeletal development.

    “Maternal thyroid disease has also been linked to an increased risk of CS, with reported ORs ranging from 1.3 to 2.11 [56, 93], consistent with the well-established role of thyroid hormones in skeletal development.”

  • The paper relies on this without support.

    Reliance on parental self-report introduces recall bias for early pregnancy exposures such as diet, supplement use, smoking, and environmental factors.

    “In addition, reliance on parental self-report introduces recall bias, particularly for early pregnancy exposures such as diet, supplement use, smoking, and environmental factors.”

  • The paper relies on this without support.

    Monozygotic twins share nearly identical genetic backgrounds.

    “Because monozygotic twins share (nearly) identical genetic backgrounds, reports of twin pairs in which both are affected by CS but with different sutures involved are particularly informative.”

  • The paper relies on this without support.

    In recent years, there has been a growing trend toward the implementation of comprehensive genetic screening in patients with non-syndromic craniosynostosis.

    “In recent years, there has been a growing trend toward the implementation of comprehensive genetic screening in patients with non-syndromic craniosynostosis, driven by advances in sequencing technologies and the increasing recognition of pathogenic variants in cases previously considered idiopathic.”
8 of 8

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Incorrect percentage of sagittal patients genetically tested

    Major

    The stated 2060 genetically tested patients are 78.1% of the 2636 identified patients with sagittal craniosynostosis, not 75.9%.

    Reported 75.9 · recomputed 78.14871

  • TWIST1 has two chromosome locations in Table 5

    Minor

    Table 5 locates TWIST1 at 11p11.2 in one row and 7p21.1 in another.

  • Conflicting counts of patients with reported germline variants

    Minor

    The abstract reports variants in 251 patients, whereas the study characteristics report pathogenic germline mutations in 259 patients.

  • AXIN2 has two chromosome locations in Table 5

    Minor

    Table 5 assigns AXIN2 to both 8p11.23 and 17q24.1.

  • Included-study count changes from 97 to 96

    Minor

    The results say 97 records passed full-text review, but the subsequent description says data were extracted from 96 included publications.

  • SMAD6 has two chromosome locations in Table 5

    Minor

    Table 5 places SMAD6 variants at both 5q31.2 and 15q22.31.

6 of 6

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Cohen MM, MacLean RE (2000) Craniosynostosis: diagnosis, evaluation, and management, 2nd ed. Oxford University Press, New York

Cited by

Sorted by citations

Related

Authors
De Gregorio, V., Tosi, D. D., Vita, A., Salvati, M., Massimi, L., Tamburrini, G., Tiberio, F., & Lattanzi, W.
Affiliations
Università Cattolica del Sacro Cuore (IT)
Corresponding author
Lattanzi, Wanda
ORCID
Venue
Child's Nervous System
Publisher
Springer Science and Business Media LLC
Published
2026-07-18
Volume
42
Issue
1
ISSN
  • 0256-7040 (ISSN-L)
  • 1433-0350
DOI
10.1007/s00381-026-07396-5
PMC
PMC13380559
OpenAlex
W7169685370
Cited by
2
References
122
Citations by year
2026: 2
FWCI
1.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Child s Nervous System (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
  • European Union—Next Generation EU—PNRR M6C2 (PNRR-POC-2023-12378222)
  • AFM Telethon (Application Number: 29548)
  • Università Cattolica del Sacro Cuore
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Craniofacial Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Pectus Deformity Diagnosis and Treatment
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
Keywords
sagittal craniosynostosis, germline genetic variants, environmental risk factors, perinatal factors, multifactorial etiology, genetic susceptibility, maternal smoking, advanced maternal age, thyroid dysfunction, infertility treatment, preterm birth, pathogenesis
MeSH terms
Craniosynostoses, Environment, Female, Humans, Male, Genetic Predisposition to Disease, Gene-Environment Interaction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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