Craniosynostosis

In the paper

“The cellular consequences of mutation are complex, including enhancement of proliferation, differentiation and apoptosis of osteoblasts bordering the cranial suture mesenchyme; premature differentiation is probably the most important factor leading to craniosynostosis.11,12”

What the sources say

• ?Not checked — no full text of the sourcecites [11] Iseki S, Wilkie AOM, Morriss-Kay GM : Fgfr1 and Fgfr2 have distinct differentiation and proliferation-related roles in the developing mouse skull vault. Development 1999; 126: 5611–5620. source
• Disputed

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

  Checked by a reasoning model — may be wrong.

  cites [12] Holmes G, Rothschild G, Roy UB, Deng C-X, Mansukhani A, Basilico C : Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology. Dev Biol 2009; 328: 273–284. sourceExperimental — accuracy not yet measured

In the paper

“Compared with single gene disorders, which often required reoperation (58% of cases), patients with chromosome abnormalities followed a less aggressive course (reoperation rate 17%) suggesting a different, secondary origin of the associated craniosynostosis.”

What the sources say

• Supported

  The Results (Surgical Prognosis and Genetic Aetiology) report repeat surgery in 58% of children with a single-gene mutation versus 17% with a chromosome abnormality. The Conclusions also describe a more indolent course in the chromosome-abnormality group and suggest a different, secondary origin. (LLM, conf=0.95)

  cites [7] Wilkie AOM, Byren JC, Hurst JA et al: Prevalence and complications of single gene and chromosomal disorders in craniosynostosis. Pediatrics 2010; 126: e391–e400. source

In the paper

“In a recent analysis of a 10-year prospective cohort of craniosynostosis presenting to our unit, a genetic diagnosis was achieved in 21% of cases, comprising 86% single gene disorders and 15% chromosome abnormalities (one patient had both).7”

What the sources say

• Supported

  The Results report 84 children with a proven genetic cause and say chromosome abnormalities contributed 15% of those cases. The Abstract Results give 86% for single-gene mutations, and the Results identify one child with both types of finding among those whose diagnosis was not clinically obvious. Although the abstract gives 14% for chromosome abnormalities, the main Results support the cited 15% figure. (LLM, conf=0.90)

  cites [7] Wilkie AOM, Byren JC, Hurst JA et al: Prevalence and complications of single gene and chromosomal disorders in craniosynostosis. Pediatrics 2010; 126: e391–e400. source

In the paper

“An important complication is low frequency hearing loss, requiring the fitting of hearing aids in B20% of patients.23”

What the sources say

• Supported

  The Results section reports that hearing loss in the Muenke syndrome cohort was more severe at low frequencies. It also states that nine subjects (22%) had been fitted with hearing aids because of the severity of their hearing loss, supporting the citing sentence's approximate 20% figure. (LLM, conf=0.94)

  cites [23] Mansour SL, Twigg SRF, Freeland RM, Wall SA, Li C, Wilkie AOM : Hearing loss in a mouse model of Muenke syndrome. Hum Mol Genet 2009; 18: 43–50. source

In the paper

“The genes most frequently mutated were FGFR2 (32% of all genetic cases), FGFR3 (25%), TWIST1 (19%) and EFNB1 (7%).”

What the sources say

• Supported

  The Results passage reports that, among 84 proven genetic cases across all birth years, mutations in FGFR2, FGFR3, TWIST1 and EFNB1 accounted for 32%, 25%, 19% and 7%, respectively. These are the four most frequent gene-level contributions reported there. (LLM, conf=0.95)

  cites [7] Wilkie AOM, Byren JC, Hurst JA et al: Prevalence and complications of single gene and chromosomal disorders in craniosynostosis. Pediatrics 2010; 126: e391–e400. source

In the paper

“Rearrangements of a polyglycine-rich tract (amino acids 82-92), which turn up occasionally during mutation screening, seem to be harmless in the heterozygous state.29”

What the sources say

• Supported

  The rearrangements section identifies length variants in the glycine-rich TWIST tract at nucleotides 244–276, corresponding to amino acids 82–92, and reports heterozygous variants in controls. The Discussion (page unavailable) reports six clinically normal carriers and concludes that the rearrangements are at most weakly pathogenic, supporting the claim’s qualified wording, “seem to be harmless.” (LLM, conf=0.90)

  cites [29] Elanko N, Sibbring JS, Metcalfe KA et al: A survey of TWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals. Hum Mutat 2001; 18: 535–541. source

In the paper

“Abnormal splicing of the IIIc exon tends to be associated with more severe limb abnormalities, so these mutations generally present with Pfeiffer or occasionally even Apert syndrome (Alu element insertions).21”

What the sources say

• Partly supported

  The Introduction (page unavailable) says most mutations altering IIIc splicing cause a Pfeiffer-like phenotype, while Alu insertions are associated with Apert syndrome. The Discussion (page unavailable) says syndactyly seems particularly severe in the Apert patients with IIIc mutations compared with those with canonical IIIa mutations. It does not establish a general tendency toward more severe limb abnormalities across all IIIc-splicing mutations or identify that severity as the reason for the syndrome presentation. (LLM, conf=0.84)

  cites [21] Bochukova EG, Roscioli T, Hedges DJ et al: Rare mutations of FGFR2 causing Apert syndrome: identification of the first partial gene deletion, and an Alu element insertion from a new subfamily. Hum Mutat 2009; 30: 204–211. sourceExperimental — accuracy not yet measured

In the paper

“Nearly all Apert syndrome mutations arise de novo, and have been shown to originate exclusively from the father.”

What the sources say

• Partly supported

  The Abstract (page unavailable) says the Apert-causing FGFR2 755C>G mutation originates exclusively from an unaffected father, while describing FGFR2 mutations more broadly as having a nearly exclusive paternal origin. The Discussion (page unavailable) refers to a high rate of de novo Apert syndrome mutations. These passages support the general pattern but do not establish that nearly all Apert syndrome mutations are de novo or that every type originates exclusively from the father. (LLM, conf=0.85)

  cites [15] Goriely A, McVean GAT, van Pelt AMM et al: Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia. Proc Natl Acad Sci USA 2005; 102: 6051–6056. sourceExperimental — accuracy not yet measured
• Supported

  The paper identifies Apert syndrome as an example of a paternal-age-effect disorder and says the causative mutations in this group nearly always originate from healthy fathers (body text, indexed under Abstract; page unavailable). Its References section (page unavailable) cites a study titled “Exclusive paternal origin of new mutations in Apert syndrome,” supporting the more specific paternal-origin statement. (LLM, conf=0.84)

  cites [16] Goriely A, Hansen RMS, Taylor IB et al: Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 2009; 41: 1247–1252. source

In the paper

“Muenke syndrome, defined by identification of the Pro250Arg substitution, is individually the most common genetic abnormality found in craniosynostosis, comprising B5% of all cases.7”

What the sources say

• Supported

  The Results identify FGFR3 P250R as the most common individual single-gene mutation and report it in 5.6% of all craniosynostosis cases born in 1998–2002. The introductory passage identifies this mutation with Muenke syndrome. (LLM, conf=0.94)

  cites [7] Wilkie AOM, Byren JC, Hurst JA et al: Prevalence and complications of single gene and chromosomal disorders in craniosynostosis. Pediatrics 2010; 126: e391–e400. source

In the paper

“This is because the vast majority of cases arise from mutations occurring in adult spermatogonia, which although subject to strong positive selection never populate large proportions of the sperm.15,16”

What the sources say

• Partly supported

  The Discussion supports positive selection of FGFR2 mutations in spermatogonial cells, and the reported sperm frequencies are small even at the highest measured levels. But the paper does not establish that the vast majority of cases originate from mutations occurring in adult spermatogonia, or that such mutations never occupy large fractions of sperm; those claims are broader than its findings. (LLM, conf=0.83)

  cites [15] Goriely A, McVean GAT, van Pelt AMM et al: Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia. Proc Natl Acad Sci USA 2005; 102: 6051–6056. sourceExperimental — accuracy not yet measured
• Partly supported

  The paper describes FGFR2 and FGFR3 mutations expanding in spermatogonia and reports low mutation frequencies in sampled sperm (no page number provided in our copy). It does not establish that the vast majority of FGF receptor mutation cases arise in adult spermatogonia or that such mutations never occupy large fractions of sperm. It also says that only a weak selective advantage per cell is needed to explain the observed sperm levels, rather than establishing strong selection. (LLM, conf=0.83)

  cites [16] Goriely A, Hansen RMS, Taylor IB et al: Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 2009; 41: 1247–1252. sourceExperimental — accuracy not yet measured

In the paper

“Where no molecular or cytogenetic diagnosis is made and the family history is negative, we suggest a sibling recurrence risk of 2% for sagittal and metopic synostosis, 5% for unicoronal synostosis and 10% for bicoronal and multisuture synostosis.”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D : Genetic study of nonsyndromic coronal craniosynostosis. Am J Med Genet 1995; 55: 500–504. source
• Partly supported

  The Discussion estimates about 5% sibling recurrence for coronal synostosis when neither parent is affected, but does not give a separate estimate for unicoronal cases. It estimates about 1%, not 2%, for sagittal synostosis. The case descriptions report unaffected siblings for metopic and multisuture cases but give neither the claimed 2% metopic estimate nor a 10% bicoronal/multisuture estimate. (LLM, conf=0.89)

  cites [42] Carter CO, Till K, Fraser V, Coffey : A family study of craniosynostosis, with probable recognition of a distinct syndrome. J Med Genet 1982; 19: 280–285. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [43] Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D : Genetic study of scaphocephaly. Am J Med Genet 1996; 62: 282–285. source

In the paper

“At the Oxford unit, the majority (B60%) of primary surgical procedures are performed between the ages of 6 months and 2 years.”

In the paper

“In the Oxford study, causative mutations were present in 11% multisuture, 37.5% bicoronal and 17.5% unicoronal synostosis, but were absent in all sagittal, metopic and lambdoid synostosis cases tested.”

In the paper

“The numbers of mutations found in the non-syndromic patients were seven in FGFR3, three in the IIIa or IIIc exons of FGFR2 and one in TWIST1.”

In the paper

“These substitutions specifically increase the affinity and broaden the specificity of FGF-ligand binding, explaining the exquisite genotypephenotype correlation.14”

What the sources say

• ?Not checked — no full text of the sourcecites [14] Ibrahimi OA, Chiu ES, McCarthy JG, Mohammadi M : Understanding the molecular basis of Apert syndrome. Plast Reconstr Surg 2005; 115: 264–270. source

In the paper

“Females have severe hypertelorism, unicoronal or bicoronal synostosis, bifid nasal tip, characteristic longitudinal nail splits (Figure 1m and o) and, at lower frequency, sloping shoulders, asymmetric nipples, bifid digits and agenesis of the corpus callosum.30”

What the sources say

• ?Not checked — no full text of the sourcecites [30] Grutzner E, Gorlin RJ : Craniofrontonasal dysplasia: phenotypic expression in females and males and genetic considerations. Oral Surg Oral Med Oral Pathol 1988; 65: 436–444. source

In the paper

“Although bicoronal synostosis is most common, Crouzon syndrome can present with late-onset pansynostosis.18,19”

What the sources say

• ?Not checked — no full text of the sourcecites [18] Hoefkens MF, Vermeij-Keers C, Vaandrager JM : Crouzon syndrome: phenotypic signs and symptoms of the postnatally expressed subtype. J Craniofac Surg 2004; 15: 233–240. source
• ?Not checked — no full text of the sourcecites [19] Connolly JP, Gruss J, Seto ML et al: Progressive postnatal craniosynostosis and increased intracranial pressure. Plast Reconstr Surg 2004; 113: 1313–1323. source

In the paper

“These mutations demonstrate pathogenic roles for steroid metabolism and hedgehog (or possibly Wnt) signalling in cranial suture development, both of which are at present poorly understood.”

What the sources say

• ?Not checked — no full text of the sourcecites [35] Huang N, Pandey AV, Agrawal V et al: Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet 2005; 76: 729–749. source
• ?Not checked — no full text of the sourcecites [36] Jenkins D, Seelow D, Jehee FS et al: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet 2007; 80: 1162–1170. source

In the paper

“Over 98% of cases are caused by specific missense mutations of FGFR2, either Ser252Trp (66%) or Pro253Arg (32%), in the linker between the IgII and IgIII domains (Figure 2a); the former substitution is associated with a higher frequency of cleft palate, but milder syndactyly.13”

What the sources say

• ?Not checked — no full text of the sourcecites [13] Slaney SF, Oldridge M, Hurst JA et al: Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Am J Hum Genet 1996; 58: 923–932.

In the paper

“Other frequent complications include cleft palate (44%) and learning disability, requiring special needs education (44%).13”

What the sources say

• ?Not checked — no full text of the sourcecites [13] Slaney SF, Oldridge M, Hurst JA et al: Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. Am J Hum Genet 1996; 58: 923–932.

In the paper

“The identification of causative mutations in EFNB1, which confer loss of function and are correspondingly diverse (whole gene deletions, intragenic nonsense and frameshifting and splice site mutations, and missense substitutions; Figure 2d) (refs.31,32), has provided an explanation for the paradoxical inheritance pattern.”

What the sources say

• ?Not checked — no full text of the sourcecites [31] Wieacker P, Wieland I : Clinical and genetic aspects of craniofrontonasal syndrome: towards resolving a genetic paradox. Mol Genet Metab 2005; 86: 110–116. source
• ?Not checked — no full text of the sourcecites [32] Twigg SRF, Matsumoto K, Kidd AMJ et al: The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males. Am J Hum Genet 2006; 78: 999–1010. source

In the paper

“Saethre-Chotzen syndrome results from haploinsufficiency of TWIST1, which may be the consequence of many different mutations, including whole gene deletions, intragenic nonsense and frameshifting mutations, and missense substitutions; note that the last category is largely confined to the highly conserved BHLH motif required for DNA binding and dimerisation (Figure 2c) (ref.26).”

What the sources say

• ?Not checked — no full text of the sourcecites [26] Kress W, Schropp C, Lieb G et al: Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome. Eur J Hum Genet 2006; 14: 39–48. source

In the paper

“The overall prevalence of craniosynostosis has been estimated at between 1 in 2100 and 1 in 2500 births.1,2”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D : Genetic study of nonsyndromic coronal craniosynostosis. Am J Med Genet 1995; 55: 500–504. source
• ?Not checked — no full text of the sourcecites [2] Boulet SL, Rasmussen SA, Honein MA : A population-based study of craniosynostosis in metropolitan Atlanta, 1989–2003. Am J Med Genet 2008; 146A: 984–991. source

In the paper

“Most mutations (94%) occur in the third extracellular immunoglobulin-like domain encoded by exons IIIa or IIIc, where they cause constitutive activation by covalent cross-linking of receptor monomers.The remainder of the mutations are scattered in seven other exons of the gene, including several mutations in the tyrosine kinase domain.20”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Kan S-H, Elanko N, Johnson D et al: Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis. Am J Hum Genet 2002; 70: 472–486. source

In the paper

“Whereas most genetically determined craniosynostosis is characterised by dominant inheritance, Antley-Bixler syndrome (features include disordered sex development and radio-humeral synostosis; mutation in POR encoding cytochrome P450 oxidoreductase) 35 and Carpenter syndrome (with polysyndactyly; mutation in RAB23 encoding RAB23, member of RAS oncogene family) 36 are recessive disorders.”

What the sources say

• ?Not checked — no full text of the sourcecites [35] Huang N, Pandey AV, Agrawal V et al: Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet 2005; 76: 729–749. source
• ?Not checked — no full text of the sourcecites [36] Jenkins D, Seelow D, Jehee FS et al: RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet 2007; 80: 1162–1170. source

In the paper

“In the female, random X-inactivation generates groups of cells that either express, or do not express ephrin-B1, and the homophilic sorting process increases the patch size of these cells, causing abnormal tissue boundaries (for example, in the coronal sutures and limbs).33”

What the sources say

• ?Not checked — no full text of the sourcecites [33] Compagni A, Logan M, Klein R, Adams RH : Control of skeletal patterning by ephrinB1-EphB interactions. Dev Cell 2003; 5: 217–230. source

In the paper

“No genotype-phenotype correlation is described, except that large deletions are associated with learning disability (not generally a feature of Saethre-Chotzen syndrome), 26,27 and occasional missense mutations in the C-terminal Twist box apparently confer increased risk of a more non-specific synostosis phenotype (with unknown penetrance).28”

What the sources say

• ?Not checked — no full text of the sourcecites [26] Kress W, Schropp C, Lieb G et al: Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome. Eur J Hum Genet 2006; 14: 39–48. source
• ?Not checked — no full text of the sourcecites [27] Johnson D, Horsley SW, Moloney DM et al: A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1. Am J Hum Genet 1998; 63: 1282–1293. source
• ?Not checked — no full text of the sourcecites [28] Seto ML, Hing AV, Chang J et al: Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations. Am J Med Genet 2007; 143A: 678–686. source

In the paper

“The Pro250Arg substitution is the exact equivalent to the Apert Pro253Arg substitution in FGFR2, and also causes liganddependent gain-of-function.24”

What the sources say

• ?Not checked — no full text of the sourcecites [24] Ibrahimi OA, Zhang F, Eliseenkova AV, Linhardt RJ, Mohammadi M : Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity. Hum Mol Genet 2004; 13: 69–78. source

In the paper

“Mosaicism for TWIST1 mutations, although theoretically possible, has not been reported; however, the sample size of de novo TWIST1 mutations is relatively small, so a cautiously low (2%) sibling recurrence risk is appropriate.”

In the paper

“Cranial sutures form very late (B16 weeks gestation) 46 compared with most other embryonic structures, therefore at the time when most routine ultrasound diagnosis is being undertaken (B20 weeks), insufficient time has elapsed for growth distortion of the skull to have occurred, except in the most severe cases.”

What the sources say

• ?Not matched

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

  cites [46] Mathijssen IMJ, van Splunder J, Vermeij-Keers C et al: Tracing craniosynostosis to its developmental stage through bone center displacement. J Craniofac Genet Dev Biol 1999; 19: 57–63.

In the paper

“Offspring risks are not well documented; they are probably low (B5%) in the case of non-syndromic sagittal, metopic and unicoronal synostosis, but likely to be substantially higher (30-50%) in bicoronal and possibly multisuture synostosis.”