Craniosynostosis

May combine two claims.

The cellular consequences of FGFR2/FGFR3 mutation include enhanced proliferation, differentiation, and apoptosis of osteoblasts bordering the cranial suture mesenchyme; premature differentiation is probably the most important factor leading to craniosynostosis.

“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”

• cites [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. sourceNot checked — no full text of the source
• 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. sourceDisputed

  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.

  Experimental — accuracy not yet measured

May combine two claims.

In the Oxford study, single-gene disorders often required reoperation (58%), whereas patients with chromosome abnormalities had a lower reoperation rate (17%).

“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.”

• 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. sourceSupported

May combine two claims.

Among genetic diagnoses in the authors' cohort, 86% were single-gene disorders and 15% were chromosome abnormalities, with one patient having both.

“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”

• 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. sourceSupported

May combine two claims.

Low frequency hearing loss is an important complication of Muenke syndrome, requiring hearing aids in about 20% of patients.

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

• 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. sourceSupported

May combine two claims.

In the authors' cohort, the most frequently mutated genes among genetic cases were FGFR2 (32%), FGFR3 (25%), TWIST1 (19%), and EFNB1 (7%).

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

• 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. sourceSupported

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

Rearrangements of a polyglycine-rich tract (amino acids 82-92) appear harmless in the heterozygous state.

“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”

• 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. sourceSupported

May combine two claims.

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

“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”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

Nearly all Apert syndrome mutations arise de novo and originate exclusively from the father.

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

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourceSupported

May combine two claims.

Muenke syndrome, defined by the Pro250Arg substitution, is the most common individual genetic abnormality in craniosynostosis, accounting for about 5% of all cases.

“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”

• 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. sourceSupported

May combine two claims.

Most FGF receptor mutation cases originate from mutations in adult spermatogonia; despite strong positive selection, these mutations never make up large fractions of sperm.

“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”

• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured

May combine two claims.

For families without a molecular or cytogenetic diagnosis and with a negative family history, sibling recurrence risk is estimated at 2% for sagittal/metopic synostosis, 5% for unicoronal synostosis, and 10% for bicoronal/multisuture synostosis.

“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.”

• cites [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. sourceNot checked — no full text of the source
• 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. sourcePartly 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)

  Experimental — accuracy not yet measured
• cites [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. sourceNot checked — no full text of the source

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

At the Oxford unit, most primary surgical procedures are performed between 6 months and 2 years of age.

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

May combine two claims.

In the Oxford study, causative mutations were detected in 11% of multisuture, 37.5% of bicoronal, and 17.5% of unicoronal synostosis cases, and in none of the tested sagittal, metopic, or lambdoid synostosis cases.

“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.”

May combine two claims.

Among non-syndromic patients, mutations were found as follows: seven in FGFR3, three in FGFR2 exons IIIa or IIIc, and one in TWIST1.

“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.”

May combine two claims.

The Apert syndrome FGFR2 substitutions increase the affinity and broaden the specificity of FGF-ligand binding, explaining the genotype-phenotype correlation.

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

• cites [14] Ibrahimi OA, Chiu ES, McCarthy JG, Mohammadi M : Understanding the molecular basis of Apert syndrome. Plast Reconstr Surg 2005; 115: 264–270. sourceNot checked — no full text of the source

May combine two claims.

Females with craniofrontonasal syndrome have severe hypertelorism, unicoronal or bicoronal synostosis, bifid nasal tip, characteristic longitudinal nail splits, and at lower frequency sloping shoulders, asymmetric nipples, bifid digits, and agenesis of the corpus callosum.

“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”

• cites [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. sourceNot checked — no full text of the source

May combine two claims.

Crouzon syndrome can present with late-onset pansynostosis, although bicoronal synostosis is most common.

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

• cites [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. sourceNot checked — no full text of the source
• cites [19] Connolly JP, Gruss J, Seto ML et al: Progressive postnatal craniosynostosis and increased intracranial pressure. Plast Reconstr Surg 2004; 113: 1313–1323. sourceNot checked — no full text of the source

May combine two claims.

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

“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.”

• cites [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. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source

May combine two claims.

The Ser252Trp substitution in Apert syndrome is associated with a higher frequency of cleft palate but milder syndactyly than Pro253Arg.

“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”

• cites [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.Not checked — no full text of the source

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

In Apert syndrome, cleft palate occurs in 44% and learning disability requiring special needs education occurs in 44%.

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

• cites [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.Not checked — no full text of the source

May combine two claims.

Causative mutations in EFNB1 confer loss of function and are diverse (whole gene deletions, intragenic nonsense and frameshifting and splice site mutations, and missense substitutions), providing an explanation for the paradoxical inheritance pattern.

“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.”

• cites [31] Wieacker P, Wieland I : Clinical and genetic aspects of craniofrontonasal syndrome: towards resolving a genetic paradox. Mol Genet Metab 2005; 86: 110–116. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source

May combine two claims.

Saethre-Chotzen syndrome results from haploinsufficiency of TWIST1, which may be caused by whole gene deletions, intragenic nonsense and frameshifting mutations, and missense substitutions; missense substitutions are largely confined to the BHLH motif.

“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).”

• cites [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. sourceNot checked — no full text of the source

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

The overall prevalence of craniosynostosis is estimated at between 1 in 2100 and 1 in 2500 births.

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

• cites [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. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source

May combine two claims.

Most mutations causing Pfeiffer and Crouzon syndromes (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 are scattered in seven other exons, including several in the tyrosine kinase domain.

“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”

• cites [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. sourceNot checked — no full text of the source

May combine two claims.

Antley-Bixler syndrome (features include disordered sex development and radio-humeral synostosis; POR mutation) and Carpenter syndrome (polysyndactyly; RAB23 mutation) are recessive disorders, whereas most genetically determined craniosynostosis is dominant.

“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.”

• cites [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. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source

May combine two claims.

In females, random X-inactivation generates groups of cells that either express or do not express ephrin-B1, and homophilic sorting increases patch size, causing abnormal tissue boundaries in coronal sutures and limbs.

“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”

• cites [33] Compagni A, Logan M, Klein R, Adams RH : Control of skeletal patterning by ephrinB1-EphB interactions. Dev Cell 2003; 5: 217–230. sourceNot checked — no full text of the source

May combine two claims.

No genotype-phenotype correlation is described for Saethre-Chotzen syndrome, except that large deletions are associated with learning disability and occasional C-terminal Twist box missense mutations may confer increased risk of a more non-specific synostosis phenotype with unknown penetrance.

“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”

• cites [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. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source
• cites [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. sourceNot checked — no full text of the source

May combine two claims.

The Pro250Arg substitution is equivalent to the Apert Pro253Arg substitution in FGFR2 and also causes ligand-dependent gain-of-function.

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

• cites [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. sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

A cautiously low 2% sibling recurrence risk is appropriate for de novo TWIST1 mutations.

“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.”

• AssumptionRests on an assumption: No cases of TWIST1 mosaicism have been reported.
• AssumptionRests on an assumption: The number of de novo TWIST1 mutations studied is relatively small.

May combine two claims.

Cranial sutures form around 16 weeks gestation, later than most embryonic structures, so by the ~20-week routine ultrasound there has been insufficient time for skull growth distortion except in severe cases.

“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.”

• 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.Not matched

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

May combine two claims.

Offspring risks are poorly documented; they are probably low (≤5%) for non-syndromic sagittal, metopic, and unicoronal synostosis, but likely much higher (30-50%) for bicoronal and possibly multisuture synostosis.

“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.”